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Bacterial estrogenesis without oxygen: Wood–Ljungdahl pathway likely contributed to the emergence of estrogens in the biosphere
Androgen and estrogen, key sex hormones, were long thought to be exclusively produced by vertebrates. The O 2 -dependent aromatase that converts androgen to estrogen (estrogenesis) has never been identified in any prokaryotes. Here, we report the finding of anaerobic estrogenesis in a Peptococcaceae bacterium ( Phosphitispora sp. strain TUW77) isolated from the gut of the great blue-spotted mudskipper ( Boleophthalmus pectinirostris ). This strain exhibits testosterone fermentation pathways, transforming testosterone into estrogens and androstanediol under anaerobic conditions. Physiological experiments revealed that strain TUW77 grows exclusively on testosterone, utilizing the androgenic C-19 methyl group as both the carbon source and electron donor. The genomic analysis identified three copies of a polycistronic gene cluster, abeABC (anaerobic bacterial estrogenesis), encoding components of a classic cobalamin-dependent methyltransferase system. These genes, highly expressed under testosterone-fed conditions, show up to 57% protein identity to the characterized EmtAB from denitrifying Denitratisoma spp., known for methylating estrogen into androgen (the reverse reaction). Tiered transcriptomic and proteomic analyses suggest that the removed C-19 methyl group is completely oxidized to CO 2 via the oxidative Wood–Ljungdahl pathway (WLP), while the reducing equivalents (NADH) fully reduce remaining testosterone to androstanediol. Consistently, the addition of anthraquinone-2,6-disulfonate, an extracellular electron acceptor, to testosterone-fed TUW77 cultures enabled complete testosterone conversion into estrogen without androstanediol accumulation (anaerobic testosterone oxidation). This finding of aromatase-independent estrogenesis in anaerobic bacteria suggests that the ancient WLP may have contributed to the emergence of estrogens in the early biosphere.
Abstract P2167: Racial and Ethnic Disparities in Neighborhood Socioeconomic Status Associated with Cardiovascular Disease and Stroke
Introduction: The role of socioeconomic status (SES) across cardiovascular diseases (CVD) is well researched at the individual-level but fails to explain the greater CVD rates among Black and American Indian and Alaska Native (AIAN) groups at every level of SES. This research investigated whether lower Neighborhood SES (NSES), a structural determinant of health, was associated with racial and ethnic disparities in CVD or stroke among aging women. Methods: The data came from the Women’s Health Initiative (WHI) cohort, consisting of 161,808 postmenopausal women with 30 years of data on stroke and CVD incidence. The NSES data were obtained from the US Census based on participant’s census tract of residence. We evaluated racial and ethnic disparities in the exposure and outcome prevalence using ANOVA. Associations between NSES and time to stroke and CVD were evaluated using multivariate adjusted Cox Regression models, and models were stratified by race and ethnicity to evaluate disparities. Results: NSES differed by race and ethnicity. Black, AIAN, and Latina groups were significantly (P<0.01) more likely to live in neighborhoods with NSES Z-scores below the population mean (Z-score=0) compared with White and Asian groups. The mean NSES Z-score among Black participants was -5.21 standard deviations below the population mean. Thirty-year CVD and stroke incidence followed the same trajectory of racial disparities. Preliminary analysis suggests results from Cox regression models will identify lower NSES to be longitudinally associated with greater stroke and CVD incidence overall, and greater effect sizes among groups experiencing structural racism. Conclusion: This research evaluates racial disparities in NSES as a structural determinant of stroke and CVD. These findings provide evidence emphasizing the urgent need for neighborhood-level interventions to address CVD disparities that coalesce in marginalized communities.
Abstract P1065: Contemporary trends and in-hospital outcomes of infective endocarditis among individuals with substance use disorders: A nationwide analysis
Background: Infective endocarditis (IE) is a serious complication linked to substance use disorders (SUD). This study aimed to examine the contemporary nationwide trends and outcomes of IE hospitalizations among individuals with SUD. Methods: We identified hospitalizations with any IE diagnosis from the Vizient ® Clinical Data Base between 2016-2023, data used with permission of Vizient, Inc. (All rights reserved). We examined IE trends in SUD vs. non-SUD individuals and used Cochrane-Armitage Test to analyze significance. Multivariable logistic regression was used to assess variables associated with in-hospital mortality among individuals with IE. Results: Among 159,045 individuals hospitalized with IE, 37,596 (23.6%) had a history of SUD. Individuals with IE associated SUD vs. non-SUD were younger (39 vs. 63 years), predominantly White (77.3%), and primarily on Medicaid (66.5%). Staphylococcus species caused 53.2% of IE associated SUD hospitalizations. IE-SUD hospitalizations rose from 58.8 per 100,000 in 2016 vs 70.7 per 100,000 in 2022, then declined to 56.7 in 2023, P<0.001. Non-SUD hospitalizations for IE increased from 233.9 per 100,000 in 2016 vs 262.9 per 100,000 in 2023, P<0.001(Figure). In-hospital mortality was lower in the IE-SUD group vs. IE non-SUD group (8.6% vs 12.8%, P<0.001). The following factors were independently associated with in-hospital mortality: older age (OR 1.016, 95% CI 1.015–1.018), fungemia (OR 2.43, 95% CI 2.20–2.68), and hemodialysis (OR 3.44, 95% CI 3.29–3.59). Conclusion: This contemporary nationwide observational analysis highlights the evolving national trends and outcomes of IE associated with SUD. Future research should explore the drivers of these trends to guide policy, with a focus on enhanced screening and preventative measures.
