PURPOSE: This study characterized nationwide trends, demographic distributions, and regional disparities in cardiac anesthesia and intraoperative transesophageal echocardiography (ITEE) in Japan. METHODS: We conducted a retrospective observational study using the National Database of Health Insurance Claims (NDB) Open Data Japan (2019-2023). Cardiac anesthesia was defined using reimbursement codes for cardiac or thoracic great-vessel surgery requiring cardiopulmonary bypass. ITEE was evaluated using add-on claims classified into two categories: ITEE for cardiac/non-cardiac surgeries, and ITEE for percutaneous interventions. Trends were assessed using linear and Poisson regression models. Age- and sex-specific distributions and regional disparities (Gini coefficients) were assessed. RESULTS: A total of 179,920 cardiac anesthesia events were identified (28.7 per 100,000 person-years), with a male predominance (male-to-female ratio, 1.6:1). Age distribution was bimodal, peaking at 0-4 and 75-79 years. Both cardiac anesthesia and ITEE use declined transiently during Japan's first coronavirus disease 2019 state of emergency in May 2020, followed by recovery in the latter half of fiscal year 2020. Age-adjusted rates of cardiac anesthesia demonstrated no significant annual change. In contrast, ITEE use increased significantly in both cardiac/non-cardiac surgeries (relative risk [RR], 1.011/year; P < 0.0001) and percutaneous interventions (RR, 1.117/year; P < 0.0001). Regional disparities in cardiac anesthesia decreased over time, with Gini coefficients declining from 0.20 to 0.15. CONCLUSION: Cardiac anesthesia remained generally stable in Japan from 2019 to 2023. Increasing ITEE, especially for percutaneous interventions, suggests evolving cardiovascular perioperative practice, although claims-based categories require cautious interpretation.

Hospitals spend billions of dollars annually on major construction projects and facility upgrades, but limited research to date has examined whether this expenditure benefits patients. Using a novel dataset of California hospital construction projects opening between 2010 and 2019, we estimate the effect of project opening on patient experience and clinical measures using a difference-in-differences framework. We find sizable, statistically significant improvements in patient experience-cleanliness, quietness at night, and likelihood to recommend-with effects persisting for at least 2 years after opening. We find no measurable impact on clinical outcomes, 30-day mortality, and readmission for heart attacks and heart failure. These results suggest infrastructure investments meaningfully affect perceived care environments but may not translate into near-term changes in clinical performance. Policymakers and hospital leaders should weigh these returns when evaluating capital expenditures and potential support for hospital construction.

Rheumatic heart disease (RHD) remains a major cause of maternal cardiovascular morbidity and mortality in low-resource settings, particularly among women of reproductive age. Physiological changes during pregnancy can unmask previously undiagnosed disease or precipitate decompensation in those with established valvular lesions. We present a case series of three women with RHD during pregnancy and the early postpartum period, highlighting the burden, clinical presentation, and management challenge in a resource-limited setting. All patients presented with advanced disease, including severe mitral stenosis, atrial fibrillation, and heart failure, with one case complicated by multivalvular involvement and reduced left ventricular function. Management focused on hemodynamic stabilization using diuretics, rate control, anticoagulation, and multidisciplinary care. Definitive interventions such as percutaneous balloon mitral valvotomy or valve replacement were indicated but deferred due to limited availability and financial constraints. All three mothers were clinically stabilized and remained alive at short-term follow-up, although one preterm neonate died from respiratory distress syndrome and Case 3 required readmission because of medication nonadherence. This series underscores the persistent burden of RHD in pregnancy in sub-Saharan Africa and highlights critical gaps in access to definitive cardiac interventions and anticoagulation monitoring. Strengthening health systems, improving access to specialized cardiac care, and implementing preventive strategies are essential to reduce morbidity and mortality associated with RHD in pregnancy in resource-limited settings.

BACKGROUND: Obesity is a major risk factor for cardiovascular disease, yet its role in cardiac arrest (CA) mortality remains a growing public health concern. This study analyzed disparities in mortality involving CA and obesity by age, sex, race/ethnicity, and geographic region. METHODS: Age-adjusted mortality rates (AAMRs) per million in adults (25 years or older) were obtained from CDC WONDER using ICD-10 codes for obesity (E66) and CA (I46). Joinpoint regression estimated Annual Percent Change (APC) and Average APC (AAPC), with significance at  < 0.05. RESULTS: Between 1999 and 2023, a total of 128,550 deaths involving CA and obesity, with most deaths in medical facilities (58.8%). The AAMR rose from 11.3 in 1999 to 32.5 in 2023 (AAPC: 4.45%, 95% CI: 3.72-5.01,  < 0.001). Men had higher AAMRs than women (24.7 vs. 19.5) and a steeper increase (AAPC: 5.34%,  < 0.001). Older adults exhibited higher AAMRs (45.2) compared to younger adults (7.0). Among racial groups, Non-Hispanic (NH) Blacks had the highest AAMR (38.4 per million), while NH Whites experienced the most significant rise (AAPC: 4.97%,  < 0.001). The West had the highest regional AAMR (29.0), while the Midwest experienced the steepest increase (AAPC: 5.7%,  < 0.001). Rural areas exhibited higher AAMRs than urban regions, both of which were trending upward. CONCLUSION: Mortality involving CA and obesity has been rising, with significant disparities in older men, NH Blacks and Whites, those from the West, and rural communities. The increasing burden underscores the need for targeted prevention strategies. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40200-026-02037-9.

