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.

INTRODUCTION/BACKGROUND:Management of relapsed mantle cell lymphoma (MCL) has included Bruton's tyrosine kinase (BTK) inhibitors for more than 10 years, but finding an optimal combination partner that meaningfully improves outcomes while limiting toxicity has been difficult. We conducted a phase 1/2 trial of ibrutinib and the proteasome inhibitor, ixazomib, in patients with relapsed/refractory MCL. PATIENTS AND METHODS/METHODS:Patients and Methods: The primary endpoint for the phase 1 study was to determine the recommended phase 2 dose (RP2D), and for the phase 2 study was the complete response (CR) rate, compared with the previously reported single-agent CR rate of ibrutinib. After the phase 1 portion of the study identified a recommended phase 2 dose of ixazomib 4 mg days 1, 8, and 15, of a 28-day cycle combined with ibrutinib 560 mg daily until progression or unacceptable toxicity. RESULTS:We enrolled 35 BTK-naïve patients to the phase 2 portion of the study. Overall response rate was 77%, and 37% of patients achieved a CR. The 2-year progression-free survival is 44%, and the duration of response is 47%. Treatment-related adverse events were common, resulting in treatment discontinuation for 37% of patients. CONCLUSION/CONCLUSIONS:Given that the progression-free survival (PFS) was not significantly improved compared to historical reports for single-agent BTK inhibitors and the high rate of treatment-related toxicity, this combination does not merit further study in this setting. Additional trials evaluating newer BTK inhibitors and alternative combination partners are warranted.

BACKGROUND/UNASSIGNED:Patients with pulmonary hypertension (PH) have previously experienced worse waitlist outcomes than peers with other diagnoses. In 2021, the Lung Allocation Score (LAS) was revised to improve the prediction of expected survival. The Composite Allocation Score (CAS) was subsequently implemented in 2023. The effects of these changes on waitlist outcomes for patients with PH are not known. METHODS/UNASSIGNED:A retrospective analysis of the United Network for Organ Sharing database was performed in 3 eras: LAS Era 1 (November 24, 2017-September 30, 2021), LAS Era 2 (October 1, 2021-March 8, 2023), and CAS Era (March 9, 2023-June 27, 2024). Unadjusted and adjusted competing risks regression analyzed waitlist outcomes within each era comparing diagnosis groups, and for PH patients across eras. RESULTS/UNASSIGNED:Adjusted waitlist mortality for PH patients was worse relative to chronic obstructive pulmonary disease (COPD) and cystic fibrosis in LAS Era 1, not significantly different from other groups in LAS Era 2, and worse relative to COPD and interstitial lung disease in the CAS Era. Waitlist mortality for PH patients was unchanged between the LAS Eras and the CAS Era. Transplantation rate for PH patients was improved in the CAS Era compared to LAS Era 2, when measures of right heart dysfunction were removed from the LAS calculations, but not compared to LAS Era 1. CONCLUSION/UNASSIGNED:In the CAS Era, PH patients continue to experience increased waitlist mortality relative to non-PH diagnoses. Waitlist mortality for PH patients has not improved in the CAS Era compared to the LAS Eras.

BACKGROUND:Early detection of oral potentially malignant disorders and oral cavity cancer can improve patient prognosis. The guideline panel addressed the use of cytology adjuncts to screen adults without mucosal abnormalities and determine the need for biopsy among adults with mucosal abnormalities. TYPES OF STUDIES REVIEWED/METHODS:The guideline panel used the Grading of Recommendations Assessment, Development and Evaluation Evidence to Decision framework to formulate recommendations. The authors conducted reviews to assess the benefits and harms of cytology adjuncts and people and clinician values and preferences as they relate to adjunct tests and biopsy of mucosal abnormalities. As part of the framework, the panel also considered resources required, equity, acceptability, and feasibility when formulating recommendations. RESULTS:The panel formulated 3 recommendations and 3 good practice statements. For adults with and without mucosal abnormalities, they formulated conditional recommendations against cytology adjuncts. Their use should be reserved for specific circumstances among adults with mucosal abnormalities when a biopsy is not possible or indicated. In the good practice statements, clinicians are urged to perform a clinical oral examination in all adult patients. CONCLUSIONS AND PRACTICAL IMPLICATIONS/CONCLUSIONS:Biopsy remains the first choice for reaching a definitive diagnosis of an oral potentially malignant disorder and oral squamous cell carcinoma, and cytology adjuncts should be reserved for specific situations when the clinician and patient agree it is the best course of action. When implementing or adapting these recommendations, local contexts should be considered to ensure equitable access to early detection.

