To qualitatively evaluate the implementation of Capacity Coaching, an intervention to address the work patients must undertake to manage their conditions, implemented as a quality improvement pilot in 1 of 2 implementing US Department of Veterans Affairs medical centers.Two Veterans Affairs medical centers in the Midwest sought to implement Capacity Coaching as a quality improvement pilot in their Patient-Aligned Care Teams for 6 months . Following the pilot, we conducted a focused ethnographic evaluation , including interviews, a focus group, and observations with staff at one site to assess the implementation of capacity coaching. Data were analyzed inductively and findings were cross-referenced with implementation theory.We found that implementation was feasible and achieved changes that were aligned with reducing patient work and increasing capacity. We found that the key facilitators for the implementation of this program were in participants making sense of the intervention (coherence) and working collectively to enact the program (collective action). The main challenges for the program were in planning the work of implementation and enrolling a diverse coalition of staff to expand referrals to the program (cognitive participation) and in evaluating the impact of the program on outcomes that upper leadership was interested in (reflexive monitoring).Implementation of Capacity Coaching is feasible in clinical practice and may be a promising intervention for the care of chronic conditions. Further research should focus on testing capacity coaching using these lessons learned. MinimallyDisruptiveMedicine (MDM).Epidemiological studies reveal that by middle age, one-half of the population already lives with 1 chronic condition and one-third already have two or more chronic conditions.work necessary to implement health interventions .capacity to implement patient work, which is the same capacity that they must use for life activities .,,,,MDM is a model of care that is oriented by an overarching conceptual model: the cumulative complexity model (CuCoM).coherence—how participants make sense of the work required to take up the intervention; cognitive participation to enroll others and plan the work; collective action to enact the work of implementing the intervention; and reflexive monitoring, to appraise if the intervention is worth the effort.,,Briefly, NPT focuses on 4 key domains: CapacityCoaching is a patient-centered intervention that has been designed in alignment with MDM. It is novel in its application of MDM but also in its combination of 2 types of interventions that have been used separately for populations with multimorbidity—intensive team-based management and coaching.http://www.mcpiqojournal.org), which was designed to support MDM in practice to understand patients’ health care workload and capacity.To date, capacity coaching remains untested. It is unknown whether it can be implemented into primary care or if implementation is successful, how it would impact patient outcomes. The purpose of this study was to understand its feasibility for implementation in practice. Understanding if this intervention is feasible to implement clinically, as well as key barriers and facilitators to its implementation, can enable the testing of capacity coaching in a larger clinical trial.Two US Department of Veterans Affairs (VA) medical centers in the Midwest sought to implement capacity coaching as a quality improvement pilot initiative in their Patient-Aligned Care Teams (PACTs). In one location, 4 PACT teams in the Women’s Health Clinic implemented the program (site 1); at the other location, the mental health care PACT in the Women’s Health Clinic implemented the program (site 2). PACT teams include physicians, nurses, social workers, pharmacists, nutritionists, and peer support specialists (PSSs). The teams were trained during a 1-day workshop delivered by one of the authors (K.R.B.); approximately 40 team members across the 5 PACTs were trained. Those trained included all members from site 1 and 2 team members from site 2. The workshop content was delivered over a single-day 8-hour session. It included training on MDM and its conceptual and theoretical models, the ICAN Discussion Aid, Capacity Coaching principles, and implementation in complex systems. It also included facilitated planning sessions for conceptualizing Capacity Coaching implementation in practice.Following the workshop, sites independently planned and implemented the program in their settings; one of the authors (K.R.B.) provided limited remote support. Following the closure of the implementation period, we returned to site 1 to understand the program’s implementation successes and challenges. While returning to both clinics would have been ideal, due to pragmatic time and funding constraints, we sought to collect data from site 1, as it was where the workshop occurred and housed 4 of the 5 PACTs trained. We used focused ethnographic methods to accomplish our aims. Focused ethnography is similar in its methods to traditional ethnography but instead focuses on answering specific questions in microcultures that exist within larger cultures.Participants were employees of site 1 and were notified 1 month before the site visit via email from clinic leadership that a researcher would be visiting. Four sources of data were collected: observations, interviews, a focus group, and artifacts. Participants were allowed to partake in as many or few data collection activities as schedules allowed. Some participants took part in all activities, whereas others only took part in one activity. All participants provided oral consent for participation in the study. Ethics approval and oversight were provided by the Mayo Clinic Institutional Review Board.The data collection period took place over 3 days on site , as well as a number of preparatory phone meetings and email exchanges. Fourteen people were invited to participate in interviews by email based on their high level of involvement in the Capacity Coaching program and role diversity; ultimately, 10 chose to participate including current and past directors of the Women’s Health Clinic, a social worker, a program manager, a nurse, a pharmacist, and a women’s health fellow. We also conducted a focus group with the current Women’s Health Clinic team and 9 hours of observation. Some interviewees also participated in the focus group; the focus group was also enriched by team members who had more minor roles in the implementation of the program. All data were collected by the lead author (K.R.B.).Observations occurred during clinic on and off hours; observations during clinic hours included patient interactions with health professionals and health professionals with each other. No patient protected health information was collected. Those observed were members of the PACTs that participated in the pilot. Observations were conducted in the Women’s Health Clinic, in the mental health clinic, and in another primary care clinic where pharmacy consultation services were provided. Observations were conducted in areas beyond the Women’s Health Clinic, the primary pilot location, because all Women’s Health Clinic staff members are not located in the same area of the center. Detailed observation notes were collected in the field, and at the end of each day, further written notes summarizing data collection activities were completed.http://www.mcpiqojournal.org). All focus groups and interviews were audio recorded and were transcribed verbatim. Artifacts provided by the team to the lead author included the final version of the implementation toolkit, workbook materials for coach-patient interactions, and template tools for documenting capacity coaching in the medical record. The implementation toolkit contained patient stories told in the first person, as recreated by staff who delivered the intervention. We did not have institutional review board approval to interview patients for this study, and therefore, patient quotes were derived exclusively from the toolkit artifact.Focus group data were collected using a semistructured interview guide informed by the NPT from the team perspective.The practice of reflexivity “involves being deliberately aware of oneself, one’s responses, and one’s internal state in relation to a specific situation.”All data sources including transcripts, artifacts, and observation notes, hereafter referred to as “source documents,” were imported into Nvivo 11 Pro for Windows  for analysis. The analysis process used procedures guided by Roper and Shapira’s process for ethnographic analysis.First, the lead author and 2 trained research assistants  listened to the audio-recorded data and read all source documents, then coded source documents inductively using line-by-line coding to develop a code book. We used this process on 3 source documents, meeting 2 to 3 times weekly to discuss newly emerging codes and codes that should be combined or reconciled. We deemed the codebook complete after coding the third source document, as no new codes were emerging. We continued to meet twice weekly to address discrepancies or potentially new codes as we coded remaining source documents using the codebook; 2 new codes emerged from the later data and were added to the codebook. In addition to our inductive codes, we included a priori deductive codes related to NPT: coherence, cognitive participation, collective action, and reflexive monitoring.,After coding, the lead author began to aggregating codes into themes using grouping and matrix functions in Nvivo 11. Coders reviewed results from the analysis to ensure that interpretations of the data remained close to the data. The lead author summarized all data into key themes found in the culture of the clinic, using CuCoM, NPT, and TPC. This step represents the use of well-fitting existing conceptual models and theories to organize the data after initial analyses in a manner that is useful for the translation of interventions into practice and is respected as particularly useful for meeting challenges in implementation of complex interventions.A core group of individuals championed the capacity coaching intervention, including a primary care physician, social worker, and PACT nurse. The social worker served as the primary project coordinator, and a research coordinator kept up with data elements used to generate the implementation toolkit. These individuals met regularly, and other clinicians and health professionals met with them periodically, particularly in the planning phases. The planning phase lasted approximately a year, and the pilot implementation lasted 6 months .At the time of the workshop, site 1 had planned to have the social worker serve as the capacity coach, and site 2 had a PSS as the capacity coach. During planning and the early pilot, it became apparent that site 1 could also be best served by a PSS as the capacity coach because patients placed value on the shared life experience of a female veteran living with chronic illness. Therefore, the PSS was brought on board by the team for site 1. The social worker then trained the PSS and supervised her throughout the intervention period.minimallydisruptivemedicine.org) Core components of the intervention delivered appear in During