Diante de dados demográficos referentes às áreas de atuação dos cardiologistas no Brasil, a coordenação do Programa de Residência Médica em Cardiologia do Instituto do Coração (PRM INCOR) entendeu a necessidade de uma atualização de seu conteúdo programático, a fim de adaptar o processo de formação à realidade profissional do cardiologista.O presente artigo tem como objetivo descrever à comunidade científica as atualizações recentemente implementadas no PRM INCOR.No artigo, descrevemos as atualizações recentes do PRM INCOR, comparando a grade teórica pregressa e a atual. Expomos também o racional por trás de tais mudanças com dados de literatura relacionados à atuação do médico cardiologista no mercado de trabalho.Houve uma redução da carga horária destinada a estágios de terapia intensiva, e um incremento nas atividades ambulatoriais relacionadas a medidas de prevenção primária e secundária. Além disso, o programa passou por uma reformulação de seu conteúdo didático, organizado agora por núcleos de competência.A atualização da grade curricular decorre da necessidade de adequar o PRM INCOR à realidade atual do mercado de trabalho brasileiro. O grupo envolvido na atualização está ciente que se trata de um processo dinâmico e que pode exigir modificações no decorrer do tempo. As doenças cardiovasculares representam uma grande preocupação no Brasil e no mundo, sendo a principal causa de morte no país e responsável por uma parcela significativa dos custos relacionados aos cuidados de saúde. No entanto, muitos brasileiros ainda não recebem cuidados cardiovasculares adequados, seja por escassez de recursos ou formação deficitária de médicos especialistas. Melhorar a formação dos profissionais de saúde pode contribuir para mudar esse cenário, embora a compreensão das mudanças necessárias nos programas de treinamento em cardiologia não seja uma tarefa fácil.Traçar paralelos entre os programas de residência em cardiologia no Brasil e em países desenvolvidos pode ajudar a identificar possíveis alvos de melhoria. Porém, é fundamental conhecer a inserção e a área de atuação dos profissionais de saúde depois de formados, para adaptar o processo de formação à realidade do mercado.1 em 2020, o número de médicos aproximou-se a meio milhão no Brasil, o que corresponde à relação de 2,4 por mil habitantes. Desses, 4,1% (n=17 802) são cardiologistas, o que coloca essa especialidade entre as 10 com o maior número de médicos, correspondendo à razão de 8,47 por 100.000 habitantes. Apesar do aumento do número de médicos, resultado da abertura de novos cursos de medicina, os profissionais ainda se encontram mal distribuídos geograficamente  e no sistema de saúde . 1 Ainda segundo este levantamento, apenas 8,16% dos cardiologistas em atividade possui o título de especialista em medicina intensiva. Apesar de não ser obrigatória a obtenção do título de especialista em terapia intensiva para realizar plantões em Unidades de Terapia Intensiva (UTI) e prontos-socorros no país, esse dado pode indicar que, o plantão nesses locais seja apenas uma etapa transitória na vida profissional do cardiologista no Brasil. Por outro lado, a preferência ou a maior duração dos estágios de emergência e UTI na grade curricular da residência, em detrimento de outras áreas clínicas, talvez não reflita o perfil profissional atual.Segundo Scheffer et al., 2 Um total de 2101 médicos responderam ao questionário, sendo que 70,5% eram portadores do título de cardiologia pela SBC e 29,5% eram aspirantes ao título; 49,3% declararam trabalhar em três ou mais locais diferentes, e 46,5% declararam ter o hospital público como local de trabalho mais frequente. Esse dado sugere que a formação do cardiologista, fundamentalmente em um hospital-escola público, traz ao médico residente aspectos práticos do cenário em que provavelmente será inserido após o término de sua formação. Outro estudo observacional transversal 3 envolvendo médicos graduados pela Faculdade de Medicina da Universidade de São Paulo (FMUSP) demonstrou que mais da metade deles trabalha tanto no setor público quanto privado, sendo que 63,4% trabalhavam em consultórios e clínicas particulares.A Sociedade Brasileira de Cardiologia (SBC) realizou, em 2017, um levantamento entre seus sócios para identificar o perfil de atuação profissional do médico cardiologista no território brasileiro. Este artigo tem como objetivo descrever as mudanças instituídas no programa de Residência Médica (PRM) do Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (PRM Incor).O PRM Incor existe desde 1982, quando aconteceu o credenciamento junto à Comissão de Residência Médica (COREME). Desde então, já foram formados 796 médicos cardiologistas vindos de todos os estados do Brasil. O PRM Incor tinha uma grade curricular que contemplava, no primeiro ano, dois meses de treinamento em urgência e emergência, um mês de treinamento em métodos diagnósticos e o restante do ano em estágios que envolviam atividades em ambulatório e enfermaria. O residente percorria as unidades de aterosclerose, coronariopatia crônica, valvopatias, insuficiência cardíaca, transplante cardíaco, hipertensão, lipídios e marcapasso. O segundo ano do programa também possuía estágios de cunho ambulatorial, como o de arritmia, miocardiopatias e doenças da aorta e cardiopatias congênitas. Além disso, havia grande concentração de atividades de terapia intensiva: cinco meses voltados exclusivamente a atividades na unidade coronariana, na UTI clínica e na UTI pós-operatória. A Apesar de se tratar de uma grade curricular extremamente competente e abrangente, a nova coordenação do programa decidiu realizar uma atualização considerando que é fundamental que o conteúdo programático da residência reflita a prática do médico cardiologista contemporâneo no país. Este processo envolveu longo período de discussão desenvolvido pelo grupo constituído por diretores de todas as unidades clínicas da instituição, incluindo docentes da Universidade de São Paulo que atuam na formação de médicos residentes há várias décadas e que estão indicados ao final deste artigo.Neste sentido, alguns pontos de mudança foram definidos: primeiramente, decidiu-se pelo desenvolvimento dos estágios em núcleos de competência, para proporcionar uma melhor organização e continuidade dos temas abordados. Essa dinâmica possibilita, também, que os núcleos unifiquem programas didáticos e organizem de forma mais centralizada as competências primordiais ao residente naqueles estágios. As Em segundo lugar, entendeu-se que a carga horária destinada a estágios de terapia intensiva era desproporcional à carga de atuação do médico cardiologista nessa área, e optou-se pela redução do tempo de estágio em UTI. Em terceiro, diante da relevante participação do médico cardiologista em atividades ambulatoriais, e dado que essas contemplam em boa parte a assistência a pacientes em busca de medidas de prevenção primária e secundária, criou-se o núcleo de prevenção. Nesse, o residente tem a oportunidade de ter contato com áreas não contempladas no programa até então, como cardiogeriatria, reabilitação cardiopulmonar e ambulatório de triagem, além de estágios pré-existentes como lípides, hipertensão, tabagismo e ambulatório de atendimento a pacientes com cardiopatias em nível secundário em unidade externa. A Para se tornar cardiologista no Brasil, é necessário, após a formação em Medicina, cursar dois anos de especialização em Clínica Médica, seguidos de dois anos de especialização em Cardiologia. Até o ano de 2021 havia duas formas de ingresso no Incor. A primeira ocorria por meio do processo seletivo de Residência Médica, cuja prova é a mesma para todos as especialidades clínicas oferecidas pela instituição, com remuneração prevista durante o período e 28 vagas ofertadas. A segunda ocorria por meio de um processo seletivo exclusivo do Incor, cujos ingressantes possuíam uma menor carga horária de trabalho e algumas diferenças em relação à grade curricular, sem remuneração prevista. Esses profissionais não recebiam automaticamente, ao término de seu treinamento, o certificado de cardiologista pelo Conselho Federal de Medicina, sendo necessário realizar a prova de título da Sociedade Brasileira de Cardiologia.Diante da necessidade