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Structural basis of SARS-CoV-2 polymerase inhibition by nonnucleoside inhibitor HeE1-2Tyr
Targeting the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 with small molecules is a promising therapeutic strategy against COVID-19, but potent and safe inhibitors are lacking. HeE1-2Tyr, a nonnucleoside inhibitor of Dengue virus RdRp, was also shown to inhibit SARS-CoV-2 RdRp in vitro and to have antiviral activity in cells, but the underlying mechanism remains unclear. Here, we elucidate the molecular mechanism of HeE1-2Tyr-mediated SARS-CoV-2 RdRp inhibition. Biochemical assays confirm that HeE1-2Tyr inhibits RdRp with an IC 50 of 5 µM and show that it competes with RNA binding to RdRp in vitro. Structural analysis using cryo-EM reveals that a stack of three HeE1-2Tyr molecules binds to the RNA binding site of RdRp. The identification of the conserved HeE1-2Tyr binding site and its intriguing inhibition mechanism of three stacked molecules that outcompete RNA may facilitate further development of pan-corona nonnucleoside inhibitors.
Abstract P3050: Diabetes Incidence Before and After the COVID-19 Pandemic Shelter-in-Place Mandate in Adults with Prediabetes
Background: We evaluated changes in type 2 diabetes (T2D) incidence associated with onset of the COVID-19 pandemic shelter-in-place (SIP) mandate; and if changes were greater among public (Medicaid) vs. commercially insured patients, and Asian, Black, and Hispanic vs. White patients, who have greater T2D risks. Methods: We examined electronic health records of 323,609 adults ages ≥18-89 years with BMI ≥25 (≥23 if Asian) and prediabetes (fasting glucose 100-125 mg/dL, or A1c 5.7-6.4%) from 1-1-2019 to 12-31-2021, at Kaiser Permanente Northern California. We defined T2D as having one inpatient discharge diagnosis or any of the following two within 24 months: A1c ≥6.5%, fasting glucose ≥126 mg/dl, random glucose ≥200 mg/dl, 2-hour 75-g oral glucose tolerance test ≥200 mg/dl, outpatient diagnosis code, and/or filled T2D medication. In a sub-analysis, we used only the first positive lab test in the T2D range. Using an interrupted time-series analysis, we evaluated whether an increase in T2D incidence was associated with the start of the pandemic SIP mandate (March 2020). The analysis was operationalized by fitting segmented linear regression models using generalized least squares, accounting for autocorrelation, and with monthly cases per 10,000 patients as the outcome. Results: In the 10 months before the pandemic SIP mandate, the average monthly T2D incidence was 12.2 cases (and 268 lab positivity cases) per 10,000 patients with stable trends. At the start of the SIP mandate, there was a nonsignificant steady increase in the monthly incidence of 0.8 (95% CI: -0.2,1.8) cases/month which persisted through 2021. There was also a steady and significant increase in the monthly lab positivity incidence rate of 8 (1, 16) cases/month, which persisted through 2021. In stratified analyses of lab positivity changes, the rate increase was similar across insurance types. However, compared to White patients, at the start of the SIP mandate, there was an immediate significantly greater increase in lab positivity of 104 (75, 133) cases/month for Hispanic patients, followed by an increase in monthly incidence that continued through 2021. There were no differences between Asian or Black and White patients. Conclusion: The COVID-19 pandemic and SIP mandate were associated with a steady increase in the T2D lab positivity rate among adults with prediabetes that persisted through 2021. The increase was larger among Hispanic compared to White patients, reflecting disparities.
Abstract P1050: Associations between Food Insecurity Trajectories in Youth and Overweight and Obesity Status in Young Adulthood
Background: Obesity is influenced by socioeconomic factors such as food insecurity (FI) over the life course. Little is known about longitudinal experiences of FI in childhood and adolescence and how these experiences relate to overweight and obesity status in adulthood. Objective: Our study aimed to investigate FI trajectories throughout youth and their associations with weight status in young adulthood. We hypothesized that trajectories indicating FI in childhood and adolescence would be associated with increased odds of being overweight and obese in young adulthood and that these associations would differ by extreme poverty status in adulthood. Methods: We used data from the Future of Families and Child Wellbeing Study, a longitudinal sample of children born in large U.S. cities between 1998-2002. We used group-based trajectory modeling to identify distinct FI trajectories from ages 3 to 15, based on survey questions approximating Hunger Vital Sign at ages 3, 5, 9, and 15. Overweight and obese status were defined using self-reported weight and height at age 22. Associations between FI trajectory and weight status were assessed using multivariate logistic regression, adjusting for relevant covariates. We stratified adjusted analyses by extreme poverty or not at age 22. Results: Of the total sample (n = 4,296), 12.2% identified as non-Hispanic White, 48.1% as female. Three distinct FI trajectories in youth were identified: 51.3% were food secure, 13.2% were food insecure, and 35.5% transitioned from food insecure-to-secure (Figure). Mean body mass index at age 22 was 27.6 (standard deviation 8.0). In adjusted analyses, young adults in the food insecure-to-secure group had higher odds of being overweight (OR 1.23, 95% CI [1.01-1.51]) compared to those in the food secure group. When stratified by poverty status, among young adults not in extreme poverty, those who were food insecure-to-secure had higher odds of being overweight (OR 1.34 95% CI [1.03-1.75]) and obese [OR 1.50, 95% CI [1.14-1.98]) compared to those who were food secure. These associations were not significant for those in extreme poverty. Conclusions: Young adults who transitioned from being food insecure to secure, particularly those not in extreme poverty, are vulnerable to having high weight status, highlighting the importance of supporting early childhood food security.
