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.

BACKGROUND:Despite a high incidence of tracheostomy-related airway complications with potentially life-threatening implications, nonsurgical tracheostomy first-responders receive limited formal education on the management of tracheostomy emergencies. While the U.K. has developed multidisciplinary guidelines and education for tracheostomy emergencies, such programs have not been widely implemented in the United States. OBJECTIVE:We evaluated the feasibility and effectiveness of an immersive virtual reality (VR) simulation training as a potential generalizable and scalable approach to tracheostomy-related emergency training. METHODS:Over the academic year 2023-2024, critical care fellows were randomized to participate in tracheostomy emergency training either via immersive VR simulation or via small group discussion sessions facilitated by expert faculty. After each case-based educational intervention, participants were asked to manage four simulated tracheostomy-related emergencies involving common tracheostomy complications. Fellow performance was evaluated using a purpose-built task trainer. Three independent and blinded graders completed fellow scoring using a checklist assessment for which validation evidence was also collected. Fellows received pre- and post-intervention surveys to measure attitudes towards VR training. RESULTS:Nineteen out of 27 eligible fellows participated in the study, managing a total of 76 simulated tracheostomy emergencies. There were 10 fellows in the VR arm and 9 fellows in the Small Group arm. Out of a total possible 26 points on the checklist assessment, fellows in the VR group scored an average of 18.03 ± 3.39 compared to the Small Group score of 16.96 ± 4.41 (P = .558). Surveys indicated improvements in fellow confidence after the training and high levels of acceptance of the VR curriculum. CONCLUSIONS:An immersive VR educational intervention for the management of tracheostomy-related emergencies was feasible and well-received by learners. There was no significant difference in post-training checklist assessment scores between the VR and Small Group participants, suggesting non-inferiority of the VR intervention, and contributing validation evidence to our task trainer simulation assessment. FUNDING/BACKGROUND:This study was funded via the APCCMPD, CHEST, and ATS Education Research Award.

PURPOSE/UNASSIGNED:Understanding medical students' readiness to perform basic entrustable professional activities (EPAs) informs tailored support during transition to residency. METHODS/UNASSIGNED:Night-onCall (NOC) was developed to assess medical student readiness to perform core EPAs on day one of internship. NOC is a complex, integrated simulation centered around three clinical cases. Assessments include standardized patient (SP), nurse (SN), physician attending (SA), and resident (SR) perspectives using clinical competency rating instruments mapped to EPAs and scored as Well Done (WD), Partly Done (PD) or Not Done (ND). Faculty rate clinical reasoning using a rubric evaluating written post-encounter notes as poor, beginning, competent, or strong. The ability to recognize lapses in patient safety is assessed based on written case responses. Medical librarians evaluate students' ability to formulate a clinical question and search for evidence. RESULTS/UNASSIGNED:Data was collected from 'near-graduates' from seven USA medical schools from 2020 to 2023 (n = 1116). Overall, SPs rated 75.0% of overall communication skills and only 56% of patient education items as WD. SNs rated interprofessional communication 57.0% WD, and SRs rated intraprofessional communication 61.0% WD. History gathering and physical exam skills varied by case. Faculty rated clinical reasoning as beginning (45%) or competent (44%) and librarians rated 16% of literature searches as WD. CONCLUSION/UNASSIGNED:Most near-graduates demonstrated competent basic patient communication skills but performed less well on patient education, communication with other team members, clinical reasoning, and accessing the evidence base to answer clinical questions. These overall trends, consistent across schools and year, provide benchmarks for clinical training.