de homogeneização na formação dos médicos na instituição, foi solicitado no ano de 2022, junto ao Ministério da Saúde e à Secretaria de Saúde do Estado de São Paulo, o aumento do número de vagas no PRM INCOR, que passou a ofertar 52 vagas, sendo que todos os aprovados passam atualmente por mesma grade curricular. Diante disso, foram extintas outras formas de ingresso.Entendemos que, para adequar o PRM em cardiologia do Incor à realidade do mercado de trabalho brasileiro, houve a necessidade de atualização da grade curricular, com destaque para atividades ambulatoriais de prevenção primária e secundária, que representam hoje parcela significativa de atuação do médico cardiologista no Brasil.O grupo envolvido na gestão do PRM INCOR está ciente de que se trata de um processo dinâmico e que pode exigir modificações. O PRM INCOR já foi implementado e está em constante monitoramento por uma Comissão criada nos anos anteriores para acompanhar e resolver demandas de médicos residentes e professores do programa. Cardiovascular diseases are a serious concern in Brazil and in the world, representing the main cause of death in Brazil, and responsible for a high proportion of health costs. However, a large part of the Brazilian population still does not receive adequate cardiovascular care, due to scarcity of resources and poor training of specialist physicians. A better education of health professionals can help to change this scenario, although understanding the necessary changes in the cardiology fellowship programs is not an easy task.Drawing a parallel between cardiology residency programs in Brazil and in developed countries can help identify potential improvement targets. However, it is essential to identify the physician’s placement and main field of work after graduation, to adapt the process of professional formation to the market reality.1 in 2020, there were nearly half million physicians in Brazil, corresponding to 2.4 doctors per thousand inhabitants. Of these, 4.1%  are cardiologists, placing Cardiology among the top ten specialties with the highest number of physicians . Despite the increasing number of professionals, resulting from the emerging of new undergraduate medical courses, the number of professionals is unequally distributed across geographical regions in Brazil  and across the health system .1 According to the same study,1 only 8.16% of professionally active cardiologists have a title of intensive care specialist. Although working shifts in the emergency department and in intensive care units (ICUs) does not require a title of specialist, this may suggest that working shifts in these locations represent only a transitory stage of their professional lives in Brazil. On the other hand, the preference for and the longer duration of internship in emergency medicine, in detriment of other areas, in the cardiology residency program, may not reflect the current professional profile of cardiologists.According to Scheffer et al.,2 A total of 2101 physicians filled out the questionnaire; 70.5% had obtained the title of cardiology specialist from the SBC and 29.5% had applied for the title; 49.3% reported to work at three or more different places, and 46.5% reported that the public hospital was the most common place of work. This indicates that the cardiology training program is mostly carried out in public hospital schools, where the physician learns much of the practical aspects of the scenario in which he/she will be probably inserted after finishing the residency. Another cross-sectional observational study3 involving physicians who graduated from the University of Sao Paulo Medical School showed that more than half of them worked both in the private and the public sectors, and 63.4% worked in private offices and clinics.In 2017, the Brazilian Cardiology Society (SBC) conducted a survey among its members to identify the professional profile of cardiologists in Brazil.This article aims to describe the changes implemented in the medical residency program (MRP) of the Heart Institute (InCor) of the University of Sao Paulo Medical School.Comissão de Residência Médica ). Since then, 796 physicians, coming from all Brazilian federative units, completed the cardiology fellowship program. The curricular track of the Incor MRP comprised, in the first year, of two months of training in urgency and emergency, one month of training in diagnostic methods, and nine months of training in outpatient and inpatient care. The intern passed through the units of atherosclerosis, chronic heart disease, valve disease, heart failure, heart transplant, hypertension, lipids and pacemaker. The second year of the program was comprised of an internship in outpatient care of patients with conditions like arrythmia, cardiomyopathies, aortic disease and congenital heart disease. In addition, there was a great number of activities focused on intensive care – five months exclusively dedicated to the training at the coronary care unit, at the medical ICU and the postoperative ICU. The Incor MRP was created in 1982, when it was accredited by the Residency Committee  of the University of Sao Paulo who have worked in residency programs for decades.Then, some change points have been defined: first, it was decided that each stage of the residency would be developed at the respective unit/center to enable better organization and continuity of the topics. This dynamic process would also allow the unification of didactic programs across the centers and the concentration of the main competencies for the interns in each stage. Second, the total workload in intensive care units determined in the fellowship program was considered disproportionate given the actual working participation of cardiologists in this area, and the total of hours the residents spent in the ICU were then reduced. Third, in light of the active participation of cardiologists in outpatient care and considering that it involves strategies of primary and secondary prevention, the division of prevention was created. In this unit, the intern has the opportunity to gain work experience in areas that were not covered by the program so far, such as geriatric cardiology, cardiopulmonary rehabilitation and outpatient screening, in addition to pre-existing fellowship, including lipids, hypertension, smoking, outpatient care of heart disease patients at secondary care level at an external clinic. In Brazil, to become a cardiologist, after graduating from medical school, the physician must complete two years of internal medicine residency, followed by two years of cardiology fellowship. Until 2021 there were two entry pathways in the InCor residency program. The first one was a selection process consisting of an exam that is the same for every clinical specialty of the institution, with a salary predicted for the entire residency period and 28 openings. The second one consisted of a selection process that was exclusive of the Incor. The interns had a lower workload, there were some differences in the rotations and no salary predicted. These physicians who have fully completed their training do not get a certificate in cardiology from the Brazilian National Medical Council, and still have to pass the Brazilian Cardiology Society exam.Considering the need to homogenize medical residency training at InCor, in 2022, the number of openings increased to 52, as requested and conceded by the Brazilian Ministry of Health and Sao Paulo State’s Secretariat of Health. All residents, once passed the exam, follow the same curricular program, and hence other entry pathways were excluded.To adapt the residency program in cardiology offered at InCor to the labor market in Brazil, we believed that an update of the curricular program was required, focusing on outpatient activities of primary and secondary prevention, which accounts for a considerable volume of the cardiologist practice in the country.The administrative board of the InCor MPR understands that this is a dynamic process that may need modification. The InCor MRP was already implemented and has been constantly monitored by a commission created in previous years to follow-up and meet the demands of resident physicians and teachers of the program.


