Background: Patients with atrial fibrillation (AF) receiving direct oral anticoagulants (DOAC) are at an elevated risk of gastrointestinal (GI) mucosal damage and bleeding. Proton pump inhibitors (PPI) are conventional gastroprotectors, but their efficacy in the lower GI tract is limited. This study evaluated the efficacy and safety of rebamipide monotherapy and combination pantoprazole-rebamipide (P + R) therapy compared to pantoprazole monotherapy in this vulnerable population. Methods: In the randomized, parallel-group, open-label, single-center REGATA trial, 210 AF patients receiving DOAC were randomized (1:1:1) to three gastroprotective regimens (n = 70 each) for 24 weeks: pantoprazole monotherapy, rebamipide monotherapy, or their combination. Efficacy analyses were performed in the per-protocol population (n = 118: pantoprazole, n = 36; rebamipide, n = 39; P + R, n = 43). The primary and secondary outcomes included composite clinical GI events (bleeding classified by ISTH/BARC, ulcers/erosions, and severe dyspepsia) and biomarkers of mucosal barrier function (fecal zonulin and calprotectin). Results: The incidence of primary efficacy endpoint events was 13.9% (n = 5; 95% CI: 3.1-25.7) in the pantoprazole group, 10.3% (n = 4; 95% CI: 2.3-21.1) in the rebamipide group, and 9.3% (n = 4; 95% CI: 2.1-18.6) in the P + R group, successfully confirming the non-inferiority hypothesis for both experimental arms within the pre-specified margin of 10% (p < 0.05). Multivariable regression analysis showed that compared with pantoprazole monotherapy, rebamipide monotherapy demonstrated an odds ratio OR of 0.71 (95% CI: 0.18-2.88, p = 0.630), while the P + R therapy was associated with an OR of 0.64 (95% CI: 0.16-2.57, p = 0.525). No major GI bleeding events or fatalities occurred; a single episode of GI bleeding (ISTH minor/BARC Type 2) was recorded in the pantoprazole arm (2.8%). Fecal calprotectin levels significantly decreased in the rebamipide group (by 37.6%, from 139 to 78 µg/g; p < 0.001) and the P + R group (by 50.0%, from 135 to 61 µg/g; p < 0.001), while no significant changes were observed in the pantoprazole group (p = 0.530). Concurrently, fecal zonulin levels, reflecting intestinal epithelial permeability, fell by 45.1% in the rebamipide arm (from 434 to 225 ng/mL; p < 0.001) and by 47.1% in the P + R arm (from 347 to 182 ng/mL; p < 0.001) compared to a minimal 3.0% fluctuation in the pantoprazole group. Conclusions: While demonstrating non-inferiority regarding primary clinical endpoints, both rebamipide monotherapy and combination (P + R) therapy achieved some advantages over pantoprazole monotherapy in decreasing subclinical GI inflammation and restoring intestinal epithelial barrier integrity.

Antithrombotic therapy is routinely prescribed to young adults after ischemic stroke to prevent recurrent vascular events. However, the long-term balance between potential benefits and bleeding risks of continued antithrombotic therapy in this population remains uncertain.

To determine the short-term and long-term risk of bleeding associated with antithrombotic therapy in young stroke survivors.

This cohort study used data from the Observational Dutch Young Symptomatic Stroke Study (ODYSSEY), a prospective, multicenter cohort study conducted in 17 hospitals in the Netherlands. Data were collected between 2013 and 2021. Follow-up data were obtained through standardized questionnaires with subsequent verification based on medical records, with data collection continuing until March 2024. Data were analyzed from October to December 2025. Participants included patients aged 18 to 49 years with a first-ever neuroimaging-proven ischemic stroke who survived the first 30 days after the index event.

Antithrombotic therapy.

The primary outcome was the occurrence of a bleeding event requiring medical evaluation. Bleeding complications were stratified by severity according to the Bleeding Academic Research Consortium criteria. Potential factors associated with bleeding risk included sex, age, stroke severity, stroke cause, vascular risk factors, and antithrombotic therapy during follow-up. As a secondary analysis, bleeding risk was compared with the recurrence risk. The estimated bleeding probability during follow-up was calculated using Kaplan-Meier survival analysis with 95% CIs.

