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Identification of cellular ion channels that facilitate Hazara nairovirus infection enables selection of clinically approved compounds with anti-nairoviral properties

Abstract The Nairoviridae family of segmented negative-sense RNA viruses includes the serious human pathogen Crimean-Congo haemorrhagic fever virus (CCHFV), associated with a case/fatality rate of up to 40% for which no approved vaccines or treatments exist. Nairoviruses internalize via endocytosis and pass through the endolysosomal network, exploiting the changing ionic environment to promote envelope fusion. Fusion is influenced by hydrogen (H + ) and potassium ions (K + ), which increase in concentration as endosomes mature, regulated by host ion channels. Using the model nairovirus Hazara virus (HAZV) of the CCHFV serogroup, we performed an siRNA screen to identify cellular ion channels involved in nairovirus infection. Most high-ranking hits belonged to K + and calcium (Ca 2+ ) channel families. Consistent with this, we showed that clinically-approved K + channel blockers quinidine, quinine and dronedarone and clinically-approved Ca 2+ channel blockers tetrandrine and nifedipine significantly reduced HAZV activities. To further probe the role of K + in HAZV infection, we used time-of-addition studies, showing K + was required during entry. Biochemical experiments showed K + expanded the pH range that promoted entry, potentially allowing endosome escape deeper within the endolysosomal network. These results show clinically-approved channel blockers effectively inhibit HAZV replication, suggesting repurposing existing therapies may represent promising avenues to block nairovirus infection.

Global biodiversity and the expanding Tree of Life

Global biodiversity is increasingly threatened, but still poorly known. Preserving higher taxa (e.g., genera, families, orders) is especially important because each higher taxon may represent more genetic, morphological, ecological, and functional diversity than a typical species within a genus. Given this, there has been considerable focus on the loss of clades and their phylogenetic diversity. However, we know little about whether there are also gains of new clades: new higher taxa that are based on newly discovered species. Here, we analyze these newly discovered branches across the Tree of Life. We estimate that >700 new genera, >20 new families, and >3 new orders are described every year, each associated with newly discovered species. The distribution of new genus-level clades largely reflects current species richness patterns among groups. Thus, they are dominated by terrestrial arthropods. At higher taxonomic ranks, the distribution of new clades among groups is increasingly unrelated to the current, known species richness of these groups, and fungi and bacteria predominate. New clades are increasingly microscopic at higher taxonomic ranks and are often marine or host associated. Overall, we suggest that the known Tree of Life is continuing to rapidly expand with many newly discovered clades, not merely contracting with recent extinctions. Discovering and describing these new clades before they disappear should be an urgent research priority. There is also a pressing need to better incorporate phylogenies into the discovery of these new higher taxa.

Abstract 14: Impact of High Intensity Interval Training versus Continuous Moderate Intensity Exercise on Cardiorespiratory Fitness for People with HIV: Results from the HEALTH Multicenter Randomized Clinical Trial

Objectives: HIV is associated with reduced cardiorespiratory fitness (CRF), a strong predictor of future cardiovascular events and mortality. Supervised exercise training programs improve CRF, but the ideal exercise training intensity is unknown among PWH. We hypothesized that high-intensity interval training (HIIT) would result in greater improvements in CRF than continuous moderate-intensity exercise (CME) without increased risk of adverse events among older sedentary adults with HIV. Methods: We conducted a multicenter randomized clinical trial of people ages 50 years and older with treated, virally-suppressed HIV, self-reported fatigue, and sedentary lifestyle. Participants were randomized 1:1 to 16 weeks of supervised HIIT or CME. Cardiopulmonary exercise testing (CPET) using a treadmill graded exercise protocol was performed prior to randomization and at 16 weeks to assess CRF, measured as peak oxygen consumption (VO 2 ). CPETs were interpreted blinded to treatment assignment. The trial was preregistered at ClinicalTrials.gov NCT04550676. Results: Among 212 PWH screened, 142 consented, 127 completed baseline CPET, 118 were randomized (110 with adequate quality CPET): 54 to HIIT and 56 to CME. Median age was 56.5 years, 12% female, and 44% were obese (BMI ≥30). At baseline, absolute peak VO 2 was 2.3 L/min and relative to body weight was 25 ml/kg/min (91% predicted peak VO 2 ). In the intention-to-treat analysis adjusted for age, sex, and site, assignment to HIIT was associated with a 0.14 L/min greater increase in absolute peak VO 2 from baseline to 16 weeks compared to CME (95% CI 0.01 to 0.27, p =0.03) and a 1.60 ml/kg/min greater increase in relative peak VO 2 (95% CI 0.23 to 2.97; p =0.023). Results were consistent in unadjusted and per-protocol analyses. Six serious adverse events (SAEs) occurred during the 16-week intervention: 4 unrelated (including 1 death), 2 related (both syncope) in the CME arm; participants were evaluated by cardiology and resumed exercise without further SAEs. There were more nonserious AEs in the HIIT group (40 versus 22 in CME group), mostly mild-moderate musculoskeletal injuries. Conclusions: Among older sedentary people with HIV, HIIT is associated with a greater improvement in CRF assessed with CPET compared to CME, without a greater risk of serious adverse events. Exercise recommendations for aging people with HIV should consider the greater cardiopulmonary benefit of HIIT compared to CME.

