Thailand has encountered an imbalanced dentist distribution and an internal brain drain of dentists from public to private health care facilities. To tackle these challenges, the compulsory service (CS) program, which has been initially implemented for physicians, was extended for dentists.This policy and workforce document review describes the background, development, and policy implementation of the CS program in Thailand during the past three decades. Outcomes after policy implementation and future directions are also discussed. The information was gathered from the relevant policy and workforce documents available from 1961 to 2021.In Thailand, junior dentists, specifically newly graduates, have to enroll in the CS program by working as oral health practitioners in public hospitals for at least 3 years. Dentists must pay a maximum fine of 400 000 baht (~ 12 571 USD) if they wish to skip the program. This fine is lowered according to the number of attending years in the program. CS program conditions are related to each university’s admission track. The CS enrolled dentists receive several financial and non-financial benefits, including educational, employment-related, and living provisions. Altogether, successive Thai governments have launched directive policies to increase dentist distribution in rural areas and their retention in public hospitals. These policies have been implemented in 3 stages: (1) increase production of new dentists, (2) allocation of newly dental graduates to public hospitals, and (3) provide benefits for working in public hospitals.During the past three decades, several public policies have been implemented to improve dentist retention and distribution to public hospitals across Thailand, particularly in rural areas. The present CS program may not completely resolve the oral health inequalities because the dentist retention rate in public hospitals depends on multi-dimensional considerations. Further modifications on the CS program and future well-planned policies are needed.The online version contains supplementary material available at 10.1186/s12960-021-00702-z. According to the World Health Organization (WHO), the health workforce is one of the key components, or ‘building blocks’, of the health system. Health workforce allocation should include comprehensive information on the health care personnel, such as the numbers, characteristics, and the location of their hometowns. In addition, this information should include whether those health personnel are currently working and/or studying, and their reasons for resignation from the health sectors . HoweverTo establish the equitable health service accessibility for rural populations, the governments and policy-makers worldwide have to confront the shortage of competent and motivated health workers. According to the WHO estimate, health workforce inadequacy is predominant in low- and middle-income countries, as well as in rural and remote areas. Despite an adequate amount of health workforces, the maldistribution still remains across the country. The issue of health workforce densities and their distribution are emphasized to achieve better health outcomes of people .In order to increase the health workforce distribution and enhance the public accessibility to health services, several countries have employed a compulsory service (CS) program . ThailanThe objective of this policy and workforce documentary review was to describe the background, development, and policy implementation of the CS program in Thailand from the start of the program in 1967 until the present date . Outcomes following past and current implementation of CS policies and future policy directions were also analyzed and discussed.The CS program in Thailand had been implemented for about three decades, initially targeting physicians 1967–1987) and later both physicians and dentists (1988 to the present). The background of the policy development and its action from the past to the present are shown in Table 967–1987 In 1967, the official directive policy was launched including enforcement measures dictating that all medical students should receive financial subsidies from the Thai government during their 6-year undergraduate education. Therefore, the newly medical graduates had to enroll in the CS program as mandated physicians in public hospitals for 3 years . Later oIn 1968, the number of medical schools and medical students per year was raised to increase the physician production rate. Public hospitals also increased to support mandated physicians . In 1973In 1978, the government established the “Project of Increased Rural Physician Production” (PIRPP) to increase the physician distribution in rural areas , 13. DatIn 1982, a similar policy was applied to newly dental graduates. This enforcement for Thai dental students was established upon the condition that they would receive financial subsidies partially provided by the government during their 6-year undergraduate education. Therefore, the newly qualified dental graduates would have to enroll in the CS program in public hospitals for at least 3 years. Otherwise, newly graduates would be fined 400 000 baht as a form of reimbursement, and such fine would be adjusted according to the number of attended years in the CS program alike the policies for the medical graduates , 18.During a period of sustained economic growth in Thailand ~ 1987–1996), several private health care facilities had emerged. The government encountered at this time “internal brain drains” from public to private health care facilities. During 1994–1995, the “Collaborative Project to Increase Production of Rural Doctors (CPIRD)” was established to increase the retention rate of mandated physicians in rural areas 87–1996, , 21.Since dentist workforce production is linked to the educational output from Thai universities, the academic admission process should be analyzed for allocating and distributing the newly dental graduates.Dental workforce production in Thailand was officially implemented in 1940 by the first Faculty of Dentistry in the Kingdom which was created at Chulalongkorn University. To date, there are 16 dental schools (12 public and 4 private schools) distributed across 4 regions; 4 Northern, 2 North-eastern, 1 Southern, and 9 Central, covering Bangkok and adjacent provinces.Some differences between public and private dental schools are noted. Because public dental schools receive financial support partially from the government, their tuition fee is lower and more fundings are offered to the students in public dental schools compared with those in private dental schools. Meanwhile, students in private dental schools tend to afford educational and living expenses. In addition, the strategies of public dental schools rather depend on and follow the government policies such as the number of new students and admission tracks.The undergraduate dental education in Thailand offers a 6-year curriculum with the Doctor of Dental Surgery (DDS) degree. Preclinical courses must be completed within the first 3 years, and clinical courses start on the 4th and end on the 6th year. To obtain a dental practicing license, all dental undergraduates must pass a national standard examination .The admission system of the undergraduate dental curriculum in Thailand had been constantly modified following educational policies and different socio-economic and political contexts. At present, there are 5 admission tracks with some differences or specific requirements between universities and faculties . Except The 1st round is the Portfolio submission, and it targets the especially talented applicants with specific skills in English language and other required scientific backgrounds for enrolling in Dentistry . As an example, the Intensive English Admission Project and the International Science Olympiads Admission Project . The 2ndThe 3rd round (Admission I) and the 4th round (Admission II) are under the responsibility of the Consortium of Thai Medical School (COTMES) and the Council of University Presidents of Thailand, respectively. Nationwide applicants can choose 10 faculties of interest and can enter into the highest-ranking faculty if they achieve a minimum score to enroll. The 5th  round is a Direct Admission one, which includes nationwide applicants and aims to fulfill the vacant seats after the 4th round .Among all the five tracks, the quota track is the only university admission track created to improve dentist workforce distribution and retention in rural areas.Civil servant: this route is available for all junior dentists from public dental schools who enter the CS program in public hospitals under the Ministry of Public Health (MoPH). Two allocation systems are available according to their admission tracks. The junior dentists from the quota admission track undergo the CS program in the predetermined provincial area, while those from the other admission tracks are allocated to the working area by drawing and casting lots. The latter is a majority of the junior dentists.The drawing and casting lots are held annually around May by the MoPH. Before 2020, the allocation system was commonly held physically in convention centers. During the COVID-19 pandemic in 2020–2021, the allocation process was changed to a virtual platform. This was the second time after 2006, the first and only time of the virtual allocation process.State enterprise employee: this employability option is available for all junior dentists from public dental schools who enter CS program in public hospitals which are not under the supervision of MoPH, such as academic and military institutions. The enrollment, commonly taken during the last academic year of the dental curriculum, includes direct application and a face-to-face interview conducted by staff from those institutions.Independent dentists: this option is open for all newly dental graduates from private schools who do not have to pay the CS program-related fine (because they were not offered the CS program). Meanwhile, the newly dental graduates from public schools who are unwilling to enter the CS program must pay a fine (400 000 Baht or ~ 12 571 USD) to their dental schools as they received a financial subsidy from the Thai government during their entire undergraduate education.Three employability routes are available for newly dental graduates according to the following categories:Moreover, it is important to note that the Thai government provides extra welfare benefits in addition to the monthly salary to further increase the retention of civil servants. Meanwhile, welfare for state enterprise employees has specific differences depending on the granting institutions.Globally, there are 3 types of CS programs: (1) the state employment program, 2) CS program without incentives, and (3) CS program with incentives . CS prog CS progrBenefits for civil servants include salary and welfare, comprising financial and non-financial compensations. In addition to the monthly salary, 4 types of financial welfare exist: (1) a professional allowance that increases depending on the highest educational degree of the civil servant; (2) a non-private practice allowance, a fixed amount for dentists who do not carry out private practice after regular working hours; (3) an allowance for dentists in rural areas that is different across the provincial areas  and (4) a shift allowance that relies on either the working duration or hours of workload , 28.Non-financial compensation for civil servants includes higher education, employment, and living provision. Oral health practitioners in public hospitals who leave for study still receive a monthly