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The METTL3 inhibitor STM2457 suppresses gastric cancer progression by modulating m6A RNA modification

Gastric cancer (GC) is one of the most common and lethal cancers globally. methyltransferase-like 3 (METTL3)-mediated N6-methyladenosine (m 6 A) RNA methylation plays a crucial role in tumor initiation and progression by regulating RNA function. STM2457, a highly efficient METTL3 inhibitor, can inhibit METTL3 activity and may serve as a potential therapeutic strategy in cancers. However, the role of STM2457 for GC cells is still unknown. In this study, we analyzed the expression profile data of GC in TCGA and GEO databases, and further explored the expression involvement of METTL3 in GC cell line, investigated the therapeutic effect of STM2457 targeted inhibition of METTL3 in GC both in vitro and in vivo experiments. The results indicated that STM2457 could suppress GC cell proliferation and migration by inhibiting METTL3, and also promoted cell apoptosis and arrest the cell cycle in S phase. In addition, STM2457 could inhibit tumor growth in subcutaneous xenotransplantation mouse model. Our findings suggested that STM2457 had great potential for the treatment of GC and could serve as a foundation for future clinical applications.

Abstract WE407: Causative Association Between Longer Leukocyte Telomere Length (LTL) and Higher Risk of Atrial Fibrillation: A Meta-analysis of Mendelian Randomization Studies

Background: Atrial Fibrillation(AF) is one of the most common cardiac arrhythmias and advancing age has been associated with increased incidence of AF. Leukocyte Telomere length (LTL) has been implicated with cardiovascular aging, but its causal association with AF and its magnitude remains to be studied. This meta-analysis aims to determine the causal association between LTL and the risk of AF using Mendelian Randomization (MR) studies. Methods: A systematic search of literature was done in PubMed, Scopus and Google Scholar for MR studies addressing the causal relation between LTL and risk of AF. Studies published upto May 2025 were screened adhering to the PRISMA guidelines. Screening and data extraction was done by 2 independent authors to assess the quality of eligible studies. Data was extracted from 4 eligible studies and methods such as inverse- variance weighted (IVW), Weighted Median Approach and MR-Egger were used to pool causal estimates. Studies were analyzed qualitatively due to underlying methodological heterogeneity and potential sources of bias were evaluated through sensitivity analyses reported in the studies. Results: Four MR studies using multiple GWAS databases explored whether LTL had a causal impact on the risk of AF. One study reported that longer LTL was significantly associated with an increased risk of AF with OR of 1.083 (95% Cl 1.009-1.164, p = 0.026) in the UK Biobank and 1.182 (95% Cl 1.039-1.344, p = 0.011) in the Finngen dataset. In contrast, three other studies found no significant causal effect of LTL on AF. A meta- analysis of these studies yielded a pooled OR of 1.08 (95% Cl, 1.01-1.16, p = 0.02), with moderate heterogeneity (I 2 =60.7%, p=0.04), suggesting a statistically significant association between longer LTL and increased AF risk. A bidirectional analysis offered a unifocal perspective, suggesting that AF may actually lead to telomere shortening, with an OR of 0.989 (95% Cl: 0.981-0.997, p = 0.007). Additional observations included associations between longer LTL and increased left ventricular volume, as well as potential protective effects of LTL against other cardiovascular diseases. Conclusion: This meta-analysis suggests a statistically significant association between longer LTL and an 8% increased odds of AF. However, these findings are also specific to the European population, underscoring the need for future MR studies in different populations to enhance generalizability.

Abstract WE404: Trends in Survival after Atrial Fibrillation in a Midwestern Community

