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Importance The prevalence of cardiovascular disease differs substantially across neighborhoods. However, few studies have examined the contribution of neighborhood-level structural racism to inequities in cardiovascular health. Objective To investigate the association between neighborhood-level manifestations of structural racism and the prevalence of cardiovascular clinical and behavioral risk factors and cardiovascular diseases. Design, Setting, and Participants This cross-sectional study consisted of 71 915 US census tracts. The Structural Racism Effect Index (SREI) was appended to the 2020 Centers for Disease Control and Prevention’s PLACES dataset. Race and ethnicity were self-reported and obtained from the 2019 American Community Survey 5-year estimates. Data analysis was conducted from June 2024 to October 2024. Exposure The SREI is a composite score of census tract measures within 9 domains affected by structural racism (built environment, criminal justice, education, employment, housing, income and poverty, social cohesion, transportation, and wealth). The SREI scores were categorized into distribution-based quintiles, where higher quintiles represented greater neighborhood structural racism. Main Outcomes and Measures Neighborhood-level prevalence of cardiovascular clinical (high blood pressure, high cholesterol, obesity, and diabetes) and behavioral (current cigarette smoking and no leisure-time physical activity) risk factors and cardiovascular disease (coronary heart disease and stroke). Multilevel-linear mixed models, adjusting for confounders, were used to estimate adjusted prevalence rate ratios (aPRR). Results Among 71 915 census tracts, neighborhoods in the highest quintiles of structural racism were more likely than neighborhoods in the lowest quintile to be in the southern region (quintile 1, 19.9% vs quintile 5, 56.8%). The proportion of the population that was Black was largest in neighborhoods in the highest quintile of structural racism (quintile 1, 2.2% vs quintile 5, 23.0%). After adjustment, compared with the lowest quintile of structural racism, the highest quintile had significantly higher prevalence rates of cardiovascular clinical risk factors, including high blood pressure (aPRR, 1.37; 95% CI, 1.37-1.38), obesity (aPRR, 1.40; 95% CI, 1.39-1.40), and diabetes (aPRR, 1.80; 95% CI, 1.79-1.81). Similarly, for cardiovascular behavioral risk factors, the highest quintile of structural racism had significantly higher prevalence rates of current cigarette smoking (aPRR, 1.84; 95% CI, 1.83-1.85) and no leisure-time physical activity (aPRR, 1.88; 95% CI, 1.87-1.89). Additionally, for cardiovascular diseases, the highest quintile of structural racism had higher prevalence rates of coronary heart disease (aPRR, 1.80; 95% CI, 1.79-1.82) and stroke (aPRR, 1.99; 95% CI, 1.98-2.00). Conclusions and Relevance In this cross-sectional study, structural racism was associated with inequities in neighborhood cardiovascular health, highlighting opportunities for place-based prevention efforts.

Abstract Purpose: AXL, a receptor tyrosine kinase related to oncogenic processes, is aberrantly expressed in various cancers and associated with treatment resistance. Enapotamab vedotin (EnaV), a novel anti-AXL human IgG1 and monomethyl auristatin E antibody–drug conjugate, demonstrated antitumor activity in preclinical models, including non–small cell lung cancer (NSCLC). This phase 1/2 study assessed the safety and preliminary efficacy of EnaV in solid tumors. Patients and Methods: This study comprised dose-escalation and dose-expansion phases; both phases investigated EnaV once every 3 weeks (Q3W) and EnaV on days 1, 8, and 15 of a 28-day cycle (3Q4W). Primary objectives determined the maximum tolerated dose (dose escalation) and safety (dose expansion). Pharmacokinetic profile, antitumor activity, and AXL expression were also assessed. Results: During dose escalation, 32 patients received EnaV Q3W; 15 received EnaV 3Q4W. The maximum tolerated dose and recommended phase 2 dose were 2.2 mg/kg in Q3W and 1.0 mg/kg in 3Q4W schedules. In dose expansion, 189 patients received EnaV Q3W; 70 received EnaV 3Q4W. Common adverse events in dose expansion included fatigue, constipation, nausea, decreased appetite, and diarrhea. Overall response rates ranged from 4.5% to 12.5% with Q3W dose schedule and from 9.1% to 11.5% with 3Q4W dose schedule. Disease control rates for NSCLC cohorts were 40.9% to 50.0%. NSCLC subset analysis demonstrated correlation between radiomics signature and disease control. The relationship between clinical activity and AXL expression was not apparent. Conclusions: EnaV had an acceptable safety profile; however, because the evaluation of antitumor activity did not show clinically meaningful responses, clinical development of EnaV was discontinued. Significance: EnaV, an anti-AXL human IgG1 and monomethyl auristatin E antibody–drug conjugate, showed single-agent antitumor activity in preclinical models. This phase 1/2 study of EnaV demonstrated a manageable safety profile and antitumor activity in selected tumor types. Further studies exploring alternative targeting modalities, patient selection, and/or combinations are needed.