Abstract P3155: Socio-Demographic Disparities in the Management Modalities of Pulmonary Embolism Amongst COVID-19 Patients: A Retrospective Population-Based Study
Introduction: Pulmonary embolism (PE) affects 60 to 70 persons per 100,000 people and causes about 7 million DALYs worldwide, making it an economically onerous handicap condition in the US. COVID-19's hypercoagulation and pro-inflammatory condition increase PE risk (OR 4.4 and RR 3.1) compared to non-COVID-19 individuals. Few studies have examined modalities and disparities in use. Aims: The study's main goal was to calculate the utilization rate and predictors of utilization of PE therapy modalities (tPA/thrombolytics, mechanical thrombectomy [MT], and surgical thrombectomy [ST]), and treatment disparities in COVID-19 patients in the US. Methods: We performed a retrospective cross-sectional observational study of a nationwide inpatient sample (year 2020) in adult hospitalizations with PE to identify patients with COVID-19. ICD-10 codes were used. Using SAS 9.4, we ran a univariate analysis using the chi-square test and multivariate survey logistic regression analysis to calculate adjusted OR and 95% CI. Results: Of 172,630 PE hospitalizations, 3124 patients had COVID-19. PE patients with COVID-19 were younger (mean age 60 vs 66) with the age group of 18-44 (2.54% vs >65-year-old 1.36%), male (1.99% vs female 1.63%), and Hispanics (4.47% vs African Americans 2.71% vs White 1.35%) in comparison to non-COVID-19. PE with COVID-19 had a higher prevalence of obesity (30.72% vs 29.6%) and diabetic mallitus (12.8% vs 9.76%). Utilization of tPA (3.36% vs 3.14%), MT (7.04% vs 5.58%), and ST (0.32% vs 0.19%) were higher amongst PE with COVID-19. tPA use was higher amongst young [OR 1.47 (95%CI 1.01-2.14), females (1.54, 1.17-2.04), and patients with diabetes mellitus (1.73, 1.18-2.53). MT use was higher amongst young (1.46, 1-2.12), African Americans (1.8, 1.45-2.24) and Hispanics (2.99, 2.06-4.35) (compared to White), patients with cardiogenic shock (3.06, 1.91-4.90), ischemic stroke (3.33, 1.55-7.15), diabetes mellitus (1.29, 1.01-1.63), and obesity (2.54, 2.15-3.0). ST use was higher amongst COVID-19 (7.48, 1.94-28.88), males (17.54, 3.5-83.33), patients with AFib (7.49, 1.68-33.49), and obesity (4.75, 1.37-16.51). Conclusion: Management discrepancies among PE patients with COVID-19 include younger age, male, African American, and Hispanic, with ischemic stroke, AFib, obesity, and diabetes using more. To reduce socio-demographic differences in COVID-19 pulmonary embolism care, personalized management techniques, and equitable healthcare resources should be developed.
Candidate transmission survival genome of <i>Mycobacterium tuberculosis</i>
Mycobacterium tuberculosis (Mtb), a leading cause of death from infection, completes its life cycle entirely in humans except for transmission through the air. To begin to understand how Mtb survives aerosolization, we mimicked liquid and atmospheric conditions experienced by Mtb before and after exhalation using a model aerosol fluid (MAF) based on the water-soluble, lipidic, and cellular constituents of necrotic tuberculosis lesions. MAF induced drug tolerance in Mtb, remodeled its transcriptome, and protected Mtb from dying in microdroplets desiccating in air. Yet survival was not passive: Mtb appeared to rely on hundreds of genes to survive conditions associated with transmission. Essential genes subserving proteostasis offered most protection. A large number of conventionally nonessential genes appeared to contribute as well, including genes encoding proteins that resemble antidesiccants. The candidate transmission survival genome of Mtb may offer opportunities to reduce transmission of tuberculosis.