A horizontally transferred bacterial gene aids the freezing tolerance of Antarctic bdelloid rotifers
Bdelloid rotifers are well known for their abilities to survive long periods of freezing as well as acquire foreign genes. Recently sequenced genomes of some bdelloid rotifers in England were found to encode several proteins similar to ice-binding proteins (IBPs) that are usually associated with freeze–thaw tolerance. Here, I describe bdelloid rotifers inhabiting an algal patch in Antarctica that have multiple homologs of these genes. Structures of the proteins predicted by AlphaFold show that they are well designed for ice-binding and a recombinant protein made for one of them showed strong ice-binding activity. The existence of multiple copies of these proteins is another characteristic of IBPs. Furthermore, multiple bdelloid rotifers in the algal patch were revived in less than an hour after storage at −25 °C for 24 y, an apparent record for laboratory-controlled studies. Several characteristics of these genes point to bacteria as their source: sequence homology, absence of introns, and a structural peculiarity so far found only in bacteria. The remarkable freezing tolerance of bdelloid rotifers can thus be at least partially attributed to horizontally acquired bacterial genes encoding IBPs.
Abstract P3085: Influence of the 5-minute Rest Period on Home Blood Pressure Monitoring in Postpartum Women
Introduction: Home blood pressure (BP) monitoring is a practical approach for out-of-office measurement, allowing confirmation of elevated BP outside of the clinic setting. Patients are instructed to complete a 5-minute seated rest prior to home BP measurements for accuracy; however, compliance with this rest period and its impact on home BP readings remain unknown. Hypothesis: We hypothesize (1) participants would not consistently complete the 5-minute rest prior to home BP measurements, and (2) readings following the 5-minute rest would be significantly lower and have higher consistency within measurements compared to non-compliant readings. Methods: Participants were postpartum women (3 months after delivery; n = 40) enrolled in the multi-site Postpartum 24/7 pilot cohort study. Participants were instructed to assess BP twice on two occasions (morning and night) for 7 days using the Omron 5 series BP monitor, with 5 minutes of quiet, seated rest before the first measurement. A thigh-worn activPAL3 micro was concurrently used to assess compliance with the 5-minute rest. Given 1-minute epoch lengths from the BP monitor data, we defined compliance as readings with at least 4 minutes of continuous sitting from the activPAL3 before the BP reading. The compliance rate was the percentage of compliant measurements. The random and fixed effects of the 5-minute rest and intraclass correlation coefficients (ICC) of BP readings were calculated using a linear mixed model. Results: Participants (mean age: 30.6 ± 4.2 years; mean body mass index: 28.7 ± 6.6 kg/m 2 ) had 1,034 BP readings, with an average of 25.9 of 28 (92.5%) requested readings per person. Of these, 47.2% of BP readings were considered compliant with the 5-minute rest. Systolic BP was significantly lower by -2.83 mmHg (95% CI: -4.21, -1.47) in rest-compliant readings compared to non-compliant readings, though diastolic BP was similar. ICCs for rest-compliant systolic and diastolic BP readings were 0.708 and 0.690, respectively, suggesting moderate consistency; the corresponding ICCs for non-compliant readings were lower at 0.598 for systolic and 0.581 for diastolic BP. Conclusions: Participants were able to complete most home BP readings but with low compliance with the 5-minute rest period, which affected systolic BP values and overall BP consistency. Future research should assess rest compliance rates in more general populations and its impact on clinical decision-making and outcomes.