Abstract Understanding tumor cell dynamics can improve prognosis and treatment but remains limited for lung adenocarcinoma in people who have never smoked (NS-LUAD). With RNA sequencing data from 684 NS-LUAD cases and validation in an independent dataset, we identified three subtypes with distinct phenotypic traits and cell compositions. Additional genomic and histologic data further characterized the subtypes. “Steady,” marked by low proliferation, high alveolar cell fraction, moderate-to-well differentiation, and fewer driver gene alterations, is linked to prolonged survival and low immune evasion. “Proliferative” shows high proliferation markers, TP53 mutations, and gene fusions. “Chaotic,” with high epithelial-to-mesenchymal transition markers, has the worst prognosis, even within stage I tumors. Lacking known molecular or histologic characteristics, this aggressive subtype is solely identified by transcriptomic data. A 60-gene signature recapitulates the classification and predicts survival even within subgroups based on tumor stage or known genomic features, emphasizing its potential for improving early-stage NS-LUAD prognostication in clinical settings. Significance: The transcriptome of 684 NS-LUAD identifies three subtypes with different cellular dynamics and genomic and morphologic features. A 60-gene signature accurately stratifies subjects for mortality risk, even in stage I, offering a potential clinically applicable tool for treatment decision-making in patients with NS-LUAD. See related commentary by Azizi et al., p. 423

Abstract INTRODUCTION M0 images were missing in Siemens ASL data in Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset, prohibiting cerebral blood flow (CBF) quantification. METHODS A conditional latent diffusion model was trained and evaluated on in‐house datasets, then applied to the Siemens data in ADNI‐3. Regional CBF differences by Alzheimer's disease (AD) stages, their accuracy for AD classification, and CBF trajectory slopes were compared between generated data (Siemens) and acquired data (General Electric). RESULTS The diffusion model generated M0 images with high fidelity (SSIM = 0.918 ± 0.023, PSNR = 31.361 ± 2.537) and minimal CBF bias (mean difference is 0.21 ± 1.58 mL/100 g/min). Both generated and acquired CBF showed similar spatial patterns and decreasing trends with AD progression in specific AD‐related regions. Generated CBF also improved accuracy in classifying AD stages compared to qualitative perfusion images. CONCLUSION This study shows the potential of diffusion models for imputing missing modalities in large‐scale studies exploring the use of ASL as a biomarker of AD. Highlights Using latent diffusion model, we can generate M0 image from control image in arterial spin labeling (ASL) with high fidelity. The generated M0 can be used for cerebral blood flow (CBF) quantification in Alzheimer's Disease Neuroimaging Initiative dataset. The performance of classification between Alzheimer's disease (AD) patients and cognitive normal people is better when using generated CBF maps than using non‐quantitative perfusion images. ASL CBF decreases with AD progression in key AD‐related brain regions.

Abstract The highest risk for liver allograft rejection is within the first weeks to months after a liver transplant; however, while later-stage mechanisms are well described, the initial window at the moment of alloantigen influx (e.g., ~ 1 h post-reperfusion) remains unmapped. T-cell priming is initiated in lymph nodes, yet these sites are rarely profiled in humans and their relationship to rejection risk is unclear. To address this gap, we profiled paired pre- and ~ 1 h post-reperfusion hepatic draining lymph nodes from liver transplant recipients using multiplexed immunofluorescence and GeoMx whole-transcriptome profiling to identify features that predict rejection versus non-rejection. Early after reperfusion, CD4 + and CD8 + T cells became proximal to macrophages in rejection compared to dendritic cells in non-rejection, which also displayed an immunoregulatory-leaning profile marked by PD-1, IDO1, and CD39, suggesting that macrophages and dendritic cells differentially influence early T-cell alloimmunity. These results provide nodal targets for precise immune modulation.