Abstract P1110: Pecan Intake Improves Lipoprotein Particle Concentrations Compared to Usual Intake in Adults at Increased Risk for Cardiometabolic Diseases: a 12-Week Randomized Controlled Trial
Background: Pecan consumption consistently improves lipids and lipoproteins, but less research has investigated the effect of pecan consumption on lipoprotein subfractions. Objectives: The aim was to investigate how substitution of usual snack foods with 57 g/day of pecans affects the concentration of lipoprotein particle subfractions, lipoprotein particle size and apolipoproteins compared to continuing usual intake after 12 weeks in adults at risk for cardiometabolic diseases. Exploratory analyses were done to evaluate early markers of insulin resistance including the Lipoprotein Insulin Resistance score (LPIR), Diabetes Risk Index (DRI), and GlycA. Methods: This is a secondary analysis of data from a 12-week randomized controlled trial including adults at risk for cardiometabolic disease. Participants were randomized to either consume 57 g/day of pecans in place of usual snacks or to continue their usual intake. EDTA plasma samples collected at baseline and after the 12 week-intervention period were used for analysis. Samples were analyzed via proton nuclear magnetic resonance spectroscopy for lipoprotein subfractions, apolipoproteins, GlycA, and branched chain amino acids. Lipoprotein subfractions and branched chain amino acids were used to calculate the LPIR and DRI. Results: The pecan group had a greater reduction from baseline in the concentrations of apolipoprotein B (apoB) (-4.38 mg/dL; 95% CI -8.02, -0.73), total LDL (-75.3 nmol/L; 95% CI -144, -6.93), total triglyceride rich lipoproteins (TRLP) (-20.4 nmol/L; 95% CI -33.8, -7.03), large TRLP (-1.47 nmol/L; 95% CI -2.69, -0.26), small TRLP (-11.3 nmol/L; 95% CI -22.4, -0.27), and the LPIR (-4.42 points; 95% CI -8.14, -0.69) and greater increases from baseline in the concentration of large high density lipoproteins (HDL) (0.35 μmol/L; 95% CI 0.07, 0.63) and HDL subspecies, H5 (0.40 μmol/L; 95% CI 0.10, 0.62) compared to the usual diet group. There were no between-group differences in branched chain amino acids or the DRI. Conclusions: Incorporating 57 g/day of pecans into the diet in place of usual snacks for 12 weeks reduced apoB, atherogenic lipoprotein subfractions, and an early marker of insulin resistance compared to usual intake.
Abstract P1037: Promoting Sustained Behavior Change and Nutrition Security in Medicaid-Enrolled Individuals with Stage 2 Cardiovascular Kidney Metabolic Syndrome (CKMS): protocol and early recruitment success of the SUSTAIN study
Introduction: Medicaid-enrolled populations are disproportionately impacted by suboptimal nutrition leading to lower Life’s Essential 8 (LE8) cardiovascular health (CVH) scores and greater prevalence of Stage 2 cardiovascular-kidney-metabolic syndrome (CKMS) as defined by the American Heart Association (AHA). With support from the AHA Health Care by Food TM Initiative and leveraging existing academic-community-government-industry partnerships, our team is assessing the feasibility, engagement, and preliminary efficacy of SUSTAIN , a novel Food is Medicine (FIM) intervention in Medicaid-enrolled individuals with Stage 2 CKMS. Hypothesis: Our overall hypothesis is that a comprehensive FIM intervention including culturally appropriate and home-delivered groceries, intensive and tailored behavioral nutrition counseling, and social care coordination will improve nutrition security and CVH compared to individuals receiving home-delivered groceries only. Methods: Informed by the socioecological model and human-centered design, SUSTAIN is a 24-week randomized controlled trial (RCT) of Medicaid-enrolled individuals (n=100) with Stage 2 CKMS to: Aim 1 : Determine the feasibility and engagement of participants in the SUSTAIN intervention compared to enhanced usual care over 24 weeks through mixed-methods measurement of participant enrollment, adherence, retention, and engagement (counseling, screenings, referrals, and uptake); Aim 2 : Determine the preliminary efficacy of the SUSTAIN intervention compared to enhanced usual care in improving behavior change as measured by nutrition security, LE8 measures, biometrics, and purchasing behaviors over 24 weeks to determine effect estimates to robustly power a future RCT. Results: Initial recruitment efforts have enrolled 46 individuals; 148 failed to meet eligibility criteria. Primary reasons for ineligibility were other diagnoses (e.g., heart failure) (n=107) and non-English speaking (n=31). A minority of participants were ineligible due to unwillingness to use mobile phone-based technology (n=2) or lack of backup form of payment for grocery vendor (n=3). Conclusions: Innovative FIM solutions are urgently needed. SUSTAIN will explicate the feasibility, engagement, and preliminary efficacy of SUSTAIN, leading to a scalable FIM nutrition-security-based model to improve CVH in Stage 2 CKMS. SUSTAIN has the potential to drive a paradigm shift in healthcare, fostering healthier, nutrition-secure and resilient communities.