Abstract P1055: Anxiety, Stress, Emotional Difficulties and Behavioral Cardiovascular Health in Childhood: The Young Hearts Study
Background: Psychosocial factors in childhood, such as emotional and behavioral difficulties, contribute to long-term cardiovascular health (CVH). However, limited research has explored the relationship between these difficulties and childhood CVH. Methods: This cross-sectional analysis includes participants aged 2-18 (N = 6,892) from the Young Hearts cohort with complete behavioral CVH (bCVH) and Strengths and Difficulties Questionnaire (SDQ) data. SDQ scores included the Total Difficulties Score (TDS), measuring emotional and behavioral difficulties, and the Prosocial Behavior Score (PBS), reflecting empathy and cooperation. We calculated bCVH scores using the Life’s Essential 8 metrics (diet, exercise, nicotine exposure, sleep, and BMI). Linear regression was used to assess associations between TDS, PBS, and bCVH, adjusting for age, sex, race/ethnicity, parental education, financial stability, food security, and health insurance status. Results: The sample had a mean age of 8.7, 48% female, 46% non-Hispanic White, 28% Hispanic, and 15% non-Hispanic Black. Higher TDS was associated with lower bCVH (-1.91; 95% CI -2.27, -1.56), while higher PBS was linked to better bCVH (1.75; 95% CI 1.41, 2.1), and physical activity largely contributed to these differences (Figure 1). Conclusion: Psychosocial difficulties and prosocial behaviors have a strong association with physical activity, making it a potential intervention target for improving childhood CV outcomes. Enhancing prosocial behaviors through interventions like social-skills training may further support both psychosocial well-being and cardiovascular health in children.
MUC5AC filaments illuminate the structural diversification of respiratory and intestinal mucins
Secreted mucins are multimegadalton glycoprotein polymers that share the function of protecting mucosal tissues but diversified for activities in different organs of the body. Structural studies of secreted mucins are complicated by the enormous sizes, flexibility, and complex supramolecular assembly modes of these glycoproteins. The two major respiratory mucins are MUC5AC and MUC5B. Here, we present structures of a large amino-terminal segment of MUC5AC in the form of helical filaments. These filaments differ from filamentous and tubular structures observed previously for the intestinal mucin MUC2 and the partial mucin homolog VWF. Nevertheless, the MUC5AC helical filaments support the proposed mechanism, based on MUC2 and VWF, for how noncovalent interactions between mucin monomers guide disulfide crosslinking to form polymers. The high-resolution MUC5AC structures show how local and limited changes in amino acid sequence can profoundly affect higher-order assembly while preserving the overall folds and polymerization activity of mucin glycoproteins. Differences in supramolecular assembly are likely to be functionally significant considering the divergence of mechanical properties and physiological requirements between respiratory and intestinal mucins. Determining the high-resolution structures of respiratory mucins provides a foundation for understanding the mechanisms by which they clean and protect the lungs. Moreover, the MUC5AC structure enables visualization of the sites of human amino acid sequence variation and disease-associated mutations.
Abstract P3129: Epigenetic gestational age predicts subclinical atherosclerosis measures from childhood through adulthood
Objective: Atherosclerosis, an aging-related disease, may begin developing in childhood. Epigenetic age is known to predict biological aging accurately, and epigenetic gestational age can predict biological maturity at birth. However, the association of biological aging at birth with atherosclerosis in later life remains unknown. We aim to examine the association of epigenetic gestational age with subclinical measures of atherosclerosis at ages 11 to 24 and their changes over time. Methods: In the Southern California Children’s Health Study, DNA methylation from newborn bloodspots of 242 participants was analyzed using the Infinium 450K array. We calculated epigenetic gestational ages with the Knight and Bohlin algorithms. Intrinsic Epigenetic Gestational Age Deceleration (IEGAD), indicating developmental immaturity at birth, was derived by regressing epigenetic age on clinical gestational age, adjusted for cell composition. Subclinical measures of atherosclerosis, including carotid intima-media thickness (CIMT) and carotid distensibility, were obtained from ultrasound images from all participants in childhood (mean age: 11.3 years, SD: 0.6) in 2007, and repeatedly obtained from a subset of 54 participants again in adulthood (mean age: 24.2 years, SD: 1.6) between 2019 and 2022. Associations between each IEGAD and subclinical atherosclerosis measures, including their changes over time, were evaluated using linear regression, adjusting for sex, race, birthweight, age and body mass index at time of ultrasound, maternal age at delivery, and maternal pregnancy complications. Results: Knight IEGAD (mean: -0.05, SD = 1.1) and Bohlin IEGAD (mean: -0.03, SD=0.78) was moderately correlated (Pearson r = 0.67, P<0.001). Each week increase in Bohlin EEGAD was associated with higher adult CIMT (β = 34.9 µm, 95% CI: 1.63, 68.2) and with more CIMT thickening from childhood to adulthood (β = 2.2 µm/year, 95% CI: 0.05, 4.36). Similarly, each week increase in Knight IEGAD was associated with reduced arterial elasticity, as measured by lower carotid distensibility, in both childhood (β = -3.22, 95% CI: -0.78, -5.67) units (10 −6 ×m 2 /Newtons) and adulthood (β = -1.99, 95% CI: -0.36, 4.34), and an annual reduction of 0.40 (-0.14, 0.94) unit/year from childhood to adulthood. Conclusion: Developmental immaturity at birth, as indicated by epigenetic gestational age, is associated with adverse subclinical atherosclerosis markers from childhood to adulthood.