Background: Contemporary data on trends in survival after incident atrial fibrillation (AF) are limited. Methods: Residents of a 27-county area in southern Minnesota and western Wisconsin with new-onset atrial fibrillation or atrial flutter between 2013 and 2023 were identified. An electronic algorithm requiring 1 inpatient code or 2 outpatient codes separated by >7 days but within 1 year was used to define AF. Patients were followed for all-cause mortality through March 31, 2025. Standardized mortality ratios of observed versus expected survival were calculated, and time trends in survival were examined using Cox regression adjusting for demographics, cardiovascular risk factors, comorbid conditions, and area-level measures of socioeconomic status and rurality. Results: There were 44,930 individuals identified with incident AF from 2013-2023 (56.4% male; mean (SD) age 72.8 (13.5) years; 95.8% were non-Hispanic white). Within the first 90 days, the risk of all-cause mortality was greatly elevated compared with individuals of a similar age and sex distribution in the general population (standardized mortality ratios 12.6, 95% CI, 12.1-13.0 and 3.8, 95% CI, 3.6-4.0 for the first 30 days and 31 to 90 days after diagnosis, respectively). This excess risk was observed for all age groups but was greatest in the youngest age group (standardized mortality ratios among 18-64 year olds for the first 30 days: 49.9, 95% CI, 44.6-55.7 and 31 to 90 days: 11.1, 95% CI: 9.4-13.1; Figure ). In the youngest age group, the excess risk persists through 5 years post AF, however, in the oldest age group the excess risk only persisted through 1 year. Survival within the first 90 days improved over the study period (adjusted hazard ratio [aHR], 0.88; 95% CI, 0.79-0.99 for 2023 vs 2013); likewise, among 90-day survivors, survival improved between 2013 and 2023 (aHR,0.82; 95% CI, 0.76-0.88). These trends were driven by improvements in the younger age groups, particularly for death among 90-day survivors (aHR for 18-64 years, 0.66, 95% CI, 0.52-0.83; 65-74 years: 0.77, 95% CI: 0.65-0.90; 75-84 years, 0.84, 95% CI: 0.75-0.95; 85+ years, 0.99, 95% CI: 0.98-1.01). Conclusion: In a Midwestern community, the excess risk of death is high within the first 90 days after incident AF. Furthermore, survival after AF has improved between 2013 and 2023, with the improvement greatest in younger age groups.

Abstract WE479: Serial Improvement In Left Ventricular Ejection Fraction Within the REGARDS Cohort Is Associated With Improved Mortality

Introduction: Left ventricular ejection fraction (LVEF) changes dynamically in patients with heart failure (HF), but data in racially and geographically diverse community-based cohorts is limited. We leveraged The Reasons for Geographic and Racial Differences in Stroke Study (REGARDS) adjudicated HF hospitalization data to assess the prognostic implications of transitions in LVEF. Hypothesis: Improvement in LVEF among persons with HF is associated with lower risk of mortality. Methods: REGARDS participants recruited from the 48 contiguous United States who experienced two or more adjudicated HF hospitalizations with available chart abstracted LVEF data were included. Baseline LVEF was categorized as preserved ( > 50%) or reduced (<50%). Changes in quantitative LVEF between first and second HF hospitalizations were calculated continuously. Multivariate Cox proportional hazard regression was used to assess the association between longitudinal changes in LVEF and mortality following the second hospitalization, adjusting for demographics, baseline LVEF category, and time between the first and second hospitalization (<1, 1-5, or >5 years). Results: Among 611 participants with > 2 HF hospitalizations, the 196 participants with complete LVEF data in from > 2 hospitalizations had a mean age of 73±10 years, 48% were women, and 55% self-reported Black race. LVEF at first hospitalization was 43±16%. The median [25 th -75 th percentile range] time between first and second hospitalizations was 343 [69, 1,129] days, and the mean change in LVEF was -2%±13%. Reduced baseline LVEF category was seen in 54% of participants. Demographics, comorbidities, and medication use were similar among those with stable (absolute LVEF change <5%), increasing, or decreasing LVEF. During follow-up after the second hospitalization, 183 participants died. In models adjusted for the baseline LVEF, a 5% percent increase in LVEF between hospitalizations was associated with 7% lower rate of mortality following the second hospitalization (HR: 0.93, 95% CI: [0.87, 0.99]; p = 0.038). Conclusion: Among participants in a national, diverse, community-based cohort with HF, increases in LVEF over serial hospitalizations associated with greater time to mortality.

SEL1L–HRD1 ERAD–autophagy interplay maintains mitochondrial homeostasis in brown adipocytes

Mitochondrial integrity is central to energy homeostasis, particularly in brown adipose tissue where dynamic remodeling fuels thermogenesis. Two major proteostatic systems, the SEL1L–HRD1 endoplasmic reticulum (ER)-associated degradation (ERAD) pathway and autophagy, have been shown to intersect in vitro, but their physiological coordination in metabolically active tissues remains unclear. Here, we demonstrate that ERAD and autophagy act in synergy to safeguard mitochondrial integrity in brown adipocytes. Using various adipocyte-specific knockout (KO) mouse models and high-resolution ultrastructural 2D and 3D imaging, we show that simultaneous deletion of Sel1L and Atg7 (double KO, DKO) causes striking mitochondrial abnormalities under room temperature, absent in single KO or Sel1L-Ire1a double knockout mice. DKO adipocytes accumulate hyperfused megamitochondria extensively penetrated by ER tubules, accompanied by ER expansion, excessive ER–mitochondrial contacts, and impaired thermogenesis. These findings reveal that SEL1L–HRD1 ERAD and autophagy cooperate, rather than act redundantly, to maintain mitochondrial integrity in brown fat, uncovering a previously unrecognized mitochondrial surveillance mechanism based on ERAD–autophagy crosstalk.