BACKGROUND: The Global Leadership Initiative on Malnutrition criteria has recommended using bioelectrical impedance analysis-derived fat-free mass index as a practical screening tool for low muscle mass. In the present study we evaluated the correlation between this index and dual-energy X-ray absorptiometry-derived appendicular skeletal muscle mass index, and developed sex-specific predictive nomograms according to the 2019 Asian Working Group for Sarcopenia criteria. METHODS: This cross-sectional analysis included 369 community-dwelling adults from the Hallym Aging Study. Body composition was assessed by bioelectrical impedance analysis and dual-energy X-ray absorptiometry. Low appendicular skeletal muscle mass index was defined as <7.0 kg/m for men and <5.4 kg/m for women. Receiver operating characteristic analysis identified optimal cutoffs. Multivariable logistic regression and sex-specific nomograms were developed, adjusting for age, albumin, creatinine, hypertension, diabetes, and dyslipidemia. Models were internally validated using 1000 bootstrap resamples. RESULTS: This index moderately correlated with appendicular skeletal muscle mass index (ρ = 0.65 in males, ρ = 0.36 in females; P < 0.001). Optimal cutoffs were 17.7 kg/m for males (area under the curve, 0.84) and 16.1 kg/m for females (0.73). This index remained independently associated with low appendicular skeletal muscle mass index after multivariable adjustment. Nomograms showed good discrimination (C-statistics = 0.78 in males, 0.73 = in females) and calibration. In females, metabolic disorders, particularly hypertension and diabetes, significantly increased this risk. CONCLUSION: Fat-free mass index is a practical marker for low muscle mass screening. However, its accuracy varies by sex and metabolic health, requiring sex-and disease-specific calibration to improve malnutrition diagnosis and sarcopenia screening.

BACKGROUND Despite the well-established epidemiological association between diabetic kidney disease (DKD) and coronary artery disease (CAD) in patients with T2DM, which reflects a core feature of cardiovascular-kidney-metabolic (CKM) syndrome, the underlying molecular mechanisms connecting these 2 conditions remain unclear. Within this integrated pathophysiological framework, the potential role of lipocalin-2 (LCN2) was investigated. MATERIAL AND METHODS A total of 917 participants with T2DM were stratified into an overall cohort and a BMI-, age-, and sex-matched sub-cohort. Serum LCN2 levels were measured. Immunohistochemistry was performed on cardiac and renal tissues from high-fat diet/streptozotocin-induced diabetic mice. Renal tubular (HK-2) and cardiomyocyte (H9c2) cells were treated with recombinant LCN2 to assess inflammatory responses. RESULTS DKD severity was identified as an independent risk factor for CAD in patients with T2DM. Serum LCN2 levels were significantly elevated in patients with DKD or CAD, and were closely correlated with DKD severity and B-type natriuretic peptide levels. Logistic regression analysis further indicated that an elevated serum LCN2 level served as an independent risk factor for the presence of DKD or CAD. Importantly, mediation analysis revealed that increased serum LCN2 may partially mediate the bidirectional association between DKD and CAD. Consistent with these clinical findings, animal experiments demonstrated concurrent upregulation of LCN2 in both the heart and kidney tissues of diabetic mice. Recombinant LCN2 dose-dependently increased interleukin-6 and tumor necrosis factor-a mRNA expression in HK-2 and H9c2 cells. CONCLUSIONS LCN2 may represent a potential biomarker and partial mediator between DKD and CAD in T2DM, potentially contributing to CKM-related organ crosstalk.

BACKGROUND Differentiating traumatic tricuspid regurgitation (TR) from infective endocarditis (IE) is clinically crucial in patients presenting with abnormal tricuspid valve findings after blunt chest trauma. Particularly, papillary muscle rupture caused by trauma can produce mobile valvular structures that closely resemble vegetations, making accurate diagnosis challenging in the acute setting. CASE REPORT A man in his 60s with pulmonary sarcoidosis was admitted after a 5-m fall, sustaining multiple fractures. Preoperative transthoracic echocardiography revealed a 7-mm mobile structure on the anterior tricuspid leaflet with flail motion and severe TR. Because of fever, IE was suspected; however, blood cultures and further investigations excluded IE. A diagnosis of traumatic TR due to papillary muscle rupture was made. Although the patient was hemodynamically stable under medical therapy, the heart team recommended surgery to prevent long-term heart failure. Four months after fracture repair, tricuspid valve repair with artificial chordae and annuloplasty was performed. The surgical findings were fully consistent with the preoperative diagnosis, and pathological examination of the ruptured papillary muscle demonstrated coagulative necrosis without significant inflammatory infiltration, supporting a traumatic etiology. At 4-year follow-up, he remains stable without signs of heart failure exacerbation. CONCLUSIONS Accurate differentiation between traumatic TR due to papillary muscle rupture and IE is essential, as misclassification may lead to unnecessary antimicrobial therapy or delayed surgical intervention. This case highlights how mobile traumatic lesions can closely mimic vegetations and underscores the importance of comprehensive evaluation to guide appropriate management and optimize outcomes.