In total, 1226 patients were included (median [IQR] age, 44 [38-48] years; 637 male [52.0%]), with a median (IQR) follow-up of 4.2 (2.2-5.9) years. During follow-up, 129 patients experienced at least 1 bleeding event, corresponding to a 5-year cumulative risk of 10.7%. The annual bleeding rate was 2.5 events per 100 person-years. Among patients receiving antiplatelet therapy, the cumulative risk of bleeding at 6 years exceeded that of recurrent vascular events (85 bleeding events [14.7%] vs 105 vascular events [12.9%]). Among patients treated with oral anticoagulants, the cumulative risk of bleeding exceeded the risk of recurrent vascular events at 5 years (22 bleeding events [24.0%] vs 19 vascular events [23.6%]).

In this cohort study, young stroke survivors receiving antithrombotic therapy were at substantial long-term risk of bleeding. Although bleeding and recurrent ischemic events may differ in their clinical consequences, these findings highlight that bleeding risk should be carefully considered throughout long-term antithrombotic therapy.

BackgroundLower extremity arterial disease (LEAD) remains a major cause of amputation, even after successful endovascular revascularization therapy (EVT). The prognostic associations of the pan-immune inflammatory value (PIV) and fibrinogen-to-albumin ratio (FAR) in LEAD remain unclear. This study investigated the associations of PIV and FAR with amputation risk and evaluated their incremental prognostic value beyond established clinical variables.MethodsIn this multicenter retrospective cohort study, 1,082 patients with LEAD who underwent EVT at four tertiary hospitals in Southwest China between January 2018 and July 2023 were analyzed. Restricted cubic spline (RCS) analyses and Cox proportional hazards regression models were used to evaluate the associations of PIV and FAR with amputation risk. Exploratory cut-off values were derived using receiver operating characteristic (ROC) curve analysis. The incremental prognostic value of adding PIV and FAR to clinical variables was assessed using time-dependent ROC analysis.ResultsDuring a median follow-up of 31 months, 198 (18.3%) patients experienced amputation. RCS revealed significant nonlinear associations of PIV and FAR with amputation risk (p for nonlinearity < 0.001). After multivariable adjustment, higher levels of both biomarkers remained independently associated with increased amputation risk (Z-PIV: HR = 1.379; Z-FAR: HR = 1.176; both p < 0.001). The addition of PIV and FAR to the clinical model enhanced time-dependent discrimination; the AUC(t) increased from 0.771 to 0.819 at 1 year, 0.766 to 0.806 at 2 years, and 0.762 to 0.807 at 3 years (all adjusted p < 0.001). Fine-Gray competing-risk analyses yielded consistent results after accounting for death as a competing event.ConclusionPIV and FAR were independently associated with amputation risk in patients with LEAD who underwent EVT. The addition of these biomarkers to established clinical variables provided incremental prognostic value and may offer additional prognostic information for risk stratification.

The MAPK-ERK1/2 pathway plays a crucial role in neurodevelopment during embryogenesis, and the hyperactivation of this signaling cascade serves as a pathological hallmark for various neurodevelopmental disorders. Germline variants in TRAF7, encoding a RING-type E3 ubiquitin ligase, are genetically associated with cardiac, facial, and digital anomalies with developmental delay (CAFDADD) syndrome; however, the downstream substrates of TRAF7 and the precise mechanism driving neurodevelopmental defects remain enigmatic. Here, we established a Traf7^R654Q/+ knock-in mouse model and patient-specific induced pluripotent stem cell (iPSC)-derived human cortical organoids (hCOs) carrying the recurrent TRAF7^R655Q mutation. Heterozygous Traf7^R654Q/+ mice exhibited remarkable growth retardation, skeletal abnormalities, and neurobehavioral deficits, whereas mutant hCOs displayed early cortical neurogenesis defects, characterized by premature neural differentiation and a depleted progenitor pool. Mechanistically, biochemical analyses revealed that TRAF7 interacts with KRAS and NRAS to promote their polyubiquitination and subsequent proteasomal degradation, maintaining physiological homeostatic control over the downstream MAPK cascade. CAFDADD-associated TRAF7 variants exert a dominant-negative effect, disrupting WT protein function and causing the posttranslational accumulation of KRAS and NRAS, which fundamentally drives constitutive MAPK-ERK1/2 pathway hyperactivation. Notably, pharmacological inhibition of MEK1/2 with selumetinib suppressed ERK1/2 hyperactivation, partially mitigated aberrant neuroepithelial morphology and neural differentiation in TRAF7^R655Q/+ hCOs, and improved brain-to-body weight ratios in Traf7^R654Q/+ mice. Together, our findings identify TRAF7 as a critical posttranslational regulator of RAS proteostasis during development and uncover a pivotal mechanistic link between impaired RAS ubiquitination and CAFDADD pathogenesis, providing preliminary clinical-front evidence for targeting the MAPK pathway to manage ongoing developmental deficits in TRAF7-associated disorders.

