Knowledge and attitude towards stroke and prehospital delay among patients and their family members under high prehospital delay in Zhejiang, China: a cross-sectional study

Objectives
To investigate the knowledge of stroke and the attitudes towards stroke and prehospital delay among patients who had an acute ischaemic stroke (AIS) and their family members.

Design
This cross-sectional study was conducted through a self-designed questionnaire.

Setting
The study took place in a Grade-A tertiary hospital in Zhejiang Province, China, between July 2023 and November 2023.

Participants
A total of 521 valid questionnaires were collected from 367 patients who had an AIS and 154 family members.

Interventions
Participants provided demographic information and answered questions related to stroke knowledge, attitudes towards stroke and prehospital delay.

Primary and secondary outcome measures
The primary outcome measures included scores on stroke knowledge, attitudes towards stroke and attitudes towards prehospital delay. Secondary outcomes focused on identifying correlations and independent factors influencing prehospital delay.

Results
The average scores for patients were stroke knowledge 8.74±6.16 (range: 0–24), stroke attitude 23.52±2.73 (range: 7–35) and prehospital delay attitude 38.65±7.68 (range: 10–50). Family members scored 12.66±6.85, 23.60±2.57 and 40.02±7.45, respectively. Significant correlations were found between stroke knowledge and attitude (r=0.2262, p

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Feasibility randomised controlled trial to assess the delivery of a novel isometric exercise intervention for people diagnosed with uncomplicated stage 1 hypertension in the National Health Service: key quantitative findings

Objectives
The aim of this study was to determine the feasibility of delivering personalised isometric exercise (IE) for people with stage 1 hypertension. Is it feasible to deliver an isometric wall squat intervention in the National Health Service and what sample size is required to conduct an appropriately powered effectiveness randomised controlled trial (RCT)?

Design
Randomised controlled open-label multicentre feasibility study of IE compared with standard care in unmedicated people with stage 1 hypertension.

Setting
Initially, the study aimed to recruit through primary care, but this process coincided with the advent of the COVID-19 pandemic. Therefore, we shifted focus to direct-to-public advertising and delivery in secondary care.

Participants
People with unmedicated stage 1 hypertension aged over 18 able to perform IE were included. Patients were excluded if average home systolic blood pressure (sBP)

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Risk of Intracranial Hemorrhage With Apixaban Versus Aspirin Therapy: A Meta-Analysis of Randomized Controlled Trials

Stroke, Ahead of Print. BACKGROUND:Oral anticoagulants are superior to antiplatelet agents for preventing cardioembolic stroke but concerns about increased risk of intracranial hemorrhage limit their use. Although rivaroxaban demonstrably increases intracranial bleeding risk compared with aspirin, the comparative risk of intracranial hemorrhage with apixaban versus aspirin remains uncertain. We aimed to clarify this risk through a meta-analysis of randomized controlled trials.METHODS:We searched PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for randomized controlled trials comparing apixaban with aspirin for ischemic stroke prevention. Studies were excluded if no intracranial hemorrhage events were reported in either arm. In the primary analysis, we used the Mantel-Haenszel method to meta-analyze the relative risk of intracranial hemorrhage with apixaban versus aspirin therapy. We conducted sensitivity analyses to examine the strength of these findings and to examine the secondary outcome of hemorrhagic stroke (which excludes epidural and subdural hematomas).RESULTS:Three randomized controlled trials met our inclusion criteria, comprising a total of 10 626 patients and 74 incident intracranial hemorrhage events. In the pooled analysis, the relative risk of intracranial hemorrhage with apixaban versus aspirin therapy was 0.67 ([95% CI, 0.43–1.08];P=0.10). These findings were consistent in sensitivity analyses utilizing alternative statistical estimators, in analyses limited to primary prevention trials, and in analyses utilizing the outcome of hemorrhagic stroke (relative risk, 0.72 [95% CI, 0.39–1.31];P=0.28).CONCLUSIONS:In randomized controlled trials evaluating ischemic stroke prevention, apixaban demonstrated a safety profile comparable—and potentially superior—to aspirin with respect to intracranial hemorrhage risk. These findings warrant a reconsideration of clinical practices that favor aspirin over apixaban, because of the concerns about intracranial hemorrhage risk.

