Citations

BACKGROUND: Unruptured intracranial aneurysms (UIAs) affect up to 5% of the population, and rupture can lead to devastating subarachnoid hemorrhage. GLP-1RAs (glucagon-like peptide-1 receptor agonists) have anti-inflammatory and vasculoprotective effects, but their impact on aneurysm stability and subarachnoid hemorrhage outcomes is unexplored. This study evaluated whether GLP-1RA use is associated with reduced rupture risk and attenuated severity in the event of a rupture. METHODS: We conducted a retrospective cohort study using the TriNetX US Collaborative Network (2016–2024). Cohort 1 included patients with newly diagnosed, untreated UIA; cohort 2 included those who suffered aneurysm rupture. GLP-1RA exposure was defined as use before or within 3 months of UIA diagnosis (cohort 1) or before rupture (cohort 2). The primary outcome was aneurysm rupture risk in cohort 1. Secondary outcomes include presentation severity, vasospasm, and mortality in cohort 2. Propensity score matching balanced demographics, comorbidities, and medications. RESULTS: After propensity score match, cohort 1 of patients with untreated UIA included 8088 GLP-1RA users and 8088 nonusers. GLP-1RA use was associated with significantly lower probabilities of aneurysm rupture at 1-year (0.65% versus 1.51%; P <0.001), 3-year (1.18% versus 1.85%; P <0.001), and 5-year (1.49% versus 2.10%; P <0.001) timepoints, representing a 48% decrease in hazards (hazard ratio, 0.52 [95% CI, 0.38–0.69]). Among patients who suffered aneurysm rupture (cohort 2, N=298 after propensity score match), prerupture GLP-1RA use (n=149) was associated with lower rates of intraparenchymal hemorrhage (17.4% versus 33.6%; P <0.001), intraventricular hemorrhage (10.1% versus 23.5%; P <0.001), and clinically significant vasospasm (10.7% versus 24.2%; P =0.002), as well as numerically lower rates of 30-day mortality (9.4% versus 14.1%; P =0.21). CONCLUSIONS: For patients with untreated UIA, GLP-1RA use was associated with a 48% reduction in aneurysm rupture risk and, among those who suffered aneurysm rupture, milder clinical and radiographic severity. These findings suggest possible neuroprotective and vascular stabilizing effects of GLP-1RAs for patients with UIA.

Abstract Heterogeneous treatment effects (HTE) are key to precision medicine, but most real-world studies lack the scale and diversity needed to detect them. While multi-site analyses offer a potential solution, data-sharing constraints often prevent access to patient-level information across institutions. We introduce POLARIS, a federated framework for time-to-event target trial emulation. POLARIS converts each site’s weighted Cox risk function into a compact tensor shared once with the coordinating center, enabling lossless reproduction of pooled estimates without sharing patient-level data. We applied POLARIS across five U.S. health systems to study risk of gastrointestinal outcomes after GLP-1 receptor agonist (GLP-1RAs) initiation versus sodium-glucose cotransporter 2 inhibitors (SGLT2is) and dipeptidyl peptidase 4 inhibitors (DPP4is). Results showed that GLP-1RAs were consistently associated with higher risks of nausea and vomiting, particularly among men, individuals with higher baseline HbA1c (≥ 8.5%), and lipid therapy. POLARIS provides a scalable solution for distributed target trial emulation and fine-grained assessment of HTE across diverse health systems.