Abstract MPWE44: A multi-ancestry blood metabolites atlas of incident stroke in ~39,000 adults

Background: A comprehensive blood metabolome fingerprint of incident stroke and the temporal variation of metabolite levels across pre-diagnostic trajectories remain poorly defined. Methods: We included 38,594 stroke-free adults from seven multi-ethnic TOPMed cohorts with 1,245 named circulating metabolites ( Fig1.a ). Incident stroke (n = 1,628) was ascertained over 7.5–19.3 years. Results from cohort-specific Cox models [adjusted for sociodemographic characteristics, behavioral factors and medications use] were pooled by random-effects meta-analysis. We examined race/ethnicity-specific associations, pre-diagnostic trajectories of metabolites, and risk prediction with metabolite panels. Results: We identified 141 metabolites (FDR < 0.05) associated with incident stroke by pooling results from 7 cohorts after multivariate adjustment, with 97 metabolites independent of major cardiometabolic traits (e.g., glucose, lipids, blood pressures; Fig1.b ). Over 80% of identified metabolites showed positive associations, predominantly belonging to phosphatidyl lipids, steroids, glutamate/glutamyl amino acids, aromatic amino acids, and ceramides ( Fig1.b,c ). Race/ethnicity stratified analyses revealed 21 out of 141 identified metabolites (FDR<0.05) exhibiting significant heterogeneities in associations with stroke across ancestry groups. Of note, 9 metabolites (e.g., MTA, HPLA, oxalate) showed stronger or even opposite associations in Hispanics compared to other ancestry groups ( Fig1.d ). In Study of Latinos (SOL, n=13,453), temporal analysis identified 3 clusters of metabolites exhibiting nonlinear variational patterns in levels throughout 12 years before stroke diagnosis. Furthermore, higher weighted scores for metabolites in clusters 1&2 were linked with elevated risk of stroke, whereas a reduced risk was found for cluster 3, in which metabolites maintained comparatively low levels throughout the pre-diagnostic process of stroke ( Fig.1e ). Adding metabolites to conventional risk factors significantly improved risk prediction of incident stroke (AUC improved from 0.78 to 0.84; p<0.001) ( Fig1.f ). Conclusion: Our study characterized most comprehensive metabolomic signatures of incident stroke to date and revealed potentially ancestry specific signals. Our results further characterized complex temporal dynamics of identified metabolites across pre-diagnostic process and reinforced the value of metabolites in stroke risk prediction.

Abstract 05: Evaluating the Implications of PREVENT Risk Estimates for Non-Cardiovascular Outcomes: The Atherosclerosis Risk in Communities (ARIC) Study

