INTRODUCTION: Visual impairment and blindness continue to represent a substantial disease burden in Hungary. According to national epidemiological data, the combined prevalence of bilateral blindness and severe visual impairment among individuals aged 50 years and older is approximately 0.9%, and international estimates suggest that around 90% of vision loss cases could be prevented or treated with appropriate care. However, the coverage of ophthalmic screening remains low, primarily due to the lack of targeted financing, limited ophthalmology workforce capacity, and the absence of a unified national screening protocol. OBJECTIVE: The aim of our study is to review the professional, organizational, financial, legal and ethical conditions for the implementation of artificial intelligence-supported ophthalmic screening in Hungary, with a particular focus on diabetic retinopathy. METHOD: We conducted a targeted narrative literature review of national epidemiological, human resource, and cost data, as well as an analysis of international diabetic retinopathy screening models and the European Union regulatory frameworks for medical devices and artificial intelligence, using sources selected based on clinical and public health relevance. RESULTS: The level of Hungarian ophthalmological screening practice is insufficient to significantly reduce the burden of preventable vision impairment, primarily due to limited human resources and funding constraints. The current human resource capacity of the Hungarian ophthalmic care system is insufficient to provide the approximately one million diabetic fundus examinations required annually according to professional guidelines. Preventive and screening activities are not organized as dedicated services but are largely delivered as part of routine ophthalmic outpatient care, without separate financing. International experience indicates that the use of artificial intelligence as a decision-support or triage tool can reduce specialist workload while maintaining diagnostic accuracy. CONCLUSION: Artificial intelligence-supported fundus screening systems have the potential to improve access to screening, consistency, and efficiency. The introduction of artificial intelligence-based fundus screening in Hungary would require the establishment of appropriate financing mechanisms, regulation of task-sharing involving optometrists and allied health professionals, and compliance with relevant regulatory and ethical frameworks. A transitional hybrid model - combining the pilot use of an internationally validated artificial intelligence system in parallel with launch of domestic development - may offer a realistic pathway toward a structured national screening program and contribute to reducing the disease burden of preventable blindness. Orv Hetil. 2026; 167(22): 865-875.

The authors present a case where the admission ECG showed extensive deep negative U-waves in the precordial leads, in addition to the precordial negative T-waves characteristic of Wellens syndrome. After stenting of the critical stenosis of the left anterior descending coronary artery, only the U-wave inversion disappeared, while the Wellens repolarization disorder persisted. The authors discuss the different dynamics of ischemic repolarization disorders in this case. Orv Hetil. 2026; 167(22): 885-888.

Biological aging is a key determinant of liver disease and mortality, but there is little evidence on noninvasive index for assessment of liver biological aging. We developed the Liver Aging Index (LAI) in the China Kadoorie Biobank (CKB, N = 21,629) using Cox-Gompertz proportional hazards model. The LAI incorporated three clinical factors (body mass index, systolic and diastolic blood pressure), eight plasma biomarkers (glucose, total cholesterol, triglycerides, high- and low-density lipoprotein cholesterol, alanine aminotransferase, aspartate aminotransferase, and γ-glutamyl transpeptidase), and two imaging biomarkers (fat attenuation parameter and liver stiffness measurement). External validation was conducted in the National Health and Nutrition Examination Survey (NHANES; N = 3412) and the VCTE-Prognosis cohort (N = 12,170, 16 global centers). Across all cohorts, the LAI demonstrated strong discrimination for all-cause mortality (AUROC: 0.764 in NHANES; 0.759 in VCTE-Prognosis), outperforming chronological age (p < 0.05). Liver aging acceleration (LAA), defined as the difference between LAI and chronological age, was associated with substantially elevated risks: each 1-SD increase in LAA conferred a 22%-85% higher risk of all-cause mortality and a 34%-170% higher risk of liver-related event or mortality. Using genetic instruments identified in CKB, we found genetic predisposition to accelerated liver aging was associated with higher risks of cirrhosis and liver cancer (HR = 3.94 [3.20-4.86] and 7.82 [2.05-29.80]), further validated in Biobank Japan. Integrating genetics and proteomics revealed novel pathophysiological involvement of amyloid-beta clearance pathway and amyloid precursor protein in liver aging. These findings demonstrate the feasibility of a noninvasive, liver-specific biological aging index and provide new insights into mechanisms underlying liver aging.

BACKGROUND: Heart failure (HF) with mildly reduced ejection fraction (HFmrEF) and heart failure with preserved ejection fraction (HFpEF) constitute a substantial clinical burden with limited therapeutic options. While sodium-glucose cotransporter 2 (SGLT2) inhibitors are established therapies for heart failure with reduced ejection fraction, their efficacy and safety profile in HFmrEF and HFpEF warrant comprehensive synthesis. OBJECTIVE: To systematically evaluate the impact of SGLT2 inhibitors on cardiovascular (CV) outcomes, functional capacity, quality of life, and safety in patients with HFmrEF and HFpEF. METHODS: Eligible studies compared SGLT2 inhibitors with placebo or standard care in patients with left ventricular ejection fraction (LVEF) > 40%. The primary outcome was defined as CV adverse events, primarily including the composite of first hospitalization for heart failure (HHF) or CV mortality (CV death), first HHF, CV death, all-cause mortality. Secondary outcomes included Kansas City Cardiomyopathy Questionnaire (KCCQ) scores, 6-minute walk test distance (6MWTD), and echocardiographic parameters. RESULTS: Eighteen randomized controlled trials comprising 18 774 patients (SGLT2 inhibitors group: 9564; control group: 9210) were included. Meta-analysis showed that SGLT2 inhibitors significantly reduced the risk of the primary composite endpoint (odds ratio [OR]: 0.71; 95% CI: 0.66-0.75, < 0.00001) and HHF (OR: 0.69; 95% CI 0.64-0.74; < 0.00001). However, reductions in CV death (HR: 0.92; 95% CI 0.84-1.00; = 0.05) and all-cause mortality (OR: 0.92; 95% CI 0.84-1.02; = 0.10) did not reach statistical significance. Subgroup analyses indicated consistent benefits across New York Heart Association classes, body mass index, and concomitant mineralocorticoid receptor antagonists use, with pronounced efficacy observed in patients with renal impairment (estimated glomerular filtration rate ≥60 mL/min/1.73 m²). Furthermore, SGLT2 inhibitors significantly improved KCCQ-total symptom score, 6MWTD, /' ratio. CONCLUSION: SGLT2 inhibitors effectively improve the risk of composite CV death and HHF in patients with HFmrEF and HFpEF, while concurrently improving functional status and quality of life. These findings support the use of SGLT2 inhibitors as a foundational therapy for these populations, although their independent effect on mortality endpoints requires further elucidation.

