Overcoming obstacles to prosthetic fittings requires frequent tryouts of sockets and components. Repetitions of interventions are upsetting for users and place substantial economic burden on healthcare systems. Encouraging prosthetic care innovations capable of alleviating clinical and financial shortcomings of socket-based solutions is essential. Nonetheless, evidence of socio-economic benefits of an innovation are required to facilitate access to markets. Unfortunately, complex decisions must be made when allocating resources toward the most relevant health economic evaluation (HEE) at a given stage of development of an innovation. This paper first, aimed to show the importance and challenges of HEEs of intervention facilitating prosthetic fittings. Next, the main trends in HEEs at various phases of product development and clinical acceptance of prosthetic care innovations were outlined. Then, opportunities for a basic framework of a preliminary cost-utility analysis (CUA) during the mid-stage of development of prosthetic care innovations were highlighted. To do this, fundamental and applied health economic literature and prosthetic-specific publications were reviewed to extract and analyse the trends in HEEs of new medical and prosthetic technologies, respectively. The findings show there is consensus around the weaknesses of full CUAs  and strengths of preliminary CUAs . However, several obstacles must be overcome before preliminary CUA of prosthetic care innovations will be routinely carried out. Disparities of methods and constructs of usual preliminary CUA are barriers that could be alleviated by a more standardized framework. The paper concludes by identifying that there are opportunities for the development of a basic framework of preliminary CUA of prosthetic care innovations. Ultimately, the collaborative design of a framework could simplify selection of the methods, standardise outcomes, ease comparisons between innovations and streamline pathways for adoption. This might facilitate access to economical solutions that could improve the life of individuals suffering from limb loss. If I have a thousand ideas and only one turns out to be good, I am satisfied.”Alfred Nobel (1833–1896) said the following about innovation “1 As defined in APPENDIX 1, these evaluations aim at understanding what is the value for money of a treatment. Simply put, payers want to make sure they get a bang for their buck!In healthcare, the difference between a “good” or a not so good innovation is made during health technology assessment (HTA) and/or health economic evaluation (HEE).This is tough question because the answer is rarely black and white. Nonetheless, addressing any concerns with socio-economical value of an intervention is a prerequisite to warrant access to market. Great but unaffordable treatments have little prospect of being adopted by healthcare policymakers.Figure 1. First, the importance and challenges of HEEs of interventions facilitating prosthetic fittings are highlighted. Next, the main trends in HEEs of new healthcare technologies are outlined with particular emphasis on specific HEEs to consider during the course of development of innovations. Then, opportunities for a basic framework of preliminary assessments during the mid-stage of development of prosthetic care innovations are suggested. Finally, the paper concludes with some calls to action to further develop preliminary assessments.The paper deals with issues of health economic assessments specific to prosthetic care innovations as presented in This introductory section highlighted (A) the needs for solutions facilitating prosthetic fittings and (B) the current challenges to produce relevant health economic evaluations of prosthetic care innovations.3 Ultimately, this process incorporates all personalized interventions performed by a prosthetist around the choice and alignment of prosthetic components as well as the management of prosthetic attachment to the residuum including design, manufacture and adjustment of socket or osseointegrated implant.4Because the everyday ability of individuals suffering from limb loss to use an artificial limb is critical to their quality of life, clinical teams made bespoke recommendations intending to maximize comfort, stability and mobility of prosthetic fittings.11 where Dillingham et al (2001) noted that 60% of amputees are satisfied with prosthetic characteristics such as weight, aesthetics and functionality  and 57% of the traumatic lower limb amputees in the study expressed some dissatisfaction with prosthetic comfort.12 Since, studies showed that the use and satisfaction of prosthetic lower limb could be significantly improved when using advanced components such microprocessor-controlled knees compared to a non-microprocessor-controlled knees.14Outcomes of prosthetic fitting depends largely on the performance of prosthetic components.17 Paterno et al (2018) and Meulenbelt et al (2009) report that that 63– 82% of lower limb amputees have problems with skin lesions.18 Turner and McGregor (2020) report that 48.0% of amputees and 65.7% of clinicians cited socket fit issues as the biggest factor impacting rehabilitation.6 And, sadly, Paterno et al (2018) and Meulenbelt et al (2009) found a 25–57% prosthetic abandonment rate and identified failed socket fit as a likely possible cause.18Satisfactory prosthetic fitting might be compromised because of incongruous shapes of residuum  and/or skin issues.3 Regular medical attention are, first and foremost, upsetting , disruptive  and costly  for users.19 Repetitions of interventions also place a substantial economic burden on healthcare systems stressed to subsidize treatments beyond minimal prosthetic care standards.22 For example, the fitting of only a single socket per year might be approved by some healthcare organizations.22In many cases, overcoming obstacles to prosthetic fitting requires frequent tryouts of components and sockets fittings.APPENDIX 1).26 Hence, efforts made by a bench of stakeholders  to develop and encourage new prosthetic care interventions to improve socket fittings and, eventually, eliminate socket attachments altogether .34 These solution-finders will be called “promoters” of prosthetic care innovations throughout this paper and are shown in relationship to other concepts presented in this paper as a regrouping of individuals suffering from limb loss, providers of prosthetic solutions and administrators of healthcare organisations (APPENDIX 1) into a single collaborative group with common goals.38Encouraging prosthetic care innovations that alleviate the clinical and financial shortcomings of current fitting options is essential , maximise functional outcomes  and, preferably, enhance quality of life .37Ijzerman and Steuten (2011) identified that in order for societal benefits to be maximized three things must occur: 1) governments need more data on benefits arising when public resources are spent, 2) companies need more data to effectively manage their product development portfolios and 3) research programs at universities may need to be actively encouraged in this direction.37 However, healthcare administrators are often obligated to confirm the value for money of interventions prior approval .53 For example, an HEE might be required to differentiate the four microprocessor-controlled knees assessed by Campbell et al (2020) all showing relative parity with regards to functional mobility, health state satisfaction and quality of life or injurious falls .14 Recommendation for one knee or the other may be based on costs reduction of prosthetic care interventions.Policymakers in healthcare organizations around the world adopt a reasoning more or less utilitarian when making decisions about medical care expenses.38 Steven et al (2019) suggested that solution developers must understand the value created by their interventions and act quickly on them to provide some forms of evidence of cost-effectiveness of their innovations.48 Failing to do so could seriously hinder access to market and adoption of their innovations. O'Malley (2010) indicated that the most common reason for the Australian Medical Services Advisory Committee to not recommend funding for new technology was not only insufficient clinical evidence but also the lack of proven cost-effectiveness presented during early stage of the examination process.54The burden of HEE of an innovation also falls onto developers and manufacturers of technological solutions including attachments , artificial limb components  and protective device .48 They specified that the value of a prosthetic care intervention could be assessed using a range of cost-benefit, cost-consequence, cost-effectiveness and cost-utility analyses considering valuations of costs  and a range of benefits. Ijzerman and Steuten (2011) specified that no single method will produce the right information for all decision makers. Each method has advantages and disadvantages and work for specific applications, as opposed to all applications.37 They suggested that a toolbox of methods must be used.Steven et al (2019) stated that HEE can be approached in a number of ways. They identified a range of approaches to compare the costs of health care services and possible cost savings which observe the consequences of an intervention and the effectiveness of that same intervention through a lens of outcomes that are valued patients, payers and providers, or which align with widely used global utility measures.Unfortunately, the multitude of HEEs often leave promoters making challenging decisions around allocation of sufficient resources toward the most relevant HEE approach at a given point of an innovation development. Facilitating this decision-making process would start with an overview of the trends and specific ways HEEs can be done at various stages of development of an innovation.This second section (A) reviewed generic pathways to assess health economic consequences of a new treatment at a given stage of product development and clinical acceptance and (B) highlighted selected studies that followed these pathways to assess prosthetic care interventions.APPENDIX 1, HEE include, but not limited to, cost-effectiveness analyses (CEA) or cost-utility analyses (CUA). These terms are often used interchangeably although they are technically looking at different types of utilities. CEAs are concerned with a particular functional outcome of a treatment . CUAs rely on self-reported quality of life status measured using standard surveys such as EQ-5D or 36-Item Short Form Survey (SF36). CUAs comparing usual and new treatments involve incremental cost-utility ratio (ICUR) based on incremental costs and utilities over time that could be compared to cost-effectiveness (CET) or, more often, willingness-to-pay (WTP) thresholds.55As described in 57Patient-centred assessments of global health-related quality of life might be influenced by prosthetic care to a certain extent. Therefore, these metrics might reflect only partially the benefits of a prosthetic intervention. However, outcomes of CUA reported in monetary units per quality-adjusted life-year (QALY) can be easily compared across other medical interventions or disease states. CUAs are commonly used to facilitate effective communication among healthcare professionals.58 Some studies provided valuable insights into ways outcomes of HEEs can facilitate the approval process of an innovation by a particular governmental healthcare system .61 Others explained the basic concepts of HEEs to clinicians and prosthetic care providers.57 Several landmark studies presented prosthetic-specific HEEs.74Promoters can be informed by an abundance of health economic research focusing on a broad range of fundamental and applied HEEs issues that could be more or less relevant .37 More recently, new insights were provided by Kannenberg and Seidinger (2019) who explained how these three types of CUAs should also be performed by prosthetic manufacturers at early, mid and late phase development of a prosthetic product.38 The authors indicated that CUA during the product's life cycle is beneficial in three ways. It allows potential cost-effectiveness to be estimated and included in investment decision processes and mitigates the risk of investing in technology unlikely to be cost-effective. It helps to prioritize between competing cost-effective concepts or technologies. It facilitates the identification of parameters having the largest impact on the likely cost-effectiveness of the product to be identified in order to best manage limited research funds.38Two studies were of particular interest because they can assist promoters to make an educated decision when choosing an HEE accordingly to the level of innovation development. Ijzerman and Steuten (2011) systematically described that early, preliminary and full CUAs can be conducted at the early, mid and late stage of clinical acceptance of any medical treatment, respectively.Figure 2 gives an overview synthesizing both approaches. Decision uncertainty and strength of evidence were suggested for early, preliminary and full CUAs during early, mid and late phase of product development (manufacturer's perspective) and clinical acceptance  of prosthetic care innovations, respectively.77 is briefly described. The decision was made to present the CUAs as they historically gained recognition starting from full, to preliminary and early CUAs rather than following the sequential timeline of their implementation. Appraisal of each type of CUAs using the CHEERS and CHEC-extended checklists were detailed in Supplementary material.Next, the general principle, expected capacity to address Consolidated Health Economic Evaluation Reporting Standards (CHEERS) and Consensus Health Economic Criteria (CHEC) extended checklists, typical strengths and weaknesses as well as selected examples of prosthetic-focused CUAs.APPENDIX 1).79 Costs, utilities and ICURs are projected using Bayesian or Markov models based on plausible information extracted from primary studies for a series of scenarios over scalable time horizons .81Traditionally, mainstream HEEs involved comprehensive or “full” CUAs essentially produced when innovations are gaining clinical acceptance after commercialisation. Full CUAs can be conducted from societal and/or healthcare perspectives. These CUAs usually rely on primary costs extracted from financial records expressed in monetary units as well as utilities measured by quality of life surveys expressed in QALY for cohorts of participants over an extended period of time (Table 2).It was postulated that conventional full CUAs should address strongly all items of the CHEERS and CHEC-extended checklists (APPENDIX 1), tend to be well worked out and, possibly, relatively low compared to early and preliminary CUAs.82 Therefore, full CUA provide strong evidence supporting robust recommendations considered by decision makers .Modelling CUAs can be comprehensive because of the breadth  and depth  of their analysis. Furthermore, uncertainty and sensibility of outcomes, shown by the size of the errors around the point estimates due to data sources  and/or to the process of evaluation .83 Evidence-based developments of new interventions takes time, particularly when the recommended clinical timelines are followed to demonstrate efficiency and safety . Several years might be needed to gather the costs and utilities required to complete primary and modelling CUAs. Consequently, mainstream CUAs can hardly inform promoters timely. Lack of timeliness is even more problematic with new prosthetic care technologies that are more susceptible to be superseded after five years.[60] Gallego et al (2011) described decisions to approve technology by committees and regulatory bodies, such as the Australian Medical Services Advisory Committee, typically occurs after the technology has evolved or is already commonly being used in practice.60 Ijzerman and Steuten (2011) also noted the problems with this approach, warning that many design decisions  are made in the early stages of product development and are difficult, expensive and/or impossible to change at a later date.37However, modelling CUAs require substantial resources. Building models is labour intensive . More importantly, Kannenberg and Seidinger (2019) noted the necessity of requiring the inclusion of outcome parameters, like health-related quality of life, in these models.74Several studies used a full CUA to assess consequences of the provision of socket based solution including advanced prosthetic components such as microprocessor-controlled knees and energy storing and return feet as well as socket-free solutions including bone-anchored prostheses.79The issue of timeliness of full CUAs could be addressed by performing preliminary CUAs of innovations that could take place sometimes around the mid-stage of product development when clinical usage is still limited to small cohorts. Preliminary CUA is an option “in-between” early and full CUAs that considered innovations with a broad range of development status. Therefore, preliminary CUAs can be conducted using a wide spectrum of methods. They can involve primary data of actual  and/or simulated  costs expressed in monetary units as well as measured  and/or guesstimated  utilities expressed in QALY for cohorts of participants over a somewhat lengthy time horizon.Table 1). It was estimated that preliminary CUAs should be capable to address 11 (58%) of items in the CHEC-extended checklists (Table 2).The assumption was made that typical preliminary CUAs have a weak and moderate capacity to address 9 (33%) and 8 (30%) of items in the CHEERS checklist, including 7 (44%) and 6 (38%) of items in the Methods as well as 2 (40%) and 2 (40%) of items in the Results sections, respectively .52 Finally, uncertainty and sensibility of preliminary CUAs might be only loosely considered and reported. Altogether, the weight of these limitations on the strength of evidence is less known weakening the recommendations. Unfavourable outcomes of preliminary CUAs might, at least, question and, possibly, stop further product commercialization and clinical considerations. A decision must be made whether favourable outcomes are deemed sufficient to pursue and eventually, readjust further developments.However, preliminary CUAs are usually built around substantial assumptions based on best-estimates of costs and utilities at the time. Typical preliminary CUAs are characterised by narrow perspective, simple scenarios, and time horizons tentatively shorter than full CUAs. Further limitations are inherent to the mismatch of costs and utilities from incongruous jurisdictions, onsets and post-operative timelines. For example, actual costs extracted from an healthcare financial system over several years might be considered against estimated utilities based on studies performed in other countries measuring quality of life six months after the intervention.53Recent examples of preliminary CUAs of innovations looked at the benefits of transfemoral and transtibial bone-anchored prostheses from government prosthetic care perspective.37 Early CUAs tend to be constructed like preliminary CUAs but they rely more heavily on sparser costs and utilities data as well as sketchier assumptions. These analyses tend to be based on best guestimates of most likely costs and utilities collected with case-series studies and/or extracted from the literature often produced outside the relevant jurisdiction.Preliminary CUAs can provide timelier assessment than full CUAs. Nonetheless, there is a current trend in health economic literature arguing that preliminary CUAs are yet to provide sufficiently timely assessment of innovations. Hence, the promotion of early CUAs, also called “iterative economic evaluations” or “very early HTA” by Ijzerman and Steuten (2011), which pointed out that attempts have already been made, using “horizon scanning systems”, to include new, emerging technologies into health policy as it is developed. Other authors have referred to this as the use of “early warning systems”.Table 1). Preliminary CUAs might be incapable to address up to 9 (47%) of items in the CHEC-extended checklists (Table 2).It was assumed that usual early CUAs have a weak capacity to address 15 (56%) of items in the CHEERS checklist including 11 (69%) of items in the Methods as well as 4 (80%) of items in the Results sections .As expected, outcomes of early CUAs are likely to have high uncertainty and sensibility leading to low level of evidence and only tentative recommendations. Early evidence of potential CUA might fast-track on-going innovation development. Limited prospects of CUA might raise questions about further allocation of resources to a product that has, ultimately, minimal chance to meet payer's expectations.This last section (A) presented the current consensus and knowledge gaps around earlier HEEs and (B) highlighted opportunities for developments of a basic framework of preliminary CUA.Table 3. Earlier CUAs have the potential to assist promoters to:There is consensus around the weaknesses of full CUAs  and strengths of early and preliminary CUAs, summarised in 52Identify evidence gaps and headroom for improvements that generate insights into potential capacity of an innovation to alleviate the financial burden of prosthetic fittings.47Educate the design of primary and modelling studies including the planning , collection  and analysing .60Fast-track approval from governing bodies like Australian Medical Services Advisory Committee. Gallego et al (2011) said that earlier CUAs can help to prioritize in which order new technologies are evaluated and allows for the fast-tracking of technologies which either have a least potential for harm or which have a great potential to benefit patients.37 However, earlier CUAs are far from being widely considered when developing new prosthetic solutions. Several obstacles must be overcome before earlier and, more particularly, preliminary CUAs of prosthetic care innovations would be routinely carried out by promoters.Ijzerman and Steuten (2011) pointed out that the emerging field of HTA research will likely gain prominence as it will help navigate the increasingly complex trade-offs that must be considered when making