Browse Articles

Subject-specific modeling of response to physical stress via hypothalamic-pituitary-adrenal and sympathoadrenal axes

The two main pathways for hormonal stress response are the hypothalamic-pituitary- adrenal (HPA) axis and the sympathoadrenal (SA) axis. The HPA axis produces and secretes cortisol, while the SA axis produces and secretes the fast-acting catecholamines, epinephrine and norepinephrine, which in turn stimulate cortisol. Since it is difficult to consistently measure or monitor their concentrations in plasma, mathematical modeling of the catecholamines and their connection to cortisol can provide more information about the acute stress response. Previous mathematical models have simulated the dynamics of the HPA axis, but a model of the SA axis has not been created nor one with the combined effects of the HPA and SA axes. We propose an extension of Bangsgaard and Ottesen’s differential equation-based HPA axis model that includes the SA axis [1]. We performed sensitivity analysis using Morris screening and estimated model parameters using constrained optimization with respect to time series data of cortisol and catecholamine dynamics under acute physical stress. After subject-specific parameter estimation, the proposed model that includes both the HPA and SA axes shows qualitative agreement with the collected data.

Abstract MPTH68: Proteinuria Reduction and Cardiovascular and Mortality Outcomes in Chronic Kidney Disease: Evidence Across the CKM Continuum

Introduction: Proteinuria reduction has consistently been associated with improved kidney outcomes in chronic kidney disease (CKD). However, whether reduction in proteinuria also translates into lower risk of specific cardiovascular outcomes remains less well established. We aimed to evaluate the association between 1-year change in proteinuria and subsequent risks of cardiovascular and mortality outcomes in CKD. Hypothesis: We hypothesized that greater reduction in proteinuria over one year would be independently associated with cardiovascular outcomes, irrespective of diabetes status. Methods: We studied 3,073 participants with established CKD in the Chronic Renal Insufficiency Cohort (CRIC) who had repeated 24-hour urine protein measurements at baseline and 1 year. Percent change in proteinuria was modeled continuously (restricted cubic splines) and categorically (≥30% vs <30% reduction). Time-varying Cox models adjusted for demographics, BMI, smoking, serum albumin, medication use, prior CVD, hemoglobin, lipids, NT-proBNP, hsCRP, HbA1c, triglycerides, eGFR, and baseline proteinuria, with follow-up starting post 1 year. Outcomes included MACE (HF, MI, or stroke), ASCVD (MI, stroke, or PAD), HF, and all-cause mortality. Results: Among 3,073 participants (mean age 58.2 ± 10.5 years; 45.5% female; median baseline 24-hour urine protein 161 mg [IQR 70–775]; 68.9% on ACEi/ARB), median follow-up ranged from 10.7–13.7 years. Event rates per 1,000 person-years were 14.8 for MACE, 8.0 for HF, 9.6 for ASCVD, and 16.6 for mortality. A ≥30% reduction in proteinuria was associated with lower risk of MACE (HR 0.78 [0.66–0.93]), HF (0.74 [0.59–0.94]), and mortality (0.78 [0.68–0.90]), but not ASCVD (0.93 [0.76–1.13]). The MACE association was primarily driven by reduced HF events. Restricted cubic splines demonstrated a linear, graded association between greater proteinuria reduction and lower risk of MACE, HF, and mortality. Associations were consistent across diabetes strata (p-interaction > 0.05). Conclusions: Across the CKM spectrum, greater reduction in proteinuria over one year was linearly and independently associated with lower risk of HF, MACE, and mortality—regardless of diabetes or CVD status. The MACE association was largely driven by lower HF events, underscoring the cardiorenal coupling of proteinuric injury. Proteinuria change represents a dynamic, actionable biomarker of CKM health and a potential surrogate endpoint for cardiorenal protection in CKD.

CCR8 Expression on Regulatory T Cells Reveals Trajectories of Tissue Adaptation and Protects Against Myocardial Infarction–Induced Tissue Damage

