Citations

Abstract Background Patients with chronic obstructive pulmonary disease (COPD) are particularly vulnerable to severe respiratory infections. While COVID-19 vaccination has demonstrated effectiveness in reducing severe disease in the general population, its real-world impact on clinical outcomes among COPD patients remains underexplored. Understanding these outcomes could strengthen vaccination advocacy and guide COPD management strategies. Research Question Does COVID-19 vaccination reduce the risk of mortality, COPD exacerbations, and mechanical ventilation in adults with COPD? Methods We conducted a retrospective, propensity-matched cohort study using the TriNetX US Collaborative Network, which aggregates de-identified electronic health records from 72 healthcare organizations. Adults with COPD were identified using ICD-10 code J44 and spirometric confirmation (FEV1/FVC ≤ 70%). Cohorts were divided by COVID-19 vaccination status, identified through CPT and RxNorm codes. The index date was defined as the earliest qualifying encounter, with outcomes assessed thereafter.Primary outcome was all-cause mortality; secondary outcomes included COPD exacerbation (J44.1) and mechanical ventilation (ICD-10-PCS 5A1945Z). Propensity-score matching (1:1) was performed on age, sex, race, comorbidities, and baseline clinical characteristics, yielding balanced cohorts (n = 3,969 each). Risk ratios (RR), hazard ratios (HR), and Kaplan-Meier survival analyses were calculated, with significance set at p < 0.05. Results After matching, median follow-up was 894 days for the unvaccinated group and 886 days for the vaccinated group. All-cause mortality 23.8% (942/3,954) in unvaccinated vs 11.1% (442/3,968) in vaccinated; RR 2.14 (95% CI 1.93-2.37); HR 1.80 (95% CI 1.60-2.02); p < 0.001. COPD exacerbations 31.3% (1,243/3,969) in unvaccinated vs 25.3% (1,006/3,969) in vaccinated; RR 1.24 (95% CI 1.15-1.33); HR 1.24 (95% CI 1.14-1.35); p < 0.001. Mechanical ventilation 1.8% (72/3,902) in unvaccinated vs 0.8% (30/3,928) in vaccinated; RR 2.42 (95% CI 1.58-3.69); HR 2.06 (95% CI 1.33-3.18); p = 0.001. Kaplan-Meier curves demonstrated consistently higher survival and event-free probabilities among vaccinated patients across all outcomes. Conclusions In this large, real-world analysis, COVID-19 vaccination was associated with significantly lower risks of all-cause mortality, COPD exacerbations, and need for mechanical ventilation. These findings emphasize the importance of vaccination as a key component of COPD care, supporting its inclusion in quality-improvement metrics and clinical counseling for patients with chronic lung disease. This abstract is funded by: None

Abstract Background Obesity contributes to worse symptoms and exacerbations in chronic obstructive pulmonary disease (COPD). Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) improve weight and metabolic profiles and have emerging pulmonary benefits. However, their real-world impact on respiratory outcomes in patients with COPD and obesity is not well established. Research Question Among obese adults with COPD, is GLP-1 RA use associated with reduced risk of COPD exacerbations, acute respiratory failure, and all-cause mortality compared with those not receiving GLP-1 therapy? Methods We conducted a retrospective, propensity-matched cohort study using the TriNetX U.S. Collaborative Network. Adults aged ≥40 years with COPD (ICD-10 J44) and BMI ≥30 kg/m² were included. The exposed cohort comprised patients prescribed GLP-1 RAs (lixisenatide, albiglutide, dulaglutide, liraglutide, semaglutide, or exenatide), while comparators had no exposure. The index event was the first date meeting inclusion criteria. Outcomes were analyzed beginning 180 days after index to minimize reverse causation, excluding those with prior events. Propensity score matching (1:1) balanced demographics, comorbidities, laboratory data, and medication use, yielding 2,795 patients per group. Primary outcomes included the risk (≥1 event within window) of COPD exacerbation, acute respiratory hypoxic and/or hypercapnic failure leading to hospitalization, and all-cause mortality. Risk difference (RD), risk ratio (RR), and odds ratio (OR) were calculated; Kaplan-Meier and log-rank testing assessed time-to-event. Results After matching, baseline characteristics were well balanced. GLP-1 RA use was associated with significantly lower risk across all outcomes:COPD Exacerbation (J44.1): 18.2% (No GLP-1) vs 11.2% (GLP-1); RD 7.0%, RR 1.63 (95% CI 1.36-1.94); p = 0.042.Acute Hypoxic and/or Hypercapnic Respiratory Failure (J96.x): 19.2% vs 11.5%; RD 7.7%, RR 1.67 (1.42-1.96).All-Cause Mortality: 14.6% vs 7.6%; RD 7.0%, RR 1.92 (1.64-2.25); p = 0.010. Kaplan-Meier survival analysis demonstrated significantly improved survival in the GLP-1 group for mortality and COPD exacerbation outcomes. Conclusions In obese adults with COPD, GLP-1 RA therapy was associated with clinically and statistically significant reductions in COPD exacerbations, acute respiratory failure, and all-cause mortality. These findings suggest that GLP-1 RAs may offer dual metabolic and pulmonary benefits and warrant evaluation as adjunctive therapy in future prospective trials. This abstract is funded by: None