investments in medical product development and ensuring access to those products.37One critical obstacle is the abundance of methods. Ijzerman and Steuten (2011) listed ten quantitative methods that could be used in earlier HTA .Figure 2). Logically, early and full CUAs are indicated at early stage and after clinical acceptance, respectively. Initial clinical evidence provided by proof of utility and case-series could be used to perform an early and preliminary CUAs. Stronger evidence gathered during cohort study and clinical trial might be deemed sufficient to conduct a preliminary or full CUAs.Another obstacle is the multiple pathways for HEE relying on the same level of clinical evidence of utilities (Table 2). Altogether, disparity of outcomes also makes earlier CUAs scoring modestly in these checklists less likely to be published. The result of this is a sparsity of publications in prosthetic-focused scientific journals, let alone heath economics journals, the latter of which are inclined to consider that socio-economic research in prosthetics is for a niche audience. Literature review and meta-analyses of health economic evaluations failing to stratify publications accordingly to the three types of CUAs might appraise unfavourably the contribution of earlier CUAs.85 Therefore, this review might skew the perception on the overall quality of health economic evaluations of prosthetic care. Earlier CUAs might score less not because they are poorly done but because they are dealing with more unreliable datasets.Disparities of methods and constructs of earlier CUAs  have ripple effects limiting implementation of earlier CUAs. Cross-comparing outcomes of earlier CUAs between innovations might be challenging to interpret. Generalization of outcomes across healthcare organisations might be limited. Earlier CUAs might show a broad level of quality when appraised with standard CHEERS and CHEC-extended checklists, primarily designed for full CUAs , assessment of outcomes  and reporting to payers .47 Indeed, each of these tasks is sufficiently codified to be individually supported by healthcare organisations . This means that most preliminary CUAs relying on estimated rather than primary costs could apply a template of schedule of allowable expenses. This typical matrix can present costs at the intersections of list of tasks in rows and timeline of interventions in columns (APPENDIX 1). Ideally, disruptive and economical innovations changing best prosthetic care practice should affect a schedule by reducing the price tag and/or the frequency of one or more tasks.One the other side, provision of prosthetic care follows a rather standardized process. Reimbursement are often made for categories of components , physical tasks  as well as specific  and generic  health-related quality of life with an innovation.52 This creates opportunities to explore the development of a basic framework including set constructs  and practical recommendations  specific to preliminary CUAs of the prosthetic care innovations (APPENDIX 1). This new approach to a preliminary CUA has the potential to simplify the selection of methods, standardise outcomes, ease comparisons between innovations and streamline pathways for adoption while facilitating the production of a body of literature on prosthetic health economics.Altogether, organisation of the delivery and assessment of prosthetic care might be sufficiently transferable across innovations to consider a more uniform approach to preliminary CUAs.This work showed that promoters must make complex decisions when attempting to establish the socio-economic values of prosthetic care innovations. It is commonly acknowledged that a unique type of CUA could not be applied at every stage of development of an innovation. Preliminary CUAs of innovations at the mid-stage of development is particularly valuable but challenging. Boundaries delineating preliminary CUAs from early and full CUA might be blurry pushing promoters to consider a wide range of methods.The outcomes suggest that there are opportunities for collective design of a basic framework of a preliminary CUA of prosthetic care innovations. However, reaching consensus around a framework can be challenging because there is no formal forum capable to organise discussions outside of usual scientific peer-review channels. There is a need for an ad-hoc reference group involving promoters and heath economists specialized in prosthetics and medical aids. Ideally, this working group should be hosted by international  or national  governing bodies. Its missions could be to develop guidelines and, possibly, standards of HEEs of prosthetic care interventions including preliminary CUAs frameworks .Ultimately, a wide adoption of a this collegial preliminary CUA framework will, hopefully, contribute to promote the routinely used preliminary CUA. It is anticipated that this framework should facilitate access to economical prosthetic care solutions improving the life of individuals suffering from limb loss worldwide.Gather an ad-hoc reference group capable of (A) monitoring the current trends in HEEs of new healthcare technologies, (B) develop guidelines and, possibly, standards of HEEs of prosthetic care interventions, (C) promote the adoption of these guideline .This working group could facilitate discussions between promoters of prosthetic care innovations around the use and validation of preliminary CUAs frameworks.Practically, these discussions should focus on the development of basic framework of a preliminary CUAs, more particularly set constructs and practical recommendations.The author is in the view that these competing interests do not conflict with the content of this manuscript. Laurent Frossard, Director and Chief Scientist Officer of YourResearchProject Pty Ltd, has worked as consultant for several organisations on non-related educational programs and projects of research focusing on recording loading data, developing of database to record clinical outcomes as well as drafting grants and manuscripts for Cognitive Institute, Exercise & Sports Science Australia, Griffith University, iPug Pty Ltd, Middlesex University, New Zealand Artificial Limb Service, Osseointegration Group of Australia Pty Ltd, OSSUR, Poly-Orthodox International, Queensland Artificial Limb Service, Queensland University of Technology, Return to Work-South Australia, South Australia Health, Tequir S.L, University of the New South Whales, University of the Sunshine Coast.This study was funded by YourResearchProject Pty Ltd.Dr Laurent Frossard is a bionic limbs scientist who is passionate about developing ground-breaking prosthetic solutions to improve the lives of individuals suffering from limb loss. He is internationally recognized as a researcher and an independent expert for his unique expertise in bionic limbs. He approaches bionic solutions from a holistic perspective, by integrating the prosthetic biomechanics, clinical benefits, service delivery, and health economics. Dr Frossard has over 25 years of experience, both in academia and in private industries in Australia, Canada, and Europe. He has collaborated with over 100 organizations worldwide. He is currently a Professor of bionics at the Griffith University, the Director and Chief Scientist Officer at YourResearchProject Pty Ltd, and Adjunct Professor at the Queensland University of Technology and the University of Sunshine Coast in Australia.


The European Academy of Paediatrics (EAP) and the European Confederation of Primary Care Paediatricians (ECPCP) emphasize the importance of promoting healthy lifestyles within the pediatric population. Many health professionals have questions concerning adequate levels of physical activity for both the healthy pediatric population and for those who may have specific complications. Unfortunately, the academic literature that provides recommendations for participation in sport activities within the pediatric population that have been published during the last decade in Europe is limited and is mainly dedicated to specific illnesses or advanced athletes and not toward the general population. The aim of part 1 of the EAP and ECPCP position statement is to assist healthcare professionals in implementing the best management strategies for a pre-participation evaluation (PPE) for participation in sports for individual children and adolescents. In the absence of a uniform protocol, it is necessary to respect physician autonomy for choosing and implementing the most appropriate and familiar PPE screening strategy and to discuss the decisions made with young athletes and their families. This first part of the Position Statement concerning Sport Activities for Children and Adolescents is dedicated to healthy young athletes. The European Academy of Paediatrics (EAP) and the European Confederation of Primary Care Paediatricians (ECPCP) emphasize the importance of promoting healthy lifestyles for the pediatric population within every age range. The main conclusion from the study entitled “Youth sport participation trends in Europe - An output of Erasmus+,” which presented the findings of an international study on the involvement rates of youth in organized sports during 2017–2020, was a noticeable decline in participation in most sports for boys and girls  is essential for appropriate physical, emotional, and psychosocial growth of the pediatric population as well for patients with different diseases –4. The bThe sudden death of a young athlete  is a tragic and rare event, reported to occur in one to two cases out of 100,000 athletes each year , 16. A lIn 2019, the American Academy of Pediatrics (AAP) published “The Fifth Edition of PPE Monograph,” which is an approach to sports PPE that should be considered by healthcare professionals as a guide to help recognize whether a particular medical condition requires special care in young athletes .In Europe, literature concerning sports PPE guidelines in the pediatric population is limited:•In 2011, recommendations for PA, recreational sports, and exercise training for children and adolescents with congenital heart disease were published by the Exercise, Basic, and Translational Research Section of the European Association of Cardiovascular Prevention and Rehabilitation, the European Congenital Heart and Lung Exercise Group, and the Association for European Paediatric Cardiology (AEPC) .•In 2012, the Polish Society of Sports Medicine (PSSM) published a position regarding age criteria during qualification for training in selected sport disciplines .•In 2017, the EAP published a resolution related to health, integrity, and doping in sports for the pediatric population and young adults .•Cardiovascular pre-participation screening recommendations for young athletes were published in 2017 by the AEPC .•Guidelines for participation in competitive sports for patients with congenital heart disease (CHD) older than 16 years were published in 2020 by the Section of Sports Cardiology and Exercise of the European Association of Preventive Cardiology Group (EAPC) and the ESC working on adult CHD and AEPC . In 2020•In 2021, the European Federation of Sports Medicine Associations (EFSMA) along with nine other organizations published “Pre-participation medical evaluation for elite athletes: EFSMA recommendations on standardized pre-participation evaluation form in European countries” .