BACKGROUND: Tissue-specific regulatory T cells (Tregs) accumulate in the heart after myocardial infarction (MI) and play a vital role in limiting inflammation and promoting tissue repair. However, the developmental trajectory of heart Tregs and the molecular cues that guide their recruitment to the heart remain poorly understood, impeding therapeutic strategies that leverage Treg-mediated cardiac protection. METHODS: We used single-cell and bulk RNA sequencing in a murine MI model to delineate the differentiation trajectory of Tregs from mediastinal lymph nodes to the heart. Functional validation was performed using Treg-specific Ccr8 (CC motif chemokine receptor 8) knockout mice ( Ccr8 flox/flox Foxp3 Cre ), Ccl1 (CC motif chemokine ligand 1) knockout mice ( Ccl1 −/− ), macrophage-targeted Ccl1 knockdown mice, Ccl1 -overexpressing mice, and DEREG mice. The CCL1-CCR8 axis was evaluated in cardiac tissues and circulating blood from patients with MI. RESULTS: Single-cell RNA sequencing revealed a stepwise differentiation of mediastinal lymph node–derived naive Tregs into heart Tregs, marked by the progressive acquisition of CCR8 expression and reparative capacity. CCR8 + Tregs in the heart exhibited enhanced immunosuppressive and tissue-repair signatures. Treg-specific Ccr8 deletion led to reduced Treg accumulation and worsened cardiac function after MI, along with increased proinflammatory macrophage features and number of CD8 + T cells and natural killer cells. In addition, Tregs promoted a shift of macrophages toward an anti-inflammatory phenotype by secreting IL-1R2 (interleukin 1 receptor, type 2). We identified cardiac macrophages as the main source of CCL1, which was essential for CCR8 + Treg recruitment. Ccl1 deficiency or macrophage-specific Ccl1 knockdown impaired Treg infiltration and aggravated ventricular remodeling; Ccl1 overexpression promoted Treg recruitment and improved cardiac outcomes. Moreover, the cardioprotective effects of CCL1 were abolished in DEREG mice upon Treg depletion and Ccr8 flox/flox Foxp3 Cre mice, establishing a CCR8 + Treg-dependent mechanism. Furthermore, circulating CCR8 + Tregs and cardiac CCL1 were elevated in humans with MI, and the presence of CCR8 + Tregs and CCL1-expressing macrophages was confirmed in the hearts of patients with MI, suggesting important clinical relevance. CONCLUSIONS: Our findings reveal a 2-phase Treg specialization process and establish the CCL1-CCR8 axis as a crucial pathway for Treg recruitment and function in the infarcted heart. Therapeutic targeting of this axis may improve immune-regulated cardiac repair after MI.

Abstract 49: Validation of Imaging-Derived Body Composition Subphenotypes Reflects Distinct Fat Distribution Patterns Associated with Different Degrees of Cardiovascular Disease Risk

Obesity affects more than one billion people and drives cardiometabolic disease risk. While traditional definitions rely on BMI, recent criteria promote direct measurement of excess adiposity, such as magnetic resonance imaging (MRI). Using MRI-derived adipose tissue (AT) data of visceral, subcutaneous, bone marrow, cardiac, renal, hepatic, pancreatic, and skeletal muscle fat with k-means clustering, we previously identified five distinct body composition subphenotypes (I–V), each displaying unique cardiovascular risk profiles. This study aimed to establish the generalizability of these subphenotypes by replication in the German National Cohort (NAKO) and validation of their association with cardiovascular disease (CVD) risk. We analyzed cross-sectional data from 29,352 individuals (44.2% female; mean age 48±12 years; BMI 26.5±4.7 kg/m2) from the NAKO baseline examination (2014–2019), who underwent comprehensive health assessments, including interviews, questionnaires, biosample collection, and whole-body MRI. Body composition subphenotypes were replicated using a cluster validation framework. Associations with 10-year CVD risk, estimated by the Framingham score, were evaluated using linear regression. The five subphenotypes (I–V) were successfully replicated. Cluster I (“lean”) was youngest, had the lowest prevalence of hypertension, hypercholesterolemia, and diabetes, and the lowest CVD risk. This cluster was the reference category in further analyses. Cluster II (“average adiposity”) showed intermediate risk factor levels and a 2-fold higher CVD risk (95% CI 1.9–2.0). Cluster III (“bone and muscle adiposity”) included older participants (56±9 years) and showed a 3.7-fold higher risk (3.6–3.8), consistent with regular age-related changes. Cluster IV (“hepato-abdominal adiposity”) had a similar age (50±10 years) as cluster II (48±10 years) but adverse cardiometabolic features, elevated liver enzymes, and 3.4-fold higher risk (3.3–3.5). Cluster V (“general and pancreatic adiposity”) had the highest burden of comorbidities, and a 5-fold higher CVD risk (4.8–5.2). With an age (59±8 years) comparable to cluster III, it represents an unhealthy ageing pattern. In conclusion, MRI robustly identifies distinct body composition subphenotypes that capture the interplay of AT depots, potentially reflect aging pathways, and show differential CVD risk. Our results highlight the potential of AT distribution for personalized risk assessment and ageing trajectories.

