Citations

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.

Expert consensus recommendations from 21 academic centers were established for appropriate radiography utilization at 12 potentially low-yield anatomic sites through a multidisciplinary process endorsed by six major American medical societies.

As an emerging tire wear-derived environmental contaminant, 6PPD-quinone (6PPDQ) has raised significant concerns regarding its neurotoxic potential, particularly for children exposed to recycled tire crumb rubber in playgrounds. However, the molecular mechanisms by which 6PPDQ influences neurological disorders such as epilepsy remain poorly understood. In this study, we employed an integrative framework combining network toxicology, bulk analysis of human epileptic brain tissues, Mendelian randomization, and molecular dynamics simulations to elucidate these mechanisms. Our findings, validated through CETSA-WB and SPR, identify 6PPDQ as a direct ligand that binds to and stabilizes neuronal TP53. Through a synergistic double-hit mechanism, 6PPDQ directly engages the TP53 pathway while simultaneously triggering microglial interleukin-6 secretion. These converging pathways lead to the suppression of the master antioxidant regulator Nrf2, resulting in glutathione depletion, excessive reactive oxygen species accumulation, and exacerbated neuronal damage under excitotoxic stress. Experimental validation using glutamate-induced HT22 cell models and microglia–neuron crosstalk systems confirmed that targeting the TP53/Nrf2 axis or scavenging ROS significantly attenuates 6PPDQ-induced neurotoxicity. Our findings highlight critical risks to pediatric neurological health posed by tire-derived contaminants and identify the TP53/Nrf2 axis as a promising therapeutic target. Furthermore, this work provides a robust scientific basis for refining risk assessment frameworks and developing regulatory strategies to mitigate environmental exposure to 6PPDQ.

Abstract Background Acute kidney injury (AKI) frequently causes remote organ injury including hepatic steatosis, yet whether lipid accumulation reflects increased synthesis or impaired clearance has not been resolved. Methods We used a murine ischemia-reperfusion AKI model. Unbiased liver proteomics was performed at 24 hours after reperfusion, and dysregulated pathways were identified by Gene Set Enrichment Analysis. Results were validated by Western blotting, qPCR, and immunohistochemistry. These findings were complemented by retrospective analysis of two ICU databases (MIMIC-IV and eICU-CRD). Results AKI significantly increased serum ALT and AST and induced hepatic lipid accumulation. Proteomic analysis revealed that key lipogenic enzymes (Scd1, Fasn, Acly, Acaca) were uniformly suppressed rather than upregulated. Proteins essential for VLDL assembly (ApoB, MTTP, ApoE) were significantly downregulated. Plasma triglycerides were decreased while liver triglycerides were increased, consistent with impaired hepatic lipid export. As in renal tubular cells, AKI also disrupted ER protein folding homeostasis in the liver, triggering ER stress. This was evidenced by upregulated levels of the ER chaperone GRP78, increased XBP1 splicing indicative of UPR activation, and elevated expression of the ER stress-induced pro-apoptotic transcription factor CHOP, suggesting that prolonged ER stress may also promote hepatocyte cell death. TLR4/MyD88 signaling was activated, yet inflammatory cytokines were paradoxically reduced, accompanied by Kupffer cell depletion (decreased F4/80) and monocyte infiltration (increased CD68). In 6,996 propensity-matched ICU patients (MIMIC-IV), AKI independently increased the risk of clinically significant liver injury 4-fold (adjusted OR = 4.41). Analysis of 22,727 patients across 208 hospitals (eICU-CRD) identified a lipid dissociation pattern: elevated triglycerides alongside decreased total cholesterol, HDL, and LDL, with dose-dependent scaling across KDIGO stages. Conclusions These data support ER stress-mediated impairment of VLDL export as a primary driver of AKI-induced hepatic steatosis. Clinical validation across two independent ICU databases identifies a dual metabolic insult: enhanced peripheral lipid delivery compounds impaired hepatic export, amplifying hepatic lipid retention. ER stress and lipid export machinery represent potential therapeutic targets for AKI-associated liver injury.

