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 assess whether adding fluoropyrimidine sensitized radiotherapy (CXRT) to adjuvant chemotherapy improves overall survival (OS) after curative intent resection of the pancreatic head. METHODS:This was a multicenter, randomized phase III, two step trial. Step 1: gemcitabine versus gemcitabine + erlotinib (previously reported). Step 2: random assignment to sixth chemotherapy cycle ± CXRT after five cycles of step 1 chemotherapy without progression. Outcomes of step 2 random assignment are reported here. Assuming 17 months median OS (chemotherapy alone), the sample size was 354 patients (hazard ratio [HR], 0.76, 80% power, one-sided α = .05, 316 OS events). OS/disease-free survival (DFS) were estimated by Kaplan-Meier and arms compared using the log-rank test. RESULTS:= .014) in node-negative patients. CONCLUSION/CONCLUSIONS:Overall, the addition of adjuvant CXRT to adjuvant gemcitabine did not statistically significantly improve OS, DFS, or increase grade 4/5 toxicity. For node-negative patients, CXRT improved OS and DFS. These results, if confirmed in studies with current or future systemic therapies, would support the use of adjuvant/neoadjuvant CXRT for node-negative patients.

BACKGROUND:Benefits from clinical guidelines often only exceed harms after 10 years (payoff time). Based on population norms, guidelines are often discontinued at 75 years of age, but survival likely differs for those with complex chronic disease. We compare estimates based on age alone versus the physiologically based Veterans Ageing Cohort Study-Charlson Comorbidity Index (VACS-CCI) among all patients in care, and among patients with diabetes or HIV. METHODS:Estimates for patients in care within the US Veterans Health Administration (VHA) with a clinic visit in 2007-17 (followed thru 2021) were compared using C-statistics, Brier Scores, and calibration curves. "Physiological age" was defined as the chronological age at which median VACS-CCI matched US population survival estimates. Among those with 10-year follow-up, we compared percent correctly classified using age ≥75 years vs. VACS-CCI score of ≥42. FINDINGS/RESULTS:Among 6.6 million (51.4% ≥ 65 years; 25.2% with diabetes; 0.5% with HIV) VACS-CCI improved discrimination over age (Overall C-statistic: 0.81 vs. 0.74; Brier Score 0.239 vs. 0.262). Among 65-year-old males-females, "physiological age" exceeded chronological age by 4.6-3.1 years overall; 8.6-7.8 years for diabetes; and 13.5-11.6 years for HIV. Compared to age ≥75 years, VACS-CCI improved correct classification of survival for 1 in 13.3 overall; 1 in 7.8 with diabetes; and 1 in 6.4 with HIV. INTERPRETATION/CONCLUSIONS:Compared to chronological age alone, VACS-CCI offers an improved method to identify those likely to reach minimum payoff time, especially for those with complex chronic diseases. Use of clinical data to assess "physiological age" could improve healthcare value. FUNDING/BACKGROUND:This work was supported by National Institutes of Health NIAAA: P01 AA029545, U24 AA020794 and the Emory Center for AIDS Research (P30AI050409).

New York City has the largest homeless population of any city in the United States, with thousands of people experiencing unsheltered homelessness on its streets. These individuals have poor health outcomes and limited connection to care. To better meet their health and social needs, New York City Health+Hospitals, the largest public hospital system in the United States, has implemented the Street Health Outreach and Wellness (SHOW) initiative to bring unsheltered New Yorkers health care, material goods, and connections to transitional housing. This article documents the evolution of the program - from its first iteration as an external contractor-staffed initiative during the coronavirus disease 2019 pandemic to its integration into the health care system in January 2023 - while also highlighting how it is currently operationalized. Since its integration, teams have completed more than 46,000 street engagements, including more than 10,000 clinical visits, 1700 connections to substance use services, and more than 500 connections to homeless shelters. The authors provide key lessons about trust-building, navigating complex organizational hierarchies and partnerships, and the importance of community-based interventions to provide homeless health care.

PURPOSE OF REVIEW/OBJECTIVE:Intraprocedural anticoagulation during percutaneous coronary intervention (PCI) remains particularly challenging in high-risk and underrepresented populations, where the balance between thrombotic and bleeding risk is complex and often unpredictable. This review summarizes contemporary evidence and remaining knowledge gaps regarding anticoagulant selection, dosing, and monitoring in patients with advanced chronic kidney disease (CKD) or end-stage renal disease, cirrhosis, nonagenarians, thrombocytopenia, chronic oral anticoagulation, mechanical circulatory support, and STEMI following fibrinolytic therapy. RECENT FINDINGS/RESULTS:These populations are frequently excluded from randomized clinical trials. In patients with STEMI following fibrinolytic therapy, optimal anticoagulation strategies remain uncertain, with evidence suggesting potential benefit of anticoagulant continuity. Mechanical circulatory support devices introduce additional complexity due to device-related thrombosis and bleeding risks, requiring dynamic, device-specific anticoagulation and monitoring strategies. Special populations such as elderly patients, cirrhosis, and CKD present unique pathophysiologic challenges, including altered pharmacokinetics and rebalanced hemostasis. Similarly, patients on chronic oral anticoagulation require individualized periprocedural strategies, as baseline therapy alone may be insufficient and supplemental intraprocedural anticoagulation is often necessary. Conventional bleeding risk scores demonstrate reduced predictive performance in these populations, highlighting important limitations in current risk stratification. Emerging evidence supports a shift toward precision-guided anticoagulation strategies that integrate actionable patient-specific factors, including renal function, platelet count, liver disease severity, and procedural complexity, along with pharmacogenomics and real-time monitoring. Advances in machine learning-based risk prediction and artificial intelligence-driven clinical decision support tools further offer the potential to enhance individualized care. However, most available evidence remains extrapolated from broader populations, and dedicated prospective studies are needed to define optimal anticoagulant selection, dosing, and monitoring strategies in these high-risk groups.