Abstract Introduction Sepsis, a dysregulated immune response to infection, accounts for nearly 11 million deaths worldwide each year and remains a major cause of hospital mortality. The absence of precision diagnostics limits efforts to characterize immune dynamics and predict clinical outcomes. We evaluated whether liquid biopsies collected at ICU admission could provide insight into sepsis biology and enable precision diagnostics. Methods We applied cell-free RNA (cfRNA) liquid biopsies as a noninvasive method to highlight signaling networks, identify tissue-specific injury, and predict immune exhaustion. We collected serial samples throughout hospitalization from a cohort of 100 patients admitted with likely sepsis to a medical ICU. Comprehensive clinical data, including inpatient laboratory values and key outcome measures such as survival and ventilator-free days, were curated. Circulating cfRNA was isolated and purified from these samples and prepared for sequencing. We generated data from 254 samples at a minimum sequencing depth of 30x. We then designed a novel deep-learning computational method to enable deconvolution to better analyze and interpret these data. Results In our cohort, a total of 84 patients were adjudicated to have sepsis by the Sepsis-3 criteria, and 25 patients died within 90 days. Differential analysis was performed comparing circulating cfRNA in these septic patients to that of healthy controls, stratified by mortality along with specified subgroups including shock on admission, ventilator dependence, and preexisting immunosuppression. We identified multiple differentially expressed transcripts between septic patients and healthy controls, with significant alterations in signaling cascades associated with mitochondrial signaling, including alterations in oxidative phosphorylation and fatty acid metabolism. Using defined ligand-receptor interaction databases, we identified key pathways associated with immune and endothelial dysfunction in sepsis. Specifically, our analysis identified numerous alterations in CXCL8 (IL-8)-associated signaling cascades (engaging CXCR1, CXCR2, SDC1-3, and ACKR). Our analyses also highlighted key tissue factor pathway inhibitor (TFPI)-associated signaling via interactions with tissue factor and low-density lipoprotein receptor-related protein 1 (LRP1). These analyses are corroborated by our new deep-learning augmented approach to deconvolution, where we demonstrate the identification of rare tissue- and cell-specific signals that are associated with increased mortality in our cohort. Conclusion Liquid biopsy approaches such as cfRNA profiling can provide insight into mechanisms underlying sepsis and may uncover underlying drivers of endothelial dysfunction. These findings support ongoing efforts to develop liquid biopsy-based diagnostics and personalized therapeutic strategies for patients at high risk for sepsis and related mortality. This abstract is funded by: NIH

Abstract Respiratory viral infections such as influenza and SARS-CoV-2 can lead to the development of chronic lung disease and impaired pulmonary function long after the recovery from acute illness. However, the mechanisms underlying these post-acute sequelae remain poorly understood. Using human lung samples from patients with post-acute sequelae of COVID-19 with pulmonary fibrosis (PASC-PF) and an aged mouse model of chronic lung disease following acute viral infection, we found that CD4+ T cells were enriched near the dysplastic Krt8Hi epithelial regions of the lung. Similarly, in aged mice, CD4+ T cells localized to Krt8Hi areas, and their spatial distribution correlated positively with the extent of epithelial dysplasia. Further analysis of bronchoalveolar lavage (BAL) fluid from COVID-19 convalescent individuals revealed a distinct population of FoxP3−PD-1HiCD4+ T cells highly expressing ICOS, CD69, and CD103 - markers characteristic of both T follicular helper (TFH) and tissue-resident memory (TRM) cells, which we have defined as tissue-resident helper (TRH) cells previously. Notably, the frequency of these TRH-like cells correlated positively with the extent of reticulate or consolidated regions on chest CT scans, indicative of lung fibrosis. Furthermore, the frequency of these cells was negatively associated with lung functional parameters including forced vital capacity (FVC). These findings suggest that PD-1HiCD4+ TRH-like cells expand in PASC and may contribute to chronic lung sequelae. Given that Bcl6 is required for TRH differentiation, we employed an aged, CD4-specific, inducible Bcl6-deficient (Bcl6iΔCD4) mouse model to evaluate the functional contribution of these cells to post viral lung fibrosis. Bcl6 deficiency led to a marked reduction in total and antigen-specific PD-1HiCD4+ TRH cells, as confirmed by flow cytometry and immunofluorescence. Strikingly, Bcl6 iΔCD4 mice displayed significantly decreased inflammatory and fibrotic lesions in the lung compared to wild-type controls. Moreover, Bcl6 iΔCD4 mice exhibited enhanced lung regeneration, evidenced by increased AT1 and AT2 epithelial cells and improved pulmonary function. Together, these findings identify Bcl6-dependent CD4+ TRH responses as key drivers of post-viral chronic lung sequelae. This study reveals a novel immunopathogenic mechanism linking persistent tissue helper memory T-cell responses to impaired lung repair and fibrosis, providing new insight into the development of post-viral lung disease and potential therapeutic targets for conditions such as respiratory long COVID. This abstract is funded by: American Lung Association, NIH