Correction: Healthy Minds Index: A brief measure of the core dimensions of well-being

Abstract TH855: Examining the Implementation of Rethink Food’s Food Is Medicine Model Leveraging Partnerships with Community-based Organizations and Restaurants

Introduction: Food insecurity affects 1.6 million New Yorkers and increases risk of cardiometabolic diseases. Traditional food assistance introduces barriers such as pantry stigma, lack of culturally centered foods, and raw ingredients requiring time and cooking skills. Food is Medicine (FIM) programs have emerged to address these gaps, yet few center on cultural relevance and community trust. Rethink Food, a non-profit organization in New York City (NYC), developed a FIM model that provides culturally tailored, nutritionally balanced hot meals at no cost. Meals are prepared by local restaurants and distributed through trusted community-based organizations (CBOs). Hypothesis: Implementation science examines how programs are adopted, adapted, and sustained in real-world settings. Assessing how Rethink Food’s model is implemented in Brooklyn, NYC will identify factors that support or hinder replicability and scalability in other urban settings. Methods: This implementation case study applied the Consolidated Framework for Implementation Research (CFIR) to guide qualitative data collection and analysis. We conducted semi-structured interviews with Rethink Food (n=2), partner CBOs (n=3), and restaurants (n=3). Deductive content analysis identified themes across CFIR domains relevant to partnerships, adaptation, and sustainability. Results: Strengths included mission alignment across partners to reduce food waste, provide culturally tailored meals, and support local restaurants. Complementary roles were key: Rethink Food provided funding and infrastructure; CBOs offered trusted spaces; and restaurants contributed culinary expertise and operational capacity. The model’s adaptability enabled tailoring across delivery settings (churches, mobile trucks) and populations. A custom program app streamlined meal scheduling, coordination, and feedback for iterative refinements. Barriers included the logistics of coordinating multiple partners and pressure from funders to reduce costs. Post-COVID declines in philanthropic funding threatened sustainability, though creative financing strategies (restaurant-led fundraising) showed promise. Conclusions: The Rethink Food model illustrates how restaurant-CBO partnerships can operationalize FIM principles by delivering culturally tailored meals to food insecure communities while supporting local food systems. This model offers a scalable, partnership-driven approach to advancing food security and cardiometabolic health through FIM.

Abstract TH877: A multi-state Causal Framework to Estimate the Effects of Treatment Regimes over the Course of Heart Disease

The development of chronic disease is a long-term process that involves multiple endpoints, and limited methods can assess the health benefits of a treatment regime over the disease course. Existing multi-state Cox models estimate survival risks by state over time, which are difficult to use when comparing the effectiveness of treatment regimes. We have proposed a discrete-time split-state framework [1], which divides disease states into substates by conditioning on past history. As this framework is both “memoryless” and “memorable”, the time-specific transition parameters can be synthesized into summary measures, substate-specific life year (SSLY), multimorbidity-adjusted life year (MALY), and disease path [2]. In this abstract, based on this framework, we propose to investigate the causal effects of static and dynamic treatment regimes on health benefits over the entire disease course, under the assumptions of constant confounders from baseline and instantaneous effects of interventions on transition rates. Our method can identify the optimal treatment regime that generates the most benefits using MALY, and illustrate the mechanisms of treatment regimes affecting disease progression using SSLY and disease path. In the application, we evaluated the cardiovascular benefits of smoking cessation, where the course of heart disease was modeled in healthy (S 0 ), at metabolic risk (S 1 ), coronary heart disease (S 2 ), heart failure (S 3 ), and mortality states (S 4 ). Compared to the regime “being a smoker in S 0 -S 4 ”, the MALY was 0.53 (95% CI: 0.21, 0.96), 6.10 (4.88, 7.19), and 4.34 (3.02, 5.47) years higher for the regimes “being a smoker in S 0 and S 1 and stop smoking if a person develops S 2 , S 3, or S 4 ”, “no smoking in S 0 -S 4 ”, and “being a smoker at the start of intervention and stop smoking if age>65y”, respectively. In summary, our method can evaluate the health benefits of treatment regimes over the disease course, and has the potential to improve the precision prevention of chronic disease. A preprint of this manuscript can be found online [3]. [1] Ding, Chen, Lin. BMC Med Res Methodol. 2025;25(1):54. [2] Ding, Lin, Meyer. doi: https://doi.org/10.1101/2024.09.18.24313882 (BMC Med Res Methodol. In revision) [3] Ding. medRxiv. doi: https://doi.org/10.1101/2025.07.25.25332203 (Stat Methods Med Res. In revision)