salary during study duration, but after graduation, they are required to go back to work at those affiliated hospitals for a specific amount of time. Other employment incentives include free dormitory, financial support for their children’s tuition, and a civil servant medical benefits scheme that covers not only the civil servants, but their family members also , 30.Successive Thai governments have launched several directive policies to increase the distribution of dentists in rural areas and augment their retention in public hospitals. We categorized the implementation of such policies into 3 stages: (1) increase production of new dentists nationwide, (2) allocation of newly dental graduates to public hospitals, and (3) enhancement of benefits for working in public hospitals. These strategies and their respective outcomes are discussed below.Each university admission track establishes the conditions of Dentistry applicants and future graduates to enter the CS program. The future dentists from the quota track must undergo CS program in the predetermined provinces, commonly located around their hometown places. Recent compiled data from Academic Affairs at Faculty of Dentistry, Chulalongkorn University showed that the dentists arising from the “Quota admission track” completed the full 3-year CS working program in higher proportion rates and had lower resignation rates during the first working year, when compared with other admission tracks Figs.  and  3. The public institutions recruit junior dentists to become state employees via face-to-face interviews during the last academic year of undergraduate education. Then, the MoPH allocates junior dentists to become civil servants at the end of the academic year by drawing and casting lots. Thus, these graduates may not get to work in their expected areas in the CS program due to a potentially limited quota for each province.According to CS program data from the Human Resource Management Department under MoPH, the dentist allocation process by drawing lots through an online platform showed that 25.6% and 26.2% of newly dental graduates failed in getting to work on their expected areas in 2020 and 2021, respectively. In addition, 0.60% and 1.13% of them, in 2020 and 2021, respectively, refused to enter the CS program and were willing to pay the fine , 34. A fAn intense policy enforcement for newly medical graduates who decided not to enter the CS program was proposed in 1968 and 1973, including a higher fine and the completion of the full 3-year CS program. These medical graduates were able to receive a graduation certificate and passport after the 3-year CS program, though an early resignation would result in the withdrawal of the medical license . At presThese directive measures and working compensation schemes may help increase the number of dentists in rural areas. However, an unequal dentist distribution between public and private health care facilities, between Bangkok and other regions, and between urban and rural areas persist for the last three decades –38. ThesDespite the existence of provisions by several public welfare schemes, the monthly income of Thai oral health practitioners in public hospitals is approximately 40.9–59.7% lower than those in private practice .In addition to financial welfare, access to higher education is also one of the factors negatively affecting dentist retention rates in public hospitals. The Thai government supports only a monthly income for CS-mandated dentists during their enrollment in continuing education programs, ignoring tuition expenses borne by junior dentists. In addition, types of dental specialties for the purpose of continuing education are limited by directive management policies of local hospitals. Consequently, junior dentists often resign from public hospitals or change their hospital affiliation whenever their continuing education aspirations do not meet their employer’s policies. Unlike in medical programs, several postgraduate dental education programs do not impose applicants to have a public institution affiliation and/or working experience in public hospitals as prerequisites to enter in such programs. Thus, the current educational benefits scheme may not be sufficient to attract the junior dentists and retain them in public hospitals.The dentist workforce production strategy should consider not only a target number of newly graduated dentists per year, but also specific characteristics that meet the requirements and demands of the different stakeholders. This strategy will ultimately make such dentist distribution more equal across the country. Establishing dental labor market needs by committees would be essential in order to annually identify the number and criteria of undergraduate dental applicants, as well as to improve the predoctoral and postdoctoral curriculum to fulfill market and public health demands. This labor market committee would be responsible for setting up a dentist production plan for a 6-year time frame , which could be adjusted by dental schools. Since newly dental and medical graduates prefer selecting workplaces that are located close to their hometowns , 15, 42,Determining underlying causes for dentists’ retention or resignation from public hospitals is necessary to set up policies for the various stakeholders. According to Herzberg's Motivation Theory , workingDuring the past three decades, several public policies have been established and implemented to improve dentist retention and distribution to public hospitals across Thailand, particularly in rural areas. The present CS program may not completely resolve the oral health inequalities because the dentist retention rate in public hospitals depends on multi-dimensional considerations. Further modifications on the CS program and future well-planned policies are needed in Thailand for proper oral health workforce development, consistent rural distribution, and long-term retention in public health system.Additional file 1: Table S1. Inflation rate of Thailand and inflation coefficient value.


Strong & Deadly Futures well-being and alcohol and drug prevention program in partnership with an Indigenous creative design agency and 4 Australian schools.There are no available school-based alcohol and drug prevention programs with evidence of effectiveness among Aboriginal and Torres Strait Islander youth. To address this, we codeveloped the Strong & Deadly Futures in reducing alcohol and other drug use and improving well-being among Aboriginal and Torres Strait Islander youth.This paper presents the protocol to evaluate the effectiveness of Strong & Deadly Futures, a web-based alcohol and drug prevention and social and emotional well-being program that delivers curriculum-aligned content over 6 lessons via an illustrated story, or health education as usual (control). Control schools will be supported to implement Strong & Deadly Futures following trial completion. Surveys will be administered at baseline, 6 weeks, 12 months, and 24 months (primary end point) post baseline. Primary outcomes are alcohol use , tobacco use (Standard High School Youth Risk Behavior Survey), and psychological distress . Secondary outcomes are alcohol and drug knowledge and intentions, alcohol-related harms, binge drinking, cannabis use, well-being, empowerment, appreciation of cultural diversity, and truancy.The target sample will be 960 year 7 and 8 students from 24 secondary schools in Australia, of which approximately 40% (384/960) will identify as Aboriginal or Torres Strait Islander. The study design is a 2-group, parallel cluster randomized controlled trial with allocation concealment. Recruited schools will be block randomized (ratio 1:1), stratified by geographical remoteness, by an independent statistician. Schools will be randomized to receive The trial was funded by the National Health and Medical Research Council in January 2019, approved by the Human Research Ethics Committee of the University of Sydney , the Aboriginal Health and Medical Research Council of New South Wales , the Western Australian Aboriginal Health Ethics Committee , and the ethics committees of each participating school, including the New South Wales Department of Education , Catholic Education Western Australia , and the Queensland Department of Education . Projected dates of data collection are 2022-2024, and we expect to publish the results in 2025. A total of 24 schools have been recruited as of submission of the manuscript.This will be the first cluster randomized controlled trial of a culturally inclusive, school-based alcohol and drug prevention program for Aboriginal and Torres Strait Islander youth; therefore, it has significant potential to address alcohol and other drug harms among Aboriginal and Torres Strait Islander youth.Australian New Zealand Clinical Trials Registry ACTRN12620001038987; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=380038&isReview=truePRR1-10.2196/34530 Despite the ongoing impacts of colonization, disempowerment, and inequity, strong cultural and community connections have persisted as sources of resilience for Aboriginal and Torres Strait Islander young people ,2. NonetSchools are an ideal setting to deliver alcohol and drug prevention education ,11. SchoStrong & Deadly Futures was codeveloped in partnership with an Indigenous Australian creative design agency (Gilimbaa) and with the leadership of Aboriginal and Torres Strait Islander youth .To address this gap, digenous ) and staprograms -25. It aStrong & Deadly Futures in reducing AOD use and enhancing the emotional and social well-being of Aboriginal and Torres Strait Islander young people. This will be the first randomized controlled trial (RCT) of a school-based, culturally relevant alcohol and drug prevention program for Aboriginal and Torres Strait Islander adolescents. It is hypothesized that Strong & Deadly Futures will be more effective than an active control group  in delaying students’ uptake of alcohol and tobacco and reducing psychological distress over a 24-month period. The secondary aims are to examine the effects of Strong & Deadly Futures on students’ alcohol and drug knowledge and intentions, cannabis use, binge drinking and alcohol-related harms, well-being and empowerment, appreciation of cultural diversity, and truancy.This paper presents a trial protocol  to evaluate the effectiveness of Strong & Deadly Futures will continue to be closely developed with Aboriginal and Torres Strait Islander communities. The first phase of the project involves establishing partnerships with local Aboriginal and Torres Strait Islander organizations to conduct community consultations and seek feedback on the program. This feedback will inform adaptations to the program to align it with local priorities and contexts. The second phase involves trialing the adapted program in a school-based RCT. An Aboriginal Reference Group will provide oversight throughout both stages of the project.Strong & Deadly Futures program and representatives from the local Aboriginal Community Controlled Health Services (ACCHS) or Aboriginal and Torres Strait Islander stakeholder organizations in participating communities. The Aboriginal Reference Group will meet annually throughout the study duration, with the possibility of out-of-session meetings as required.An Aboriginal Reference Group will provide oversight and guidance through the consultation, school-based trial, and dissemination phases of the study. The Reference Group will comprise experts involved in the development of the In line with best practices in Aboriginal and Torres Strait Islander health research , we willAn Aboriginal or