Infection is a common indication and complication for extracorporeal membrane oxygenation (ECMO), and adult ECMO recipients face increased nosocomial infection risk. Effective antimicrobial dosing in these patients remains difficult due to pharmacokinetic (PK) and pharmacodynamic (PD) alterations driven by critical illness and extracorporeal circuits. In this narrative review we aim to discuss the potential impact of ECMO on antimicrobial PK and dosing requirements. Findings across studies show heterogeneity in dosing practices and indicate that inter-patient variability is influenced more by critical illness and organ dysfunction than ECMO alone. Standardized dosing protocols remain lacking, and in the absence of robust guidelines, current best practice involves applying PK/PD principles, using therapeutic drug monitoring, and individualizing dosing strategies. Across all antimicrobial drug classes, robust prospective studies linking PK/PD targets to clinical outcomes are lacking. Future research should focus on prospective trials correlating dosing regimens with meaningful clinical endpoints to refine evidence-based antimicrobial guidance. These efforts are essential to developing evidence-based dosing recommendations and optimizing antimicrobial stewardship in this high-risk population.

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.

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.

Primary graft dysfunction (PGD) is a proinflammatory syndrome occurring within the first days following lung transplantation. It is initiated by ischemia-reperfusion injury and perpetuated by donor and recipient immunologic factors, resulting in alveolar damage and progressive hypoxemic respiratory failure.¹ PGD is a known risk factor for both early allograft failure and chronic lung allograft dysfunction (CLAD).² Incidence of severe PGD remains high at 10-25%, though is variable; risk factors for PGD include center experience, underlying recipient disease type, size matching, donor lung storage conditions, operative time, and post-operative management.² Strategies to prevent PGD or mitigate the long -term consequences after it develops, are sorely needed. However, lack of specificity of the current PGD definition may hamper further progress in the field, especially as it pertains to the development of robust and relevant clinical trials. We propose that future modifications of the PGD definition incorporate more objective surrogates of allograft injury and subsequent diffuse alveolar damage, which may improve our ability to accurately study disease pathogenesis and improve outcomes.

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:Although germline genetic testing can inform medical management for patients with prostate cancer (PCa), data are limited regarding patient-reported outcomes (PROs) after germline genetic testing for PCa. Recall and comprehension of germline genetic testing results, uptake of post-test clinical recommendations, and psychological impact of germline genetic testing among patients with PCa were evaluated. METHODS:This is a secondary analysis of data from the PROCLAIM trial. PROs were analyzed overall and by germline genetic testing results. Differences between groups were determined by two-tailed Fisher's exact test with significance set at p < 0.05. RESULTS:Among 494 patients with informative survey responses, 60% and 71% accurately recalled and interpreted their germline genetic testing results, respectively, with the highest rates among patients with negative results and the lowest among those with variant of uncertain significance-only (VUS) results. Among 42/55 (76%) patients with positive results for whom clinicians made germline genetic testing-informed recommendations, 39 (93%) completed or planned to complete >1 clinical recommendation. Conversely, no further recommendations were made for 160/221 (72%) and 211/218 (97%) patients with VUS and negative results, respectively. However, 57% (213/371) of these patients indicated that they or their family members intended to pursue clinical management strategies that were not recommended by their clinicians. Of the patients who responded to the survey, >90% of patients reported no post-germline genetic testing increase in their level of concern for themselves or their family members. CONCLUSION/CONCLUSIONS:germline genetic testing for patients with PCa did not cause appreciable psychological harm to the tested patients. Furthermore, patients with positive results had a high uptake of clinician-recommended management strategies. Of note, there were inconsistencies in the understanding of VUS results, with some clinicians making recommendations not warranted by personal/family history; conversely, some patients pursued management strategies not recommended by their clinicians. This suggests that educational efforts are needed in the communication of germline genetic testing results and clinical recommendations to patients.