Abstract TU197: Associations Between Individual, Psychosocial, and Neighborhood-Environment Correlates with Sedentary Time in Mexican Heritage Women: Results from the SOL CASITAS Study

Introduction: Among Hispanic/Latina women, sedentary behavior is associated with adverse cardiometabolic biomarker profiles, but little is known about which variables contribute to sedentary time more. Hypothesis: We tested the hypothesis that demographic variables (e.g., education, employment status), psychosocial variables (e.g., depressive symptoms, caregiver burden), and neighborhood-environmental variables (e.g., walkability, neighborhood aesthetics) would be associated with sedentary time among women of Mexican heritage. Methods: The SOL CASITAS study assessed women of Mexican heritage residing in southern San Diego. Sedentary time was measured using an accelerometer for one week. Demographic, psychosocial, and perceived neighborhood-environment variables were assessed using surveys. 3 separate unweighted linear models were used to examine the relative contribution of each variable on the outcome variable of percent sedentary time out of total wear time. Model 1 included demographic variables only; model 2 included demographic and psychosocial variables; and model 3 included demographic, psychosocial, and neighborhood-environmental variables. Results: 358 participants were included with a mean age of 59±10.5 years. Participants averaged 11.2±1.5 hours of sedentary time per day. 17.3% of participants had obtained at least a high school diploma. Only 29.5% were employed full time. The majority (85.28%) were born outside the U.S. There were no significant associations (p < 0.05) between demographic, psychosocial, or neighborhood-environmental variables with percent sedentary time in any model. However, there were a few suggestive associations: 1) Greater than high school education was associated with 23% higher percent sedentary time compared to less than a high school education (p-value 0.08); 2) Higher caregiver burden was associated with 20% higher percent sedentary time (p-value 0.09); and 3) Higher participant-rated score of neighborhood aesthetics was associated with 7% lower percent sedentary time (p-value 0.12). Conclusions: Additional research is needed to understand correlates of sedentary time among women of Mexican heritage, and future studies should consider additional domains such as characteristics of the home environment.

Hierarchical whole-brain modeling of critical synchronization dynamics in the human brain

The brain operates at the critical transition between order and disorder which supports optimal information processing. Whole-brain computational modeling is a powerful tool for uncovering the system-level mechanisms behind large-scale brain activity in both healthy and pathological states. However, most previous approaches have focused on either functional connectivity or criticality, making it difficult to capture both aspects simultaneously. Here, we introduce a method based on a Hierarchical Kuramoto model that incorporates two levels of hierarchy. In our model, each node contains a large number of coupled oscillators, which allows us to examine both local synchronization and long-distance interactions between brain regions. The model produces critical-like dynamics marked by emergent long-range temporal correlations (LRTCs) and both interareal phase synchronization and amplitude cross-correlations (CC) during the transition from asynchronous to synchronous states. Notably, structure–function coupling shows distinct patterns: correlations with structural connectivity peak at criticality for LRTCs and CC, but decay for local and interareal phase synchronization. Comparisons with human resting-state magnetoencephalography (MEG) data reveal that the model’s behavior most closely resembles MEG phase synchronization and multipeak power spectra on the subcritical side of an extended critical regime, supporting the hypothesis that the human brain operates in this state.

Causes of morbidity and mortality in free-ranging Eurasian lynx (Lynx lynx) in Switzerland, 2000–2022

Health monitoring based on post-mortem examination is essential for the management of endangered animal species. This is especially true for reintroduced species living in small populations with low genetic diversity, such as the Eurasian lynx ( Lynx lynx ) in Switzerland. Thanks to systematic post-mortem examinations, the Institute for Fish and Wildlife Health (FIWI), University of Bern, has acquired a comprehensive view of the lynx health in Switzerland. This study provides an updated overview of the causes of morbidity and mortality in the Eurasian lynx in Switzerland from 2000 to 2022. A total of 346 necropsied lynx (found dead, euthanized, or culled) were included in this study, and a cause of death (COD) was identified in 318 of them (91.9%). Overall, the main COD was blunt trauma (n = 183, 52.9% - largely vehicular collision). Starvation, resulting from the separation of dependent juveniles from their mother, was the second most frequent COD (n = 63, 18.2%). Fatal infectious diseases were relatively low (n = 32, 9.2%). However, we documented some significant pathogens such as canine distemper virus (CDV) and metastrongyloid nematodes. Illegal killing was confirmed in 23 cases (6.6%). Of note, illegal killing is likely underestimated in this study, given that radio-collared lynx were found to be proportionally more often illegally killed than the unmonitored ones found by chance. Furthermore, most individuals were found to be affected at least by one non-specific, mild to moderate inflammatory process of unknown origin, such as interstitial pneumonia (n = 59) or interstitial nephritis (n = 25). Additionally, cardiac changes of variable severity were observed in 125 lynx, and severe soft tissue mineralization was detected in 10 individuals. The frequency of these findings warrants further investigation. Thus, this study confirms the importance of systemic post-mortem examination and general health surveillance of free-ranging Eurasian lynx in Switzerland, in support of translocation projects, conservation of the species, and to provide a better understanding of their pathologies.