Torres Strait Islander facilitator will be employed in each community to conduct local consultations and support research implementation in schools. Facilitators may be recruited from the local ACCHS or the participating trial school. The consultation role will involve recruiting local community members and organizing and facilitating the consultations. School-based project support will include supporting teachers with the cultural aspects of the program, as well as assisting with survey administration and measurement of implementation fidelity through lesson observations. Facilitators will attend a series of training workshops with the research team before community consultations and commencement of the trial and will be provided with a handbook outlining the research process, methods, and program content. Facilitators will receive regular supervision and mentoring from the research team and will be provided with opportunities to participate in conferences and workshops throughout the study.Consultations will be conducted in each community to obtain local feedback to inform adaptations to the program to align with the local context.Within the local community of schools enrolled in the trial, facilitators will conduct 2 separate consultation sessions with (1) Aboriginal or Torres Strait Islander adults and (2) Aboriginal or Torres Strait Islander young people aged 12-16 years. Participants will be recruited using a variety of channels, including through the local ACCHS, word of mouth, social networking, and by distributing flyers at community events and health or youth services. Written consent from adults, young people, and parents or carers of young people will be obtained before the consultations.The research team will also conduct 1:1 semistructured interviews with 1-2 teaching staff from the participating trial school to discuss the feasibility and acceptability of the program in the classroom. Written consent will be obtained before the interviews.Consultations with Aboriginal and Torres Strait Islander community members will be conducted using a culturally appropriate research yarning method ,28. ReseStrong & Deadly Futures, which are based on a large body of existing evidence regarding effective prevention strategies in mainstream and Indigenous populations. A summary of the consultation feedback and the resulting changes will be disseminated by facilitators to the local community.Once the community consultations are complete, the research team will synthesize the feedback and create local adaptations of the program in conjunction with oversight and guidance provided by the Aboriginal Reference Group. Program adaptations may involve changes to illustrations, cultural elements, and language. However, the adaptations will not alter the core prevention, harm minimization, and educational components of Participants will be year 7 and 8 students from 24 government, Catholic, and independent schools in New South Wales (NSW), Queensland (QLD), and Western Australia (WA), Australia. Students in year 8 (aged approximately 12-13 years) will be the primary target group for program implementation. However, schools will also have the flexibility to enroll year 7 students owing to diversity in community needs expressed during our formative consultations  and variStrong & Deadly Futures group (to implement the program in 2022) or the active control condition . Allocation will be concealed and implemented by an independent statistician using the blockrand function in R  ) and take into account clustering of data at the school level. Multilevel modeling accounts for the expected correlations between repeated measurements from the same individual and between individuals in the same school, which would otherwise violate the assumptions of independence in traditional regression models. The models will take into account individual differences at baseline, estimating participant-specific starting points and change over time from these baseline levels. The randomly allocated groups  and project manager (KR) will take responsibility for the management and quality control of the study data. Web-based survey data will be collected via REDCap, a secure web-based data management and survey platform that complies with Australian standards in security, ethics, and integrity. Survey data will be stored at the University of Sydney, and all database files will be password-protected with only direct research personnel having access to the databases. Research staff with access to the data will have appropriate training to maintain confidentiality, data integrity, and basic data security measures.After all trial assessments are completed, the research team will travel to the participating schools and communities to report and gain feedback on the interpretation of the aggregated findings of the study. A summary of the trial results will also be provided to all participating schools and communities at the conclusion of the study. This report will aggregate findings across the trial and not identify results for any individual school or student. Schools and facilitators will be able to distribute the results to participating students, staff members, and parents. Schools will be given the option of opting in to be acknowledged in publications for their participation in the trial. The results will be disseminated broadly through peer-reviewed publications in medical, health, and education journals. The findings will also be disseminated at Aboriginal-specific forums and events, at national and international scientific conferences, and through webinars and seminars.The trial was funded by the National Health and Medical Research Council in January 2019 and approved by the Human Research Ethics Committee of the University of Sydney , the Aboriginal Health and Medical Research Council of New South Wales , the Western Australian Aboriginal Health Ethics Committee , and the ethics committees of each participating school, including the NSW Department of Education , Catholic Education Western Australia , and QLD Department of Education . The projected dates of data collection are 2022-2024, and we expect to publish the results in 2025. A total of 24 schools have been recruited as of submission of the manuscript.The aim of this paper was to describe the study protocol to evaluate the first web-based well-being and alcohol and drug prevention program for Australian secondary school students that was developed to be culturally appropriate and empowering for Aboriginal and Torres Strait Islander youth. Program effectiveness will be evaluated through a cluster RCT in 24 schools across 3 Australian states. The trial will be powered to detect medium effects (0.3) within the Aboriginal and Torres Strait Islander sample. It is hypothesized that the program will reduce alcohol, tobacco, and cannabis use and improve well-being relative to health education as usual.Strong & Deadly Futures, spanning the program planning, development, and now methodology and implementation of the RCT. This continuing priority is reflected through the involvement of Aboriginal investigators (MD and JW) and the strategic oversight and direction provided by the Aboriginal Reference Group. To ensure Strong & Deadly Futures addresses the needs of geographically and culturally diverse communities, we will employ a local Aboriginal facilitator to lead consultations with the Aboriginal and Torres Strait Islander community of each participating school. Community members will identify local alcohol, drug, and well-being priorities for young people and provide feedback on the relevance and appropriateness of cultural content, which will be used to adapt the program to the region. Community participation will ensure that the program is aligned with local values and priorities and meets local needs, which is expected to enhance longer-term sustainability.Aboriginal and Torres Strait Islander leadership and input have been prioritized since the inception of Strong & Deadly Futures will provide teachers with an evidence-based resource for preventing alcohol and drug use among young people that is accessible, engaging, scalable, and easy to implement.Participatory research approaches have been recognized for their potential to empower Indigenous communities and improve health disparities , but areA limitation of the study protocol is the use of self-report measures to obtain data on alcohol and drug use. However, self-report measures have shown good discriminant  and predStrong & Deadly Futures program, which was codeveloped in collaboration with an Indigenous creative design agency and with Aboriginal and Torres Strait Islander and non-Indigenous students, has the potential to address this critical need using a strengths-based approach while promoting Aboriginal and Torres Strait Islander culture within culturally and geographically diverse classrooms.No culturally appropriate school-based alcohol and drug prevention programs have been rigorously evaluated and demonstrated to be effective for Aboriginal and Torres Strait Islander youth. The


KL2 Visiting Scholars Program was developed to promote collaborative cross-CTSA training, leverage academic strengths at host CTSAs, and support the career development of participating scholars through experiential training and the development of new partnerships. This manuscript provides a detailed programmatic description and reports outcomes from post-visit and outcomes surveys. Since 2016, 12 scholars have completed the program, with 6 scheduled to complete it in 2021. Post-visit surveys (n = 12) indicate all scholars reported the program valuable to career development, 11 reported benefit for research development, and 11 expansion of collaborative networks. Outcomes surveys (n = 11) revealed subsequent scholar interaction with host institution faculty for 10 scholars, 2 collaborative grant submissions (1 funded), 2 planned grant submissions, 1 published collaborative manuscript, and 3 planned manuscript/abstract submissions. The Visiting Scholars Program is a cost- and time-efficient program that leverages the academic strengths of CTSAs. The program enhanced KL2 scholar training by expanding their professional portfolio, promoting research development, and expanding collaborative networks. Resources to support the program are shared in this report to expedite the development of similar programs at regional and national levels.CTSI Career Development Award (KL2) programs provide junior faculty with protected time and multidisciplinary, mentored research training in clinical and translational science research. The  In 2018, the University of Cincinnati Center for Clinical and Translational Science and Training (UC CCTST) joined to expand the program partnership. The purpose of the Visiting Scholars Program has been to promote collaborative cross-CTSA training, leverage academic strengths at host CTSAs, and support the career development of our scholars through experiential training and the development of new partnerships. Scholars are competitively selected and have the opportunity to meet with faculty with similar research interests at the host institution. During their visit, scholars provide a formal presentation on their work, consult with senior research faculty, and visit with other KL2 scholars and CTSA program directors at the host institution. The first scholar exchange occurred in 2017. Since that time, 12 scholars have participated in the program and 6 more are scheduled to participate in 2021.A). Each participating CTSA KL2 Director sends the announcement to its own scholars encouraging them to apply by a specified date that is agreed