Notch signaling drives intestinal graft-versus-host disease in mice and nonhuman primates.

Notch signaling promotes T cell pathogenicity and graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (allo-HCT) in mice, with a dominant role for the Delta-like Notch ligand DLL4. To assess whether Notch's effects are evolutionarily conserved and to identify the mechanisms of Notch signaling inhibition, we studied antibody-mediated DLL4 blockade in a nonhuman primate (NHP) model similar to human allo-HCT. Short-term DLL4 blockade improved posttransplant survival with durable protection from gastrointestinal GVHD in particular. Unlike prior immunosuppressive strategies tested in the NHP GVHD model, anti-DLL4 interfered with a T cell transcriptional program associated with intestinal infiltration. In cross-species investigations, Notch inhibition decreased surface abundance of the gut-homing integrin α4ß7 in conventional T cells while preserving α4ß7 in regulatory T cells, with findings suggesting increased ß1 competition for α4 binding in conventional T cells. Secondary lymphoid organ fibroblastic reticular cells emerged as the critical cellular source of Delta-like Notch ligands for Notch-mediated up-regulation of α4ß7 integrin in T cells after allo-HCT. Together, DLL4-Notch blockade decreased effector T cell infiltration into the gut, with increased regulatory to conventional T cell ratios early after allo-HCT. Our results identify a conserved, biologically unique, and targetable role of DLL4-Notch signaling in intestinal GVHD.

Fidelity of D.A.R.E. Officers' Delivery of "keepin' it REAL" in Elementary & Middle School.

The goal of the current study is to examine the degree to which measures of quality of implementation and student engagement moderate pretest-posttest changes in mediating variables that are targeted by DARE "keepin' it REAL." DARE officers (10 elementary school, five middle school) taught DARE "keepin' it REAL lessons to 1,017 elementary students (480 boys and 534 girls) and 435 middle school students (217 boys and 215 girls). We examined teachers' and students' ratings of elementary and middle schools in response to DARE officers' delivery of the program. HLM analyses revealed that students' engagement was a significant and meaningful predictor of changes in targeted mediators. Teachers' ratings of student responsiveness added little in terms of understanding these outcomes with main effects observed only for students' ability to respond to bulling and students' estimates of peer drug use. Teachers' ratings of the quality of officer implementation, on the other hand, did add to understanding students' outcomes. Effects were seen for three (peer norms about drug use, decision-making (DM) skills, intentions to avoid drug use) out of six outcome variables and suggest a stronger positive effect for elementary versus middle school students. At least for these three outcomes, understanding quality of implementation added to our ability to interpret results. Specifically, in addition to students' engagement, quality of implementation (which varied by grade) contributed to achieving positive changes in students' outcomes.

Self-harm in university students: A comparative analysis of data from the Multicentre Study of Self-harm in England.

BACKGROUND: Increases in poor mental health and suicide have been identified among university students in the UK. However, little is known about self-harm in this group. AIMS: To describe and identify care needs of university aged-students who self-harm via comparisons with an age-equivalent non-student group who self-harm. METHODS: Observational cohort data from The Multicentre Study of Self-harm in England were used to investigate students aged 18 to 24 years who presented to emergency departments for self-harm, 2003 to 2016. Data were collected via clinician reports and medical records from five hospitals in three English regions. Characteristics, rates, repetition, and mortality outcomes were investigated. RESULTS: The student sample included 3491 individuals (983, 28.2 % men; 2507, 71.8 % women; 1 unknown) compared to 7807 (3342, 42.8 % men; 4465, 57.2 % women) non-students. Self-harm increased over time in students (IRR 1.08, 95%CI 1.06-1.10, p < 0.01) but not in non-students (IRR 1.01, 95%CI 1.00-1.02, p = 0.15). There were differences in monthly distribution of self-harm with more presentations by students in October, November, and February. Characteristics were broadly similar, but students reported more problems with studying and mental health. Repetition (HR 0.78, 95%CI 0.71-0.86, p < 0.01) and mortality (HR 0.51, 95%CI 0.33-0.80, p < 0.01) were lower in students than non-students. CONCLUSIONS: Self-harm in students may be directly related the student experience, such as academic pressure, relocation, and the transition to independent living. Wellbeing initiatives targeting these factors, alongside mental health awareness training for academic and non-academic staff may help to support students at risk.