•In 2021, the ESC published guidelines on the task force for cardiovascular disease prevention in clinical practice .Age-specific pre-participation cardiovascular evaluation (PPCE) proposals for Swiss pediatric and adolescent athletes (under 18 years of age) were published in 2022 .According to the WHO glossary of terms, PA is defined as “any active bodily movement resulting from the contraction of skeletal muscles that raises energy expenditure above resting metabolic level” . The typThere are various types of sport activity which can be defined under different settings  such as:•Leisure sports: recreational PA without pressure to play, continuous play, or play at a higher intensity based on the willingness of the subject. Any participants may stop or lower the intensity of their involvement at any time.•Competitive sports: organized, competitive, and skillful PA within established rules of the sport.•Exercise training: specialized, structured, planned methods and programs of PA used to enhance a participant's physical abilities.A young athlete is defined as an individual, either amateur or professional, who participates in regular training and official sports competitions , 37. AllExercise trainings are specialized and planned methods and programs of PA for increasing functional capacity, performance, or cardiorespiratory fitness , 40. RecPediatric and adolescent athletes who are younger than 18 years of age may be defined as participating in competitive sports at a high level if they are practicing in a team setting for at least 6 h per week . Not allIn 2014, the United States Olympic Committee along with the National Governing Bodies used the long-term athlete development principles to create the American Development Model . They crIn 2012 in Europe, the Polish Society of Sports Medicine (PSSM) published its position regarding age criteria during qualification for training in selected disciplines in the pediatric population . The criIndividual differences in growth and maturation can lead to unforeseen consequences in competitive sports and an increased risk of injury, especially in athletes who are constitutionally smaller and/or delayed in maturation. Therefore, there has been a long tradition of proposals for selecting athletes based on physical characteristics rather than chronological age. This strategy is called “bio-banding” and involves grouping and/or assessing athletes based on size and/or maturity status rather than chronological age . AccordiThe main scope of sports PPE is to maximize safe participation. It should be individually adjusted to the participant especially during obligatory general pediatric consultations between the age of 0 and 18.The objectives of the PPE are as follows , 52–56:•Primary objectives: disclosure of defects that may limit participation and determine conditions that may be life-threatening or disabling.•Secondary objectives: an indication of the general health of a child, examination of the level of maturation, provisions enabling an opportunity to answer questions, and introduction of the athlete into local sports.•Other objectives: classification of an athlete according to individual qualifications, compliance with legal and insurance requirements for athletic programs, and provision of opportunities for children to compete.In European countries, local and state requirements determine who has the authority to perform a PPE. General practitioners are responsible for conducting a PPE for children wishing to participate in sports, but in some countries, the determination of sport eligibility depends on the opinion of sport and exercise medicine (SEM) specialists, especially for top-level competitive sports , 57–62. The examination should be performed several weeks before a sporting event allowing time for additional examinations or treatment if needed. The AAP recommends a PPE at least 6 weeks prior to the beginning of the season to allow additional assessment and/or rehabilitation prior to competition . This maDepending on governmental, state, or sport society requirements, a PPE should be repeated at least every 1–2 years or more frequently for selected sports or for selective health problems in athletes, especially in top-level athletes , 67, 68.The diagnostic components of PPE are health status, anthropometry, functional capacity, and exercise capacity. For the PPE, both the American and European Societies currently recommend a thorough investigation of personal history, family history, and a limited physical examination to determine the general health of the athlete , 64, 66.The EFSMA emphasizes the need for an implementation of a standardized PPE among European countries to ensure the best care for adult athletes . Until nThe pre-participation evaluation does not only focus on elements that determine known problems that affect sport involvement . During The past several years, especially during the COVID-19 pandemic, has seen a rapid growth of electronic sports (eSports) media, thanks to the increasing availability of online games and broadcasting technologies , and numwIt has been reported that in up to 58% of young athletes who do not positively pass the PPE screening, the decision to deny may be based on medical history alone or dizziness with exercise, history of asthma, body mass index (BMI), elevated systolic blood pressure, visual acuity, heart murmur, or problems detected during musculoskeletal examination . A pre-pPersonal history should identify past red flags and present medical conditions as well as previous surgeries and associated consequences such as past injuries, history of passing out, episodes of syncope or dizziness, any medicines currently being taken, vaccinations, history of allergies and anaphylaxis, infection diseases, headache, seizures, and any potential cardiovascular warning signs  , 56. BoyIt is very important during a PPE to inquire about the actual type, amount, and intensity of exercise training, associated chest pain or heart palpitations experienced during or post exercise, trouble breathing during exercise, dizziness or syncope during exercise, and the presence of excessive, unexpected, or unexplained fatigue during exercise.During a PPE, the consulting physician should inquire about dietary habits and eating disorders. Suggested diets for young athletes were presented in a Position Statement of the American Dietetic Association, Dietitians of Canada, and the American College of Sports Medicine . FurtherThe PPE family history is designed to recognize athletes at risk, especially in those with a family history including SAD. Most sudden deaths have been attributed to congenital or acquired cardiovascular malformations , 79. Oth•Died of heart problems or had sudden cardiac arrest before the age of 50 years or died for no apparent reason before the age of 50 years .•Had any type of heart problem, primary pulmonary hypertension, arterial hypertension, family and hypercholesterolemia.•Had syncope, presyncope, or unexplained seizures.•Had significant arrhythmia, an ablation procedure, an implanted pacemaker, or defibrillator.•Had exercise-induced asthma.•Had any of the following genetic disorders including hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), Marfan syndrome, and Ehlers–Danlos syndrome and channelopathies such as Brugada syndrome (BRS), long-QT syndrome (LQTS), or short-QT syndrome (SQTS).Sudden death in young athletes is rare and is usually caused by a genetic or congenital structural cardiac disorder –85, so dPhysical examinations must primarily screen the musculoskeletal, cardiovascular, and nervous systems. Abnormal breath sounds in the lungs should be diagnosed. The PPE may also include a dental and vision evaluation (risk of soft tissue lesions). The evaluation of vision can be performed using a standard vision chart (standard Snellen eye chart) with specification on the use of glasses or contact lenses.A critical component of a PPE is an anthropometric examination that includes somatoscopy, taking into account measurement of weight, height, BMI, sitting height, body composition, and girth measurements , 85, 86.Evidence for injury incidence and the long-term effects of participating in sports in the pediatric population are limited , 87, 88.The first component of the orthopedic PPE is a complete history of previous injuries and surgeries. A previous musculoskeletal injury is a major risk factor for re-injury, especially if the original injury was not rehabilitated properly , 94.The second component of the orthopedic PPE is the physical examination. The examination should evaluate spinal anomalies, deformity, and back pain . Back paSuggested examples of quick musculoskeletal examinations are offered by the American Medical Society for Sports Medicine (AMSSM) in online educational resources . In 2021The neurological assessment is focused on the abnormal conditions observed during present and previous examinations , 101. YoAn abdominal assessment can be brief in the absence of a significant history of gastrointestinal –106 or nMost of the cases of SAD occur in individuals with a pre-existing cardiac abnormality, and in young athletes (<35 years), instances of SAD are mostly due to inherited or congenital cardiac disorders. In 2005, the Study Group of Sports Cardiology of the Working Group on Cardiac Rehabilitation and Exercise Physiology and the Working Group on Myocardial and Pericardial Diseases of the ESC published a common European protocol for cardiovascular pre-participation screening of young competitive athletes for the prevention of SAD which are termed “the Lausanne recommendations” . A positIt is obligatory during a PPE to inquire about cardiovascular disease in family history , 113 witThe use of an electrocardiogram (ECG) is proposed as a screening tool in young athletes to identify potentially life-threatening arrhythmias , structural congenital heart disease, and cardiomyopathies , 111. DaThere are no routine laboratory tests that have been proven to be useful and cost-effective as elements of a PPE . RoutineThe female athlete triad syndrome with symptoms of amenorrhea, decreased bone mineral density , and disordered eating may appear in the absence of a balanced diet –125. Thewww.wada-ama.org)  .Sports recommendations for young athletes should also be concerned with the particular form of PA. Healthcare providers should recognize individual risks for the pediatric athlete in participating in the sport discipline chosen, because some sport disciplines may have particular constraints and may be subject to specific medical examinations. According to the government regulations in France, sport disciplines with a higher risk of injury for athletes are as follows , 132: , and some other types of PA have a high risk of collision or trauma  , 28, 133The safe age categories for combat sport disciplines are proposed below with criteria that are considered in the most frequently practiced sport disciplines: (1) participation in boxing for children and youth is not recommend, and (2) children younger than 12 years may participate only in non-contact sports involving training and competition in a form of technique demonstration or directed combat with task performance. They can participate in competition with non-contact activities. In disciplines not involving kicking or hitting, children can participate in training and competition from the age of 9–10 years in accordance with the regulations of sport federations, and (3) youth older than 12 years, who have participated in training and non-contact disciplines for at least 9 months, may participate in classes and training sessions and compete in combat sports with limited contact if the training or competition does not involve fighting using hand or leg blows with full force .In all combat sports that include hitting or kicking, or use of weapons, participants should use protection for the mouth, genitals, breast (girls), and other body parts according to regulations . Table 5After the results of the PPE are analyzed, athletes will likely be classified according to one of the following :•Medically eligible for sports performance without restriction.