Potassium-competitive acid blockers (P-CABs) are newly introduced gastrointestinal protectants, but their interaction with clopidogrel remains uncharacterized. Proton pump inhibitors (PPIs) are often coprescribed with clopidogrel, despite potential pharmacodynamic interactions. This study evaluated the effectiveness and safety of P-CAB and PPI coadministered with clopidogrel in patients with ischemic stroke. This population-based, longitudinal, retrospective cohort study used the Korean National Health Insurance Service database, covering 51.4 million individuals (≈97% of the Korean population) from 2016 to 2022. Patients with incident ischemic stroke were identified using predefined criteria. Propensity score matching compared the 6-month incidence of major adverse cardiovascular events (including myocardial infarction, stroke recurrence, and all-cause mortality) and gastrointestinal bleeding among 3 cohorts: clopidogrel alone, clopidogrel+P-CAB, and clopidogrel+PPI. Between 2017 and 2021, 40 752 of 65 180 patients with incident stroke (62.5%) received clopidogrel. A total of 6680 patients (16.4%) formed the clopidogrel-alone cohort, 578 (1.4%) the clopidogrel+P-CAB cohort, and 8806 (21.6%) the clopidogrel+PPI cohort. During the follow-up period, stroke recurred in 268 patients (4.0%) receiving clopidogrel alone, 26 patients (4.5%) receiving clopidogrel+P-CAB, and 431 patients (4.9%) receiving clopidogrel+PPI. After propensity score matching, the clopidogrel+P-CAB cohort showed a higher risk of major adverse cardiovascular events (hazard ratio [HR], 2.40 [95% CI, 1.18-4.85]) and stroke recurrence (HR, 2.64 [95% CI, 1.27-5.47]) than the clopidogrel-alone cohort. The clopidogrel+PPI cohort also had an increased risk of major adverse cardiovascular events (HR, 1.38 [95% CI, 1.17-1.63]) and stroke recurrence (HR, 1.41 [95% CI, 1.20-1.67]) relative to clopidogrel alone. Among PPIs, esomeprazole was associated with a higher risk of major adverse cardiovascular events (HR, 1.46 [95% CI, 1.10-1.92]) and stroke recurrence (HR, 1.50 [95% CI, 1.13-2.00]). Gastrointestinal bleeding did not differ significantly among the clopidogrel-alone, clopidogrel+P-CAB, and clopidogrel+PPI cohorts. Concomitant use of P-CABs or PPIs with clopidogrel was associated with an increased risk of ischemic events in patients with stroke. P-CABs or PPIs should, therefore, be prescribed cautiously for patients with stroke treated with clopidogrel.

Adverse pregnancy outcomes are linked to increased risk of maternal cardiovascular disease. However, the association between preterm delivery (PTD) and long-term risk of stroke in the mother remains uncertain, particularly in the case of spontaneous PTD. A systematic review and meta-analysis were performed to provide an up-to-date synthesis of the evidence on the association between PTD and long-term maternal stroke. PubMed, CINAHL, and Web of Science were searched for relevant articles published between January 1, 2000, and May 6, 2025. Eligible studies included cohort and case-control studies examining populations of parous women. Primary exposure was defined as any PTD; secondary exposures were spontaneous PTD and medically indicated PTD. The primary outcome was defined as any stroke; secondary outcomes were ischemic and hemorrhagic stroke. Two reviewers screened studies, extracted data, and performed quality assessments. Pooled unadjusted and adjusted effect estimates (as defined by the original study) were calculated separately using random effects inverse variance models. Eleven thousand twenty-five studies were screened for eligibility. Across 21 studies including a total of 8.7 million participants, PTD was consistently associated with increased stroke risk. The follow-up period ranged from 8 to 57 years. The primary meta-analysis demonstrated a positive association between any PTD and any stroke (adjusted risk ratio [aRR], 1.66 [95% CI, 1.34-2.05]). A high level of heterogeneity was observed (I2=97%, τ2=0.15), possibly due to variations in exposure definition, outcome ascertainment, and follow-up durations. Spontaneous PTD (aRR, 1.37 [95% CI, 1.15-1.64]) and medically indicated PTD (aRR, 2.08 [95% CI, 1.70-2.54]) were associated with any stroke. PTD was positively associated with ischemic (aRR, 1.59 [95% CI, 1.45-1.75]) and hemorrhagic stroke (aRR, 1.44 [95% CI, 1.06-1.94]). Women who have experienced a PTD, including spontaneous PTD, may be at increased risk of stroke in later life. These women may benefit from targeted cardio-metabolic preventive interventions postpartum to reduce their risk.