the 6-month implementation at site 1, 21 patients went through the program. Patients interacted with the coach between 3 and 6 times, depending on their needs. This process comprised a total of 21 in-person encounters and 42 telephone encounters. At the conclusion of the pilot, the team developed a freely available Capacity Coaching toolkit to help other VAs implement the program , there was no clear evidence from ethnographic observations that the program had impact elsewhere in the center.Although formal outcomes were not collected from the program’s implementation, interviews and artifacts reflected success stories in patients’ ability to access and use health care and enact self-care, as well as their outcomes and quality of lifeParticipants’ stories and artifacts illustrated that the implementation of the Capacity Coaching program positively acted upon each construct of the TPC .Table 2PBeyond the impact of the program and its alignment with the principles of MDM, the remainder of the data were primarily focused on stories that were illustrative of the success and the challenges of implementation. These factors can be broken down into the 4 constructs of NPT: coherence, cognitive participation, collective action, and reflective monitoring . The priA surprising finding that emerged outside of the conceptual models and theories was the applicability of the capacity coaching curriculum beyond patients living with chronic conditions. One participant highlighted that she took the skills from the workshop and applied it to working with nursing students.Key findings are summarized in This evaluation was conducted after the pilot concluded, and no continued Capacity Coaching activities occurred during the time the data were collected. This means that the robustness of the evaluation relies on participants’ memories of the previous 2 years and may only capture key highlights of what occurred. Second, the evaluation was entirely qualitative, which means the impact of the program on patients’ health outcomes and quality of life relies entirely on anecdotal cases documented by staff. This limitation exists because of the narrow scope of the grant funding for the program, as well as the heterogeneous nature of the small patient population that participated in the pilot.Importantly, even in this brief pilot of the Capacity Coaching program, it satisfied the components of MDM and addressed key needs of patients living with multimorbidity not addressed by other recent chronic care interventions, such as being agnostic to the chronic condition(s), acknowledging and reducing patient work, and supporting patients’ capacity holistically.Positive changes in a variety of outcomes have been elusive when testing team-based management interventions for multimorbidity.The HWC literature has lacked clarity in defining coaching..It is important that future research of Capacity Coaching and MDM-driven interventions incorporate the implementation learnings of this study. First, implementation was a complex process of integrating a new way of working into the primary care team, which filled much of the 6-month pilot period. There was little time to enroll others and to plan expansion or evaluation. Second, critical challenges in the cognitive participation of the full primary care team could potentially have been better addressed with a longer-term cultural change approach. Curriculum to consider includes Leadership Saves Lives (LSL), which was previously applied to address the problem of post–heart attack mortality.This study represents the first implementation and evaluation of Capacity Coaching. It found that the program was feasible to implement in team-based primary care and adhered to principles of MDM. We saw substantial success of the implementation in participants making sense of the intervention (coherence) and working collectively to enact the program in the pilot period (collective action). Implementation challenges occurred in planning the work of implementation and enrolling a diverse coalition of clinical staff to expand referrals to the program (cognitive participation) and in evaluating the impact of the program on outcomes that upper leadership was interested in to continue the program beyond the grant funding period (reflexive monitoring). These challenges suggest the potential positive impact of incorporating existing culture-change curriculum, such as LSL, to facilitate implementation.


The New Mexico Graduation Reality and Dual-role Skills (GRADS) program provides services for expectant and parenting students at high schools. The GRADS program has operated since 1989, serving more than 17,000 youth. This study summarizes the GRADS program model and program administrators’ lessons learned from implementing this comprehensive, large-scale program.The GRADS program is a multicomponent intervention that can include a classroom intervention, case management, linkages to child care and health care, and support for young fathers. The program aims to support expectant and parenting youth in finishing high school, delaying a repeat pregnancy, promoting health outcomes for their children, and preparing for college and career. This study presents program administrators’ lessons learned to increase understanding of how to implement a statewide program to support expectant and parenting students.During the 2010–2017 school years, the GRADS program operated in 26–31 sites each year, serving a total of 2691 parenting youth. Program administrators identified lessons learned from implementing the GRADS program during that period of expansion, including allowing variation across sites based on resources and needs, providing centralized implementation support, fostering buy-in from school and district leaders, and collecting consistent data to better understand participant outcomes.Although not based on a rigorous impact or implementation study, this article provides lessons learned from a statewide, school-based program that may be a promising way to serve a large number of expectant and parenting youth and help them overcome challenges for completing high school. What is already known on this subject? Some school-based programs implemented across a small set of schools have been found to be effective in promoting outcomes for expectant and parenting youth.What this study adds? This article provides lessons learned from statewide implementation of a potentially promising school-based program to support expectant and parenting youth. Although this paper does not assess the effectiveness of the program, it illuminates important information for researchers and practitioners about a program that is flexible in addressing the range of multifaceted needs of expectant and parenting youth.Although the national teen birth rate has decreased significantly over the past several decades, New Mexico continues to have a high rate, with 27.9 births per 1000 females ages 15–19, compared to 18.8 for the United States as a whole  face myriad challenges to high school graduation. Barriers may include lack of child care, financial struggles, housing instability, and limited access to health care  program has provided school-based services to address the multifaceted needs of more than 17,000 EPY NM GRADS . The priThis paper describes the approach of the GRADS program and program administrators’ lessons learned from implementation during the 2010–2017 PAF funding and expansion period. Because some smaller scale school-based programs have been found to be effective in promoting EPY outcomes  or in the community, linkages to child care, and support for young fathers.With a focus on college and career readiness, the GRADS classroom intervention is a primary component of the GRADS program. Students can take the class for up to four years as an elective course and receive credit for participation. GRADS classroom intervention implementation schedules vary by site, with some sites having a 50-min class every day and others having a 90-min class a few times a week, but all must meet the state minimum requirements for class length. Participants receive a variety of resources and support to stay in high school, graduate, pursue postsecondary education and career opportunities, and attain self-sufficiency. Specifically, the GRADS class focuses on 10 competencies, including personal development, pregnancy and wellness, postpartum and neonatal care, parenting, child development, relationships, economic independence, and career development. Each GRADS student has a notebook that includes activities and content in each of the 10 competencies.FLASH, a comprehensive sexual education curriculum that covers topics such as pregnancy prevention, sexually transmitted infections, healthy decision making and communication skills, abstinence, and birth control ; behavioral health services; concrete supports for basic needs such as food, clothing, transportation and housing; early childhood services (discussed more below); academic support and planning; and workforce training and supports.In addition, case managers focus on improving participants’ school outcomes by monitoring attendance and academic performance and by assisting youth in addressing challenges with attending school or completing schoolwork. They also support participants in making up missed material from school absences related to medical appointments, childbirth, or extended hospital stays.Recognizing that a lack of child care can be a substantial barrier to completing high school for young parents, the GRADS program supports participants in finding child care services. At 24 GRADS sites, licensed Child Development Centers provided onsite child care for GRADS program participants during the PAF funding period. In sites without onsite child care centers, GRADS staff linked young parents to community child care centers. Through child care subsidies administered by the New Mexico Children, Youth & Families Department, GRADS participants can be reimbursed for their child care expenses. At all sites, GRADS staff can also provide referrals to participants to early childhood services like home visiting and early intervention services, based on participant needs.In some sites with onsite child care, GRADS participants can work part-time at the child care center and earn child development credit hours. These positions give EPY the opportunity to observe child care center staff modeling effective parenting and to learn successful child care strategies. Working in the child care centers also allows EPY to apply the parenting skills and child development information taught in the classroom intervention.All program sites are expected to provide tailored support for young fathers, but the intensity of these services may vary by site. To serve young fathers effectively, more than half of the GRADS sites hired a fatherhood mentor to provide onsite fatherhood services during the PAF funding period. Mentors provide young fathers with ongoing support related to staying in school and preparing for graduation to address the particular challenges that young fathers may face. Services include outreach to fathers, individual case management sessions, and fatherhood groups. Fatherhood groups meet once or twice a month and may cover topics like communication and