Abstract MP05: Consuming Pecans as a Snack Improves Lipids/Lipoproteins Compared to Usual Diet in Adults at Increased Risk for Cardiometabolic Diseases: A Randomized Controlled Trial
Background: Nut intake is associated with lower risk of cardiometabolic diseases through reductions in low density lipoprotein cholesterol (LDL-C) and triglycerides and improvements in measures of glycemic control. The cardiometabolic effects of pecan consumption have been less studied in comparison with other nuts. Objectives: The aim of this trial was to examine how substitution of usual snack foods with 57 g/day of pecans affects lipids and lipoproteins and measures of glycemic control compared to continuing usual dietary intake after 12-weeks in individuals at increased risk for cardiometabolic diseases. Methods: A 12-week single-blinded, parallel, randomized controlled trial was conducted. Adults with overweight or obesity and with ≥1 criterion for metabolic syndrome who were free from cardiovascular disease and type 2 diabetes were included. Participants were provided with 57 g/day of pecans and instructed to replace the snacks usually consumed with the provided pecans. The control group was instructed to continue consuming their usual intake. Lipids/lipoproteins and glycemic outcomes (i.e., fasting plasma glucose, hemoglobin A1C and insulin) were measured over two days approximately 24 hours apart at baseline and after 12 weeks. The between-group difference in the change from baseline for each outcome was evaluated by linear regression with adjustment for the baseline value, age, sex and body mass index. Results: In total, 138 participants (46 ± 13 years, 29.8 ± 3.7 kg/m 2 ; 59% female) were randomized. Both groups had 69 participants. Compared to the usual diet group, pecan intake reduced total cholesterol (-8.1 mg/dL; 95% CI -14.5, -1.7), LDL-C (-7.2 mg/dL; 95% CI -12.3, -2.1), non-HDL-C (-9.5 mg/dL; 95% CI -15.3, -3.7), and triglycerides (-16.4 mg/dL; 95% CI -30.0, -2.9) from baseline to 12 weeks. No between-group differences were observed for high-density lipoprotein cholesterol (HDL-C) or measures of glycemic control. Conclusions: Replacing usual snacks with 57 g/day of pecans for 12 weeks improved lipids and lipoproteins in adults at increased risk for cardiometabolic diseases.
The effect of salt additives on the glycine crystallization pathway revealed by studying one crystal nucleation at a time
Molecular-level understanding of the early stage of crystallization remains a significant challenge. For a wide range of fundamental research and applications, it is of great importance to understand the mechanism of crystal polymorph selections in different solvents or in the presence of additives. We studied glycine crystallization in aqueous solution with or without the addition of sodium chloride (NaCl), one crystal nucleation at a time, using the recently developed single-crystal nucleation spectroscopy (SCNS). It has been reported that glycine forms γ-glycine when salt is added to aqueous solution, and the mechanism has been considered as a classical nucleation where γ-glycine forms directly as a crystal nucleus. Our study shows that metastable polymorph β-glycine forms first in aqueous solution both with or without NaCl through a nonclassical nucleation pathway. NaCl can stabilize the metastable β-glycine over several hours and also prevent it from converting to α-glycine. Eventually γ-glycine nucleates on the surface of β-glycine and then grows while dissolving the mother β-glycine. The crystal habit of β-glycine suggests that the stabilization by NaCl occurs at its polar face. SCNS provides crucial information to accelerate the investigation of the early stage of crystallization toward the rational control of polymorphisms.