Abstract P1153: Hypoxia Response Markers are Associated with Early Metabolic Imbalance: The U.S. National Health and Nutrition Examination Survey
Introduction: The metabolism spectrum considers cardiometabolic health&disease as a series of four distinct categories, with progressing onset and severity of the underlying pathophysiology (Fig. 1). While prediabetes and metabolic syndrome are widely recognized categories, early metabolic imbalance (EMI) has largely been overlooked. Prevalent in teens and young adults, EMI is characterized by compensated insulin resistance, where fasting glucose, triglycerides, HDL cholesterol (HDL), and hemoglobin A1c are all within normal limits. Thus, EMI does not meet the criteria for prediabetes or metabolic syndrome and eludes risk screening for type 2 diabetes and ASCVD. In EMI, high circulating insulin overproduces nitric oxide, possibly leading to oxidized hemoglobin and a subclinical impairment of oxygen delivery to cells and tissues. Here, we investigated the association of hypoxia response markers with EMI in the U.S. population. Hypothesis: Individuals with EMI show a compensatory response suggestive of subclinical hypoxia. Methods: The fasting subsample from the 2015-2018 U.S. National Health&Nutrition Examination Survey was analyzed: 6,227 observations representing 270.2 million people in the U.S. ages 12 and up. Population-weighted multinomial logistic regression was performed using Stata v18.5. The outcome variable was cardiometabolic health, categorized into 1 of 4 groups: healthy balanced metabolism, EMI, prediabetes/dyslipidemia (PD), or type 2 diabetes/ASCVD (Fig. 1). EMI was defined using prognostic insulin cutpoints derived from timeROC analysis of the CARDIA cohort. The 1° exposure was blood hemoglobin concentration. Resting pulse rate, serum globulin/albumin ratio (chronic inflammation), and serum GGT (cell damage) were 2° exposures. The adjusted covariates are listed in Table 1. To quantify association, the effect size was relative risk ratio with 95% confidence interval and p-value. Results: After adjusting for covariates, markers of the hypoxia response (hemoglobin, resting pulse rate, globulin/albumin ratio, GGT) were elevated in EMI compared with healthy balanced metabolism (Table 1, bottom panel). These increases were not apparent from a simple inspection of the unadjusted median values (top panel). Conclusion: EMI includes an insidious compensatory response to hypoxia. This observation is consistent with prior observations that dysfunctional hemoglobin is coupled to poor metabolic health. Further investigation is warranted.
Structure of activity in multiregion recurrent neural networks
Neural circuits comprise multiple interconnected regions, each with complex dynamics. The interplay between local and global activity is thought to underlie computational flexibility, yet the structure of multiregion neural activity and its origins in synaptic connectivity remain poorly understood. We investigate recurrent neural networks with multiple regions, each containing neurons with random and structured connections. Inspired by experimental evidence of communication subspaces, we use low-rank connectivity between regions to enable selective activity routing. These networks exhibit high-dimensional fluctuations within regions and low-dimensional signal transmission between them. Using dynamical mean-field theory, with cross-region currents as order parameters, we show that regions act as both generators and transmitters of activity—roles that are often in tension. Taming within-region activity can be crucial for effective signal routing. Unlike previous models that suppressed neural activity to control signal flow, our model achieves routing by exciting different high-dimensional activity patterns through connectivity structure and nonlinear dynamics. Our analysis of this disordered system offers insights into multiregion neural data and trained neural networks.
Abstract 062: Disease Trajectories of Cardiometabolic Diseases and Depression: Transition Patterns, Multiomics Signatures, Prognosis and Prediction
Objective: Cardiometabolic diseases (CMDs) and depression, among the most prevalent physical and mental diseases, frequently co-occur and are associated with a higher risk of premature mortality. However, the trajectories of their multimorbidity occurrence, underlying biological mechanisms, and early prediction remain poorly understood. Methods: This study was conducted on 467,592 UK Biobank participants without baseline CMDs and depression. CMDs included type 2 diabetes, coronary artery disease, stroke, and heart failure. Multistate models were used to investigate transition probabilities and identify multiomics signatures for transitions from baseline to single morbidity and to multimorbidity. Multiomics prediction models were constructed using least absolute shrinkage and selection operator Cox regression. Model performance was evaluated by the change of Harrell's C statistic (Δ C-statistic) compared to the demographic model and area under receiver-operating characteristic curves (AUCs). Results: During a median follow-up of 14.6 years, 64,442 participants developed CMDs alone, 17,533 developed depression alone, and 6104 developed multimorbidity. Depression preceding CMDs showed a 2.5% higher 15-year multimorbidity probability and 1.2% higher 5-year mortality risk than the reverse sequence. Multimorbidity was associated with a 14-26% higher mortality risk and 3.6-3.8 years shorter survival time compared to those without CMDs or depression. Distinct and shared multiomics signatures underlying disease trajectories were identified. Valine, leucine, and isoleucine biosynthesis and cytokine-cytokine receptor interaction pathways were implicated in both CMDs and depression progression. Proteomics scores showed superior prediction performance across nine disease transitions, with Δ C-statistic ranging from 0.07 for health-death to 0.22 for health-depression-CMDs-death, compared to the genomics (0-0.04) and metabolomics (0-0.16) scores. For 15-year outcome prediction, the proteomics scores model achieved AUCs of 0.65-0.87 for various transitions, significantly outperforming traditional risk factors-based and other omics models. Conclusions This study revealed distinct transition patterns, identified associated multiomics signatures, and constructed multiomics prediction models for the multimorbidity cluster of CMDs and depression.