BACKGROUND: Periodontitis is a prevalent chronic inflammatory disease with a systemic inflammatory burden and is implicated with vascular pathology. This systematic review and meta-analysis evaluates the association between varying severities of periodontitis and ischemic stroke with various diagnostic criteria. METHODS: Following PRISMA 2020 (PROSPERO:1161816), PubMed (MEDLINE), Web of Science, and Scopus were searched from January 2000 to January 2026. Studies with clinically or radiographically diagnosed adult periodontitis patients were included. Studies reporting hazard ratios (HRs) and odds ratios (ORs) for ischemic stroke or cardiovascular outcomes with clear diagnosis and outcome definition were considered eligible. Study characteristics, diagnosis methods, periodontitis severity, outcomes, outcome ascertainment, follow-up duration, effect measures with 95% confidence intervals, and adjustment variables were extracted. The study quality was assessed using the Newcastle-Ottawa Scale (NOS). RESULTS: Fifteen studies met the inclusion criteria: seven cohorts and eight case-controls. Pooled estimates showed an increased risk of ischemic stroke with periodontitis (HR = 1.24; 95%CI, 1.11-1.38; OR = 4.59; 95%CI, 1.81-11.62). Subgroup analysis revealed that severe periodontitis (OR = 4.19; 95%CI, 3.14-5.59) confers a greater risk than moderate disease (OR = 1.63; 95%CI, 1.16-2.29). New classification diagnostic criteria (AAP/EFP, CDC/AAP) produced stronger associations, OR = 5.35 (95%CI, 3.35-8.55), and a longer follow-up (≥ 15 years) amplified the risk (HR = 1.80; 95%CI, 1.33-2.44), supporting temporality. CONCLUSIONS: Severe periodontitis is significantly associated with ischemic stroke, with a consistent severity-related trend across studies. Therefore, meticulously diagnosed advanced periodontitis should be considered as a probable vascular risk factor and should prompt interdisciplinary management and patient education. PLAIN LANGUAGE SUMMARY: Gum disease (periodontitis) is a very common long-term inflammatory disease that affects the supporting tissue of the teeth. Increasing evidence suggests that periodontitis may also influence the general health of a person. In this study we focused particularly on ischemic stroke, the most common type of stroke. We analyzed data from multiple long-term research studies to determine if the severity of gum disease influences the risk of a person developing ischemic stroke. We found that the severe form of gum disease is significantly associated with ischemic stroke risk compared with individuals with healthy gums or a milder form of gum disease. This association is stronger in studies that used standardized diagnostic criteria and in studies with longer follow-up periods. This suggests that a systematically diagnosed severe gum disease is most likely to contribute to stroke development over time. These findings highlight the importance of early detection to properly manage gum disease. Closer collaboration between dental and medical professionals may improve preventive efforts and patient outcomes.

This paper provides both effortless augmentation of data and efficient creation of images according to the image input size of deep learning models by converting almost all numerical data into 24-bit images of particular standards. As cardiovascular disease is a cause of mortality, artificial intelligence-based architectures may play an important role here, and predicting survival from heart failure is a great challenge. For this purpose, we adjust the image input size according to different deep learning architectures by using the automated feature engineering technique in the approach, which can be easily used in different numerical datasets. Afterward, we horizontally augment the transpose of the new features obtained, thus creating the 8-bit rectangular coded images. After converting these images to 24-bit, we rotate them into multiples of 15° using different coefficients to augment the dataset. We train the ResNet18 and ResNet50 architectures using these images in the new data. According to the findings, the performance metrics (Accuracy, Sensitivity, Specificity, and F1 Score) are quantified as 0.9331-0.9610-0.8742-0.9512 for ResNet18 and 0.9617-0.9743-0.9349-0.9718 for ResNet50. Evaluated alongside current literature, these findings confirm that the proposed methodology represents an innovative, competitive, and highly applicable solution for heart failure classification. The proposed novel method allows numerical data to be evaluated as image representations and, accordingly, to be easily utilized in image processing, data augmentation, and similar techniques.