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Targeted Screening of Unruptured Intracranial Aneurysms in Female Smokers: Inconsiderate Overdiagnosis or Chance for Better Health?

Stroke, Ahead of Print. BACKGROUND:Aneurysmal subarachnoid hemorrhage (aSAH) causes a substantial proportion of all deaths among middle-aged people, especially women. Because female smokers in particular have a high risk of aSAH and subarachnoid hemorrhage deaths, targeted screening of 50- to 60-year-old female smokers could be justified as a preventive action to reduce premature deaths and morbidity.METHODS:This prospective screening study has been performed at Helsinki University Hospital in the Department of Neurosurgery in 2 phases during 2020 and 2023 to 2024. To minimize recruitment bias, the Helsinki Biobank and THL Biobank were responsible for sending out preliminary invitation letters to self-caring 50- to 60-year-old women (mean, 56 years) who were known to be active smokers. We informed the potential candidates about the study and answered any questions before their decision to participate. Once written consent was provided, participants filled in a detailed questionnaire on lifestyle and health, and underwent computed tomography angiography analysis. We studied the prevalence of unruptured intracranial aneurysms among the study participants. Moreover, we assessed immediate morbidity, mortality, and costs related to screening.RESULTS:Of the 458 preliminary invitation letters, 160 potential participants initially replied. Of these, 116 returned questionnaires and written consents. Ultimately, 108 smoking women underwent computed tomography angiography imaging. Eleven unruptured intracranial aneurysms were found in 11 (10%) female smokers, 1 of which was intracavernous and extradural. Two women were operated on without complications—1 with a middle cerebral artery aneurysm and 1 with a posterior communicating artery aneurysm. Most (n=8) patients with small (

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Burden of Cardiovascular Outcomes After SARS-CoV-2 Infection in South Korea and Japan: A Binational Population-Based Cohort Study

Circulation, Ahead of Print. BACKGROUND:Despite the significant global impact of the COVID-19 pandemic, limited studies have investigated the long-term cardiovascular sequelae of SARS-CoV-2 infection, particularly among Asian populations. This large-scale, population-based binational cohort study with long-term follow-up aimed to investigate the association between SARS-CoV-2 infection and the risk of cardiovascular events.METHODS:We used binational, large-scale, and population-based cohorts, including a Korean nationwide cohort (K-COV-N; discovery cohort; n=18 989 129) and a Japanese nationwide cohort (Japan Medical Data Center; validation cohort; n=12 218 680). Individuals aged 20 years or older were included from January 1, 2020, to December 31, 2022. We assessed the long-term risk of incident cardiovascular outcomes after SARS-CoV-2 infection. The primary outcome was the risk of cardiovascular diseases based onInternational Classification of Diseases, Tenth Revisioncode diagnosis. After propensity score–based overlap weighting, Cox proportional hazard models were used to estimate adjusted hazard ratios for cardiovascular outcomes. We assessed the time attenuation effect of cardiovascular outcomes after SARS-CoV-2 infection. Multiple subgroup analyses were conducted by 16 cardiovascular outcomes, COVID-19 severity, vaccination, and SARS-CoV-2 strain.RESULTS:In the overlap-weighted discovery cohort, 7 960 357 individuals were included (mean age, 48.52 years [SD, 9.33]; men, 4 283 878 [53.82%]). SARS-CoV-2 infection was associated with a long-term increased risk of overall cardiovascular outcomes (adjusted hazard ratio, 1.62 [95% CI, 1.60–1.64]), particularly ischemic heart disease (1.81 [95% CI, 1.77–1.84]), heart failure (1.79 [95% CI, 1.73–1.85]), cerebrovascular disorders (1.65 [95% CI, 1.60–1.69]), major adverse cardiovascular events (1.65 [95% CI, 1.60–1.70]), inflammatory heart diseases (1.53 [95% CI, 1.31–1.80]), dysrhythmia (1.44 [95% CI, 1.42–1.46]), and thrombotic disorders (1.42 [95% CI, 1.35–1.48]). The increased risk persisted up to 18 months, with the highest association observed for 1 to 6 months after infection. The risk of cardiovascular diseases was pronounced with COVID-19 severity; however, it decreased with the administration of complete vaccination and subsequent booster doses. A similar risk of cardiovascular outcomes existed across every SARS-CoV-2 era (pre-delta, delta, and omicron). Similar patterns were observed in the validation cohort. The absolute risk of cardiovascular disease events after SARS-CoV-2 infection remained remarkably low (2.12% versus 1.31% in the noninfected population), particularly stroke (0.24% versus 0.13%) and ischemic heart disease (0.73% versus 0.39%).CONCLUSIONS:This binational study observed associations between SARS-CoV-2 infection and cardiovascular events during extended follow-up across viral eras. Complete vaccination was linked to lower cardiovascular events. However, the absolute risk of cardiovascular disease events after SARS-CoV-2 infection remained remarkably low, particularly for stroke and ischemic heart disease. Although these findings suggest ongoing vigilance and preventive measures remain crucial, they should be interpreted within the context of these low absolute risks when considering long-term cardiovascular complications.