Abstract 031: Associations of Adipokines with 6-Year Progression of Cardiovascular-Kidney-Metabolic Syndrome: The Atherosclerosis Risk in Communities (ARIC) Study
Background: Adipose tissue and its signaling molecules are central to cardiovascular-kidney-metabolic (CKM) syndrome development. High levels of pro-inflammatory adipokines and low levels of anti-inflammatory adipokines have been linked with worsening metabolic health and increased cardiovascular disease (CVD) risk. However, there have not yet been investigations of how adipokines relate to changes in CKM health over time. Methods: We examined 7695 White and Black ARIC participants without baseline CVD and with adipokine measurements and data required to assess CKM stage at both Visits 2 (1990-92) and 4 (1996-98), an approximate 6-year interval. CKM stage was defined as stage 0: no CKM risk factors; stage 1: excess/dysfunctional adiposity; stage 2: metabolic risk factors (hypertension, diabetes, metabolic syndrome, hypertriglyceridemia) and/or moderate to high risk chronic kidney disease (CKD); stage 3: ≥ 20% predicted CVD risk using the PREVENT calculator or very high risk CKD, and stage 4: overt CVD overlapping with CKM risk factors. Among those in CKM stages 0-3 at Visit 2 (baseline), we used logistic regression to evaluate the associations of higher levels of adiponectin, leptin, and resistin at Visit 2 (modeled per 1-SD and according to tertiles) with the odds of progression to a higher CKM stage by Visit 4. Results: The mean age was 57 years (56% female, 79% White). At baseline, 6% had stage 0 CKM syndrome, 24% had stage 1 CKM syndrome, 68% had stage 2 CKM syndrome, and 2% had stage 3 CKM syndrome. Overall, 33% of participants progressed to a worse CKM stage during the 6 years of follow-up. After adjustment for sociodemographics, lifestyle factors, and CKM stage at baseline, higher adiponectin (per 1-SD) was associated with 24% lower odds of progressing to a worse CKM stage (OR 0.76, 95% CI[0.71, 0.81]). Conversely, higher leptin and resistin (per 1-SD) were associated with 29% (OR 1.29, 95% CI[1.19, 1.39]) and 9% (OR 1.09, 95% CI[1.03, 1.15] higher odds of CKM stage progression, respectively. Graded associations with similar directionality as those described were seen when baseline adipokine levels were modeled in tertiles (Table). Conclusion: Adipokines are significantly associated with CKM syndrome progression. These proteins may help to inform the prediction and prevention of a worsening trajectory of CKM syndrome over time.
Abstract P3103: Circulating and tissue levels of omega-3 fatty acids and incident peripheral artery disease: an individual participant-level pooled analysis of prospective studies
Background: Evidence from observational studies and randomized trials suggest a favorable role of omega-3 fatty acids on cardiovascular outcomes. However, whether omega-3 fatty acids may reduce the incidence of peripheral artery disease (PAD) is not known. Aims: We prospectively evaluated blood and adipose tissue levels of alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), docosahexaenoic acid (DHA), and the sum of EPA and DHA, with respect to incident PAD. Methods: We included 11 prospective studies from a global consortium up to May 2023 with measurements of ALA, EPA, DPA, or DHA (as a % of total fatty acids) in blood or adipose tissue among adults (age≥18), who were free of coronary artery disease, stroke, and PAD at baseline, and assessed incident PAD events. Each cohort conducted de novo individual-level analyses with a prespecified analytical plan and harmonized definitions for exposures, outcomes, covariates (including demographics, cardiovascular risk factors, medication use, and omega-6 fatty acid levels), and subgroups. Pooled hazard ratios (HRs) were calculated using inverse-variance weighted meta-analysis. Results: Among 142,316 participants from North America, Europe, and Australia followed for a weighted median of 13.7 years (range of median follow-up: 9.8 to 26.2 years), 1,842 incident cases of PAD were ascertained. In multivariable-adjusted pooled analysis, very long-chain EPA, DPA, DHA, and EPA+DHA each associated with lower PAD incidence, with HRs (95% CI) per interquintile range of 0.79 (0.69, 0.91), 0.80 (0.68, 0.95), 0.74 (0.64, 0.85), and 0.79 (0.69, 0.90), respectively ( P <0.01 for each) ( Figure 1 ). Long-chain ALA was not associated with PAD, 1.14 (0.98, 1.33). Heterogeneity between studies was low to moderate ( I 2\ ranging from 0% to 57%). Results were broadly consistent in prespecified subgroups by age, sex, smoking status, prevalent diabetes, and biomarker lipid fraction. Conclusion: In this large international consortium, objective levels of very long-chain, but not long-chain, omega-3 fatty acids inversely associated with incident PAD. Our data suggest a protective role for very long-chain omega-3 fatty acids in the development of PAD, supporting the need for further mechanistic studies and appropriately powered randomized controlled trials.