Introduction: In response to the growing burden of poor cardiovascular-kidney-metabolic (CKM) health, the PREVENT equations were developed to incorporate emerging risk factors and improve contemporary cardiovascular risk prediction. Poor CKM health has multiorgan consequences that extend beyond the cardiovascular system, yet the implications of PREVENT risk estimates for non-cardiovascular disease (non-CVD) outcomes are presently unclear. Methods: We performed a prospective analysis of 11,132 participants at ARIC Visit 2 (1990–1992) without baseline CVD. PREVENT-CVD 10-year risk estimates were calculated using Visit 2 data and categorized as <5%, 5 to <7.5%; 7.5 to <10%; 10 to <15%; 15 to <20%; and ≥20%. Multivariate cause-specific Cox regression was performed to estimate associations of higher PREVENT-CVD risk categories with the non-CVD outcomes of incident chronic kidney disease (CKD), dementia, cancer mortality, non-CVD mortality and all-cause mortality over 10 years and through 12/31/23. For those who had events, median time-to-event by quantile regression from age 60 was calculated for each PREVENT category. For each outcome, 10-year risk discrimination was assessed by calculating Harrell’s C-statistics. Results: Within the study population (mean age 57 years; 57% women; 25% Black adults), 4,173 participants developed CKD, 2,802 developed dementia, 1,943 died from cancer, 5,069 died from non-CVD causes, and 7,232 died from any cause. There was a dose–response increase in the hazards of each non-CVD outcome with higher PREVENT-CVD risk categories (Table 1). At 10 years, PREVENT-CVD ≥20% (versus <5%) was associated with HRs of 9.81 (95% CI 6.56-14.68) for incident CKD, 5.79 (95% CI 2.15-15.58) for dementia, 3.08 (95% CI 1.86-5.00) for cancer mortality, 4.84 (95% CI 3.33-7.03) for non-CVD mortality and 8.89 (95% CI 6.62-11.92) for all-cause mortality. Significant associations were also seen at full follow-up. Higher PREVENT categories were associated with progressively shorter time-to-event for all non-CVD outcomes (Figure), with non-CVD and all-cause mortality occurring ~11 and 13 years earlier with PREVENT-CVD ≥20% versus <5%. PREVENT improved 10-year risk discrimination beyond age alone for most non-CVD outcomes (Table 2). Conclusion: Higher PREVENT-CVD scores suggest greater risk and shorter time to event for multiple non-CVD outcomes. Employing strategies to enhance CKM health likely has implications for global clinical outcomes.

Research on the integrated technology of bearing structure reconstruction and support control in high risk area of top coal roadway in thick coal seam

Abstract TH849: Machine Learning-Based Magnetic Respiratory Sensing Technology and Hypergraph Network Modeling of Respiratory and Cardiovascular Comorbidity

Background: Cardiovascular diseases (CVDs) are a leading cause of death globally, and coexisting respiratory diseases (RDs) amplify clinical risk and care complexity. A noninvasive approach that both classifies respiratory disease from bedside signals and characterizes CVD-RD comorbidity could improve early diagnosis, triage, and longitudinal management. Hypothesis: We hypothesize that features derived from breath signals can accurately distinguish healthy individuals from multiple RDs using machine learning (ML), and that high-order comorbidity network modeling can reveal age-stratified patterns linking RDs with CVDs. Methods: Magnetic Respiratory Sensing Technology (MRST) recordings of normal breathing, breath-holding, and deep breathing were obtained from 306 participants (122 healthy, 32 with COVID-19, 152 with other RDs (e.g., influenza/pneumonia and tuberculosis)). A total of 225 time/frequency/morphology-based features were extracted from the breath signals. A logistic regression (LR) model was trained on our dataset to detect RDs using five-fold cross-validation. A binary LR model was also trained to classify healthy versus non-healthy. In addition, age-stratified (≤45, 45–65, >65 years) comorbidity hypergraph networks were constructed to capture higher-order co-occurrence among RDs and CVDs. Results: The multiclass LR model achieved a mean accuracy of 87.8 ± 2.4% across five folds, demonstrating effective discrimination of five RDs from breath signals alone; the binary LR model achieved a superior mean accuracy of 97.0 ± 0.6%. Comorbidity network analysis showed prominent age-related patterns. In the youngest group (≤45 years), networks were sparse and centered on influenza/pneumonia with weak links to chronic lower RDs, tuberculosis, and CVDs. In middle age (45–65 years), network density increased, with hypertensive diseases, influenza/pneumonia, and chronic lower RDs forming strong connections that marked emerging CVD–RD overlap. In older adults (>65 years), networks were highly interconnected; hypertensive and ischemic heart diseases functioned as hubs linking multiple RDs, consistent with escalating comorbidity severity. Conclusions: A combined framework integrating MRST-derived features, ML classification, and comorbidity network modeling can diagnose RDs categories noninvasively and capture well the progression of CVD-RD comorbidity. This approach can support early screening, comorbidity monitoring, and treatment personalization.

Abstract TH898: Cardiovascular Health by Life's Essential 8 in Southeast Asian Adults in the United States