OBJECTIVE The aim of this study was to evaluate freedom from tumor progression and clinical outcomes in older adults with small- to medium-sized vestibular schwannoma (VS) managed by observation versus stereotactic radiosurgery (SRS) to better inform optimal management in this patient population. METHODS In this international multicenter study, patients aged ≥ 60 years with Koos grade I or II VS managed by observation or SRS were retrospectively reviewed. Propensity score matching was conducted using patient characteristics, tumor size, and hearing assessments. Outcome measures of freedom from tumor progression, serviceable hearing preservation (SHP), and neurological function (tinnitus, vestibulopathy, House-Brackmann grade, and trigeminal nerve function) were assessed for both groups. RESULTS The observation and SRS groups each comprised 51 matched patients (median age 68 years for both). Ipsilateral serviceable hearing was observed at presentation for 35 patients in each group. The median follow-up duration was 39 months in the observation group versus 27 months in the SRS group (p = 0.5). Tumor progression was significantly lower with SRS than with observation (2% vs 52.9%, p < 0.001). The rate of 5-year freedom from tumor progression was 100% in the SRS group versus 43% (95% CI 29%–64%) in the observation group. The rate of 10-year freedom from tumor progression was 90% (95% CI 73%–100%) in the SRS group versus 20% (95% CI 8.5%–49%) in the observation group. At the last follow-up, hearing loss occurred in 42.9% of the observation group and 51.4% of those who underwent SRS (p = 0.5). The 3-year SHP rate was 68% (95% CI 53%–88%) versus 65% (95% CI 49%–85%) (p = 0.8), and the 5-year SHP rate was 53% in both groups (95% CI 36%–78% in the observation group and 95% CI 35%–79% in the SRS group, p = 0.8). The composite endpoint of tumor progression and/or worsened neurological outcome, including hearing loss, tinnitus, vestibulopathy, facial nerve dysfunction (House-Brackmann grade), or trigeminal dysfunction, demonstrated a significantly lower rate in the SRS group (17.6%) compared with the observation group (66.7%) (p < 0.001). CONCLUSIONS SRS in older patients for management of Koos grade I or II VS resulted in significantly superior rates of freedom from tumor progression, comparable hearing preservation rates, and significantly higher rates of favorable overall radiographic and neurological outcomes than observation alone. Compared with observation, SRS might be the preferred management option in this patient population.

ABSTRACT Novel β-lactam/β-lactamase inhibitors (βL/βLIs) are important therapies for carbapenem-resistant Pseudomonas aeruginosa (CRPA). However, the global extent of resistance to these agents and the impact of resistance on patient outcomes are unclear. We therefore evaluated patients with CRPA isolates at 35 hospitals (nine countries) from December 2018 to November 2019. Antimicrobial susceptibility testing was performed at a central laboratory by agar dilution for ceftolozane-tazobactam (C/T) and ceftazidime-avibactam (CZA) and by broth microdilution for imipenem-relebactam (I/R). Characteristics and outcomes, including desirability of outcome rankings (DOOR), were compared between patients infected with isolates not susceptible vs susceptible to each agent. Of 800 CRPA isolates, susceptibility to C/T, CZA, and I/R was 69%, 67%, and 33%, respectively. USA isolates ( n = 526) were more frequently susceptible to these agents than isolates from other countries ( n = 274; C/T: 83% vs 42%; CZA: 77% vs 47%; I/R: 37% vs 23%; P < 0.001 for each comparison) and isolates with carbapenemases ( n = 157) were less frequently susceptible than isolates without carbapenemases ( n = 643; C/T: 7% vs 84%; CZA: 24% vs 77%; I/R: 6% vs 39%; P < 0.001 for each comparison). Thirty-day mortality and DOOR were similar overall in patients infected with isolates not susceptible vs susceptible to each βL/βLI. However, the adjusted probability of a better DOOR outcome for a randomly selected patient with bacteremia due to a C/T-not susceptible vs -susceptible isolate was 38.2% (95% confidence interval, 25.6%–52.7%). Resistance to novel βL/βLIs, especially I/R, is common in CRPA, particularly outside the USA and in carbapenemase-producing isolates. Additional treatment options are needed for CRPA infections.