•Medically eligible with recommendation for further management.•Not medically eligible for sports performance: for all sport disciplines or a selected discipline, temporary or constantly contraindicated.Healthcare professionals should provide written guidelines with restrictions and permissions regarding adequate levels of PA and exercise. Determination of sports eligibility depends on historical and current examination findings and the sport in which the athlete desires to participate. Fever, acute illness, and viral myocarditis are conditions temporarily limiting sport participation. Limiting activity is also important for preventing complications such as dehydration or thermoregulatory problems. Some athletes will require further re-evaluation  , 99, 100Serious consideration needs to be given to RTP policies regarding COVID-19 infections in the pediatric and adolescent population. The AAP guidance from 2022 suggested that all eligible participants should receive a primary course of COVID-19 vaccine or booster doses when recommended . A histoThe decision to return to PA after COVID-19 should take into account the duration of the disease, the severity of respiratory or cardiac symptoms , as wellWhen returning to PA, children and adolescents should gradually increase the frequency, training volume , and intensity of activity to avoid injury. Based on an assessment of current and previous activity levels, young athletes should return to activity at 25%–50% of the volume and intensity at which they were participating previously . FinallySport and exercise medicine is a new multidisciplinary medical specialty that supports all subjects and patients who want to engage in PA, exercise, and sports. These medical specialists are also experts regarding the performance of athletes while maintaining their health . In EuroCurrently, there are no uniform and accepted guidelines for a PPE protocol to be implemented by primary care physicians in Europe for the general pediatric population. The first part of the EAP and the ECPCP position statement presents and summarizes the criteria which are considered to be the most frequently practiced in sports PPE based on expert opinion, reflecting an analysis of the current literature. The aim of this statement is to assist health professionals in implementing the best management programs for sports PPE in individual children and adolescents.In the absence of a uniform protocol, it is necessary to respect physician autonomy for choosing and implementing the most appropriate and familiar PPE screening strategy and to discuss the decisions made with young athletes and their families . This fi1.The utility of the sports PPE in the healthy population has been questioned in recent years, but the EAP and the ECPCP strongly recommend performing such evaluation in children and adolescents because the main scope of sports PPE is to maximize safe participation in the pediatric population of athletes.2.In European countries, local and state requirements determine who is authorized to carry out sports PPE: usually these are general practitioners or pediatricians, but in some countries, the determination of sports eligibility depends on the opinion of the sport and exercise medicine specialist, especially for top-level competitive sports.3.The timing of the sports PPE should be several weeks before a competition in order to incorporate additional examinations or treatment if needed and should be repeated at least every 1–2 years or more frequently depending on government, state, or sport society requirements, in selected type of sports or for selective health problems in athletes, especially in top-level athletes.4.In the opinion of the EAP and the ECPCP, sports PPE should include diagnostic elements such as health status, anthropometry, functional capacity, and exercise capacity. The PPE history is designed to identify athletes at risk, especially in athletes with a family history of sudden death. Parental verification of individual and family history is recommended. A physical examination should include an evaluation of biological maturation and vital signs such as visual acuity and a cardiovascular, pulmonary, abdominal, skin, genitalia, neurologic, and musculoskeletal assessment.5.The EAP and the ECPCP recommend educating athletes during the PPE in topics such as injury prevention or concussion, first-aid and external defibrillator–cardioverter support performance, dietary counseling, the effects of nutritional supplements, and doping practices.6.Because most of the cases of cardiac death in pediatric athletes occur during exercise in individuals with pre-existing cardiac abnormalities, mostly due to inherited or congenital cardiac disorders, the EAP and the ECPCP strongly recommend to apply protocol proposed by the ESC for a cardiovascular PPE of athletes for the prevention of SAD; the so-called “the Lausanne recommendations.”7.In the opinion of the EAP and the ECPCP, an electrocardiogram is a very sensitive screening tool for young athletes to determine heart disease or cardiomyopathies. According to ESC recommendations, it is recommended to include an ECG in a PPE cardiovascular screening before practicing sports.8.Healthcare providers should recognize the individual risks of a pediatric athlete participating in a chosen sport discipline because some sport disciplines may have particular constraints and are subject to a specific medical assessment.9.Young athletes should be classified as (1) medically eligible for sports performance without restriction, (2) medically eligible with recommendation for further evaluation, or (3) under treatment or not medically eligible for sports performance for all sport disciplines or a selected discipline temporary or constantly contraindicated. Young athletes should receive recommendations regarding appropriate levels of PA and exercise.10.The EAP and the ECPCP encourages collaborative decision-making with the athlete and his or her family or caregiver.11.Serious consideration needs to be given to return-to-play policies regarding COVID-19 infections in the pediatric and adolescent population. The EAP and the ECPCP strongly recommend that a history of COVID-19 infection and symptoms also be included in the PPE, and any young athlete who tests positive for current COVID-19 infection, even if asymptomatic, should cease all trainings and games until medical approval is obtained.12.The aim of presented first part of the EAP and the ECPCP position statement is to assist healthcare professionals in implementing the best management strategies for sports pre-participation in individual children and adolescents.13.In the absence of a uniform sports PPE protocol for children and adolescents in Europe, this EAP and ECPCP statement is not a formal recommendation for PPE, but rather a summary of practical applications and suggestions based on a current narrative review. In the opinion of the EAP and the ECPCP, it is necessary to respect physician autonomy for choosing and implementing the most appropriate and familiar PPE screening strategy and to discuss the decisions made with young athletes and their families.


The increasing availability of RNA structural information that spans many kilobases of transcript sequence imposes a need for tools that can rapidly screen, identify, and prioritize structural modules of interest.RNA Structural Content Scanner (RSCanner), an automated tool that scans RNA transcripts for regions that contain high levels of secondary structure and then classifies each region for its relative propensity to adopt stable or dynamic structures. RSCanner then generates an intuitive heatmap enabling users to rapidly pinpoint regions likely to contain a high or low density of discrete RNA structures, thereby informing downstream functional or structural investigation.We describe https://github.com/pylelab/RSCanner).RSCanner is freely available as both R script and R Markdown files, along with full documentation and test data ( RSCanner identifies and analyzes modules of high BPC across any RNA target of interest, regardless of length. RSCanner scans an RNA secondary structure model in windows, calculates relative BPC, and applies a Shannon entropy (SE) filter derived from base-pairing probabilities to identify regions where a high degree of secondary structure coincides with regions that are conformationally restricted or conformationally variable. In doing so, RSCanner enables the user to quickly pinpoint regions of high and low density of discrete RNA structures, which can significantly facilitate the choice of candidate regions for biochemical and structural analysis, as well as aid in downstream experimental design.We previously introduced a strategy for computing stable BPC along the length of long RNA molecules such as viral genomes, thereby providing a means for selecting transcript modules for subsequent structural investigation . In the in silico calculation  genomic RNA structure . First, RSCanner allows the user to define several parameters. The sliding window size for BPC and/or SE smoothing and the bin size for the histogram can be changed to generate graphs of varying granularity. The lower and upper nucleotide bounds for visualization can also be altered, allowing the user to zoom in on specific regions of interest on the RNA. Furthermore, the stringency for filtering structure counts can be adjusted by individually varying the cut-off values for BPC and SE. For example, to increase the stringency, the user could increase the BPC cut-off value from the 25th to the 75th percentile  and/or dIn addition to the HCV structure, we also applied RSCanner to other structured RNAs to illustrate its applicability to cases with and without experimental constraints: the HIV RNA genome, the SARS-CoV-2 Spike subgenomic RNA (sg-Spike), and the GRS1 long noncoding RNA (lncRNA GRS-1) . The SHAbtad111_Supplementary_DataClick here for additional data file.