Assessing implementation fidelity is highly recommended, but successful approaches can be challenging. Family Planning Elevated (FPE) is a statewide contraceptive initiative which partnered with 28 health clinics across Utah. To assess implementation fidelity, we developed in-situ high-fidelity simulation training to both determine clinic adherence to FPE and offer education to implementing teams. This study aimed to develop, pilot, and assess the use of simulation as a tool for measuring implementation fidelity.We developed two simulation scenarios to determine implementation fidelity: one scenario wherein a client is seeking a new method of contraception and another in which the same client has returned to discontinue the method. Both simulations contained multiple aspects of program implementation . We then offered simulations to all FPE partner organizations. To assess simulation training as a tool for determining implementation fidelity, we developed strategies aligned with each aspect of an adapted RE-AIM framework, including pre-post surveys, acceptability and self-efficacy testing, a checklist for programmatic adherence, field notes, action planning and analysis of monitoring data.p =  < 0.001), increased ability to identify FPE-eligible clients (p = 0.02) and heightened self-efficacy in helping clients select a method (p = 0.03). Participants were satisfied with the simulations, with most (84.1%) reporting that the simulation exceeded their expectations.Fifteen clinical sites and 71 team members participated in the in-situ simulations. Assessment of the checklist showed that 90% of the clinics successfully demonstrated key program components, including person-centered counseling techniques such as sitting at the patient’s level (95.8%); asking open-ended questions (100%); and explaining how to use the contraceptive method selected (91.7%). More than half of clinics fell short in programmatic areas including: confirmation that the FPE program covered same-day intrauterine device insertion (54.2%), and education on health risks associated with the selected contraceptive method (58.3%). After simulation, participants reported improved knowledge of how FPE works (Highly-realistic in-situ family planning simulations are acceptable to participants, positively change knowledge and clinical team confidence, and can identify systems gaps in clinical care and program implementation. Simulation offers a reciprocal way of monitoring implementation fidelity of a family planning access initiative.NCT03877757.This project was determined to be exempt by the IRB of the University of Utah, the larger Family Planning Elevated program under which this pilot study was nested is registered at ClinicalTrials.gov Identifier: The online version contains supplementary material available at 10.1186/s12913-022-08332-4. In-clinic simulations on family planning counseling and provision can be used with interprofessional teams in a variety of clinical settings to improve provider knowledge, self-efficacy and systems challenges.Simulation trainings represent a potential research and programmatic tool that can be used in the ongoing challenge to understanding how a program is being implemented in real world settings (implementation fidelity).how the program is being implemented at each of the unique sites [implementation fidelity (IF), or how closely the implementing sites deliver the program as intended [Unlike the tightly controlled parameters of clinical trials, public health interventions are introduced into systems that are unpredictable, dynamic, and highly complex , 2. Publue sites , 4. Specintended . While iintended , 7. The intended , 8. Bothintended , are logintended . Qualityintended –12. In aIn 2019, the Family Planning Division at the University of Utah began implementation of a statewide contraceptive initiative, Family Planning Elevated (FPE). The Family Planning Elevated Contraceptive Access Program (FPE CAP) is the clinic-focused element of the initiative, aimed at improving contraceptive access through the health system. Clinics who were interested in participating in FPE CAP completed a detailed application. The application collected information regarding the populations served, organizational readiness to provide contraceptive care, data systems used, and each organization’s specific training and resource needs. For organizations who were accepted into FPE CAP, the program offered a tailored package for each participating organization, based on their size, populations served, budgetary needs, and training requirements. The FPE CAP package for each site included reimbursement for contraceptive methods and services for clients who fell in the coverage gap, technical assistance on contraceptive and logistical topics, education and clinical training on contraceptive provision, and cash grants for equipment and personnel expenses . The proand provide an educational benefit to the participating clinics. We wanted to measure fidelity in a way that was supportive of our relationships with the clinical sites, did not make the clinic staff feel like we were evaluating them individually, and improved sites’ ability to provide person-centered contraceptive care. Additionally, we wanted to observe specific components of programmatic fidelity in action, and we knew that simply observing routine patient visits would leave to chance which elements of the program we could observe. To meet our goals of 1) assessing implementation fidelity and 2) providing beneficial learning opportunities to the clinics, our team piloted the use of highly-realistic in-situ simulation trainings with our partner family planning clinics. Simulations with facilitated debriefs have been widely utilized to foster interprofessional teamwork and communication [When determining an approach to examine implementation fidelity at each of the clinical partners sites, FPE program staff wanted to simultaneously assess fidelity nication  improve nication , 16, andnication –19. To oThe aim of this study was to develop, pilot, and assess the use of simulation as a tool for measuring implementation fidelity. Additionally, we evaluated if the simulation trainings could benefit not only FPE’s evaluation of programmatic implementation, but also simultaneously aid the clinics in achieving program adherence, improve clinic team knowledge of programmatic elements, and provide real time feedback to program designers to inform iterative implementation. Each facility received one 4-h simulation training workshop, and participants completed pre- and post- test. Simulation trainings were conducted onsite at all primary care clinic organizations participating in Family Planning Elevated. These sites included community health centers, private clinics, and county health departments.Family Planning Elevated and the LIFT Simulation Design Lab collaborated to create a clinic-based simulation training. Each FPE CAP organization received a simulation training after they had been participating in the program for one year (of a two-year program). Each training lasted four hours and involved multiple members of the clinical team, including clinical coordinators or managers, front-desk staff, medical assistants, and providers. The trainings included: 1) a 45-min discussion ; 2) twoThe process evaluation component of the simulation training involved a facilitated discussion about the current implementation of FPE at the clinic site. The process evaluator asked open-ended questions about barriers and facilitators of FPE implementation, including the aspects of FPE that have been the most difficult to implement, and programmatic successes in the first year of implementation.After the process evaluation, participants were invited to engage in the simulation scenarios. In both scenarios, we used a simulated patient actor (SP) to allow providers the opportunity to practice the clinical and interpersonal skills needed during intrauterine device (IUD) contraceptive counseling and removal appointments. See Fig. To support simulation of the IUD removal, we used a hybrid simulator called PartoPants™  with an Both scenarios involved a patient actor (GG). During the simulation, the actor followed prompts that introduced learning objectives and known barriers to family planning service access. These prompts included asking about FPE eligibility (income and immigration status), contraceptive method efficacy, mechanism of action, method cost, and availability of same day IUD placement and follow-up. Simulations were conducted in English or Spanish (with clinic interpreters) depending on the desire of the clinic and the language typically spoken by their patients.neutral party (LIFT Simulation Design Lab), where both teams identified goals for improving program implementation at the site.After each simulation, the entire clinic team participated in a facilitated debrief, discussing the scenario and talking through various aspects of the participants’ experience. This debrief provided opportunities for the FPE program team to clarify programmatic elements about FPE, educate the clinical staff on new/updated clinical best practices, and collaboratively discuss barriers to FPE implementation at the clinic site. Following the two simulations and debriefs, the clinic and programmatic teams engaged in an action planning session led by a The components of this study are presented here in accordance with an adapted RE-AIM framework . The RE-To assess whether simulation had effects on targeted outcomes we developed a checklist of FPE-specific elements inherent in a standard contraceptive counseling visit  independently reviewed the recorded simulations and completed the simulation checklists. Prior to coding, members