Multilevel irreversibility reveals higher-order organization of nonequilibrium interactions in human brain dynamics
Information processing in the human brain can be modeled as a complex dynamical system operating out of equilibrium with multiple regions interacting nonlinearly. Yet, despite extensive study of the global level of nonequilibrium in the brain, quantifying the irreversibility of interactions among brain regions at multiple levels remains an unresolved challenge. Here, we present the Directed Multiplex Visibility Graph Irreversibility framework, a method for analyzing neural recordings using network analysis of time-series. Our approach constructs directed multilayer graphs from multivariate time-series where information about irreversibility can be decoded from the marginal degree distributions across the layers, which each represents a variable. This framework is able to quantify the irreversibility of every interaction in the complex system. Applying the method to magnetoencephalography recordings during a long-term memory recognition task, we quantify the multivariate irreversibility of interactions between brain regions and identify the combinations of regions which showed higher levels of nonequilibrium in their interactions. For individual regions, we find higher irreversibility in cognitive versus sensorial brain regions while for pairs, strong relationships are uncovered between cognitive and sensorial pairs in the same hemisphere. For triplets and quadruplets, the most nonequilibrium interactions are between cognitive–sensorial pairs alongside medial regions. Combining these results, we show that multilevel irreversibility offers unique insights into the higher-order, hierarchical organization of neural dynamics from the perspective of brain network dynamics.
Abstract P1082: Estimating the Burden of Undiagnosis HFpEF in the Community
Objective: Over 3 million Americans have heart failure with preserved ejection fraction (HFpEF). Effective guideline directed medical treatments (GDMT) are increasingly available but patients with HFpEF are likely under-detected (particularly women) and not receiving GDMT. Limited data are available informing the extent of HFpEF under-detection in the community. Hypothesis: Among patients with undifferentiated dyspnea and a high risk for unrecognized HFpEF, fewer than 50% will receive a HFpEF diagnosis during two years of follow-up; underrecognition will be greater among women. Methods: We identified 22,134 patients aged ≥30 in the Rochester Epidemiology Project (a medical records linkage system comprising a 27-county region of southeastern Minnesota and western Wisconsin) with evidence of unexplained dyspnea (≥2 ICD codes for dyspnea separated by >1 day) without prior documented etiology including HF or lung disease, during the time period 2018-2022. We calculated the recently validated HFpEF-Age-BMI-Atrial Fibrillation (HFpEF-ABA) score to estimate the probability of underlying HFpEF. Cox proportional hazards models regressed risk for incident HFpEF diagnosis on HFpEF-ABA score (dichotomized as ≥80% vs. <80%) with multivariable adjustment for sex, race and ethnicity. HRs(95%CIs) are presented. Results: Patients were 59±16 yrs, 50.8% women, 88.6% white, 3.1% Black, 3.7% other race, 4.6% Hispanic. Atrial fibrillation prevalence was 9.4% and mean BMI=31.4±7.8. Prevalence of HFpEF-ABA≥80% was 22.4%(n=4,958): 22.7% among women and 22.1% among men. The cumulative incidence of clinically-recognized HFpEF diagnosis at two years follow-up was 9.7% among women and 12.8% among men (log-rank p<0.01). HFpEF incidence was elevated with high HFpEF-ABA scores(≥80%): HR(95%CI) among women=3.72 (3.35, 4.14), and men=3.42 (3.11, 3.76). Among those with clinically diagnosed HFpEF during follow-up, mean time from date of first dyspnea ICD code to HFpEF diagnosis was 1.26 years overall: 1.31 and 1.21 years in women and men, respectively (p=0.05). Conclusions: One in five patients with undifferentiated dyspnea have probable undiagnosed HFpEF, and of that group, only 30% receive a clinical diagnosis, requiring an average of over 1 year to be recognized. The rate of diagnosis is even lower among women than men. Further study is warranted to implement evidence-based algorithms supporting detection of undiagnosed HFpEF in the community, especially in women.
Abstract MP23: Environmental Justice and Atherosclerotic Cardiovascular Disease Risk among Asian American, Native Hawaiian, and other Pacific Islander Subgroups: The PANACHE Study
Introduction: Environmental pollution is a risk factor for cardiovascular disease. Few environmental justice studies have examined the burden of pollution among Asian American, Native Hawaiian, and other Pacific Islander (AANHPI) subgroups. The California Environmental Protection Agency CalEnviroScreen is an environmental justice mapping tool that identifies disadvantaged communities with a high burden of multiple pollutants. Methods: The study included 562,538 AANHPI and 1,891,203 non-Hispanic White adults aged ≥30 years who received health care from Kaiser Permanente Northern California during 2012-2022 and had no prior cardiovascular disease. We linked the CalEnviroScreen 2.0 score to the census tract of each person in the study at baseline. CalEnviroScreen designates “disadvantaged communities” as the census tracts with the highest statewide quartile of the score. Atherosclerotic cardiovascular disease (ASCVD) events were ascertained through 2023 using discharge diagnosis codes and death certificates. We fit Cox proportional hazards models to examine the association between statewide quartiles of the CalEnviroScreen score with incident ASCVD, adjusting for age, sex, AANHPI subgroups, diabetes, hypertension, dyslipidemia, chronic kidney disease severity, body mass index, and current and former tobacco use. Results: CalEnviroScreen scores differed by AANHPI subgroups (p-value <0.0001). The Southeast Asian subgroup had the highest percentage of adults living in a CalEnviroScreen disadvantaged community (23.0%), followed by Native Hawaiian/Pacific Islander (12.9%), Vietnamese (11.7%), and Filipino (8.5%; Figure ). In contrast, only 6.9% of non-Hispanic White adults lived in a CalEnviroScreen disadvantaged community. Living in a disadvantaged community was associated with a 23% increased risk of incident ASCVD (adjusted hazard ratio 1.23, 95%CI 1.19-1.27) compared to the lowest quartile of the CalEnviroScreen score, adjusting for demographics and clinical cardiovascular risk factors. Conclusions: In a large, community-based AANHPI cohort in California, we found differences in the burden of pollution across AANHPI subgroups. Living in a community with a high pollution burden was associated with an increased adjusted risk of incident ASCVD. Environmental pollution may be a factor contributing to disparities in ASCVD among AANHPI subgroups.