Abstract Rationale Eosinophilic airway inflammation in COPD is associated with more frequent exacerbations,lower lung function,and corticosteroid responsiveness.DNA methylation captures information about genetic factors and environmental exposures, but is under-studied in eosinophilic COPD.We hypothesized that sputum cell methylation patterns reflect genomic regulation of inflammatory endotypes in COPD by DNA sequence variation. Methods We analyzed DNA previously extracted from induced sputum cells for a prior study(PMID38261629) for which sufficient quantity DNA remained for methylation arrays.For this analysis,we focused on n = 132 SPIROMICS participants with ≥20 pack-years smoking history.Samples were stratified into tertiles based on sputum eosinophil proportions,previously determined from sputum cell differential analysis by the centralized sputum analysis core for SPIROMICS(Univ of North Carolina).We assessed proportion of DNA methylation (β values) spanning 936,866 CpG sites using the Illumina Infinium Methylation EPICv2.0 BeadChip Array,which we transformed into M values(meffil R package). To identify differentially methylated regions (DMRs)(FDR&lt;0.05 in minimum of 2 CpG sites per gene region),we contrasted CpG β values between the high-eosinophil and low-eosinophil tertiles(N = 44 each),using the DMRcate package.We tested for enrichment of genes overlapping with significant DMRs using Enrichr (GWAS Catalog 2025 gene set library).To identify genetic variants associated with DNA methylation levels,we performed Methylation Quantitative Trait Loci (meQTL) analysis using TensorQTL.For each CpG site,we tested associations with SNPs within a ± 500 kb window (cis-meQTL).The linear regression model included age,sex,BMI,smoking status,smoking pack-years,study site,inhaled corticosteroid use, the first two genetic principal components, cell-type proportions (macrophages/monocytes, neutrophils, squamous epithelial cells, lymphocytes), and eosinophil tertile . Significant meQTLs were identified at an FDR&lt;0.05 using Benjamini-Hochberg correction. Results A total of 532 eosinophil-associated DMRs (FDR &lt; 0.05) were identified between the high- and low-eosinophil groups,encompassing 446 unique genes.The top enriched pathways related to counts of eosinophils (adjusted p = 0. 00002464), lymphocytes (adjusted p = 0.0001860), and the sum of eosinophils-plus-basophils (adjusted p = 0.0001860).We identified 18,432 significant SNP-CpG/meQTL pairs (FDR &lt; 0.05),suggesting extensive genetic influence on airway DNA methylation patterns.Among the n = 521 eosinophil-associated CpGs that overlapped with meQTLs,rs55687040 (TENT2,a gene involved in mRNA and miRNA processing) is a GWAS locus for FEV1/FVC ratio (PMID: 26634245), suggesting possible genetic control of airway eosinophilic methylation signatures. Conclusions Our findings disclose distinct DNA methylation signatures associated with sputum eosinophil proportion in COPD.A subset of these CpGs are regulated by genetic variants,suggesting an integrated genetic-epigenetic mechanism underlying airway eosinophilic inflammation with the potential to influence COPD risk and severity. This abstract is funded by: SPIROMICS was supported by contracts from the NIH/NHLBI (HHSN268200900013C, HHSN268200900014C, HHSN268200900015C, HHSN268200900016C, HHSN268200900017C, HHSN268200900018C, HHSN268200900019C, HHSN268200900020C), grants from the NIH/NHLBI (U01 HL137880, U24 HL141762, R01 HL182622, and R01 HL144718), and supplemented by contributions made through the Foundation for the NIH and the COPD Foundation from Amgen; AstraZeneca/MedImmune; Bayer; Bellerophon Therapeutics; Boehringer-Ingelheim Pharmaceuticals, Inc.; Chiesi Farmaceutici S.p.A.; Forest Research Institute, Inc.; Genentech; GlaxoSmithKline; Grifols Therapeutics, Inc.; Ikaria, Inc.; MGC Diagnostics; Novartis Pharmaceuticals Corporation; Nycomed GmbH; Polarean; ProterixBio; Regeneron Pharmaceuticals, Inc.; Sanofi; Sunovion; Takeda Pharmaceutical Company; and Theravance Biopharma and Mylan/Viatris.

Abstract Rationale To construct multi-trait polygenic scores (PRS) predicting chronic obstructive pulmonary disease (COPD) and exacerbations, validate their performance in diverse cohorts, and identify PRS-related proteins for potential therapeutic targeting. Methods PRSmix+, a multi-trait PRS framework, is used to train a composite PRS (PRSmulti) in COPDGene non-Hispanic white participants (n = 6,647). Associations of PRSmulti with COPD status (GOLD 2-4 vs. GOLD 0 or ICD) and exacerbation frequency were tested in COPDGene African American (n = 2,466), ECLIPSE (n = 1,858), MassGeneral Brigham Biobank (n = 15,152), and All of Us (n = 118,566). Protein prediction models were applied to GWAS summary statistics from traits contributing to PRSmulti and were validated with proteomic data in COPDGene (n = 5,173) and UK Biobank (n = 5,012). Results PRSmix+ selected 7 traits for PRSmulti. In multivariable models, PRSmulti was associated with COPD status (meta-analysis random effects (RE) OR 1.58 [95% CI: 1.28-1.94]) and exacerbation frequency (meta-analysis RE beta 0.21 [95% CI: 0.11-0.31]), with higher effect sizes observed in smoking-enriched cohorts. PRSmulti outperformed traditional single-trait PRS in all tested cohorts. Using protein prediction models, we identified 73 proteins associated with the PRS that were also validated with measured protein levels in COPDGene and UK biobank. Of these proteins, 25 were linked to approved or investigational drugs. Notable targets include AGER (RAGE), IL1RL1, and SCARF2, all implicated in COPD pathogenesis and exacerbations. Conclusions Multi-trait PRS improves prediction of COPD and exacerbation risk. Integration with proteomic data identifies druggable protein targets, offering a promising avenue for precision medicine in COPD management. Trial registration. COPDGene: NCT00608764; ECLIPSE: NCT00292552. This abstract is funded by: NIH and the COPD Foundation