Dual-encoder contrastive learning accelerates enzyme discovery

The ability to engineer enzymes for desired reactions is a cornerstone of modern biotechnology, yet identifying suitable starting proteins remains a critical bottleneck. Although contrastive learning offers a compelling computational approach for enzyme discovery, these models have yet to be implemented at scale or proven effective in real-world experimental settings. Here, we present Horizyn-1 , a computationally efficient deep learning framework that enables large-scale reaction-to-enzyme recommendation validated through comprehensive experimental testing. Leveraging a combination of reaction fingerprints and protein language models, we trained Horizyn-1 on millions of reaction–enzyme pairs to achieve state-of-the-art performance, recovering an enzyme with correct activity within the top 100 hits for over 75% of test reactions. We experimentally validate Horizyn-1 across three enzyme discovery scenarios: identifying enzymes for orphan reactions, predicting enzyme promiscuity for both characterized and uncharacterized enzymes, and discovering enzymes for nonnatural biochemical reactions including lysine-driven transaminations that enable efficient synthesis of noncanonical amino acids. On underrepresented reaction classes, we find that fine-tuning with fewer than 10 additional reactions can dramatically improve performance. Furthermore, a logarithmic scaling of model performance with training dataset size suggests continued improvement with larger and more diverse reaction datasets. Horizyn-1 addresses the critical bottleneck of sourcing initial enzymes for optimization campaigns, enabling efficient and scalable in silico screening for enzymes with desired activities and promising to accelerate future efforts in biocatalysis and metabolic engineering.

Outcomes of acute meningitis according to immunosuppression status: 15-year retrospective cohort

Acute meningitis remains a primary global health concern. Immunosuppressed patients have risks due to atypical clinical presentations and a broader range of causative pathogens. We aimed to describe the outcomes and clinical features of acute meningitis according to immunosuppression status. We performed a retrospective cohort study of adults with acute meningitis from January 2009 to December 2023. Patients with postsurgical meningitis were excluded. Outcomes and demographic, clinical, and laboratory features were compared using non-parametric statistical tests, and mortality was analyzed using multivariate logistic regression. Among 189 patients, 96 (51%) were immunosuppressed. The median age was lower in immunosuppressed patients (36 vs. 50 years, p < 0.01). There were no differences in symptoms; the classical triad was present in only 21% vs. 19%. Immunosuppressed patients had lower CSF glucose levels (59% vs. 39%, p = 0.004). Overall mortality was 20%, with no significant difference by immune status. Independent predictors of death included age over 50 years (OR 2.9), altered mental status (OR 4.7), and bacterial meningitis (OR 2.3). Acute meningitis in immunosuppressed hosts shows attenuated inflammatory CSF profiles and a broader etiologic spectrum. Immunosuppression was not independently associated with in-hospital mortality.

Abstract 13: Brain Proteomic Profiles Associated with Frailty and Motor Function Trajectories in Community-Dwelling Older Adults

Introduction: Motor function decline and increase in frailty accelerate with aging and are associated shorter lifespan. These functional changes have been associated with age-related changes in brain activity, but the precise molecular pathways involved remain unclear. Hypothesis: Motor function and frailty trajectories are associated with specific brain proteins in older adults. Methods: Our study included 813 adults from the Religious Orders Study and the Rush Memory and Aging Project (mean age=80.7 yr at baseline and 89.4 yr at death). Antemortem global motor function was assessed objectively by 10 performances, and frailty was assessed based on BMI, fatigue, gait, grip strength, and physical activity, with up to 26 repeated annual assessments ( Fig. A ). Slopes of changes in motor function and frailty were estimated using linear mixed-effects models. Proteomic profiling of dorsolateral prefrontal cortex tissues was conducted using isobaric tandem mass tag (TMT) peptide labeling coupled with LC-MS. Diet was assessed annually using a food frequency questionnaire. Linear regression was used to assess associations between diet, brain proteins, and motor function and frailty slopes. Results: Of the 8780 brain proteins measured, multivariable analysis identified 53 associated with motor function decline (P-adjusted<0.05; Fig. B ). These proteins are enriched in pathways such as mitochondrial dysfunction, mTOR signaling, and estrogen receptor signaling for motor-associated proteins, leading by proteins including PRKAB2, MAPK1, and NDUFB3 ( Fig. B-C ). In addition, frailty progression was associated with 176 brain proteins (P-adjusted<0.05; Fig. D ), leading by NRN1, MACROD1, and PPP1CB, with pathway enrichment in respiratory electron transport, sirtuin signaling, and mitochondrial dysfunction ( Fig. D-E ). Furthermore, higher consumptions of fish and EPA+DPA were inversely associated with frailty slope (P<0.05). Among frailty-associated brain proteins, fish and DPA intake were associated with Paralemmin-3 (FDR=0.03). Conclusions: Motor function decline and increase in frailty are associated with alterations of brain proteins enriched in mitochondrial, mTOR, and energy metabolism-related signaling pathways. Fish intake, which is related to less frailty, is associated with Paralemmin-3 (involved in brain mitochondrial function).