Acute myocardial infarction (AMI) is an increasing cause of morbidity and mortality in Sub-Saharan Africa (SSA) but is often underdiagnosed and undertreated. To address this gap, the Multicomponent Intervention to Improve Myocardial Infarction Care (MIMIC) was developed and implemented to improve evidence-based AMI care. The aim of this study was to explore stakeholder perceptions of the acceptability of MIMIC following its implementation.

This qualitative study involved in-depth interviews with 20 key stakeholders (physicians, nurses, administrators, and patients diagnosed with AMI) who participated in MIMIC during the first year of implementation in the emergency department (ED) of a regional referral center in northern Tanzania. Purposive sampling was used to recruit diverse participants. Interviews were guided by a semi-structured interview guide informed by the Theoretical Framework of Acceptability (TFA). Interview transcripts were thematically analyzed by a team of coders using an inductive, grounded theory approach guided by the seven TFA domains.

Nineteen major themes emerged across all TFA domains. Overall, participants described MIMIC as acceptable, minimally burdensome, and well-aligned with professional and ethical values. Perceived effectiveness was most emphasized, with staff citing improvements in AMI recognition, electrocardiogram (ECG) and troponin testing, and use of evidence-based therapies. Most components were described as effective and easily integrated into existing workflows. Patients valued the educational pamphlet for improving knowledge and self-efficacy, though staff expressed concerns about distributing it during acute care, contributing to inconsistent delivery. Champions were viewed as key in promoting adherence and sustaining implementation.

MIMIC was found to be acceptable in all seven TFA domains among ED providers and patients, with perceived effectiveness driving positive attitudes across stakeholder groups. MIMIC's co-design approach likely contributed to high intervention acceptability. Patient education strategies may require adaptation to improve fidelity. These findings support continued implementation and targeted adaptation of MIMIC.

Intracerebral hemorrhage (ICH), the most fatal stroke subtype, causes severe acute brain injury and frequent multiple-organ dysfunction, with renal impairment representing a common and severe complication. ICH patients are susceptible to secondary acute kidney injury (AKI), and many of those who progress to chronic kidney disease (CKD) or even end-stage renal disease. Although these adverse clinical outcomes are closely associated with the bidirectional brain-kidney axis, the precise molecular and pathological mechanisms underlying ICH-related AKI and subsequent CKD progression remain poorly elucidated. The AKI and CKD after ICH are mediated by multiple interconnected pathological mechanisms governed by the dysregulated brain-kidney axis, including sympathetic nervous system (SNS) overactivation, excessive stimulation of hypothalamic-pituitary-adrenal (HPA) axis and the renin-angiotensin-aldosterone system (RAAS), systemic inflammation, oxidative stress injury, and uremic toxin accumulation. These mediators fuel a bidirectional pathogenic cycle between the brain and kidney, while shared microvascular vulnerability as well as hemodynamic characteristics of both organs facilitate such inter-organ crosstalk. Brain-kidney axis dysfunction represents the core pathogenesis underlying ICH-induced secondary renal impairment. Clinical interventions should adopt a brain-kidney co-protection strategy, combining neuroprotective, renoprotection, and targeted pathway-based therapies.

There is a paucity of research on school-based health education and services for cardiometabolic conditions, particularly at the national level.

To describe the health education and health services related to cardiometabolic health provided by US public high schools.

This survey study included US public high schools who responded to the principal and lead health education teacher surveys as part of the School Health Profiles data collection in 2022. Data were analyzed between September 2025 and July 2026.

School-level characteristics included enrollment size, urbanicity, region, neighborhood income-to-poverty ratio, and racial and ethnic composition.