of the research team demonstrated the use of the checklist, oriented the coders and practiced coding. All simulations were double coded to assess for agreement between reviewers on programmatic constructs. We calculated kappa statistics to assess inter-rater agreement between coders.To evaluate the effectiveness of simulation as a learning opportunity for clinic staff, we assessed changes to knowledge and self-efficacy through pre- and post-simulation training evaluations , one medical assistant (MA) or registered nurse, and a front desk staff member. Most trainings also included members of the clinic’s administrative team and additional providers and clinic support staff. Due to precautions around COVID-19, we limited most simulations to six or fewer clinic participants. The clinics were spread across the state with two-thirds of clinics located in an urban center vs rural community. Eight were FQHCs, 3 public health department contraceptive clinics, and 4 private practice. Forty percent of the clinics that specialize in reproductive health services, while the remaining 60% provided comprehensive health services.Checklists were coded for a total of 15 simulation videos. To adapt to the COVID-19 pandemic, several clinics implemented programmatic changes in their approach to family planning visits, which resulted in widespread discrepancies in front-desk/MA practices across clinic sites. For example, to limit clinic staff and patient exposure, some clinics had MAs conduct the initial client intake by phone prior to the clinic visit. Because of this, we opted to limit our assessment of the checklist (and inter-rater agreement) to the provider component of the first scenario since it captured the most learning objectives and remained largely consistent despite fluctuating pandemic restrictions throughout the study period. Kappa scores for this scenario were 0.71 , indicating substantial agreement between the reviewers.Across the 15 simulations, coders agreed that more than 90% of the clinics were: introducing themselves to the patient (100%); sitting at the patient’s level (95.8%), asking open-ended questions (100%); asking about previous contraceptive experiences (91.7%); answering the patient’s questions in an affirming, normalizing manner (100%); clearly explaining how to use the contraceptive method selected (91.7%); and sharing clinically accurate information (100%). Coders noted that more than half of clinics fell short in a number of areas including: medical assistant did not confirm the patient could receive their selected contraceptive method same-day (54.2%), and providers did not explain the health risks associated with the contraceptive method selected by the patient (58.3%). Coders also identified programmatic areas that ultimately were coded as “not applicable” or not occurring in the simulation scenarios within clinic sites, namely: the front desk person introducing themselves (50%), the front-desk person identifying the patient’s income level as Medicaid-eligible (66.7%), the front-desk person telling the patient that they qualify for FPE (54.2%), and the medical assistant providing accurate information about the FPE program to the patient (45.8%).To measure our second component of intervention effectiveness—participant programmatic knowledge and self-efficacy—we conducted surveys before and after each training. These.assessments showed changes in self-reported understanding of the FPE program and beliefs in individual and clinic abilities to support contraceptive clients; for more than half of the surveys questions asked, the difference between participants’ pre/post responses was statistically significant at the 0.05 level. Table Post-simulation evaluations were positive, with most participants (84.1%) reporting that the simulation exceeded their expectations; that they would be able to apply what they learned in their clinical work (84.4%); and that they would strongly recommend the simulation training to a colleague (81.3%).n = 2), the end of the second simulation differed from sites without an onsite pharmacy and allowed for pharmacist participation and simulated dispensing of emergency contraception. Finally, for the final participating site (Southeastern clinic), we implemented simulation training at the outset of their partnership with FPE, rather than at the one-year marker. We did this due to feedback received from other participating sites that they wished they’d had access to simulation training earlier in the program, rather than at the program midpoint.The content of the simulations remained consistent across implementation; however, several aspects of the simulations changed in response to various circumstances. As mentioned, the COVID-19 pandemic limited the number of clinic staff participating in each simulation training to six. For two sites, we limited the simulation to the first scenario to accommodate time limitations. For clinics with an onsite pharmacy  universally, clinics struggled to determine client eligibility for the FPE CAP program; and 2) even when clinics did understand eligibility components of the program, there were clients who could significantly benefit from program participation, but who fell outside of the eligibility criteria. The simulations were a useful backdrop to provide clinic education and support for addressing eligibility, but also led to the FPE team making internal changes to the program to better meet clinic and client needs . The tension between programmatic fidelity and flexibility is not a new finding. A 2010 study on implementation fidelity found that perfect adherence to the intervention protocol was less predictive of good intervention outcomes than a moderate level of adherence, and pointed to the need for practitioner flexibility and interventions that adapt to the context of the setting . The useOur study did not find changes in the number or proportion of FPE clients served at clinical sites following the simulation training. There are several potential reasons for this. First, it is possible that the simulation training penetrance was not sufficient to make significant changes in program implementation. It is unknown what exact threshold of training  is needed to ensure there is diffusion of the concepts enough to create the cultural change needed to sustain clinical practice changes. As programmatic assessment, not clinical behavior change, was the main purpose of these simulation trainings, we did not conduct a study design with multiple simulations to assess whether the number of exposures to the simulation training was associated with changes in program implementation, but future research should assess this dose/response relationship. It is also possible that the clinical adaptations in response to the ongoing COVID-19 pandemic limited our ability to determine change pre- and post- simulation exposure. As previously noted, simulation trainings largely took place after March 2020 and many sites explained that they changed practices in response to pandemic limitations, which ultimately affected the number of clients they could see. Finally, and importantly, the simulations were conducted in the middle of the intervention. Much of the learnings that lead to program adaptations focused around the creation of additional supporting materials for the clinics and “exception” clarifications that could have resulted in increased utilization had they been identified and adapted earlier on in the program implementation. Ultimately, we learned that simulation earlier, with increased dosing and for a wide audience may have the potential to influence program ultization.As with all studies, this study has several limitations. First, while clinics were obligated to participate in simulations as part of their program requirements, the providers who attended the simulations chose to do so themselves or were selected by program administrators. It is thus possible that selection bias influenced those who felt favorably about the FPE program and its mission to participate in the trainings. Second, group size limitations, due both to the pandemic and simulation in general, meant that the entire clinic team did not participate in simulation trainings, which limited the generalizability on the reach of this type of intervention within clinical sites. Additionally, although timing and logistical constraints meant that some sites were limited to only the first scenario, we did not have a large enough sample size to stratify results in a meaningful way by the number of simulations. As a result, there may be a dose/response relationship between the amount of simulation and its impact that we are unable to determine. Further research is needed to understand the role simulation can play in the introduction of new clinical protocols and to understand the dissemination of that innovation across a clinical team and a clinic system.Highly realistic family planning simulations that occur in the clinical setting are acceptable to participants, positively change knowledge and clinical team confidence, and can identify systems gaps in clinical care and program implementation. Working with low-cost materials, facilitated simulation, debriefing and action planning can be used to assess implementation fidelity in a way that is acceptable, non-threatening and effective. This could be relevant to many programs that are looking for ways to monitor program implementation fidelity in ways that are reciprocal and beneficial to the implementation teams as well as providing an opportunity for feedback and collaborative iterative growth of a program to meet the needs of the implementers.Additional file 1: Additional file 2:


Background: Traditionally, the United States Medical Licensing Examination (USMLE) Step 1 3-digit score has been used as a metric to stratify plastic surgery residency candidates. The transition to a pass/fail exam may impact the manner in which integrated plastic surgery residency program directors (PS-RPD) evaluate candidates. It may also limit opportunities for applicants to differentiate themselves from their counterparts.Methods: A 14-question survey was distributed via email to 76 PS-RPDs collected from the American Medical Association (AMA) residency program site, FRIEDA. It was sent three times from March 3 - March 14, 2020. McNemar tests were performed on the current metrics of evaluation in comparison to metrics expected to be used in the absence of a 3-digit Step 1 score, assuming a P < 0.05 level for statistical significance. Results: Of the 76 integrated plastics programs surveyed, 24 PS-RPDs responded (31.6% response rate); 91.3% of PS-RPDs strongly disagree or disagree that Step 1 should be pass/fail; 78.3% of PS-RPDs strongly disagree or disagree that diversity will increase. The top five evaluation metrics PS-RPDs expect to utilize following the transition to pass/fail are: letters of recommendation , Step 2 score , research , elective rotation , and personal knowledge of the applicant . Conclusions: In the absence of a Step 1 score, PS-RPDs may require more holistic metric(s) to evaluate the best fit for their program. This study found that PS-RPDs expect their candidate evaluation process to remain highly similar with the only statistically significant change being an increased emphasis on the candidate's Step 2 score.  The United States Medical Licensing Examination (USMLE) Step 1 score is an essential tool used by residency programs to select applicants to interview . OfficiaOn February 12, 2020, the National Board of Medical Examiners (NBME) and the Federation of State Medical Boards (FSMB) announced that the USMLE Step 1 will change its grading system from a three-digit numeric score to a pass/fail grade -15.In this study, we surveyed integrated plastic surgery program directors from programs across the United States as a means to better understand how candidate evaluation is expected to change secondary to USMLE Step 1 becoming pass/fail. This is meant to be a resource for future applicants as they strive to maximize their chances of successfully matching into a plastic surgery residency position. A total of 82 PS-RPDs’ email addresses were obtained from the American Medical Association (AMA) residency program site FRIEDA. Of the 82 residency programs, six of the email addresses were returned as undeliverable. The correspondence began on March 2, 2020 with an invitation email to all 82 programs. Three subsequent survey invitations were sent to the programs between March 3 and March 9, 2020. PS-RPDs who elected to participate utilized a link provided to the REDcap survey which remained unlinked to their email to preserve complete program directors’ anonymity. After completion of the survey, program directors were able to view a graphic summary of the survey data collected until it was closed on March 14, 2020, at 12 pm CST. Refer to the Appendices for the survey questions.In order to identify which metrics will become more important during future candidate evaluation, program directors were provided with a list of 18 metrics based on the program directors’ survey from the National Residency Match Program ,17. The Statistical software SPSS version 26  was used to analyze the qualitative and quantitative data. Frequency distribution was considered for all survey questions to find evidence of outliers and potentially statistically significant information. Descriptive statistics were used to summarize participant responses as relevant to the objective and further elucidate the characteristics of the programs that participated in the study. Cross tabulation of current evaluation metrics with expected evaluation metrics was used to describe how PS-RPDs foresee the new pass/fail system impacting candidate evaluation. McNemar tests were performed on the current metrics of evaluation in comparison to metrics expected to be used in the absence of a 3-digit Step 1 score. DemographicsOf the respondents (n=24), 79.2% represent university-based plastic surgery residency programs. The respondents represent a wide range of experience as PS-RPDs with 41.7% having 0-5 years of experience, 25% having 5-10 years of experience, and 33.3% having over 10 years of experience “Placing more less qualified residents in subspecialties that requires higher level functions. Therefore decreasing the overall quality of the end product of these specialties and patients will suffer for it.” (R0477)“More resources [will be] required by program staff who are already overworked” (R0487)Diversity Among Plastic Surgery ResidentsUSMLE states that “maintaining 3-digit score reporting on the Step 1 exam may limit diversity” . However“The USMLE step 1 was an item that allowed an applicant from a lesser known school, a DO, or a foreign medical grad to be compared against others….Those fortunate to go to the top schools will have a great advantage now that one of the only ways an applicant from a lesser known background could stand out.” (R0445)Evaluation of Plastic Surgery Residency CandidatesPlastic surgery residency program directors were asked to select their current top five of 1the 8 metrics used to evaluate candidates. Under the current 3-digit USMLE Step 1 scoring system, the most commonly selected metric was Letters of Recommendation (95.7%) followed by Step 1 Score (80.0%), Elective Rotations (56.5%), Grades (43.5%), and Personal Knowledge of Applicant (43.5%) Table . As an iProgram directors were then asked to select their expected top five out of 17 metrics to be used to evaluate candidates with the new pass/fail system. The expected top five weighted metrics are; letters of recommendation , step 2 score , research , elective rotation , and personal knowledge of the applicant  (Table “We will use Step 2 scores instead of Step 1 scores as we need a mechanism to be able to select candidates from hundreds of applicants.” (R0549)“I assume that many programs will use Step 2 scores to screen applicants.” (R0447)Transition to New Candidate Evaluation MetricsThe USMLE announced in February, 2020 their intention to introduce the new Step 1 pass/fail scoring system beginning in January, 2022 [PS-RPDs are faced with the challenge of evaluating a high volume of residency candidate applications quickly and thoroughly. Of PS-RPDs in this study, 66.7% use Step 1 as a cut-off metric to screen candidates for interviews  that they are unlikely to adjust their current evaluation process until candidates no longer apply with a 3-digit score. This transition phase particularly impacts candidates who may receive a 3-digit score, but will apply to residency with other applicants that received a pass/fail score. As the unprecedented shift in Step 1 scoring continues to develop, it will likely leave medical students unsure of how best to differentiate themselves from their peers.Some limitations of this study are the inherent challenge that some program directors may be more or less inclined to respond, resulting in the potential for nonresponse bias. Additionally, this survey was conducted shortly after the USMLE announced the change in the scoring system which has provided the opportunity for program directors to develop new systems to adjust to the challenges of evaluating applicants.The need to evaluate residency candidates holistically is not disputed. However, in the absence of a 3-digit Step 1 score, PS-RPDs will have less measured criteria to evaluate candidates to ensure the best fit between candidates and programs. This study demonstrates that 91.3% of PS-RPD disagree that Step 1 should be a pass/fail exam and they subsequently expect to increase their utilization of an applicant's Step 2 score . Although the USMLE Step 1 pass/fail scoring system may ensure the appropriate basic science knowledge, the qualitative feedback in this study highlights the scoring change will make it increasingly difficult for highly qualified candidates to differentiate themselves from their peers when applying for an integrated plastic surgery residency position.


Decoy receptor 3 (DcR3) is a soluble receptor for Fas ligand, LIGHT and TL1A, but it also exerts effector functions. Previously, we found that DcR3 is upregulated in the serum and lesional skin of patients with psoriasis and is upregulated by EGFR activation in proliferating primary human epidermal keratinocytes. However, the functional role of intracellular DcR3 in keratinocyte differentiation is still incompletely defined. Herein, primary cultured human epidermal keratinocytes were differentiated by phorbol 12-myristate 13-acetate (PMA) treatment, calcium treatment and cell confluence, which are three standard in vitro differentiation models. We found that the constitutive expression of the DcR3 gene and protein was progressively suppressed during terminal differentiation of keratinocytes. These changes were correlated with downregulation of EGFR activation during keratinocyte differentiation. EGFR inhibition by gefitinib further decreased confluence-induced suppression of DcR3 mRNA expression, and, vice versa, knocking down DcR3 expression attenuated EGFR and EGFR ligand expression as well as EGFR activation. Under conditions without a change in cell growth, DcR3 silencing reduced the expression of involucrin and transglutaminase 1 but enhanced the induction of the terminal differentiation markers keratin 10 and loricrin. Of note, DcR3 interacted with PKCα and PKCδ and enhanced PKC activity. In keratinocytes with PKCα and PKCδ silencing, differentiation