Abstract P1111: Metabolomic Architecture of Different Composition of Fat, Carbohydrates, and Proteins in Randomized Weight-Loss Diet Intervention Trial
Background and Aims: Low-calorie weight loss diets with different macronutrient compositions have shown to result in clinically meaningful long-term weight loss. We aimed to identify plasma metabolites that significantly changed over two years in an intervention trial of low-calorie weight-loss diets with varying amounts of fats, carbohydrates, and proteins, and to investigate which changes in plasma metabolites are linked to better long-term weight loss. Materials and methods: The present study included participants who were randomly assigned to one of 4 diets in the POUNDS Lost trial. Untargeted plasma metabolomics was performed; changes in 856 metabolites across various metabolic pathways from baseline to the end of the two-year intervention were calculated in 533 participants. Results: We observed 571 metabolites (67%) showing statistically significant changes ( P- FDR < 0.05) following the two-year diet intervention (Figure panel a). We also identified core metabolites that significantly changed across all diet groups as well as specific metabolites that changed only in each of the 4 diet groups (panel b). Of the significantly modified metabolites by diets, 239 were significantly associated with 2-year weight changes, while others were not linked to weight loss (panel c). When stratifying by diet group, we identified 230 metabolites related to weight loss in response to one of the 4 diet interventions, including 22 metabolites within the lactoyl amino acid pathways, which showed the strongest sub-pathway associations with weight changes over two years in all diet groups. Conclusion: Our study identified core and specific metabolic pathways associated with changes in all or each of three macronutrients that contribute to better long-term weight loss.
Input-driven circuit reconfiguration in critical recurrent neural networks
Changing a circuit dynamically, without actually changing the hardware itself, is called reconfiguration, and is of great importance due to its manifold technological applications. Circuit reconfiguration appears to be a feature of the cerebral cortex, so understanding the dynamical principles underlying self-reconfiguration may prove of import to elucidate brain function. We present a very simple example of dynamical reconfiguration: a family of networks whose signal pathways can be switched on the fly, only through use of their inputs, with no changes to their synaptic weights. These are single-layer convolutional recurrent network with local unitary synaptic weights and a smooth sigmoidal activation function. We generate traveling waves using the high spatiotemporal frequencies of the input, and we use the low spatiotemporal frequencies of the input to landscape the ongoing activity, channeling said traveling waves through an input-specified spatial pattern. This mechanism uses inherent properties of marginally stable, dynamically critical systems, which are a direct consequence of their unitary convolution kernels: every network in the family can do this. We show these networks solve the classical connectedness detection problem, by allowing signal propagation only along the regions to be evaluated for connectedness, and forbidding it elsewhere.
Abstract P2137: Depressive symptoms during late pregnancy are associated with higher cardiovascular disease risk 2-7 years after delivery.
Background: Adverse pregnancy outcomes (APOs) are risk factors for future cardiovascular disease (CVD). APOs are more common among individuals who experience depression during pregnancy, and depression is a well-established CVD risk factor in non-pregnant populations. The purpose of the present study was to evaluate the relationship between depressive symptoms in pregnancy and future CVD risk, and to determine whether this relationship was mediated by APOs. Methods: This secondary analysis of the multisite prospective nuMoM2b-Heart Health Study included 4,050 participants (M age =27.6±5.6 years), with complete longitudinal data for variables from early pregnancy to 2-7 years post-delivery. Participants self-reported depressive symptoms on the Edinburgh Postnatal Depression Scale (EPDS) at 6-13 (early pregnancy) and 22-29 (mid-pregnancy) weeks of gestation. APOs were collected prospectively and adjudicated and included small-for-gestational-age birth, hypertensive disorders of pregnancy, gestational diabetes mellitus, placental abruption, and preterm birth. CVD risk factors, assessed at 2-7 years after delivery (follow-up interval M =3.2±0.9 years), were modeled as a higher order latent factor indicated by intermediate latent factors: insulin resistance (glucose and insulin), adiposity (waist circumference and BMI), blood pressure (SBP and DBP), and dyslipidemia (triglycerides and HDL cholesterol). Structural equation modeling was used to test whether APOs (present or absent) mediated the relationship between mid-pregnancy EPDS scores and latent CVD risk 2-7 years post-delivery, covarying for EPDS scores in early pregnancy (approximating pre-pregnancy), length of follow-up interval, smoking history, age, education, and income. Results: The model adequately fit the data (CFI=.96; RMSEA=.058; SRMR=.04). The direct effects of APOs ( β =.26, p <.01) and late pregnancy EPDS scores ( β =.13, p <.01) on latent CVD risk were significant. BMI ( r =.16), waist circumference ( r =.15), and HDL cholesterol ( r =-.13) were the CVD risk factors most strongly associated with late pregnancy EPDS scores ( r range=|.04-.16|). The indirect effect of EPDS scores on CVD risk through APOs was not significant ( p >.6). Discussion: Depressive symptoms in mid-pregnancy were associated with higher CVD risk 2-7 years after delivery, but this effect was not mediated by experiencing APOs. Future studies should evaluate whether pregnancy interventions to improve mood reduces subsequent risk of CVD.