Abstract INTRODUCTION To examine the generalizability of Alzheimer's disease (AD) biomarker models in real‐world older adults, we examined AD biomarker relationships with cognition in two multicenter cohorts that differ with respect to recruitment approach and health risk factors but were matched on a variety of characteristics. METHODS We compared harmonized health and demographic data, AD and cerebrovascular biomarkers, and cognitive performance in the community‐recruited U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) Imaging substudy and a matched sample from the Alzheimer's Disease Neuroimaging Initiative (ADNI) which recruited primarily from academic specialty clinics. RESULTS Elevated β‐amyloid (Aβ) and tau were associated with cognitive performance in ADNI but not U.S. POINTER. Findings were consistent across different cohort matching schemes, and were not explained by discrepancies in vascular risk. DISCUSSION The role of Aβ and tau in cognitive performance may be reduced in real world samples compared to academic specialty clinics.

Abstract Background Single breath diffusing capacity of the lung for carbon monoxide (DLCO) remains the most widely used test to assess pulmonary gas exchange. GLI DLCO reference equations are based on a larger, more diverse dataset and offer age-specific and internally consistent reference values. However, their impact on interpretation in a real-world population remains uncertain. Research Question Describe the direction and magnitude of DLCO interpretation changes resulting from our multicenter PFT laboratory transition from Miller to GLI reference equations. Study Design and Methods In this multicenter cross-sectional study, we reanalyzed 88,060 DLCO measurements in a large pulmonary function laboratory database performed between 2016 and 2022 using GLI and Miller reference equations, stratified by self-reported race and ethnicity. Baseline patient characteristics and lung function measurements were summarized with continuous characteristics as median (IQR) and categorical variables as n (%). Kruskal-Wallis test was used to evaluate the difference between GLI and Miller DLCO % predicted difference between races, and two-by-two and four-by-four tables were generated to summarize the proportion of concordance and discordance of GLI to Miller severity levels. A repeated measures multivariable logistic regression was used to evaluate discordance between GLI and Miller severity and patient characteristics (age, sex, race, and BMI). Results We included 63,357 individuals with 88,060 PFT visits; 91.6% (58,076) identified as Caucasian, 5.2% (3,262) as Black, 1.4 % (895) as Asian, and 1.8% (1,113) as mixed/other race. Fifty-one percent were female with an median age of 64 years (range: 5- 85). 7.4% (6509) of DLCO results were discordant, with 0.5% (n = 439) abnormal by GLI only, and 6.9% (n = 6070) abnormal by Miller only. Compared to the Miller, GLI interpretations were associated with a greater shift toward normal interpretations. Younger age, lower BMI, female sex, and being of NE Asian, SE Asian, or Other/mixed race compared to Caucasian were associated with higher odds of discordance in DLCO severity/normal classification. Interpretation The use of GLI reference equations substantially alters the interpretation of DLCO results, shifting a meaningful subset of patients from abnormal to normal classification. While GLI reference equations offer more comprehensive, population-based approach, it is crucial to place these interpretations within the context of the patient presentation until further investigations more clearly define the clinical implications of these transitions. This abstract is funded by: none

