Faculty Bibliography

OBJECTIVES/OBJECTIVE:The gut microbiome plays a crucial role in regulating systemic immunity and has been implicated in several chronic inflammatory diseases. Intestinal expansions of Ruminococcus gnavus (RG), a dominant gut commensal, correlate with disease flares in lupus nephritis (LN), but the underlying mechanism remains unknown. METHODS:In a Pilot cohort of patients with biopsy-proven LN, subsetted by gut microbiota community, immune status was characterised using bulk-blood RNA sequencing libraries, serum levels of representative host proteins, and levels of immunoglobulin (Ig)G antibodies to the novel lipoglycan (LG) produced by pathogenic RG strains. A Validation LN cohort was evaluated for blood transcriptomic profiles and levels of anti-LG antibodies. In murine models, mechanistic hypotheses were tested after RG gut colonisation or after intraperitoneal injection with an LG preparation, with outcomes determined by transcriptomic analyses, platelet functional readouts, and tissue histology. RESULTS:In a Pilot cohort of patients with LN, RG gut expansions were associated with high-level platelet, neutrophil, and monocyte activation. Serum levels of platelet factor 4 and release of neutrophil extracellular traps (NETs) were significantly higher in patients with high serum IgG antibody against the novel RG-specific LG, a marker of in vivo immune exposure. An LN Validation cohort confirmed these correlates and showed that anti-LG antibodies serve as a surrogate for thromboinflammatory profile in this LN-associated endotype. In mice, gut colonisation with LG-producing RG strains or a single LG injection caused megakaryocytosis and platelet activation; RG colonisation with LG-producing strains induced tubulointerstitial injury with NETosis. In vivo responses to LG toxin were Toll-like receptor 2-dependent. CONCLUSIONS:Gut expansions of the RG pathobiont may contribute to autoimmune pathogenesis through the LG toxin and cause LN flares through thromboinflammatory mechanisms in this previously unrecognised LN endotype.

OBJECTIVE:To develop, implement, and assess the utility of a standardized letter of evaluation (SLOE) for OBGYN residency applicants in the US. DESIGN/METHODS:OBGYN program directors (PDs) were surveyed over 2 consecutive years and asked to estimate the percentage of applicants submitting an SLOE and to indicate its helpfulness compared to traditional letters of recommendation. Sub-group analysis by program type was performed. In 2023, comments for improvement were collected and analyzed for themes using a large language model. SETTING/METHODS:OB/GYN residency programs in the United States. PARTICIPANTS/METHODS:OB/GYN PDs in the United States. RESULTS:The survey was completed by 254 of 293 (86.7%) of PDs in 2022 and 253/293 (86.3%) in 2023. From 2022 to 2023, there was no difference in the estimated percentage of applicants who submitted an SLOE to a program (median 50%-74%), though in 2023, university and combined university-community programs estimated receiving higher percentage of applicants submitting SLOEs compared to community and military programs (p < 0.001). Over the study period, the favorability of the SLOE improved, and feedback indicates a need for continued improvement in the SLOE process, including faculty development, standardization, and more honest assessment of applicants. CONCLUSIONS:An SLOE was submitted by most applicants to OBGYN residency programs. Iterative modification of the SLOE based on PD, applicant, and faculty advisor feedback is needed to assess its utility in the application process.

Breast cancer remains the second leading cause of cancer-related mortality among women, with triple-negative breast cancer (TNBC) exhibiting a particularly poor five-year prognosis. Here, we demonstrated that, among genetic and pharmacological perturbations targeting DNA replication, suppression of DNA polymerase epsilon (POLE) induced a potent, TNBC-specific gene expression signature enriched in inflammatory cytokines that are transcriptional targets of NF-κB. TNBC cells exhibited markedly higher levels of DNA damage and canonical NF-κB activation compared to luminal breast cancer cells. Notably, NF-κB activation in this context depended on the canonical component RELA but not the non-canonical component RELB. Mechanistically, ATM, STING, and RIG-I each contributed to NF-κB activation following POLE suppression. POLE suppression in an in vivo murine TNBC model led to cancer cell-intrinsic elimination of tumor burden and increased immune cell infiltration. Together, these findings support a model in which replication stress from POLE inhibition triggers robust NF-κB-mediated inflammation and immune microenvironment remodeling in TNBC and can independently trigger tumor eradication. These results suggest a potential therapeutic avenue for targeting POLE in TNBC.