parenting skills, negotiating relationships with the mother of the child, and setting academic goals. This program component is supported by statewide contractors, such as Fathers New Mexico, who provide technical assistance and other support to GRADS sites.Although GRADS is a longstanding program, these lessons learned focus on the 2010–2017 PAF funding period. During each year of the PAF funding period, the program had between 26 and 31 sites each year , including in some of the largest metropolitan areas like Albuquerque and Las Cruces. Most program sites had a GRADS program prior to 2010 and may have enhanced existing components during the PAF funding period. Eleven sites were onboarded during the PAF funding period.Lessons learned from program administrators during the implementation of the GRADS program can inform other practitioners or policymakers interested in serving EPY through a multicomponent, school-based program.PED and the state GRADS office allow for variation in the specific components implemented at each GRADS site, and sites can decide how to adopt them based on their resources and participant needs. For instance, if site staff know they have a large number of young fathers that need additional support, they can have a more robust fatherhood services component, including hiring a fatherhood mentor. Similarly, for the case management services, sites can determine whether to hire a separate case manager or if the GRADS classroom teacher will serve as the case manager in addition to providing the classroom intervention. One program administrator explained that this flexibility allowed sites to implement the GRADS program even if they were not able to hire additional support staff like case managers.With the flexibility of GRADS program delivery, sites can tailor the program to their population and even choose to augment the GRADS program with more services. In one site, school staff recognized participants had a particular challenge with transportation to school, so they added transportation services for GRADS participants. Likewise, sites can tailor services to fit the particular cultural needs of their youth. For example, one site that predominantly serves Navajo youth provides culturally responsive onsite child care by displaying the names of colors and numbers in the Navajo language (Diné Bizaad) and including Navajo cultural objects in the child care center. Other sites offer Spanish-language materials or support, if needed.Although GRADS is a relatively diffuse program with sites across the state of New Mexico, the PED and state GRADS office staff help to provide centralized support for all GRADS sites. PED and the state GRADS office have institutional knowledge of the program that they share with sites at the start of the program or as sites face new implementation challenges. Prior to each school year, the state GRADS office trains any new teachers and staff on the program, offering a variety of resources and curricula to support implementation. Following that, the GRADS classroom teachers or other site staff can reach out to the state office any time they have questions or concerns, which can be particularly helpful for staff new to the program. All GRADS teachers participate in annual training, receive ongoing technical assistance, and can access a variety of resources to assist them in addressing the 10 competencies and meeting student learning goals. In addition, the state office harnesses the experience and expertise of the longtime GRADS teachers to support implementation. For instance, veteran GRADS classroom teachers serve as regional mentors and share expertise with newer staff. As described earlier, the state GRADS office and PED have also supported additional consultants and TA providers to provide support to teachers at various times.The state GRADS office has a technical assistance coordinator, who visits all sites at least once, with new sites receiving multiple visits in their 1st year of implementation. Each visit involves an onsite review of the program with the classroom teacher and other staff as available, to ensure effective program implementation and improve the program over time. During these visits, state office staff discuss strengths and areas of improvement with local GRADS staff in order to meet the needs of EPY in the following areas: implementation of GRADS program components, data submission, participating in trainings and technical assistance opportunities, and collaboration with school and community partners at that site. The site visit may also include a review of the GRADS students’ notebooks to ensure that the classroom intervention is addressing the 10 competencies. GRADS state staff may have conversations with the principal about program effectiveness, including whether the teacher is the best fit for the program. As one program administrator noted, this on-the-ground support allows state staff to better understand the resources and needs of each site and to provide tailored recommendations to each site.The state GRADS office dedicates time to build and sustain buy-in from school and district leaders for the GRADS program. When first recruiting schools, the state office highlights the GRADS program’s goal of helping young parents graduate, which mirrors the principal’s or superintendent’s own goals around supporting the academic success of all students, including young parents. Understanding their shared goals helps school leaders become more invested in the program, strengthening the program’s sustainability efforts. In addition, program administrators noted that having a planning period to onboard sites was helpful. During the planning period, they invite school and district leaders to events and trainings, so they fully understand the program before it comes to their school. As part of the planning period, the state GRADS office asks school and district leaders to select the GRADS classroom teacher and other staff. By working to identify staff that will work best for the GRADS program, school and district leaders gain greater ownership in the program and better understand its role in their schools. With strong support and buy-in for the program, principals and superintendents can provide on-the-ground leadership.Likewise, the state office and PED continue to engage with these local leaders to maintain their support for GRADS over time. This strategy is particularly important for addressing the challenge of turnover among school or district leaders. Because new administrators may not be as supportive of or knowledgeable about the GRADS program as prior administrators, the state office prioritizes early and frequent engagement with the new administrators similar to their initial engagement efforts for new sites. They also provide school leaders at each site with an annual fact sheet on GRADS students’ outcomes at their site. PED and the state GRADS office invite superintendents and principals to attend the biannual in-person trainings and give them a platform to share their experiences through roundtable and panel discussions.During the PAF funding period, GRADS program staff collected some data on the participants at each site and reported this information to PED and the state GRADS office. Using a paper form, site staff tracked the number of participants in the program each year and collected data on their repeat pregnancies and senior graduation rates, based primarily on staff knowledge of these outcomes . State staff used this data to calculate repeat pregnancy rates and senior graduation rates for each site and across sites, monitor the program, and make program improvements.Although this data can provide some insights into how the program may influence participants’ outcomes, it does not come from a rigorous evaluation. In particular, state staff did not have a comparison group to serve as a counterfactual for these outcomes, and site staff did not track outcomes for participants longitudinally or if they dropped out of the program. Programs should consider how to collect reliable longitudinal data, including on a comparison group of youth similar to their own participants. Such data allows for more rigorous assessment of program impacts. As described in Zief et al. in this issue, another PAF grantee used administrative data across multiple agencies to track outcomes for participants and comparison group students, which was a low-cost evaluation option and worked well because the grantee could access strong existing administrative data systems. Alternatively, programs can collect survey or interview data from participants and comparison group youth, which may be more time- or labor-intensive for programs but allow for the collection of tailored information about program outcomes, including those tied specifically to program logic models.The experiences of implementing the GRADS program can help inform the development, implementation, and evaluation of multifaceted programs that serve EPY across many sites. Most EPY face challenges with finishing high school and require targeted support to address those challenges. The GRADS program is structured to support these common challenges through case management; child care services or referrals; linkages to health care; support for young fathers; and a classroom-based intervention that covers topics related to family planning, parenting, and college and career readiness. During the PAF funding expansion period, the GRADS program was implemented at 36 sites across New Mexico, an effort that required strong centralized support from a statewide GRADS office, along with flexibility to address the specific needs of each site. Other practitioners or policymakers interested in implementing a statewide, multifaceted, and school-based program for EPY should consider lessons learned from the GRADS program: (1) allow for variation to the program model across sites to provide meaningful services for EPY at each site because each site will have unique needs based on its specific population of EPY; (2) have clear lines of communication and provide centralized monitoring and support to site staff; (3) invest in building and maintaining principal and superintendent support for the program to strengthen program sustainability over time; and (4) collect data longitudinally and aim to assess comparable control participants to allow for rigorous assessment of whether the program is working as intended.Although this paper describes a potentially promising school-based support program for EPY, it has limitations. First, the program has not been evaluated in a rigorous impact or implementation study. The findings from these lessons are based on the experiences of program administrators; youth or site-level staff may have different lessons learned. Finally, the article describes one program, implemented in one state, and it is not clear if the program components would be well suited to different state contexts.Despite these limitations, this article provides important information about the components of a school-based program for EPY. More research is needed to evaluate the New Mexico GRADS program and other school-based programs. Future research should include an experimental design to assess multiple potential outcomes associated with the program.