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SEW2871 Attenuates Blood-Brain Barrier Damage and Neuropathological Outcomes Related to Cerebral Small Vessel Disease

Stroke, Ahead of Print. BACKGROUND:Blood-brain barrier (BBB) dysfunction contributes to the pathogenesis of cerebral small vessel disease. This study assessed SEW2871, a selective agonist of sphingosine-1-phosphate receptor 1, as a potential novel therapy for small vessel disease by targeting BBB damage using a rat model of small vessel disease.METHODS:Twelve-week male and female spontaneously hypertensive rat stroke-prones were subjected to unilateral carotid artery occlusion (UCAO) and Japanese permissive diet (JPD). Three doses of SEW2871 (0.5, 1.0, and 5.0 mg/kg, delivered every other day up to 5 weeks) were tested. Dynamic body weight, oxygen saturation, and SEW2871 plasma concentration were evaluated. BBB permeability, white and gray matter lesions (white matter lesions and gray matter lesions), and cerebral blood flow (CBF) were assessed with preclinical magnetic resonance imaging at 2 and 5 weeks after UCAO/JPD onset. Cognitive outcomes were evaluated using Morris Water Maze during week 5 of UCAO/JPD.RESULTS:We found that SEW2871 delayed the occurrence of UCAO/JPD-induced chronic hypoxic hypoperfusion in the spontaneously hypertensive rat stroke-prones. Magnetic resonance imaging showed increased BBB permeability, white matter lesions and gray matter lesions, and decreased CBF at 2 and 5 weeks after UCAO/JPD onset. T2-weighted and fractional anisotropy magnetic resonance imaging showed that all doses of SEW2871 demonstrated a protective effect on white matter lesions and gray matter lesions with the most significant improvements in the 1.0 mg/kg group. Dynamic contrast-enhanced magnetic resonance imaging and arterial spin labeling maps showed significantly reduced BBB leakage and improved CBF in 0.5 and 1.0 mg/kg groups. Immunohistochemical analysis for serum IgG extravasation and microglia/macrophage activation in rat brains verified the protective effects of SEW2871 on BBB leakage and neuroinflammation. Morris Water Maze test revealed a significant improvement in spatial memory in 0.5 and 1.0 mg/kg groups compared with the vehicle animals.CONCLUSIONS:Long-term treatment with SEW2871 mitigated BBB leakage and brain injury, improved CBF and cognitive impairment in the spontaneously hypertensive rat stroke-prone model of small vessel disease. SEW2871 is effective at all doses, while the 1.0 mg/kg dose demonstrated exceptional protection against the neuropathological cascades associated with small vessel disease.