D.A.R.E./keepin' it REAL elementary curriculum: Substance use outcomes.

In response to a need to implement an evidence-based prevention program, D.A.R.E. America adopted keepin' it REAL. The program was previously developed and tested in middle school settings. As part of its adoption, an elementary version of the program was developed. This study tests the effectiveness of keepin' it REAL when delivered to fifth graders. The intervention was delivered to two cohorts of students, the first in the 2019-2020 school year, the second in the 2020-2021 school year. Pretest surveys were completed by 6,122 students. The COVID-19 pandemic interfered with posttest and follow-up data collection. At immediate posttest, 2,049 students (33.5%) completed analyzable posttest surveys. One year after the pretest, 1,486 (24.3%) students completed usable follow-up surveys. We used algorithmically generated cases (virtual controls) that use treatment cases' pretest psychosocial scores to assess program effectiveness. When compared to virtual control cases, the program had identifiable improvements in both a key psychosocial measure and in terms of deterring the onset of 30-day alcohol use, drunkenness, and vaping. Outcomes suggest that the delivery of elementary school keepin' it REAL by D.A.R.E. officers is having a positive effect in terms of deterring the onset of alcohol use and vaping.

The characteristics, life problems and clinical management of older adults who self-harm: Findings from the multicentre study of self-harm in England.

BACKGROUND: Older adults have a high risk of suicide following self-harm. Contemporary information on self-harm in this population is needed to inform care provision. OBJECTIVES: To examine subgroup differences in the incidence of self-harm, sociodemographic and clinical characteristics, preceding life problems and outcomes in individuals aged 60 years and over presenting to hospital following self-harm. METHOD: Data on Emergency Department (ED) presentations for self-harm from 2003 to 2016 from three centres in the Multicentre Study of Self-Harm in England were analysed. Changes in self-harm rates were examined using Poisson regression. Univariable logistic regression was used to investigate factors associated with 12-month self-harm repetition. RESULTS: There were 3850 presentations for self-harm by 2684 individuals aged 60 years and over. Self-harm rates increased over time for 60-74-year-old men (Incident Rate Ratio = 1.04, 95% Confidence Interval 1.02-1.06, p < 0.0001). Problems most frequently reported to have preceded self-harm were mental health (40.5%) and physical health (38.3%) concerns. Problems with alcohol, finances, employment and relationship with partner were found more frequently in 60-74-year-olds compared with those aged over 74 years. Physical health problems were common with increasing age, as were problems with alcohol for men. One in ten (10.8%) individuals presented to hospital with self-harm within 12 months of their index presentation. CONCLUSIONS: Self-harm-related ED attendances in older men have increased, particularly for men aged 60-74 years. Prevention and clinical management should involve a comprehensive psychosocial assessment to target common precipitants for the wide range of problems preceding self-harm and may include support with physical and mental wellbeing and advice on safer alcohol use.

Impact of the COVID-19 Pandemic on Medical Students' Perceptions of Health Care for Vulnerable Populations.

BACKGROUND AND OBJECTIVES: The COVID-19 pandemic highlighted the shortcomings of our health care delivery system for vulnerable populations and created a need to rethink health disparity education in medical training. We examined how the early COVID-19 pandemic impacted third-year medical students' attitudes, perceptions, and sense of responsibility regarding health care delivery for vulnerable populations. METHODS: Third-year family medicine clerkship students at a large, private medical school in Philadelphia, Pennsylvania responded to a reflection assignment prompt asking how the COVID-19 pandemic impacted their thoughts about health care delivery for vulnerable populations in mid-2020 (N=59). Using conventional content analysis, we identified three main themes across 24 codes. RESULTS: Students recognized homeless individuals and Black, indigenous, and persons of color (BIPOC) as vulnerable populations impacted by the pandemic. Students reported causes of vulnerability that focused heavily on social determinants of health, increased risk for contracting COVID-19 infections, and difficulty adhering to COVID-19 prevention guidelines. Notable action-oriented approaches to addressing these disparities included health care reform and community health intervention. CONCLUSIONS: Our findings describe an educational approach to care for vulnerable populations based on awareness, attitudes, and social action. Medical education must continue to teach students how to identify ways to mitigate disparities in order to achieve health equity.