Asia Pacific Cohort StudiesCollaboration),Initial funding has been provided by a fellowship from the Wellcome Trust Centre for GlobalHealth Research at Imperial College London . Additional funding is being provided byan International Training Fellowship from the Wellcome Trust (214185/Z/18/Z). At the time ofwriting, the daily operations and pooled database are hosted at Imperial College London,though a mid-term goal is to transfer this expertise and operations to LAC. Thecollaboration relies fundamentally on a strong regional network of health researchers andpractitioners.IJE online. We invited all eligible cohorts to join the CC-LAC requestingaccess to anonymized individual-level data. Third, enquiries among LAC researchers alsohelped identify or approach principal investigators of the identified cohorts. LAC membersof the Non-Communicable Disease Risk Factor Collaboration (NCD-RisC)IJE online. The project procedures were approved by the InstitutionalReview Board at Universidad Peruana Cayetano Heredia (UPCH), Lima, Peru.We have harmonized and pooled approximately population-based cohort data oncardio-metabolic risk factors and outcomes, i.e. participants were not recruited based ondisease (e.g. cohort of stroke survivors) or risk factor (e.g. cohort of smokers) history.Data have been collated by the CC-LAC, a LAC network of health researchers andpractitioners. The database was collated using multiple data identification sources. First,we accessed publicly available cohort data through each study’s website or data repository.Second, we conducted a systematic search in Medline, Embase and SciELO, a LAC-based searchengine to identify cohort studies with peer-reviewed publications in regional journals. Thesearch query included country terms (countries in LAC), cohort studies (e.g. cohort stud*),and cardiovascular outcomes (e.g. stroke); the search query is available in ,2 or >80 kg/m2), systolic blood pressure (<70 mmHg or>270 mmHg), diastolic blood pressure (<30 mmHg or >150 mmHg), total cholesterol(<1.75 mmol/L or >20.00 mmol/L), high-density lipoprotein (HDL)-cholesterol(<0.40 mmol/L or >5.00 mmol/L), and fasting glucose (<2.50 mmol/L or>30.00 mmol/L) (IJE online p. 07). Notably, BMI was computedbased on measured weight and height in all but one Mexican cohort,Data sources were included in the CC-LAC database if they had at least a baseline and onefollow-up round, included LAC populations living in LAC, and participants were not recruitedexclusively based on the presence of a risk factor or disease. No restrictions were setregarding a minimum sample size at baseline or follow-up duration, sex or age profiles.Anonymized individual record data were received, harmonized and pooled by the CC-LAC. Duringthe harmonization process, we excluded participants who by the time of the baselineassessment had had a cardiovascular event .Implausible values in selected risk factors were excluded as follows:At the time of writing, i.e. first datalock on 29 March 2020, 32 cohorts with data oncardiovascular outcomes have been pooled. Seven additional cohorts have joined the CC-LACbut are currently working to provide cardiovascular outcomes, thus these 7 cohorts have notbeen pooled yet. To date, the CC-LAC is therefore a consortium of 39 cohorts in 13 LACcountries .,IJE online. Among those cohorts we currently have pooled, there are two multi-country studies: Centrode Excelencia en Salud Cardiovascular para América del Sur (CESCAS) Cohort The aforementioned 7 cohorts that have not been pooled because cardiovascular outcomes arenot yet available include: CRONICAS Cohort Study (Peru),The pooled dataset including all cohorts is not designed to be fully representative of thepopulations of regions and countries in which they have been conducted. Nevertheless, theresults provided by this consortium will be informative for most of the LAC region, wherelarge, longitudinal and multi-country studies remain insufficient in the field ofcardiovascular diseases risk prediction. This consortium aims to advance the regionalscientific evidence by overcoming the limitations of individual cohorts, e.g. studies withsmall sample size or limited number of events, while building upon a strong collaborativenetwork of investigators.The CC-LAC has pooled the baseline assessment and the latest follow-up available for eachcohort; for the purpose of this consortium all subjects have been followed once, i.e. atbaseline and one follow-up. All pooled individuals have the outcomes of interest, eithernon-fatal or fatal cardiovascular events (or censored). At the time of the first datalock,the 32 pooled cohorts had a mean follow-up time to the first cardiovascular non-fatal/fatalevent of 8.50 (median = 8.80) years, ranging from <1.0 to 27.7 years.n = 27 409) of the pooled sample had <5 yearsof follow-up, 59.3% (n = 103 254) between 5 and 9 years and 25.0%(n = 43 517) >10 years of follow-up.IJE online, show further information on these variables at follow-uprounds. In addition to clinical cardio-metabolic risk factors, we have pooled two relevantsocio-demographic indicators: place of residence  and schooling (years ofeducation). IJE online.Two outcomes of interest have been harmonized and pooled, these are non-fatal and fatalcardiovascular events: haemorrhagic and ischaemic stroke, myocardial infarction (includingrevascularization), and mortality due to these conditions, as well as sudden death. Whererelevant, these outcomes have been adjudicated or extracted from reliable sources, such asclinical records or death registries. Details on the ascertainment methods of these outcomesare provided in At the time of the first datalock, data from 174 180 individuals have been pooled: 171 937(98.7%) have complete follow-up or were censored (e.g. lost-to follow-up or death by othercauses), 578 (0.3%) have had a first non-fatal cardiovascular event and 1665 (1.0%) haveexperienced a fatal cardiovascular event .,This is the first of a series of anticipated outputs and therefore constitutes a keyinitial publication to provide a general overview of this regional long-needed endeavour.This cohort profile aims to inform the international research and clinical community aboutour ongoing efforts and inform them of our anticipated forthcoming outcomes. Our ongoingwork includes: (i) age-specific risk estimates of cardio-metabolic risk factors oncardiovascular non-fatal and fatal outcomes; (ii) comparative risk assessment of currentversus ideal levels of cardio-metabolic risk factors based on regional age-specific riskestimates and survey data; and (iii) a novel risk score for cardiovascular events based onLAC hazard estimates, and country-specific re-calibration with LAC population-basedestimates of risk factors. Although other relevant efforts have provided cardiovascular riskcharts for LAC,Besides scientific publications and other relevant outputs, CC-LAC has found that severalcohort studies have been conducted in LAC and provide strong data to advance the knowledgeof cardiovascular health in LAC. Probably, these cohort studies were not included inprevious international cohort data pooling efforts because of language barriers or becauseLAC cohorts are rather young, i.e. started mostly in the 2000s. Moreover, CC-LAC hasdemonstrated that it is feasible to conduct a large-scale cohort data pooling effort acrossLAC. We encourage other research groups working in different fields across health sciences to also embark onsimilar efforts. .,The main strength of the CC-LAC is its regional scope and the large sample size. Asdiscussed before (see ‘Why was the cohort set up?’ section), LAC has not participated inother global cohort data-pooling efforts to study cardiovascular risk factors and outcomes,leaving room to study cardio-metabolic risk estimates in this region. This work is thereforethe first-ever cohort data-pooling study in LAC, which will ultimately produce solidevidence to guide clinical and public health practice in LAC. Previous data-pooling effortsin LAC have only focused on cross-sectional or survey data, and have shown relevantdifferences in relation to high-income countries.Data pooling comes with methodological challenges. Understanding the heterogeneity amongcohorts in terms of population and sampling methodology, as well as variables collection andascertainment, is relevant to find the best way to pool and harmonize available cohort data.Additional sources of heterogeneity, such as different levels of non-response rates, wouldbe a limitation of any cohort data-pooling project. Future results should be interpretedconsidering all this and other limitations specific to each research question.Like other cohort pooling studies, among the weaknesses we should point out theheterogeneity in the definition of cardiovascular events. Although pooled cohorts havefollowed adjudication processes, or these outcomes were based on death certificates, datawere sometimes registered as 10th revision of the International Statistical Classificationof Diseases and Related Health Problems (ICD-10) codes or in broader categories (e.g.cardiovascular deaths). This prevents us from studying some specific outcomes, such ashaemorrhagic versus ischaemic stroke. This is not a criticism of our cohorts, but a call tohealth and vital registries authorities as well as science funders in LAC. Opportunities foradditional follow-up rounds of established cohort studies, or to conduct follow-up rounds oflarge projects that may have been initiated as cross-sectional surveys could be supported.In this regard, for example, the PERU MIGRANT Study was established as a cross-sectionalproject,The lack of novel or more sophisticated cardio-metabolic risk factors may be a limitationas well; these could include inflammation markers (e.g. high-sensitive C-reactive protein)or lipid biomarkers (e.g. apolipoproteins). Some of the pooled cohort studies have,nevertheless, stored blood samples from their baseline rounds. We strongly believe thatCC-LAC will enhance visibility of LAC cohort studies and promote regional collaboration. Inthe future, additional risk factors may be measured in some cohorts or new follow-up roundsmay be conducted to overcome current limitations.Data availability will be prioritized among CC-LAC members. New LAC cohort studies arewelcomed to join the CC-LAC. Expressions of interest in additional collaborations will bereceived and handled by the CC-LAC steering committee. For further details on our work,please contact the corresponding author.Profile in a nutshellWe set up the Cohorts Consortium of Latin America and the Caribbean (CC-LAC) tofill knowledge gaps in cardiovascular medicine and prevention relevant to LAC. TheCC-LAC is uniquely positioned to study long-term effects of cardio-metabolic riskfactors and outcomes in LAC, providing relevant and strong local evidence as well aspragmatic tools to advance clinical medicine and public health in LAC.A total of 32 cohorts have been pooled, with an additional 7 cohorts that have notdocumented cardiovascular outcomes yet. Three of the 32 cohorts started before 1990(6.4% of pooled sample), 9 in the 1990s (7.0%), 