Current Alzheimer's disease therapies offer limited efficacy and are often accompanied by significant side effects, underscoring the urgent need for new treatment strategies. Enhancing autophagy represents a promising therapeutic approach, yet most known autophagy inducers act through the mTOR-dependent pathway, which broadly affects cellular metabolism and proliferation, and their clinical potential is further limited by poor blood-brain barrier (BBB) penetration. To address these twin challenges, an artificial intelligence (AI)-driven platform named DeepDrugDiscovery was developed, shifting the focus from traditional structure-based screening toward a mechanism-centric strategy for identifying mTOR-independent autophagy enhancers with brain penetrability. The platform screened over one million molecules and identified two lead compounds, Ombuin and 2-Hydroxycinnamic acid, which were experimentally shown to clear pathogenic tau and amyloid-β aggregates and restore memory function in both worm and mouse models of Alzheimer's disease. Notably, Ombuin exhibited robust brain exposure, confirming accurate BBB prediction. Released as an open-source resource, DeepDrugDiscovery demonstrates a scalable, AI-powered pipeline for discovering mechanism-based therapeutics.

BACKGROUND: Intravenous (IV) iron supplementation is an important strategy for correcting iron deficiency in patients with heart failure with reduced ejection fraction (HFrEF). Despite guideline recommendations, real-world implementation remains inconsistent. OBJECTIVE: This study aimed to evaluate the real-world impact of IV iron therapy on clinical outcomes in patients with HFrEF and iron deficiency. METHODS: This retrospective cohort study included adult patients with HFrEF and iron deficiency, who were admitted between January 2022 and May 2024 and received IV iron during hospitalization. Clinical outcomes included all-cause mortality and rehospitalization within 12 months of discharge and were analyzed using Kaplan-Meier survival curves. Changes in laboratory values from baseline to 12 months were compared using paired t-tests or Wilcoxon signed-rank tests. RESULTS: Among 124 patients, death or rehospitalization occurred in 81 (65%), including 14 (11%) deaths, and among 119 discharged alive, 75 (63%) were rehospitalized within 12 months. Mean hemoglobin increased by 1.1 g/dL (95% confidence interval [CI] = 0.5 to 1.7; n = 46), median ferritin by 44 ng/mL (interquartile range [IQR] = 8.4-372; n = 23), transferrin saturation by 4% (IQR = 0-13; n = 22), and left ventricular ejection fraction (LVEF) by 3% (95% CI = -2 to 7; n = 33). CONCLUSION AND RELEVANCE: Among patients with HFrEF and iron deficiency who received IV iron during hospitalization, improvements in anemia and iron parameters and modest increases in LVEF were observed, while rehospitalization remained common. Real-world practice was characterized by lower cumulative dosing and barriers to outpatient continuation of IV iron therapy, which may have attenuated clinical benefit. Further research should define optimal dosing, improve outpatient delivery, and clarify the role of oral iron when IV iron is unavailable or not tolerated.

BACKGROUND: Although recommended, shared decision making (SDM) is not widely adopted for primary prevention of cardiovascular (CV) disease. Champions may influence peer adoption if they are enthusiastic and skilled. We describe adoption of an SDM conversation aid for CV risk reduction (CV Prevention Choice) by champions and early adopters in a pragmatic implementation trial and consider their influence on uptake in clinics. METHODS: We embedded the SDM tool in the electronic health record in three U.S. health care systems. Eight of their 15 affiliated clinics deployed a champion implementation strategy. Adopters used the SDM tool in ≥ 2 routine clinical encounters. Superusers had ≥ 20 encounters. Penetration was the proportion of adopters among eligible clinicians. Adoption and penetration were assessed in the usual care (early adoption), active implementation, and maintenance implementation phases. Thematic analysis methods were used to analyze qualitative data from individual interviews and periodic reflections. RESULTS: Between May 2021 and January 2025, 37 interviews with clinicians and other staff and 65 periodic reflections were completed. Among 176 clinicians, 55% (n = 97) used CV Prevention Choice at least once and 42% (n = 76) adopted it. Champions and other opinion leaders gave presentations and demonstrated their practice, but targeted individual persuasion and group dialogue were less common, especially when champions appreciated peers' preferences. Champions used the tool more frequently (median = 93, IQR 53-150) than non-champions (median = 16, IQR 4-50), although only 4 of the top 20 users were champions. Clinics with champions had higher penetration rates (50% vs 29%) and lower rates of one-time tool use than clinics without champions (17% vs 33%). CONCLUSION: Champions, superusers, and other opinions leaders may influence peer adoption of clinical innovations by sharing their experience, but group discourse may be needed to build the case for uptake of innovations. Superusers may be impactful in clinics without formal champions. TRIAL REGISTRATION: The protocol described herein was registered with ClinicalTrials.gov on 22 June 2020 (No. NCT04450914).