Abstract WE414: Serum Sortilin as a Predictor of Endothelial Dysfunction and Vascular Complications

Objective: This systematic review aimed to evaluate the role of serum sortilin as a reliable biomarker for vascular stenosis or calcification, with a focus on its potential to predict cardiovascular morbidity and mortality. Background: Vascular calcification and stenosis are major contributors to cardiovascular disease, strongly linked to morbidity and mortality worldwide. Reliable biomarkers to promptly predict fatal outcomes are still lacking, as current diagnostic methods are often invasive or limited in sensitivity. Sortilin, a multifunctional membrane glycoprotein involved in lipoprotein metabolism and vascular remodeling, has emerged as a potential mediator linking dyslipidemia, inflammation, and atherogenesis. Studies suggest that elevated serum sortilin levels may contribute to endothelial dysfunction, vascular calcification, and plaque instability through enhanced low-density lipoprotein uptake and smooth muscle cell proliferation. key processes driving vascular and myocardial injury. Methods: We systematically searched databases such as PubMed, Embase, Medline, Cochrane Library, and Google Scholar to identify research papers investigating the association between serum sortilin levels and vascular calcification or stenosis. Eligible observational studies that were published between March 2017 to September 2025 were included. To eliminate risk of bias we performed quality assessment using the New Castle Ottawa scale. Results: Six observational studies encompassing 1,583 patients were analyzed. Multivariate logistic regression consistently identified elevated serum sortilin as a significant predictor of endothelial injury, vascular calcification, and stenosis. Receiver operating characteristic (ROC) analyses showed a significant association between higher sortilin levels and vascular dysfunction, while Pearson’s correlation and Kaplan–Meier survival curves further demonstrated its link with adverse vascular outcomes. Conclusion: The results demonstrated that elevated serum sortilin levels were significantly associated with vascular dysfunction and cardiovascular mortality, suggesting its potential as a novel biomarker for early detection and precise risk stratification. Further research is needed to elucidate this association.

Abstract TU182: Identification of Epigenomic and Transcriptomic Markers of Coronary Artery Calcium: The Coronary Artery Risk Development in Young Adults (CARDIA) Study

Background: Coronary artery calcium (CAC) is a strong predictor of incident atherosclerotic cardiovascular disease (ASCVD) and is routinely used to clarify ASCVD risk. While different omic data types have been independently studied in relation to CAC, integrative multi-omic analyses remain limited, particularly in population-based cohorts. By combining epigenetic and transcriptomic data, we aim to delineate novel pathways that contribute to CAC development. Methods: We included 2,421 CARDIA participants at exam year 25 (mean age 50) with blood leukocyte DNA methylation (DNAm) and bulk RNA-seq data, and contemporaneous computed tomography CAC measurements. CAC outcomes were assessed as: binary (present vs absent), categorical (0, <100, ≥100), and continuous (log-transformed Agatston score). Epigenome-wide association studies (EWAS) were performed to assess associations between DNAm sites and CAC outcomes. Differential gene expression (DGE) analyses were performed to assess associations between transcriptomic markers and CAC outcomes. All models were adjusted for age, sex, race, and CARDIA center. Significant DNAm sites and transcripts shared across all three CAC outcomes were mapped to their respective (most proximal) genes, generating two distinct gene sets—one for epigenomic and one for transcriptomic data. We then compared these gene sets to identify overlapping genes associated with CAC across both omic types. Separately, pathway enrichments were assessed for each EWAS and DGE analysis and compared. Results: We identified 815, 1855, and 1546 DNAm sites and 256, 459, and 505 transcripts significantly associated with binary, categorical, and continuous CAC, respectively (FDR q<0.05). Across the three CAC outcomes, 655 DNAm sites and 198 transcripts were shared. Gene mapping of these shared DNAm sites and transcripts yielded two omic-specific gene sets; comparison of the sets revealed nine overlapping genes (Table 1). Pathway enrichment analyses of aggregated EWAS (Figure 1A) and DGE (Figure 1B) results highlighted prominent biological processes implicated in atherosclerosis. Conclusions: Epigenomic-transcriptomic integration in a population-based cohort identified convergent molecular signatures and pathways associated with CAC, which may represent coordinated epigenetic and transcriptional regulation of CAC. Future multi-omic studies leveraging longitudinal profiling may further clarify molecular mechanisms and inform prevention strategies.