15 in the 2000s (80.5%) and 5 since2010 (6.1%) for a total of 174 180 participants at baseline. Precisely 16.9% of theparticipants are men, and the mean age is 47.6 (46 in women and 55 in men)years.Pooled cohorts include baseline and one follow-up round. The mean follow-up time is8.50 years (range: <1.0–27.7).We have pooled cardio-metabolic risk factors: anthropometrics, blood pressure,lipid and diabetes biomarkers, and non-fatal  and fatal  cardiovascular outcomes.Currently, data are not available for collaborations outside the consortium.Steering committee : Rodrigo M Carrillo-Larco ; Mariachiara Di Cesare ; Ian R Hambleton ; Anselm Hennis ; Vilma Irazola ;Dalia Stern* ; Catterina Ferreccio* ; Paulo Lotufo* ;Pablo Perel ; Edward W Gregg ; Majid Ezzati ; Goodarz Danaei ; J Jaime Miranda .Cohort collaborators :Carlos A Aguilar-Salinas *;Ramón Alvarez-Váz *; Marselle B Amadio *; Cecilia Baccino *; Claudia Bambs *; João LuizBastos *; Gloria Beckles *; Antonio Bernabe-Ortiz *; Carla DO Bernardo *; Katia V Bloch*; Juan E Blümel *; Jose G Boggia *; Pollyanna K Borges*; Miguel Bravo *;Gilbert Brenes-Camacho *; Horacio A Carbajal*; Maria S Castillo Rascon *; Blanca H Ceballos *; Veronica Colpani *; Susana CConfortin *; Jackie A Cooper *; Adrian Cortés-Valencia *; Sandra Cortes *; Roberto S Cunha*; Eleonora d'Orsi *; William H Dow *; Walter GEspeche *; Flavio D Fuchs *; Sandra C Fuchs *; Suely GA Gimeno *; Donaji Gomez-Velasco*; Clicerio Gonzalez-Villalpando*; María-Elena Gonzalez-Villalpando *; David A Gonzalez-Chica *; Gonzalo Grazioli *; Ricardo O Guerra*; Laura Gutierrez *; Fernando L Herkenhoff *; Andrea RVR Horimoto *; Andrea Huidobro *; Elard Koch *; Martin Lajous *; Maria Fernanda Lima-Costa *; Ruy Lopez-Ridaura *; Alvaro CC Maciel*; Betty S Manrique-Espinoza *; Larissa P Marques *; Jose G Mill *; Leila BMoreira *; Lariane M Ono *; Oscar M Muñoz *; Karen Oppermann *;Sergio V Peixoto *; Alexandre C Pereira *; Karen G Peres *; Marco A Peres *; Nohora I Rodriguez *; RosalbaRojas-Martinez *; Luis Rosero-Bixby*; Adolfo Rubinstein *; Alvaro Ruiz-Morales *; Martin R Salazar *;Aaron Salinas-Rodriguez *; Ramon A Sanchez*; Ione JC Schneider *; Thiago LN Silva *;Nelson AS Silva *; Liam Smeeth *; Poli M Spritzer *; Fiorella Tartaglione *; JorgeTartaglione *IJE online.Strategic Award, Wellcome Trust-Imperial College Centre for Global Health Research(100693/Z/12/Z). Imperial College London Wellcome Trust Institutional Strategic Support Fund[Global Health Clinical Research Training Fellowship] (294834/Z/16/Z ISSF ICL). R.C.-L. issupported by a Wellcome Trust International Training Fellowship (214185/Z/18/Z).dyaa073_supplementary_dataClick here for additional data file.


The development of tumor cells inside the lymphatics or blood vessels is known as lymphovascular invasion (LVI). The correlation between LVI, lymph node metastasis (LNM), and the diagnosis of superficial esophageal carcinoma (SEC) remains unclear.We searched Embase, PubMed, Web of Science, and Cochrane Library databases for prospective articles to better understand the relationship between LVI, LNM, and SEC diagnosis.P = 0.02). LNM rate was higher in SEC patients with LVI than SEC patients without LVI . No obvious publication was found.We included 23 articles containing data for 4749 patients (range: 54–598) in our meta-analysis. The hazard ratio between LVI and overall survival (OS) was 1.85 with 95% confidence interval (CI) (1.10–3.11, The results indicate that LVI plays a dominant role in the prognosis of LNM in SEC and in the prognostic prediction for SEC. Superficial esophageal carcinoma (SEC) can be classified as submucosal T1b), mucosal (T1a), or intraepithelial (Tis) irrespective of lymph node metastasis (LNM). Patients suffering from SEC have a better chance of survival after esophagectomy compared to those with advanced esophageal carcinoma (EC). According to the Japanese criteria, the depth of tumor invasion is subclassified into six layers. The mucosa is subdivided into the intraepithelial (m1) region, lamina propria m2), and muscularis mucosa (m3) while the submucosa is homogeneously classified into three sections: inner (sm1), middle (sm2), and deep submucosa (sm3) [b, mucosa, and musThe development of tumor cells inside the lymphatics or blood vessels is known as lymphovascular invasion (LVI). Lymphatic vessels are believed to play a crucial role in LNM and their presence increases the micro-metastatic risk in locoregional malignancy . Though We searched the Embase, PubMed, Web of Science, and Cochrane Library databases for prospective articles. The search terms used were (lymphovascular invasion (LVI) OR lymph vessel invasion OR angiolymphatic invasion OR lymphatic invasion) AND  OR submucosal esophageal carcinoma OR mucosal esophageal cancer OR T1 esophageal carcinoma). We conducted a manual search of the results to identify the prospective studies relevant to our investigation. We then performed preliminary screening by checking the titles followed by the abstracts. Relevant studies were confirmed after reviewing the full text. In the present study, we regarded lymphatic invasion as LVI.Studies were considered eligible based on the following criteria: (1) SEC; (2) hazard ratio (HR) for prognosis and odds ratio (OR) for LNM; (3) papers published in English; (4) the latest or most relevant articles published by the same group/author.The exclusion criteria were as follows: (1) duplicate conference papers, reviews, reports, abstracts, and letters; (2) studies about other cancer types, animal models, esophageal cancer cell lines, and treatment methods; (3) lack of data on prognosis or LNM; (4) studies published in languages other than English; (5) esophagogastric junction cancer (EJC).https://www.cebm.net/wp-content/uploads/2018/11/Prognosis.pdf). The detailed quality assessment of these studies was displayed in a Table Each selected article was reviewed by two independent authors based on the exclusion and inclusion criteria above. When a discrepancy arose, a third author was involved to resolve the differences. Quality assessment was performed using the Newcastle-Ottawa Scale (NOS)  and all Two independent authors collected data from the studies. The following information was extracted: surname of the first author, follow-up years, region, sample size for the research, treatment characteristics, histology type, depth of invasion, staining methods, the percentage of patients with LVI, information about OS, and LNM and NOS scores. All of the collected information is listed in Table 2 metric were used to test the heterogeneity of the pooled results. I2 < 25% indicated no heterogeneity; I2 = 25–50%, moderate heterogeneity; I2 = 50–75%, medium heterogeneity; and I2 > 75%, extreme heterogeneity. We used a fixed-effect model (the Mantele Haenszel method) for I2 < 50% with P > 0.05 in this meta-analysis. If not, a random-effect model was appropriate for our analysis. We used meta regression and subgroup analysis to explore heterogeneity when necessary [P value and P ≤ 0.05 was considered statistically significant. Statistical analysis was performed using the Stata/SE version 12.0 for Windows .We investigated the correlation between LVI, prognosis, and LNM in SEC patients. HR and OR were effective for the prognosis and LNM with 95% CI individually. Worse prognosis for SEC was indicated by an HR value > 1. Cochrane’s Q test  and the Iecessary . Begg’s We retrieved 603 articles after removing duplicates but excluded 487 articles that were either case reports or only abstracts. A few of the excluded articles were review articles and others contained information about other cancer conditions. Articles published in languages other than English were also excluded. We identified 116 potential articles for full-text review. We excluded 93 articles for the following reasons: 25 were about EJC; 67 lacked data relevant to LVI, prognosis, or LNM; and retrieval of the full text was not possible for six articles; one was excluded due to the same author and institution. The remaining 23 articles, which included information for 4749 patients (range: 54–598), were included in the meta-analysis  and the pooled OS showed medium heterogeneity based on random effect model . The pooled results from 20 studies in multivariate analysis suggested that LVI significantly increased the risk for LNM .The pooled results showed that patients in the LNM-positive group had an advanced LVI detection rate  or for LNM . The funnel plots were displayed in Fig. There was no evidence of publication bias for OS as demonstrated by Begg’s test . LVI significantly reduces OS in patients with SEC. This conclusion should be clarified with caution due to medium heterogeneity. Additionally, LVI and LNM are strongly correlated  in patients suffering from SEC. These results suggest that LVI is an important prognostic factor for patients with SEC with regard to predicting LNM and survival.Our study demonstrated that SEC patients with LVI have a poor OS  and include high-grade dysplasia, intramucosal cancer (T1a), and tumors infiltrating the submucosa (T1b) . .ReportP = 0.004, I2 = 0.0%), and LVI significantly increases the risk of LNM in SEC . Reports describing the relationship between LVI, LNM, and OS in SEC indicate that LVI raises the possibility of LNM, leading to a poor OS.During the early stage of esophageal cancer, LVI is regarded as a potential prognostic factor in predicting LNM. Current research has demonstrated that patients with T1b esophageal cancers without LVI have a significantly higher survival rate up to 5 years higher those with LVI . A largeEsophagectomy and other non-surgical options including chemotherapy and radiotherapy are the mainstream treatments for esophageal cancer. However, endoscopic resection (ER) is the diagnostic and radical choice for the treatment of SEC with a low possibility of LNM. The Japan Esophageal Society published a guideline in 2014 recommending ER as the best treatment option for T0 and T1a lesions located within the limits of the mucosal layer and not associated with LNM. The treatment can still be applied for lesions that infiltrate the muscularis mucosae or the inner submucosa (T1b-SM1) but the risk of LNM exists for these cases. Hence, other classifications for superficial carcinomas (T1b-SM2 and T1b-SM3) should not be treated with endoscopy alone due to the high rates of metastasis . ER can This study does have some limitations. First, we used only studies published in English for our meta-analysis. Consequently, studies reporting negative results may have been overlooked. Next, the stages, treatment, staining method, and adjuvant therapy differed for each study. In addition, the heterogeneity of OS was medium. The subgroup analysis was unable to carry out due to limited studies. Few studies provided Kaplan-Meier curves and we calculated the HR and 95% CI where necessary. Therefore, we strongly recommend interpreting the results with caution.SEC patients with positive LVI indicated poor prognosis compared with patients without LVI. Therefore, the association between LVI and LNM in SEC patients was close.


