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:The optimal number of pulsed field ablation (PFA) applications during atrial fibrillation (AF) ablation is unclear. We hypothesized that the number of PFA applications would predict atrial tachyarrhythmia (ATA) recurrence rates. OBJECTIVE:To determine whether higher numbers of PFA applications would decrease ATA recurrence rates. METHODS:We studied cases of patients with AF undergoing first-time ablation with PFA between 5/6/24 and 10/7/24. All patients underwent pulmonary vein and posterior wall isolation. The primary outcome was ATA recurrence. Additional outcomes included stroke, post-procedural acute kidney injury (AKI), total procedure time, and major periprocedural complications. Univariable and multivariable analyses were performed to determine if the number of PFA applications predicted ATA recurrence. RESULTS:In a cohort consisting of 177 patients, univariable and multivariable analysis showed that the number of PFA applications split at the smallest quartile (< 57 applications) versus the largest three quartiles (≥ 57 applications) was the strongest predictor of ATA recurrence (p = 0.03). ATA recurrence at 1 year (29% vs. 8%; p < 0.01) and AF burden on continuous monitor (4% vs. 0%; p < 0.01) was higher with the standard (< 57 applications) vs higher (≥ 57 applications) PFA dose groups. When comparing the standard versus higher PFA dose groups, there was no difference in total procedure time (106 vs. 107 min; p = 0.77), major periprocedural complications (0% vs. 2%; p = 0.33), or post-procedural AKI (2% vs. 2%; p = 0.69). CONCLUSION/CONCLUSIONS:Increasing number of PFA applications is associated with reduced ATA recurrence. A higher number of PFA applications may decrease ATA recurrence without affecting procedure times or complication rate.

BACKGROUND/UNASSIGNED:Skilled nursing facilities (SNFs) play a critical role in postacute recovery for older adults with heart failure (HF), yet the transition from SNF to home remains a vulnerable and understudied phase of care. Although discharge guidelines emphasize clear communication, HF-specific self-care education, medication management, and follow-up coordination, little is known about how these practices are implemented during SNF-to-home transitions. METHODS/UNASSIGNED:We conducted a convergent mixed-methods study across 4 nonprofit SNFs, integrating data from postdischarge patient and caregiver surveys, structured medical record abstraction of discharge instructions, and semi-structured staff interviews. Eligible patients were Medicare beneficiaries aged ≥65 years discharged from SNF to home following HF hospitalization, with SNF stays ≤60 days. Quantitative data were analyzed using descriptive statistics, while qualitative data underwent thematic and directed content analysis. Findings were triangulated across data sources to identify key challenges and actionable strategies. RESULTS/UNASSIGNED:Among 150 respondents, 59% reported receiving written discharge instructions; however, HF-specific self-care elements (eg, daily weight monitoring, low salt diet) were documented in only 15% to 41% of instructions. Although 87% reported receiving a medication list, only 53% had it reflected in the discharge instructions, and adherence support was infrequently addressed (24%). Follow-up coordination was similarly discordant: 37% of respondents reported a scheduled primary care appointment, compared with 13% documented in discharge instructions. Staff interviews revealed nonstandardized discharge workflows, workforce constraints, and reliance on verbal education, contributing to variability in patient preparation and communication across care settings. CONCLUSIONS/UNASSIGNED:SNF-to-home transitions after HF hospitalization are marked by discordance between patient-reported education and written documentation, as well as inconsistent medication and follow-up coordination. These gaps represent modifiable vulnerabilities during a high-risk recovery period. Standardized HF-focused discharge workflows and strengthened cross-setting communication may improve transitional care, while long-term solutions must address structural and workforce constraints.

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).

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.

Learning health systems (LHSs) integrate evidence generation, implementation, and evaluation into routine care, enabling health systems to continuously improve quality of care and patient safety. Advances in artificial intelligence (AI), data infrastructure, and rapid evaluation methods have created a pivotal opportunity to accelerate this transformation. Effective LHSs embed pragmatic trials, human-centered design, and continuous monitoring to deploy innovations efficiently while maintaining ethical and operational standards. Key challenges include premature deployment, poor ethical oversight, a lack of funding, clinician burden, and misaligned incentives for payers and providers. Strategic actions - investing in infrastructure, scaling learning, aligning collaborators, and leveraging AI - can bridge the gap between discovery and practice, ensuring that health systems translate innovation into measurable value.