BACKGROUND: Short-term air pollution exposure may exacerbate respiratory health outcomes in vulnerable populations, particularly those with pre-existing cardiovascular conditions. Given the persistent burden of COVID-19 pneumonia, there is a need to better understand how environmental exposures influence risk of COVID-19 pneumonia. OBJECTIVE: We aimed to explore whether associations between short-term particulate matter (PM) exposure and COVID-19 pneumonia risk are stronger among those with pre-existing cardiovascular conditions. METHODS: We used NYC COVID-19 hospitalization records (March-December 2020; N = 15,361) and defined short-term PM as a 7-day residential ZIP Code average prior to and including hospitalization, using Environmental Protection Agency (EPA) Community Multiscale Air Quality (CMAQ) modeled data. Pre-existing cardiovascular conditions included 15 ICD-coded circulatory conditions (e.g. myocardial infarction, atrial fibrillation, ischemic heart disease). Modified Poisson regression estimated risks of acute respiratory distress syndrome, pneumonia, ventilation use, and dialysis use, and Cox hazards regression estimated COVID-19 fatality risk and length of stay, adjusting for age, sex, smoking status, and environmental vulnerability. Relative excess risks of interaction (RERI) estimated additive interaction between short-term PM exposure and cardiovascular conditions on risk of COVID-19 pneumonia during hospitalization. Targeted maximum likelihood estimation estimated average treatment effects (ATE) of short-term PM exposure on COVID-19 pneumonia, among those with and without cardiovascular conditions. RESULTS: Short-term PM and pre-existing cardiovascular conditions together increased pneumonia risk from July to December 2020. For example, joint exposure to an interquartile range increase in short-term PM and pre-existing myocardial infarction amplified pneumonia risk (RR:1.67; 95%CI:1.41,1.99), with smaller increases observed for PM alone (RR:1.03; 95%CI:0.95,1.12) or myocardial infarction alone (RR:1.34; 95%CI:1.14,1.58). Upper-quartile short-term PM increased pneumonia risk only among individuals with cardiovascular conditions (ATE:0.05, 95%CI:0.02,0.08). IMPACT: COVID-19 pneumonia drives substantial hospitalizations, but little is known about the link between environmental exposures and pneumonia. We aimed to examine whether short-term air pollution influences pneumonia risk, and if pre-existing cardiovascular conditions modify this link. We found that pre-existing cardiovascular conditions increase vulnerability to short-term air pollution, amplifying COVID-19 pneumonia risk during hospitalization. These study findings may help identify populations that may be more vulnerable to the effects of short-term air pollution exposure during future respiratory infectious disease outbreaks.

Heterozygous loss-of-function variants in Neurabin I (PPP1R9A), responsible for encoding a cytoskeletal scaffolding protein essential for synaptic plasticity, are recurrently associated with neurodevelopmental and neuropsychiatric disorders, yet their direct effects on human neuronal maturation remain unclear. Here, we establish the first comprehensive human mechanistic model of PPP1R9A haploinsufficiency using an isogenic CRISPR/Cas9-engineered iPSC system differentiated into cortical neurons to define dosage-dependent functional consequences. PPP1R9A neurons exhibited pronounced hyperspinogenesis and increased neuritic complexity, indicative of aberrant structural maturation; however, whole-cell patch-clamp recordings revealed impaired intrinsic excitability, including reduced action potential firing, altered waveform properties, and defective axo-somatic coupling, uncovering a striking dissociation between neuronal morphology and function. Long-read single-cell transcriptomics and quantitative proteomics identified coordinated downregulation of ion channel and synaptic transmission pathways, including genes essential for sodium channel function and glutamatergic signaling, together with disruption of synaptic vesicle cycling, axon guidance, and neurodevelopmental programs. Pseudotime trajectory analysis further demonstrated delayed neuronal differentiation, with mutant neurons accumulating at intermediate developmental states rather than acquiring mature cortical identities. Importantly, molecular rescue experiments confirmed causality, as restoration of full-length PPP1R9A expression robustly normalized transcriptional and synaptic signaling programs, whereas allele-specific antisense oligonucleotide-mediated suppression of the mutant transcript achieved only partial rescue. Taken together, these findings establish PPP1R9A haploinsufficiency as a driver of impaired molecular, electrophysiological, and developmental maturation in human cortical neurons, providing a human-specific mechanistic framework linking reduced Neurabin I dosage to neurodevelopmental and psychiatric disease risk.

Acute myocardial infarction is increasingly recognized in younger adults, but the angiographic and early clinical profile of ST-segment elevation myocardial infarction among patients with substance use disorder remains incompletely defined. This single-center prospective observational cohort study evaluated the angiographic and early in-hospital profile after primary percutaneous coronary intervention in patients with and without substance use disorder. A total of 175 patients formed the final analytic cohort, including 75 patients with substance use disorder confirmed by DSM-5 criteria supported by point-of-care urine toxicology screening and 100 patients without substance use disorder. Patients with substance use disorder were younger, exclusively male, and had fewer traditional cardiometabolic co-morbidities. In unadjusted analyses, they more often had single-vessel coronary disease and more frequent glycoprotein IIb/IIIa inhibitor use, whereas angiographic thrombus presence was similarly frequent in both groups. After multivariable adjustment, the associations with single-vessel disease and glycoprotein IIb/IIIa inhibitor use were not statistically robust. Patients with substance use disorder presented with a distinct baseline and procedural profile, but adjusted analyses did not support an independent association with the principal angiographic or procedural outcomes assessed, supporting careful toxicology assessment and thrombus-focused procedural planning while avoiding causal interpretation.