The program can be obtained free of charge directly from theinternet repository  In spite of its old age, the testing of Hardy-Weinberg proportions still is a kind ofwarhorse/cornerstone in population genetics. For example, the test is used extensivelyon a routine basis to exclude samples with gross molecular typing defects from theusually very large sets of genetic markers presently used in various types of populationgenetic analyses.Still on the subject of growing old, the program presented here was the master thesis ofthe first author There exist many good population genetics programs, freely available in the internet;among other tasks, they provide adequate chi-squared and exact (computer simulated)testing for Hardy-Weinberg proportions. An in-depth analysis of the available computerprograms for population genetics analysis is found in There exists also an incredible number of stand-alone computer programs that efficientlycope with the testing of HW proportions. Many among these programs can be executeddirectly from the www internet  and the simplicity of datainput, our program is, in its turn, much simpler than the ones cited above, which makesit more user-friendly. In fact, its handling is so simple, direct and uncomplicated thatit can be also used as a basic teaching tool in population genetics classes. Unlikeother similar programs currently in use, our program tests the genotype proportions, inthe two-allele case, using a large number of alternative methods; also in the two-allelecase, the results are conveniently plotted using an alternate (isosceles) ternary systemin which there is no distortion of genotype and allele frequencies. And, for thegeneralized case of any number of alleles segregating at an autosomal locus, besides theexact (bootstrap) probability of the null hypothesis of HW equilibrium, the programcalculates exact (bootstrap) and approximate  95% confidence intervals for all the observed and expected frequencies of thepossible genotypic classes. More importantly, people with only minimally basic computerskills can use our program without any difficulty, as (1) the data to be analyzed aredirectly entered in text boxes inside prompting windows in a graphic environment; and(2) the output images and texts can be easily obtained and stored.https://github.com/Lemes-RenanB/HardyWeinbergTesting. The program is theintellectual property of its authors, and as such, any use of it or of the materialsincluded in it must contain an explicit reference to its origin. Feedback from users iswelcome and will be used to improve the program and to correct unforeseen flaws. Theprogram software is free and as such it comes with no warranty.The present program was adapted and updated from the original VISUAL BASIC (© MicrosoftInc.) version The program can be executed through the file HW_TEST.exe within the folder HW_TEST afterunpacking the downloaded zipped file. The HW_TEST folder will contain the executable(compiled) file HW_TEST.exe, the corresponding application distribution (tokenized) fileHW_TEST.tkn, a set of static and dynamic link library files necessary to run thecompiled program . The user’s manual and the source code of thesoftware (HW_TEST.bas) are also available in the same repository.When the program icon (or the corresponding executable file) is activated, an interfacegraphic window will be displayed in the computer’s screen. If the number 2 is entered, the user is prompted with a two-allele window. The pdf user’s manual,besides reviewing in detail the statistical methods used, contains all figures showingin detail the program’s interface windows.The text that follows corresponds to this two-allele case. The generalized case of nalleles will be dealt with at the end of this section.The user should select, from the left-sided list on the two-allele window, the tests tobe performed. The option ‘Chi-square without correction’ is pre-selected and will alwaysbe performed by the program. To run all available tests, the user should click themessage bar “Select all”. The user should then enter on the right-sided genotype fieldsthe absolute frequencies of observed genotypes to be tested. The program will not accepttotal sample sizes of observed data less than 5 or two null entries. There is no sense,either, in testing sample sizes of the order of 20 or less, because rarely the nullhypothesis of HW ratios is rejected with such small sample sizes. Also, if the HW nullhypothesis is rejected with sample sizes of this order of magnitude, the possibility ofgenotype misclassification typing errors should be seriously considered. Actually, theuse of the present program in quality control of laboratory typing, even when dealingwith larger sample sizes, is very important. Such deviations from HW proportions,besides resulting from low quality genotyping, could also be due to the effects ofevolutionary selection processes, especially when limited to specific genomic regions.The program performs the tests listed below . SummaryChi-squared HW tests with and without continuity correctionG (log-likelihood) tests with and without continuity correctionFisher’s exact testHogben/Levene’s chi-squared methodCannings & Edwards chi-squared methodHaldane’s exact testexact test based on computer bootstrap simulationsThe routine that performs the exact test based on computer bootstrap simulations startsby extracting the allele frequencies p and q of A and a alleles from the set of observeddata  and then calculates the probability ofoccurrence of the sample under the hypothesis of Hardy-Weinberg equilibrium:0 = N!/(2N)!.(nA!na!2nAa) /(nAA!nAa!naa!) =N!/(2N)!.(2D+H)!(H+2R)!2H /(D!H!R!).P2 = [(2D+H)/2N]2, this indicates that anAA homozygous genotype was obtained among the N of the sample; if the random number islarger than p2, but smaller than p2+2pq = 1-q2 = 1 -[(H+2R)/2N]2, this indicates that a heterozygous genotype Aa wasgenerated; and, finally, if the random number is larger than 1-q2, thegenotype is aa. The process is then repeated N-1 times, and in each instance the randomnumber generated is compared to p2 and 1-q2. When the computergenerates the N individuals of the sample, the frequencies p and q of A and a allelesare calculated from the numbers of AA-, Aa-, and aa-generated individuals. The computerrepeats this process t times . After eachsimulation the computer calculates the value of the probability Pi ofoccurrence of the sample under the hypothesis of Hardy-Weinberg equilibrium:The program generates a normalized random number between 0 and 1; if the number issmaller than or equal to pi =N!/(2N)!.(2Di+Hi)!(Hi+2Ri)!2Hi/(Di!Hi!Ri!).Pi is then compared to P0, the probability ofoccurrence of the observed sample under the hypothesis of HW equilibrium. The exactprobability P, obtained after t simulations, is given by P = T/t (our program uses t =1000 and P = T/1000), where T is the number of times in which Pi is smallerthan or equal to P0.This probability PA standard program text output obtained by running the program with the genotype data D =N(AA) = 119, H = N(Aa) = 42 and R = N(aa) = 39 and selecting all tests provided can befound in the user’s manual.2,P(AB) = 2pq, P(BB) = q2}, the program simulates also 1,000 populations withfrequencies {d = D/N, h = H/N, r = R/N}, where D, H and R are the observed numbers ofsampled genotypes AA, AB and BB respectively. The two sets of scatter population pointsare then plotted , q2 +pqFLL} and {p2 + pqFUL, 2pq(1-FUL),q2 + pqFUL} with lower and upper limits FLL = +√(3.841/N) and FUL = - √(3.841/N)  = p plotted  on an is plotted  that sho3.841/N) .The program also calculates approximate 95% confidence intervals and exact confidenceintervals of genotype frequencies, the latter based on algorithms that use randomnumbers to simulate genetic populations as described above.If a number larger than 2 is entered  into the initial input window, theuser is prompted with a k-allele window.-6 should be consideredcautiously because they could result exclusively from genotyping errors with a largeprobability.As in the two-allele case, in order to avoid running problems, the user should not usesmall total sample sizes . Many null entries should also be avoided; in the common case when some ofthese occur, and especially when the total sample size is relatively small, the user isadvised to properly agglutinate some value classes, thus reducing the number of allelesand improving the power of the test and the performance of the program. Just like in thetwo-allele case, there is no sense at all, either, in testing sample sizes of the orderof 10 k or less, for the reasons already explained. And for any sample size, obtainedtest probability values of the order of less than 10In the k-allele case the program performs the chi-squared test and the exact test basedon computer bootstrap simulations.0: P(AA) = pi2, P(AB) = 2piqj, ...} tested by Pearsonsnon-parametric chi-squared statistics χ2 = Σ(oij –eij)2/eij = Σ(oij2 / eij) – N, where oij is the genotype observedabsolute frequency, eij its corresponding expected figure in HW proportions,N the total sample size and the summation takes place from i = j = 1 to i = j = k. Asthere are k different alleles and the k(k+1)/2 expected genotype absolute frequenciesare calculated conditional to the sample size N and to the fixed value of k-1 differentallele frequencies extracted from the same sample, the number of degrees of freedom ofthe HW chi-squared test is calculated after k(k+1)/2 - k = k(k-1)/2. No continuitycorrection is applied to the test, since this is appropriate only for the two-allelecase.As in the two-allele case, in the n-allele case Hardy-Weinberg (HW) equilibrium isusually a null hypothesis {HIn the k-allele case, the program (a) performs a test based on computer bootstrapsimulations, generating 1,000 populations in expected HW proportions, from which anexact P test probability is constructed; and (b) calculates approximate 95% confidenceintervals and also exact confidence intervals of genotype frequencies, based onalgorithms that use random numbers to simulate genetic populations .As in the 2-allele case, an example standard text output  is shownin the user’s manual.