Lymphatic vessels activate anti-tumor immune surveillance and support metastasis. Whether there are distinct lymphatic phenotypes that govern immunity and metastasis remains unclear. Here we reveal that cytotoxic immunity normalizes lymphatic function and uncouples immune and metastatic potential. We demonstrate that intratumoral lymphatic vessel density negatively correlates with cytotoxic immunity and that IFNγ reprograms the intratumoral lymphatic state. Lymphatic deletion of Ifngr1 expanded the intratumoral lymphatic network and drove the emergence of a tip-like state that promotes lymph node metastasis but not dendritic cell migration or response to immune checkpoint blockade (ICB). Mechanistically, IFNγ restrains proliferation and cell state programs through inhibition of mitochondrial respiration. Lymphatic-specific inhibition of mitochondrial complex III restrained the intratumoral tip-like state, blocked metastasis, and enhanced the response to ICB. Our data reveal that IFNγ induces a metabolic and phenotypic switch in tumor-associated lymphatic vessels that blocks regional metastasis and reinforces immune surveillance.

BACKGROUND:Delayed diagnosis of venous thromboembolism (VTE) is prevalent among hospitalized patients, yet case identification is challenging and feedback limited. OBJECTIVE:To develop a large language model (LLM)-based electronic-trigger to identify VTE diagnostic delays. METHODS:All admissions to internal medicine (IM) residents at NYU Langone Health between January 2022 and December 2023 (n = 20,843) were included. Using an open-source LLM, prompts were validated to detect (1) residents considering VTE in admission notes and (2) VTE confirmation in five types of imaging reports (n = 100 for each prompt validation set). The validated prompts were applied to determine discordance between admission note differential omitting VTE and imaging report confirming VTE. Two hospitalists reviewed discordant cases using a validated tool to identify diagnostic delays. Hospitalizations were labeled as diagnostic delays, in-hospital complication, or false-positive. Based on in-hospital complication and false-positive patterns, exclusion criteria were implemented. Positive predictive value (PPV) and negative predictive value (NPV) were calculated. RESULTS:The LLM prompts correctly classified admission notes and VTE imaging studies with high accuracy (range 98%-100%, n = 699 VTE cases identified). Of the 137 diagnostic delays the LLM-based electronic-trigger identified, 31 were true-positives, 60 in-hospital complications, and 46 false-positives. 4.4% of all VTE hospitalizations had a diagnostic delay. With the exclusion criteria, the PPV was 48% (95% confidence interval [CI], 35%-62%) and NPV was 95% (95% CI, 87%-98%). CONCLUSIONS:We developed the first LLM-based electronic-trigger to identify VTE diagnostic delays, with higher performance than existing non-LLM electronic-triggers. LLM-based approaches can facilitate diagnostic performance feedback and are scalable to other conditions and institutions.