Acute kidney injury (AKI) is a common and potentially serious complication, yet population-level data on its burden and determinants remain limited. We quantified AKI incidence, temporal trends, and risk factors across a complete healthcare system. We conducted a population-based cohort study including all adult residents of Stockholm, Sweden (2017-2021) using the SCREAM project. AKI events requiring hospitalization or occurring during hospital stays were identified using a composite algorithm incorporating laboratory-based KDIGO creatinine criteria, ICD-10 diagnoses, and acute dialysis procedure codes. We calculated annual incidence rates, temporal trends using Poisson regression, and incidence rate ratios for selected demographic, clinical, and laboratory-defined risk factors. Among approximately 1.9 million adults annually, 0.6-0.7% experienced AKI each year (71-95 per 10,000 person-years). AKI occurred in 5.8-7.8% of hospitalizations, with only 30% reaching KDIGO stage 2-3. From 2017 to 2021, AKI incidence increased by 26% (95% CI 1.23-1.29). Populations at highest risk of AKI were largely consistent over the years, and included older adults, men, and individuals with uncontrolled diabetes, prior AKI, hypertension, heart failure, kidney transplantation, and multiple myeloma. Lower eGFR and higher albuminuria were associated with markedly higher AKI risk in a graded manner. COVID-19 infection was associated with a six-fold higher AKI risk in 2020, but marked attenuation in 2021 suggests it does not explain the overall upward trend. This region-wide analysis quantifies the contemporary burden of AKI and identifies high-risk populations that may benefit from targeted prevention and monitoring strategies.

The aim of this study was to examine the frequency and impact of diabetes (DM) in South Asian (SA) compared with white North American (WNA) patients with ST-elevation myocardial infarction (STEMI). Consecutive patients undergoing primary percutaneous coronary intervention (PPCI) for STEMI between 2016 and 2018 were included for analysis. Patients with and without DM were divided into distinct cohorts. Cardiovascular outcomes at one-year, including mortality and composite major adverse cardiovascular events (MACE), were compared between SA and WNA in each cohort. Overall, 1303 patients underwent PPCI for STEMI. Average age for patients was 63.81±12.48yrs, 73.4% were male and 27% had DM at the time of presentation. Patient ethnicity was distributed as 407 (31%) SA and 896 (69%) WNA. DM was significantly more frequent in SA compared with WNA (34% vs. 24%, p<0.01). In the DM cohort, SA were more likely to have multivessel disease on coronary angiography (SA 55% vs. WNA 44%, p=0.04), and had significantly increased mortality (SA 14% vs. WNA 7%, p=0.04) and mortality/MACE (SA 22% VS. WNA 12%, p<0.01) one-year after PPCI. In multivariate analysis of one-year outcomes amongst DM, SA ethnicity was an independent predictor of both mortality (OR 2.82, 95% CI 1.15, 6.89) and mortality/MACE (OR 2.62, 95% CI 1.33, 5.16). In the non-DM cohort, SA ethnicity was not associated with outcomes or presence of multivessel disease. In conclusion, SA compared to WNA with STEMI were more likely to have DM, while SA ethnicity amongst DM patients conferred worsened one-year prognosis for cardiovascular outcomes.

Valvular heart disease (VHD) contributes substantially to cardiovascular mortality. We evaluated long-term VHD mortality trends among older adults to inform healthcare planning. CDC WONDER mortality data (1999-2023) were analyzed for adults aged ≥65 years to calculate age-adjusted mortality rates (AAMRs). Joinpoint regression identified temporal trends, alongside a subtype analysis stratifying AAMRs by nonrheumatic aortic (ICD-10 I35), mitral (ICD-10 I34), tricuspid (ICD-10 I36), and chronic rheumatic (ICD-10 I05-I09) valve disorders. Age-period-cohort modeling assessed generational effects, and ARIMA models projected mortality rates through 2040. Among 1,204,490 VHD deaths, the AAMR declined from 1999 to 2018 (annual percent change [APC] -0.87) but significantly increased from 2018 to 2023 (APC 1.52). Nonrheumatic aortic valve disorders accounted for the vast majority of deaths, demonstrating a continuous decline (APC -0.20). Tricuspid valve disorders showed a sustained rise (APC 7.30), mitral valve disorders exhibited a biphasic pattern reversing after 2012, and chronic rheumatic diseases showed a post-2017 resurgence. Mortality was highest among non-Hispanic White individuals, men, nonmetropolitan residents, and in the West. Age-period-cohort analysis demonstrated generational divergence: recent cohorts experienced lower mortality at ages 65-69, whereas adults aged ≥85 years faced progressively higher risks. Forecasting models project the recent resurgence will transition into a sustained plateau, stabilizing at 109.2 deaths per 100,000 population through 2040. Ultimately, after two decades of decline, the VHD mortality trend reversed course and is projected to remain stably elevated. This disproportionate impact among the oldest-old and rural populations underscores the need for targeted strategies to mitigate widening disparities.

