Faculty Bibliography

OBJECTIVE:Platelets are mediators of inflammation with immune effector cell properties, and have been implicated in the pathogenesis of systemic lupus erythematosus (SLE). This study investigated the role of platelet associated lectin galactoside-binding soluble 3 binding protein (LGALS3BP) as a mediator of inflammation in SLE, and a potential biomarker associated with clinical phenotypes. METHODS:We performed RNA sequencing on platelets of patients with SLE (n=54) and age, sex, and race-matched controls (n=18) and measured LGALS3BP in platelet releasate and in circulating serum. We investigated the association between levels of LGALS3BP with the prevalence, disease severity, and clinical phenotpyes of SLE, and studied platelet-mediated effects on myeloid inflammation. RESULTS:). Platelet-released LGALS3BP was highly correlated with circulating LGALS3BP (R = 0.69, p < 0.0001). Circulating LGALS3BP correlated with the SLE disease activity index (R = 0.32, p = 0.0006). Specifically, circulating LGALS3BP was higher in SLE patients with lupus nephritis than those with inactive disease (4.0 μg/mL vs 2.3 μg/mL, P < 0.001). IFN-α induced LGALS3BP transcription and translation in a megakaryoblastic cell line (MEG-01) cells in a dose-dependent manner. Recombinant LGALS3BP and platelet releasates from SLE patients enhanced pro-inflammatory cytokine production by macrophages. CONCLUSIONS:These data support that platelets act as potent effector cells contributing to the pathogenesis of SLE by secreting proinflammatory LGALS3BP, which also represents a novel biomarker of SLE clinical activity.

BACKGROUND:The clinical heterogeneity of SLE with its complex pathogenesis remains challenging as we strive to provide optimal management. The contribution of platelets to endovascular homeostasis, inflammation and immune regulation highlights their potential importance in SLE. Prior work from our group showed that the Fcγ receptor type IIa (FcγRIIa)-R/H131 biallelic polymorphism is associated with increased platelet activity and cardiovascular risk in SLE. The study was initiated to investigate the platelet transcriptome in patients with SLE and evaluate its association across FcγRIIa genotypes and distinct clinical features. METHODS:Fifty-one patients fulfilling established criteria for SLE (mean age = 41.1 ± 12.3, 100% female, 45% Hispanic, 24% black, 22% Asian, 51% white, mean SLEDAI = 4.4 ± 4.2 at baseline) were enrolled and compared with 18 demographically matched control samples. The FCGR2a receptor was genotyped for each sample, and RNA-seq was performed on isolated, leukocyte-depleted platelets. Transcriptomic data were used to create a modular landscape to explore the differences between SLE patients and controls and various clinical parameters in the context of FCGR2a genotypes. RESULTS:There were 2290 differentially expressed genes enriched for pathways involved in interferon signaling, immune activation, and coagulation when comparing SLE samples vs controls. When analyzing patients with proteinuria, modules associated with oxidative phosphorylation and platelet activity were unexpectedly decreased. Furthermore, genes that were increased in SLE and in patients with proteinuria were enriched for immune effector processes, while genes increased in SLE but decreased in proteinuria were enriched for coagulation and cell adhesion. A low-binding FCG2Ra allele (R131) was associated with decreases in FCR activation, which further correlated with increases in platelet and immune activation pathways. Finally, we were able to create a transcriptomic signature of clinically active disease that performed significantly well in discerning SLE patients with active clinical disease form those with inactive clinical disease. CONCLUSIONS:In aggregate, these data demonstrate the platelet transcriptome provides insight into lupus pathogenesis and disease activity, and shows potential use as means of assessing this complex disease using a liquid biopsy.

