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.

PURPOSE/OBJECTIVE:To develop Trainee Attributable & Automatable Care Evaluations in Real‑Time (TRACERs) for inpatient diabetes management, collect validity evidence for their use in formative assessment, and explore performance variation across residents and institutions. METHOD/METHODS:In 2023, a multi‑institutional team created two TRACERs based on type 2 diabetes guidelines-discourage bolus‑only insulin (TRACER #1) and encourage basal (± bolus) insulin (TRACER #2)-for internal medicine residents at three large residency programs. Residents were attributed to inpatient admissions based on placing the most medication orders in the first 12 hours. Structured queries extracted 35 discrete variables from the electronic health record (EHR). Two experts per institution reviewed random admissions (July-August 2022) to establish criterion validity. A retrospective cohort (July 2020-June 2023) added validity evidence. RESULTS:Automated extraction achieved ≥96% sensitivity and ≥95% specificity when compared to manual review. Among 615 residents attributed to 6,192 admissions of patients with type 2 diabetes at high risk for hyperglycemia, TRACER #1 occurred in 42.6% (1,689/3,965) of admissions at Program A, 28.9% (408/1,410) at Program B, and 26.7% (218/817) at Program C. TRACER #2 occurred in 44.9% (367/817) of Program C admissions versus 24.2% (959/3,965) at Program A and 28.2% (397/1,410) at Program B (all P < .001). Four resident-level insulin‑ordering profiles were identified-consistent basal-bolus insulin use (most guideline-concordant), basal-predominant, bolus-predominant, and bolus-only (most guideline-discordant)-with between‑resident variation exceeding between‑program differences. Longitudinally, cohort-level trends masked opposing individual trajectories-some residents improved with exposure while others worsened-and performance tertiles were distinguishable early in training. CONCLUSIONS:TRACERs revealed substantial institution‑ and resident‑level variation in insulin‑ordering practices, including guideline deviations, demonstrating potential for real‑time formative feedback. Multi‑institutional implementation highlighted scalability barriers, including EHR heterogeneity and workflow‑dependent attribution, underscoring the need for continued refinement and broader validation.

Hepatitis B virus (HBV) mother-to-child transmission (MTCT) remains a major challenge in Uganda, where 43% of births occur at home, and access to timely birth dose (BD) vaccination is limited. We evaluated the impact of combining universal three-dose (3D) infant vaccination, targeted BD vaccination, and maternal antiviral treatment for high viral load (HVL) mothers on HBV prevalence among infants. In a prospective 18-month cohort study at five regional maternity hospitals, HIV-negative pregnant women were screened for HBsAg. HBsAg-positive mothers were stratified by HBV DNA into HVL (≥ 20,000 IU/mL), low viral load (LVL), or LVL on treatment. HVL mothers received Tenofovir Disoproxil Fumarate plus Lamivudine in the third trimester. Infants of HBsAg-positive mothers received BD vaccination within 24 h and the 3D pentavalent series; infants of HBsAg-negative mothers received the 3D series only. All infants were tested for HBsAg at nine months. Of 19,053 mothers screened, 3.46% were HBsAg-positive (n = 660). Among HVL mothers (n = 80), 96.3% initiated antivirals; none of their infants who received both BD and 3D tested HBsAg-positive. Among LVL mothers not on treatment (n = 558), the prevalence of infection at nine months was 0.4% despite full vaccination. No infections occurred among LVL mothers on treatment or among infants of HBsAg-negative mothers. Overall infant HBsAg prevalence was 0.19%, with an adjusted national estimate of 0.02%. Integrating maternal antiviral prophylaxis, targeted BD vaccination, and universal 3D vaccination achieved near-elimination of HBV MTCT in this setting. Nationally scaling this strategy could enable Uganda to meet the WHO target of less than 0.1% infant HBV prevalence before 2030 and serve as a model for other high-burden countries with significant rates of home births.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Degeneration of the central autonomic network with relative sparing of peripheral autonomic neurons underlies neurogenic orthostatic hypotension in patients with multiple system atrophy (MSA). Ampreloxetine, a novel, selective, norepinephrine (NE) reuptake inhibitor, allows once-daily dosing to precisely target residual peripheral autonomic neurons. Based on the hypothesis that patients with MSA would be most responsive and the substantial unmet need for symptomatic therapy in this population, an MSA subgroup analysis was prespecified. METHODS:We conducted a run-in 4-week, parallel-group, randomized controlled trial (SEQUOIA), followed by a pivotal enriched randomized withdrawal (RW) trial with 16-week open-label treatment and 6 weeks of 1:1 RW (REDWOOD). Inclusion criteria for the MSA subgroup included (1) probable or possible MSA, (2) 3-minute orthostatic blood pressure (BP) fall >20/10 mm Hg, and (3) dizziness or lightheadedness score >4 points. Outcome measures included self-reported symptom burden captured on the 10-item OH Questionnaire (OHQ). Differences were analyzed using logistic regression and mixed-model repeated measures analysis. RESULTS:= 0.015). Standing BP remained unchanged from open-label in the ampreloxetine group (systolic: 5.6 ± 4.1; diastolic: 3.7 ± 2.9 [SE] mm Hg) but fell after placebo withdrawal (systolic: -10.0 ± 4.5; diastolic: -6.0 ± 3.1 mm Hg). The catecholamine profile was consistent with NE transporter inhibition. There were no observed increases in supine BP. DISCUSSION/CONCLUSIONS:In a prespecified subgroup analysis of MSA participants in the REDWOOD trial, patients randomized to placebo worsened, whereas those who were randomized to treatment maintained their open-label level of function. TRIAL REGISTRATION INFORMATION/UNASSIGNED:REDWOOD trial, NCT03829657; first submitted to registry January 10, 2019; first participant enrolled February 22, 2019. SEQUOIA trial, NCT03750552; first submitted to registry November 20, 2018; first participant enrolled January 24, 2019. See ClinicalTrials.gov for full-protocol and statistical analysis plan. CLASSIFICATION OF EVIDENCE/METHODS:This study provides Class III evidence that in patients with MSA who had symptomatic benefit on orthostatic hypotension with ampreloxetine, there was no difference in the odds of treatment failures between those maintained on ampreloxetine and those withdrawn to placebo.