Abstract TU225: Decadal Shifts in the Burden of Non-Rheumatic Valvular Heart Disease Among OECD Countries From 1990-2021: An Insight from the Global Burden of Disease Study 2021

Background: Non-Rheumatic Valvular Heart Disease (NRVHD) is the 5 th leading cause of death amongst all cardiovascular disease in organization for economic cooperation and development (OECD) countries. Method: Using GBD 2021 meta-tool, we estimated incidence, prevalence, deaths, disability-adjusted life years (DALYs) due to NRVHD by age, sex, year and location across the 38 OECD countries from 1990-2021. Result: From 1990-2021, the average annual percentage change (AAPC) in the age-standardized incidence rate (ASIR) per 100,000 rose by 55%, and prevalence rate (ASPR) increased by 54%. Conversely, the mortality rate (ASMR) fell by 45%, and DALYs rate (ASDALR) decreased by 87%. Nationally, from 1990-2021, the highest AAPC in ASIR observed in Estonia increasing by 2.43% and Portugal by 2.25%, while the US saw a more modest rise of 0.5%. The ASMR increased most notably in Poland by 5.51%, followed by Lithuania at 4.57%, Czechia at 4.39%, and Latvia at 4.115%. In terms of the ASDALR, Poland experienced a 4.41% increase, Lithuania 3.18%, and Latvia 3.08%. From 1990-2021, ASIR rose by 47% for males and 58% for females; ASMR decreased by 43% and 48%, respectively; ASDALR fell by 82% for and 90% respectively, indicating a more pronounced decline in female disease burden. Conclusion: There was a significant increase in the incidence and prevalence rates of NRVHD, indicating growing healthcare challenges. However, reductions in mortality and DALY rates suggest improvements in medical treatments and prevention strategies.

Phosphate scarcity governs methane production in the global open ocean

The observed supersaturation of methane (CH 4 ) in open-ocean surface waters implies widespread CH 4 production within the well-oxygenated mixed layer, driving emissions of this potent greenhouse gas to the atmosphere. The dominant CH 4 production pathway that explains this phenomenon remains poorly understood, although candidates include production during photosynthesis, zooplankton metabolism, and dissolved organic matter cycling. Here, we construct a data-assimilating model of the open-ocean CH 4 cycle to test which hypothesized mechanism is most consistent with the observed global CH 4 distribution. We find that only linking methane production to phosphate (PO 4 ) scarcity can explain the observed supersaturation pattern, which is highest in subtropical gyres where PO 4 is in short supply. These findings suggest that CH 4 release during PO 4 -limited cleavage of the organic compound methylphosphonate is the dominant production pathway in the open ocean. Because this process is confined to the stratified low latitude surface, it is uniquely suited to efficiently emit the CH 4 it produces to the atmosphere (>90%), before the CH 4 mixes to depth and undergoes oxidation (<10%). As predicted future ocean warming and stratification exacerbates PO 4 scarcity over coming centuries, our model predicts that oxic CH 4 production and the resulting CH 4 emissions will increase up to twofold, contributing to a suite of positive feedback between climate warming and natural greenhouse gas sources.

Factors associated with insomnia, anxiety, and depression among antenatal women in China: A cross-sectional hospital-based study