Abstract P3101: Predictive Modeling of Glycemic Variability and its Association with Metabolic Health: A Precision Nutrition Approach Using Korean National Data
The global burden of metabolic diseases, particularly diabetes and hyperglycemia, presents ongoing challenges for effective treatment and management. Conventional glycemic control strategies may not be suitable for healthy individuals and those with prediabetes. To enhance the personalized characterization of glycemic variability (GV), which reflects long-term glycemic trends rather than short-term responses to individual meals, this study developed a predictive model for Time in Range (TIR). This model enables monitoring of metabolic effects associated with lifestyle choices without the need for a continuous glucose monitoring system (CGMS). To estimate TIR, we applied a backward elimination linear regression model to optimize predictions based on lifestyle factors such as physical activity, sleep, stress, and dietary intake from 48 CGMS clinical study participants. The model showed a strong correlation between predicted TIR and actual metrics (R = 0.743, p < 0.001). Using data from 24,564 adults from the Korean National Health and Nutrition Examination Survey, we confirmed the association between predicted TIR values and metabolic health indicators. The results demonstrated a significant association between predicted TIR and reduced risk of metabolic diseases, particularly hypertension (Q1 vs. Q5: OR = 0.87; 95% CI = 0.79–0.95) and hypercholesterolemia (Q1 vs. Q5: OR = 0.82; 95% CI = 0.73–0.92). These findings may contribute to the development of precision nutrition-based healthcare for personalized prevention and management of metabolic diseases.
Abstract P1047: Pre- and Perinatal Determinants of Cardiovascular Health Trajectories Across Childhood and Adolescence
Introduction: The American Heart Association put forth the Life’s Essential 8 construct to assess cardiovascular health (CVH) status based on 8 health and behavioral factors. However, few studies have identified early-life determinants of CVH trajectories from childhood to adolescence, important life stages during which health behaviors and disease precursors are established. We sought to address this research gap in Project Viva, a prospective pre-birth cohort in Boston. Methods: We included 1,338 children with data on ≥3 CVH metrics in early childhood (median age 3.2y; range 2.8–6.2y) or ≥4 metrics in mid-childhood (7.7y; 6.6–10.9y), early adolescence (13.0y; 11.9–16.6y), or late adolescence (17.5y; 15.4–20.1y). We derived CVH score (range 0-100 points) at each life stage and used segmented mixed-effect models to estimate three CVH trajectory parameters: timing of inflection point when CVH score declines; slope before and after the inflection. Linear regression models evaluated associations of pre- and perinatal factors with each trajectory parameter, adjusting for maternal sociodemographic characteristics at enrollment. Results: The mean (SD) CVH score was 82.7 (8.4) in early childhood, 84.3 (8.2) in mid-childhood, 82.2 (9.7) in early adolescence, and 74.2 (11.4) in late adolescence. Estimated age of inflection when CVH score declined was 10.2y (0.7) for males and 10.0y (0.6) for females. Prepregnancy overweight or obesity (vs. healthy or under-weight), smoking during pregnancy (vs. never), and being weaned or formula-fed (vs. breastfeeding) in the first 6 months were each associated with persistently lower CVH from childhood to adolescence. Prepregnancy obesity (vs. healthy- or under-weight) was associated with later inflection (β 0.1y; 95% CI 0.0, 0.2) and slower subsequent CVH score decline (0.2 points/y; 0.1, 0.4). Gestational hypertension or preeclampsia (vs. normal blood pressure) was associated with faster CVH score gain before inflection (0.3 points/y; 0.1, 0.5), earlier timing of inflection (-0.1y; -0.2, 0.0), and faster CVH score decline (-0.3 points/y; -0.5, -0.1), while smoking during pregnancy (vs. never) was associated with later inflection (0.2y, 0.1, 0.3). Conclusions: This study provides insights into potentially modifiable pre- and perinatal factors of CVH trajectory across childhood and adolescence. Future work should examine whether early-life interventions addressing these factors would be effective in optimizing CVH in children.
Hypercholesterolemia-induced LXR signaling in smooth muscle cells contributes to vascular lesion remodeling and visceral function
Vascular smooth muscle cells (VSMC) are the most abundant cell type in the artery’s media layer and regulate vascular tone and lesion remodeling during atherogenesis. Like monocyte-derived macrophages, VSMCs accumulate excess lipids and contribute to the total intimal foam cell population in human coronary plaques and mouse aortic atheroma. While there are extensive studies characterizing the contribution of lipid metabolism in macrophage immunometabolic responses in atherosclerotic plaques, the role of VSMC lipid metabolism in regulating vascular function and lesion remodeling in vivo remains poorly understood. Here, we report that the liver X receptor (LXR) signaling pathway in VSMC is continuously activated during atherogenesis. Notably, we found that LXR deficiency in SMCs under hypercholesterolemic conditions influenced lesion remodeling by altering the fate of dedifferentiated SMCs and promoting the accumulation of VSMC-derived transitional cells. This phenotypic switching was accompanied by reduced indices of plaque stability, characterized by a larger necrotic core area and reduced fibrous cap thickness. Moreover, SMC-specific LXR deficiency impaired vascular function and caused visceral myopathy characterized by maladaptive bladder remodeling and gut lipid malabsorption. Mechanistically, we found that the expression of several genes involved in cholesterol efflux and FA synthesis including Abca1 , Srebf1 , Scd1 , Scd2 , Acsl3, and Mid1ip1 was downregulated in mice lacking LXRαβ in SMCs, likely contributing to the phenotypic switching of VSMC in the atherosclerotic lesions.