Abstract Background Breast cancer (BC) diagnosed during pregnancy or postpartum often presents with aggressive features, potentially influenced by hormonal, immunological, and tissue remodeling changes. Studies have suggested that postpartum BC may be associated with worse outcomes, though most evidence is retrospective and constrained by methodological limitations. This study evaluated associations between pregnancy history, recency of childbirth, and long-term outcomes in a prospective cohort of young patients with early-stage BC. Patients and Methods Patients aged ≤40 years with stage I–III BC enrolled in the Young Women’s Breast Cancer Study were categorized at diagnosis as nulligravid, nulliparous, pregnant, or parous (≤5 vs 5 to 10 years postpartum). Analyses were stratified by BC subtype (estrogen receptor-positive [ER+]/HER2−, HER2+, and triple-negative [TNBC]), with distant recurrence-free survival (DRFS) as the primary endpoint. Results Among 859 patients, 257 (29.9%) were nulligravid, 50 (5.8%) nulliparous, 37 (4.3%) pregnant, and 515 (60.0%) parous. Pregnant patients had proportionally more TNBC, nodal involvement, T3/T4, and grade 3 tumors. After 11.1 years median follow-up, pregnancy or postpartum status was not independently associated with DRFS in multivariable models adjusted for age, tumor characteristics, and treatment, with consistent findings across ER+/HER2−, HER2+, and TNBC subtypes. Sensitivity analyses, including further categorization of postpartum diagnoses (&lt;2 vs 2 to 5 years), yielded consistent results. Conclusions Pregnancy history and recency of childbirth were not independently associated with long-term DRFS. Despite more aggressive features at diagnosis, patients diagnosed during or after pregnancy had comparable outcomes after adjustment, suggesting no adverse prognostic impact. Clinical trial registration NCT01468246 (https://clinicaltrials.gov/study/NCT01468246? term=NCT01468246&rank=1).

Abstract Background T cell activation and polarization drive atherosclerosis. Among the mediators underlying T cell polarization, the epigenetic enzyme EZH2 catalyses the repressive mark H3K27me3. In humans, EZH2 is upregulated in T cells in advanced atherosclerosis, whereas its deficiency in T cells in mice limits plaque formation via an anti-inflammatory response. Emerging evidence indicates that EZH2 can also regulate lncRNAs and miRNAs by depositing H3K27me3 at their loci, repressing transcription. Purpose We hypothesize that EZH2 governs lncRNAs and miRNAs expression in T cells in the context of atherogenesis. Methods CD4+ T cells were isolated from spleens of atherosclerosis-prone T cell-specific Ezh2 (Ezh2cd4)-KO mice and WT littermates. Small RNA-seq (SMARTer® smRNA-Seq) and transcriptomic profiling (Prime-seq) were performed. Differential expression was assessed using edgeR. Selected miRNAs were validated by RT-qPCR. Putative miRNA targets were retrieved from miRTarBase (v. 8) and TargetScan, and gene ontology enrichment was performed using Metascape. Results In CD4+ T cells from Ezh2cd4-KO mice, 41 out of 2,950 mature miRNAs were differentially expressed (log2FC &gt; |0.8|, FDR &lt; 0.05), with 27 upregulated and 14 downregulated. Top upregulated miRNAs included miR-125a-5p, miR-130a-3p, miR-744-5p, miR-181a-5p, miR-181b-5p, miR-374b-5p, miR-99b, miR-3085, and miR-7049-3p. RT-qPCR confirmed that expression of miR-125a-5p, miR-181a-5p, miR-181b-5p, and miR-99b-5p were upregulated in Ezh2-deficient murine CD4+ T cells. GO enrichment analysis of downregulated genes revealed enrichment of IL-4, IL-9, IL-10, and TGF-β pathways, suggesting their relevance in T-cell function and differentiation. In human Jurkat T cells, pharmacological EZH2 inhibition using GSK126 or tazemetostat resulted only in the upregulation of miR-125a-5p and miR-99b-5p, confirming the conservation of the mechanisms in humans. Integration of our Prime-seq transcriptomics and smallRNAseq datasets with human and mouse predicted and experimentally validated targets of miR-125a-5p and miR-99b-5p identified six conserved target genes: STAT1, FAM169B, NDRG3, PSMB9, TRIB1, and RAB3IP. Conclusions Our findings indicate that Ezh2 represses miRNA expression in T cells during atherogenesis, thereby possibly promoting differentiation toward pro-atherogenic subsets while restraining anti-atherogenic transcriptional programs. Further research is needed to elucidate the underlying mechanisms. Ezh2-regulated miRNAs may represent promising targets to direct T cell plasticity to combat atherosclerosis.