INTRODUCTION/BACKGROUND:Patients with a suspected high-consequence infectious disease (HCID), such as Ebola virus disease, may require routine laboratory testing to guide management. We assessed the capabilities of frontline hospitals and the barriers they face performing laboratory testing for patients with a suspected HCID. METHODS:A one-time confidential REDCap survey querying capabilities to safely perform laboratory tests that the Centers for Disease Control and Prevention considers critical for patients with a suspected HCID was sent to 95 institutions in Baltimore, MD, Boston, MA, New York City, NY, and Washington, DC, from January to May 2025. RESULTS:Fifty (53%) institutions responded, mostly teaching hospitals (96%), with 24% reporting prior experience evaluating a patient with suspected Ebola virus disease. While many hospitals could perform on-site blood gas (70%), hemoglobin/hematocrit (68%), and lactate (68%) tests on a suspected HCID patient, fewer could safely perform a chemistry panel (64%), a urinalysis (60%), a complete blood count with differential (56%), and a malaria rapid diagnostic test (RDT) (48%) on a suspected HCID patient. The five tests respondents most often considered extremely or very important were hemoglobin/hematocrit (91%), chemistry panel (90%), CBC with differential and platelet count (89%), malaria RDT (88%), and blood gas (88%). Reported barriers to performing routine laboratory testing included issues related to patient and staff safety, infection control, lack of appropriate space, and funding. CONCLUSIONS:Our survey identified several barriers to implementing safe laboratory testing. The inability to conduct these laboratory tests may result in delays in care when an HCID is suspected.

IMPORTANCE/UNASSIGNED:Remote patient monitoring (RPM), including self-measured blood pressure monitoring with clinician review and telehealth-supported feedback, can support hypertension management. However, RPM use and related care continuity after switching from Medicare fee-for-service (FFS) to Medicare Advantage (MA) remain unclear. OBJECTIVE/UNASSIGNED:To compare RPM adoption, clinician continuity, and hypertension-related acute care utilization among beneficiaries who remained in Medicare FFS vs switched to MA plans, categorized as value-based contract (VBC) proxy or non-VBC. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This cohort study with an observational difference-in-differences design with propensity score matching used data from 2016 to 2022 Medicare enrollment, FFS claims, and MA encounter data. Beneficiaries were aged 65 years or older with prevalent diagnosed hypertension in 2018 and continuous enrollment in Parts A and B in 2018. Treated groups switched from FFS to MA in January 2019 and remained enrolled through 2022; comparators remained in FFS. Follow-up extended from January 1, 2019, through December 31, 2022. Data analysis was conducted from April to July 2025. EXPOSURE/UNASSIGNED:Switching from Medicare FFS to MA-VBC proxy or MA non-VBC in 2019. MAIN OUTCOMES AND MEASURES/UNASSIGNED:The primary outcome was annual RPM adoption during hypertension-related visits; secondary outcomes included clinician loss without replacement, clinician switching or substitution, and hypertension-related emergency department (ED) visits and hospitalizations. RESULTS/UNASSIGNED:Matched samples included 281 620 beneficiaries, with 46 833 MA-VBC proxy plan switchers and 46 833 FFS comparators (27 920 [59.6%] aged 71 years or older and 27 685 female [59.1%] in each group) and 93 977 MA non-VBC switchers and 93 977 FFS comparators (67 188 [71.5%] aged 71 years or older; 53 122 female [56.5%] in each group). Common comorbidities included diabetes, chronic kidney disease, and heart failure. Switching to MA was associated with lower RPM adoption in 2022 (MA-VBC proxy: odds ratio [OR], 0.55; 95% CI, 0.42-0.72; -0.63 percentage points; non-VBC: OR, 0.73; 95% CI, 0.54-0.99; -0.52 percentage points), greater clinician loss without replacement (MA-VBC proxy: OR, 1.27; 95% CI, 1.23-1.32; 3.41 percentage points; MA non-VBC: OR, 1.09; 95% CI, 1.06-1.12; 0.83 percentage points), and higher hypertension-related hospitalizations (MA-VBC proxy: OR, 1.75; 95% CI, 1.48-2.06; MA non-VBC: OR, 1.94; 95% CI 1.71-2.19; 1.56 percentage points in both comparisons). Event-study analyses showed postswitch divergence through 2022. CONCLUSIONS AND RELEVANCE/UNASSIGNED:In this cohort study of older Medicare beneficiaries with hypertension, switching from FFS to MA was associated with lower RPM adoption, greater clinician discontinuity, and higher hypertension-related acute care use. These findings suggest that continuity safeguards and clearer payment or quality incentives during MA transitions may support remote monitoring and clinician follow-up for hypertension.