Abstract P3147: Prevalence of Self-Reported Depression among Jackson State University African American Students, Data from a 2023 Cross-Sectional Survey
Background: Mental illnesses are prevalent health conditions in the United States. More than 1 in 5 US adults experience mental illness. According to the CDC, the prevalence of mental health illness and depression among US adults aged 18 and older is 12.5% and 5.0%, respectively. In 2019, 19.2% of adults had received mental health treatment in the past 12 months. Mental illnesses cost America $192.2 billion in lost earnings per year. Therefore, as research is limited, the purpose of this study is to examine mental illness, especially depression, among Jackson State University (JSU) students. Material and Methods: A cross-sectional study was designed and applied. Data were collected in 2024, targeting African American students of JSU. The survey tool was adopted from the Youth Risk Behavior Surveillance System conducted by the Centers for Disease Control and Prevention. Students were asked, “During the past 12 months, did you ever feel so sad or hopeless almost every day for two weeks or more in a row that you stopped doing some usual activities?” Descriptive and Chi-square tests were applied in this study. Results: Three hundred ninety-eight African American JSU students, 74.4% females, participated in our study. Findings showed that 185 students (46.5%) responded that they were depressed in the last 12 months. In addition, depression was significantly more prevalent among females than males (54.1% vs. 37.5%, p-value< 0.01). The odds ratio for depression was 1.96 with 95 % CI: 1.16- 3.33 among females compared to males, suggesting that females had a 1.96 higher likelihood of depression compared to males. Conclusion: The findings indicate that self-reported depression was high among JSU students, especially among African American female students. Factors associated with high depression among JSU students need to be investigated. Furthermore, mental health awareness and services must be visible on the JSU campus.
Abstract P1080: Barriers and Facilitators to Treatment Adherence: An Exploration of the Lived Experience of Patients with Heart Failure
Background: Research suggests that only ~50% of patients with HF meet recommended medication adherence; rates of overall treatment adherence, which additionally includes lifestyle changes and cardiac rehabilitation attendance, are even lower. Drivers of treatment nonadherence in this population remain poorly understood. This qualitative study aims to identify barriers and facilitators of treatment adherence among patients with HF. Methods: We recruited 19 adult patients with a diagnosis of HF from 2 clinics in Kentucky to participate in interviews. All patients had access to a phone to facilitate the interview and were free of genetic heart conditions. Treatment adherence was defined as a patient’s ability to follow the recommended treatment prescribed by their healthcare provider. A semi-structured interview guide was used to ask patients about experiences, habits, barriers, and facilitators to engaging in their HF treatment. Six patients participated in follow-up interviews to assess the study team’s interpretation of their prior responses and to ask clarifying questions to ensure saliency of the findings. Results: Over half of the participants identified physician communication as crucial to their experience, specifically: open dialog, honest explanations of treatment side effects, and willingness to listen. Many patients identified goal setting as critical to their treatment adherence, especially after initial diagnosis. By setting small, obtainable goals with their medical team, patients described feelings of increased self-confidence and reported making positive lifestyle changes. Rising cost of medication, food, and other therapies were identified as adherence barriers. Finally, 42% of patients discussed having significant fear regarding their HF diagnosis which began after a precipitating traumatic event, such as a hospitalization or heart attack, and persisted years later. However, some patients found this fear to be a motivation to make and maintain lifestyle changes. Several patients also expressed feelings of depression or isolation resulting from reduced autonomy. Conclusion: These qualitative findings suggest that patients are more likely to engage with their treatment plan when they have effective communication with their physician, set obtainable goals, and are able to afford both food and medication. Interventions to improve outcomes for patients with HF should focus on the patient-doctor relationship and connection to available financial resources.
Urban highways are barriers to social ties
Urban highways are common, especially in the United States, making cities more car-centric. They promise the annihilation of distance but obstruct pedestrian mobility, thus playing a key role in limiting social interactions locally. Although this limiting role is widely acknowledged in urban studies, the quantitative relationship between urban highways and social ties is barely tested. Here, we define a Barrier Score that relates massive, geolocated online social network data to highways in the 50 largest US cities. At the granularity of individual social ties, we show that urban highways are associated with decreased social connectivity. This barrier effect is especially strong for short distances and consistent with historical cases of highways that were built to purposefully disrupt or isolate Black neighborhoods. By combining spatial infrastructure with social tie data, our method adds a dimension to demographic studies of social segregation. Our study can inform reparative planning for an evidence-based reduction of spatial inequality, and more generally, support a better integration of the social fabric in urban planning.