markers were differentially affected. In conclusion, DcR3 expression in keratinocytes is regulated by EGFR and forms a positive feedback loop to orchestrate constitutive EGFR and PKC activity. During differentiation, DcR3 is downregulated and involved in modulating the pattern of terminal differentiation. A protein linked to cancer and various inflammatory diseases may also be an important driver for the skin condition in psoriasis. The outer surface of the skin is formed by cells called keratinocytes, which transition from a highly proliferative state to a fully mature state where they no longer divide. This developmental process is disrupted in psoriasis. Researchers led by Wan-Wan Lin at National Taiwan University, Taipei, have now identified a prominent role for a protein called decoy receptor 3 (DcR3), which is a biomarker for a variety of disorders and is also abnormally expressed in keratinocytes in psoriatic lesions. Lin and colleagues demonstrated that DcR3 interacts with multiple cellular signaling pathways that coordinate cell differentiation. These findings reveal how aberrant DcR3 activity might lead to the abnormal keratinocyte developmental behavior observed in psoriasis. A high DcR3 serum level has been established as an index of poor prognosis for cancer patients. Recently, DcR3 has also been shown to perform various nondecoy  functions by acting as an effector molecule via interactions with heparan sulfate proteoglycans (HSPGs), such as syndecan 2 and CD44v36. DcR3 has been suggested to be a critical factor involved in the pathogenesis of multiple autoimmune and inflammatory diseases in addition to cancers3. The serum level of DcR3 is regarded as a biomarker of inflammation status in various diseases, including Crohn’s disease7, systemic lupus erythematosus8, rheumatic diseases9, acute respiratory distress syndrome10 and kidney diseases11.Decoy receptor 3 (DcR3) is a member of the tumor necrosis factor receptor (TNFR) superfamily and is a 33 kDa glycosylated soluble factor lacking a transmembrane domain. DcR3 is able to exert its function via its decoy functions, including neutralizing Fas-ligand (FasL), lymphotoxin-like; exhibits inducible expression; and competes with HSV glycoprotein D for HVEM, a receptor expressed by T lymphocytes (LIGHT), and TNF-like molecule 1 A (TL1A) to inhibit apoptosis and promote angiogenesis. DcR3 has been reported to be elevated in serum and tumor samples of different cancers and is regarded as a biomarker in cancer progression12. To accomplish intact and functional cornification, epidermal keratinocytes need to express distinct differentiation marker proteins, such as transglutaminase (TGase), involucrin, keratin 1/10, loricrin and profilaggrin13. The epidermal growth factor receptor (EGFR) expressed in keratinocytes plays a unique role in controlling skin cell proliferation, differentiation, disorders and cancers14. During keratinocyte differentiation, EGFR expression and activity are downregulated16. Aberrant activation of EGFR leads to overproliferation of keratinocytes, contributing to psoriasis, while EGFR inhibitors switch keratinocytes from a proliferative to a differentiative phenotype, thus affecting epidermal development and barrier function17.Epidermal keratinocytes are the principal cellular component in the skin; these cells progressively differentiate from proliferative cells in the stratum basale to form the outermost layer of the keratinized stratum corneum19, and clinical studies have shown that the DcR3 level is elevated in the serum of patients with psoriasis and that DcR3 is overexpressed in the epidermal layers of psoriatic skin lesions21. Moreover, we previously demonstrated that EGFR activation is involved in upregulating DcR3 gene expression in keratinocytes through the NF-κB pathway21. Although DcR3 is present in keratinocytes and is a skin marker for psoriasis, its biological action in keratinocytes remains elusive. Therefore, in this study, we explored the role and molecular mechanism of DcR3 in keratinocyte differentiation and its relationship to EGFR. Our data revealed that DcR3 can cooperate with EGFR to modulate keratinocyte differentiation; in addition, for the first time, we identified protein kinase C (PKC) isoforms as intracellular targets of DcR3 in the regulation of keratinocyte differentiation. The novel functions of DcR3 in the regulation of keratinocyte terminal differentiation may account for its pathological role in psoriasis.Regarding skin biology, DcR3 is detected in primary human keratinocytes21. Experiments were conducted according to the principles of the Declaration of Helsinki and approved by the Ethics Committee of Mackay Memorial Hospital (13MMHIS048). Written informed consent was obtained from donors before experiments. NHEKs were cultured in Keratinocyte-SFM  supplemented with EGF (0.1–0.2 ng/ml), bovine pituitary extract (20–30 mg/ml), and 0.1% penicillin-streptomycin. In some experiments, culture medium without EGF was used. NHEKs were used for experiments within 3 passages. For cell differentiation, we used the confluence, PMA and calcium models as we previously described22.Primary normal human epidermal keratinocytes (NHEKs) were isolated from normal adult human foreskin and cultured as described previouslyAntibodies directed against JNK1, ERK2, PKCα, PKCδ, EGFR, TGase 1, and involucrin, and horseradish peroxidase-coupled secondary antibodies were purchased from Santa Cruz Biotechnology . Antibodies against human keratin 10 and loricrin were purchased from Covance . Antibodies against phosphorylated JNK, ERK, and EGFR were purchased from Cell Signaling Technology . Enhanced chemiluminescence reagent was obtained from PerkinElmer . Myelin basic protein (MBP) was purchased from Sigma–Aldrich .siRNA experiments were performed by using siRNAs targeting human DcR3, PKCα, and PKCδ and a nontargeting siRNA as the control . NHEKs at approximately 50% confluence were transfected with 100 nM siRNA with DharmaFECT Transfection Reagent following the manufacturer’s instructions. Cells were harvested at the indicated time points.Equal amounts of soluble protein were loaded and electrophoresed on SDS–PAGE gels and were then transferred to Immobilon-P membranes . Specific protein bands were detected with enhanced chemiluminescence detection reagent.23. The primers used to amplify DcR3 (NM_003823.3) were designed with Primer Express Software .The procedure was carried out as previously described, and the primers used to amplify the housekeeping gene cyclophilin A and human involucrin, TGase 1, keratin 10, loricrin, EGFR, amphiregulin, HB-EGF and transforming growth factor-α (TGF-α) were described previouslyTo determine the relative cell number, NHEKs transfected with the indicated siRNA were cultured in medium with or without growth factors for 5 days. After rinsing with phosphate-buffered saline (PBS), cells were fixed with methanol for 10 min at room temperature and were then stained with 0.1% crystal violet. The relative cell number was determined by measuring the absorbance of the dissolved dye at 540 nm after elution with 33% acetic acid.2HPO4, 0.1 M citric acid (pH 7.8)). After another centrifugation step, the pellet was stained with 80 μg/ml PI, and the cell cycle distribution was analyzed by flow cytometry  as described previously16.After DcR3 knockdown, NHEKs were cultured in medium with or without growth factors. To generate the cell growth curve, the number of cells per well was determined 2 and 5 days after knockdown, and the fold change relative to the initial number of cells was calculated. To determine the cell cycle distribution, cells were collected, washed with ice-cold PBS, and fixed with 70% (v/v) ethanol in PBS overnight at −20 °C. The supernatant was removed after centrifugation, and the pellet was resuspended in DNA extraction buffer  were used to determine amphiregulin levels in cell culture supernatants according to the manufacturer’s instructions.24. An anti-PKC antibody was applied, and MBP was used as the substrate.Equal amounts of soluble protein were used for measurement of total kinase activity with a PKC kinase activity kit  according to the manufacturer’s instructions. For the PKCα and PKCδ kinase assays, immunoprecipitation followed by an in vitro kinase assay was carried out as described previouslyt test was used to assess the statistical significance of the differences. A P value < 0.05 was considered statistically significant.Data are expressed as the mean ± S.E.M. of at least 3 independent experiments, and Student’s To induce cell differentiation, three classical in vitro differentiation models—phorbol 12-myristate 13-acetate (PMA)-induced, calcium-induced and cell confluence-induced differentiation—were used. Our data showed that DcR3 mRNA expression was constitutively detected in proliferating NHEKs and that after PMA (30 nM) treatment, DcR3 mRNA expression was transiently increased within 6 h and was then time-dependently suppressed upon PMA-induced NHEKs differentiation  and is mediated by NF-κB and JNK signalingion Fig. . Likewision Fig. .Fig. 2EG21. We found that gefitinib enhanced confluence-induced and calcium-induced but not PMA-induced suppression of DcR3 mRNA expression . Moreover, the transient effects of PMA (within 6 h) and calcium (within 12 h) on upregulating DcR3 gene expression were not altered by gefitinib. Collectively, these data suggest that the decrease in DcR3 expression after progressively longer periods under each differentiation condition might be ascribed to decreased EGFR activation, particularly in the confluence-induced and calcium-induced models. On the other hand, the transient induction of DcR3 expression by PMA (within 6 h) and calcium (within 12 h) was