upon by the participating institutions. Interested scholars respond to their home CTSA KL2 Director indicating their intent to apply, followed by formal application submission . Applicants in their second year of training are given priority consideration. The summer and winter months are more difficult to schedule exchange experiences due to holidays, vacations, and in winter, possible inclement weather for traveling.B). The host CTSA also contacts the scholar to request potential dates for their visit and then develops and schedules an itinerary. Typically, a visiting scholar will spend one full day visiting the host institution. See Table Once selected, KL2 scholars are notified by their host CTSA KL2 Director, with the host CTSA taking responsibility for developing the visiting scholar’s itinerary. The host institution contacts the faculty members identified by the scholar (as part of the application process), as well as additional faculty identified by host CTSA leadership that may further enhance the scholar’s experience. Identified faculty receive a letter that provides an overview of the Visiting Scholars program, a copy of the visiting scholar’s NIH biosketch and CV, and an invitation to meet with the scholar , calendar invitations are sent to all participants, and plans for marketing the scholar’s presentation are finalized. The visiting scholar is provided with hotel recommendations, parking directions and passes, a campus map, contact information for key personnel during the visit, and any other assistance to make their visit a positive experience. The cost of meals is managed by the host institution, while travel costs for the visit are managed by the scholar’s home institution.Once a final visit is confirmed, a formal invitation with a final itinerary is sent to the visiting scholar by the host institution’s CTSA KL2 Director  (Table E) and two open-ended items. Open response items included: (1) What were the things you found most useful regarding this Visiting Scholar Program? and (2) What were the things that could be improved regarding this Visiting Scholar Program?Following their visit, scholars were asked to complete a brief outcomes survey in June 2020. The survey was administered and completed using REDCap, and included items to identify ongoing professional interactions resulting from the exchange and types of outcomes resulting from those interactions (Table F). The Institutional Review Boards (IRB) at each participating institution provided independent confirmation that these quality assurance/quality improvement evaluations did not meet the federal definition of research.To evaluate longer-term outcomes and impact of the KL2 Visiting Scholar Program, scholars were invited to complete an Since the program began, a combined 60 scholars across the 3 CTSA institutions have been eligible to participate . To date, 20 scholars have applied to participate in the program, 12 scholars have been accepted and completed the program (no drop-outs to date), and 6 scholars are currently scheduled to complete the program during the 2020–2021 academic year , the Indiana Clinical and Translational Sciences Institute, and the University of Cincinnati Center for Clinical and Translational Science and Training, the Visiting Scholar Program was successful in promoting the career development of KL2 scholars from all three institutions. Among 60 scholars who were eligible to participate, 20 (33.3%) applied for participation, and 18 (30%) were selected. Two applicants were not selected for program participation because the proposed networking opportunities were not strong. Program participants were representative of the broader population of eligible participants in terms of professional discipline, with female representation higher 78% vs. 65%) and underrepresented persons lower  reported that the program supported research development and was effective in expanding their collaborative networks Table . More spFor longer-term outcomes, a majority (10 of 11) of participants reported subsequent contact with investigators they met during their visit, including two collaborative grant submissions (one funded) and one collaborative manuscript submission 2- to 3-year post-program completion, as well as future plans for collaborative grant and manuscript submissions Table . Given tThe overall impact of the program may be underreported, as 2- to 3-year intervals may not be adequate for collaborations to mature and translate into measurable outcomes such as joint grant submissions and publications. We recommend that outcomes be assessed at least annually  for at least 5 years following completion of the Visiting Scholar Program to fully capture the impact of the program on career development. We also recommend the addition of interviews to obtain more robust feedback and overcome the limitations of open-ended survey items . While tD: Funding Announcement for details).Program improvements and modifications have occurred based on informal meetings with participating scholars and program directors. For example, based on informal feedback received from the first cohort of KL2 Visiting Scholars in 2018, we created a funding opportunity to promote and accelerate new research collaborations between visiting scholars and faculty at the host CTSA. To be eligible, the proposed multi-PI projects needed to involve collaboration between KL2 scholars who participated in the program and a faculty member at the host institution. Multi-PIs were required to have a full-time faculty appointment at their own CTSA institution, and scholars must have successfully completed their KL2 program at the time of pilot award funding. Funding was provided by the CTSAs of the collaborating multi-PIs, with funds spent at the CTSA that contributed funding . Budget requests could not exceed $25,000 per CTSA . Interested collaborators were asked to submit a joint letter of intent and biosketches for initial review. Upon invitation, the Multi-PIs were invited to submit a full proposal for a standard NIH-type study section review , and breakfast and lunch for the scholar. Some host institutions scheduled the scholar presentations to occur during the lunch hour and provided food for individuals attending the invited presentation. The scholars’ CTSA covered other travel costs  that were manageable, given the proximity between CTSA institutions .There are modest administrative costs associated with managing the program and developing itineraries for visiting scholars, which are subsumed within the CTSA and KL2 program budgets. Finally, there are costs to the scholars in time spent in preparing program applications and preparation for the invited presentation and program. The program is highly scalable, with costs of expanding the program associated primarily with increased travel costs to the scholars. Opportunities for hosting the Visiting Scholar Program using virtual tools are also possible, which would significantly reduce travel costs and could increase institutional efficiency by providing guidance on program support. We have provided appendix materials to reduce the cost of program development by other CTSA’s or national programs supported virtually.Several opportunities for programmatic improvement are apparent. For instance, we currently rely heavily on scholar mentors and KL2 program leadership to prepare visiting scholars to perform effectively and professionally in their roles as visiting scholars. The opportunity to provide training for effective engagement in visiting scholar invitations to both optimize performance and career development through the training of all KL2 scholars is a future opportunity. For example, leveraging the communicating science program at the Indiana CTSI to assist visiting scholars with their presentations, offer constructive criticism, or provide cross-institutional workshops . SeveralThe visiting scholars program is in the early stages of development and as a previously mentioned assessment of outcomes can be improved through an extended evaluation period and the addition of post-visit interviews. We anticipate that improvements to the program, including increased scholar support in the areas of communicating science and building networks, along with sustained availability of pilot grants will expand the number of visiting scholars who report sustained interdisciplinary collaborations and related outcomes.In summary, the KL2 Visiting Scholar Program is a cost- and time-efficient program for enhancing KL2 scholar career development by leveraging the academic strengths of CTSAs to promote research development and expand professional collaborative networks. Resources developed to support the integrated UK CCTS, IN CTSI, and UC CCTST programs provided with this report should expedite the development of similar regional program development as well as national virtual visiting scholar opportunities.


The detection of anti-phosphatidylethanolamine autoantibodies (aPEs) has been proposed to improve the diagnosis and management of patients presenting clinical manifestations of antiphospholipid syndrome (APS), such as thrombosis, and who are persistently negative for conventional markers. After selecting the most specific ELISA for their detection, we evidenced the interest of aPEs in the exploration of thrombosis when APS conventional markers were negative through a 1-year retrospective study including 1131 consecutive patients routinely tested for aPEs. To validate this result, we assessed aPEs in a newly selected population of 77 patients with unexplained deep vein thrombosis (DVT). With a total prevalence of 19.5%, we confirmed the interest of aPE detection in patients with unexplained DVT who were devoid of other aPLs markers. Since endosomal compartment, a source of ROS production, has been recently identified as the cellular target of aPEs in vitro, we then investigated an association between aPE positivity and reactive oxygen species (ROS) production by measuring the production of thiobarbituric acid-reactive substances. We showed, for the first time, a significant association between aPE positivity and systemic ROS production in patients which led us to hypothesize a new mechanism of action of aPEs in thrombosis through a signaling related to oxidative stress. Although numerous antiphospholipid autoantibodies (aPL) target anionic phospholipid, aPEs are directed against a zwitterionic neutral phospholipid made up of a glycerol molecule esterified by two fatty acids and a phosphoethanolamine residue. PE is a dominant aminophospholipid of most living organisms, asymmetrically distributed in the biological membrane and mainly located in its inner leaflet ,2,3,4. P 0.0001) . Several 0.0001) . Since e 0.0001) ,14. Ther 0.0001) . TBARs m 0.0001) .The aim of the present study was thus to investigate the clinical interest of aPE detection using a specific in-house-developed ELISA, and to analyze the potential association between aPE positivity and ROS production in patients with unexplained deep vein thrombosis. To compare the efficiency between the in-house-developed and commercially available ELISAs for specifically detecting aPEs, we used sera from 67 patients whose samples were sent to our department at the Immunology Laboratory of Conception Hospital  for the routine detection of IgG-aPE and IgM-aPE autoantibodies in addition to other conventional aPL. The sera were stratified as follows: 23 IgG-aPE positive (18 IgG/IgM-aB2GPI negative and 5 IgG-aB2GPI positive), 26 IgG/IgM-aPE negative (13 IgG-aB2GPI positive and 13 IgM-aB2GPI positive) and 18 IgM-aPE positive . The average age of patients was 50.1 ± 18 years, of