Moyamoya disease (MMD) has a strong genetic basis, with the rare RNF213 p.Arg4810Lys variant (rs112735431) representing a major risk factor, while the broader genetic architecture and disease-relevant vascular cell types remain incompletely understood. We conducted a genome-wide association study in Japanese individuals (n=47 656; 401 MMD cases and 47 255 controls). Population-level features at MMD risk loci were examined by regional allele frequency and haplotype analyses. We performed single-nucleus RNA-seq of superficial temporal arteries from patients with MMD (n=3). Cell type-specific enrichment of genome-wide association study signals was assessed using the Single-Cell Disease Relevance Score. Endothelial signatures were validated by integration with publicly available single-cell data sets from controls (n=5) and immunohistochemistry for candidate markers (n=1). Beyond rs112735431, we identified a genome-wide significant signal in the HDAC9-TWIST1 region (rs12530920; P=3.3×10-14; odds ratio, 1.77). Conditional analysis on rs112735431 revealed a protective RNF213 missense variant, p.Asp1331Gly (rs8074015; P=3.7×10-9; odds ratio, 0.53), whose minor allele was mutually exclusive with rs112735431-A on haplotypes. Population analysis revealed geographic variation and extended haplotype structure of the rs112735431-A allele in Japan. Single-nucleus RNA-seq identified a mesenchymal-like endothelial cell (MEC) population with selective FN1 expression. Genome-wide association study-prioritized disease genes were strongly enriched in MECs. MECs showed mesenchymal pathway activation with a regulatory program distinct from canonical endothelial states. The proportion of MECs was markedly increased in MMD (72% versus 28% in controls), and fibronectin 1 (FN1) expression in endothelial regions was confirmed by immunohistochemistry. Our findings identify a protective RNF213 p.Asp1331Gly variant (rs8074015) that is mutually exclusive with the known rs112735431-A allele. Genetic risk converges on an MEC state markedly expanded in MMD.

Anxiety and depression are common neuropsychiatric sequelae after subarachnoid hemorrhage (SAH), yet the underlying neural mechanisms remain poorly understood. The CRF (corticotropin-releasing factor) system in the medial prefrontal cortex (mPFC) is critical for emotional regulation and stress adaptation; however, its involvement in SAH-induced affective disorders has not been defined. SAH was induced by endovascular perforation. Anxiety and depressive-like behaviors and mPFC electrophysiological activity were assessed using behavioral paradigms and in vivo recordings. Functional alterations of mPFC CRF neurons were evaluated by immunohistochemistry, fiber photometry, and patch-clamp recordings. Chemogenetic and optogenetic approaches were used to selectively manipulate CRF neurons. Neuronal tracing, pathway-specific optogenetics, and adeno-associated virus-mediated ablation of mPFC CRF neurons were used to dissect circuit mechanisms. Proteomics, immunogold electron microscopy, immunohistochemistry, and adeno-associated virus-based modulation of SYT (synaptotagmin) 9 were performed to investigate molecular contributors to mPFC CRF neuron dysfunction. SAH induced pronounced anxiety and depressive-like behaviors. mPFC CRF neurons exhibited structural disruptions, reduced calcium dynamics, and impaired excitatory synaptic transmission after SAH. Chemogenetic or optogenetic activation of mPFC CRF neurons ameliorated these behavioral deficits, whereas local CRF supplementation in the mPFC was ineffective. Approximately 35% of mPFC CRF neurons received basolateral amygdala inputs, and optogenetic activation of the basolateral amygdala→mPFC pathway improved behavioral outcomes; these effects were abolished by CRF neuron ablation. Proteomic analysis identified SYT9 as one of the most significantly downregulated proteins, predominantly enriched in CRF neurons. SYT9 overexpression restored CRF neuron activity and mitigated SAH-induced behavioral abnormalities. Dysfunction of mPFC CRF neurons is a key contributor to anxiety and depression after SAH. Basolateral amygdala inputs modulate mPFC CRF neuron activity, and SYT9 downregulation represents a critical molecular mechanism underlying their impairment. These findings identify mPFC CRF neuronal dysfunction as a core pathological feature of SAH-induced affective disorders and provide mechanistic insight into potential therapeutic targets.