BACKGROUND: Substance use disorder (SUD) is a debilitating neuropsychiatric condition characterized by persistent compulsive drug use and associated cognitive and psychiatric impairments. Emerging evidence suggests that neuroinflammatory pathways contribute to the pathophysiology of SUD. However, the relationships between neuroinflammatory-related biomarkers and psychiatric symptomatology in SUD remain poorly understood. This study aimed to investigate neuroinflammatory-related biomarkers and their association with psychiatric symptom changes in individuals with SUD. METHODS: Participants with SUD (N = 100) at three local facilities in the North West Province of South Africa were enrolled. At baseline and following three weeks of treatment, psychiatric symptoms were assessed using the Brief Psychiatric Rating Scale (BPRS). Serum levels of superoxide dismutase (SOD), glutathione (GSH), glutathione disulphide (GSSG), tryptophan, kynurenine (KYN), kynurenic acid (KYNA), serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), cortisol and serum S100 calcium-binding protein B (S100B) were measured. RESULTS: Over the 3-week treatment period BPRS scores and serum levels of tryptophan, 5-HT, 5-HIAA, KYN, KYNA, cortisol and GSH decreased, whereas SOD, S100B and GSSG levels increased. Baseline BPRS correlated with baseline serum levels of 5-HIAA, KYNA and GSSG. A decrease in BPRS correlated with baseline levels of 5HIAA, KYN and KYNA, as well as with 3-week changes in levels of select biomarkers (∆tryptophan, ∆5-HT, ∆5-HIAA, ∆KYN, ∆KYNA, ∆GSSG and ∆cortisol). CONCLUSION: The results suggest that baseline 5-HIAA, KYN and KYNA may predict psychiatric symptom improvement whereas tryptophan, 5-HT, 5-HIAA, KYN, KYNA, GSSG and cortisol may explain the neurobiological basis of changed psychiatric symptomatology.

BACKGROUND: Malaria remains a major cause of childhood morbidity and mortality in Cameroon. The COVID-19 pandemic disrupted access to healthcare and the continuity of malaria control programmes; however, its impact on reported incidence among children under 5 years of age, and its regional heterogeneity, remain insufficiently studied. We aimed to estimate the impact of the COVID-19-related interruption on reported malaria incidence among children under five years of age in Cameroon, nationally and by region, using routine DHIS2 surveillance data from 2017 to 2022. METHODS: We conducted an interrupted time series (ITS) study using monthly DHIS2 data from January 2017 to December 2022. Reported malaria incidence among children under 5 years of age was modelled using negative binomial regression (NB2) with a population offset. Two interruption points were defined a priori: March 2020 and January 2022. The model controlled for monthly fixed effects, long-lasting insecticidal net (LLIN) distribution activity, seasonal malaria chemoprevention (SMC) activity, the paediatric consultation rate, and one-month lagged rainfall. Inference relied on Newey-West HAC-robust standard errors (lag = 12). Regional ITS models, counterfactual analysis, and sensitivity analyses complemented the primary analysis. RESULTS: In March 2020, reported incidence showed an immediate 36.9% decline relative to the pre-pandemic trend (D1: IRR = 0.631; 95% CI 0.539-0.738; p < 0.001), followed by a positive slope change of 3.1% per month (P1: IRR = 1.031; 95% CI 1.017-1.045; p < 0.001). The second interruption point was not associated with any significant change in level or slope. The LLIN distribution indicator was inversely associated with reported incidence (IRR = 0.978; 95% CI 0.960-0.997; p = 0.024). Counterfactual analysis estimated a deficit of 69,708 notifications over 2020-2021, followed by an excess of 74,831 in 2022. Marked regional heterogeneity was observed, with particularly severe initial declines in the Centre (IRR = 0.467) and East (IRR = 0.544) regions. CONCLUSIONS: The COVID-19 pandemic was associated with a substantial initial disruption in reported childhood malaria incidence in Cameroon, followed by a progressive recovery with marked territorial disparities. These findings support strengthening the continuity of malaria services during crises and maintaining high-quality surveillance systems to enable regionally tailored programmatic decision-making.

BACKGROUND: Optimization of HbA1c, blood pressure and cholesterol, referred to as the "ABCs", is central to the management of diabetes. However, the age-specific associations of these factors with mortality in patients with diabetes remains unclear. METHODS: In this prospective cohort study, 43,732 Chinese adults aged ≥ 40 years with diabetes were included from the China Cardiometabolic Disease and Cancer Cohort (4C) Study. Participants were stratified by age (< 55, 55-<65, 65-<75, ≥ 75 years). Cox proportional hazards regression and Fine-Gray competing risk models were employed to estimate the associations of HbA1c, systolic blood pressure (SBP), and low-density lipoprotein cholesterol (LDL-C) with all-cause, cardiovascular, and non-cardiovascular mortality across age groups. Relative importance and population attributable fractions (PAFs) were computed for each metabolic factor. RESULTS: During a median follow-up of 10.1 years, 3,975 deaths were documented. Age significantly modified the associations of HbA1c, SBP, and LDL-C with all mortality outcomes (all P for interaction < 0.05). Among participants aged < 75 years, HbA1c showed graded positive associations with all-cause, cardiovascular, and non-cardiovascular mortality. The SBP thresholds associated with increased mortality risk were 140 mmHg in those aged < 65 years and 160 mmHg in those aged 65-<75 years. Among those aged ≥ 75 years, however, the patterns of these associations differed markedly. Elevated mortality risk was observed only at HbA1c ≥ 9%, with a hazard ratio (HR) of 1.51 (95% confidence interval [CI]: 1.19-1.91) for all-cause mortality and a subdistribution hazard ratio (SHR) of 1.70 (95% CI: 1.23-2.36) for cardiovascular mortality, while SBP showed no significant association with any mortality outcome in this age group. Moreover, LDL-C emerged as a significant risk factor for cardiovascular mortality. Compared with participants with LDL-C < 1.8 mmol/L, those with LDL-C of 1.8-<2.6 mmol/L exhibited a significantly higher risk (SHR: 1.86; 95% CI: 1.11-3.11). Additionally, LDL-C had the largest PAF for cardiovascular mortality (9.6%) within this age group. CONCLUSIONS: The impacts of ABC factors on mortality risk vary substantially by age among adults with diabetes. In patients aged ≥ 75 years, less stringent glycemic and blood pressure targets may be appropriate, whereas lipid management remains critically important for reducing cardiovascular mortality.