Background Mental health challenges, including insomnia, anxiety, and depression, are common among antenatal women and can affect both maternal and fetal outcomes. This study explores the determinants of these conditions in antenatal women in China, aiming to inform the design of mental health interventions and preventive strategies for this population. Methods A cross-sectional survey design was employed in this hospital-based study targeting antenatal women at a tertiary hospital in China, conducted from May 2024 to March 2025 during routine antenatal visits. Validated questionnaires assessed insomnia, anxiety, and depression. Multiple linear and logistic regression analyses identified factors associated with symptom severity and occurrence, while Structural Equation Modeling (SEM) was used to explore the relationships and mediating effects between biological and social factors, insomnia, anxiety, and depression. Results The participants had a mean age of 31.48 ± 6.94 years, with most being married (90.7%), living in urban areas (74.3%), and having undergraduate/college education (45.8%). Significant predictors of insomnia included geographical location, with those in central (OR = 1.818, 95% CI: 1.500–2.204) and southern areas (OR = 1.368, 95% CI: 1.143–1.637) showing higher odds compared to the northern region. Living in rural areas (OR = 0.796, 95% CI: 0.718–0.845) and higher education levels (OR = 1.544, 95% CI: 1.012–2.355) were associated with lower odds. Other significant factors included the number of live births and household composition. For anxiety, older age (OR = 0.955, 95% CI: 0.937–0.973) and rural living (OR = 0.675, 95% CI: 0.539–0.845) decreased odds, while living with others (OR = 3.726, 95% CI: 2.463–5.639) increased the risk. Significant predictors of depression included geographical location (central areas: OR = 1.508, 95% CI: 1.106–2.055), income level, and number of live births. The logistic regression Area Under the Curve (AUC) were 0.579 for insomnia, 0.603 for anxiety, and 0.567 for depression. SEM demonstrated an excellent model fit (CFI = 0.994, TLI = 0.999, RMSEA = 0.014). Insomnia was strongly predicted by geographic location, education, and number of live births. In turn, insomnia significantly predicted anxiety (β = 0.741) and depression (β = 0.138). The model explained 54.9% of the variance in anxiety and 70.6% of the variance in depression, indicating partial mediation. Conclusion This study identifies the multidimensional factors influencing antenatal women’s insomnia, anxiety, and depression in China, particularly highlighting the roles of geographical location, current living situation, and household composition. These factors were consistently associated with all three outcomes. Targeted interventions targeting these specific risk factors are recommended to improve the mental health of antenatal women.

Abstract TU248: Loneliness and Days at Home Before and After Cardiovascular Disease Hospitalization: the REasons for Geographic And Racial Differences in Stroke (REGARDS) Study

Background: Social factors may influence older adults’ ability to recover or “bounce back” after a hospitalization for cardiovascular disease (CVD). Loneliness is a potentially modifiable social factor that could be intervened upon post-hospitalization. Objective: To evaluate the association of self-reported loneliness prior to CVD hospitalization (myocardial infarction, heart failure, or stroke) with days at home, defined as being alive and without inpatient, emergency department, observation unit, or skilled nursing facility care. Methods: Loneliness was assessed longitudinally using a single item approximately every 2 years in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study and dichotomized as <1 or ≥1 day in the prior week. The loneliness assessment before and closest to adjudicated CVD hospitalization was selected. Linked Medicare claims were used to detect healthcare utilization. We estimated the probability of being home on each day during the year before and after hospitalization among participants surviving at least that long using a generalized estimating equation with logit link, binomial distribution, exchangeable correlation structure, and restricted quadratic splines for time, allowing for discontinuity at hospitalization and interactions between time and loneliness. Results: Among 1,780 participants with a CVD hospitalization, mean age at hospitalization was 77.9 years (SD 7.2 years), 45.7% were women, 30% Black and 70% White, and 42.4% were hospitalized for myocardial infarction, 37.5% for heart failure, and 33.4% for stroke; 23.5% reported being lonely at least 1 day in the prior week during the most recent assessment prior to hospitalization. Predicted probabilities and 95% confidence intervals for being at home in the year before and after CVD hospitalization are depicted in the Figure . Conclusions: Older adults who felt lonely had similar probability of being at home as those who were not lonely prior to CVD hospitalization, but they had lower probability of being home following CVD hospitalization. Findings suggest that loneliness may identify individuals particularly susceptible to poor recovery after CVD events.

Abstract WE432: Estimated optimal individualized diabetes risk prediction from preventive interventions in the US general population

Introduction: We previously developed a type 2 diabetes (T2D) risk prediction model with guideline-recommended prevention intervention effects. We lack population-level estimates of potential benefits for use of this model among US adults. Objective: To estimate 3-year predicted risk for T2D with an established model that includes individualized preventive intervention effects for metformin therapy and intensive lifestyle and summarize predicted benefits among the US adult population. Methods: Data for 4545 participants (age 20-80 years) without diabetes from the National Health and Nutrition Examination Survey (NHANES) cycles 2015-2020. The risk prediction model included empirical data for fasting glucose, glycated hemoglobin, body mass index, triglycerides, age, and sex and previously estimated intervention effects for metformin and lifestyle. We calculated 3-year predicted risk of incident diabetes conditional on the participant initiating lifestyle, metformin, or no intervention (placebo) and summarized risk estimates and the optimal prevention strategy (lowest predicted risk) for each participant overall and according to demographic and clinical subgroups. We used NHANES fasting sample weights and accounted for the stratified, clustered sample design. Results: The weighted NHANES sample represented 193,087,634 US adults (mean age 46 years, 52% female, 61% with prediabetes). The overall mean 3-year predicted risk for type 2 diabetes in this sample was 12.5% (95% CI: 11.8, 13.2) for placebo, 10.5% (95%: 10.1, 10.9) for metformin, 5.8% (95% CI: 5.5, 6.0) for lifestyle, and 5.5% (95%CI: 5.2, 5.7) when everyone is assigned their optimal intervention strategy ( Table ). The optimal intervention strategy was lifestyle for 91% of the analytic sample (91% for those with prediabetes and 90% for those with normal glucose), proportions consistently observed across demographic (Figure 1) and clinical subgroups (Figure 2) except for when body mass index ≥35 kg/m 2 , where metformin was the optimal preventive strategy for >40%. Conclusion: These findings highlight the potential for improving efficiency and maximizing individual and population-level benefits by identifying an individual’s optimal T2D prevention strategy and helping target preventive care.