Opioid use disorder (OUD) and related overdose deaths have become a crisis of epidemic proportions in the United States. In 2018, over 10 million people age 12 years or older misused opioids.Substance use is also correlated with increased physical and mental health disorders, and developmental challenges among youths. Medication-assisted treatment (MAT) has been reported to reduce mortality, opioid use, and human immunodeficiency virus and hepatitis C virus transmission while increasing treatment retention in adults. The San Bernardino County Youth Opioid Response (SBCYOR) program was formed to explore best practices for youths at risk of opioid use disorders and/or overdose. SBCYOR is a coalition of professionals in healthcare, behavioral health, public education, law enforcement, emergency medical services (EMS) agencies, and juvenile detention centers throughout San Bernardino County, California. SBCYOR focuses on high-risk and addicted individuals between the ages of 12 to 24 years in San Bernardino County’s correctional system. It utilizes a strategy of collaboration, prevention, risk mitigation, medication, psychological treatment, and community outreach. This study aimed to evaluate the implementation and progress of SBCYOR. The rate of opioid use and dependency has increased to the point of being a major public health priority in the United States over the last decade. In 2018, the National Survey on Drug Use and Health (NSDUH) reported that 10.3 million people aged 12 years or older have misused opioids [The youth populations aged 12-24 years) are particularly vulnerable and have also been affected by the opioid crisis. Youths may lack prefrontal cortical function leading to behavior inhibition and risk aversion . This co years arThe office of the Surgeon General has stated that medication-assisted treatment (MAT) combined with psychosocial therapy and community-based recovery support is the gold standard for treating opioid addiction . HoweverTreatment strategies for OUD are complex and multifactorial. Recent emphasis on MAT in conjunction with cognitive behavioral therapy (CBT) has shown to be effective in treating OUD in adults . AlthougThe San Bernardino County Youth Opioid Response (SBCYOR) program was formed to help mitigate the spread of OUD, increase access to MAT and reduce the risk of overdose for the youth populations. The program is a part of the California Youth Opioid Response  Project. SBCYOR is a coalition of professionals in healthcare, behavioral health, public education, law enforcement, emergency medical services (EMS) agencies, and juvenile detention centers throughout the county. It focuses on high-risk and addicted individuals between the ages of 12 to 24 years in San Bernardino County’s correctional system. The program utilizes a strategy of collaboration, prevention, risk mitigation, medication, psychological treatment, and community outreach. Its goal is to integrate the county’s available resources into a continuum of care to enable the youths of the community to grow into productive members of society, free of the burden of opioid use exposure, disorder and associated risks. The objective of this study is to evaluate the implementation and sustainability of the SBCYOR program and its effects in the community to date.This is a prospective observational study of youths aged 12 to 24 years identified through San Bernardino County’s correctional, educational, and healthcare systems. Data were extracted from the electronic health records (EHR) of the county’s Department of Probation, the Sheriff’s Department, and Arrowhead Regional Medical Center (ARMC), a county owned and operated safety net hospital. San Bernardino County (SBC) is the largest geographic county in the United States with a diverse population of 2.2 million people. According to the 2018 Census data, the racial makeup of SBC was 52.3% Latino, 29.8% White, and 8.0% African American . The couPatients enrolled in the program were tracked and results from data were reported to YOR California, in compliance with state and federal regulations. This study was approved by the ARMC Institutional Review Board. Eligibility for inclusion in this study was between age 12 to 24 years with a reported history of opioid use, the presence of opioid on a screening drug test, physical signs of drug use, or evidence of overdose or withdrawal. Physical signs of drug use included the presence of track marks, lethargy, flu-like symptoms, unexplained somnolence or respiratory depression. A Clinical Opiate Withdrawal Scale (COWS) score was used to assess the degree of opioid withdrawal.Exclusion criteria was age less than 12 or greater than 24 years, refusal of enrollment, hypersensitivity to recommended medication, inability to obtain consent, active withdrawal from alcohol or benzodiazepine, or medical frailty. Medical frailty was determined by an attending emergency physician in consultation with other subspecialties, after a thorough evaluation of the patient’s medical history and present illness. Examples of medical fragility include decompensated heart failure, severe liver disease, or poorly controlled psychosis.The program required participating providers to obtain an X waiver. The X waivered providers received extensive training and education in key aspects of MAT including identification of individuals who may benefit from treatment, safe and appropriate use of Federal Drug Administration-approved medications, strategies for communicating and educating patients and their families, and coordinating care with other community infrastructure.SBCYOR implemented its community outreach program in phases Table  with regPhase 1: Definition of goalsAfter a thorough situation analysis, SBCYOR agreed to focus on four primary objectives to guide design and implementation of the program. These four primary objectives were:To decrease the morbidity and mortality in the target populationTo increase access to effective treatment including medication assisted treatmentTo decrease the stigma associated with OUD within the communityTo improve continuity of care for the target populationPhase 2: Planning & developmentTo achieve these goals, SBCYOR reached out and connected with the community, healthcare providers, and county agencies. Team members attended community events, gathered and shared information and resources, and provided education for families to recognize addiction as a chronic medical condition, the signs and symptoms of OUD. Emphasis was placed on reducing exposure to opioid use and prevention of overdose. Because OUD in youth can begin with appropriately prescribed opiates, health care providers were educated about risk mitigation for patients and household members. Mitigation efforts also included education and access to naloxone . The coalition also explored the formation of a referral network, connecting patients to the existing resources for behavioral counseling services and MAT within the community and the county.SBCYOR established treatment protocols and safe prescribing practices amongst youths with OUD, allowing X waivered providers to initiate MAT by prescribing buprenorphine/naloxone. The X waivered providers also assessed youths at risk for OUD, and performed interventions deemed appropriate. Leadership of the program connected with established OUD treatment programs such as the California Bridge (CA-BRIDGE) project, an initiative which developed hospitals’ emergency departments into primary access points for treating acute symptoms of OUD. SBCYOR integrated with CA-BRIDGE’s established network, coordinated by ARMC, to help transition youths to outpatient-based MAT clinics for continued therapy.Phase 3: Establishing coalitionSBCYOR collaborated with local and county agencies to form a coalition. These agencies included school district leadership, law enforcement, EMS, correctional facilities, behavioral health centers, and hospitals. Specifically, SBCYOR connected with the county’s Department of Probation, Department of Behavioral Health, the Sheriff’s Department, ARMC, and the Inland Empire Opioid Crisis Coalition (IEOCC). Site champions within each organization were identified and enrolled into the effort. Once the coalition was established, these agencies were invited to actively participate in planning, refining, and eventual implementation of the program. SBCYOR also reached out to community resources such as the local Harm Reduction Coalition and MAT clinics of the California Hub and Spoke System (CA H&SS) who also became key partners.Phase 4: ImplementationThe program officially launched on August 1, 2019. The coalition provided site-specific training and technical assistance for healthcare providers in the detention facilities that would have encounters with the target population. Screening assessment tools were created for nursing staff in the detention centers to streamline the process for appropriate referrals and treatment. Figure Designated case managers and substance use navigators (SUNs) helped guide patients through the complexities of the healthcare system, addressing their specific needs. They connected patients to outpatient MAT centers based on specific needs such as insurance coverage, transportation, and appropriate referrals for comorbid conditions. The SUN is expected to play a significant role in a patient’s recovery, facilitating social support to help with living situations and dealing with external stressors. Most importantly, the SUN provided the patient with a constant point of contact whenever needed.Phase 5: Outcome measuresAll eligible youths identified by the