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Interventional effects of modified constraint-induced movement therapy on upper limb function in patients who had a stroke: systematic review and meta-analysis

Objectives
To systematically evaluate the intervention effect of modified constraint-induced movement therapy (m-CIMT) on upper limb function in patients who had a stroke.

Design
Systematic review and meta-analysis.

Data sources
A computer-based search was conducted in PubMed, Cochrane Library, Embase, Web of Science and China National Knowledge Infrastructure for randomised controlled trials (RCTs) on the intervention effect of m-CIMT on upper limb function in patients who had a stroke, with the search conducted up until 23 May 2024.

Eligibility criteria
We included only RCTs in which patients who had a stroke performed m-CIMT or m-CIMT in addition to the control group, and the outcome was upper limb function.

Data extraction and synthesis
Data extraction and synthesis used the reporting checklist for systematic review based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The risk of bias and methodological quality of included studies were evaluated by two independent investigators under the guidance of Cochrane risk of bias. Effect sizes were pooled, funnel plots were created and subgroup analyses were conducted using Stata V.17.0. If I² >50%, a random-effects model was applied; otherwise, a fixed-effects model was used. Publication bias was assessed through funnel plots and Egger’s test. In the presence of publication bias, a trim-and-fill method was employed for further examination. The quality of evidence was evaluated using GRADEpro.

Results
A total of 16 studies including 612 patients were included. Rehabilitation outcomes were assessed using the Fugl–Meyer Assessment (I²=90.34%), Motor Activity Log—Quality of Movement (I²=36.02%), Motor Activity Log—Amount of Use (I²=65.76%), Action Research Arm Test (I²=62.66%) and the Wolf Motor Function Test (I²=36.78%). Low-level evidence suggests that m-CIMT improves upper limb function in patients who had a stroke (all p2 months’ (p=0.005). Intervention periods of ‘2–4 weeks’ (p=0.008) and ‘5–12 weeks’ (p

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Network Meta-Analysis of 4 Rehabilitation Methods With rTMS on Upper Limb Function and Daily Activities in Patients With Stroke

Stroke, Ahead of Print. BACKGROUND:Stroke is one of the leading causes of disability and death worldwide, often leading to physical paralysis and cognitive dysfunction, seriously affecting patients’ quality of life, and increasing economic burden. Repetitive transcranial magnetic stimulation (rTMS), a noninvasive brain stimulation technique, has been used in stroke rehabilitation, but the difference in efficacy among rehabilitation methods combined with rTMS is unclear. In this study, we compared the effects of 4 rehabilitation methods, namely, clinical routine rehabilitation therapy, smart rehabilitation therapy, behavioral rehabilitation therapy, and Chinese traditional rehabilitation therapy (CTRT) combined with rTMS on the upper limb function and activities of daily living of patients with stroke through a reticulated meta-analysis, which provided a basis for clinical optimization of rehabilitation strategies.METHODS:Six databases, namely, PubMed, Embase, Web of Science, Cochrane, EBSCO, and China National Knowledge Infrastructure, were systematically searched, and 24 randomized controlled trials with a total of 868 patients with stroke were finally included. The primary outcome indicators were upper limb Fugl-Meyer assessment and activities of daily living (Barthel index, modified Barthel index, and functional independence measure were included). Network meta-analysis was performed using Stata 17.0 to assess the relative effect of each combined intervention and examine the consistency of direct and indirect evidence.RESULTS:In this study, a total of 24 randomized controlled trials involving 868 patients with stroke were included. CTRT combined with rTMS had the most significant upper limb Fugl-Meyer assessment improvement CTRT (standardized mean difference [SMD], 1.23 [95% CI, 0.95–1.52];P