Abstract P2103: Associations between the Plasma Proteome and a Polygenic Risk Score for Abdominal Aortic Aneurysm: The Atherosclerosis Risk in Communities Study (ARIC)
Introduction: Abdominal aortic aneurysm (AAA), characterized as bulging of the abdominal aorta, is life-threatening when it ruptures. While genetic susceptibility is a known risk factor for AAA, novel mechanisms associated with genetic risk have yet to be explored. This study aims to investigate the associations between the plasma proteome and genetic susceptibility for AAA, measured through a polygenic risk score (PRS). Methods: We constructed a PRS for AAA for participants in the ARIC Study, an ongoing community-based prospective cohort, based on summary statistics from a recent genome-wide association study (GWAS) for AAA (PMID: 37845353). Applying Bayesian regression with continuous shrinkage priors, we calculated the PRS for each participant using SNP dosages available from ARIC and genome-wide SNP weights from the AAA GWAS. We included 8978 European American (EA) participants as the discovery sample (52.9% female, mean age = 57.2) and 2672 African American (AA) participants as the replication (62.9% female, mean age= 56.3) sample. We measured plasma levels for 4955 proteins by SOMA scan v4 from samples collected at ARIC visit 2. We performed linear regression to evaluate the relationship between the AAA PRS and each of the 4955 plasma proteins, controlling for potential confounders. We used the following strategy to interpret PRS-protein associations in the discovery in EAs: Priority 1: 118 proteins that were previously associated with individual AAA risk variants in ARIC (PMID: 36579647); Priority 2: agnostic scan among the remaining 4837 proteins. Bonferroni correction for multiple testing was applied to the two groups of proteins separately in EAs. Uncorrected p<0.05 was applied in AAs. Results: In EA participants, 8 proteins were associated with the AAA PRS among the 118 priority proteins (p < 4.24 * 10 -4 ) and 1 protein was associated with the AAA PRS in the agnostic scan of the remaining proteins (p < 1.03 * 10 -5 ), for a total of 9 significant proteins: S100A13, TBCA, LRRN1, CRIP1, IL6R, PLA2G7, C5orf38, PCDHB10, and MMP12. Of the 9 proteins, IL6R was replicated in AA participants (p<0.05) with the consistent direction of association. Conclusion: Identifying the circulating proteomics signature for genetic susceptibility of AAA can further our understanding of AAA etiology and provide valuable insights into robust target interventions in preventing AAA.
Abstract P1167: Racism-Related Stress Related to Carotid-Femoral Pulse Wave Velocity in Cohort of Midlife Latinas
Background: Cardiovascular disease (CVD) is one of the leading causes of death among women in the U.S, with an increased risk among Latinas. One-third of Latinas report experiences of racism and discrimination in the U.S. Psychological stress has been demonstrated to worsen CVD risk factors such as blood pressure, insulin resistance, and adverse lipid profile. However, there is limited consensus surrounding the relationship between racism-related stress and subclinical CVD in the Latina population. Thus, this study examines the relationship between sociocultural stress and carotid-femoral pulse wave velocity (cfPWV), a subclinical marker of CVD, in midlife Latinas. Methods: A cross-sectional analysis was conducted using baseline data from 31 women enrolled in an ongoing longitudinal study of midlife Latinas. Participants were eligible if they self-identified as Latinas between the ages of 40 and 60 years old and were perimenopausal. Women with a history of CVD, or moderate to major depression (PH9 >10) were excluded. Racism-related stress was assessed using the Hispanic Women Social Stress Scale. Physical and anthropometric measures (e.g., weight, waist circumference, blood pressure, lipid profile) were collected during a clinical exam. Sociodemographic factors and medical history were self-reported using an interviewer-administered questionnaire. cfPWV was assessed using the Vicorder® device. Descriptive statistics and Pearson correlations were conducted (α = 0.1). Results: Participants were on average aged 47.1 ± 4.1 years, with 71% reporting having been born outside of the continental United States. At baseline, average cfPWV was 5.4 ± 0.7 m/s. Respondents had an average of 26.3 ± 25.1 on the Hispanic Social Stressor Scale (0-120) and over half (n=16) reported an experience of racism. When considering the total sample, cfPWV did not differ between women who reported at least one experience of racism (5.39 ± 0.73 m/s) compared to those who had no experience (5.75 ± 0.71 m/s). Among women who reported an experience of racism, greater severity of stress was positively correlated to cfPWV (r=0.58, p=0.02). Conclusions: In this cross-sectional analysis of midlife Latinas, the severity of racism-related stress was positively correlated to arterial stiffness. Findings support prior reports that greater exposure to racism worsens CVD risk. Additional data are necessary to further explore the impact of racism on CVD risk in this population.
