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:Central nervous system (CNS) involvement in multidrug-resistant tuberculosis (MDR-TB) is associated with high morbidity, and evidence guiding the use of standardized all-oral regimens in intracranial disease is limited. We describe radiographic evolution of a presumed cerebellar tuberculoma during BPaLM-based therapy for MDR-TB. METHODS:We report the clinical course, microbiologic data, treatment regimen, and serial neuroimaging of a man in his 30s with pulmonary MDR-TB, pleural involvement, and a small peripherally enhancing cerebellar lesion compatible with a tuberculoma. RESULTS:The patient presented with respiratory symptoms and mild headache, and was diagnosed with cavitary pulmonary tuberculosis, pleural involvement, and a small left cerebellar lesion. Further evaluation showed no ataxia, dizziness, or focal neurologic deficits. Sputum acid-fast culture was positive for Mycobacterium tuberculosis, and rapid molecular testing demonstrated rifampin resistance. Whole-genome sequencing confirmed resistance to rifampin, isoniazid, and ethambutol, and did not identify mutations associated with resistance to pyrazinamide, fluoroquinolones, linezolid, clofazimine, or bedaquiline. Treatment was transitioned to BPaLM (bedaquiline, pretomanid, linezolid, moxifloxacin) with adjunctive corticosteroids early in the course. Sputum cultures converted to negative approximately 6 weeks after treatment initiation. Serial brain MRI demonstrated progressive reduction in lesion size at 9 weeks, residual punctate enhancement at 21 weeks, near-complete resolution by 44 weeks, and complete radiographic resolution on subsequent imaging. The patient completed 52 weeks of therapy and remained clinically stable, without neurologic deficits or relapse more than 2 years after treatment completion. CONCLUSION/CONCLUSIONS:This case describes radiographic resolution of a small presumed cerebellar tuberculoma during extended BPaLM/BPaL-based therapy for disseminated MDR-TB, highlighting the evidence gap for standardized all-oral regimens in CNS drug-resistant tuberculosis.

INTRODUCTION/BACKGROUND:-variation with greater time post-9/11/2001 will be a mortality risk-factor associated with cross sectional BMI and longitudinal weight-variation. METHODS:-variation. RESULTS:-variation (OR = 1.18; 95% CI 1.06, 1.27 and OR = 1.17; 95% CI 1.07, 1.27 respectively). INTERPRETATION/CONCLUSIONS:-variation and weight-variation may reflect concurrent metabolic and pulmonary instability that increase vulnerability to death.

PURPOSE/OBJECTIVE:Cancer is the leading cause of death for Chinese Americans, and research on optimal psychosocial interventions is scarce. Understanding the specific experiences of Chinese Americans with cancer is essential for developing supportive interventions. This study is a qualitative analysis of patient narratives collected from an Expressive Helping intervention, obtained from Chinese Americans with cancer to explore their experiences and meaning making of their cancer diagnosis and treatment journeys. METHODS:Thirty-one participants completed four 20-min writing sessions related to their cancer experiences. Informed by the Common-Sense Model of illness self-regulation, we used iterative, blended deductive-inductive coding and conducted a thematic analysis to explore meaning making, illness perception/narrative, and peer-helping recommendations. RESULTS:Significant themes were identified at the intrapersonal, interpersonal, and organizational/community levels. Participants felt initial disbelief and distress at the cancer diagnosis, which were attenuated through reframing of their experiences and finding support from various sources. Participants were also worried about burdening their families with their diagnosis but subsequently came to appreciate their support. They described challenges with navigating the healthcare system but appreciated having access to trusted providers and modern medicine. Patients also provided advice to support other patients on their cancer journey. CONCLUSION/CONCLUSIONS:Understanding the factors that influence the mental health of patients with cancer and survivors is key to informing responsive supportive strategies. Our analysis of expressive writing narratives by Chinese Americans with cancer illuminates their unique challenges and myriad ways they find resilience and acceptance.