Abstract Rationale Advances in bronchoscopic technology, including robotic-assisted bronchoscopy (RaB) and cone-beam CT (CBCT), have enabled biopsy of multiple nodules in a single procedure. Here we present the procedural characteristics, safety, diagnostic yield, and use of linear endobronchial ultrasound (EBUS) staging in patients with multifocal pulmonary nodules biopsied under a single anesthesia event. Methods This multi-center, retrospective observational study included adults undergoing RaB biopsy of multifocal peripheral pulmonary lesions and lymph node assessment under a single anesthesia event at six U.S. centers from 11/2019 - 8/2025. Procedures utilized either the Ion (Intuitive) or Monarch (Ethicon) systems under general anesthesia. De-identified demographic, radiologic, procedural, pathologic, and safety data were collected in a secure centralized database. Safety outcomes included pneumothorax and its sequelae, hypoxia, and infectious complications. Diagnostic yield was determined using the 2024 ATS/ACCP consensus statement. NGS adequacy was reported from two health systems with well-defined criteria for sufficiency and standard institutional practices for sending NGS testing on both nodules. Statistical analyses utilized included descriptive statistics, t-tests, chi-squared/Fisher’s tests where appropriate, and logistic regression. Results Among 191 patients, 177 underwent biopsy of two and 14 of three nodules. Lymph nodes were sampled in 167 (87.4%), with 18 (10.8%) positive for malignancy; notably, 17 of 18 (94%) patients with nodal metastases had at least one fully solid nodule. Complications occurred in 20 patients (10.5%), including pneumothorax in 14 (7.3%), with 4 (2.1%) requiring tube thoracostomy. There were no cases of bilateral pneumothorax. Transient hypoxia occurred in 3 patients (1.6%) and 3 developed outpatient-managed bronchitis. Seven patients (3.7%) required unplanned admission. Overall diagnostic yield was 72.2%, with 122 (63.9%) patients having two diagnostic nodules and 33 (17.4%) having two non-diagnostic nodules. Bronchus sign (OR 2.9, p = 0.003), radial EBUS use (OR 2.6, p = 0.025), and CBCT use (OR 2.4, p = 0.021) were associated with procedures having two diagnostic nodules. At sites with standardized NGS adequacy reporting, 74 of 81 malignant nodules (91%) provided sufficient tissue for NGS. Conclusions •Single-procedure biopsy of multifocal pulmonary nodules is feasible, safe, and achieves industry-standard strict diagnostic yield. •Complications are slightly higher than single-nodule procedures. Serious events were rare. •17 of 18 patients with malignant nodal disease had at least one fully solid nodule; no patients with two pure ground glass nodules had nodal metastasis. •NGS testing was feasible and adequate on the majority of samples, aiding clinicians in staging multifocal nodules. This abstract is funded by: None

Abstract Rationale Inflammatory bowel disease (IBD) is increasingly recognized as a systemic disorder, with extraintestinal manifestations (EIMs) involving multiple organ systems. Pulmonary involvement, particularly interstitial lung disease (ILD), remains an underrecognized manifestation of IBD. Its prevalence, clinical characteristics, and risk factors in IBD remain poorly defined. Methods We conducted a retrospective study of adults (≥18 years) with IBD who had at least one encounter in our health system between January 1, 2013 and December 31, 2023. IBD, and ILD cases were identified using ICD-9/ICD-10 codes, with ILD diagnoses confirmed by thoracic radiologists. Demographic, clinical, pulmonary, smoking, medication, and surgical data were abstracted. Associations between patient characteristics and ILD were evaluated using both a cohort design and a matched case-control design (1:3 ratio). Mortality was assessed using a Cox proportional hazards model with ILD as a time-dependent covariate. Results Among 875 patients with IBD, 109 (12%) had ILD. Radiographic patterns included nonspecific interstitial pneumonia (NSIP, 27%), indeterminate (26%), definite/probable UIP (24%), hypersensitivity pneumonitis (15%), and organizing pneumonia (8%). Pulmonary function testing demonstrated predominantly restrictive physiology and impaired diffusion capacity. In multivariable analysis, higher BMI (OR 1.04), bronchiectasis (OR 2.65), ex-smoking (OR 2.15), and use of adalimumab (OR 2.04) or infliximab (OR 2.14) were independently associated with ILD. The matched case-control design confirmed these findings and also identified older age (OR 1.04) as a significant factor. ILD was strongly associated with mortality (HR, 3.78; 95% CI, 2.50-5.72; p < 0.001). Conclusions ILD occurs in a meaningful subset of patients with IBD and is associated with older age, higher BMI, prior smoking, bronchiectasis, and TNF inhibitor use. ILD confers a markedly increased risk of death, highlighting the importance of early recognition and close monitoring in this population. This abstract is funded by: None