which 18 were male and 49 were female.A retrospective study was also performed on 2255 patients who had their aPE antibodies quantified at the Immunology Laboratory of Conception Hospital  over a period of 1 year. Among these, 1124 patients were excluded from the study because of the lack of their clinical and biological data.Therefore, the size of the population enrolled in the study reached 1131 patients. The collected clinical and biological data were the following: age, sex, medical departments, dosage of IgG- and IgM-anti-B2GPI, IgG- and IgM-aCL, platelet count, number of thromboses and their characteristics , and obstetric complications .Arterial thromboses included: myocardial infarction, stroke, or any other acute thrombotic event involving the arterial vascular system.Venous thromboses included: deep vein thrombosis, pulmonary embolism, or any other acute thrombotic event involving the venous vascular system.An event was considered as recurrent when the number of events was greater than or equal to 2. To confirm the interest of quantifying IgG- and IgM-aPE antibodies in patients with clinical symptoms of APS in the absence of conventional autoantibodies, a cohort of 77 patients with deep venous thrombosis (DVT) who were negative for conventional antiphospholipid autoantibodies were selected after careful clinical examination and normal biological screening including prothrombin time (PT), activated partial thromboplastin time (aPTT), D-dimer, fibrinogen, factor VIII level, lupus anticoagulant (LA), anti-cardiolipin, and anti-β2 glycoprotein I antibodies. LA was assessed using two clotting times: partial thromboplastin time–lupus anticoagulant (PTT-LA) and diluted Russel viper venom time (dRVVT). Inherited thrombophilia etiologies were also ruled out by researching antithrombin (AT), protein C (PC) and protein S (PS) deficiencies, factor V Leiden (FVL), and the G20210A prothrombin mutation (PTM).All samples were taken from a declared Biobank (DC 2012-1704) in compliance with ethical directives. This study was approved and registered by the Assistance Publique Hôpitaux de Marseille and fulfilled local requirements in terms of data collection, patients’ consent, and protection of data (RGPD/APHM 2019-108). This study was conducted according to the Declaration of Helsinki.®, Nunc®, Rockilde, Denmark) were coated (30 µL/well) either with a solution containing 50 µg/mL PE from egg yolk  or with the solvent absolute ethanol , used to determine the non-specific binding of each sample. The plates were dried by evaporation at 18 °C and blocked by incubating with 10% fetal calf serum  in PBS for 1h at room temperature (RT). Finally, plates were dried using nitrogen gas.Irradiated polystyrene microtiter plates  was added (100 µL/well) and the plate was incubated at 37 °C for 15 min (IgG-aPE) or 20 min (IgM-aPE). Then, optical density (OD) was measured at 405 nm. OD for each sample was obtained by subtracting the OD of the non-coated well from that with antigen. The cut-off levels for IgG-aPE and IgM-aPE were determined with 100 sera from age- and sex-matched healthy blood donors, corresponding to the 99th percentile of control group values. These cut-off values were 0.47 and 0.68 OD, corresponding to the following arbitrary units: 18 and 59 U/mL for IgG-aPE and IgM-aPE, respectively.Sera were diluted 1:100 in 10% FCS-PBS and added in duplicate to coated and non-coated wells (100 µL/well) and incubated for 1h at RT. After the washing step (three times with PBS), 100 µL of alkaline-phosphatase-conjugated goat anti-human immunoglobulin  IgG (diluted 1:5000 in PBS-FCS) or IgM (diluted 1:2400 in PBS-FCS) were added in each well. Following 1h incubation at RT and the washing step, a phosphatase substrate para-nitrophenylphosphate, pNPP   and manufactured by Aesku . As mentioned by the manufacturer and highlighted in the datasheet, AESKULISA Ethanolamine-GM is a solid-phase enzyme immunoassay coated with purified phosphatidylethanolamine and native human B2GPI proteins.2-glycoprotein, the binding site) and incubated for 1h at RT. After the first adsorption, a second adsorption was carried out by the same procedure and this adsorption procedure was repeated identically up to four times. The efficiency of the adsorption procedure was verified by the IgG-aB2GPI assay on the sera processed before and after the adsorption experiments.The adsorption experiments were carried out as follows. Briefly, sera were selected for IgG-aB2GPI positivity as confirmed by the IgG-aB2GPI ELISA kit from Orgentec. Two hundred microliters of diluted patient’s sera (1:100) were added to 1µg B2GPI-coated plate (human βg at 4 °C for 10 min), 300 µL of serum was deproteinized in 10% trichloroacetic acid  containing 2.90 mmol of ethanolicbutylatedhydroxytoluene  to avoid further peroxidation. After vortexing and centrifugation (2500× g at 4 °C for 15 min), the supernatants were stored at −80 °C until use. Samples were then aliquoted (200 µL) and 200 µL of 8.1% sodium dodecylsulfate, 1.5 mL of 20% acetate buffer (pH = 3.5), 1.5 mL of freshly prepared 0.8% thiobarbituric acid (Sigma-Aldrich Co.) and 600 µL of water were then successively added. The test tubes containing glass beads were heated at 100 °C for 60 min and cooled with tap water. Then, 4 mL of n-butanol and 1 mL of water were added into each tube. After vortexing for 5 min, the mixture was centrifugated (2000× g for 3 min) to obtain a rapid separation between organic and aqueous phases. The upper organic phase was pipetted off and the pink pigment was measured using a spectrofluorimeter at an excitation wavelength of 515 nm and an emission wavelength of 553 nm . A standard curve of TBARs was obtained after overnight hydrolysis in a solution containing 1 mmol of tetraethoxypropane (Sigma-Aldrich Co.) in 0.1 N HCl at RT.Serum TBARs concentration was assessed according to Uchiyama and Mihara method  modifiedt-test was used to compare aPE ELISA optical densities before and after serum adsorption on B2GPI. Student’s t-test was used to compare the mean values of TBARs levels. Dot plots, box plots and statistical calculations were performed with GraphPad Prism version 5.03 . The threshold for statistical significance was set at p = 0.05. Effect size (Cohen’s d) and power value were calculated using pwr library of R software version 3.6.0 .Statistical analysis comparing the positivity or negativity of IgG and IgM aPE with the presence or absence of the other studied parameters was performed using the Chi-2 method. The concordance between the in-house-developed and commercial aPE ELISA was evaluated using Cohen’s Kappa coefficient, which takes on the value: zero if there is no more agreement between two tests than expected by chance; 1 if there was a perfect agreement. Kappa values below 0.4 were considered as poor agreement. Paired sample To check ELISA specificity for aPE detection, we first compared our in-house ELISA to the commercial one. To this end, sera from 67 patients explored in the routine practice were analyzed. From the 23 patients who tested positive for IgG-aPE in the in-house ELISA, only 8 sera were positive when tested using the commercial kit. Besides, among the 18 IgM-aPE positive sera, only 5 were found to be positive using the commercial kit . AccordiSera from a total of 1131 patients including 848 women (75%) and 283 men (25%), with a mean age of 46 ± 16 years were used to quantify aPE antibodies using the in-house-developed ELISA. Patients’ serum samples were addressed to our laboratory by departments of neurology (35.2%), internal medicine (32.6%), thrombosis exploration (15.1%), dermatology (8.8%), hematology (2.7), infectious diseases (2.4%), gynecology (1.2%), nephrology (1.1%), post-emergency medicine (1.1%) and others . Geologically, all patients were from southeast France.Clinical and biological data collected from all patients  revealedp = 0.06), but no clear association with fetal loss (p = 0.83), or other obstetrical complications (p = 0.12) were obtained. We also noted a trend towards statistical significance between the association of aPEs and infertility (p = 0.06). Clinical association was further analyzed according to the aPE isotype. No significant association was found between IgM-aPE and all the clinical contexts described in p = 0.04) but no association with obstetrical manifestations  were positive for conventional aPL, and the majority of them  had unexplained thrombosis without conventional aPL markers. In this subgroup of patients without conventional aPL, we found 24 patients with deep vein thrombosis, 12 strokes, and 9 with pulmonary embolism. A total of 26 patients had isolated thrombosis and 17 patients had recurrent thrombosis.p = 0.03). The higher the level of IgG-aPE, the greater the risk of developing thrombosis. Moreover, the level of IgG-aPE was significantly associated with the recurrence of thrombotic events (p = 0.02). . .As it has been reported that aPEs could stimulate the ROS pathway, we investigated whether the production of ROS was associated with aPE positivity. As unexplained thrombosis is one of the most prevalent clinical contexts associated with aPE positivity, we explored 77 patients with unexplained DVT, all negative for conventional aPL. We found a total prevalence of 19.5% for aPEs (14.3% IgG-aPE and 5.2% IgM-aPE) which confirms the results obtained from the retrospective study. We then measured the concentration of TBARs in the serum of patients with DVT. According to the availability of the samples, a total of 22 samples were tested. In these experiments, the concentration of TBARs informed the systemic level of lipoperoxydation resulting from ROS production. As shown in The interest of using aPEs as biomarkers has been poorly studied in the literature and actions for their detection are not systematically performed in routine clinical practice. In this study, we evidenced the interest of aPEs in the exploration of APS, especially when conventional markers were negative, using the results obtained from 1131 unselected patients and 77 selected patients with unexplained DVT. We showed, for the first time in patients with unexplained thrombosis, that oxidative stress was higher in aPE-positive than in aPE-negative patients, raising an interesting hypothesis on the mechanism of action of aPE in thrombosis. p = 0.001) [Other studies have highlighted the importance of testing aPEs in cases of thrombosis ,11. In p= 0.001) , such an= 0.001) .Until now, PE has appeared as a major anticoagulant factor involved in the anticoagulant C protein pathway. In fact, it has been suggested that the inhibitory effect of aPEs on this anticoagulant pathway is one of the mechanisms leading to thrombosis ,21,22. HHere, we showed for the first time that aPE-mediated thrombotic effects are regulated through ROS signaling. Indeed, we found that TBARs production was significantly higher in aPE-positive thrombotic patients than in negative ones. Intracellular ROS such as superoxide anion and hydrogen peroxide are directly involved in platelet activation and thrombus formation ,14. ThusIn conclusion, we demonstrated that aPEs should be assessed in thrombotic patients, especially when other aPLs markers are absent. The detection must be performed by using an ELISA with PE as the sole coating antigen. Finally, we show for the first time an association between aPE positivity and the systemic effect of ROS generation, suggesting a new mechanism of action of aPEs through ROS signaling in the thrombotic process. Studies are now necessary to confirm this concept in a larger cohort of patients and pave the way for investigating novel therapeutic strategies.