BACKGROUND:The Movement Disorder Society (MDS) research criteria for possible prodromal multiple system atrophy (PP-MSA) have not been prospectively validated. OBJECTIVE:To evaluate the diagnostic performance of the PP-MSA criteria in a longitudinal cohort of patients with pure autonomic failure (PAF) and to assess whether additional clinical features improve their predictive value. METHODS:Seventy-six patients with PAF enrolled across eight centers in the Natural History Study of the Synucleinopathies were followed for ≥6 years or until phenoconversion. Participants were classified according to MDS PP-MSA criteria and followed for development of MSA, Parkinson's disease, or dementia with Lewy bodies. Diagnostic performance was assessed longitudinally. Analyses were repeated using a stricter olfactory threshold (University of Pennsylvania Smell Identification Test [UPSIT]≤28) as an exclusion criterion. RESULTS:Thirty-eight participants met PP-MSA criteria, of whom 12 phenoconverted to MSA within 6 years. Sensitivity was 100% at year 1 and 92% at year 6, whereas specificity ranged from 56% to 67%. Positive predictive value (PPV) ranged from 21% to 34%. Applying a stricter olfactory threshold improved specificity (90%-97%) and PPV (53%-83%), with a modest reduction in sensitivity (to 83%). Participants who phenoconverted to MSA were younger, had more severe urinary dysfunction, and greater orthostatic heart rate responses. CONCLUSIONS:The PP-MSA criteria demonstrate high sensitivity but limited specificity in patients with PAF. A stricter olfactory threshold improves diagnostic performance and may enhance cohort enrichment for clinical trials. © 2026 International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

BACKGROUND:The current classification of pulmonary hypertension (PH), based largely on expert opinion, has limitations in prognostication and guiding therapies. We hypothesize that novel PH clusters that predict survival will reveal mechanistic phenotypes associated with biomarkers of vascular health across all PH groups. METHODS:We first identify novel PH clinical clusters by performing unsupervised clustering analysis on the CC-PH (Cleveland Clinic PH) registry (N=1529). We develop classification models to predict the new PH clusters and then apply them to the multicenter PVDOMICS (Pulmonary Vascular Diseases Phenomics) cohort (N=853) for validation. We compare transplantation-free survival across the new PH clusters. We quantify metabolites of the arginine-nitric oxide pathway and D-dimer levels and calculate global arginine bioavailability (arginine/[ornithine+citrulline]) to assess endothelial function and activation in the new clusters and link these biomarkers to clinical outcomes. RESULTS:Clustering analysis identify 3 clear clusters in CC-PH that are validated in PVDOMICS and outperform conventional classifications in predicting transplantation-free survival. The phenotype associated with the worst survival is characterized by reduced lung diffusion capacity, decreased arginine bioavailability and nitrate levels, and elevated D-dimer levels, consistent with loss of pulmonary microcirculation and endothelial dysfunction. CONCLUSIONS:We identify new informative PH phenotypes associated with mortality and defined by biomarkers of endothelial function and activation. Loss of endothelial health and pronounced pulmonary vascular rarefication contribute more substantially to mortality across the spectrum of PH than right heart function. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02980887.

Atherosclerotic cardiovascular disease (ASCVD) and cancer are increasingly recognized as interconnected diseases linked by shared immune mechanisms rather than merely overlapping risk factors. Common exposures such as smoking, obesity, diabetes, and dyslipidemia, together with aging and clonal hematopoiesis of indeterminate potential (CHIP), establish a chronic inflammatory milieu that drives both pathologies through coordinated reprogramming of myeloid and lymphoid compartments. Within this framework, a forward cardio-oncology axis is increasingly recognized, in which cancer therapies including chemotherapies, radiation, and immune checkpoint inhibitors induce cardiovascular injury, manifesting as cardiomyopathy, accelerated atherosclerosis, and immune-mediated myocarditis. Complementing this, a reverse axis has emerged in which cardiovascular injury states such as myocardial infarction, ischemia, and heart failure actively promote cancer initiation and progression through hematopoietic remodeling, extracellular vesicle-mediated communication, cardiac-derived factors, and immunosuppressive myeloid bias. At the tissue level, immune checkpoint pathways including PD-1, PD-L1, CTLA-4, LAG-3, and TIM-3 form spatially organized regulatory networks within atherosclerotic plaques. Their therapeutic perturbation restores T cell activity but may disrupt local immune homeostasis and promote plaque instability. In parallel, inflammatory cytokines such as IL-1β, IL-6, and TNF-α, often amplified by CHIP-associated clones, provide a mechanistic bridge linking atherogenesis with tumor immune evasion. Together, these observations support a unified view of ASCVD and cancer as immune-driven diseases connected by bidirectional axes of interaction. This review integrates emerging mechanistic and clinical evidence and outlines how immune-based stratification and targeted modulation of inflammation may enable more precise management of patients at the intersection of cardiovascular disease and cancer.