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Changes in 3D Chromatin Organization Drive Topologically Determined Gene Expression in the Poststroke Mouse Cortex

Stroke, Ahead of Print. BACKGROUND:Recent advances in high-throughput transcriptomics have revealed extensive gene expression changes during cerebral ischemia. However, the changes in 3-dimensional chromatin architecture and long-range chromatin looping between genes and distal regulatory elements that drive these gene expression changes remain virtually unexplored. In this study, we map the landscape of the dynamic alterations in topologically associated domains and chromatin loops in the ischemic cortex and evaluate their contributions to poststroke transcriptional changes.METHODS:We used genome-wide chromatin conformation capture (Hi-C) to profile changes in the 3-dimensional chromatin architecture in the cerebral cortex of adult mice following a 1-hour middle cerebral artery occlusion and 6 hours of reperfusion or sham treatment. We conducted RNA sequencing to identify the differentially expressed genes that are concomitantly altered in association with the stroke-induced topologically associated domains and loops.RESULTS:We identified 293 altered topologically associated domains following stroke, harboring a total of 60 upregulated differentially expressed genes and 106 downregulated differentially expressed genes. Chromatin looping analysis identified 4323 differentially altered loops in response to stroke, of which 1583 had enriched interactions and 2741 had diminished interactions. These loci included previously unknown enhancer and silencer elements, which were linked to a total of 88 upregulated and 96 downregulated genes. Upregulated genes associated with altered topologically associated domains and loops were linked to endothelial and immune cell functions, suggesting a role for dynamic chromatin remodeling in the poststroke cerebrovascular and neuroimmune response. Conversely, downregulated genes were associated with neuronal and synaptic functions, suggesting a role in poststroke neuronal fate.CONCLUSIONS:This study is the first to map changes in the 3-dimensional chromatin of the adult cerebral cortex following ischemic stroke. Our findings reveal novel regulatory elements directly associated with stroke-altered genes that may be involved in the regulation of these genes via dynamic changes in chromatin architecture and looping characteristics to fine-tune their expression.

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Perioperative Stroke: Mechanisms, Risk Stratification, and Management

Stroke, Ahead of Print. Perioperative stroke, defined as a cerebrovascular event occurring during surgery or within 30 days postoperatively, remains a devastating complication associated with substantial morbidity, disability, mortality, and increased healthcare utilization. Although overall incidence is relatively low—up to 1% in most surgical populations—it is significantly elevated in cardiac, major vascular, and neurosurgical procedures, often exceeding 5%. The rising prevalence of perioperative stroke, primarily driven by an aging surgical population burdened by multiple chronic vascular conditions and increasingly eligible for high-risk surgical interventions, underscores the urgency of optimizing preventive and management strategies. This review synthesizes insights into patient- and procedure-related risk factors, highlighting the intricate interplay of embolic, thrombotic, and hypoperfusion mechanisms underpinning perioperative ischemic strokes. Key patient-specific risks include advanced age, recent cerebrovascular events, atrial fibrillation, carotid stenosis, and chronic cardiovascular comorbidities. Procedural factors, such as the type and complexity of surgery, intraoperative hypotension, and vascular manipulations, further modulate stroke risk. Emphasizing an evidence-based approach to risk mitigation, this review examines preoperative risk stratification, intraoperative techniques designed to minimize cerebral embolization and preserve adequate perfusion, and structured postoperative protocols aimed at rapid stroke detection. Acute management complexities are also discussed, with careful consideration of intravenous thrombolysis and mechanical thrombectomy in the postoperative setting. Finally, gaps in current guidelines and promising areas for future research are identified, advocating a multidisciplinary approach involving neurology, surgery, anesthesiology, and allied specialties to enhance patient outcomes and reduce the perioperative stroke burden.