The practice of yoga has been shown to have numerous benefits for both physical and mental health, and it has gained popularity worldwide as a form of exercise and relaxation. However, yoga postures can be complex and challenging, especially for beginners who may struggle with proper alignment and positioning. To address this issue, there is a need for a dataset of different yoga postures that can be used to develop computer vision algorithms capable of recognizing and analyzing yoga poses. For this we created the image and video datasets of different yoga asana using the mobile device Samsung Galaxy M30s. The dataset contains images and videos of effective (right) and ineffective postures for 10 Yoga asana, with a total of 11,344 images and 80 videos. The image dataset is organized into 10 subfolders, each with "Effective (right) Steps" and “Ineffective (wrong) Steps" folders. The video dataset has 4 videos for each posture, with 40 videos demonstrating effective (right) postures and 40 demonstrating ineffective (wrong) postures. This dataset benefits app developers, machine learning researchers, Yoga instructors, and practitioners, who can use it to develop apps, train computer vision algorithms, and improve their practice. We strongly believe that this type of dataset would provide the foundation for the development of new technologies that can help individuals improve their Yoga practice, such as posture detection and correction tools or personalized recommendations based on individual abilities and needs. Specifications Table•Yoga image and video dataset has significant value for individuals and organizations interested in studying and improving Yoga practice.•This dataset provides a collection of high-quality images and videos of correct and incorrect Yoga postures captured under different backgrounds and lighting conditions.•The dataset contains 11,344 number of images and 80 number of videos of various stepwise correct (right) and incorrect (wrong) Yoga postures.•This dataset is useful in the field of biomechanics, physiology, and sports sciences. It is also useful to analyze the posture of individuals in different poses, assess the impact of different postures on the body, and investigate the benefits Yoga practice.•This dataset is beneficial for app developers, machine learning researchers, Yoga practitioners and Yoga instructors.•Machine learning researchers can use this dataset to train computer vision algorithms to recognize and classify different Yoga postures automatically and the app developers can use the dataset to create Yoga apps that provide users with visual guidance on how to perform each pose and track their progress.1The main objective to crate this dataset is to develop fitness and wellness applications that offer personalized Yoga instruction and feedback based on real-time analysis of the user's posture. By studying images and videos of correct posture and technique, practitioners can learn how to adjust their own posture and movements to optimize their practice. Additionally, this dataset could be used for research purposes, such as developing automatic posture recognition models to improve Yoga practice.2The term "Yoga asana" refers to the various physical postures or positions that are performed in the practice of Yoga, with the aim of enhancing flexibility, strength, balance, and relaxation The dataset comprises both images and videos depicting right and wrong postures for a variety of Yoga asanas. The focus of the dataset is on 10 specific Yoga postures, namely Anantasana ; Ardhakati Chakrasana ; Bhujangasana ; Kati Chakrasana ; Marjariasana ; Parvatasana (Mountain Pose); Sarvangasana ; Tadasana ; Vajrasana ; and Viparita Karani . The Image dataset comprises a total of 11,344 images and is organized into 10 subfolders, each corresponding to a specific Yoga asana. Within each subfolder, there are two additional folders labelled "Right Steps" and "Wrong Steps". The "Right Steps" folder contains several subfolders, each representing a specific step in the correct sequence of the Yoga asana and displaying the corresponding images. On the other hand, the "Wrong Steps" folder includes multiple subfolders, each showing images of a incorrect steps in the sequence of the Yoga asana. The details of Yoga asana image numbers are presented in The Yoga asana video dataset consists of 8 videos for each posture, comprising 4 videos demonstrating the effective posture from 4 different angles and 4 videos exhibiting the ineffective posture from 4 different angles. This dataset includes a total of 80 videos for 10 Yoga asanas, with 40 videos demonstrating the effective postures captured from 4 different angles, and 40 videos illustrating the ineffective postures from 4 different angles. The details of Yoga asana video numbers are presented in The Yoga asana image dataset is important for improving Yoga practice, enhancing teaching, supporting research, advancing technology, and promoting accessibility. Previous research works have created Yoga datasets, however those datasets do not cover effective and ineffective ways of doing yoga asana ,14. MoreTherefore these datasets have limitations in Artificial Intelligence or Machine learning based applications to detect ineffective ways of doing asana. Furthermore, those datasets contain either images or videos. To address these limitations of existing datasets we created this dataset that contains various images and videos of incorrect postures in Yoga asanas which is important to help in identifying and correcting common mistakes made during the practice of Yoga. The dataset provides a visual reference for the correct alignment and posture in each yoga pose, allowing practitioners to improve their practice and avoid injury. Yoga instructors can use the dataset to demonstrate correct postures and alignment, which can enhance the quality of instruction and help students achieve optimal results. By studying the incorrect posture images, practitioners and instructors can better understand the mistakes that are commonly made and can work to correct them. The dataset can be used by researchers to investigate the effects of Yoga on the body and to develop new techniques and practices to improve overall well-being ,5. Addit33.1The high-definition rear camera of mobilephone was used to capture the photographs and videos of different Yoga asanas postures. All the photographs and videos were taken with a mobile same camera and separated into different folders based on their type of Yoga asana and "Right" and "Wrong" steps. During February 2023 to March 2023 pictures and videos of different Yoga asana posture image and videos captured in natural and artificial light, from various angles, and different background. This type of diverse dataset of Yoga asana images and videos captured in different lighting conditions and angles can benefit computer vision research, improve user experience in Yoga applications, enhance research on the impact of Yoga on health, and increase accessibility for people with different abilities and body types.3.2The dataset was created using a Samsung Galaxy M30s Mobile with a 48 megapixel camera for image capturing and video recording. Multiple photos and videos were taken for each Yoga asana, including effective and ineffective postures. Images were saved in JPG format, while videos were saved in MP4 format. The images were captured in different outfits, environmental settings, lighting conditions, backgrounds, and from various angles. Videos were recorded from four different angles, which included front, left side, right side, and back side, and featured instructions in English.3.33.3.1The Yoga Dataset consist of folders labelled as "Right" and "Wrong." One of the author of the datasets is assistant professor at the department of Yoga and Naturopathy, Vishwakarma University, Pune. He provided guidance and instructions to yoga performers, ensuring they performed the correct and effective yoga poses and postures. The criteria for determining the "Right" postures were based on the book titled "Daily Yoga Practice Routine" 3.3.2The images were captured and videos recorded at various environmental locations. The effective Yoga asana postures are performed as described in the book Daily Yogapractice Routine The videos were recorded with same mobile device. The videos have a frame width of 1280 pixels and a frame height of 720 pixels. The frame rate of the videos is 30.01 frames per second. The audio bit rate ranges from 255-257 kbps, and the audio sample rate is 48.000 kHz. The videos are recorded in MP4 format. The videos were categorized into ten separate folders, further divided into "Right" and "Wrong" categories. These categories contained four distinct angles of both the correct and incorrect postures, recorded in English language with detailed information about the proper and improper techniques. The created dataset is uploded on Zenodo in original raw format and it is publicy available to dowload The person present in dataset images and videos is one of the author of this dataset. He provided written informed consent to being included in the study and allowing their data to be shared publicly. We confirm that we don't have any conflict of interest.The research presented in this paper did not conduct the animal or human studies. No ethical approval was necessary for this research, and no living organism was subjected to any harm.Yogesh Suryawanshi: Conceptualization, Methodology, Data curation, Writing – original draft. Namrata Gunjal: Conceptualization, Writing – review & editing. Burhanuddin Kanorewala: Data curation, Methodology. Kailas Patil: Supervision, Validation, Writing – review & editing.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.


NA), while another would be to remeasure gland volume at each new magnetic resonance imaging scan . In addition, little is known about the predictive value of serial PSAD in comparison to PSA. We applied a long short-term memory recurrent neural network to an AS cohort of 332 patients and found that serial PSADNA significantly outperformed both PSADA and PSA for follow-up prediction of PCa progression because of its high sensitivity. Importantly, while PSADNA was superior in patients with smaller glands (BGV ≤55 ml), serial PSA was better in men with larger prostates of >55 ml.The global uptake of prostate cancer (PCa) active surveillance (AS) is steadily increasing. While prostate-specific antigen density (PSAD) is an important baseline predictor of PCa progression on AS, there is a scarcity of recommendations on its use in follow-up. In particular, the best way of measuring PSAD is unclear. One approach would be to use the baseline gland volume (BGV) as a denominator in all calculations throughout AS  and PSA density (PSAD) are the mainstay of active surveillance in prostate cancer. Our study suggests that in patients with a prostate gland of 55 ml or smaller, PSAD measurements are a better predictor of tumour progression, whereas men with a larger gland may benefit more from PSA monitoring. The past decade has witnessed a global increase in the uptake of active surveillance (AS) for management of patients with low-risk or favourable intermediate-risk prostate cancer (PCa) NA), while another would be to remeasure gland volume whenever a new MRI scan is performed . Intuitively, PSADA is the preferred approach given its ability to provide more accurate values with dynamic increases in prostate volume in patients on AS NA is easier to implement in routine clinical practice and there is no evidence regarding its comparative performance to either serial PSADA or PSA alone. In addition, the predictive performance of longitudinal PSA, PSADA, or PSADNA may vary for different BGVs. Specifically, in patients with smaller prostates, even a modest increase in volume may lead to a considerable decrease in PSAD, while this effect would be the opposite in men with larger glands. In this study we tested these hypotheses using machine learning for longitudinal predictive modelling of the risk of PCa progression in patients on AS using serial PSA, PSADA, and PSADNA.We have encountered several clinical questions in our practice. First, while PSA density (PSAD) is an important baseline predictor of PCa progression on AS NA and follow-up gland volumes for PSADA were calculated from MRI scans according to Prostate Imaging-Reporting and Data System guidelines We included 332 patients enrolled on our previously described AS programme NA significantly outperformed both PSADA and PSA for prediction of PCa progression  and larger (>55 ml) BGV  BGV D. The saA values F. For par values E.NA and PSA cutoffs sufficient to trigger unscheduled MRI or biopsy was beyond the scope of this study, our data provide several observations to be tested in future work. First, regardless of BGV, a consistent increase in PSADNA beyond the median value of 0.18 ng/ml/ml was a characteristic feature of progressors that could be first noted 3 yr before their clinical reclassification , are the following: None.Funding/Support and role of the sponsor: This research was supported by the National Institute for Health and Care Research (NIHR) Cambridge Biomedical Research Centre (NIHR203312). The study sponsor did not play a role in data collection and analysis. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. The authors also acknowledge support from Cancer Research UK , the CRUK National Cancer Imaging Translational Accelerator (C42780/A27066), and the Engineering and Physical Sciences Research Council Imaging Centre in Cambridge and Manchester. Nikita Sushentsev acknowledges support from the Gates Cambridge Trust. Oleg Blyuss acknowledges support from Cancer Research UK and EPSRC joint award EDDCPJT/100022.