Abstract TH820: Effects of a Dietary Approaches to Stop Hypertension Diet on Circulating and Fecal Lactate Levels in Type 2 Diabetes: Findings from the DASH4D Randomized Clinical Trial

Introduction: Lactate is a major mitochondrial fuel source, the main precursor for gluconeogenesis, and a multifunctional signaling molecule. Elevated circulating lactate is associated with increased type 2 diabetes (T2D) risk, and dietary carbohydrate changes can alter lactate in people without T2D. Whether the Dietary Approaches to Stop Hypertension (DASH) diet alters circulating lactate, and/or fecal lactate (reflecting gut microbial fiber fermentation), is not known. Further, whether these changes correlate with liver function, as the liver converts lactate to glucose via gluconeogenesis, is unknown. Hypotheses: A high-fiber DASH-style diet will lower plasma lactate and raise fecal lactate; reduced sodium intake will not affect either outcome. Plasma lactate will be positively correlated with glucose and liver enzymes. Methods: DASH4D is a randomized 4-period crossover feeding trial of a DASH-style diet modified for people with T2D (DASH4D diet) vs. typical U.S. (comparison) diet, each with a higher and lower sodium version, among 102 adults with T2D. Plasma and fecal samples were collected pre-randomization and at the end of each 5-week feeding period. Lactate was measured using gas chromatography-mass spectrometry (MS)/MS. We used linear mixed effects models to examine effects of diet and sodium content on end-of-period plasma and fecal lactate. We assessed within-individual correlations between lactate, glucose, and liver enzymes (alanine (ALT) and aspartate (AST) aminotransferases, gamma glutamyl transferase (GGT), and alkaline phosphatase (ALP)) using repeated-measures correlations analysis. Results: There were 97 participants (mean age 67 (sd: 8.9) years, 66% female, 89% Black) with plasma, and of those 83 with fecal, samples from both pre-randomization and ≥2 feeding periods. The DASH4D (vs. comparison) diet lowered plasma lactate by -86.0 µM (95%CI:-168.9, -3.2), while sodium content had no effect ( Figure 1 ). Neither the DASH4D diet nor sodium content affected fecal lactate. Plasma, but not fecal, lactate was positively associated with glucose and liver enzymes ALT, AST, and GGT ( Figure 2 ). Conclusions: The DASH4D diet lowered plasma, but not fecal, lactate in adults with T2D. These results suggest that dietary effects on plasma lactate are related to endogenous metabolism, not bacterial lactate production. Plasma lactate positively correlated with glucose and liver enzymes, further implicating changes in host metabolic processes with DASH4D diet.

Abstract TH837: Lifestyle Medicine Healthcare Model Strengthens Primary Care Delivery for Noncommunicable Diseases in Sri Lanka

Introduction: Sri Lanka’s healthcare system faces increasing strain from noncommunicable diseases (NCDs), which cause 81% of deaths and 77% of disability-adjusted life years, with cardiovascular diseases contributing the largest share. Primary care challenges include limited consultation times, ineffective NCD management frameworks, high healthcare utilization, and inadequate social prescribing pathways. This study synthesizes evidence from Sri Lanka and comparable low- and middle-income countries (LMICs) to develop a conceptual framework for strengthening primary healthcare-based NCD management employing lifestyle medicine and health promotion principles. Methods: We conducted a Sri Lanka–focused scoping review and conceptual framework synthesis to develop an evidence-informed model for integrated NCD care. Searches across PubMed, Scopus, Cochrane, Embase, and Google (2000–2025) identified peer-reviewed and gray literature. Sri Lanka–based studies were prioritized, supplemented by comparable evidence from other LMICs and a Sri Lanka pilot project. Using Jabareen’s iterative conceptual framework analysis, we mapped the literature, identified key concepts, clustered them into categories, and integrated these into higher-order domains through repeated comparison and refinement. Author discussions validated the emerging framework, resulting in a coherent, evidence-informed model for integrated NCD care delivery in a resource-constrained setting. Results: Evidence supported five pillars: (a) group consultations (virtual, hybrid, or in-person) improved engagement, adherence, and satisfaction; (b) health promotion by trained facilitators enhanced self-efficacy and sustained lifestyle change; (c) social prescribing through community-based programs strengthened follow-up and reduced utilization; (d) technology-assisted follow-up improved continuity and accountability; and (e) innovative financing models (public–private partnerships, social impact bonds) promoted cost-effectiveness and sustainability. Synthesizing these findings yielded the Lifestyle Medicine Healthcare Model (LMHM)—a feasible, equity-focused framework linking intervention components, behavioral mechanisms, and contextual enablers for scalable NCD care in Sri Lanka. Conclusion: The LMHM offers a potentially sustainable, cost-effective approach that integrates group consultations, health promotion, social prescribing, and technology-assisted follow-up to promote lasting health behavior change in primary care.