BACKGROUND: Aspirin remains the cornerstone of antiplatelet therapy for acute myocardial infarction (AMI); however, its use is limited in patients with aspirin intolerance, hypersensitivity, or high bleeding risk. Indobufen, a reversible cyclooxygenase-1 inhibitor, has emerged as a potential alternative, yet its cardioprotective effects beyond platelet inhibition and the underlying mechanisms remain incompletely understood. METHODS: Clinical serum samples were collected from patients with ST-segment elevation myocardial infarction (STEMI) receiving aspirin or indobufen therapy. In parallel, myocardial infarction was induced in mice by left anterior descending coronary artery ligation, and neonatal rat cardiac fibroblasts (NRCFs) were subjected to hypoxia in vitro. Cardiac function, fibrosis, autophagy, apoptosis, and oxidative stress were evaluated using echocardiography, histology, immunostaining, western blotting, and transmission electron microscopy. Publicly available single-cell RNA sequencing data were analyzed to explore relevant cellular pathways. RESULTS: In STEMI patients, indobufen treatment was associated with lower circulating levels of cardiac troponin I, thromboxane B₂, IL-1β, and IL-12, along with increased IL-10 levels than aspirin treatment, and these associations remained significant after multivariable adjustment for baseline clinical characteristics. In vivo, indobufen improved cardiac function and attenuated myocardial fibrosis, accompanied by modulation of autophagy-related signaling, reduced apoptosis, and alleviation of oxidative stress. In vitro, indobufen attenuated hypoxia-induced cardiac fibroblast activation, apoptosis, and mitochondrial dysfunction, whereas aspirin exerted limited effects under the same conditions. Mechanistically, indobufen was associated with increased activation of AKT and AMPK signaling pathways and coordinated modulation of autophagy-related proteins. Further pharmacological inhibition of AMPK partially attenuated the autophagy-related effects of indobufen, suggesting that AMPK signaling contributes, at least in part, to the cytoprotective effects of indobufen. CONCLUSIONS: These findings suggest that indobufen may exert myocardial protective effects beyond platelet inhibition, potentially through AKT/AMPK-associated regulation of autophagy, apoptosis, and fibroblast activation. These findings provide a rationale for further investigation of indobufen as a potential alternative antiplatelet strategy in myocardial infarction.

BACKGROUND: Over the last decades, the sphingosine kinase 1 (SK1)/sphingosine1-phosphate (S1P) axis has attracted increasing attention in cardiovascular research due to its effects under acute or chronic stress conditions. Despite this, the specific role of this molecular pathway in human heart failure (HF) remains poorly defined. Likewise, the potential of circulating S1P as a biomarker of HF has not been fully established. METHODS AND RESULTS: To this aim, we enrolled 28 patients with HF and 16 non-HF controls. We observed that serum S1P levels were significantly reduced in HF patients compared with controls, and S1P was positively associated with left ventricular ejection fraction (EF). Further, ROC analysis demonstrated a moderate discriminatory capacity of S1P for HF. However, this relationship was partly influenced by age, as S1P levels were inversely correlated with age. Among laboratory parameters, circulating S1P levels were inversely associated with serum creatinine, suggesting a potential link between S1P signaling and cardiorenal dysfunction. Next, In differentiated human AC16 cardiomyocytes, acute β-adrenergic stimulation with isoproterenol increased SK1 and PCNA expression, whereas prolonged stimulation reduced SK1 levels, indicating a biphasic regulation of the SK1/S1P axis under sustained adrenergic stress. Similarly, hypoxic insult in AC16 cells resulted in a significant reduction in SK1 levels and increased p53 levels. Finally, in AC16 incubated withwith human blood serum from HF patients we observed a robust reduction in SK1 compared with cells incubated with control serum. CONCLUSIONS: In conclusion, this study supports SK1/S1P axis as an adaptive cardioprotective mechanism activated during acute stress that becomes impaired in chronic HF-related stress. Although the association between circulating S1P and myocardial SK1 requires further investigation, reduced circulating S1P was consistently associated with HF and impaired cardiac function, supporting its potential value as a biomarker and highlighting the SK1/S1P axis as a promising therapeutic target.

BACKGROUND: Phenotypic switching of smooth muscle cells is a core event in atherosclerosis, and atherosclerosis is recognized as a smooth muscle cell-driven tumor-like disease. Paeoniflorin (PF), a bioactive monoterpene glycoside isolated from Paeonia lactiflora and Paeonia veitchii, which exerts beneficial effects on both cardiovascular diseases and tumors. However, whether it ameliorates atherosclerosis by mediating the phenotypic switching of VSMC to enhance plaque stability remains unclear. The present study aims to clarify the plaque-stabilizing efficacy of paeoniflorin and unravel its underlying mechanisms. METHODS: In vitro, tunicamycin induced VSMC to establish a phenotypic switching model. In vivo, ApoE mice were fed a high-fat diet to induce atherosclerosis. Aortic tissue pathological changes were measured by Oil Red O staining, H&E staining, Sirius red staining, Masson staining, immunofluorescence, and fluorescence staining. Western blotting was employed for mechanistic studies. RESULTS: Our results indicated that PF significantly reduced GRP78 and vimentin expression in VSMC, while increased calponin expression. PF significantly improved cardiac function in ApoE mice, reduced inflammatory factors, oxidative stress, plaque area and necrotic core regions, while increased plaque collagen content and fibrous cap thickness. Furthermore, PF downregulated the expression of aorta GRP78, CHOP, vimentin, osteopontin, KLF4, and MMP2, while upregulated α-SMA and calponin expression. Concurrently, PF activated the AMPK/PPARδ signaling pathway, inhibited GRP78 and vimentin expression, enhanced calponin expression, and improved atherosclerosis. CONCLUSIONS: This study demonstrated that PF inhibited ER stress-induced VSMC phenotypic switching by activated the AMPK/PPARδ signaling pathway, thus enhanced atherosclerosis plaque stability.