OBJECTIVES/OBJECTIVE:To evaluate whether real-time electronic health record (EHR)-based secure messaging between emergency department (ED) clinicians and prior discharge teams influences ED disposition decisions for patients re-presenting within 30 days of hospital discharge. MATERIALS AND METHODS/METHODS:This 18-month pre-post study included 27 592 ED revisit encounters across 3 campuses within one academic healthcare system. Robotic process automation generated a real-time EHR secure message connecting the ED attending with the index hospitalization discharge team during the ED disposition window. The primary outcome was the proportion of encounters resulting in ED disposition changes. Secondary outcomes included length of stay and messaging engagement by service, hospital campus, and time of day. RESULTS:Systemwide, inpatient readmissions rates were unchanged (49.4% vs 48.6%, P = .149), and observation status increased (7.0% vs 8.0%, P < .001). At one campus where messaging was paired with proactive care coordination, inpatient admissions decreased (56.9% vs 54.1%, P = .029) and treat-and-release increased (36.8% vs 39.6%, P = .024). Overall, 61.8% of messages received a response, but engagement did not correlate with disposition changes systemwide. DISCUSSION/CONCLUSIONS:Disposition changes occurred only where messaging was integrated with care coordination workflows with the operational capacity to act, indicating that real-time communication alone is insufficient without supporting infrastructure. CONCLUSION/CONCLUSIONS:Real-time EHR messaging may be most effective when paired with structured care coordination models rather than deployed as a standalone alerting tool.

PURPOSE/UNASSIGNED:This study aims to characterize demographic characteristics of transgender and nonbinary (trans) medical students and their training experiences. METHODS/UNASSIGNED:We conducted cross-sectional analyses of responses to the Association of American Medical Colleges Graduation Questionnaire (2016-2023) to characterize trans medical students using measures of race, ethnicity, age, and medical school region; assess overall satisfaction with medical training; and evaluate time to graduation, all compared to cisgender peers. RESULTS/UNASSIGNED:< 0.001). CONCLUSION/UNASSIGNED:With higher odds of being unsatisfied with their education, additional research must identify and develop interventions to improve their training experience.

PURPOSE/OBJECTIVE:The ASPIRE trial evaluated frontline anastrozole, palbociclib, trastuzumab, and pertuzumab in patients with HR-positive, HER2-positive metastatic breast cancer (MBC). METHODS:This phase I/II trial enrolled patients with previously untreated, HR-positive, HER2-positive MBC. In Phase I, patients received escalating doses of palbociclib with trastuzumab, pertuzumab and anastrozole, using a 3 + 3 dose escalation design, and primary endpoint was maximum tolerated dose (MTD). Phase II followed an optimal Simon two-stage design where all patients received palbociclib at the MTD, plus anastrozole, trastuzumab, and pertuzumab and the primary endpoint was clinical benefit rate (CBR) in the first six months. Secondary endpoints included progression free survival (PFS), overall survival (OS) and safety. RESULTS:In Phase I, no dose limiting toxicities were observed at the 100mg (N = 3) or 125mg (N = 6) dose levels, and thus, 125mg was the MTD. An additional 23 patients were enrolled to Phase II, with a total of 29 patients in the response-evaluable population. The primary endpoint of CBR was 97% (N = 28; 95% CI: 82-99%). At a median follow-up of 45.3 months, median PFS was 24.9 months (95% CI: 17.2-44.8). Median OS was not reached at a follow-up of 39.4 months. Most common treatment-related adverse events (TRAEs) were neutropenia, leukopenia, diarrhea, and anemia. Grade 3-4 TRAEs occurred in 62% (N = 18) of patients and most were hematologic. CONCLUSIONS:The combination of anastrozole, palbociclib, trastuzumab, and pertuzumab demonstrated promising activity in this single-arm trial of patients with HR-positive, HER2-positive MBC and warrants further study in randomized trials. The regimen could provide a chemotherapy-free alternative.