To maintain blood homeostasis, millions of terminally differentiated effector cells are produced every day. At the apex of this massive and constant blood production lie hematopoietic stem cells (HSCs), a rare cell type harboring unique self-renewal and multipotent properties. A key feature of HSCs is their ability to temporarily exit the cell cycle in a state termed quiescence. Defective control of cell cycle progression can eventually lead to bone marrow failure or malignant transformation. Recent work in embryonic stem cells has suggested that cells can more robustly respond to differentiation cues in the early phases of the cell cycle, owing to a discrete chromatin state permissive to cell fate commitment. However, the molecular mechanisms tying cell cycle re-entry to cell fate commitment in adult stem cells such as HSCs remain elusive. Here, we report that the chromatin-associated Sin3B protein is necessary for HSCs' commitment to differentiation, but dispensable for their self-renewal or survival. Transcriptional profiling of hematopoietic stem and progenitor cells (HSPCs) genetically inactivated for Sin3B at the single cell level reveals aberrant cell cycle gene expression, correlating with the defective engagement of discrete signaling programs. In particular, the loss of Sin3B in the hematopoietic compartment results in aberrant expression of cell adhesion molecules and essential components of the interferon signaling cascade in LT-HSCs. Finally, chromatin accessibility profiling in LT-HSCs suggests a link between Sin3B-dependent cell cycle progression and priming of hematopoietic stem cells for differentiation. Together, these results point to controlled progression through the G1 phase of the cell cycle as a likely regulator of HSC lineage commitment through the modulation of chromatin features.

PROBLEM/OBJECTIVE:Residency program directors use clerkship grades for high-stakes selection decisions despite substantial variability in grading systems and distributions. The authors apply clustering techniques from data science to identify groups of schools for which grading distributions were statistically similar in the internal medicine clerkship. APPROACH/METHODS:Grading systems (e.g., honors/pass/fail) and distributions (i.e., percent of students in each grade tier) were tabulated for the internal medicine clerkship at U.S. MD-granting medical schools by manually reviewing Medical Student Performance Evaluations (MSPEs) in the 2019 and 2020 residency application cycles. Grading distributions were analyzed using k-means cluster analysis, with the optimal number of clusters selected using model fit indices. OUTCOMES/RESULTS:Among the 145 medical schools with available MSPE data, 64 distinct grading systems were reported. Among the 135 schools reporting a grading distribution, the median percent of students receiving the highest and lowest tier grade was 32% (range: 2%-66%) and 2% (range: 0%-91%), respectively. Four clusters was the most optimal solution (η2 = 0.8): cluster 1 (45% [highest grade tier]-45% [middle tier]-10% [lowest tier], n = 64 [47%] schools), cluster 2 (25%-30%-45%, n = 40 [30%] schools), cluster 3 (20%-75%-5%, n = 25 [19%] schools), and cluster 4 (15%-25%-25%-25%-10%, n = 6 [4%] schools). The findings suggest internal medicine clerkship grading systems may be more comparable across institutions than previously thought. NEXT STEPS/CONCLUSIONS:The authors will prospectively review reported clerkship grading approaches across additional specialties and are conducting a mixed-methods analysis, incorporating a sequential explanatory model, to interview stakeholder groups on the use of the patterns identified.

Background/Objective: A growing number of biomedical doctoral graduates are entering the biotechnology and industry workforce, though most lack training in business practice. Entrepreneurs can benefit from venture creation and commercialization training that is largely absent from standard biomedical educational curricula. The NYU Biomedical Entrepreneurship Educational Program (BEEP) seeks to fill this training gap to prepare and motivate biomedical entrepreneurs to develop an entrepreneurial skill set, thus accelerating the pace of innovation in technology and business ventures. Methods: The NYU BEEP Model was developed and implemented with funding from NIDDK and NCATS. The program consists of a core introductory course, topic-based interdisciplinary workshops, venture challenges, on-line modules, and mentorship from experts. Here, we evaluate the efficacy of the core, introductory course, Foundations of Biomedical Startups, through the use of pre/post-course surveys and free-response answers. Results: After 2 years, 153 participants (26% doctoral students, 23% post-doctoral PhDs, 20% faculty, 16% research staff, 15% other) have completed the course. Evaluation data show self-assessed knowledge gain in all domains. The percentage of students rating themselves as either competent or on the way to being an expert in all areas was significantly higher post-course (P < 0.05). In each content area, the percentages of participants rating themselves as very interested increased post-course. 95% of those surveyed reported the course met its objectives, and 95% reported a higher likelihood of pursuing commercialization of discoveries post-course. Conclusion: NYU BEEP can serve as a model to develop similar curricula/programs to enhance entrepreneurial activity of early-stage researchers.