Primary outcomes were health education provided to students (and separately) to parents and families on chronic disease prevention, nutrition, and physical activity and provision of school-based health services. These services included identifying and tracking students with a current diagnosis of diabetes, hypertension, or obesity; providing referrals for those confirmed or suspected to have these cardiometabolic conditions; and providing a full- or a part-time registered nurse, a school-based health center, daily medication administration for students with chronic conditions, case management for students with chronic conditions, and an insurance protocol for students with chronic conditions.

A total of 3371 high schools were included in the principal survey (776 small, 1422 medium, and 1173 large) and 3044 high schools were included in the teacher survey (641 small, 1321 medium, and 1082 large). In 2022, 89.0% (95% CI, 87.4%-90.3%), 95.5% (95% CI, 94.3%-96.4%), and 98.1% (95% CI, 97.3%-98.7%) of schools provided health education on chronic disease prevention, nutrition, and physical activity, respectively, to students, while 43.5% (95% CI, 41.3%-45.7%), 50.9% (95% CI, 48.7%-53.1%), and 50.8% (95% CI, 48.6%-53.0%) provided information on chronic disease prevention, nutrition, and physical activity, respectively, to families. Schools tracked diabetes (96.3%; 95% CI, 95.5%-97.0%) more frequently than hypertension (64.9%; 95% CI, 63.0%-66.6%) and obesity (38.6%; 95% CI, 36.8%-40.4%); similarly, schools provided referrals for diabetes (52.1%; 95% CI, 50.3%-54.0%) more frequently than for hypertension (48.5%; 95% CI, 46.6%-50.4%) and obesity (41.6%; 95% CI, 39.8%-43.5%). Most schools reported having a full- or part-time registered nurse (90.9%; 95% CI, 89.8%-91.9%), but only 29.3% (95% CI, 27.7%-31.1%) reported having a school-based health center.

In this survey study of US public high schools, gaps in cardiometabolic health education and services were identified. These findings may inform future programs to improve cardiometabolic health among adolescents.

Cardiac aging increases susceptibility to cardiovascular diseases. Cellular senescence may be involved in the development of age-related cardiac diseases. Extensive evidence derived from both clinical and experimental studies suggest that the Type 2 Angiotensin II receptor (AT2R) exerts a potent cardioprotective effect, however, its potential contribution to age-related cardiac complications remains unknown. In this study we used AT2R knockout (AT2-KO) and wild-type mice (WT) both aged (18-21-month-old) and young (4-5-month-old) and evaluated the repercussions cardiac of aging. Old AT2-KO mice exhibited impaired systolic and diastolic cardiac function and exacerbated fibrosis accompanied by increased fibrotic markers expression. The absence of AT2R accelerated the cardiac senescence process in old mice, evidenced by early increase in p53 and p21. In addition, aged AT2-KO mice showed increased expression of Senescence-Associated Secretory Phenotype (SASP) components, activation of cardiac NF-kB and NLRP3-inflammasome followed by increased levels of cardiac IL-1β and IL-18 compared to aged WT mice. AT2R deficiency also resulted in significant DNA damage even in young animals and it was associated with a 5-month reduction in median lifespan (26 months for AT2R-KO vs. 31 months for WT). These findings suggest potential mechanisms whereby AT2R acts as a key mediator of cardiac senescence and cardioprotection during aging.

Prediabetes is a major international problem that confers an increased risk for T2DM and CVD. There is scantly data on the role of cellular inflammatory pathways in prediabetes. We investigated the relationship between prediabetes and cellular biomarkers of inflammation.

This study included patients with prediabetes (n=47) and controls (n=55). Fasting blood samples were obtained for circulating biomarkers and monocyte isolation. Also subcutaneous adipose tissue biopsies were performed in a subgroup.

Circulating biomarkers of inflammation were increased with prediabetes even following age adjustment. In monocytes there was a significant increase in TLR2 and its downstream signaling pathways including NFkB and P38 MAPkinase activity. In adipose tissue NLRP-3 inflammasome activity quantified by caspase1 was significantly increased whilst there was a trend to significance for IL-1beta. Also mast cells in AT were significantly increased.

In patients with prediabetes we present novel data supporting increased cellular pathways of inflammation in both monocytes and adipose tissue further underscoring the pro-inflammatory state of prediabetes as an important potential mechanism for the increase risk for T2DM and CVD.