Transplantation is the optimal treatment for most patients with end‐stage kidney disease but organ shortage is a major challenge. Normothermic machine perfusion (NMP) has been used to recondition marginal organs; however, mechanisms by which NMP might benefit organs are not well understood. Using pairs of human kidneys obtained from the same donor, we compared the effect of NMP with that of cold storage on the global kidney transcriptome. We found that cold storage led to a global reduction in gene expression, including inflammatory pathway genes and those required for energy generation processes, such as oxidative phosphorylation (OXPHOS). In contrast, during NMP, there was marked upregulation OXPHOS genes, but also of a number of immune and inflammatory pathway genes. Using biopsies from kidneys undergoing NMP that were subsequently transplanted, we found that higher inflammatory gene expression occurred in organs with prolonged delayed graft function (DGF). Therefore, we used a hemoadsorber (HA) to remove pro‐inflammatory cytokines. This attenuated inflammatory gene expression increased OXPHOS pathway genes and had potentially clinically important effects in reducing the expression of a DGF‐associated gene signature. Together, our data suggest that adsorption of pro‐inflammatory mediators from the perfusate represents a potential intervention which may improve organ viability. A gene signature associated with reduced delayed graft function after kidney transplantation that increases during machine normothermic perfusion further increases if cytokines are removed from the perfusate during perfusion. DBDDeceased brain deathDCDDeceased circulatory deathDGFDelayed graft functionECDExtended criteria donorsHSPHeat Shock proteinsHAHemoadsorberILInterleukinNMPNormothermic machine perfusionOXPHOSOxidative phosphorylation1Kidney transplantation represents the optimal treatment for most patients with end‐stage kidney disease, with benefits for both quality and quantity of life.Normothermic machine perfusion (NMP) allows transplanted organs to be perfused with warm, oxygenated red blood cells, in the absence of circulating immune components, including complement and neutrophils.Here we took an unbiased approach to address these two questions using transcriptomic analysis of human kidney biopsies taken at the start and end of NMP to assess global changes in gene expression. We used pairs of human kidneys from a single donor enabling a comparison of the effect of different interventions in organs with an identical genetic background and were able to assess the impact of those changes on a prediction of graft outcome.22.1We investigated the transcriptional changes associated with organ preservation and NMP in two independent studies, each with five pairs of kidneys, making a total of 10 pairs/20 human kidneys. Of these, two were from DBD and eight from DCD donors Table . In thes2.2TNF as well as IL1B and the neutrophil‐recruiting chemokines CXCL8 (IL8) and CXCL2 were among the most upregulated genes in 2‐hour NMP biopsies  were increased when the HA was present  and negatively (DOWN) regulated genes (ranked by log fold change) which correlated with the length of DGF in the 33 clinical trial samples Figure . We founOverall, the transcriptional changes we have identified suggest that NMP has potential benefits over cold storage in terms of its effects on energy generation in the kidney. However, during perfusion, some bioactive molecules are released from the kidney into the perfusion circuit, generating an amplification loop that drives inflammation when they reenter the kidney. Removal of these molecules interrupts this loop, and may be useful to reduce inflammation and increase energy generation, further enhancing the beneficial effects of NMP and reducing susceptibility to DGF Figure .3Our data show that cold storage is effective in limiting substantial changes in gene expression. This is in keeping with rodent models, where kidneys stored for up to 18 hours in cold storage showed little change in the expression of pro‐inflammatory cytokines, including IL1β, TNF, and IL6.NMP had the opposite effect to cold storage on OXPHOS and glycolysis pathway genes, increasing their expression, with the potential to increase the cellular capacity to generate ATP and to restore homeostasis. Of note, hypothermic oxygenated perfusion of human kidneys has also been shown to increase ATP levels compared with cold storage et alA recent paper by Hameed TNFA signaling via NFkB pathway genes and lower expression of genes associated with OXPHOS. These data suggest that kidneys with increased OXPHOS and decreased immune signaling may present better potential as donor kidneys, but this conclusion requires validation in a larger prospective study.In our analysis of kidneys undergoing NMP in the context of a clinical trial, we correlated gene expression signatures with length of DGF rather than DGF incidence . Notably, kidneys with a duration of DGF of 1 day or less were highly transcriptionally similar to those with no DGF, likely reflecting dialysis requirement due to peri‐operative‐associated hyperkalemia rather than bona fide DGF. We found that a longer DGF was associated with higher expression of We also assessed the molecular processes that correlate with urine output and renal blood during NMP. These parameters have previously been used, along with a number of other measures, to generate a quality assessment score of perfused kidneys. High values of urine output and renal blood flow have been considered to reflect a more viable graft.During 4 hours of NMP, there was an induction of inflammatory genes in the kidney. However, it is worth noting that current clinical practice involves 1 hour of NMP only, and this effect may not be evident over a shorter perfusion time. However, longer perfusion may have benefits in terms of restoration of oxygenation and energy generation, and in our experiment, the negative effects of immune gene induction could be substantially negated by the introduction of a cytosorb HA to the perfusion circuit. These data indicate that inflammatory mediators generated by the kidney during the course of NMP enter the perfusion circuit and are capable of exacerbating sterile inflammation, and that their removal ameliorates the induction of inflammation pathway genes observed during NMP. Importantly, we showed that the addition of the HA affects the expression of genes that are associated with worse outcomes clinically. Our DGF gene signature was derived from samples undergoing NMP as part of a clinical trial assessing its efficacy, allowing us to robustly link the changes we observed in our paired kidney studies with clinical endpoints in kidneys undergoing transplant. However, its application in the context of a clinical trial will be needed to definitively prove the utility of its application to kidneys pretransplant. The HA is nonspecific and may remove molecules which are helpful, in addition to those which are detrimental to the organ. We found that the net effect of the HA on the kidney transcriptome appeared beneficial, but it may be that a refinement to specifically remove proven, deleterious mediators may be even more effective.The kidney pairs we used were from the same individual and were therefore genetically identical and had experienced a similar environment throughout the life of the donor. We confirmed that their time 0 transcriptome was extremely similar . However, these biopsies sample a small part of the kidney, and kidney pairs could be asymmetrically affected by pathology, for example, cysts, or small vessel disease. An additional caveat is that all kidneys used in the intervention experiments presented here were declined for transplantation and some represent transplanted organs at the lower end of the quality spectrum. Nevertheless, we observed highly reproducible results when comparing gene pathways in groups of five kidneys. We were also able to demonstrate that kidneys from DCD and DBD had a similar response to perfusion. By combining this with our curated post‐NMP DGF signature, we were able to predict potential clinical benefits. This experimental approach could be employed as a preclinical tool to screen future interventions for potential therapeutic efficacy to enable the rational selection of candidate interventions for clinical trials.In summary, our study provides the first global transcriptional profile of human kidneys undergoing NMP, resolving the differing molecular pathways that are activated in NMP compared with cold storage, and showing that the deleterious effects of bioactive molecules produced or released from the kidney during NMP can be reversed by the addition of a HA. Furthermore, this intervention reduced the expression of genes associated with prolonged DGF providing a strong mechanistic rationale for applying such an intervention to a future clinical trial. Our data also have implications for perfusion strategies beyond the kidney, including in liver and lung transplantation, suggesting that the removal of bioactive molecules from perfusates should be investigated in these contexts where NMP is increasingly used. Finally, our study highlights the utility of global transcriptional profiling in paired kidneys for assessing novel interventions to perfused organs; transcriptional changes precede changes in protein abundance  and tens of thousands of gene transcripts can be readily measured. Thus, RNA measurement has the potential to provide an early, sensitive readout of cellular function of human organs retrieved for transplantation that can be applied to future studies.American Journal of Transplantation.The authors have no conflict of interest to disclose as described by the J.R.F., S.H., M.L.N., and M.R.C. designed the study and interpreted the data. J.R.F., S.H., T.M., C.J.W, A.F., and T.C.D. performed the experiments. J.R.F., S.H., and M.R.C. created figures and tables. M.R.C. wrote the main manuscript. J.R.F. and S.H. created the methods and figure legends, J.R.F, S.H., and M.L.N. edited the manuscript. Click here for additional data file. Click here for additional data file. Click here for additional data file. Click here for additional data file.