Data Science-Driven Analysis of Substrate-Permissive Diketopiperazine Reverse Prenyltransferase NotF: Applications in Protein Engineering and Cascade Biocatalytic Synthesis of (-)-Eurotiumin A.

Prenyltransfer is an early-stage carbon-hydrogen bond (C-H) functionalization prevalent in the biosynthesis of a diverse array of biologically active bacterial, fungal, plant, and metazoan diketopiperazine (DKP) alkaloids. Toward the development of a unified strategy for biocatalytic construction of prenylated DKP indole alkaloids, we sought to identify and characterize a substrate-permissive C2 reverse prenyltransferase (PT). As the first tailoring event within the biosynthesis of cytotoxic notoamide metabolites, PT NotF catalyzes C2 reverse prenyltransfer of brevianamide F. Solving a crystal structure of NotF (in complex with native substrate and prenyl donor mimic dimethylallyl S-thiolodiphosphate (DMSPP)) revealed a large, solvent-exposed active site, intimating NotF may possess a significantly broad substrate scope. To assess the substrate selectivity of NotF, we synthesized a panel of 30 sterically and electronically differentiated tryptophanyl DKPs, the majority of which were selectively prenylated by NotF in synthetically useful conversions (2 to >99%). Quantitative representation of this substrate library and development of a descriptive statistical model provided insight into the molecular origins of NotF's substrate promiscuity. This approach enabled the identification of key substrate descriptors (electrophilicity, size, and flexibility) that govern the rate of NotF-catalyzed prenyltransfer, and the development of an "induced fit docking (IFD)-guided" engineering strategy for improved turnover of our largest substrates. We further demonstrated the utility of NotF in tandem with oxidative cyclization using flavin monooxygenase, BvnB. This one-pot, in vitro biocatalytic cascade enabled the first chemoenzymatic synthesis of the marine fungal natural product, (-)-eurotiumin A, in three steps and 60% overall yield.

Stromal Notch ligands foster lymphopenia-driven functional plasticity and homeostatic proliferation of naive B cells.

In lymphopenic environments, secondary lymphoid organs regulate the size of B and T cell compartments by supporting the homeostatic proliferation of mature lymphocytes. The molecular mechanisms underlying these responses and their functional consequences remain incompletely understood. To evaluate homeostasis of the mature B cell pool during lymphopenia, we turned to an adoptive transfer model of purified follicular B cells into Rag2-/- mouse recipients. Highly purified follicular B cells transdifferentiated into marginal zone-like B cells when transferred into Rag2-/- lymphopenic hosts but not into wild-type hosts. In lymphopenic spleens, transferred B cells gradually lost their follicular phenotype and acquired characteristics of marginal zone B cells, as judged by cell surface phenotype, expression of integrins and chemokine receptors, positioning close to the marginal sinus, and an ability to rapidly generate functional plasma cells. Initiation of follicular to marginal zone B cell transdifferentiation preceded proliferation. Furthermore, the transdifferentiation process was dependent on Notch2 receptors in B cells and expression of Delta-like 1 Notch ligands by splenic Ccl19-Cre+ fibroblastic stromal cells. Gene expression analysis showed rapid induction of Notch-regulated transcripts followed by upregulated Myc expression and acquisition of broad transcriptional features of marginal zone B cells. Thus, naive mature B cells are endowed with plastic transdifferentiation potential in response to increased stromal Notch ligand availability during lymphopenia.

Implementing and Evaluating a Fellowship for Community-Based Physicians and Physician Assistants: Leadership, Practice Transformation, and Precepting.