Background: Cardiovascular disease burden and risk factors have been shown to differ across Asian American subgroups, with notably high prevalence of elevated cholesterol and diabetes in Southeast Asians. Cardiovascular health (CVH) and its associations with demographic and sociocultural factors in Southeast Asians in the US are incompletely understood. We hypothesized that lower socioeconomic position, greater psychological stressors, and differences in sociocultural beliefs in Southeast Asians would be associated with lower CVH. Methods: Adults who self-identified as Southeast Asian were surveyed with standardized, validated questionnaires. CVH was assessed by calculating the composite LE8 score as per the AHA guidelines. The association of LE8 score with demographic, social, psychological, and cultural beliefs was evaluated with the Wilcoxon Rank Sum test. Results: Of 34 Southeast Asian adults surveyed (n=22 women, n=12 men, mean age 43 years, SD 15.8 years), the average LE8 score was 82.3 (SD 12.2). The most suboptimal LE8 component scores were BMI (mean 73, SD 30) and blood glucose (mean 69.2, SD 33.9). The most optimal LE8 component score was nicotine avoidance (mean score 94.6, SD 18.9). Overall, a lower LE8 score was significantly associated with birth outside the United States, education attainment lower than a Bachelor's, annual household income lower than $75,000, and less symptoms of anxiety (p<0.01 all). Of note, strength of cultural beliefs was not significantly associated with a higher LE8 score. Conclusions: This pilot study is the first to characterize CVH in Southeast Asians in association with demographic, sociocultural, and psychological factors. Preliminary data highlights various factors that could contribute to a higher LE8 score in this population, such as nicotine avoidance, more physical activity, and healthcare-seeking behaviors.

Abstract MPWE48: Metabolomics-Based Reclassification of Ultra-Processed Foods and Risk of Cardiometabolic Outcomes

Introduction: Ultra-processed foods (UPFs) are commonly treated as a single category, yet they encompass nutritionally heterogeneous products with potentially differential health effects. Existing classifications, such as Nova, primarily focus on food processing without accounting for biological heterogeneity, limiting precision in risk estimation. Hypothesis: We hypothesized that plasma metabolites could help to define UPF subclasses with divergent associations with type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD), and all-cause mortality. Methods: We analyzed 248,092 UK Biobank participants with NMR-based plasma metabolomics (168 metabolites with absolute quantification) and a subset of 59,898 participants with at least 2 repeated 24-hour dietary recalls. Using elastic-net regression, we derived a metabolomic profile score predictive of incident T2DM from 23 metabolites and classified 81 UPF items as Healthy (β<0; false discovery rate (FDR)<0.05), Unhealthy (β>0; FDR<0.05), or Indeterminate (FDR>0.05) based on their associations with the T2DM metabolomic score. The metabolomic score and intakes of UPF subgroups were then related to incident T2DM, CVD, and death using multivariable Cox models. Results: During follow-up of approximately 0.9 million person-years, 2,113 T2DM, 2,465 CVD, and 3,767 all-cause death events were documented. A higher T2DM metabolomic score was associated with an higher risk of T2DM (Q5 vs Q1 HR [95% CI]: 12.66 [9.41–17.03]), CVD (1.63 [1.35–1.98]), and all-cause death (1.28 [1.11–1.49]). The Unhealthy UPF category included 40 foods, while the Healthy UPF category included 19 foods. Total UPF intake was significantly associated with a higher risk across endpoints (1.47 [1.26–1.71], 1.50 [1.30–1.73], and 1.24 [1.11–1.39] for T2DM, CVD, and death, respectively), but an increased risk was only found for the intakes of Unhealthy UPF (1.76 [1.50, 2.06], 1.49 [1.30, 1.72], 1.31 [1.17, 1.47], respectively). The Healthy UPF score showed inverse associations with T2DM and CVD (0.75 [0.65, 0.87] and 0.86 [0.73, 0.99], respectively), but no significant association with mortality. Conclusions: Metabolomics-enabled subclassification revealed heterogeneity within UPFs, with excess cardiometabolic risk driven by a subset of Unhealthy UPFs and inverse associations observed for Healthy UPFs. These findings underscore the need for biologically informed dietary guidance and reformulation beyond a single “total UPF” metric.

Influence of salicylic acid on plant defense, growth and biochemical composition of Salix alba infected with Lymantria obfuscata in Kashmir

Abstract 17: Aberrant Heart Rate Variability in Late Midlife Associates with Future Cognitive Decline: Findings From the 1946 British Birth Cohort