OBJECTIVES: To evaluate a laboratory-integrated CDSS for lipid monitoring after cardiovascular risk classification. METHODS: An opportunistic laboratory-based CDSS was implemented at Hospital La Fe (València), for primary care lipid requests. Cardiovascular risk was assigned hierarchically by combining direct ESC/EAS guideline-based clinical staging with structured reuse of Lp(a)-adjusted SCORE2-, SCORE2-OP-, or SCORE2-Diabetes-based risk estimations generated by a separate CDSS. The highest risk category prevailed, and new relevant conditions triggered automatic reassessment. LDL-C target attainment was evaluated when TG were < 400 mg/dL, whereas non-HDL-C was used for TG ≥400 mg/dL. Above-target results generated an interpretive report for clinicians. Lipid control, lipid lowering treatment (LLT) exposure, direct staging conditions, age patterns, and longitudinal treatment trajectories were analyzed. RESULTS: During the first 4 months, the CDSS evaluated 9507 eligible requests: 7353 (77.1%) were very high risk, 1881 (20.1%) high risk, 210 (2.2%) moderate risk, and 63 (0.7%) low risk. Lipid target attainment was 14.9%, 7.8%, 25.2%, and 57.1%, respectively. Poor lipid control remained high across age strata, particularly in moderate- to very-high-risk patients. Poor control persisted despite 79.4% recorded LLT exposure in off-target very-high-risk patients. Non-HDL-C assessment was required in 93 patients with TG ≥400 mg/dL, none of whom achieved lipid targets. In the subgroup of 330 patients previously stratified by the separate SCORE2-based CDSS, without direct staging criteria or baseline LLT, 85.2% had baseline poor lipid control; 39.1% initiated LLT during follow-up, and 23.1% subsequently achieved lipid targets. CONCLUSIONS: This CDSS enabled automated risk reassessment and longitudinal lipid target monitoring in primary care.

OBJECTIVE: Drug-induced bipolar disorder (BD) is easily neglected clinically. We mined the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database to screen high BD-risk drugs and assess BD risk warnings in drug labels. METHODS: Data were extracted from the FAERS database spanning the first quarter of 2004 to the third quarter of 2025. Preferred terms (PTs) related to BD, including 'bipolar disorder', were identified using the Medical Dictionary for Regulatory Activities (MedDRA v27.1). Generic drug names were standardized via the DrugBank database. Sex-stratified and BD subtype-stratified disproportionality analyses were performed. RESULTS: A total of 23,607,454 adverse event reports were analyzed, with 17,620 cases linked to BD. Varenicline (537 cases) was associated with the highest number of BD reports. Based on disproportionality analysis, the top five medications with the highest reporting odds ratios (RORs), proportional reporting ratio (PRR), empirical bayes geometric mean (EBGM) and information component (IC) were pizotifen, tafenoquine, flupenthixol, naltrexone, and pemoline. Among the top 50 medications, 44 (88%) lacked any mention of BD risk in their prescribing information. Time-to-onset analysis revealed that 51% of cases (n = 993) occurred within 0-30 days of drug exposure. Signals differed markedly by sex: varenicline showed higher male risk, while esomeprazole and oxycodone carried mild female-specific risks. Naltrexone strongly associated with BD-I and oxcarbazepine with BD-II, with elevated subtype-specific RORs limited by small subtype samples. CONCLUSION: Most high BD-signal drugs lack label warnings. Drug-induced BD presents distinct sex and subtype-specific risks, requiring gender- and subtype-personalized clinical monitoring.

Metamorphosis is a critical ontogenetic transition for marine bivalves, marking the shift from planktonic to benthic lifestyles, where successful transformation dictates survival. The razor clam Sinonovacula constricta is economically important; however, low larval metamorphosis rates remain a major bottleneck in seedling production. To elucidate the mechanisms governing this process, we performed a comparative transcriptome analysis of S. constricta larvae at pre- and post-metamorphosis stages using Illumina sequencing. A total of 3701 differentially expressed genes (DEGs) were identified, including 3254 up-regulated and 447 down-regulated genes. Functional annotation of the respective top 20 significantly up-regulated and down-regulated DEGs indicated their potential pivotal roles in signal transduction (e.g., up-regulated: CAV1, CHRNA2; down-regulated: APP, NOTCH1), cellular proliferation and differentiation (e.g., up-regulated: TUBA, EGF1; down-regulated: KIF23, TTC25), transcriptional and epigenetic regulation (e.g., up-regulated: NFIL3; down-regulated: OVO, HMX1), substance transport (e.g., up-regulated: LRP2, LRP1B; down-regulated: SLC51A, Slc33a1), substance metabolism (e.g., up-regulated: CPK3, CYP26A1; down-regulated: RDMT1, ADAC), immunomodulation (e.g., up-regulated: CPN2, CRISP2), and protein homeostasis (e.g., up-regulated: HSP27, NAS-27). Functional enrichment analysis further revealed that DEGs were significantly enriched in pathways related to signal transduction and developmental regulation (e.g., Ras, TNF), cell death and homeostasis (e.g., apoptosis), immune responses (e.g., Toll-like receptor), energy metabolism (e.g., lipid), cardiovascular related (e.g., Fluid shear stress), cell junction and architecture (e.g., Tight junction), and infectious disease (e.g., measles). These results suggest a synergistic interplay between signaling, apoptosis, immunity, and metabolism during S. constricta metamorphosis. This study advances our understanding of marine bivalve metamorphosis and offers candidate genes for further mechanistic studies.