INTRODUCTION: Formal training in practice transformation, leadership, clinical education, and/or the time to gain these skills are limited postresidency for primary care physicians and physician assistants. Therefore, we created a novel Primary Care Champions fellowship program that provides practical experiences in education, practice transformation, and leadership for primary care physicians and physician assistants in community practice. The purpose of this study is to describe the fellowship and evaluate feedback from the first cohort. METHODS: In the Jefferson Primary Care Champions Fellowship, fellows are provided protected time from clinical obligations to engage in didactic, informal, and experiential learning. They meet monthly and participate in student precepting training and receive mentorship from senior clinician administrators, scientists, educators, and population health researchers to hone skills for leadership and practice transformation endeavors. Cohort one began in September 2018. All fellows were family physicians from community-based practices in Philadelphia, PA (N = 4) and selected in collaboration with their practice leadership. Mixed-methods postprogram evaluations included Organizational Readiness Assessment and qualitative feedback. RESULTS: Fellows denoted individual time, small-group mentorship, protected project time, and open-robust discussions about primary care most useful. Three fellows reported that they plan to continue their practice-improvement projects postfellowship and one published her initial project findings and reflections. DISCUSSION: Overall feedback from the first cohort was positive. Fellows greatly appreciated structured time to explore primary care interests, contemplated long-term career prospects, and considered leadership opportunities. Cohort two is currently underway and cohort three is in recruitment.

A Novel Curricular Approach to Teach Quality Improvement and Health Disparities in a Family Medicine Clerkship.

Background and Objectives: Medical schools must integrate educational curricula that teach how to apply quality improvement principles to improve care for vulnerable populations. In this report, we describe the development, implementation, and evaluation of a combined quality improvement (QI) and health disparities curriculum for third-year family medicine clerkship students. Methods: After conducting an educational needs assessment, we developed a health disparities curriculum focused on QI principles for the family medicine clerkship. From November 2019 through August 2021, third-year medical students (N=395) completed the curriculum. The curriculum was delivered in an asynchronous online format, followed by a small group collaboration project to design and present a QI intervention through process mapping. Students also completed an individual reflection assignment that focused on care for vulnerable populations. Pre- and post assessment questions were administered on Qualtrics, after review by the clerkship director, research faculty and staff, and content experts for content and item validity. We analyzed quantitative data using SPSS version 27 software and used paired t tests for pre/post comparisons. Results: In total, 392 students completed the preassessment survey, 395 students completed the postassessment surveys, and 341 had matching study identifiers. Pre-to-post assessment survey evaluations showed statistically significant changes for nine out of nine QI knowledge questions (P<.001), knowledge regarding a community health needs assessment (P<.001), and knowledge about caring for vulnerable populations (homeless, veterans, immigrants/refugees; P<.001). Conclusions: Preliminary evaluation of a combined QI and health disparities curriculum shows improvement in students' self-reported knowledge of use of a community health needs assessment, QI principles, and care for vulnerable populations.

Evaluation of a Quality Improvement Experience for Family Medicine Clerkship Students.

BACKGROUND AND OBJECTIVES: There is emphasis on systems-based practice competencies and quality improvement (QI) training in postgraduate medical education. However, we lack effective approaches to provide experiences in these areas during undergraduate medical education. To address this, we developed a novel approach to providing didactic and experiential learning experiences in QI during a third-year family medicine clerkship. METHODS: We implemented and evaluated a QI curriculum combining self-directed learning with real-world experience to increase knowledge and confidence in the plan-do-study-act (PDSA) process for family medicine clerkship students. Students collaborated and presented their change ideas in a "Shark Tank" format for practice leaders at the end of their rotation. We used pre- and postcurriculum surveys to assess knowledge of and comfort with completing QI projects. RESULTS: Three hundred eighty-nine students completed precurriculum surveys and 242 completed postcurriculum surveys. Pre- and postlearning evaluations revealed an increase in agreement or strong agreement with self-reported understanding of specific QI topic areas of 50%. Almost all (91.3%) reported feeling confident or reasonably confident in their ability to create change in health care after exposure to the curriculum, compared with 66.3% in the precurriculum survey. One-third of students (34%) reported intent to complete the Institute for Healthcare Improvement Open School curriculum in QI. CONCLUSIONS: Self-directed learning about QI, combined with practice observation, small-group discussion and presentation in a Shark Tank format was effective and engaging for learners. Students had limited preexisting knowledge of QI principles, suggesting a need for preclinical exposure to this topic. The family medicine clerkship provides an ideal environment for teaching QI.

A qualitative analysis of third-year medical students' reflection essays regarding the impact of COVID-19 on their education.