The 2025 World Allergy Organization (WAO) Guidelines for the Classification, Diagnosis, and Treatment of Hereditary Angioedema (HAE) with Consideration of Worldwide Disparities provide a comprehensive, evidence-informed, and globally applicable framework for the care of this rare and potentially life-threatening disorder. HAE is a genetic disease characterized by recurrent episodes of subcutaneous and submucosal swelling, most commonly mediated by bradykinin, and is associated with substantial morbidity, impaired quality of life, and a lifelong risk of fatal laryngeal edema. The Guidelines were developed by an international panel of 40 experts from 22 countries, with representation from all world regions, reflecting the commitment of WAO to geographic diversity, inclusiveness, and global relevance. The development process for these guidelines followed a structured and transparent methodology that integrated systematic literature review, appraisal of real-world evidence, and application of the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework adapted for rare diseases, complemented by a formal Delphi consensus process. This approach was specifically designed to address the limitations of conventional evidence hierarchies in rare disorders, while ensuring clinical applicability across heterogeneous healthcare systems and resource settings. A central element of the guidelines is an updated classification of HAE based on underlying pathophysiology and disease endotypes. The traditional distinction between HAE types 1 and 2 is unified under the term HAE with C1 inhibitor deficiency (HAE-C1-INH), reflecting shared biological mechanisms and management principles. The guidelines also recognize an expanding spectrum of HAE with normal C1 inhibitor (HAE-nC1-INH), including forms associated with pathogenic variants in F12, PLG, ANGPT1, KNG1, MYOF, HS3ST6, CPN1, and DAB2IP, as well as cases with currently unidentified genetic causes. The diagnostic strategy emphasizes early clinical recognition based on characteristic features, including recurrent angioedema without urticaria, abdominal or laryngeal involvement, early symptom onset, and family history. A simplified diagnostic algorithm is proposed, prioritizing the C1 inhibitor functional assay as the preferred initial test when performed in a reliable specialized laboratory. Alternative diagnostic pathways are outlined for settings with limited access to specialized testing, including pragmatic combinations of biochemical assays and selective use of genetic testing, particularly relevant for HAE-nC1-INH and family screening. Management recommendations address on-demand treatment of acute attacks, short-term prophylaxis, and individualized long-term prophylaxis. Universal access to on-demand therapy is emphasized for all patients with confirmed HAE, including those who are asymptomatic, given the unpredictable nature of attacks and lifelong risk. Long-term prophylaxis is addressed within a treat-to-target framework aimed at achieving complete disease control and sustained improvement in health-related quality of life, with regular reassessment and shared decision-making. Empowering patients and caregivers through structured education, access to appropriate medications, and integration with specialized referral centers is associated with earlier treatment, reduced healthcare utilization, and improved equity of care and reduced avoidable morbidity and mortality worldwide. The 2025 WAO Guidelines for Hereditary Angioedema establish an evidence-informed, patient-centered, and forward-looking framework for the classification, diagnosis, and management of HAE. By integrating advances in pathophysiology, diagnostics, and therapeutics with global expert consensus and real-world considerations, the guidelines aim to support consistent, equitable, and high-quality care for patients with HAE across regions and healthcare systems.

Endoscopic ultrasound (EUS) guided ablation is an evolving minimally invasive approach for treating pancreatic lesions. While current guidelines do not yet recommend routine use, EUS ablation offers targeted, organ-sparing therapy that bridges the gap between surveillance and surgical resection. Techniques are evolving but data is available for ethanol ablation, intralesional chemoablation, radiofrequency ablation, among many others. For pancreatic cystic lesions and neuroendocrine tumors, EUS ablation achieves promising complete and partial response rates and favorable safety profile. Early studies in unresectable pancreatic adenocarcinoma show technical feasibility, safety, and potential synergy with systemic therapy. This review summarizes the current literature on EUS-guided ablation, highlighting clinical outcomes, limitations, and techniques, while emphasizing the need for further research to define optimal patient selection and long-term efficacy.

BACKGROUND:Timely transport of critically injured patients by Emergency Medical Services to verified trauma centers significantly reduces morbidity and mortality. Prior studies demonstrate that undertriage in the prehospital setting impacts outcomes, with rural communities facing additional geographic and systemic barriers to timely trauma care. The area deprivation index, a validated measure of neighborhood-level socioeconomic disadvantage, is associated with poorer health outcomes and may further influence access to trauma centers. Yet, the association between socioeconomic deprivation, rurality, and trauma center transport remains poorly defined. This study aimed to evaluate the extent of urban-rural inequities in Emergency Medical Services transport of critically injured patients to verified trauma centers across all regions of the United States and to assess the association between area deprivation index and likelihood of transport to a trauma center. METHODS:We identified all Emergency Medical Services transported critically injured patients meeting Centers for Disease Control and Prevention field triage criteria for trauma center transport in the National Emergency Medical Services Information System from 2018 to 2022 and mapped Zone Improvement Plan (ZIP) Codes containing verified trauma centers (Levels I-V) using data from the American College of Surgeons, the Trauma Center Association of America, and the American Trauma Society. The cohort was stratified by regions in the United States: Northeast, Midwest, South, and West. The incident scene area deprivation index was obtained from the Neighborhood Atlas at the census block group level. The total number and percentage of patients located in urban and rural Zone Improvement Plan (ZIP) codes transported either to a confirmed trauma center (via the National Emergency Medical Services Information System data) or to a Zone Improvement Plan (ZIP) code that contains a trauma center and the area deprivation index distribution in tertiles (low area deprivation index, moderate area deprivation index, and high area deprivation index) within regions in the United States were calculated with their statistical significance derived from t tests and analyses of variance with post hoc Tukey tests. RESULTS:A total of 36,897,269 critically injured patients met the inclusion criteria, of which 19,874,008 (53.86%) were brought to a trauma center. When stratified by rurality, 7,608,704 (54.01%) and 12,265,304 (53.77%) of critically injured patients within rural and urban areas, respectively, were transported to a trauma center. When comparing across regions, the Northeast region of the United States had the lowest percentage of critically injured patients being transported to a trauma center, whereas the Midwest region had the highest percentage (44.04% vs 67.40%; P < .001). When stratified by rurality, 35.33% vs 46.92% of critically injured patients within rural versus urban areas of the Northeast were transported to a trauma center, whereas 65.47% vs 68.57% of critically injured patients within rural versus urban areas of the Midwest were transported to a trauma center (P < .001). When evaluating area deprivation index, critically injured patients who were injured in more disadvantaged versus advantaged Zone Improvement Plan (ZIP) codes had a higher percentage of patients being transported to a trauma center even when controlling for rurality (56% vs 47%; P < .001). CONCLUSION/CONCLUSIONS:Substantial geographic inequities in the Emergency Medical Services transport of critically injured adult patients to verified trauma centers, varied by geographic region, rurality, and neighborhood-level socioeconomic disadvantage that exist. These findings highlight the complex and regionally variable landscape of trauma access in the United States and underscore the need for targeted, equity-focused strategies to optimize prehospital triage and ensure timely, trauma-informed care across diverse communities.