BACKGROUND: Osteoporosis is a major complication in patients with arthritis, yet the long-term protective effect of physical activity (PA) and its underlying mechanisms are not fully understood. METHODS: This study utilized two large aging cohorts, the U.S. Health and Retirement Study (HRS) and the English Longitudinal Study of Ageing (ELSA). All exposures and outcomes, including PA and physician-diagnosed arthritis and osteoporosis, were based on self-reported data. Cross-sectional analyses assessed the association between PA and arthritis-osteoporosis comorbidity. Longitudinal Cox models examined the effect of baseline PA on new-onset osteoporosis in patients with arthritis. Subgroup, E-value, and mediation analyses were performed to explore effect heterogeneity, robustness, and the mediating role of depression. An exploratory reverse analysis assessed the association of PA with new-onset arthritis in osteoporosis patients. RESULTS: Among 20,175 HRS and 10,525 ELSA participants in the cross-sectional analysis, and 8032 HRS and 2984 patients with arthritis in the prospective analysis, PA was associated with lower comorbidity prevalence (HRS: OR = 0.78; ELSA: OR = 0.69). In longitudinal analyses, active PA was independently associated with reduced osteoporosis risk (HRS: HR = 0.86; ELSA: HR = 0.70) in patients with arthritis. The effect was more pronounced in younger patients and those with heart disease or depression. In HRS, depression significantly mediated 36.55% of the protective effect, whereas this mediation pathway was non-significant in ELSA. No significant association was found between PA and new-onset arthritis in osteoporosis patients. CONCLUSION: Regular physical activity was associated with a lower risk of osteoporosis in patients with arthritis; the association may be partly explained by improvements in depressive symptoms. Promoting PA should be integral to clinical management.

Steroid hormones regulate ovarian development, but hsd3b7 function in fish remains unclear. In this study, we cloned full-length hsd3b7 cDNA from Qihe gibel carp (Carassius gibelio var. Qihe) and generated a polyclonal antibody. Real-time PCR, Western blotting, and immunohistochemistry revealed widespread hsd3b7 expression in brain, heart, spleen, muscle and ovary. During ovarian development and maturation, hsd3b7 mRNA expression peaked at 150 days after hatching (dah) and remained at a relatively high level until 720 dah. Immunohistochemical analysis further revealed that Hsd3b7 protein was localized in both gonadal germ cells and somatic cells, suggesting its involvement in ovarian development and maturation. To further investigate its function, hsd3b7 was knocked down for 30 days by ovarian injection of double-stranded RNA (dsRNA) during the previtellogenic stage. Silencing of hsd3b7 markedly inhibited ovarian development, with most oocytes remaining at phase II. In addition, the expression levels of the germ cell marker genes vasa and piwil, as well as the cell proliferation-related genes pcna and ki-67, were significantly reduced. Protein interaction analysis suggested that Hsd3b7 is associated with several steroidogenic enzymes, including Cyp19a1a, Cyp11c1, Hsd17b3, and Hsd17b7. Moreover, hsd3b7 knockdown altered the expression of genes involved in steroidogenesis and lipid accumulation, and significantly affected serum E2 and total cholesterol levels. Collectively, these findings indicate hsd3b7 regulates ovarian development and maturation via steroid hormone synthesis and lipid metabolism, providing insights for addressing precocious maturation in Qihe gibel carp.

Diabetes Mellitus is a major metabolic disorder affecting over 800 million people worldwide, with significant health risks including cardiovascular diseases, kidney failure, and neuropathy. Among women, diabetes during pregnancy - both pre-existing and gestational - poses severe complications for maternal and fetal health. This study develops a comprehensive mathematical model capturing the dynamics of diabetes among women, emphasizing pregnancy-associated transitions. The total female population is divided into fertile and non-fertile groups, each further subdivided into eleven compartments representing different diabetic and pregnancy states. The model incorporates hereditary factors, social transmission, comorbidities, and lifestyle influences. Using a system of nonlinear differential equations, the work demonstrates positivity, boundedness, and quasi-steady-state (QSS) reduction, thereby simplifying the high-dimensional system while retaining essential pregnancy dynamics. This framework provides insight into how social interactions, lifestyle changes, and pregnancy contribute to diabetes progression, offering a foundation for targeted public health strategies to manage diabetes in women of reproductive age. Partial Rank Correlation Coefficient (PRCC) analysis shows that equilibrium diabetes prevalence is controlled by demographic inflow, whereas pregnancy complications are driven by progression dynamics.