BACKGROUND: The COVID-19 pandemic fundamentally changed every aspect of healthcare delivery and training. Few studies have reported on the impact of these changes on the experiences, skill development, and career expectations of medical students. METHOD: Using 59 responses to a short reflection essay prompt, 3rd year medical students in Philadelphia described how the COVID-19 pandemic affected their education in mid-2020. Using conventional content analysis, six main themes were identified across 14 codes. RESULTS: Students reported concerns regarding their decreased clinical skill training and specialty exposure on their career development due to the loss of in-person experience during their family medicine clerkship. A small number felt very let down and exploited by the continued high cost of tuition while missing clinical interactions. However, many students also expressed professional pride and derived meaning from limited patient and mentorship opportunities. Many students developed a new sense of purpose and a call to become stronger public health and patient advocates. CONCLUSIONS: The medical field will need to adapt to support medical students adversely impacted by the COVID-19 pandemic, from an educational and mental health standpoint. However, there are encouraging signs that this may also galvanize many students to engage in leadership roles in their communities, to become more empathetic and thoughtful physicians, and to redesign healthcare in the future to better meet the needs of their most vulnerable patients.

Self-harm in children and adolescents by ethnic group: an observational cohort study from the Multicentre Study of Self-Harm in England.

BACKGROUND: Studies report an increasing incidence of self-harm in children and adolescents, but the extent to which this is seen in different ethnic groups is unclear. We aimed to investigate rates of emergency department presentations for self-harm in children and adolescents by ethnicity, as well as to examine their demographic characteristics, clinical characteristics, and outcomes. METHODS: In this observational cohort study, we used data on hospital emergency department presentations for self-harm in children and adolescents aged 10-19 years between 2000 and 2016 from the Multicentre Study of Self-harm in England. This study collects data from five general hospitals in Manchester, Oxford, and Derby in the UK, and defines self-harm as any act of intentional self-injury or self-poisoning, regardless of intent. All children and adolescents aged 10-19 years for whom ethnicity data were available were included. Mortality follow-up was available through linkage with mortality records from the Office for National Statistics. Rates of self-harm over time, demographic and clinical characteristics, and self-harm methods were investigated by ethnic group. Risk of repeat self-harm and mortality following an initial presentation for self-harm was compared by ethnic group using Kaplan-Meier curves and Cox proportional hazards models. FINDINGS: Of 14 894 individuals who presented at hospitals with self-harm, 11 906 had data for ethnicity, of whom 10 211 (85·8%) were White, 344 (2·9%) were Black, 619 (5·2%) were South Asian, and 732 (6·1%) were other non-White. Rates of self-harm were highest in White children and adolescents but increased between 2009 and 2016 in all ethnicities. Mean annual rates of self-harm per 100 000 population were 574 for White, 225 for Black, 260 for South Asian, and 344 for other non-White groups. Increases in rates of self-harm between 2009 and 2016 appeared slightly greater in Black groups (incidence rate ratio 1·07 [95% CI 1·03-1·11]), South Asian groups (1·05 [1·01-1·09]), and other non-White groups (1·11 [1·06-1·16]) than in White groups (1·02 [1·00-1·03]). Children and adolescents from a minority ethnic background were more likely to live in areas of high deprivation and were less likely to receive a specialist psychosocial assessment than were White children and adolescents. Children and adolescents from minority ethnic groups were also less likely to repeat self-harm. However, there were no differences in suicide mortality by ethnic group, although the numbers were small. INTERPRETATION: Minority ethnic children and adolescents accounted for an increased proportion of self-harm presentations to hospital over time compared with White ethnic groups. The minority ethnic groups also tended to be more socioeconomically disadvantaged and were less likely to receive a psychosocial assessment. Socioeconomic disparities need to be addressed, and equitable access to culturally sensitive comprehensive psychosocial assessments must be ensured. FUNDING: UK Department of Health and Social Care.

Discovery of first-in-class inhibitors of ASH1L histone methyltransferase with anti-leukemic activity.