Microglial fructose metabolism is essential for glioblastoma growth

Glioblastoma (GBM) remains one of the most aggressive and treatment-resistant brain tumors in adults. Its immune microenvironment is dominated by tumor-associated macrophages, including both infiltrating monocytes and brain-resident microglia. While metabolic rewiring of infiltrating myeloid cells has been shown to support tumor progression, the role of microglial metabolism in GBM remains incompletely understood. Here, we demonstrate that microglia uniquely express the fructose transporter GLUT5 and are the only immune cells in the GBM microenvironment capable of metabolizing fructose. Using murine orthotopic glioma and Replication-Competent Avian sarcoma leuko virus Splice acceptor (RCAS)-derived tumor models, we show that global deletion of GLUT5 confers profound resistance to tumor growth. This effect is driven by loss of fructose metabolism in microglia and occurs independently of contributions from peripheral immune compartments. In GLUT5-deficient mice, tumors exhibit increased infiltration and activation of both innate and adaptive immunity, including enhanced antigen presentation, clonal expansion of CD8+ T cells, and increased cytokine production. Depletion of B-cells or CD8+ T cells abrogated survival phenotypes in knockout mice, demonstrating that GLUT5 suppresses adaptive immunity. These findings identify microglial fructose metabolism as a critical regulator of immune suppression in GBM and suggest that targeting this pathway may improve immunotherapeutic responses.

Correction: Child training in the Child ViReal Support Program: Combining iVR-based cognitive training and CBT techniques in a pilot study

Abstract 59: A Prospective Study of E-cigarette Use and Risk of Incident Hypertension in U.S. Adults

Background: Electronic cigarette (e-cigarette) has now become the second most popular tobacco product in the United States (U.S.). However, due to the relatively recent market entry of e-cigarettes, longitudinal evidence regarding their associations with cardiometabolic outcomes, which take time to develop, remains limited. Objectives: To supplement scientific evidence on cardiometabolic effects of e-cigarette use (vaping), using longitudinal data from Wave 1 to 5 (2013-2019) of the Population Assessment of Tobacco and Health (PATH) Study. Methods: This study included 13,098 participants aged 18 and older who had no history of hypertension at baseline enrollment in Wave 1 and completed follow-up questionnaires from Wave 2 to 5. Hypertension outcome was self-reported (N=1,831). E-cigarette use was categorized as “non-use” (N=8,001), “former use” (N=4,409), and “current use” (N=688), with current vapers defined as those reported both a history of vaping and recent vaping in order to examine the health effects of continued e-cigarette use. Weighted Cox models were used to assess the association between e-cigarette use and hypertension incidence, stratified by age groups. The model was adjusted for combustible cigarette use, sex, race, education, poverty, and alcohol consumption. Results: Compared with non-vapers, current vapers had a significantly increased risk of incident hypertension (HR=1.27, 95% CI: 1.04, 1.56). However, no such association was observed among former vapers (HR=1.01, 95% CI: 0.89, 1.15). Both former (HR=1.29, 95% CI: 1.05, 1.58) and current (HR=1.33 95% CI: 1.07, 1.66) smokers were associated with elevated risk of incident hypertension compared with non-smokers. Conclusions: To our knowledge, this study is the first to present the association between e-cigarette use and incident hypertension in a nationally representative cohort. One major strength of this study is that it demonstrates the significant effect of e-cigarette use that is independent of the traditional risk factor and strong confounder, combustible cigarette use. The findings highlight the negative impacts of e-cigarettes use on hypertension and underscore the importance of public health interventions targeting this modifiable risk factor to reduce the cardiovascular health burden in U.S. adults. Further study with longer follow up periods are needed to capture more incidences in order to increase statistical power for stratifying analyses across age groups and sexes.