county health staff within the Probation and Sheriff’s Departments detention centers were tracked. Similarly, information on all youths who received MAT through Arrowhead Regional Medical Center (ARMC) were collected. Data collection was reported by providers and tabulated by the SUN. Providers were able to notify the SUN through phone calls, HIPAA compliant emails, or the consult function of the electronic record. Once the patient was released from a facility, the SUN followed the youth via individualized home visits, phone calls or video telehealth visits.Data were collected and reviewed weekly by the program director and steering committee. A more detailed analysis of the compiled data was performed monthly and quarterly. Based on the observations and findings of these analyses, the program was continually refined accordingly. The goal was to identify areas of need for immediate attention and/or resources diversion.Phase 6: SustainabilityWhile the SBCYOR program was created through grant funding from the Substance Abuse and Mental Health Services Administration response to the opioid epidemic, it was important to institutionalize practices and partnerships to gain financial independence with the goal of becoming less reliant on future grant funds. Thus, the program focused on embedding best practices and workflows at an organizational level to be integrated into funding systems of each coalition partner. The MAT program in each institution is now integrated into the standard medical services provided by physicians and advanced providers and has become part of standard practice.After initial preparation and coordination with the grant originating organization, California Institute for Behavioral Health Solutions (CIBHS), implementation of the SBCYOR program was initiated in August 2019. The core operations team was formed and members were assigned roles and responsibilities. A timeline was created with goals and milestones established. The core team set out to secure site champions at contributory facilities. These facilities included California University of Science and Medicine (CUSM) and its affiliated hospital, ARMC, along with West Valley Detention Center, SBC Juvenile Detention Center, and local school districts as target sites. A website and online social media presence were created to announce the launch of the program and give a point of contact for the community.Over the next three months, policies and procedures were created and the medical staff at participating institutions were trained. The program implementation was piloted in the juvenile detention center and later expanded to the adult detention center. By October 2019, 90% of the healthcare staff in the detention centers received training on OUD and MAT. The educational team members also reached out to train other county’s facilities and programs, such as halfway houses, public schools, and law enforcement agencies.In December 2019, an agreement with local Probation leadership was reached to include the opioid use disorder and naloxone (Narcan) training into the permanent training protocol for the probation academy program. The program trains 150-300 new officers per year. Narcan training was incorporated into standard departmental training for all officers, with 550 additional officers trained per year. In order to reach the largest audience, SBCYOR is working with the local school districts to bring the educational teams to junior high and high schools.In the first quarter , the program screened 520 youths, and seven (1.3%) of those screened were referred for evaluation into YOR services. Of the first seven referred, one (14.3%) youth met criteria for treatment by Behavioral Health (BH). The same youth also received MAT therapy. Enrollment increased in the second quarter , with 3244 youths screened and 37 (1.1%) referred for treatment. Among those who were referred, 13 (35.1%) youths received BH, and 10 (27%) youths received both MAT and BH. In the third quarter , 1929 youths were screened, with 51 (2.6%) of them referred. Among those who were referred, 43 (84.3%) youths received BH, and 10 (19.6%) youths received MAT and BH. The total number of patients referred for evaluation  and received treatment  both increased from Q2 to Q3. In total, 60% (57/90) of patients referred for evaluation were successfully enrolled into treatment. Table The decrease in total screens from Q2 to Q3 is thought to be a consequence of the current COVID-19 pandemic. During Q3, California Governor Gavin Newsome issued stay-at-home orders to mitigate the spread of the SARS-CoV-2, the coronavirus that is responsible for COVID-19. The crime rates in SBC saw a subsequent drop when compared to 2019 . This liData collection became more detailed as the program grew and developed. By Q3, SBCYOR was able to tabulate and evaluate demographic data for all patients who were enrolled into the system. Table Opioid use disorders are chronic conditions with substantial personal and societal costs . The patSubstance use disorder is a medical condition with structural and chemical brain changes . Dugosh Subramaniam et al. demonstrated that youths suffering from OUD commonly have multiple comorbidities, including polysubstance abuse, psychiatric disorders, hepatitis C infection, a history of high-risk sexual and criminal behaviors . They arOpioid use disorder also places a significant burden of cost on society affecting health care, social service, and justice systems. A strong effort must be made to target this group early with both preventative and therapeutic options in order to mitigate downstream effects. People affected by OUD are often ashamed of their problem. They fear social stigma associated with drug use, and implications with law enforcement involvement . This prHistorically, substance use disorder treatment of any kind, nationally and statewide, has been offered under the Substance Abuse Prevention and Treatment Block Grant. Multiple public systems have responded to growing community needs resulting in diverse and uncoordinated approaches. Discrete system and programming responses has resulted in an inability to share data. This lack of data sharing has been a significant barrier to forming a coordinated effort in developing a continuity of care for these patients. Previous efforts at forming a centralized database in San Bernardino County for all partners have been limited, and often lacking vital elements of the patient’s health history, such as medication, dosage, and response to treatment. This adversely impacts the delivery of care as the patient moves along the spectrum of recovery , 29. WhiThis crisis affects more than just the individuals who misuse opioid medications and illicit drugs. Repercussions of this crisis reverberate throughout the entire community. The stigma surrounding OUD and deficits in current treatment strategies must be addressed. Among the youth population, OUD is a growing concern. Any strategy will need to understand the systemic barriers and be sensitive to unique attributes of this population. Without a cultural transformation of the system, no recovery program can be successful long-term. Actions to address the crisis requires the endorsement from the community and coordination from multiple agencies and organizations. Without active support from the county organizations, public schools, law enforcement agencies, local fire departments, social services and department of behavioral health, it would be impossible to reach affected youths and provide them with essential and ongoing care. As such, SBCYOR has successfully brought together community stakeholders, especially public service entities on the frontlines of the epidemic. Together, community partners can disseminate information, provide support, offer an alternative to drug use, and participate in therapeutic interventions. Consideration must be given to local, state, and federal regulations to this socially sensitive field of medicine.The greatest challenge moving forward for continued implementation of programs such as SBCYOR is securing the commitment of agencies to the implementation of best practices. Procuring on-going funding is necessary; however, much can be achieved by system, organizational, practitioner commitment to change. There has been significant financial, government, and community support to initiate this campaign, but to this point, further funding beyond the first year of implementation has not been secured. Additionally, in light of a new challenge in response to the COVID-19 pandemic, the coalition plans to utilize telemedicine and other available technologies in an effort to prevent delay in screening, care and treatment. Ultimately, the organizational will, innovations, and pathways must be established for continued funding without dependence on grants. This may be achieved by refining the logistics, bringing more OUD awareness, and government and community buy-in.Opioid use disorder is a chronic condition with substantial health, economic and social costs. SBCYOR was created as a coalition to help fill a gap in the national effort to address the opioid use crisis in SBC. It specifically targets youths aged 12-24 years in SBC suffering from OUD. Early results of SBCYOR suggested that the coalition has enrolled youths in MAT programs and provided an integrated response, showing promising results, and has successfully partnered with community stakeholders. Future systematic implementation of various clinical and administrative integration strategies is needed in order to ensure a better continuum of care and success of this program.