Introduction Social media platforms, particularly X (formerly Twitter), play an influential role in professional networking and information dissemination. This study aimed to examine X usage trends among faculty in a single department of surgery at a large academic institution. Methods Faculty X accounts were analyzed from January to June 2022. Metrics such as follower count, number of accounts followed, and post (formerly: tweets) types (original/quoted reposts) were studied. Themes of posts were categorized as personal, promotional, educational, or related to academic events/conferences. Associations between faculty rank, division, gender, and post metrics were explored using Mann-Whitney U and Kruskal-Wallis tests. Results Of 133 faculty members, 53 (39.85%) had X accounts, with 3 excluded due to privacy settings. A total of 3476 posts were analyzed, averaging 0-34 posts/month per faculty. Categories included professional (63%, n = 2174), educational (19%, n = 653), and personal (13%, n = 436). No significant associations were found between faculty gender/division and posting rates. However, faculty rank correlated significantly with primary post categories ( P < 0.01). Associate professors, and professors posted more about academic events (2% and 1%) than instructors or assistant professors (1%). The most followed faculty actively promoted colleagues’ work through reposting. Conclusion Less than half the faculty in a single department of surgery engaged with X. Those active predominantly used it for promotion, followed by education and personal use. Adoption remains limited, highlighting opportunities for growth in utilizing X for academic dissemination.

Abstract Disclosure: N.M. Singh Ospina: None. Y. Chen: None. F. Du: None. J.P. Brito: None. H. Shao: None. Q. Liu: None. R.G. McCoy: None. T. Jiao: None. Background: The levothyroxine dose for patients with hypothyroidism is highly correlated with weight. In patients with hypothyroidism, TSH measurements are used to assess the adequacy of levothyroxine dosing.Since type 2 diabetes (T2D) and obesity are two common comorbidities for patients with hypothyroidism, and the significant weight loss associated with Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RAs) therapy, the initiation of GLP-1 RA on levothyroxine users may significant increase the need for levothyroxine dose reduction potentially requiring additional TSH tests to assure control. Objectives: To evaluate the timing and frequency of TSH testing within one year of initiation of GLP-1, or sodium-glucose co-transporter 2 (SGLT-2) inhibitors, in patients with T2D on levothyroxine treatment. Methods: We identified a cohort of T2D patients using 15% of Medicare fee-for-service claims data from 2005 to 2020. Cohort entry was defined by the initiation of GLP-1 or SGLT2. Patients needed to continuously receive the same dose of levothyroxine for &gt;6 months and have at least 1 TSH measurement before the index date. We excluded patients with hyperthyroidism, thyroid cancer, end-stage renal disease, HIV/AIDs, organ transplant, or who received medications that affect thyroid levels before the index date. The primary outcome was the timing and frequency of TSH testing within one year after GLP-1 RA initiation. Demographics, comorbidities, and medication use were balanced using 1:1 propensity score matching based on the index date. Results: After matching, no significant demographic differences were observed among the 2,107 patients in GLP-1 RA and SGLT-2 groups, respectively. Overall, 32.1%, 32.3%, and 35.6% were aged 65-70, 70-74, and over 75, with 69.3% female and 87.9% white. In the year before the index date, the average number of TSH tests was higher in the GLP-1 RA (1.16 ± 1.27) compared to the SGLT2 (1.07 ± 1.18, p-value: 0.001). In the year after the index date, the average number of TSH tests declined to 0.93 ± 1.18 for GLP-1 and 0.89 ± 1.13 for SGLT2 (p-value: 0.03). Most patients (48.6 vs. 49.5%) had no TSH tests, 41.3 vs. 40.6% had 1-2 tests, and 10.1 vs. 9.9% had more than 2 tests in the GLP-1 RA and SGLT-2 group, respectively. Fewer patients (32.3 vs. 33.6%) were tested within 0-6 months while the majority (67.7 vs. 66.5%) waited longer than 6 months. The relative risk of TSH testing between the GLP-1 RA group and the SGLT2 group was 1.03 (95% CI: 0.98 to 1.08) 1-year before the index date and 1.00 (95% CI: 0.94 to 1.06) 1-year after the index date. Conclusions: Despite the potential impact of GLP-1 RA on levothyroxine dosing, on average, half of patients did not receive a TSH test after treatment initiation. There were no significant differences in TSH testing patterns between GLP-1 and SGLT2 groups, with similar test frequencies and timing observed. Presentation: Saturday, July 12, 2025