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Validation and Feasibility of PETS-Stroke: A Patient-Reported Measure of Treatment Burden After Stroke

Stroke, Ahead of Print. BACKGROUND:Treatment burden is the workload of health care for people with long-term conditions and the impact on wellbeing. A validated measure of treatment burden for use as an outcome measure in stroke trials is needed. We adapted a patient-reported measure of treatment burden in multimorbidity, Patient Experience With Treatment and Self-Management (PETS), version 2.0, to create a stroke-specific measure, PETS-stroke, and examined its psychometric properties.METHODS:We conducted an observational cohort study. Stroke and transient ischemic attack survivors were recruited between February 2022 to June 2023 from 10 hospitals in the United Kingdom and through the Scottish Health Research Register. Participants completed the PETS-stroke questionnaire along with 3 other patient-reported measures (the Stroke Southampton Self-Management Questionnaire, the Satisfaction With Stroke Care Measure, and the Shortened Stroke Impact Scale). We performed confirmatory factor analysis to test the factor structure of the PETS-stroke. We assessed Spearman rank correlations between PETS-stroke and other patient-reported measures to determine convergent validity. An intraclass correlation coefficient was performed to assess test-retest reliability. Proportions of missing data along with feedback from qualitative interviews were used to determine feasibility. T-tests were conducted to examine variations in PETS-stroke scores based on multimorbidity and socioeconomic factors.RESULTS:Three hundred eighty-one participants were included (mean age, 68.2 [SD, 11.2] years; female, 43.3%). The best fit was achieved with a 9-factor structure, and internal consistency was good (Omega values, 0.729–0.921). The factor loadings for the individual indicator items across 8 of the 9 domains were moderate to strong. All domains of PETS-stroke showed moderate to strong correlations with at least one other patient-reported measure. Test-retest reliability was good for all domains (intraclass correlation coefficient >0.7). Qualitative feedback on feasibility was positive: participants found the questionnaire to be easy and quick to complete, and missing data were within acceptable limits for 7 domains. PETS-stroke scores significantly differed based on multimorbidity in 3 domains and in 8 domains based on socioeconomic status.CONCLUSIONS:Psychometric performance suggests that PETS-stroke is a valid and feasible measure of treatment burden after stroke.

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Multicenter SPAN Trial of Fasudil in Ischemic Stroke

Stroke, Ahead of Print. BACKGROUND:The SPAN (Stroke Preclinical Assessment Network) is a confirmatory multicenter trial network to test cerebroprotective interventions in experimental acute stroke. In a first-of-its-kind trial, SPAN tested 6 interventions in a rodent model of transient focal ischemic stroke. Here, we report the efficacy of fasudil, an isoform-nonselective rho-associated kinase inhibitor, on primary and secondary outcomes in the SPAN trial.METHODS:Fasudil was administered at 10 mg/kg intraperitoneally every 12 hours for 6 doses starting 5 minutes before reperfusion in a 60-minute endovascular filament middle cerebral artery occlusion model. The active treatment arm (n=345) was compared with the pooled intraperitoneal and intravenous vehicle arms (n=344). In addition to healthy young mice, the trial included aging mice (16±1 months), diet-induced obese mice, and spontaneously hypertensive rats. The a priori fasudil substudy design stipulated the modified corner test performance on day 28 as the primary end point and separate analyses for mice and spontaneously hypertensive rats using the modified intention-to-treat cohort.RESULTS:Fasudil improved the primary outcome end point in mice (probabilistic index point estimate, 0.57;P=0.022). The effect appeared stronger in aging mice and when ischemia was induced during the active circadian stage. Fasudil did not show any benefit in the spontaneously hypertensive rats. Alternative analyses using the per-protocol population and imputation generally yielded similar conclusions.CONCLUSIONS:Our results reveal a favorable therapeutic profile for fasudil, supporting future translational development of rho-associated kinase inhibitors in ischemic stroke.

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