Reading impairments are common in stroke-induced aphasia and limit participation in functional and leisure activities. Traditional rehabilitation strategies show limited generalization, underscoring the need for novel interventions targeting residual neural networks. This feasibility randomized controlled trial evaluated real-time functional magnetic resonance imaging (fMRI) neurofeedback intervention for poststroke reading deficits. Subacute left-hemisphere stroke survivors and healthy controls completed 3 weekly fMRI neurofeedback and 10 out-of-scanner practice sessions. Stroke participants were randomized to contingent neurofeedback (based on left supramarginal gyrus activity; N=4) or noncontingent neurofeedback (shuffled feedback from another participant; N=3). Healthy controls (N=4) received contingent neurofeedback and served as a normative reference. Primary outcomes were changes from baseline to postintervention (≈3 weeks) in task-based brain activity (motor imagery/word/nonword reading>baseline), resting-state connectivity, and reading aloud. Reading comprehension was a secondary outcome. Group×session effects were tested using repeated-measures analyses and planned contrasts. Task fMRI revealed training-related activation increases in the left supramarginal gyrus (z=4.7; cluster-corrected P=0.05) and broader reading network in the contingent neurofeedback group, particularly during nonword reading. Activation increases in the noncontingent stroke group and healthy controls were more widespread and less reading-specific. Resting-state fMRI revealed greater integration among motor, auditory, and language networks in the contingent groups, with more disorganized patterns in the noncontingent group (permutation P=0.01; Δr=-0.1 to 0.1). No changes were observed in reading aloud. A significant group×session interaction was found for Reading Comprehension Battery for Aphasia, second edition (F[2, 8]=8.00; P<0.05; η2=0.67). The contingent neurofeedback stroke group improved more than healthy controls (mean difference in Reading Comprehension Battery for Aphasia, second edition, change=9.75 [95% CI, 1.99-17.51]; t[6]=3.07; P<0.05) and noncontingent neurofeedback stroke group (Reading Comprehension Battery for Aphasia, second edition, change=11.42 [95% CI, 1.12-21.71]; t[5]=2.85; P<0.05). These findings support the feasibility of targeting the residual reading network during early recovery using fMRI neurofeedback. Confirmation of these preliminary effects awaits completion of the ongoing randomized controlled trial. URL: https://www.clinicaltrials.gov; Unique identifier: NCT04875936.