BACKGROUND: Dementia is frequently underdiagnosed in its early stages, but changes in healthcare utilization may precede diagnosis by several years. We examined healthcare patterns and chronic conditions before cognitive impairment among the Atherosclerosis Risk in Communities (ARIC) study participants to better understand this pre-diagnostic period. METHODS: We included ARIC visit 6 (2016-2017) participants with continuous 5-year prior Medicare coverage (2011-2018) and used negative binomial regression to compare longitudinal trends in hospitalization in participants with Part A coverage, and emergency department (ED) and ambulatory care use in participants with Part A&B coverage, in the 5 years prior to and 1 year following an incident dementia according to ARIC syndromic classification. Inverse probability weights were used to balance participants with and without incident dementia on baseline age, race, sex, education, and prevalent comorbidities. Principal diagnosis discharge codes were used to assess chronic conditions associated with hospitalization and ED visits, whereas all available diagnosis codes were used for ambulatory care visits. RESULTS: Among 3,923 eligible participants (mean age 79.6 ± 4.8 years; 59% women; 24% Black), 325 (8.3%) were classified as incident dementia at ARIC visit 6 or 7. During 5 years prior to visit 6, participants with incident dementia compared with non-dementia participants, had on average higher use of inpatient (0.12 vs. 0.08 hospitalizations per 6-month) and ED services (0.28 vs. 0.18 visits per 6-month) but lower ambulatory care use (3.53 vs. 3.76 visits per 6-month). Participants with incident dementia experienced more frequent hospitalizations for acute myocardial infarction (3.8% vs. 1.7%), chronic kidney disease (4.1% vs. 2.6%), congestive heart failure (4.7% vs. 1.6%), and stroke/TIA (8.5% vs. 2.6%), and more frequent ambulatory care visits for atrial fibrillation (23% vs. 15%), than non-dementia participants within 5 years prior to incident dementia. CONCLUSIONS: Compared with non-dementia participants, those with incident dementia had higher average hospitalization and ED utilization but lower ambulatory care visits, with differences observable 3 years before incident dementia. Cardiovascular disease and concomitant cerebrovascular disease are important contributors to dementia. Close monitoring of healthcare-seeking patterns may help identify individuals at high risk of dementia earlier in the disease course. TRIAL REGISTRATION: Not applicable.

BACKGROUND: Atherosclerosis (AS)-associated cardiovascular disease is the main cause of global mortality. The excessive retention of glycated low-density lipoprotein (G-LDL) under the vascular endothelium promotes AS. In addition, G-LDL supports a role in promoting the expression of scavenger receptor A (SR-A), increasing SR-A-mediated transcytosis of G-LDL in endothelial cells (ECs), consequently accelerating the progression of atherosclerosis. However, the underlying mechanism used by G-LDL to promote SR-A expression has not been elucidated, thus representing the aim of this work. METHODS: The protein-protein interaction of the E3 SUMO ligase KRAB structural domain-associated protein 1 (KAP1) and SR-A were confirmed by co-immunoprecipitation (co-IP)-based immunoblotting and immunofluorescence in human umbilical vein endothelial cells (HUVECs). G-LDL uptake and transcytosis in KAP1-silencing or overexpressing HUVECs were assessed. The effect of KAP1 on de-ubiquitination and SUMOylation of SR-A was determined by co-IP-based immunoblotting. The role of KAP1 on G-LDL-induced atherosclerosis was tested by adenovirus-mediated knockdown in ApoE mice. RESULTS: KAP1 was identified as an enhancer of SR-A, promoting its expression. KAP1 bound to SR-A and promoted SUMO1 modification of the SR-A lysine (K)22, which hampers K48-linked ubiquitination and proteasomal degradation of SR-A. KAP1 deficiency attenuated G-LDL-induced SR-A activation both in vitro and in vivo, reduced aortic G-LDL retention, and consequently, atherosclerotic vulnerable plaque formation in murine models. CONCLUSIONS: This study identifies a SUMOylation-ubiquitination crosstalk that governs SR-A stability, revealing KAP1 as a key molecular switch controlling SR-A turnover in endothelial cells. These findings provide a mechanistic basis for how G-LDL accelerates atherosclerosis.