The transition from medical student to resident is a pivotal step in the medical education continuum. For applicants, successfully obtaining a residency position is the actualization of a dream after years of training and has life-changing professional and financial implications. These high stakes contribute to a residency application and Match process in the United States that is increasingly complex and dysfunctional, and that does not effectively serve applicants, residency programs, or the public good. In July 2020, the Coalition for Physician Accountability (Coalition) formed the Undergraduate Medical Education-Graduate Medical Education Review Committee (UGRC) to critically assess the overall transition to residency and offer recommendations to solve the growing challenges in the system. In this Invited Commentary, the authors reflect on their experience as the trainee representatives on the UGRC. They emphasize the importance of trainee advocacy in medical education change efforts; reflect on opportunities, concerns, and tensions with the final UGRC recommendations (released in August 2021); discuss factors that may constrain implementation; and call for the medical education community-and the Coalition member organizations in particular-to accelerate fully implementing the UGRC recommendations. By seizing the momentum created by the UGRC, the medical education community can create a reimagined transition to residency that reshapes its approach to training a more diverse, competent, and growth-oriented physician workforce.

The transition from undergraduate medical education (UME) to graduate medical education (GME) constitutes a complex system with important implications for learner progression and patient safety. The transition is currently dysfunctional, requiring students and residency programs to spend significant time, money, and energy on the process. Applications and interviews continue to increase despite stable match rates. Although many in the medical community acknowledge the problems with the UME-GME transition and learners have called for prompt action to address these concerns, the underlying causes are complex and have defied easy fixes. This article describes the work of the Coalition for Physician Accountability's Undergraduate Medical Education to Graduate Medical Education Review Committee (UGRC) to apply a quality improvement approach and systems thinking to explore the underlying causes of dysfunction in the UME-GME transition. The UGRC performed a root cause analysis using the 5 whys and an Ishikawa (or fishbone) diagram to deeply explore problems in the UME-GME transition. The root causes of problems identified include culture, costs and limited resources, bias, systems, lack of standards, and lack of alignment. Using the principles of systems thinking (components, connections, and purpose), the UGRC considered interactions among the root causes and developed recommendations to improve the UME-GME transition. Several of the UGRC's recommendations stemming from this work are explained. Sustained monitoring will be necessary to ensure interventions move the process forward to better serve applicants, programs, and the public good.

INTRODUCTION/BACKGROUND:Enteric infection with Clostridioides difficile , Escherichia coli subtypes, and norovirus is commonly detected in flares of inflammatory bowel disease (IBD). We associated the gut microbiome during flare complicated by a gastrointestinal pathogen with outcomes of IBD. METHODS:We performed a cross-sectional study of 260 patients (92 IBD and 168 non-IBD) with a gastrointestinal polymerase chain reaction panel positive for C. difficile, E. coli , or norovirus, or negative during an episode of diarrhea from 2018 to 2020, and 25 healthy controls. Clinical variables, IBD status, and 2-year outcomes were collected. Using 16S rRNA sequencing, we measured the effect size of the gut microbiome on IBD characteristics and outcomes. RESULTS:There were major differences in the gut microbiome between patients with and without a pathogen and IBD. In IBD, a higher proportion of patients without a pathogen required hospitalization and IBD therapies at flare and within the 2 years after flare, driven by a milder disease course in flares complicated by an E. coli subtype or norovirus. Examining the contribution of clinical covariates, the presence of IBD, and C-reactive protein, C. difficile had a greater relative influence on the gut microbiome compared with the presence of an E. coli subtype or norovirus. In patients with C. difficile or no pathogen, lower microbiome diversity at flare was associated with adverse IBD outcomes over 2 years. DISCUSSION/CONCLUSIONS:Distinctive pathogen-specific gut microbiomes were associated with subsequent IBD outcomes. These findings may have direct implications for the management of IBD flares complicated by enteric pathogens.