BACKGROUND:Clinical practice guidelines (CPGs) were developed to standardize and optimize cancer care delivery in low- and middle-income countries (LMICs). The aim of this scoping review is to identify implementation science (IS) frameworks and strategies to promote CPG adoption and adherence in LMICs. METHODS:We identified studies that describe, develop, reference, or utilize IS frameworks or strategies to deliver or evaluate adoption of oncology CPGs in LMICs. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR), we searched Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), African Journals Online, Latin American and Caribbean Health Sciences Literature, Scopus, Web of Science, and PsycINFO on 3/21/2022, 12/20/2022, 01/26/2024, and 10/03/2025. Publications in all languages and of all study types were eligible for inclusion. Titles, abstracts, and full text were screened by two reviewers with conflicts resolved by a third reviewer. Excluded studies did not use an IS framework or strategy, did not focus on cancer care, or were conducted in a high-income country. RESULTS:Searches identified 17,806 unique publications for title/abstract screening. 182 studies met criteria for full-text review; 35 were included. Twenty-four studies were country-specific, most commonly India (n = 5) and Nigeria (n = 5). The most frequent CPGs referenced were national/country-specific guidelines (n = 13) and Breast Health Global Initiative (BHGI) guidelines (n = 9). Only 16 full-text publications described original research to promote or evaluate evidence-based CPG interventions in LMICs. Established IS frameworks used in more than one study were the Exploration, Preparation, Implementation, and Sustainment (EPIS) framework (n = 2) and Consolidated Framework for Implementation Research (CFIR) (n = 2). CONCLUSIONS:There is limited research utilizing IS frameworks and strategies to promote CPG adoption and adherence in LMICs and substantial heterogeneity in reporting. Greater utilization of IS frameworks, strengthening implementation capacity and improving consistency in reporting, are needed to improve CPG uptake in LMICs. SYSTEMATIC REVIEW REGISTRATION/BACKGROUND:Open Science Framework (https://osf.io/nb75s).

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.

IMPORTANCE/UNASSIGNED:Buprenorphine-naloxone and extended-release (XR) naltrexone are both efficacious medications for opioid use disorder that reduce unregulated opioid use and improve opioid cravings and treatment retention. While prior comparative effectiveness studies demonstrated superiority of buprenorphine-naloxone over XR naltrexone for relapse and treatment retention, the comparative effectiveness of both treatments for all-cause mortality and nonfatal opioid overdose outcomes has not been rigorously tested. OBJECTIVE/UNASSIGNED:To compare the effectiveness of buprenorphine-naloxone vs XR naltrexone after medically managed opioid withdrawal (MMOW) treatment. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This observational comparative effectiveness study using a target trial emulation framework leveraged individually linked administrative data from the Massachusetts Public Health Data Warehouse to emulate the protocol of the Extended-Release Naltrexone vs Buprenorphine for Opioid Treatment randomized clinical trial. Participants included adults 18 years or older who were discharged from MMOW in Massachusetts between January 1, 2014, and December 31, 2018. Individuals could meet eligibility criteria more than once. Data were analyzed from December 22, 2023, to January 30, 2025. EXPOSURES/UNASSIGNED:Initiation of buprenorphine-naloxone or XR naltrexone therapy within 28 days of MMOW discharge. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Estimated 24-week cumulative incidence of all-cause mortality and nonfatal opioid overdose using inverse probability weighting to adjust for baseline and time-varying confounding. RESULTS/UNASSIGNED:A total of 36 752 unique individuals who met eligibility criteria were identified and contributed 106 052 MMOW discharge episodes; 79 089 (74.6%) episodes were among individuals who were male and 44 463 (42.1%) were among individuals aged 18 to 29 years. By 28 days after MMOW discharge, initiation of buprenorphine-naloxone was observed among 14 194 discharge episodes (13.4%) and initiation of XR naltrexone was observed among 4734 (4.5%) episodes. The adjusted 24-week cumulative incidence of all-cause mortality after MMOW discharge was 1.4% (95% CI, 1.2%-1.7%) for buprenorphine-naloxone and 1.4% (95% CI, 1.1%-1.8%) for XR naltrexone, corresponding to a risk difference of 0.0 percentage points (pp) (95% CI, -0.4 to 0.4 pp). The adjusted 24-week cumulative incidence of nonfatal opioid overdose after MMOW discharge was 11.6% (95% CI, 10.8%-12.3%) for buprenorphine-naloxone and 13.9% (95% CI, 12.9%-15.0%) for XR naltrexone, corresponding to a risk difference of 2.3 pp (95% CI, 1.2-3.6 pp). CONCLUSIONS AND RELEVANCE/UNASSIGNED:In this comparative effectiveness study of buprenorphine-naloxone vs XR naltrexone, initiating buprenorphine-naloxone after MMOW discharge was associated with a lower risk of nonfatal opioid overdose at 24 weeks than initiating XR naltrexone, but a similar risk of all-cause mortality.