BACKGROUND: Visceral leishmaniasis (VL) is an emerging infectious disease caused by the genus Leishmania and shares clinical features with some types of leukemia. METHODS: In a retrospective study (2020-2022), bone marrow aspirates (BMAs) from 52 children with leukemia in Ardabil Province, northwestern Iran, were examined for the presence of VL via microscopy and specific polymerase chain reaction (PCR) methods. Additionally, the results of a systematic review of the literature on VL in these patients were reported. RESULTS: In our retrospective study, microscopic investigations of BMA slides from 52 children with leukemia did not reveal Leishmania amastigotes. However, PCR detected amastigotes in three BMAs (5.8%). Simultaneously, a systematic review was designed, and 53 cases of VL with leukemia were retrieved. Half of these cases were from Brazil. Most cases were observed in children and adolescents (77.3%), with a higher prevalence in men (67.8%). The most common clinical and laboratory findings were: splenomegaly (96%), fever (90.5%), and anemia (92%). Acute lymphoblastic leukemia (ALL) was the most prevalent type of leukemia (66%). The systematic review on diagnostic accuracy showed that the serological method (sensitivity: 85%) proved to be more reliable than the microscopic method (sensitivity: 55%), while the PCR method detected all cases of leishmaniasis. Patients treated with anti-Leishmania drugs improved, except for one patient whose VL was reactivated one year later. CONCLUSION: VL should be added to the list of possible differential diagnoses of leukemia patients, particularly in endemic areas, and physicians' awareness of this condition prevents unnecessary invasive diagnostic procedures. CLINICAL TRIAL NUMBER: Not applicable.

This study investigates the role and underlying mechanisms of total flavones of Rhododendron (TFR) in blood-brain barrier (BBB) disruption following transient bilateral common carotid artery occlusion-induced cerebral ischemia/reperfusion (I/R), focusing on whether A2 astrocyte polarization mediates the protective effects of TFR. RNA sequencing analysis was performed to elucidate the molecular mechanisms underlying the differential effects of A1 and A2 astrocytes on endothelial function. TFR treatment significantly reduced Evans blue (EB) extravasation and attenuated the downregulation of claudin-5, ZO-1, occludin, and CD31 in mouse hippocampal tissues. Furthermore, TFR enhanced the production and release of cystathionine-β-synthase (CBS)-derived HS from astrocytes. Both TFR and TFR-induced A2 astrocytes promoted the expression of tight junction proteins in endothelial cells (ECs) following oxygen-glucose deprivation/reoxygenation (OGD/R). RNA sequencing revealed upregulation of Caspase-11 in A1 astrocytes and downregulation in A2 astrocytes. Moreover, A1 astrocytes exhibited increased expression of matrix metalloproteinase (MMP)-9 and TNF-α, whereas A2 astrocytes showed elevated levels of IL-10. Collectively, these findings indicate that TFR mitigates BBB disruption after cerebral I/R through dual mechanisms: directly upregulating tight junction proteins in brain microvascular endothelial cells and indirectly promoting astrocyte polarization toward the A2 subtype, which is associated with reduced Caspase-11 expression, enhanced IL-10 secretion, and increased CBS-derived HS production.

BACKGROUND: Black birthing people face higher rates of severe maternal morbidity (SMM), a disparity that was exacerbated during the COVID-19 pandemic. METHODS: This study utilized secondary population data from the New Jersey Integrated Population Health Data Project, including birth records, hospitalization discharge data, and COVID-19 testing records from 2019 to 2021 (N = 207,790). We employed path analysis with weighted least squares mean and variance adjusted (WLSMV) estimation to examine the direct and indirect associations of Black/African American identity with (1) experiencing any SMM and (2) the cumulative burden of SMM, mediated by physiological risk factors and indicators of healthcare access and utilization. RESULTS: We find that identifying as Black was directly and indirectly linked to both having any SMM type (β = 0.19) and a greater cumulative maternal morbidity burden (β = 0.10). Consistent with a potential mediation role, metabolic, cardiovascular, and respiratory conditions, obesity, and COVID-19 hospitalization were indirectly associated with maternal morbidity among Black birthing individuals. However, among those who had at least one type of SMM, only cardiovascular and metabolic conditions remained significantly associated with cumulative burden of maternal morbidity. CONCLUSION: Our findings emphasize that Black/African American identity and Medicaid enrollment are associated maternal morbidity, while clinical conditions (particularly cardiovascular and metabolic diseases) emerge as key correlates of SMM severity. Addressing these disparities requires a dual approach: strengthening clinical care models while concurrently addressing structural inequities that perpetuate maternal health disparities.

BACKGROUND: The United States (U.S.) currently lacks a Federal occupational heat standard and hot weather threatens the safety and health of farmworkers who often work under extreme heat conditions. Chronic disease and related risk factors can enhance worker susceptibility, yet prior studies on heat vulnerability in farmworkers used small samples over short time periods, leaving knowledge gaps about the scope of the problem. OBJECTIVE: To describe temperature exposures and characteristics, including cardiovascular disease (CVD) and risk factors (diabetes, high blood pressure, elevated cholesterol), of a U.S. national sample of farmworkers over a 21-year period. METHODS: We obtained demographic and health data on farmworkers from the U.S. National Agricultural Workers Survey (NAWS) and publicly available temperature data from 1999 to 2020. We aggregated temperature datasets to six NAWS regions and calculated average daily mean temperature days above four absolute thresholds of 32.2-40.6 Celsius (°C) and seasonal average summertime temperatures to represent potential exposure of the survey population. We used joinpoint regression to describe temporal patterns in temperatures and the prevalence of CVD outcomes within the repeated cross-sectional NAWS data. Multivariate logistic regression analysis was used to explore patterns in CVD outcomes across farmworker characteristics. RESULTS: Farmworkers (n = 44,388) were predominantly Hispanic (81%) and male (73%) with 33% below the poverty level and 40% receiving benefits from needs-based government programs. Seasonal temperatures experienced overall increasing trends, and all regions experienced days over heat thresholds. Prevalence of diabetes, high blood pressure, and CVD generally increased over the study period, with some diminishing trends for diabetes and high blood pressure after 2017. SIGNIFICANCE: Increasing prevalence of CVD and related risk factors, combined with the aging workforce and other social vulnerabilities, support targeted actions to mitigate heat-related health risks and ensure safety and health provisions for this essential workforce. IMPACT STATEMENT: Elevated temperatures pose a risk of morbidity and mortality for farmworkers and outdoor workers in general. We present evidence from a nationwide survey that U.S. farmworkers, while generally younger and healthier than the population as a whole, experience potential vulnerability to heat as their prevalence of cardiovascular disease, average age and risk factors have risen nationally over 21 years. These results highlight the need to pass and implement heat standards and policies to ensure the safety and health of this essential workforce, in light of the absence of such standards in all but five states.