Abstract TH826: Impact of Glucagon-Like Peptide-1 Receptor Agonists on Asthma Exacerbations Among Individuals with Type 2 Diabetes and Asthma: A Target Trial Emulation Study

Background: There is evidence that several treatments for type 2 diabetes may reduce asthma exacerbations, but prior studies had small sample sizes and short follow-ups. The objective is to assess the impact of glucagon-like peptide-1 receptor agonists (GLP-1Ra) compared to dipeptidyl peptidase-4 inhibitors (DPP-4i) and sodium-glucose cotransporter 2 inhibitors (SGLT-2i) on asthma exacerbations among adults with type 2 diabetes and asthma. Methods: We used TriNetX electronic medical records from 79 U.S. healthcare organizations from January 2015 to November 2023. We emulated a trial comparing GLP-1Ra’s to DPP-4i’s and another comparing GLP-1Ra’s to SGLT-2i’s, focusing on the impact on asthma exacerbations for adults diagnosed with asthma and type 2 diabetes. The study population included adults aged 18 years or older without other recently prescribed second-line antidiabetic medications. We followed individuals until their first asthma exacerbation, death, or the end of 12 months of follow-up, and we pre-defined asthma exacerbation as a composite of asthma-related hospitalizations, emergency room visits, or new systemic corticosteroid use. We used stabilized inverse probability weights to balance baseline covariates and pooled logistic regression to estimate risk ratios with bootstrapping for confidence intervals. Subgroups included obesity, sex, recent metformin use, asthma severity, and initiation year. Results: The study included 10,173 new users on GLP-1Ra’s (n=4,499), DPP-4i’s (n=3,169), and SGLT-2i’s (n=2,478). The 12-month risk ratio (RR) for asthma exacerbations was 0.93 (95% confidence intervals [CI], 0.83–1.05) for GLP-1Ra versus DPP-4i, suggesting a nominally lower exacerbation risk. No statistically significant difference in the likelihood of asthma exacerbations was observed between GLP-1Ra and SGLT-2i (RR 1.04, 95% CI 0.92–1.15). Differences between GLP-1Ra’s and DPP-4i’s were largely driven by fewer asthma-related hospitalizations with GLP-1Ra’s (RR 0.76, 95% CI 0.59–0.98). Sensitivity and subgroup analyses were consistent, with lower risks among individuals with obesity and those initiating therapy in more recent years. Conclusions: In this large, diverse U.S. cohort, GLP-1Ra initiation was not associated with significant differences in 12-month asthma exacerbation risks compared with SGLT-2i’s or DPP-4i’s, although exploratory analyses suggested fewer hospitalizations compared with DPP-4i’s and potential benefit among individuals with obesity.

Abstract TH964: Trends in cardiovascular disease risk factors and predicted 10-year risk among adults with hypertension in Thailand, 2011–2018

Background: Cardiovascular disease (CVD), especially ischemic heart disease and stroke, is a leading cause of death in low- and middle-income countries (LMICs), including Thailand. There has been limited evidence regarding the predicted CVD risk among Thai individuals with hypertension (HTN). We examined trends in CVD risk factors and predicted 10-year CVD risk from 2011 to 2018 and evaluated the potential impact of optimizing modifiable risk factors. Methods: We conducted a serial cross-sectional study using data from the Thailand DM/HT study. The predicted 10-year CVD risk was calculated based on World Health Organization risk scores. The laboratory-based model included age (years), sex (men and women), SBP (mmHg), diabetes (yes/no), current smoking status (yes/no), and total cholesterol (TC) (mmol/L). The non-laboratory-based approach used body mass index (BMI) instead of TC and diabetes mellitus. High predicted CVD risk was defined as a risk score of ≥ 20%. Generalized linear models were used to assess mean and prevalence trends between 2011 and 2018. Results: A total of 226,420 Thai adults with HTN were included. Between 2011 and 2018, the prevalence of CVD risk factors, including smoking, diabetes, uncontrolled HTN (≥140/90 mmHg), and hyperlipidemia, declined significantly. However, obesity (BMI ≥25 kg/m 2 ) increased from 44.9% to 48.0% ( p -trend <0.001). Using the non-laboratory model, the mean predicted 10-year CVD risk rose from 7.7% (2011) to 8.0% (2014), and then declined to 7.8% (2018), with high-risk prevalence being 1.5% (2011) and 1.4% (2018). In the laboratory-based model, the mean predicted risk decreased from 8.9% (2011) to 8.4% (2018) ( p -trend = 0.001), with high-risk prevalence declining from 4.2% to 3.1% ( p -trend = 0.0001). The most significant reduction in predicted risk was obtained by lowering SBP to less than 120 mmHg. Simultaneously, smoking cessation, preventing diabetes mellitus, optimizing HTN control, and managing hyperlipidemia (TC<4 mmol/L) can reduce the prevalence of high-risk conditions by 3.1% overall, 5.1% in men, and 2.0% in women. Conclusion: From 2011 to 2018, Thailand saw improvements in CVD risk factors among people with HTN, despite a rise in obesity rates. Optimizing modifiable risk factors, especially hypertension control, can lower CVD risk. Our results have implications for health policy and public health initiatives in Thailand and other LMIC, which can reduce cardiovascular disease in the population.