PURPOSE External beam radiation therapy (EBRT) has gained delayed acceptance as a recommended first-line treatment modality for patients with hepatocellular carcinoma (HCC), given limited evidence that it improves overall survival (OS). We analyzed individual patient data (IPD) from an international cohort to assess OS among patients with HCC treated with EBRT. METHODS We performed a systematic review of publications that assessed EBRT, met prespecified technical standards for HCC, and reported OS (search date December 15, 2022). Corresponding authors were invited to submit IPD for the study. We performed Kaplan-Meier survival analyses to determine OS and restricted mean survival time (RMST) stratified by Barcelona Clinic Liver Cancer (BCLC) stage and treatment status (ie, treatment-naïve and experienced). We performed random effects Cox proportional hazards modeling to assess clinical characteristics associated with OS. RESULTS Data were provided on 4,913 patients treated with EBRT with a median follow-up time of 5.0 years. The median OS was 6.8 years (95% CI, 5.7 to 8.7) for BCLC-0 and 4.6 years (95% CI, 4.1 to 5.1) for BCLC-A. Among treatment-naïve patients, the median OS was not reached (95% CI, 8.6 to not reached) for BCLC-0 and was 5.4 years (95% CI, 4.5 to 6.7) for BCLC-A. In multivariable models, more advanced BCLC stage, higher tumor burden, worse performance status, and Child-Pugh class B or C were associated with a higher risk of mortality. Ablative radiation dose and more recent year of treatment were associated with a reduced risk of death. CONCLUSION To our knowledge, this study represents the largest multinational cohort of patients with HCC treated with EBRT. OS outcomes with EBRT for very early- and early-stage HCC appear to be comparable with resection, thermal ablation, and other ablative locoregional therapies. These data support the inclusion of EBRT in the BCLC HCC clinical decision-making process.

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.

Introduction Historic series have demonstrated the importance of construct rigidity in the treatment of pelvic discontinuities, but there remains limited data comparing different constructs, especially contemporary cup-cages and custom triflange components. The aim of this study was to evaluate reconstructive constructs with emphasis on implant survivorship, radiographic results, complications, and clinical outcomes. Methods We reviewed 184 revision THAs with unilateral pelvic discontinuity at a single institution between 1998–2022. Mean age was 66 years, 83% were female, and mean BMI was 29 kg/m2. Constructs included uncemented cup and plating (n=66, 36%), cup-cages (n=59, 32%), jumbo uncemented acetabular components (n=30, 16%), conventional antiprotrusio cages (n=16, 9%), and custom triflanges (n=13, 7%). Since 2013, 73% of cases were treated with either a cup-cage or custom triflange. Acetabular distraction (n=36, 20%) and porous augments (n=33, 18%) were used as adjuncts. Mean follow-up was 8 years. Results The 5-year survivorships free of revision for aseptic loosening, any revision, and any reoperation were 92%, 79%, and 75%. Of 43 revisions, the most common indications were aseptic loosening (n=15) and dislocation (n=15). For each construct, the 5-year survivorships free of revision for aseptic loosening were 100% (triflange), 94% (cup-cage), 92% (uncemented jumbo acetabular component), 90% (plating), and 86% (conventional anti-protrusio cage). Radiographic analysis demonstrated discontinuity healing in 85% of unrevised patients. Of the 15 re-revisions for aseptic loosening, 92% involved loss of fixation from inferior hemipelvis. There were 63 complications with dislocation (n=32), nerve palsy (n=10), and wound problems (n=9) most common. Mean Harris hip scores improved from 51 to 70 at 5 years. Conclusion In this series, the 5-year survivorship free from aseptic loosening was very good (92%), especially with contemporary techniques like custom triflange (100%) and cup-cage constructs (94%). Survivorship free from any revision (79%) and reoperation (75%) remain lower due to dislocation and infection.