BACKGROUND: Pharmacological inhibition of sclerostin (SOST) is clinically applied to treat osteoporosis. However, large-scale randomized controlled trials have reported conflicting findings regarding the cardiovascular effects of SOST inhibition. This study aimed to evaluate whether sustained SOST inhibition, mimicked by instrumental genetic variants, is associated with the altered risk of cardiovascular diseases (CVDs). METHODS: The individual-level genomic data were obtained from the UK Biobank, including 377,585 participants in the genome wide association study (GWAS) for estimated heel bone mineral density (eBMD). Summary-level genetic data for CVDs were retrieved from publicly available GWASs, with sample sizes ranging from 332,477 to 1,030,836 participants. The conditional quantile-quantile (QQ) plot was used to visualize the genetic pleiotropy between circulating SOST, eBMD and CVDs. By integrating genetic, transcriptomic, and proteomic data, Mendelian randomization was performed to assess the relationship between exposures and CVDs. RESULTS: We observed polygenic overlap between circulating SOST and eBMD as well as atrial fibrillation (AF). Trans-protein quantitative trait loci (pQTLs) around the B4GALNT3 gene, instead of the genetic variants across the genome, could be instrumental variables to proxy the therapeutic effect of SOST inhibition. Further, increasing level of B4GALNT3 gene expression in several tissues was associated with a decreased level of circulating SOST. Consistently, in vitro evidence validated that B4GALNT3 overexpression significantly decreased SOST protein secretion. Notably, increasing level of B4GALNT3 gene expression in the same tissues was also associated with increased eBMD and higher risk of AF. The proxied SOST inhibition (instrumented by B4GALNT3 genetic variants) had a significant causal effect on increased eBMD (β-coefficient=0.034, SE = 0.007, P = 2.81 × 10) and increased risk of AF (OR = 1.353, 95%CI = 1.077-1.701, P = 0.009). The results were replicated in the MR analyses with different instrumental variables based on different linkage disequilibrium (LD) thresholds. CONCLUSIONS: This multi-omics study suggested that reduced circulating SOST was associated with an increased risk of AF, which warrants attention in patients undergoing SOST inhibition treatment.

Elephant populations are threatened by elephant endotheliotropic herpesvirus-hemorrhagic disease (EEHV-HD), a fast-acting infection that often kills very young elephants before they reach maturity. Because it strikes calves at a critical age for survival of the species, EEHV-HD is a major challenge for global conservation. Understanding how the disease causes such severe illness is essential to improving outcomes. In other hemorrhagic diseases, dangerous blood clots form when immune cells release sticky webs of DNA called neutrophil extracellular traps (NETs). We investigate whether this process occurs in elephants with EEHV-HD. Here we show, for the first time, that elephant heterophils (neutrophils) release NETs when stimulated, including by plasma from sick elephants. Tissue samples from fatal cases show large amounts of NETs, suggesting they play a harmful role in disease progression. Encouragingly, known NET inhibitors prevent this response in vitro. Our findings reveal that uncontrolled NET formation likely contributes to EEHV-HD and identify a new potential treatment strategy. Blocking NETs could be combined with existing therapies to improve survival of affected calves, offering a promising way to support elephant health and conservation.

BACKGROUND: Cardiovascular disease (CVD) mortality is rising in Sierra Leone, but the health-system drivers of this trend are not well characterised. We mapped health-system barriers and facilitators for CVD care in Sierra Leone using a systems lens tied to universal health coverage (UHC). METHODS: We conducted a scoping review following PRISMA-ScR guidelines. We searched MEDLINE, Embase, Scopus, Global Health, and African Journals Online (1 Jan 2000 - 10 May 2025), Of 498 unique records, we included 40 sources reporting CVD-relevant data. Findings were mapped to WHO health-system building blocks, and synthesised narratively. RESULTS: Our findings show a health system shaped by path dependence: investments in infectious disease programmes have strengthened vertical delivery platforms with limited integration of non-communicable disease services. Facility readiness averaged 41% for HIV services versus 16.8% for cardiovascular care. An urban risk paradox was identified: urbanisation increased the odds of hypertension (OR 1.46) and diabetes (OR 1.84), while primary care infrastructure remained more oriented toward rural maternal health. Service delivery was undermined by diagnostic gaps; limited access to neuroimaging for stroke was associated with a threefold increase in mortality. High out-of-pocket costs narrowed effective coverage toward wealthier groups, and recurrent medicine stockouts reinforced distrust and disengagement from formal care. Scalable enablers included task-sharing, digital tools, pooled procurement, and community engagement. CONCLUSION: Strengthening task-shared primary care, ring-fenced CVD budgets, pooling drug procurement, and improving digital infrastructure could accelerate UHC-effective coverage in Sierra Leone. Evidence on cost-effectiveness and socio-cultural determinants remains limited and should guide implementation research.