Mutually exclusive alternative pre-mRNA splicing promotes adaptive metabolic stress signaling by JNK

The JUN NH 2 -terminal kinase (JNK) signal transduction pathway is activated during the hepatic metabolic stress response. The JNK1 and JNK2 pre-mRNAs expressed by hepatocytes exhibit mutually exclusive inclusion of exons 7a or 7b that encode a segment of the substrate binding site that is required for selective protein phosphorylation. We established mice with conditional inclusion of exons 7a or 7b to test the function of these JNK spliceoforms. We report that the JNK2 7b spliceoform plays a key role in the hepatic metabolic stress response. This function of JNK2 7b is mediated by coordinated mechanisms that independently regulate circadian gene expression and phosphorylation of Retinoid X Receptor α (RXRα) on Ser 265 . This analysis identifies an important role for JNK2 7b in the hepatic adaptive response to metabolic stress.

Correction: Progression of carotid intima-media thickness, visceral fat accumulation and metabolic derangement in people living with HIV initiating antiretroviral therapy: A prospective cohort study at Thailand’s tertiary care center

Abstract MPWE35: Postmenopausal Endogenous Sex Hormone Levels and Mild Cognitive Impairment and Dementia Risk in the Women’s Health Initiative

Introduction: Women are disproportionately likely to develop dementia, but there is an incomplete understanding of sex-specific risk factors for cognitive impairment. Whether postmenopausal levels of endogenous sex hormones are associated with later-life brain health is unclear and warrants further investigation. Hypothesis: Among postmenopausal women, lower levels of estradiol (E2) and sex hormone binding globulin (SHBG) are associated with a greater risk of incident mild cognitive impairment (MCI) or probable dementia (PD). Methods: We conducted a nested cohort study of women who were enrolled in the Women’s Health Initiative (WHI) hormone therapy (HT) trials and were part of separate ancillary studies that measured sex hormones in baseline blood samples and that annually assessed women for incident MCI and PD, adjudicated by study clinicians. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between log-transformed baseline E2 and SHBG levels and a combined endpoint of MCI or PD, adjusted for relevant confounders, right-censoring at death or loss to follow-up. The Cox stratification procedure was used to account for trial arm participation (HT vs. placebo). Results: The analysis included 2,081 participants with a median follow-up time of 7 years. The mean baseline age was 71 years (SD 4.0). There were 567 women who developed MCI/PD. In base models (adjusted for age, age at menopause, baseline BMI), higher baseline E2 and SHBG levels were associated with greater MCI/PD risk (per 1 SD change in hormone level: HR for E2: 1.12 [95% CI 1.02-1.23], HR for SHBG, 1.18 [95% CI 1.07-1.30]. In models additionally adjusted for baseline physical activity, alcohol use, smoking, education, cardiovascular comorbidities, and time-varying occurrence of stroke during follow-up, the association between E2 levels and MCI/PD was no longer significant (HR 1.08, 95% CI 0.98-1.19), but remained significant for SHBG (HR 1.26, 95% CI 1.14-1.39). Conclusions: Among postmenopausal women, our findings suggest a significant association between higher baseline SHBG levels and risk of MCI/PD, in the direction opposite to our hypothesis. Future work is planned to examine the role of other hormones (testosterone) and of postmenopausal E2, SHBG, and testosterone levels in relation to cognitive trajectories over time.

Abstract TH917: Food Insecurity Among Older Adults with Coronary Heart Disease: 2014-2024 Trends in the United States