Introduction: Autonomic nervous system dysfunction has been demonstrated in Alzheimer’s disease. Impaired autonomic function represented by aberrant heart rate variability (HRV) may precede cognitive decline in older age. However, longitudinal evidence linking midlife HRV to later-life cognition is limited, and prior studies have typically assessed only a narrow range of cognitive domains. We hypothesized that loss of normal HRV in late midlife would be associated with future cognitive decline, as evidenced by poorer performance on global cognitive tests such as Addenbrooke’s Cognitive Examination–III (ACE-III) and trajectories of decline in verbal memory and visual search speed. Methods: The sample consisted of 1,032 participants from the Medical Research Council National Survey of Health and Development, a British cohort born in 1946. HRV measurements from a 3-lead ECG taken at age 60-64 included SDNN (standard deviation of normal-to-normal beats), HFn (normalised high frequency) power, LFn (normalised low frequency) power, PSD 2 (power spectral density) and HRV triangular index. The association of HRV with three types of cognitive outcomes were tested: single time point ACE-III score at 68-70 years using generalised linear models; and longitudinal verbal memory and visual search speed trajectories produced from four repeat tests between ages 43 and 70 using linear mixed models and growth curve modelling. Results: LFn power, HFn power, and the LF/HF ratio were significantly associated with ACE-III scores in univariate models (p <0.05). In models adjusted for sex, socioeconomic position across life, psychological well-being, BMI, prior stroke, and systolic blood pressure, higher LFn power (β = 0.11, 95% CI 0.03, 0.20, p = 0.005) and lower HFn power (β = −0.09, 95% CI −0.20, −0.03, p = 0.007) remained independently associated with a higher ACE-III score. Increased PSD 2 predicted greater decline in verbal memory (β = −4.66, 95% CI −8.1, −1.2, p = 0.008), while reduced SDNN (β = 0.31, 95% CI 0.01, 0.62, p = 0.044) and HRV triangular index (β = 1.5, 95% CI 0.06, 2.9, p = 0.043) were associated with greater decline in visual search speed. Conclusions: Vagally mediated HRV measures were associated with global cognitive dysfunction in later life and 27-year trajectories of decline in verbal memory and visual search speed. These findings suggest that aberrant HRV in late midlife may serve as a non-invasive biomarker of ongoing and future cognitive decline.

Abstract TU230: Cholesterol Management Gaps Before a Recurrent Coronary Event: Insights From the Get With The Guidelines – Coronary Artery Disease Registry

Introduction: Guidelines recommend that patients with coronary artery disease (CAD) lower their low-density lipoprotein cholesterol (LDL-C) using maximally tolerated statin therapy to prevent recurrent events. Gaps in ambulatory LDL-C management (i.e., non-use of statins and elevated LDL-C) may reflect missed opportunities for secondary prevention and, if frequent, may warrant quality improvement interventions. Research question: What is the proportion of known CAD patients who do not take a statin or have elevated LDL-C before a recurrent event? Methods: We analyzed the prevalence of non-statin use and an LDL-C level ≥70 mg/dL in patients ≥18 years of age in the Get With The Guidelines-CAD registry who had known CAD and were hospitalized for a new myocardial infarction or unstable angina in 2023-2024. Data collection on statin use and LDL-C at the initial evaluation is optional in the registry. Information on the intensity of statin therapy is not available. Results: After excluding 17% of patients without data on prior statin use, 34,003 were included in the analysis (mean age 68 years; 71% male; 73% white). Overall, 31.6% of patients did not use a statin. No statin use was more prevalent among women than men, and less prevalent among Black vs White patients ( Table 1 ). LDL-C was not documented in 30.7% of patients. An LDL-C ≥70 mg/dL was more common in patients not taking vs those taking a statin (74.6% and 49.8%, respectively, multivariable-adjusted prevalence ratio 1.45; 95% CI 1.41, 1.48). Women were more likely than men to have an LDL-C level ≥70 mg/dL among those taking and not taking a statin, separately ( Table 2, Panel A). Black and Hispanic patients were more likely to have an LDL-C level ≥70 mg/dL compared to their white counterparts among those taking a statin, but there were no statistically significant differences by race/ethnicity among those not taking a statin ( Table 2, Panel B). Among patients discharged alive, 93.6% were prescribed a statin, and 85.2% were prescribed a high-intensity statin. Conclusion: The current results reveal that more than 30% of known CAD patients do not receive guideline-recommended statin therapy before a recurrent event. Furthermore, half of the patients taking a statin and three out of four of those not taking a statin have an LDL-C level above the guideline-recommended thresholds. Urgent, targeted quality improvement initiatives are needed to address these gaps and reduce the burden of recurrent CAD hospitalizations.