S-nitrosylation-triggered secretion of mycobacterial PknG leads to phosphorylation of SODD to prevent apoptosis of infected macrophages
The tuberculosis-causing agent Mycobacterium tuberculosis (M.tb) establishes its niche inside macrophages by secretion of several virulence factors and engaging many host factors. Mycobacterial infection of macrophages results in a proinflammatory trigger–mediated secretion of TNFα. Protein kinase G (PknG), a Serine/Threonine kinase, is essential for mycobacterial survival within the macrophage. Pathogenic mycobacteria, upon infection, can trigger the secretion of proinflammatory cytokine TNFα, but whether secreted PknG plays any role in TNFα secretion at early stages of infection remains undeciphered. Moreover, at early infection stages, prevention of macrophage apoptosis is vital to successful mycobacterial pathogenesis. Our studies show that mycobacteria-secreted PknG can dampen the expression and concomitant secretion of proinflammatory TNFα. During early infection, M.tb infection–induced generation of reactive nitrogen intermediates (RNI) leads to S-nitrosylation of PknG on Cys109, thereby enabling its secretion into macrophages. Upon M.tb infection, secreted S-nitrosylated PknG phosphorylates macrophage Silencer of Death Domains (SODD) at Thr405, as identified through our phosphoproteomic studies. Thereafter, phosphorylated SODD, through an irreversible binding with the TNFR1 death domain, prevents Caspase8 activation and concomitant extrinsic apoptotic trigger. Moreover, alveolar macrophages from mice infected with PknG-knockout M.tb also exhibited SODD phosphorylation and hindered Caspase8 activation to prevent extrinsic macrophage apoptosis. Therefore, this work exhibits S-nitrosylation-mediated secretion of PknG to induce phosphorylation of macrophage SODD, which, through irreversible interaction with TNFR1, prevented extrinsic macrophage apoptosis at the early stages of infection.
Abstract P3128: Statins and Insulin Resistance in a Pediatric Preventive Cardiology Practice
Introduction: Statins are prescribed to lower LDL-C in children with familial hypercholesterolemia and other dyslipidemias that accelerate atherosclerosis. Associations between statin use and type 2 diabetes mellitus are reported in adults; there are scant studies in the pediatric literature. Objective: To determine if statin use is associated with higher HbA1C and HOMA-IR (homeostatic model assessment for insulin resistance) in children prescribed statins compared to non-statin users in a large pediatric preventive cardiology practice. Methods: Clinical data for patients prescribed statins were analyzed from 2003 through 2024, comparing HbA1C and HOMA-IR, and other characteristics at baseline, early follow-up (6 months) and late follow-up (3 years) post-statin initiation to statin non-users. Linear regression models were used to analyze baseline differences in HbA1C and HOMA-IR in the statin vs. non-statin groups, adjusted for age, sex, and BMI. A linear mixed effect model was used to analyze the longitudinal outcomes of HbA1C and HOMA-IR in the statin vs. non-statin groups. Results: In 757 patients with available data (406 prescribed statins), 51.5% were female with a mean age of 13.8 years at baseline. HbA1C and HOMA-IR were lower at baseline in the statin group vs. non-statin group (5.22% vs. 5.32% and 2.56 vs. 3.78 respectively, p <0.001). At 6 months post-statin initiation, HOMA-IR increased by 0.2 units more per month in the statin group than the non-statin group (p=0.03); the HbA1C rose by 0.01% more per month in the statin vs. non-statin group, approaching statistical significance (p=0.05). At 3 years post-statin initiation, the rate of change in HOMA-IR did not differ between the groups (p=0.78). However, at 3 years, the HbA1C rose by 0.0053% more per month in the statin group vs. non-statin group (p<0.001). Conclusion: In this large clinical pediatric cohort spanning over 20 years, there was a higher rate of rise of HOMA-IR early on (6 months) in those prescribed statins vs. statin non-users; after 3 years, the rate of rise of HbA1C was higher in the statin group, but HOMA-IR did not differ. Differences in HbA1C and HOMA-IR between the statin and non-statin groups, while statistically significant, were small and not likely clinically meaningful; values were more strongly driven by BMI category. Further research is needed; in the interim, clinical monitoring of HbA1C in children prescribed statins may be warranted.