Introduction: The “Food is Medicine” movement calls upon medical and public health fields to recognize the role of food in chronic diseases, including heart disease. However, food insecurity may be a major barrier to health solutions that target dietary risk factors. The purpose of this study was to characterize trends in food insecurity among older adults, specifically considering those with coronary heart disease (CHD). Hypothesis: We assessed the hypothesis that adults aged ≥65 years with CHD would have higher levels of food insecurity compared to the general population. Methods: Annual survey data on older adults (≥65 years) from the National Health Interview Survey (2014-2024) were used; the annual analytic sample size ranged from 8,567 to 14,860. CHD was measured by self-report of a physician diagnosis. Food insecurity was assessed using the 11-item adult-focused questions of the validated questionnaire by the United States Department of Agriculture’s (USDA) Food Security Survey Model (FSSM) and was defined as ‘low’ and ‘very low’ food security. Survey weights were used to account for the complex survey sampling design. Differences in the prevalence of food insecurity were assessed across sociodemographic characteristics using chi-square tests. Results: Among all older adults, food insecurity in the total sample ranged from 3.54% (SE 0.26) in 2021 to 6.47% (SE 0.39) in 2014. Among older adults with CHD, food insecurity ranged from 5.24% (0.72) in 2021 to 9.18% (1.16) in 2016. Since 2019, adults with CHD have experienced disproportionately higher levels of food insecurity than the general population; in 2024, 7.42% of those with CHD reported food insecurity. In 2024, among older adults with CHD, those who identified as female (11.48% vs 4.92% males; p<0.001), non-Hispanic Black or Hispanic (Black 16.53% and Hispanic 20.64% vs 5.40% non-Hispanic White; p<0.001), living in single adult households (10.61% vs 6.28% ≥2 adult-household; p=0.02), and having a disability (11.26% vs 5.47% with no disability; p=0.002) were more likely to report food insecurity. Conclusion: Older adults with CHD experience higher levels of food insecurity than the general population. Continued monitoring of trends in food insecurity is needed. Health solutions focusing on dietary risk factors for chronic diseases should consider individual and structural barriers to healthy dietary patterns, including food insecurity, especially for those with CHD.

Abstract TH825: Diabetic Ketoacidosis in Patients Treated with GLP-1 Agonists and SGLT2 Inhibitors: A Case Series and Clinical Implications in Cardiovascular Care

Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) are known to have cardioprotective effects. Their use can reduce major adverse cardiovascular events (MACE) both in patients with or without established cardiovascular disease. Euglycemic diabetic ketoacidosis (EDKA) is rare, but the advent of sodium-glucose cotransporter 2 inhibitors (SGLT2is) has been associated with an increase in its incidence. The most common side effects of GLP-1RAs are gastrointestinal, mainly nausea, but also vomiting and diarrhea. Dehydration is a precipitating factor of diabetic ketoacidosis (DKA). It is possible that the concomitant treatment with an SGLT2i and a GLP1-RA increases the risk of EDKA. We present a case series of that. Case Reports: Case 1: A 43-year-old woman with with a history of DM2 and hypertension was found to have EDKA after presenting with worsening of nausea and vomiting associated with a recent increase in the dose of tirzepatide. Her other DM2 medications included metformin, empagliflozin and insulin. She had a history of one prior DKA episode. Case 2: A 57-year-old man with a history of DM2, hypertension and hyperlipidemia was found to have EDKA after presenting with nausea and vomiting associated with a recent increase in the dose of dulaglutide. His other DM2 medications were metformin and empagliflozin. He had a history of a prior DKA episode. Case 3: A 65-year-old woman with a history of DM2 was found to have EDKA after presenting with nausea and vomiting associated with a recent initiation of semaglutide. Her other DM2 medications were metformin, empagliflozin and insulin. She had a history of a prior DKA episode. Discussion: All 3 patients had a temporal association between initiation or increasing the dose of the GLP-1RA and GI symptoms of nausea and vomiting that preceded EDKA. All 3 patients had uncontrolled diabetes mellitus (DM), and had a history of prior DKA. As both GLP-1RAs and SLGT2is are cardioprotective medications, it is important to identify the risk factors for DKA to guide the decision to treat patients who have them properly to minimize the possibility of this complication. Conclusion: Awareness of side effects of GLP-1RAs and SGLTis is key in attempting to minimize complications. It is important to identify patients at risk for EDKA, and to focus on educating patients on seeking medical care promptly should these side effects or concerns for EDKA develop.

When does higher credit lower forest area? Amazon contexts change credit’s impacts

Economic activities have transformed over half of the Earth’s surface and the large-scale conversion of rural forests to agropastoral production is ongoing. Raising access to credit may lead producers to expand at the expense of the forest or, instead, invest to raise yields, reducing forest loss per unit output. Looking across Brazil’s enormous Amazon, we show that extremely different local contexts differ in terms of which effect of credit dominates. We distinguish those contexts using factors that affect cattle and crop production. For each of these two outputs, we find distinct credit impacts by context. Cattle credit raises deforestation where pasture expands over native forest on far frontiers. Crop credit raises deforestation where farms expand over pasture and forest remnants. Understanding impacts heterogeneity can help to reduce losses of rural forests, even while credit is supporting local economies.