Diabetes mellitus (DM) is an escalating global public health concern, with a rapidly increasing burden in low- and middle-income countries, including Bangladesh. Despite its growing prevalence and associated complications such as cardiovascular disease, kidney failure and stroke, comprehensive evidence on its determinants and predictive modeling at the population level remains limited. This study aimed to predict the DM and identify its associated risk factors using ensemble machine learning (EML) approaches among adults in northern Bangladesh. A community-based cross-sectional study was conducted among 1408 adults in Dinajpur district between March 25 and June 5, 2025, using structured and pilot-tested questionnaires administered through face-to-face interviews. Feature selection was performed using Recursive Feature Elimination, Random Forest importance and Best First Search methods. Six machine learning models were developed, followed by a stacking ensemble model to enhance predictive performance. Model evaluation was based on accuracy, precision, recall, F1-score, and area under the receiver operating characteristic curve (AUC). Model interpretability was assessed using SHAP analysis, and findings were validated using multivariable logistic regression. The prevalence of DM was 15.1% in the study population. Among individual models, LightGBM demonstrated the highest performance (accuracy: 89.44%; AUC: 0.958 [95% CI 0.945-0.973]), followed by XGBoost (accuracy: 88.69%; AUC: 0.955 [95% CI 0.945-0.972]). The stacking ensemble model outperformed all base learners, achieving an accuracy of 91.67% and an AUC of 0.967 (95% CI 0.957-0.981). SHAP analysis identified age, family history of diabetes, BMI, weight, dietary behaviors (particularly low vegetable intake and added salt/sugar), family income, and gender as key predictors. Multivariable logistic regression confirmed these findings, showing that advancing age especially 51-60 years, female gender, family history of diabetes, hypertension, kidney disease and low vegetable consumption were independently associated with DM. Therefore, stacking-based ensemble learning significantly improves the predictive accuracy of DM while enabling robust identification of key risk factors. The consistency between machine learning and traditional statistical approaches strengthens the validity of the findings. These results highlight the importance of integrating advanced analytical methods into public health research to support early detection, targeted prevention, and evidence-based decision-making in resource-constrained settings such as northern Bangladesh.

Interleukin-17A (IL-17A) is a key cytokine in inflammation and autoimmunity. However, its systemic correlates, particularly in a high HIV burden population, are not fully elucidated. This study aimed to identify the sociodemographic, clinical, inflammatory, metabolic, and renal factors independently associated with plasma IL-17A levels. This was a cross-sectional study of 226 adults recruited from Livingstone University Teaching Hospital, Zambia. Sociodemographic and clinical data were collected using standardized methods, and plasma biomarkers were measured using validated assays. Associations with IL-17A were assessed using multivariable linear regression models constructed using a theory-driven approach. A base clinical model was specified a priori, followed by models incorporating metabolic and inflammatory variables. A final parsimonious model was developed, and sensitivity analyses were conducted, separating by HIV status.The cohort was predominantly female (68.6%) and included a high proportion of people living with HIV (64.2%), most of whom were receiving integrase inhibitor-based therapy. In the base clinical model, HIV status was positively associated with IL-17A; however, this association was no longer significant after adjustment for inflammatory markers. In the final model, IL-1 (β: 1.32, 95% CI: 0.60-2.04, p < 0.001) and IL-6 (β: 16.02, 95% CI: 8.19-23.84, p < 0.001) were positively associated with IL-17A, while soluble ST2 (β: -23.86, 95% CI: -41.99 to -5.73, p = 0.010) was inversely associated. Plasma potassium showed a modest positive association (β: 5.83, 95% CI: 0.37-11.29, p = 0.036), but this was not retained in analyses restricted to people living with HIV and in HIV negative individuals. Clinical and metabolic variables were not consistently associated with IL-17A after adjustment. In this high HIV-burden population, IL-17A levels were primarily associated with inflammatory cytokines rather than HIV status or metabolic factors. The attenuation of the HIV association after adjustment suggests that IL-17A was more closely associated with broader inflammatory activity than with HIV status itself. The observed association with plasma potassium was not robust and should be interpreted as exploratory. These findings highlight the role of IL-17A within a coordinated inflammatory network and underscore the need for longitudinal studies to clarify causal pathways.

Atrial Fibrillation (AFib) is the most common sustained cardiac arrhythmia and is associated with substantial morbidity and mortality, including increased risk of stroke and heart failure. Accurate detection of AFib in long-term electrocardiographic (ECG) monitoring is essential for timely diagnosis and early clinical intervention, particularly in ambulatory settings using wearable devices. In this study, we evaluate the performance of a lightweight convolutional neural network (CNN) for automated AFib detection, initially trained on the CinC2021 dataset and subsequently fine-tuned with real-world wearable ECG data. The model was validated across three independent datasets: InCorDB, CODE15, and the TRAdA cohort, with the latter representing long-term ECG monitoring from wearable devices. The TRAdA cohort comprised 173 subjects (87 with AFib and 86 healthy subjects) with continuous ECG recordings obtained over 24 h in Phase 1 (56 subjects) and 7 days in Phase 2 (117 subjects). In total, the dataset included 165,175 annotated ECG segments, including 24,252 AFib episodes. The fine-tuned model demonstrated superior performance compared to the original model on the TRAdA cohort, indicating improved adaptation to wearable ECG signals. On the Phase 2 dataset, the fine-tuned model achieved higher specificity (0.971 vs. 0.914), F1-score (0.891 vs. 0.777), area under the receiver operating characteristic curve (AUC; 0.992 vs. 0.988), and accuracy (0.969 vs. 0.924), highlighting its enhanced ability to detect AFib in extended real-world monitoring scenarios. These findings demonstrate that the domain adaptive fine-tuning significantly enhances AFib detection in long-term wearable ECG monitoring. Our findings support the feasibility of lightweight deep learning models for reliable AFib screening in real-world ambulatory settings.