BACKGROUND:Epigenetic modification of the APOL1 gene carrying risk alleles (G1 and G2) may represent a therapeutic strategy for APOL1-related kidney diseases. However, DNA methylation changes associated with APOL1 have not been thoroughly characterized. METHODS:) and with urine albumin-to-creatinine ratio (ACR). Methylation patterns were additionally assessed for differentially methylated regions and associations with kidney function. We further evaluated whether APOL1 risk-associated CpGs can modulate the relationship between APOL1 risk alleles and kidney function measures. RESULTS:and ACR. APOL1 risk-associated CpGs showed significant interactions with APOL1 risk alleles in relation to kidney function. CONCLUSION/CONCLUSIONS:APOL1 risk alleles are associated with complex DNA methylation alterations across the APOL1-APOL4-MYH9 region, potentially regulating multiple genes within this locus. APOL1 risk-associated CpGs may represent therapeutic targets for APOL1-related kidney diseases.

INTRODUCTION/UNASSIGNED:Platelet hyperreactivity is linked to inflammation and cardiovascular risk in nonpregnant populations, but its relationship to placentally mediated pregnancy outcomes is undefined. We prospectively evaluated platelet hyperreactivity in pregnancy and subsequent ischemic placental disease (IPD), and examined aspirin's (ASA) effect on platelet activity by baseline platelet phenotype. METHODS/UNASSIGNED: RESULTS/UNASSIGNED:Of 66 pregnant participants recruited, 61 had first-trimester LTA; 20 (32.8%) had platelet hyperreactivity. Participants with hyperreactivity were more likely to develop IPD than those without (55% versus 24%, adjusted odds ratio [aOR] 3.77 (95% CI [1.05-13.53]), with consistent directionality across individual components despite low event frequencies. Participants with platelet hyperreactivity showed greater platelet aggregation to ADP, collagen, and low-dose AA. Platelet transcriptomic profiling distinguished participants with versus without platelet hyperreactivity and revealed differential expression of pathways related to platelet activity, energy metabolism, and immune regulation. Among 45 high-risk participants recommended ASA, those with hyperreactivity exhibited higher AA-induced aggregation (24% vs 12.5% platelet aggregation, p=0.01) despite similar serum TxB2 levels. CONCLUSION/UNASSIGNED:First-trimester platelet hyperreactivity was present in approximately one-third of participants and was independently associated with increased risk of IPD. Participants with platelet hyperreactivity demonstrated distinct transcriptomic signatures and greater platelet aggregation despite ASA use. Together, these findings support a contributory role for platelets in placental ischemic pathology and highlight the need to elucidate mechanisms and develop platelet-targeted preventive strategies.

Treatment selection in breast cancer is guided by risk assessment using molecular subtypes and clinicopathological characteristics. However, current approaches lack the precision required for optimal clinical decision-making. To address this, we use data from 8161 patients to develop and evaluate an AI test integrating digital pathology with clinical data. The AI test provides a robust method for predicting disease-free interval (C-index: 0.71 [0.68-0.75], HR: 3.63 [3.02-4.37, p < 0.001]). In a direct comparison, the AI test displays numerically higher discrimination (C-index: 0.67 [0.61-0.74]) than the standard-of-care 21-gene assay (C-index: 0.61 [0.49-0.73]). Across molecular subtypes, the AI test demonstrates robust prognostic performance, including in triple negative breast cancer (C-index: 0.71 [0.62-0.81], HR: 3.81 [2.35-6.17, p=0.02]), where no guideline-recommended assays currently exist. These findings highlight the potential of AI-based pathology tests as a promising tool for improved risk stratification across all major subtypes, with implications for clinical decision-making.