PROBLEM/OBJECTIVE:Graduate medical education requires learners to acquire broad clinical exposures to meet core competencies for unsupervised practice, but variability in clinical learning environments and reliance on resource-intensive assessments hinder precise assessment of trainees' clinical experiences. Electronic health records hold promise for precision medical education, yet manual mapping of International Classification of Diseases, Tenth Revision (ICD-10) codes to specialty-specific clinical practice domains limits scalability. APPROACH/METHODS:The authors leveraged electronic health record data and artificial intelligence (AI) to map residents' encounter diagnoses to the American Board of Emergency Medicine's Model of the Clinical Practice of Emergency Medicine (MCPEM). Resident encounters across 3 sites at a single academic system (January 1 to October 31, 2023) were analyzed with an AI model, mapped to MCPEM categories with ICD-10 descriptors, and quantified with vectors to match to the closest MCPEM category. Faculty raters validated the most common mappings iteratively, which were subsequently integrated into interactive learner dashboards. OUTCOMES/RESULTS:Among 119,320 encounters, 5,960 unique ICD-10 descriptors (1,126 stem codes) were identified. For the 650 most common diagnoses, 507 (78.0%) of emergency department diagnosis text descriptors were determined as valid mappings to an MCPEM subcategory. In mappings where faculty were discordant with the lowest distance mapping, 171 of 305 alternative subcategory mappings (56.0%) achieved agreement, increasing the concordance between reviewers to 515 of 650 (79.2%) overall. Interactive dashboards displayed resident-level case mix mapped to MCPEM categories, with anonymized peer comparisons and program-level aggregates, enabling identification of patterns and gaps by domain. NEXT STEPS/CONCLUSIONS:Planned work includes iterating AI-automated mappings by expanding inputs beyond diagnoses, engaging wider stakeholder review of mapping validations, and assessing generalizability to other specialties' content outlines to produce a scalable and reproducible model to increase the precision of feedback loops to inform graduate medical education, the clinical learning environment, and training design.

Greater adherence to plant-based diets is associated with health benefits. Dietary intake can modify DNA methylation patterns, but it is unknown whether plant-based diets in a largely non-vegetarian population are associated with DNA methylation-based epigenetic aging measures. We examined the associations between 4 different types of plant-based diets indices (PDI) [overall PDI, provegetarian diet, healthy PDI, and unhealthy PDI] and epigenetic aging. We used data from the Atherosclerosis Risk in Communities (ARIC) Study (N=2,810) and National Health and Nutrition Examination Survey (NHANES, N=2,056). PDIs negatively scored higher intake of animal products and positively scored higher intake of all or selected plant foods (overall PDI and provegetarian diet), healthy plant foods (healthy PDI), and unhealthy plant foods (unhealthy PDI). Associations were examined with GrimAge version2, HannumAge, and PhenoAge in each study. Estimates were meta-analyzed using fixed effects model. Each standard deviation (SD) higher in the overall PDI, provegetarian diet, and healthy PDI was associated with decelerated GrimAge2 (range of β = -0.28 to -0.16, P for all tests <0.05). Higher overall PDI and provegetarian diet was associated with decelerated PhenoAge and HannumAge (overall PDI only). No significant association was observed for unhealthy PDI. Following diets rich in plant foods and low in animal products may slow biological aging.

BACKGROUND:Genetic determinants of resilience remain poorly defined beyond family studies. OBJECTIVES/OBJECTIVE:The purpose of this study was to perform an unbiased study of individuals with discordance between clinical/genetic risk and atherosclerotic burden to discover novel genetic pathways underpinning atherosclerosis. METHODS:We used 2 genotyped cohorts with well-defined coronary anatomy: PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) (discovery cohort: coronary computed tomography angiography) and CATHGEN (CATHeterization GENetics) (validation cohort: invasive angiography). Resilience was defined as high clinical and polygenic risk of coronary artery disease (CAD), yet without coronary plaque. Resilient individuals were compared to patients with obstructive CAD (oCAD) (stenosis ≥70%) using genome-wide association analyses at variant, gene, and pathway levels. RESULTS:In PROMISE (n = 605), 46 (8%) were resilient and 88 (15%) had oCAD. In CATHGEN (n = 3,236), 127 (4%) were resilient and 1,852 (57%) had oCAD. Clinical risk factors and polygenic risk scores were similar between resilient and oCAD patients in both cohorts. Variant- and gene-level analyses did not yield genome-wide significant signals. Pathway-level analyses identified 4 resilience-associated pathways in PROMISE that replicated in CATHGEN: adipocytokine signaling, fatty acid metabolism, fatty acid degradation, and vascular smooth muscle contraction. CONCLUSIONS:Resilience to CAD-defined as the absence of coronary atherosclerosis despite high clinical and polygenic risk-is present in both lower- (PROMISE) and higher-risk (CATHGEN) cohorts and is linked to protective variants in metabolic and vascular pathways. This unbiased, proof-of-concept approach reveals biologically plausible targets for replication and mechanistic studies in larger imaging-based genetics cohorts.