Abstract TH952: Self-reported stress overload experience, autonomic tone and acute mental stress cardiovascular reactivity: The African-PREDICT study

Background: Stress, stress perceptions, appraisals and perceived individual ability to manage stress significantly impact cardiovascular health in humans, yet this relationship is complex and multi-factorial. The Stress Overload Scale (SOS) and its sub-domains Event Load (EL) and Personal Vulnerability (PV) may identify individuals at a higher risk for stress-related cardiovascular health concerns. Yet whether the cardiovascular reactivity patterns, autonomic tone and cardiovascular risk differ based on these self-reported stress-subdomains are unknown. We investigated the relationship between SOS and its subscales with acute stress-induced cardiovascular reactivity markers and resting markers of autonomic tone. Methods: In 610 South Africans (46% Men, 45% Black African, 20-30 years) the SOS and subscales EL and PV, assessed stress overload. We determined those with a total SOS score, and combinations High-EL-High-PV; Low-EL-low-PV; Low-EL-High-PV and High-EL-Low-PV, using established sub-domain cut-points for the SOS scale. An acute mental stress task was administered for 1-minute and hemodynamic reactivity for systolic-and diastolic BP, heart rate (HR), stroke volume (SV), cardiac output (CO), total peripheral resistance (TPR), arterial compliance (Cwk) and left-ventricular ejection fraction (LVEF) were measured. Ambulatory BP and heart rate variability (HRV) was assessed. Results: Of the 610 participants, 25% (n=151) were High-EL-High-PV; 27% (n=163) Low-EL-Low-PV; 29% (n=174) Low-EL-High-PV and 19% (n=122) High-EL-Low-PV. Within each group, sex and ethnicity did not differ significantly. Depressed HRV was the highest in the high-EL-high-PV group ( P <0.01), with the low-EL-high-PV also indicating depressed-HRV compared to the low-PV groups (all P <0.02). High-EL-low-PV had greater acute hemodynamic reactivity compared to the other groups (all P <0.05). In the two high-PV groups, increases in CO, TPR and decreases in CwK associated with PV (all P <0.03). In the High-EV-Low-PV group, increases in CO, HR, SV and Cwk and decreases in TPR associated inversely with PV ( P <0.001) and positively with EL ( P =0.014). Conclusion: Perceived personal vulnerability consistently associated with autonomic tone and acute hemodynamics, with greater PV adversely impacting acute hemodynamics, and possibly future cardiovascular risk. However, a low PV, despite a high EL, is linked to compensatory, physiologically advantageous autonomic tone and acute hemodynamic stress responses.

Analytical modeling of pcm-based cooling system for lithium-ion batteries

Abstract WE496: Variation in Risk Factor Control in Patients with Atrial Fibrillation by Race and Ethnicity: A Nationwide Study

Introduction: Atrial fibrillation (AF) is a common arrhythmia associated with stroke, death, and complications that are more prevalent among AF patients from minoritized groups. Those with comorbid risk factors (RF), including diabetes, hyperlipidemia, hypertension, obesity, alcohol use, and tobacco use, are at higher risk of poor AF outcomes. Little is known of how well these RFs are controlled among AF patients and whether such control differs by race/ethnicity. We examined variation in RF control in AF patients managed in the Veterans Health Administration (VA). Methods: We conducted a retrospective cohort study of VA patients with incident AF from 1/1/2014 to 12/31/2024. Our independent variables were race (American Indian/Alaska Native [AIAN], Asian, Black, multiracial, White) and Hispanic ethnicity. Our primary outcome was RF control, defined using validated AHA Life’s Essential 8 categorization (optimal, intermediate, and poor) for hemoglobin A1c and cholesterol levels, blood pressure, and body mass index (BMI). We also assessed presence of an alcohol or tobacco use diagnosis. A score of 100 represented optimal control for each RF, and we calculated cumulative mean scores (max=600) by race/ethnicity. We used logistic regression to model the likelihood of achieving an optimal score for each RF and general linear modeling to estimate mean differences in cumulative RF score between racial/ethnic groups, adjusting for demographic, clinical, and socioeconomic factors. We used multiple imputation to account for missing RFs. Results: Our cohort included 192,564 patients with AF (0.5% AIAN, 1.2% Asian, 9.3% Black, 3.9% Hispanic, 0.6% multiracial, 84.5% White; mean age 73.3 years). Figure 1 shows RF control by race/ethnicity. In adjusted models, Black patients were less likely to have optimal control for diabetes, hyperlipidemia, blood pressure, and alcohol use compared to White patients ( Figure 2 ). Asian, Hispanic, and Black patients were more likely to have optimal BMI levels compared to White patients. Black patients had a significantly lower cumulative RF score (-3.92; 95% CI, -5.03, -2.83) compared to White patients. Conclusion: In a large, nationwide cohort of AF patients, we found marked variation in key cardiometabolic RF control. Given disparities in AF complications, our understanding of the drivers of poor RF control in minoritized populations and the development of interventions to address them is critical to improving the health of AF patients.