Coronary heart disease (CHD) and diabetes mellitus frequently co-occur through shared mechanisms such as oxidative stress and inflammation. Whether specific dietary antioxidants mitigate CHD-diabetes comorbidity remains unclear. Using National Health and Nutrition Examination Survey (NHANES) 2005-2018 data (n = 9,279), we developed an interpretable machine-learning pipeline in which standardisation and Synthetic Minority Over-sampling Technique (SMOTE) were embedded inside each fold of tenfold cross-validation to prevent data leakage. Six algorithms (Random Forest, Light Gradient Boosting Machine (LightGBM), K-nearest neighbours, Naive Bayes, support vector machine, eXtreme Gradient Boosting (XGBoost)) were compared on discrimination, calibration and decision-curve net benefit. XGBoost achieved the highest AUC-ROC (0.774, 95% CI 0.759-0.788); Random Forest showed the lowest Brier score (0.111), the calibration slope closest to unity (0.939) and the highest net benefit, and was retained for interpretation. Weighted-quantile-sum regression showed an inverse association between the antioxidant composite and comorbidity risk (OR per quantile 0.87, 95% CI 0.80-0.95; P = 0.001). In mutually adjusted logistic regression, only magnesium retained an independent protective association (per 1 SD: OR 0.80, 95% CI 0.66-0.96; P = 0.016). SHAP identified theobromine (0.020) and lycopene (0.016) as leading protective contributors. Findings support targeted dietary-antioxidant strategies as candidate modifiable factors for cardiometabolic comorbidity prevention.

Endothelial dysfunction plays a key role in the development of diabetic cardiomyopathy (DCM), but the underlying mechanisms of endothelial dysfunction remain to be elucidated. Recent studies have revealed that dysregulated mitochondrial dynamics contributes to the development of cardiac microvascular dysfunction. Fission-1 (FIS1), a key effector of mitochondrial fission, functions as an outer mitochondrial membrane adapter that recruits dynamin-related protein-1 (Drp1) from the cytosol to the outer mitochondrial membrane for activating mitochondrial fission. The present study screened a library targeting deubiquitinases, and identified the regulatory role of USP33 on FIS1-dependent mitochondrial fission. We found USP33 silencing elevated FIS1 protein expression and resulted in excessive mitochondrial fission in endothelial cells, which in turn impaired mitochondrial function and worsen endothelial and cardiovascular dysfunction in DCM. Mechanistically, USP33 interacted with FIS1 at the TPR2 domain and promoted FIS1 degradation via lysosomal degradation. Further studies revealed that USP33 stabilized autophagy-related 7 (ATG7) at protein level by blocking K63-linked ubiquitination of human ATG7 at K48 (mouse K44) site. This process led to lysosomal degradation of FIS1 via ATG7-mediated autophagy. In summary, our findings reveal that USP33 plays a critical role in endothelial dysfunction in DCM and demonstrate that ATG7-FIS1 pathway acts as one of the potential downstream mechanisms.

Sedentary ageing is linked to low cardiorespiratory fitness and the development of a small, stiff heart - risk factors for heart failure. Endurance exercise training reverses the effects of sedentary ageing on the heart when started in middle age; however, blunted training responses of females have been reported. Differences in baseline cardiac size or exercise-induced cardiac remodelling may underly sex differences in trainability. Therefore, we investigated whether sex and left ventricular end-diastolic volume indexed to body surface area (LV EDVi) influence the cardiovascular response to endurance training. Twenty-eight sedentary adults [15 females; age: 54 ± 5 years, peak oxygen uptake ( ): 28.8 ± 4.8 mL min kg) completed 2 years of training, with cardiorespiratory fitness and LV EDVi assessed following 10 months of progressive training and an additional 14 months of maintenance training. The increase in peak (sex × time: P < 0.001) of females after 2 years (∆ = 0.27 ± 0.14 L min) was ∼50% of the increase of males (∆ = 0.53 ± 0.20 L min), resulting from smaller increases in peak cardiac output (sex × time: P = 0.005) and stroke volume (sex × time: P = 0.013). However, LV EDVi at rest, an index of exercise-induced cardiac remodelling, increased during the progressive training phase (main effect: P < 0.001) independent of sex (sex × time: P = 0.888) despite females having smaller EDVi throughout the study (main effect: P = 0.004). Males (r = -0.650, P = 0.016) and females (r = -0.776, P < 0.001) with the smallest initial resting LV EDVi experienced the greatest increase in EDVi with training. Overall, structured endurance exercise training in middle-aged females resulted in blunted increases in cardiorespiratory fitness compared to males despite both sexes experiencing similar degrees of cardiac remodeling. KEY POINTS: Endurance exercise training reverses the effects of sedentary ageing on the cardiovascular system if started in middle age, but the response to training could be modified by sex and baseline cardiac size and function We observed blunted increases in cardiorespiratory fitness of middle-aged females compared to males with 2 years of endurance training, which were attributable to attenuated increases in peak stroke volume and cardiac output in females Both males and females experienced similar degrees of exercise-induced cardiac remodelling, with people with the smallest hearts experiencing the greatest increase in left ventricular end-diastolic volume index for each sex Our data demonstrate that the improvement in cardiorespiratory fitness with endurance exercise training is influenced by sex, but that the degree of cardiac remodelling with training in previously sedentary adults is not different between sexes, nor impaired by having a smaller pre-training left ventricular end-diastolic volume.