independent of EGFR activity.Next, we treated NHEKs with the EGFR inhibitor gefitinib to determine whether endogenous EGF/EGFR autocrine activity is involved in regulating DcR3 expression, as we previously observed for exogenous EGF in keratinocytesion Fig. . Moreove. The immunoblotting results further revealed correlated changes in the protein expression levels of these differentiation markers during growth to confluence. The confluence-dependent increases in involucrin and TGase 1 expression were reduced but the increases in keratin 10 and loricrin expression were enhanced by siDcR3 treatment  of NHEKs with or without DcR3 silencing . Then, we treated siDcR3 cells separately with each type of CM and tested the ability of these CMs to restore the actions of DcR3 in siDcR3 cells. As shown in Fig. DcR3 is a soluble factor, and extracellular DcR3 has been shown to produce biological responses via the neutralization of identified TNF superfamily ligands, i.e., FasL, LIGHT and TL1A, or via a nondecoy function30, and our previous study revealed the ability of exogenous DcR3 to activate PKC in monocytes31. Therefore, we clarified the functional relationship between DcR3 and PKC in keratinocyte differentiation. We first determined the effect of DcR3 silencing on PKC isoform expression. As shown in Fig. To understand the possible molecular mechanism by which intracellular DcR3 controls gene expression, we considered the potential actions of PKC isoforms. Previously, PKCα and PKCδ have been documented to control keratinocyte differentiation3. Although DcR3 has a decoy function in neutralizing FasL, LIGHT and TL1A, recent evidence indicates that DcR3 can also act as an extracellular effector of “nondecoy” biological functions34. A further study using a fragment of the DcR3 protein without a decoy function indicated that the DcR3-mediated nondecoy function is mediated via crosslinking of heparin sulfate proteoglycans such as syndecans and CD44v34. In addition to acting as an inflammatory biomarker, DcR3 serves as a novel physiological regulator in keratinocytes. To date, the study of DcR3 in skin is still quite limited. Previously, we and others detected DcR3 in human primary keratinocytes and found that its expression was decreased by UV light18 but increased by EGF and TGF-α21. To date, the cellular function of DcR3 in keratinocytes remains unclear. In this study, quantitative real-time PCR analysis revealed downregulation of DcR3 mRNA expression during keratinocyte differentiation induced by calcium, PMA, and cell confluence. The immunoblot results further revealed decreased DcR3 protein expression in keratinocytes during differentiation. We also found, for the first time, novel intracellular actions of DcR3 in modulating the gene expression of keratinocyte markers, suggesting that DcR3 can regulate cellular functions in addition to performing decoy and nondecoy functions as a secreted protein. In keratinocytes, intracellular DcR3 can enhance PKCα/δ activity, which might be involved in controlling keratinocyte homeostasis during differentiation.DcR3 has been demonstrated to perform multiple immune system-related functions upon inflammation and is a critical factor involved in the pathogenesis of multiple diseases in addition to cancers. It is regarded as a potential biomarker for predicting inflammatory disease progression and cancer metastasis37. Our previous study showed that DcR3 is mainly expressed in the upper epidermal layer in psoriatic skin21, which is characterized by reduced loricrin and keratin 10 expression but increased TGase 1 and involucrin expression40. In this study, we demonstrated that DcR3, like EGF, as previously reported, is involved in upregulating TGase 1 and involucrin but downregulating keratin10 and loricrin gene expression. The alterations in these differentiation genes upon DcR3 silencing actually mimic the effects of EGFR inhibition. In this context, previous studies demonstrated that EGFR activity is involved in the differential regulation of keratinocyte differentiation genes, i.e., upregulation of involucrin and TGase 1 but downregulation of keratin 10 and loricrin41. Moreover, our data revealed that DcR3 is involved in maintaining constitutive EGFR activity, possibly by promoting the expression of endogenous EGFR ligands  and EGFR. The reduced EGFR expression caused by DcR3 silencing also led to the attenuation of EGFR signaling elicited by EGF. Thus, we suggest that the positive regulatory role of DcR3 in EGFR signaling might involve mediation of EGFR-dependent regulation of keratinocyte differentiation. On the other hand, upregulation of DcR3 expression by EGF and TGF-α via EGFR-mediated IKK/NF-κB and JNK pathways has been demonstrated in keratinocytes21. Therefore, we suggest that DcR3 and EGFR activation form a positive feedback loop and that DcR3 might mediate the regulatory functions of EGFR in keratinocyte differentiation, which might accelerate the pathogenesis of skin disorders such as psoriasis. Accordingly, in addition to the previous idea that combined treatment with a differentiation-promoting agent and an EGFR inhibitor may be an additional approach for the management of hyperproliferative skin diseases41, silencing DcR3 provides another promising alternative strategy.In normal skin, EGFR activity is usually high in the basal layer but low in the upper layers. In psoriasis, maintenance of EGFR activity can be observed in the upper epidermal layer42. On the other hand, the positive EGFR-DcR3 loop mentioned above was verified by additional findings. First, during keratinocyte differentiation induced by PMA treatment, calcium treatment or cell confluence, EGFR activity was time-dependently decreased gradually. This change in EGFR activity kinetics occurred in parallel to the downregulation of DcR3 mRNA expression. Second, the observation that suppression of DcR3 gene expression was enhanced by the EGFR inhibitor gefitinib during differentiation in the models suggests the role of EGFR in DcR3 gene expression. However, before the time-dependent decrease in DcR3 during keratinocyte differentiation, we observed transient induction of DcR3 expression by PMA (within 6 h) and calcium (within 12 h) treatment, and this effect was independent of EGFR activity. Currently, we do not have other data to clarify the mechanisms and cellular functions of this transient increase in DcR3 gene expression.In this study, we also excluded the possibility that DcR3-mediated regulation of differentiation marker expression results from an indirect action on cell growth. We found that DcR3 silencing does not alter cell growth, possibly because the initiation of keratinocyte differentiation is not inseparably associated with cell cycle arrest34. Despite accumulating lines of evidence indicating the effector function of extracellular DcR33, only a limited understanding of the mechanism of action has been obtained. In this respect, extracellular DcR3 can interact with heparin sulfate proteoglycans (HSPGs), such as syndecans and CD44v3, in myeloid cells4, induce M2 macrophage polarization via epigenetic regulation34, and induce monocyte adhesion via activation of FAK31. Despite these findings, the possible intracellular action of DcR3 is totally unknown. In this study, we identified a novel intracellular target of DcR3. We demonstrated the interactions of intracellular DcR3 with PKCα and PKCδ and found that these interactions contribute to constitutive PKC activation. Because resting PKC activity can be controlled by EGFR43 and regulate keratinocyte differentiation45, we speculate that DcR3-mediated regulation of keratinocyte differentiation might involve PKC activity.To date, the nondecoy functions of DcR3 responsible for some cellular functions and therapeutic potentials have been documented. These include driving dendritic cell and macrophage polarization toward Th2 phenotypes and M2-like phenotypes, respectively46. Other ligands neutralized by DcR3, such as FasL and LIGHT, have been shown to regulate keratinocyte death46, keratinocyte-mediated skin inflammation and fibrosis48, but their effects on keratinocyte differentiation are unknown. Although we cannot exclude the possibility of interactions between DcR3 and these ligands in regulating keratinocyte differentiation, more studies are required to explore other possible soluble factors regulated by DcR3 in keratinocytes.Our study also showed the role of the extracellular action of DcR3 in keratinocyte differentiation. Via the conditioned medium approach, we found that exogenous DcR3 reversed the effects of DcR3 silencing on upregulating keratin 10 and loricrin gene expression but failed to change DcR3 silencing-induced downregulation of TGase 1 and involucrin. These findings not only reveal the gene-specific regulation by DcR3 and EGF but also indicate that DcR3 serves as an effector via its extracellular action. Several lines of evidence indicate that TL1A may be involved in the pathogenesis of psoriasisIn summary, we demonstrated a new function of DcR3 in impairing keratinocyte differentiation. Via a reciprocal and positive feedback loop formed with EGFR, DcR3 promotes TGase 1 and involucrin expression, and it can also interact with the PKCα/δ isoforms to support PKCα/δ activity. In addition, extracellular DcR3 can negatively regulate keratin 10 and loricrin expression via an unidentified mechanism of action. Collectively, these findings indicate that keratinocyte-derived DcR3 can integrate EGFR and PKC signaling to promote TGase 1 and involucrin expression but inhibit keratin 10 and loricrin expression via extracellular and intracellular mechanisms of action. Dysregulation of the EGFR-DcR3 axis leads to impaired keratinocyte differentiation in psoriasis.