Abstract P2087: Sex Disparities in Acute Myocardial Infarction Identification and Treatment.
Background: Early identification and diagnosis are pivotal in the management of patients with acute myocardial infarction (AMI). The American Heart Association / American College of Cardiology (AHA/ACC) guidelines recommend obtaining an electrocardiogram (ECG) for patients who present to the emergency department (ED) with ischemic symptoms within 10 minutes of arrival. This is an important step in ensuring early administration of reperfusion therapy for those with an ST-elevation myocardial infarction (STEMI). A goal of ≤90 min or ≤ 120 min when transfer is involved is recommended for door-to-balloon (DTB) procedure time to reduce the risk of poor outcomes. However, past research has shown that sex disparities exist in ED triage and timely treatment of patients experiencing an AMI. The aim of this study was to assess sex differences in timely identification and treatment of patients presenting to the ED with AMI. Methods: We performed a retrospective cross-sectional analysis of 874 STEMI (234 females and 640 males) and 1,650 Non-STEMI (NSTEMI; 556 females, 1095 males) patients that presented to two urban EDs between January 1, 2022, and March 31, 2024. Sex differences in time to ECG (STEMI and NSTEMI) and DTB (STEMI only) were compared continuously, as well as categorically based on AHA/ACC recommendations (ECG delay: >10 min, DTB delay: >90 min or >120 min with transfer). Continuous variables were compared using a multi-factor analysis of variance and categorical variables were tested using chi-square test of association. Results: Median time to ECG was 4.0 min longer for female compared to male STEMI patients, and 2.5 min longer for female vs male NSTEMI patients (ECG delay: 20.3% of female vs. 11.6% of male STEMI patients and 29.3% female vs. 20.3% of male NSTEMI patients). EMS activation time to ECG was also longer in females (+7.4 min for female STEMI patients and +2.9 min for female NSTEMI patients, compared to male counterparts). Similarly, DTB was 28.0 min longer when no transfer was involved and 15.2 min longer with transfer in female compared to male STEMI patients (DTB delay: 40.6% female vs. 37.0% male STEMI patients). Conclusion: In AMI patients presenting to the ED, female sex was associated with a significantly longer time to ECG. Female STEMI patients also had longer DTB times, which is associated with poorer outcomes. Initiatives are needed to understand these sex disparities and achieve the AHA/ACC guidelines for both time to ECG and DTB.
Abstract P1176: The Association of Urinary Incontinence, Physical Activity, and Cardiovascular Disease Risk in Women
Introduction: Urinary incontinence (UI) is a common condition among women. Emerging evidence indicates UI might contribute to lower physical activity (PA) levels. Thus, women with UI may have increased risk for inactivity and related cardiovascular disease (CVD). Hypothesis: Women with UI, compared to women without UI, will 1) have higher odds of being inactive or insufficiently active, and 2) have higher odds of cardiovascular risk factors or diagnosed cardiovascular disease. Methods: This retrospective observational study used electronic medical records to capture data on UI diagnosis, self-reported moderate-to-vigorous PA using the Exercise Vital Sign, Atherosclerotic Cardiovascular Disease (ASCVD) risk factor components and the diagnosis or management of CVD using ICD-10 codes, and demographic information. Multinomial logistic regression assessed the association of UI and PA classification (inactive: 0 min/week, insufficiently active: 1-149 min/week, and active ≥150 min/week). Multiple variable logistic regression models assessed associations of UI with CVD risk calculator components and diagnosed CVD. All models adjusted for age, race, body mass index, and tobacco use. Results: Of 20,155 women who were included in analysis (mean age 50.36±16.42 years), 1,085 (5.4%) had a UI diagnosis. Women with UI were on average 11.4 years older than those without UI. A greater proportion of those with UI were current or former smokers compared to those without UI. Activity classification did not differ in those with and without UI. Those with UI had greater odds of type 2 diabetes (aOR 1.25, 95% CI: 1.06-1.48), dyslipidemia (aOR 1.37, 95% CI: 1.19-1.58), stroke (aOR 1.55, 95% CI: 1.06-2.25), and coronary artery bypass grafts (aOR 3.17, 95% CI: 1.45-6.95) than those without UI (Table 1). Conclusions: UI was not associated with PA classification; future studies should investigate whether increasing PA among women with UI can mitigate associations of UI and CVD risk. Women with UI also present with risk factors for CVD and the association should be further studied. Additionally, women with CVD should be screened for UI.