Characterizing the relationship between DNA methylation and circulating proteins is critical to understanding the epigenetic regulation of the human plasma proteome. Here, we performed an epigenome-wide association study (EWAS) of 5,032 circulating proteins in 1,449 White and 315 Black participants from the Atherosclerosis Risk in Communities (ARIC) cohort. We identified 12,500 significant protein quantitative trait methylation (pQTM)-protein associations involving 1,647 proteins. Among 7,796 unique pQTMs, 14.7% were classified as cis-pQTMs, which were enriched for fundamental cellular processes, whereas trans-pQTMs were predominantly linked to immune-related functions. Trans-pQTMs also exhibited stronger associations with demographic, lifestyle, and clinical traits compared with cis-pQTMs. We identified proteins such as GM2A and EPHB6 whose expression appears to be strongly associated with DNA methylation, suggesting potential as targets for epigenetic-based therapeutic interventions. Together, these findings demonstrate the extensive impact of DNA methylation on the circulating proteome through cis- and trans-regulatory mechanisms and underscore the influence of population-level traits on epigenetic regulation. These findings highlight a broad impact of DNA methylation on circulating proteins through both cis- and trans-regulatory mechanisms and the roles of population-level phenotypes.

IMPORTANCE/UNASSIGNED:Limited research exists on sex, racial, and ethnic disparities in required graduate medical education (GME) resident competency ratings across specialties during sensitive periods when career decision-making occurs. Rating disparities using an antideficit-based approach measured by exceptionally high ratings are underexplored in GME. OBJECTIVE/UNASSIGNED:To assess the association of exceptionally high ratings in the Accreditation Council for Graduate Medical Education (ACGME) Milestones during time-sensitive training periods across specialties with differences among residents' characteristics, including sex, race, and ethnicity. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This cross-sectional analysis was conducted between March 15 and December 31, 2025, using 2018 to 2021 Association of American Medical Colleges and ACGME data. Postgraduate year (PGY) 2 residents training at US ACGME-accredited emergency medicine, family medicine, internal medicine, obstetrics and gynecology, pediatrics, and surgery residency programs between 2018 and 2021 who self-reported sex, race, or ethnicity were studied. EXPOSURE/UNASSIGNED:Required Milestones ratings at the end of PGY-2 training associated with resident sex and race or ethnicity (underrepresented in medicine [URiM] and Asian), while controlling for preresidency Step 2 Clinical Knowledge examination scores. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Proportion and adjusted odds ratios (AORs) for exceptionally high resident-level ratings (80th percentile level) across competencies in interpersonal and communication skills, medical knowledge, patient care, practice-based learning and improvement, professionalism, and systems-based practice. RESULTS/UNASSIGNED:Among 19 492 PGY-2 residents across 1754 programs, 10 384 (53.3%) were female, 28 (0.14%) American Indian or Alaskan Native, 4327 (22.2%) Asian, 1106 (5.7%) Black, 1008 (5.2%) Hispanic or Latinx, 3 (0.02%) Native Hawaiian or Pacific Islander, 12 269 (62.9%) White, 751 (3.9%) reporting 2 or more races, and 3423 (17.6%) classified as URiM. Exceptional rating differences were identified by sex, race, and ethnicity. Across all specialties, female residents had greater odds for 80th percentile ratings (AOR, 1.12; 95% CI, 1.05-1.21; P < .001); whereas when compared with White residents, URiM residents (AOR, 0.68; 95% CI, 0.62-0.76; P < .001) and Asian residents (AOR, 0.67; 95% CI, 0.60-0.74; P < .001) were less likely to have 80th percentile ratings than White residents. Within specialties, URiM residents in emergency medicine, family medicine, internal medicine, obstetrics and gynecology, and surgery were less likely to have 80th percentile ratings, whereas Asian residents in family medicine, internal medicine, pediatrics, and surgery were also less likely than White residents. CONCLUSION AND RELEVANCE/UNASSIGNED:In this cross-sectional national study of residents, exceptionally higher ratings were associated with differing resident characteristics during crucial career planning phases. These results suggest the need for more studies to explore factors of resident success during GME training.