Hypomethylating agents (HMA) and allogeneic hematopoietic stem cell transplantation (alloHSCT) have both demonstrated remissions in VEXAS; however, comparative data is lacking. We conducted a multicenter, retrospective analysis of 66 patients diagnosed with VEXAS syndrome treated with HMA (n = 35) or alloHSCT (n = 31). Baseline characteristics such as genetics, co-morbidities, and performance status were balanced between the groups, except older age in the HMA group. Median follow-up from therapy initiation was 18 months (95% CI: 11-26), and 14 (21%) deaths were reported (alloHSCT n = 3; HMA n = 11). Among all evaluable patients within the alloHSCT cohort, all patients achieved molecular remission, and a substantial proportion of patients discontinued glucocorticoids (58%). In contrast, HMA therapy was associated with lower but meaningful rates of molecular remission (22%) and glucocorticoid discontinuation (6%). In a real-world setting, HMA therapy was associated with a high discontinuation rate related to toxicity or lack of response. On multivariable analysis adjusted for age and Charlson Comorbidity Index, alloHSCT was associated with improved overall survival (HR = 0.20, 95% CI: 0.05-0.81; p = 0.024). This association remained consistent across multiple ancillary sensitivity analyses, including restriction to transplant-eligible patients, patients aged ≤ 75 years, 1:1 matching, and propensity score-based weighted analyses. Although limited by retrospective design, these findings suggest that alloHSCT remains an attractive and potentially curative strategy in selected patients with VEXAS. Prospective validation of these findings is warranted.

Advanced gastrointestinal cancers remain a major global health challenge, with rising incidence especially among younger populations. Systemic chemotherapy continues to be the mainstay of care for most patients, but balancing treatment benefit with tolerability is an ongoing concern. Many patients, especially older adults and those with significant medical comorbidities, may struggle with standard dosing due to side effects, yet they are often underrepresented in clinical trials. As a result, real-world practice often relies on adjusting drug doses and schedules to reduce toxicity without compromising outcomes. Personalizing systemic therapy based on patient factors like age, fitness, and individual response can help improve tolerability and maintain quality of life. Emerging evidence supports the use of modified dosing and frequency, but prospective data remain limited. In this review, we discuss current approaches to optimizing systemic therapy for advanced gastrointestinal cancers and the need for practical, patient-centered care pathways.

BACKGROUND:The clinical and economic impact of breast cancer screening varies based on the modality, frequency, and age of the screened population. OBJECTIVE:To characterize changes in use and cost of breast cancer screening for older women. DESIGN/METHODS:Serial cross-sectional study using data from SEER-Medicare, 2009-2019. PARTICIPANTS/METHODS:Women 67 and older enrolled in Medicare fee-for-service. MAIN MEASURES/METHODS:Screening use and cost by age, frequency, and modality. We further categorized screening as cost-effective or cost-ineffective based on published economic analyses rather than guidelines. Cost-effective screening included biennial mammography among women < age 80, while cost-ineffective screening included annual mammography, addition of digital breast tomosynthesis (DBT), screening ultrasound, and any screening among women 80 and older. We estimated total annual spending on screening in Medicare fee-for-service, inflated to 2019 dollars. KEY RESULTS/RESULTS:Our sample included a mean of 229,683 (range 222,400- 244,793) Medicare beneficiaries annually. Biennial screening was stable among women 65-79, at 11.2% (95% CI 11.0-11.4) in 2009 and 11.9% (95% CI 11.7-12.0) in 2019. Annual screening was also stable at 32.5% (95% CI 32.3-32.7) in 2009 and 30.0% (95% CI 29.8-30.2) in 2019. Among women 80 and older, screening (annual or biennial) declined from 19% (95% CI 18.8-19.3) to 12.9% (95% CI 12.7-13.2). Between 2009-2019, use of DBT rose from 0% to 70.3% of screened women. Total spending on cost-effective screening rose from $569 million per year to $735 million per year, a 29% increase. Spending on cost-ineffective screening rose from $548 million to $1.025 billion, an 87% increase. By 2019, spending on cost-ineffective screening accounted for 58% of total spending. CONCLUSIONS:Screening costs for older women have risen, driven by expenditures on technologies that may not be cost-effective. Reducing use of low value screening could result in savings that could be reallocated toward high value screening and follow up testing.