One in eight individuals worldwide lives with a mental health disorder. For many European countries, the prevalence is even higher, with one in four people reporting mental health problems [1]. Three-quarters of all mental health disorders develop before age 25, with many presenting initially in undiagnosed forms already in the mid-teens and eventually manifesting as severe disorders and lasting into old age [2]. There is also growing evidence that mental health disorder symptoms cross diagnoses and people frequently have more than one mental health disorder [3]. One in eight individuals worldwide lives with a mental health disorder. For many European countries, the prevalence is even higher, with one in four people reporting mental health problems . Three-qMental health problems are not only prevalent, enduring in nature and complex, but also closely interconnected with many aspects of life, and therefore disabling. They increase the risk for school drop-out, are a major cause of work absenteeism, presenteeism, and incapacity to work, are closely related to poverty, negatively impact family lives, increase social isolation, and decrease life expectancy by 15 to 20 years, mostly due to somatic disorders . AccordiAlready before the COVID-19 pandemic, the societal cost of mental health disorders exceeded 4% of GDP (over EUR 600 billion) across the 28 European Union countries. Direct health care costs (EUR 190 billion) were estimated overall to be lower than the economic impacts of lower employment and productivity of people with mental health issues (EUR 260 billion), similar in size to spending on social security programs (EUR 170 billion) [Although effective and cost-effective early detection and interventions exist, there are numerous unmet needs along the mental health care pathways. Navigating the mental health services system is often complex for patients and families due to fragmented or disrupted services (in-patient and outpatient care) and discontinuity of care  . PolicieValue-based healthcare is gaining traction in Europe as the desired solution or path forward in improving health systems. Achieving high value for patients must become the overarching goal of health care delivery, with value defined as the health outcomes achieved per money spent . The appIn 2019, the European Brain Council (EBC) initiated a second research project on the Value of Treatment (VOT2) focused on early detection and continuity of care for persons living with selected mental disorders. The research project – which combines care pathways analysis and economic analyses – included three case studies related to anorexia nervosa (AN), autism spectrum disorder (ASD), and major depressive disorder (MDD). It aimed to identify treatment gaps, assess the potential outcomes and costs of optimized care, and provide policy recommendations. Case studies were analyzed in collaboration with EBC’s scientific societies and patient organizations in line with the research framework.lack or delayed detection in more than 50% of cases,long waiting times and duration of untreated illnesses including over one-year delays in access to screening and diagnosis (ASD), or specialist treatment (AN),fragmentation and lack of collaboration between services offering different treatment options,disruption of the continuity of care between various service levels and along the life course,large within- and between-country service and practice variations,high out-of-pocket expenses for patients and families,lack of organized support for families caring for children impacted by the disorders, andvery limited systematic and comparable data on epidemiology, guideline adherence, patient and family outcomes, and costs, limiting robust socio-economic assessments.In light of the complexity of mental health care pathways and their national variations, these case studies focused on specific aspects of early intervention and continuity of care provision, including the transition of care for AN, early intervention including associated epilepsy in ASD, and the value of an optimal stepped care model for MDD. Mapping surveys in multiple European countries demonstrated major treatment gaps. Those surveys were followed by an assessment of the potential health and healthcare cost impacts of closing these gaps in optimized care pathway models  and resulted in care improvement recommendations. All three case studies found:In the case of AN, reducing the three main treatment gaps by 50% in terms of improved waiting times, specialist service access, and transition support could reduce the disease burden substantially. Early diagnosis and medication treatment of autistic children with epilepsy was shown to be cost-effective, and country-specific strategies would make the economic case even stronger. Reducing treatment gaps in the detection and treatment of MDD is likely to achieve better outcomes at increased short-term costs. However, investigated optimization strategies for MDD represent overall good value at the currently applied cost-effectiveness thresholds across all modeled countries if implementation costs remain below certain limits.The VOT2 case studies found that, although established clinical guidelines are available for AN, ASD, and MDD, there are major geographical care variations in Europe, leading to reduced effectiveness and efficiency and substantial negative health impacts. Due to the lack of relevant surveillance and monitoring tools, the magnitude of these care variations remains unknown. Furthermore, outcome and cost estimates remain limited due to the underdeveloped evidence base. Nevertheless, the case studies confirm the added value of early detection and intervention and the implementation of a continuous and comprehensive healthcare approach as opposed to fragmentation in separate medical  “silos.” Analyzing multiple diseases jointly also made the resulting conclusions more impactful for public health and reinforced the call for pan-European actions.On the other hand, harmonization towards one “gold standard” European care pathway that includes early detection and intervention for mental disorders is unlikely to be optimal or feasible. When considering that the richest and the poorest EU-27 countries vary in their relative GDP per person by almost five-fold, there are non-negligible differences in terms of what services and interventions may be seen as the best value and affordable in the given healthcare system emerge. Future efforts towards optimal mental health care pathways will require both explicit value and affordability considerations and the alignment of relevant public reimbursement plans in order to reduce the already immense economic burden on patients and families. Some elements of an enabling ecosystem, however, remain universal as shown in Value-based digital care including technology and digital treatments New treatment paradigms and access Patient engagement through personalized treatment and support, and the use of Patient-Reported Outcomes (PROs) Patient participation in key clinical decisions and policy discussionsCollaboration in monitoring and research via data sharing and infrastructure Defined EU policy areas around healthcare systems and related policy/regulatory initiatives include:The above-identified research and public health policy gaps and opportunities at the EU level need to be addressed in combination with harmonized, national-level actions. These should include country-specific guideline adaptations, integrated service optimization, the development of adaptive payment schemes, improved routine care, outcome and cost data collection and linkage through national registries, (bio)data banks and cost databases, and greater investment in mental health promotion and mental ill-health prevention beyond the healthcare system, especially during early childhood and adolescence. Building a strong foundation for mental health and investing in optimal interventions tailored to the young generation advances socio-economic development. Hopefully, this will be addressed by the European Commission in the development of a comprehensive strategy for mental health in the EU to be released during the second quarter of 2023.


The patterns of communication among different chondrocyte subtypes in human cartilage degeneration and regeneration help us understand the microenvironment of osteoarthritis and optimize cell-targeted therapies. Here, a single-cell transcriptome dataset of chondrocytes is used to explore the synergistic and communicative patterns of different chondrocyte subtypes. We collected 1600 chondrocytes from 10 patients with osteoarthritis and analyzed the active communication patterns for the first time based on network analysis and pattern recognition at the single-cell level. Manifold learning and quantitative contrasts were performed to analyze conserved and specific communication pathways. We found that ProCs (Proliferative chondrocytes), ECs (Effector chondrocytes), preHTCs (Prehypertrophic chondrocytes), HTCs (Hypertrophic chondrocytes), and FCs (Fibrocartilage chondrocytes) are more active in incoming and outgoing signaling patterns, which is consistent with studies on their close functional cooperation. Among them, preHTCs play multiple roles in chondrocyte communication, and ProCs and preHTCs have many overlapping pathways. These two subtypes are the most active among all chondrocyte subtypes. Interestingly, ECs and FCs are a pair of “mutually exclusive” subtypes, of which ECs are predominant in incoming patterns and FCs in outgoing patterns. The active signaling pathways of ECs and FCs largely do not overlap. COLLAGEN and LAMININ are the main pivotal pathways, which means they are very important in the repair and expansion of joint homeostasis. Notably, only preHTCs assume multiple roles  and are involved in multiple communication pathways. We have examined their communication patterns from the perspective of cellular interactions, revealed the relationships among different chondrocyte subtypes, and, in particular, identified a number of active subtypes and pathways that are important for targeted therapy in the osteoarthritic microenvironment. Our findings provide a new research paradigm and new insights into understanding chondrocyte activity patterns in the osteoarthritic microenvironment. Chondrocytes, along with matrix and fibers, make up cartilage and are the only cell type in cartilage6. In view of the fact that senescence or degeneration of chondrocytes will result in a loss of cartilage integrity, many studies have focused on the apoptosis of OA chondrocytes in an attempt to find out mechanisms affecting the development of OA from the perspectives of chondrocyte differentiation and growth9. Chondrocytes differentiate and develop in several stages: quiescent, proliferative, prehypertrophic, hypertrophic, and finally calcified into bone11.Osteoarthritis (OA) is a chronic joint disorder that disrupts the metabolism of joint tissues. It is accompanied by inflammation and bone degeneration, and is closely associated with aging16. Different chondrocytes play different roles in cartilage formation. Existing studies on single-cell transcriptomes have identified seven subtypes of chondrocytes: effector chondrocytes (ECs), fibrocartilage chondrocytes (FCs), hypertrophic chondrocytes (HTCs), homeostatic chondrocytes (HomCs), proliferative chondrocytes (ProCs), regulatory chondrocytes (RegCs), and prehypertrophic chondrocytes (preHTCs)15. Researchers have identified ProC, preHTC, and HTC as more active chondrocyte groups whose functional characteristics have been extensively studied13. ProC present in the proliferative zone of the joint growth plate has the function of preventing hypertrophic differentiation at the top layer, while the differentiation at the lower layer near preHTC and HTC is unrestrained19. Hypertrophic differentiation can also be regulated by preHTC20. Chondrocyte mineralization in