ASH1L histone methyltransferase plays a crucial role in the pathogenesis of different diseases, including acute leukemia. While ASH1L represents an attractive drug target, developing ASH1L inhibitors is challenging, as the catalytic SET domain adapts an inactive conformation with autoinhibitory loop blocking the access to the active site. Here, by applying fragment-based screening followed by medicinal chemistry and a structure-based design, we developed first-in-class small molecule inhibitors of the ASH1L SET domain. The crystal structures of ASH1L-inhibitor complexes reveal compound binding to the autoinhibitory loop region in the SET domain. When tested in MLL leukemia models, our lead compound, AS-99, blocks cell proliferation, induces apoptosis and differentiation, downregulates MLL fusion target genes, and reduces the leukemia burden in vivo. This work validates the ASH1L SET domain as a druggable target and provides a chemical probe to further study the biological functions of ASH1L as well as to develop therapeutic agents.

Self-harm and the COVID-19 pandemic: A study of factors contributing to self-harm during lockdown restrictions.

INTRODUCTION: The COVID-19 pandemic and resulting public health measures may have major impacts on mental health, including on self-harm. We have investigated what factors related to the pandemic influenced hospital presentations following self-harm during lockdown in England. METHOD: Mental health clinicians assessing individuals aged 18 years and over presenting to hospitals in Oxford and Derby following self-harm during the period March 23rd to May 17, 2020 recorded whether the self-harm was related to the impact of COVID-19 and, if so, what specific factors were relevant. These factors were organized into a classification scheme. Information was also collected on patients' demographic characteristics, method of self-harm and suicide intent. RESULTS: Of 228 patients assessed, in 46.9% (N = 107) COVID-19 and lockdown restrictions were identified as influencing self-harm. This applied more to females than males (53.5%, N = 68/127 v 38.6%, N = 39/101, χ2 = 5.03, p = 0.025), but there were no differences in age, methods of self-harm or suicide intent between the two groups. The most frequent COVID-related factors were mental health issues, including new and worsening disorders, and cessation or reduction of services (including absence of face-to-face support), isolation and loneliness, reduced contact with key individuals, disruption to normal routine, and entrapment. Multiple, often inter-connected COVID-related factors were identified in many patients. CONCLUSIONS: COVID-related factors were identified as influences in nearly half of individuals presenting to hospitals following self-harm in the period following introduction of lockdown restrictions. Females were particularly affected. The fact that mental health problems, including issues with delivery of care, predominated has implications for organisation of services during such periods. The contribution of isolation, loneliness and sense of entrapment highlight the need for relatives, friends and neighbours to be encouraged to reach out to others, especially those living alone. The classification of COVID-related factors can be used as an aide-memoire for clinicians.

Self-harm during the early period of the COVID-19 pandemic in England: Comparative trend analysis of hospital presentations.

BACKGROUND: The COVID-19 pandemic and public health measures necessary to address it may have major effects on mental health, including on self-harm. We have used well-established monitoring systems in two hospitals in England to investigate trends in self-harm presentations to hospitals during the early period of the pandemic. METHOD: Data collected in Oxford and Derby on patients aged 18 years and over who received a psychosocial assessment after presenting to the emergency departments following self-harm were used to compare trends during the three-month period following lockdown in the UK (23rd March 2020) to the period preceding lockdown and the equivalent period in 2019. RESULTS: During the 12 weeks following introduction of lockdown restrictions there was a large reduction in the number of self-harm presentations to hospitals by individuals aged 18 years and over compared to the pre-lockdown weeks in 2020 (mean weekly reduction of 13.5 (95% CI 5.6 - 21.4) and the equivalent period in 2019 (mean weekly reduction of 18.0 (95% CI 13.9 - 22.1). The reduction was greater in females than males, occurred in all age groups, with a larger reduction in presentations following self-poisoning than self-injury. CONCLUSIONS: A substantial decline in hospital presentations for self-harm occurred during the three months following the introduction of lockdown restrictions. Reasons could include a reduction in self-harm at the community level and individuals avoiding presenting to hospital following self-harm. Longer-term monitoring of self-harm behaviour during the pandemic is essential, together with efforts to encourage help-seeking and the modification of care provision.

Critical Race Theory as a Lens for Examining Primary Care Provider Responses to Persistently-Elevated HbA1c.