Abstract WE429: United States Climate Vulnerability Index and Atherosclerotic Cardiovascular Disease Risk Prediction

Introduction: Climate-amplified weather events are known to increase Atherosclerotic Cardiovascular Disease (ASCVD) risk, particularly coronary heart disease (CHD) – the most common form of ASCVD. The U.S. Climate Vulnerability Index (CVI) is a novel summary metric of 184 health, infrastructure, and socioeconomic measures that represent community-level vulnerabilities to climate risks, allowing us to quantify the impact of climate change on health outcomes. In this study, we created a CVI-modified PREVENT model for ASCVD and compared it to the Base PREVENT models. Hypothesis: Adding CVIs to PREVENT models improves the accuracy and calibration of 10-year ASCVD risk prediction. Methods: We utilized the REasons for Geographic and Racial Differences in Stroke- Myocardial Infarction cohort, which includes 30,239 adults aged ≥ 45 years from 48 contiguous states enrolled 2003-07 who were followed for 10+ years. We applied the PREVENT equations to REGARDS-MI data using cause-specific Cox models with multiple imputation to predict 10-year ASCVD risk. Bootstrapping was used to estimate c-statistics, calibration slopes, and 95% confidence intervals. Standardized net benefit was used to approximate clinical utility. Results: Our sample included 23,678 participants (41% male; 42% Black, median age: 64) without ASCVD. Over a median 10 years, we observed 2081 ASCVD, 1207 CHD, and 970 stroke events. C-statistics and calibration slopes for CVI-modified and original PREVENT models were similar: Female CVI 0.73 (0.71, 0.74) and calibration slope: 0.95 (0.88, 1.04) vs Female NoCVI 0.72 (0.70, 0.74) and calibration slope: 0.96 (0.88, 1.05) | Male CVI 0.69 (0.67, 0.70) and calibration slope: 0.94 (0.86, 1.03) vs Male NoCVI 0.68 (0.67, 0.70) and calibration slope 0.95 (0.87, 1.04). Adding the CVI yielded clinically meaningful utility at low thresholds (i.e. 5%) for females compared the current PREVENT models in the prediction of ASCVD, but does not improve prediction for males. We observed similar patterns for stroke and CHD outcomes. Conclusions: Adding CVI to the PREVENT equations resulted in only minor improvements in accuracy and calibration, which may be due to use of area-level measures for climate change. We note small changes in the standardized net benefit for females compared to males with inclusion of CVI.

Reprogrammed SimCells for antimicrobial therapy

Antimicrobial resistance (AMR) is a critical global health challenge. In this study, we developed a platform based on chromosome-free and nonreplicating simple cells (SimCells, size 1 to 2 µm) and mini-SimCells (size 100 to 400 nm) for targeted pathogen elimination. Engineered with surface-displayed nanobodies, SimCells and mini-SimCells selectively bind bacteria expressing specific antigens (e.g., OmpA in Escherichia coli ). The selective interactions facilitate close SimCell-pathogen proximity, enabling two antimicrobial mechanisms: direct injection of toxic effectors into bacterial cytoplasm via a heterologous expression of type VI secretion system (T6SS), and enzymatic conversion of aspirin into catechol by engineered salicylate hydroxylase, leading to sustained local production of hydrogen peroxide (H 2 O 2 ). Our results demonstrate that both reprogrammed SimCells and mini-SimCells can eliminate target E. coli with high specificity and efficiency. Multidose reprogrammed mini-SimCell treatment led to a 10 3 -fold selective reduction of targeted bacteria in mixed microbial communities, with minimal disruption to nontarget bacteria. We demonstrate that reprogrammed mini-SimCells, engineered with nanobody targeting outer membrane protein OmpA of the clinically relevant multidrug-resistant pathogen E. coli ST131, achieved elimination efficiencies over 97% at 24 and 48 h. This modularized “plug-and-play” antimicrobial platform provides a highly specific, efficient, and adaptable solution for combating diverse AMR pathogens.