the surrounding matrix is inseparable from HTC22. The roles of different subtypes of chondrocytes have been well studied, but the relationships among them are rarely probed. In particular, little is known about how these subpopulations collaborate and communally promote the development of OA in the arthritic microenvironment and what the common patterns of communication among them are. The communication patterns of these chondrocytes are of great importance for understanding OA homeostasis and repair.In recent years, with the application of single-cell sequencing technology in osteoarthritis, more discoveries have been made regarding both the differentiation and the subtypes of chondrocytes23. For the first time, the communication patterns among different subtypes of chondrocytes at the single-cell transcriptome level are compared, which lays the foundation for a further understanding of the osteoarthritic microenvironment.To investigate the communication patterns among chondrocytes, we adopted network analysis and pattern recognition at the single-cell level in an attempt to figure out how incoming and outgoing signals coordinate with one another in chondrocytes. We also performed manifold learning and quantitative contrasts to identify conserved and specific pathways in chondrocytes13. Specimens containing all layers of cartilage were individually extracted from the tibial plateau region, following the methodology described in earlier studies25. The result indicated that the strengths of interactions among ECs, FCs, and HTCs were strong  PreHTC, EC, and ProC, which play a predominant role in incoming patterns and a supplementary role in outgoing patterns; 2) HomC, HTC, and FC, which play a supplementary role in incoming patterns and a predominant role in outgoing patterns  in cellular subtypes and their roles. Essentially all chondrocyte subtypes act as influencers in COLLAGEN and LAMININ, while EC and proC play multiple roles including sender, receiver, mediator, and influencer Fig. A,B,G,H. We found that proCs were mainly active in COLLAGEN and LAMININ, and that proCs were not more active in other pathways than preHTC. preHTC was involved in different pathways and served multiple roles Fig. A–L. In TTo explore which ligand-receptor pairs are involved in intercellular communication, we further analyzed their activity in active signaling pathways. We found that COLLAGEN and LAMININ have more ligand-receptor pairs, and that ITGAV, ITGB1, ITGA10, COL4A1, COL4A2, and COL9A3 are the main COLLAGEN pathways  Cell subtypes with active or more robust communication can be selected as alternative cells for cell therapy. Some of the predominant cell populations we identified in OA, such as ProCs and preHTCs, could be used as alternative cell types for subsequent clinical trials and clinical observations. For example, the identification and input of dominant cells after total joint replacement surgery in OA or the reduction or reversal of the proportion of cellular senescent cell subtypes are beneficial to the repair of arthritis patients. There is also the repair of arthritic stem cells, where the use of our method (using pattern recognition and manifold learning) allows for the rapid targeting of dominant stem cells, thus targeting the selection of cells that have a beneficial effect on arthritis recovery. (2) Interacting relationships between cell ligand receptors, which we can subsequently develop relevant inhibitors to block, interfering with these arthritis-related communications with a view to achieving therapeutic effects. To provide new ideas and therapeutic options for arthritic chondrocytes and their development. (3) In the era of individualized precision medicine, there are a small number of differences in cell subtypes for each individual. By detecting these cell subtype differences, we can use our method to perform rapid screening, reduce errors and discrepancies, effectively deal with the differences at the individual cell level in each patient, reduce experimental financial overheads and time consumption, and improve reproducibility and reliability. (4) It is important to note that the communication patterns among cells in this study are based on single cell transcription in osteoarthritis, with limited information on the spatial distribution of chondrocytes. The future application of single-cell spatial transcriptome and spatial subcellular proteome technologies in osteoarthritis is expected to provide a more realistic picture of the evolutionary trajectory and spatial status of different molecules of chondrocytes during the development of osteoarthritic inflammation39, and to provide key cell subtypes and their distribution patterns for targeted drug and cellular immunotherapy40.In conclusion, we have looked at their communication patterns from the point of view of cellular interactions, shown the relationships between different chondrocyte subtypes, and in particular found a number of active subtypes and pathways that are important for targeted therapy in the osteoarthritic microenvironment41. In order not to affect the number of inferred ligand-receptor pairs, the expression matrix needs to be averaged by default by cellchat's “trimean” gene expression values for each cell group, which is a statistically robust method for averaging gene expression. For signal genes of interest, average expression values were checked using the function computeAveExpr , type = “truncatedMean”, trim = 0.1). A signal communication network was mainly inferred with the function computeCommunProb, cellchat <- computeCommunProb(cellchat). Individual signaling pathway profiles for ligand-receptor pairs were inferred with the function computeCommunProbPathway, cellchat <- computeCommunProbPathway(cellchat). Single-cell transcriptome dataset of chondroprogenitors and their differentiation from GSE160625.Raw RNA-seq data for OA chondrocyte single cells were obtained from the GEO (Gene Expression Omnibus) database (GSE104782). We used the R package cellchat for cell–cell communication analysis, which required the entering of normalized scRNA-seq mean expression data values and cell annotation information into cellchat to construct a cellchat-compliant object formatIn order to infer the roles played by different cell subpopulations in cell communication , we adopted a weighted directed network approach, using cellchat's netAnalysis_computeCentrality and netAnalysis_signalingRole_ network functions for derivation. The parameters are: cellchat <- netAnalysis_computeCentrality  and netAnalysis_signalingRole_network . Next, different incoming and outgoing signals were calculated by harmonizing cell communication patterns using selectK and selectK. Parameters were set to calculate the number of intercellular communication patterns using identifCommunicationPatterns and netAnalysis_river or netAnalysis_dot functions were employed to calculate specific pathways and visualize the assumed signaling patterns. Finally, similar signals were grouped by clustering and grouping to form different sets of signals that facilitate the exploration of heterogeneity between signaling pathways. Functions for signal clustering, grouping, and visualization include computeNetSimilarity, netEmbedding, netClustering, and netVisual_embedding.The number and strength of interactions among single cell transcriptome expression profiles were inferred using cellchat’s function compare interactions. To determine which cell groups showed significant variation in interactions, interactions among different cell groups were compared: par, xpd = TRUE) netVisual_diffInteraction ; netVisual_ diffInteraction . The heatmap visualization of the number of interactions and the intensity of the interactions was performed using the netVisual_heatmap function. The netAnalysis_signalingRole_scatter function was used to identify cell populations that differ significantly among data sets in terms of signals sent or received.Supplementary Information.


Children and adolescents living with Type 1 Diabetes (T1DM) in India face multitude of challenges including lack of free supply of insulin, syringes, glucose measuring devices and strips, lack of structured diabetes education and counselling, and inadequately trained health care professionals.Government of India took initiative to launch the National Programme for Prevention and Control of Cancer, Diabetes, Cardiovascular Diseases and Stroke (NPCDCS) in the year 2008.,Extensive literature search revealed that in developing countries, there is no structured health program for T1DM which is implementable, deliverable, replicable, scalable and pharmaco-economically viable.We have embarked upon implementing a pilot model project for the management of T1DM in selected districts of West Bengal. This is a project-in-innovation, wherein a chronic care model is being developed for providing comprehensive health care for T1DM. The program is being implemented initially in five selected districts of West Bengal. Once the services get established successfully at these health facilities, the program will be scaled up to cover the remaining 23 health districts of West Bengal and later the whole country could possibly benefit from this model if proven to be beneficial and scalable.The program focuses on providing comprehensive health care services for these children by utilizing the existing health care delivery system and piggy backs on the NPCDCS program. Comprehensive health care services at out-patient department (OPD) basis includingdetection, management of disease and complications, appropriate referral, and rehabilitation, counselling services, building registry of T1DM patients, training human resources, and capacity building at the community level are important components of the program.Existing NCD clinics of each district hospitalhas been upgraded to T1DMclinic once a week after initial inspection and careful supervision. Existing identified human resources of each district hospital have been trained to provide comprehensive health care for T1DM. Each district hospital has been tagged with a medical college in the state for providing on-site training and hand-holding initially for six months. Children and adolescents with T1DM receive effective treatment at these clinics along with free provision of insulin, glucose measuring devices and strips, routine anthropometric examination, required laboratory investigations, monthly follow up care services, emergency care services and timely referral to tertiary health care facility when necessary.Structured diabetes education is being provided to the children and their caregivers in the form of counselling services at OPD basis by trained nursing staff, distribution of T1DM education booklets and quarterly educational camps. Children and adolescents with T1DM and their caregivers are trained for self-management, self-monitoring of blood glucose, insulin dose adjustment, sick day rules, nutrition and exercise, and awareness regarding complications. Counselling is the cornerstone for effective management of T1DM because proper self-care ensures good glycemic control and psychological well-being. Children and their caregivers also have access to telephonic contact with trained program coordinator for emergency management. Web-based application has been developed where every treatment detail is recorded and updated in the form of initial, monthly and annual visit formats.Through this program, long term sustainability of the interventions may be ensuredand mayimprove survival and quality of life of children and adolescents suffering from T1DM, bringing relief to a large section of the community across all classes irrespective of their financial status.We are hopeful that in the long run juvenile NCD program will be launched in India based on our model of care for T1DM.Conceptualization: Sujoy GhoshWriting – original draft: Masuma YasminWriting– review & editing: Pradip MukhopadhyayNone.