OBJECTIVES We aimed to characterize the frequency of major complications of acute COVID-19 and multisystem inflammatory syndrome in children (MIS-C) and adolescents present at 6 months after initial presentation. METHODS The Pediatric Research Immune Network on SARS-CoV-2 and MIS-C (PRISM) study was a prospective cohort at 20 US pediatric academic medical centers. Individuals aged younger than 21 years meeting any of the following were enrolled: SARS-CoV-2 detection within 7 days, Centers for Disease Control and Prevention (CDC) MIS-C criteria, or CDC MIS-C criteria except having involvement of 1 organ system. The study was designed to assess the proportion of children with major complications (cardiovascular, pulmonary, gastrointestinal/hepatic, renal, and/or neurologic) 6 months after presentation. RESULTS Data were analyzed on 229 hospitalized participants: 59 with COVID-19 (mean age 10.4 years; SD, 5.5) and 170 with MIS-C (mean age 10.1 years; SD, 4.8). Overall, 42.8% were female, making up 55.9% and 38.2% of the COVID-19 and MIS-C groups, respectively. Overall, the frequencies of major complications at 6 months after initial presentation were: 16/195 (8.2%) cardiovascular, 11/154 (7.1%) pulmonary, 11/154 (7.1%) gastrointestinal/hepatic, 3/152 (2.0%) renal, and 3/189 (1.6%) neurologic. Organ system complications did not differ significantly between the COVID-19 and MIS-C groups. Six of 14 (42.9%) COVID-19 and 21/26 (80.7%) MIS-C participants with at least 1 six-month complication had no underlying medical condition that may have been associated with their complication(s). CONCLUSIONS Major complications were infrequent but observed in children without underlying medical conditions, underscoring the importance of prospective follow-up to optimize management and elucidate the complications associated with severe SARS-CoV-2 infection in children.

Abstract Background Previous studies evaluated large language model (LLM) performance on the American Society of Nuclear Cardiology (ASNC) Board Preparation Exam. Without domain-specific context, the best model (GPT-4o) achieved 63.1%, below the estimated 65% passing threshold and the 78% mean score of human fellows-in-training (FITs). Providing textbook context improved GPT-4o to 73.8% on text-only questions, but still fell short of human trainees. Whether next-generation LLMs with retrieval-augmented generation (RAG) can exceed this gap is unknown. Methods Claude Opus 4.7 and GPT-5.5 were administered all 168 questions (141 text-only, 27 image-based) from the 2023 ASNC Board Preparation Exam across 5 iterations each, using RAG with a nuclear cardiology textbook, companion atlas, and ASNC clinical guidelines. Claude used local FAISS-based semantic retrieval; GPT-5.5 used Azure’s cloud-hosted vector store. Performance was compared to prior LLM results and 13 human FITs. Results Across 5 iterations, Claude Opus 4.7 achieved a mean accuracy of 86.3% ± 1.4% (text 88.8%, image 73.3%). GPT-5.5 achieved 86.7% ± 2.2% (text 88.5%, image 77.0%) but refused a mean of 12.2 questions (7.3%) per iteration due to safety filters. Both models surpassed the human FIT mean (78.0%) and the estimated passing threshold. Compared to GPT-4o without context (63.1%), this represents a 23-percentage-point improvement in 18 months. Conclusion Next-generation LLMs with RAG now surpass average human trainee performance on nuclear cardiology board preparation questions, suggesting significant potential as educational tools and knowledge-reference aids in cardiovascular imaging. Condensed Abstract Across 5 iterations each, Claude Opus 4.7 and GPT-5.5 with retrieval-augmented generation achieved mean accuracies of 86.3% and 86.7% on the 2023 ASNC Board Preparation Exam (168 questions), both surpassing the mean human fellow-in-training score of 78%. GPT-5.5 refused a mean of 12.2 questions (7.3%) per iteration due to safety filters. These results represent a 23-percentage-point improvement over the best prior LLM without context (63.1%), demonstrating that RAG-enhanced LLMs have reached human-level proficiency in nuclear cardiology knowledge. Graphical Abstract Overview of the three-study research arc evaluating LLM performance on the 2023 ASNC Board Preparation Exam. Study 1 (2024) tested four LLMs without context (best: GPT-4o, 63.1%). Study 2 (2025) added textbook context to GPT-4o (73.8%). Study 3 (2026, current) evaluated Claude Opus 4.7 and GPT-5.5 with retrieval-augmented generation across 5 iterations each (mean 86.3% and 86.7%, respectively), both surpassing the human fellow-in-training mean of 78%. Right panel shows the performance scale with key thresholds.