Abstract WE416: A Novel Poly-Metabolite Score of Soy Product Intake is Prospectively Associated with Cognitive Function

Introduction: Soy intake improves dementia risk factors in clinical trials. However, population studies reported inconsistent associations with cognitive outcomes, likely due to self-report bias. We aimed to develop an objective poly-metabolite score (PMS) for soy intake and test its association with cognition. Methods: The PMS was derived for self-reported soy intake in 9,992 participants from the Canadian Longitudinal Study on Aging (CLSA) and externally validated in 80 participants from the Protein and Blood Pressure (ProBP) Trial, where participants received soy protein, milk protein, and carbohydrates supplement in a random order for 8 weeks each, separated by 3-week washouts. Plasma metabolomics were profiled using the untargeted Metabolon platform. CLSA participants were randomly split into training (80%) and testing (20%) sets. Candidate metabolites were identified by comparing very frequent consumers (>7 times/week) with never consumers in the training set. An elastic net regression with 10-fold cross-validation was used to construct the PMS, optimizing for AUC and model parsimony. PMS sensitivity and specificity were tested in ProBP by comparing post–soy vs. baseline and soy vs. non-soy interventions. Cognition in CLSA was assessed at baseline and 3-year follow-up using a neuropsychological test battery for memory, executive function, and global cognition. Associations between PMS and cognition were examined using linear regression adjusted for age, sex, race, education, smoking, drinking, physical activity, BMI, SBP, depression, diabetes, cardiovascular disease, hypertension medication, and baseline cognition (for longitudinal outcomes). Results: The final PMS contains 153 metabolites, including soy biomarkers (daidzein sulfate), gut microbiota products (4-ethylphenylsulfate), and internal metabolites. The PMS showed robust discrimination (AUC Training =0.84, AUC Testing =0.80, AUC ProBP =0.78). In ProBP, PMS increased substantially after soy protein diet compared with baseline (Cohen's d=0.67, p=2.9×10 -8 ) and non-soy diet (Cohen's d =1.11, p=8.6×10 -16 ). In CLSA, higher PMS was associated with better memory at baseline (β=0.46, p<0.0001) and 3-year follow-up (β=0.35, p=0.0003), and nominally with global cognition (β=0.14, p=0.02 at baseline; β=0.11, p=0.03 at follow-up). Conclusion: We developed a PMS of habitual soy intake that generalizes across populations and interventions. This PMS was positively associated with memory and global cognition.

Abstract MPWE36: Proteomics Reveals Altered Muscle Structure and Organization Pathways in Older Adults with Peripheral Neuropathy

Objectives: Peripheral neuropathy (PN) of the lower extremities is highly prevalent among older adults, even in the absence of diabetes, and has been linked to substantial morbidity and mortality. However, the biologic pathways underlying PN remain poorly understood. We examined the proteomic profiles of community-dwelling adults aged 70–95 years to identify proteins and pathways associated with PN. Methods: We conducted a prospective cohort analysis within the Atherosclerosis Risk in Communities (ARIC) Study among participants who underwent a monofilament insensitivity test for PN between 2016 and 2017 (ARIC Visit 6). PN was defined as loss of sensation at one or more foot sites. Blood samples collected at Visit 5 (2011-2013) were assayed using the SomaScan 5k proteomics platform. Logistic regression models were used to assess associations between 4,955 proteins and PN adjusting for demographic and clinical covariates. Statistical significance thresholds were set at P < 0.05 (nominal) and P < 0.05/4,955 (Bonferroni correction). Proteins meeting Bonferroni-corrected significance were carried forward for pathway analysis. Over-representation analysis (ORA) was then performed by mapping significant proteins to the Gene Ontology database to identify biological pathways associated with PN. Results: Among 2,514 participants (median age 74.0 years; 43% male; 16% Black adults; 31% with diabetes), 39% had PN based on monofilament testing. After adjustment for demographic and clinical covariates, PN was associated with 301 proteins at the nominal threshold, of which 11 (including Carbonic anhydrase 3, Seizure 6-like protein, Myomesin-2, Alpha-actinin-2, Myosin light chain 6B, and Myosin-binding protein C) remained significant after Bonferroni correction ( Figure ). ORA of the Bonferroni-significant proteins revealed enrichment in biologic processes related to muscle cell development, differentiation, and assembly of structural units (sarcomeres and myofibrils) ( Figure ). Conclusions: Older adults with PN, as detected by monofilament testing, show altered protein expression in pathways related to muscle development and organization. These pathways may explain previous observations in aging population linking PN to reduced functional decline and an increased risk of falls and related morbidities.