Purpose: Although psychological distress is common among Latinos in the United States, they underutilize mental health services. We describe a community-based program to manage stress and reduce depressive symptoms among low-income Spanish-speaking Latinos.Methods:Mentes Positivas en Acción (MPA) (Positive Minds in Action) is an 8-week group program, delivered by trained promotores in community settings and evaluated through a randomized feasibility study. Participants were randomly assigned to an immediate MPA treatment group or a delayed-intervention control group. Outcomes assessed at baseline and 8 weeks included stress  and depressive symptoms (PHQ-9); higher scores indicate worse health. Repeated-measures analysis of variance examined group×time interaction effects for group differences in change from baseline to 8 weeks. The control group offered the program after the 8-week assessment, completed an additional assessment at the end of the program (16 weeks); t-tests assessed within-group changes.Results: Most participants were female, born in Mexico, and spoke only Spanish. Group×time interaction effects were significant for both outcomes. Mean PSS scores improved in the treatment group but not the control group . Mean PHQ-9 scores improved more in the treatment group than the control group . Within-group analyses of the control group found significant improvements in stress  and depressive symptoms .Conclusions: This study provides preliminary evidence of the effectiveness of a community-based promotor-delivered program to manage stress and reduce depressive symptoms among vulnerable underserved Latinos in the United States. With a median age of about 30 years,2 compared with 55 years for whites in the United States,3 maintaining the health of this young workforce is essential to the socioeconomic future of our country. One area requiring focused attention is promoting their mental health and well-being. Almost half of adult Latinos living in the United States report that their situation has worsened over the past few years.5 In addition, a worsening anti-immigrant climate in the decade leading up to the 2016 election has been followed by mainstreaming of ideologies against immigrants who were once on the fringes of society.6 Anti-immigrant policies contribute to stress and a myriad of psychosocial problems for immigrant Latinos and their families, with job and housing discrimination as major concerns.7–9 Also, these policies and accompanying discrimination portend greater difficulty in recruiting and retaining immigrant populations in clinical research.11In 2018, Latinos constituted 18% of the U. S. population (60 million), and they are projected to make up 28% (111 million) by 2060.12 Low income, limited English proficiency, lack of health insurance, and cultural barriers are among the leading obstacles that hinder Latinos' ability to access help for stress and depression-related symptoms, especially those who speak primarily Spanish.14Despite their elevated risk for depression, Latinos underutilize mental health services.15 Promotores  are being trained increasingly to deliver community-based interventions, with positive results among communities suffering health disparities.17 Promotores can easily establish rapport and transmit self-care knowledge and model desired behaviors.19 Although promotor-delivered mental health interventions can be effective in underserved populations, a few have focused on Latinos.21One approach to increasing access to mental health services is to provide low-cost culturally appropriate interventions in Spanish that can be delivered in community settings.Mentes Positivas en Acción (MPA) (Positive Minds in Action), which is delivered by trained promotores and aims at managing stress and reducing depressive symptoms in community-dwelling Latinos. We first tested its feasibility in a single-arm pilot study of Spanish-speaking Latinos, observing pre–post intervention reductions in general stress and depressive symptoms.22 This article reports results of a randomized feasibility study of MPA, delivered in the community to low-income Spanish-speaking Latinos who indicated that they were feeling stressed or depressed. We also report our experiences of recruiting and retaining Latinos within the worsening environment for immigrants.To meet this need, we developed This study was a real-world community-based randomized feasibility trial of the MPA program, conducted between February 2016 and March 2017. The 8-week MPA consists of weekly 2-h group classes of four to six participants, led by two trained promotores. There were two experimental conditions: The treatment group received the MPA program immediately (hereafter referred to as the “treatment group”) and the delayed-intervention control group received the program 8 weeks later, after the 8-week assessment (hereafter referred to as the “control group”). We examined the effectiveness of MPA in reducing stress and depressive symptoms at 8 weeks. After the 8-week assessment, individuals in the control group were offered the program, after which they completed a 16-week assessment to measure changes in outcomes. The University of California San Francisco Institutional Review Board approved the study protocol; written informed consent was obtained from all participants.The study was conducted in partnership with Monument Impact, a nonprofit community-based organization in Concord, California that serves disadvantaged residents through programs promoting mental and physical health and building workforce skills. Monument Impact has a promotores service delivery model and was interested in adding MPA to their programs. Monument Impact provided space for participant screening and intervention delivery.Study participants were Spanish-speaking Latinos residing in Concord, CA. Inclusion criteria were: (1) age >18 years, (2) self-identified as primarily Spanish-speaking Latino, and (3) endorsed questions of either: “Are you living with a lot of stress?” or “Are you feeling depressed?” Participants were not required to meet diagnostic criteria for depression or generalized anxiety disorder or a threshold for stress symptoms. Participants were recruited through flyers posted at Monument Impact and other Concord locations, and by word of mouth. Individuals were asked to call Monument Impact for more information, and a trained bilingual, bicultural Research Associate (RA) briefly described the program. The RA explained that if they agreed, they would be randomized to begin the program immediately or wait 8 weeks. Interested individuals were screened for eligibility; those eligible made an in-person appointment where written informed consent was completed . The consent form indicated that they would receive a $150 gift card for completing the study. Participants then completed the baseline assessment, which took ∼30 min. Each participant was assigned a code number, which was recorded on a card and placed in a box to be randomized later. Thus, they left without knowing their randomization group.Rolling enrollment was used to ensure four to six participants in each group-based MPA program. Once 12 people were enrolled, that group was randomly assigned. Participants' codes were placed in a box and the Principal Investigator randomly (blinded) chose participants to be in the treatment or control group, assuring sufficient participants for each group . ParticiTo maximize retention, promotores made weekly phone calls to participants in the treatment group to remind them of the sessions. For those in the control group, during the seventh week of the waiting period, the RA contacted them to schedule their 8-week assessment and inform them of the program's start date, time, and location.23 It is based on an integration of three evidence-based programs designed to teach Latinos skills for preventing and managing stress and depressive symptoms.25 Adaptations to enhance cultural sensitivity included content adaptation, tailoring the language to low literacy, using metaphors, and accommodating participants' work schedules.23The 8-week MPA program is a manualized, group-based program to manage stress and reduce depressive symptoms in lower income Spanish-speaking Latinos. It consists of weekly 2-h classes of four to six participants each, led by a team of two promotores. The MPA program development included addressing the stigma of stress and depression and optimal delivery mechanisms.26The underlying theoretical approach was the Social Cognitive Theory. The program emphasized cognitive–behavioral coping skills, including mood management, cognitive reframing, increasing pleasant activities, and social skills training, all aimed at increasing self-efficacy for managing mood; the conceptual model is depicted in 27Weekly sessions took place in Monument Impact's conference room and in other community organizations. Program content included: what is stress and how to manage it, relaxation techniques, personal affirmations, what is depression and how to manage it, how thoughts affect mood, and how to manage negative thoughts. Each week, promotores distributed a packet of that week's material to be inserted in a binder, thus the binder eventually included all program contents. Each session began with a relaxation exercise and homework review. Participants were encouraged to take turns reading and discussing the manual, and to share personal stories related to the program. Each session included a homework assignment . The session ended with participants and promotores sharing expressions of personal gratitude. Based on other stress management programs, we required that participants attend at least four of the eight sessions to be considered as having completed the program and received the core program components.22 Promotores were required to attend all training sessions and were given $150 on completion of the training and another $150 when they completed the delivery of the MPA program. They were assigned to lead MPA sessions in pairs. The same teams delivered the program to treatment and control group participants and were blinded to treatment group assignment.Promotores were recruited through the Monument Impact promotores program and by word of mouth. A total of 16 promotores participated in this study. The majority were female (75%) and born in Mexico. Age ranged from 27 to 67 years . All promotores had children, and 68.8% were partnered; 75% reported a family annual income between $20,000 and $50,000. Nearly one-third (31.3%) completed less than 12 years of formal education, and 43.8% completed some college. Their mean years of experience as promotores was 4.7 years (SD=3.7), with a range of 2–16. The MPA promotores' training is detailed elsewhere.The PI and RA assessed fidelity of intervention delivery through direct observation of two sessions (selected at random by the PI or RA) of each 8-week MPA group program, including those delivered to treatment and control group participants. They did not announce