INTRODUCTION: Clinical inertia remains a persistent problem in the treatment of diabetes in clinical care. Primary care provider behavior is thought to be a significant contributor to diabetes clinical inertia. This study used the lens of Critical Race Theory to examine whether provider's diabetes management activities differ by patient race and frame implications for future research. METHODS: Chart abstractors retrospectively reviewed a random sample of charts from primary care patients with persistently-elevated HbA1c to assess providers' diabetes management activities in the subsequent year. Provider activities aligned with the American Diabetes Association's standards of medical care and included HbA1c test ordering, documentation of patient medication adherence, counseling on lifestyle modification, lifestyle modification referral, endocrinologist participation in care, and medication titration. Differences in provider actions by patient race (Black, white, or other) were examined using chi-square tests. RESULTS: A total of 188 patient charts were reviewed. For all provider actions, there were statistically-significant differences by patient race. Black patients were least likely to be counseled on dietary changes (72.0%) or physical activity (57.7%) by their primary care provider, but most likely to be referred to an outside specialist for this counseling (46.2%). Black patients were also least likely to have medication adjustments made (72%). DISCUSSION: Study findings showed an association between provider diabetes management behaviors and patient race, Future studies showed explore providers' racial beliefs, attitudes and clinical decision-making, and patients' experiences with historical exclusion from medical care and racism in healthcare encounters In addition, more research is needed to explore the role of structural racism in clinical inertia.

Organizational Readiness to Change: Quality Improvement in Family Medicine Residency.

INTRODUCTION: Primary care is evolving to meet greater demands for the inclusion of collaborative health care quality improvement (QI) processes at the practice level. Yet, data on organizational preparedness for change are limited. We assessed the feasibility of incorporating an organizational-level readiness-to-change tool that identifies factors relevant to QI implementation at the practice level impacting new family medicine physicians. METHODS: We assessed organizational readiness to change at the practice level among residents participating in a team-based QI training curriculum from April 2016 to April 2019. Seventy-six current and former residents annually completed the modified Organizational Readiness to Change Assessment (ORCA) survey. We evaluated QI and leadership readiness among five subscales: empowerment, management, QI, QI leadership (skills), and QI leadership (ability). We calculated mean survey scores and compared across all 3 years. Resident interviews captured unique perspectives and experiences with team-based activities. Qualitative analysis identified emergent themes. RESULTS: Residents completed 73 modified ORCA surveys (96% response rate). Compared to years 2016-2019, 2018 results were highest in mean negative responses for the QI subscale (24.62, SD 6.70). Four volunteers completed postsurvey interviews. Qualitative analysis identified issues concerning communication, team collaboration, practice site functioning, and survey relevance. CONCLUSIONS: Our study determined that miscommunication and practice site disruptions undermine organizational-level readiness to change, as measured by the ORCA tool which was part of a multimethod assessment included within a team-based QI training curriculum. Training programs undergoing curricula transformations may feasibly incorporate ORCA as a tool to identify impediments to collaborative practice and inform resource allocation important for enhancing physician training in QI leadership.

Development of humanized mouse and rat models with full-thickness human skin and autologous immune cells.

The human skin is a significant barrier for protection against pathogen transmission. Rodent models used to investigate human-specific pathogens that target the skin are generated by introducing human skin grafts to immunocompromised rodent strains. Infection-induced immunopathogenesis has been separately studied in humanized rodent models developed with human lymphoid tissue and hematopoietic stem cell transplants. Successful co-engraftment of human skin, autologous lymphoid tissues, and autologous immune cells in a rodent model has not yet been achieved, though it could provide a means of studying the human immune response to infection in the human skin. Here, we introduce the human Skin and Immune System (hSIS)-humanized NOD-scid IL2Rγnull (NSG) mouse and Sprague-Dawley-Rag2tm2hera Il2rγtm1hera (SRG) rat models, co-engrafted with human full-thickness fetal skin, autologous fetal lymphoid tissues, and autologous fetal liver-derived hematopoietic stem cells. hSIS-humanized rodents demonstrate the development of human full-thickness skin, along with autologous lymphoid tissues, and autologous immune cells. These models also support human skin infection following intradermal inoculation with community-associated methicillin-resistant Staphylococcus aureus. The co-engraftment of these human skin and immune system components into a single humanized rodent model could provide a platform for studying human skin infections.