Great earthquakes along the Nankai megathrust in south-western Japan feature in the top priority list of Japan’s disaster management agenda. In May 2019, an alert system was incepted to issue public warnings when the probability of an earthquake occurrence along the Nankai megathrust became higher than usual. One of the cases that trigger the issuance of public warnings is when a great earthquake occurred and another one of the same scale is anticipated within a short period of time. Although such “twin ruptures” have occurred multiple times along the Nankai megathrust, the quantification of the probability of such twin ruptures has never been attempted. Based on global statistics and local earthquake occurrence history, we estimated the probability of a successive occurrence of two M8 or larger earthquakes within 3 years globally and along the Nankai megathrust to be 5.3–18% and 4.3–96%, respectively. The timing of the second earthquake followed the Omori–Utsu law in global statistics, which allowed the estimation of the probability for the successive occurrence of Nankai megathrust earthquakes in arbitrary time frames. The predicted probability for the one-week timeframe was 100–3600-fold higher than that of the norm, endorsing the necessity for the warning scheme. In Japan, the Earthquake Research Committee (ERC) of the Headquarters of Earthquake Research Promotion of Japan provides long-term (commonly 30 to 100 years) evaluations of the occurrence potentials of both inland and subduction-zone earthquakes in Japan2, which are then used for the creation of the probabilistic seismic hazard map3. The Uniform California Earthquake Rupture Forecast, Version 3 (UCERF3), is the latest official earthquake rupture forecast of the state of California in the United States, providing authoritative estimates of the probability of long-term fault rupture as well as the short-term probability of aftershocks4. In New Zealand, GeoNet, the official source of geological hazard information in New Zealand, provides time-varying probabilities of earthquake occurrence5. These operational earthquake forecasts mainly focus on either long-term probabilities or short-term aftershock probabilities. Operational short-term forecasting of great earthquakes has still been challenging.The methods of probabilistic earthquake forecasts have been implemented in a number of earthquake-prone countries11. These earthquakes commonly rupture the megathrust fault that separates the overriding Amurian Plate from the Philippine Sea Plate, subducting from the Nankai Trough  9.0 in north-eastern Japan that occurred in March 2011 was preceded by an SSE, which had started a month before18, associated with foreshock migrations19. As SSEs are abundant along the Nankai megathrust, their use in earthquake forecasting has been discussed actively26. These led to a government study group to state “We can qualitatively regard, though with uncertainty, that the probability of earthquake occurrence has become higher than normal when the state of plate locking is changed, for example by expansion or acceleration of a slow slip” (translated to English by the authors)27.For over a decade, slow slip events (SSEs) have preceded great subduction zone earthquakes on multiple occasionsThe high probability of an earthquake occurrence, its social impacts, historical evidence of the successive occurrence of past Nankai megathrust earthquakes, and the discovery of precursory SSEs worldwide have prompted the Japanese Government to introduce a new warning scheme in May 2019 against forthcoming great Nankai megathrust earthquakes. Under this scheme, the Japan Meteorological Agency warns the public when the probability of a great Nankai megathrust earthquake increases to a level exceeding the norm. An earthquake of Mw 7.0 or larger around the megathrust and an abnormal slow slip on the megathrust can trigger these warnings.A major drawback of this scheme is that a warning is not accompanied by the probability of earthquake occurrence. This constrains appropriate public response to the threat as, conventionally, decision making is based on the chance of an event occurring and its consequences. Given the current knowledge in seismology, accurately predicting a future event is not possible. However, predicting likely scenarios and their rough probability rates could assist the society in formulating countermeasures and responding effectively to the warnings. Considering the history of multiple twin ruptures, the successive occurrence of M8-class earthquakes is a likely and most concerning case for the Nankai megathrust. Therefore, probability estimation for such an occurrence is a particular need of the society. Here, we aimed to estimate the probability of successive great earthquake occurrence along the Nankai megathrust.28, which were reflected in the official guidelines for disaster management measures in response to warnings29.On the basis of global earthquake statistics, we first inferred the probabilities of successive occurrence of an earthquake of Mw 7.0 or larger and an earthquake of Mw 8.0 or larger. This was conducted by independent verification and elaboration of the findings of a previous studyWe referred to earthquakes of Mw larger than or equal to 8.0 as “M8 + earthquakes”. Similarly, we referred to earthquakes of Mw larger than or equal to 7.0 and smaller than 8.0 as “M7-class earthquakes”. We calculated the probabilities of an M7-class or M8 + earthquake, followed by another M8 + earthquake nearby, along with their probability gains and confidence intervals  Comprehensive Earthquake Catalog32. Inclusion criteria for these data sets were as follows: (1) earthquakes in all regions without area restrictions and (2) subduction zone earthquakes only. A previously reported approach was adopted28 with modifications. The previous study used only the ISC-GEM ver 6.0 Global Instrumental Earthquake Catalogue, did not assess restricting the area to subduction zones, and did not evaluate the uncertainties.We used two global earthquake catalogues, namely the International Seismological Centre-Global Earthquake Model (ISC-GEM ver 6.0) Global Instrumental Earthquake CatalogueThe probabilities calculated using the ISC-GEM ver 6.0 Global Instrumental Earthquake Catalogue and ANSS Comprehensive Earthquake Catalog data sets for all the regions and subduction zones were consistent , respectively. The confidence intervals were usually wide  owing to the small sample size , respectively  from one study for the 1605 earthquake  may indicate high probability of successive Nankai megathrust earthquakes in short time intervals compared to the global average 5.3%–18%). In particular, if we took the “four-out-of-six” case Section “”, the 3-8%. In pa3, Table 29. Equally importantly, the sharp rise in the cumulative probability for 24 h to a few days  scale in the ISC-GEM ver 6.0 Global Instrumental Earthquake Catalogue is moment magnitude (Mw), whereas the ANSS Comprehensive Earthquake Catalog is a composite catalogue and includes different magnitude scales. We selected events of M 7.0 or larger  global data without any further restriction and (2) global data restricted to subduction zone earthquakes, selecting events within a 200-km-wide band along the trench axes (excluding outer-rise areas) and 100-km deep or shallower  model44, which assumes a quasi-periodical earthquake occurrence in the presence of steady stress loading. The BPT model is adopted by the ERC2 to calculate the long-term earthquake occurrence probability of major faults in Japan. Adopting the BPT model with the same average recurrence interval of 90 years, fluctuation parameter of 0.24, and the elapsed time since the last earthquake of 75 years leads to a value approximately twice the base rate . Using a longer average recurrence interval of 120 years, which may be a valid assumption considering the historical records .Regarding the 1498 Meio earthquake, the rupture along the Tonankai segment and a part of the Tokai segment is definite, whereas the rupture along the Nankai segment is still under debate47. It is inferred from the historical and geological data that the shallow portion of the Nankai and Tonankai segments had ruptured48, although some researchers question the rupture on the Nankai megathrust and suggest a great earthquake along the Izu-Bonin Trench as the tsunami source49.The 1605 rupture is characterized by extensive tsunami damage along the Pacific coast in western Japan and a lack of reports of the damages attributed to the strong ground motions37. The 1854 Ansei Tokai earthquake rupturing the Tonankai segment was followed by the Ansei Nankai earthquake rupturing the Nankai segment approximately 30 h later14. The 1944 Showa Tonankai earthquake was followed by the 1946 Showa Nankai earthquake 2 years and 14 days later, rupturing similar but smaller areas of the Tonankai and Nankai segments, respectively17.Numerous studies have been published on the 1707 Hoei, 1854 Ansei Tokai, 1854 Ansei Nankai, 1944 Showa Tonankai, and 1946 Showa Nankai earthquakes, implying greater certainty of the earthquakes occurring after 1707. The 1707 Hoei earthquake was associated with a single rupture along the Nankai and Tonankai segments14.M8 + earthquakes that ruptured only the Tokai or Hyuganada segments are not known, although the Hyuganada segment exhibited M ~ 7.5 earthquakesSupplementary Information.Supplementary Data.