BACKGROUND:Preadmission functional status has important predictive values for outcomes among hospitalized patients, and may facilitate healthcare resource allocation including early palliative care referral. OBJECTIVES/OBJECTIVE:To compare acute healthcare and palliative care utilization among hospitalized patients with different levels of baseline functional impairment. METHODS:We conducted a retrospective cohort study of adult patients ≥ 18 years discharged from a quaternary academic hospital between July 1, 2022, and December 31, 2024, with baseline functional status assessed on admission via Karnofsky Performance Status (KPS) scale. Using electronic health records and billing data, we collected patients' socio-demographic information, clinical characteristics, and utilization of acute healthcare and palliative care. RESULTS:Among 18,049 patients, baseline functional impairment was classified as mild (KPS 70%-100%): 13,411 (74.3%), moderate (KPS 50%-60%): 2953 (16.4%), severe (KPS30%-40%): 974 (5.4%) and very severe (KPS 10%-20%): 711 (3.9%). Overall, 2089 (11.6%) patients had a intensive care unit (ICU) admission, 1574 (8.7%) received palliative care consultation, and 1021 (5.6%) died in the hospital. In generalized linear models stratified by functional status category, increasing severity of functional impairment was significantly associated with increasing ICU admission, ICU and hospital length of stay, in-hospital mortality, and receipt of palliative care intervention. Mean number of days between admission and palliative care consultation was significantly decreased among patients with very severe impairment when compared with those with mild impairment (5.3 vs. 6.7 days, p < .001). CONCLUSIONS:Baseline functional status assessment may offer an easy-to-measure guide for timely inpatient palliative care intervention among patients at elevated risk for in-hospital morbidity and mortality.

Patients with paroxysmal nocturnal hemoglobinuria (PNH) on anti-C5 often experience extravascular hemolysis with anemia. Iptacopan, the first oral proximal complement inhibitor targeting factor B, has shown efficacy and safety in PNH patients. APPULSE-PNH (NCT05630001), a phase 3b, single‑arm, open-label trial, enrolled adult patients with PNH and hemoglobin ≥10 g/dL on stable anti-C5 for ≥6 months. Patients switched to iptacopan monotherapy (200 mg twice daily; 24 weeks). Primary endpoint: mean hemoglobin change from baseline across four visits (Days 126-168). At baseline, 57.7% of patients had elevated absolute reticulocyte counts (ARCs; above ULN = 123 × 10⁹/L) and 50% had C3 deposition on red blood cells (RBCs) >10%, indicative of extravascular hemolysis. There was a statistically significant increase in hemoglobin during the trial; adjusted mean change from baseline (95% CI) was +2.0 g/dL (1.7-2.3) overall, and in patients with baseline hemoglobin <12 g/dL and ≥12 g/dL, +2.4 (2.0-2.7) and +1.4 (1.0-1.8), respectively. Patients maintained transfusion independence, 92.7% with hemoglobin ≥12 g/dL. Adjusted mean change from baseline (95% CI) in lactate dehydrogenase and ARC were -1.3% (-6.6 to 4.3) and -89.2 × 10⁹/L (-95.5 to -82.9), respectively. Mean (SD) proportion of C3d+ PNH RBCs, assessed by flow cytometry, decreased from 11.0% (8.6) to 0.2% (0.7) at Day 168. No patients had breakthrough hemolysis or major adverse vascular events. FACIT-Fatigue and treatment satisfaction scores improved by Days 84 and 168. Safety showed consistency with previous iptacopan PNH trials. Iptacopan improved hematologic outcomes in PNH patients with hemoglobin ≥10 g/dL on anti-C5, maintaining control of intravascular hemolysis and resolving extravascular hemolysis.