In silico evaluation of FDA-approved antivirals and corticosteroids against SARS-CoV-2

Abstract TU192: Large-scale proteomic analysis of valvular calcification: The Atherosclerosis Risk in Communities (ARIC) Study

Background: Valvular heart disease shares risk factors with atherosclerosis, but its pathophysiology is not fully understood. We aimed to conduct a large-scale proteomic analysis for aortic valve calcification (AVC) and mitral valve calcification (MVC), an early manifestations of valvular heart disease, and compare the results with coronary artery calcification (CAC), a representative marker of atherosclerosis. Hypothesis: Certain proteins will be uniquely associated with AVC or MVC. Methods: We first studied 1,704 ARIC participants (mean age 74 [SD 4] years, 61% female, 17% Black), with data on 4,955 plasma proteins (SomaLogic) at Visit 5 (2011-13) and AVC, MVC, and CAC by cardiac CT at Visit 7 (2018-19). We used linear and logistic regression adjusted for traditional risk factors, modeling AVC, MVC, and CAC as continuous (log Agatston score) and as binary (≥75th vs <75th age and sex-specific percentile) outcome variables. Then, we tested whether proteins significant in both models for either AVC or MVC are associated with incident cardiovascular disease (CVD), including coronary heart disease, stroke, and heart failure, using multivariable Cox models. We applied a false discovery rate (FDR) p<0.05 to account for multiple comparisons. Results: The median (IQR) Agatston score was 0 (0-58) for AVC, 0 (0-115) for MVC, and 244 (38-767) for CAC. For linear regression, 70 proteins were significantly associated with MVC. For AVC, tumor necrosis factor receptor superfamily member 11B (TNFRSF11B) was the only significant protein in linear models, which was one of the 70 proteins associated with MVC. Out of the 70 MVC proteins, 10 were also significant in logistic regression models. WAP four-disulfide core domain protein 2 (WFDC2) and interleukin-18–binding protein (IL-18BP) showed the strongest positive associations in MVC. TNFRSF11B was not significantly associated with AVC in a logistic regression. None of those 10 MVC proteins were associated with CAC. In survival analysis using Visit 2 (1990-92) as baseline, 9 of the 10 MVC proteins were associated with incident CVD. For example, WFDC2 and IL-18BP had hazard ratios of 1.86 (95%CI 1.71-2.03) and 1.39 (1.27-1.53), respectively. Conclusions: We identified more proteins associated with MVC than AVC, which did not overlap with each other or CAC, suggesting distinct pathophysiology across vascular diseases and atherosclerosis. Notably, most of those MVC proteins were independently associated with future CVD.

Abstract TU189: ABO Blood Type Modifies the Association Between Fiber Intake and Incident Cardiovascular Disease: The Role of Gut Microbiota and Circulating Metabolites

Introduction: ABO blood type is related to cardiovascular disease (CVD) and influence gut microbiota (GMB). ABO antigen glycans in the gut may influence GMB composition, with effects further modulated by fiber intake. Hypothesis: Higher fiber intake is associated with lower CVD risk and favorable GMB and blood metabolite profiles in O blood group but not in non-O blood group. Methods: We examined associations of total, soluble, and insoluble fiber intake with CVD risk in 11,238 participants free of CVD at baseline from the Hispanic Community Health Study/Study of Latinos during ~12 years of follow-up, stratified by O (53%) and non-O blood groups. In subsamples (N up to 3940), we identified fiber-associated GMB species and serum metabolites in O and non-O blood groups separately, followed by examining their associations with cardiometabolic traits and CVD risk. Results: Higher fiber intake, especially insoluble fiber, was associated with lower CVD risk in O blood group (4 th vs. 1 st quartile: HR: 0.37; 95% CI: 0.19–0.72), but not in non-O group ( P -interaction = 0.02; Fig. A ). Insoluble fiber intake, specifically in O blood group, was associated with differences in 14 GMB species (e.g., increased Butyrivibrio crossotus ) and 50 metabolites (35 are known to relate to GMB), compared to 6 GMB species and 22 metabolites specifically in non-O group. An overall higher fiber-related serum metabolite profile (indicated by an O-specific metabolite score) was associated with a higher fiber-related GMB profile (O-specific GMB score; Fig. B ), more favorable cardiometabolic traits (Fig. C) and lower CVD risk (Fig. D ). No such associations were observed in non-O group. The interaction between ABO blood type and insoluble fiber intake on CVD risk was attenuated ( P -interaction = 0.07) after additional adjustment for O-specific metabolite score. Conclusions: ABO blood group modifies the association between fiber intake and CVD, which might be related to different GMB and blood metabolite profiles associated with fiber intake between O and non-O blood groups.