ahead of time which sessions they would visit. A 16-item structured rating scale was used to rate the extent to which each team delivered the program as intended. Examples of items include the frequency with which the promotores followed the manual, explained concepts in words that participants could understand, guided participants to practice cognitive reframing, and emphasized the homework. Response options were 1=not at all, 2=a fair amount, 3=a great deal, and 4=consistently. After the first of two observed sessions per group program, the observer provided feedback to promotores by using the fidelity ratings. Fidelity scores were calculated at the session and team levels. For each directly observed session, scores from all 16 items were averaged to get a total  fidelity score. To calculate overall fidelity scores for each team, fidelity scores were averaged across all group programs they delivered.All participants were assessed in Spanish at baseline and 8 weeks. Control group participants who completed the program (8 weeks after starting their program) were assessed at the end (16 weeks after baseline). Most assessments were self-administered, although the RA administered questionnaires to a few low-literacy participants. For practical purposes and since this was a real-world translation study, blinded assessments were not possible.28 The modified scale consisted of the seven negatively worded statements . Each item is rated from 0 to 4, with 4 indicating high stress. This modification was done to improve its psychometric properties in a study of Mexican immigrant women; the 7-item PSS demonstrated good reliability .22Perceived stress was measured by using a modified Perceived Stress Scale (PSS).30 This 9-item self-report measure assesses the frequency of symptoms on a 4-point scale . Total scores range from 0 to 27, with higher scores indicating more symptoms. Basic demographic characteristics were assessed, including age, years of education, language, family annual income, and health insurance.To measure depressive symptoms, we used the Spanish version of the PHQ-9 that has been found to have good internal consistency reliability among Latinos (α=0.85).t-tests and chi-square tests of independence were conducted to examine whether there were significant differences among participants at baseline regarding demographic characteristics. Due to significant differences at baseline in participants' partnered status, we controlled for partnered status when testing the results of outcome variables.Independent samples' We calculated means and standard deviations for perceived stress and depressive symptoms. Using an intention-to-treat approach and repeated-measures analysis of variance, we assessed changes over time (baseline to 8 weeks) in stress and depressive symptoms in the immediate treatment versus control group.t-tests of change scores.To explore within-group changes in the control group after completing the program, we compared control group scores at the 8-week assessment  with 16-week scores (after program completion) by using A total of 170 individuals contacted Monument Impact about the study. Of these, 18 could not be reached by phone. Of the remaining 152 who were contacted, 12 were no longer interested after hearing details about the program and study. Thus, 140 (82%) individuals consented and were enrolled . ParticiWe randomly assigned 70 participants to the treatment group and 70 to the control group. Of these, 61 (87%) treatment group and 29 control group participants (41%) completed the 8-week assessment . The othn=35) attended all eight sessions, and 93% (n=65) attended six or more sessions. Among control group participants, all 29 who completed the 8-week assessment agreed to begin the program; more than half (n=14) attended all 8 sessions, and 38% (n=10) attended 6 or more sessions. At baseline, there were no differences in demographic characteristics between treatment and control groups, except partnered status (p<0.0001), with control group participants more likely to be partnered . For depressive symptoms, the treatment group improved from 7.8 (SD=6.7) to 2.1 (SD=2.8), considered as remission of symptoms that were mild at baseline; however, in the control group, depressive symptoms improved slightly from 7.5 (SD=6.7) to 7.2 (SD=6.1) .At 8 weeks , there wp<0.000). Mean depressive symptom scores improved from 7.2 (SD=6.1) to 3.3 (SD=5.0) , considered as remission of symptoms that were mild at baseline.Within-group changes in the control group demonstrated significant improvements in stress and depressive symptoms after completing the program . Mean stIn this study, we tested the feasibility and preliminary effectiveness of a community-based, promotor-delivered stress management program among Spanish-speaking Latino men and women. Compared with a delayed intervention control group, the immediate treatment group reported significant improvements on perceived stress and depressive symptoms. The results provide preliminary evidence of the effectiveness of MPA in reducing stress and depression among a high-risk vulnerable group of Latino immigrants.31 Our academic–community partnership with Monument Impact allowed us to access promotores and participants. We utilized this important community asset to house the project, while building its capacity to deliver a stress management program. We believe that this enhanced community trust in the program. To mitigate known challenges of recruitment, attendance, retention, and acceptability of behavioral programs among Latino immigrants, we emphasized community engagement methods for translating evidence-based interventions for underserved populations.27 Studies that engage the communities affected by health disparities are more likely to reach vulnerable populations.33Promotores delivered the program with excellent fidelity, demonstrating knowledge of stress and mood management techniques, consistent with other studies of promotor-delivered stress management programs.30 In spite of this, we experienced difficulties retaining participants, primarily among the control group during the 8-week waiting period for the intervention. One possible explanation is inactivation of cell phones, given that many immigrants have temporary cell phone plans, or change plans frequently. Another is that participants may not have answered the follow-up phone call attempts due to distrust of unknown telephone numbers in an anti-immigrant climate. Fear of deportation and a desire to remain hidden are common in research with this population,34–36 and this may have contributed to low retention.Community interest in MPA was enhanced by its being offered in Spanish, consistent with previous research.23 Stigma is often associated with low reporting and utilization of behavioral services among low-income Latino.37Participants reported mild levels of stress and depression at baseline. Self-reporting of stress and depression symptoms among Latino immigrants is not well understood.Study limitations include that this was a self-selected sample, as individuals had to contact Monument Impact to participate. Further, results may only generalize to Spanish-speaking Latinos of Mexican origin; however, the cultural elements of the intervention should apply to other Latino groups. We experienced differential attrition by experimental group, with a higher dropout rate in the control group, which could have introduced bias and overestimation of program effectiveness. Collecting data in future studies that could help shed light on barriers to attendance and engagement is advised.Our study suggests that promotor-delivered programs such as MPA that support the mental health of Latinos may increase access to much needed services, especially among immigrant populations. Further, offering these services within trusted community organizations whose staff understand the cultural and social context for Latinos could help address their underutilization of mental health services. Further extensions of the program might include formation of clinic-community organization partnerships for further testing and dissemination of the program. In addition, testing the program among those with more severe symptoms of depression or anxiety is needed.Further research on the promotor-delivered MPA program is needed to better understand contextual factors and conditions in real-world settings that contribute to better program uptake and positive outcomes. Future translational research could help identify any needed adaptations to the MPA program for use among Latinos with more severe symptoms of depression or anxiety, and its effectiveness in these populations. Translational research could also be conducted to investigate the relevance of the MPA program for other minority and immigrant populations.38 Addressing barriers to access to culturally adapted stress management programs by training promotores is a promising approach.39 Vulnerable populations such as lower-income Latinos typically live in high-stress environments and have a limited sense of control. Acquisition of stress management skills constitutes a critical practical intervention. The mental health needs of a growing Latino population in the United States must be supported by community programs offered by promotores and other community practitioners that enhance skills for coping with stressful situations.23The study fills a gap in needed research that tests culturally congruent, evidence-based interventions delivered in the community to reach lower-income Latinos.Implementation of this study sparked interest from local community health organizations, which recognize the need and disparities among Latinos accessing behavioral health programs. John Muir Health, a major local health care stakeholder, funded subsequent delivery of MPA by Monument Impact through John Muir Health's Community Benefit Programs. John Muir Health's role in sustaining MPA is driven by the organization's goals of overcoming barriers to mental health care in the Spanish-speaking community. Since this study was completed in 2017, MPA has been delivered by promotores to more than 600 participants in the community. John Muir's evaluation of the MPA (with no control or comparison group) in these participants has yielded similar results in terms of pre–post improvements in stress and depressive symptoms. Changes to the MPA program since this study include providing childcare for participants, program evaluation by participants, and attrition follow-up. Also, since the study was completed, referrals of individuals by community clinics to the MPA program have included individuals experiencing mild to severe stress and depressive symptoms. The growing number of Latinos in the United States and their limited access to culturally and linguistically congruent programs behooves finding feasible solutions and creative ways to ameliorate the behavioral health disparities that exist among Latinos and potentially other underserved at-risk groups.