Tenecteplase improves reperfusion and functional outcomes compared with alteplase in patients with large vessel occlusion. We assessed whether this superiority varies with thrombolysis-to-puncture time (TTP). This retrospective analysis of a prospective multicenter cohort included patients with large vessel occlusion who received bridging therapy with either tenecteplase or alteplase between January 2022 and September 2025. Patients were stratified by TTP (<60 versus ≥60 minutes). We subsequently assessed the association of TTP with efficacy and safety outcomes between the alteplase and tenecteplase groups using multivariable logistic regression adjusted for age, baseline National Institutes of Health Stroke Scale score, and time from stroke onset to arterial puncture. Functional independence was defined as a modified Rankin Scale score of 0 to 2 at 3 months. Of 1106 patients who received bridging therapy, 1003 were included in the primary analysis (tenecteplase, 488; alteplase, 515). The median age was 68 (interquartile range, 58-75) years in both groups, with males comprising 64.3% and 66.0%, respectively. Tenecteplase was associated with superior 3-month functional independence compared with alteplase (53.6% versus 48.1%; adjusted odds ratio, 1.37 [95% CI, 1.03-1.82]). This benefit was concentrated in patients with a TTP <60 minutes, where tenecteplase yielded higher rates of both early recanalization (19.0% versus 9.1%; adjusted odds ratio, 2.36 [95% CI, 1.32-4.23]; Pinteraction=0.047) and functional independence (61.0% versus 49.0%; adjusted odds ratio, 1.77 [95% CI, 1.13-2.77]; Pinteraction=0.111). No between-agent differences were significant with TTP ≥60 minutes. Safety outcomes were comparable, but each 30-minute TTP increase independently elevated hemorrhagic risks for both agents. The recanalization superiority of tenecteplase over alteplase is time-dependent, evident only within a TTP <60 minutes. Although the translation of this advantage into functional outcome was not statistically modified by time, optimizing workflow to achieve this rapid window maximizes the potential benefit of tenecteplase, which should be prioritized in capable settings.

Cerebral infarction is a frequent and serious complication of tuberculous meningitis (TBM), contributing substantially to morbidity and mortality. Moreover, studies on infarct patterns and associated factors/predictors remain limited in TBM. ACT-TBM trial (Aspirin or Clopidogrel Therapy in the Treatment of Tuberculous Meningitis) evaluated the efficacy and safety of adjunctive antiplatelet therapy (aspirin or clopidogrel) to standard antitubercular therapy in TBM for the occurrence of stroke or cerebral infarction. Here, we conducted a secondary analysis of the ACT-TBM trial to characterize the patterns, associated factors, and predictors of cerebral infarction in TBM. We utilized data of 237 patients from the ACT-TBM randomized controlled trial conducted at 2 tertiary centers in India (2019-2023). Serial magnetic resonance imaging and magnetic resonance angiography were performed at baseline, 1 month, and 3 months in the primary trial. Cerebral infarctions were categorized by size, vascular territory, and number. Multivariable logistic regression models were performed using variables with P<0.1 on univariable analysis and clinical relevance. Model estimates are reported as adjusted odds ratios (aORs) with 95% CIs. Of the 237 patients enrolled, 226 were included after excluding 11 with missing imaging or incomplete follow-up data. Among these, 84 (37%) had cerebral infarction. Median age of the entire cohort was 26 years (interquartile range, 20-36), and 134 (59.29%) were females. Multiple infarcts were observed in 66 (78.6%) patients. Most frequent location of infarction was in the basal ganglia (n=61, 72.6%), subcortical white matter (n=44, 52.4%), and cortex (n=32, 38.1%). Arterial occlusion occurred in 49 (61.25%) patients with cerebral infarction versus 35 (25.55%) without (P<0.001). In multivariable adjusted models, Grade 3 TBM (aOR, 3.94 [95% CI, 1.19-13.08]; P=0.025), and arterial occlusion (aOR, 4.43 [95% CI, 2.19-8.96]; P<0.001) were associated with infarction. Among those with infarction, 27 (32.14%) patients (13.17% of the available cohort) developed new infarctions on follow-up. Modified antitubercular therapy (antitubercular therapy; aOR, 3.10 [95% CI, 1.18-8.09]; P=0.021) and arterial occlusion (aOR, 4.23 [95% CI, 1.40-12.75]; P=0.01) significantly predicted new infarctions. Presence of exudates was associated with arterial occlusion (aOR, 2.86 [95% CI, 1.08-7.56]; P=0.034). Cerebral infarction is common in TBM and associated with disease severity and arterial occlusion. Modified antitubercular therapy predicted new infarcts, while basal exudates were associated with vascular occlusion, highlighting the need for vigilant monitoring and optimized therapeutic strategies.