BackgroundInflammation has an important impact on the pathological progression associated with ischemic stroke. Serum uric acid (UA) to lymphocyte ratio (ULR) is a biomarker that responds to the level of inflammation but is not definitively associated with the clinical outcomes in patients with acute ischemic stroke (AIS).MethodsThe data were obtained from the Third China National Stroke Registry (CNSR-III). Enrolled AIS patients were grouped by ULR quartiles at admission. The outcomes were poor functional outcomes (modified Rankin Scale [mRS] score of 3–6 or 2–6) and all-cause mortality at 3 months and 1 year. The associations of ULR with the risk of poor functional outcome and all-cause mortality were analyzed by multivariable logistic regression and Cox proportional hazards regression.ResultsA total of 8,241 patients were included from the CNSR-III study. After adjusting for confounders, it was found that patients in the highest ULR quartile had higher mRS scores of 2–6 (odds ratio [OR], 1.33; 95% confidence interval [CI], 1.15–1.53) and 3–6 (OR, 1.35; 95% CI, 1.16–1.57) at the 3-month follow-up. Additionally, the highest ULR quartile was associated with an increased risk of all-cause mortality at the 3-month follow-up (hazard ratio [HR], 1.97; 95%CI, 1.22–3.18). Similar results were observed at the 1-year follow-up.ConclusionElevated ULR increased the risks of poorer functional outcomes and all-cause mortality in the AIS patients. However, this observational study was limited by potential unmeasured confounders, selection bias, residual confounding, and restricted generalizability to other populations.

Chronological age is a strong predictor of poor outcomes after ischemic stroke but may not fully capture underlying biological vulnerability. This study investigated whether age-related brain atrophy and plasma YKL-40, a marker of astroglial inflammation, mediate the association between age and the one-year risk of ischemic stroke recurrence or all-cause mortality. Data were obtained from 4,305 participants enrolled in the Third China National Stroke Registry. Baseline brain atrophy was quantified from structural T1-weighted MRI using an automated deep learning–based pipeline (FastSurfer), yielding hemispheric cortical and white matter volumes that were modeled as indicators of a latent atrophy construct. Structural equation modeling was applied to estimate direct and indirect pathways linking age, brain atrophy, YKL-40, and one-year composite outcomes, adjusting for sex, atrial fibrillation or flutter, hypertension, and diabetes, with indirect effects evaluated using 5,000 bootstrap resamples. The total effect of age on one-year outcomes was not significant (β = −0.011; 95

Introduction Systemic inflammation is associated with poor outcomes in symptomatic intracranial atherosclerotic stenosis (sICAS); however, the underlying mechanisms remain unclear. We investigated whether urinary albumin-to-creatinine ratio (UACR), as a clinically accessible marker of endothelial dysfunction-related microvascular injury, may mediate the association between inflammation and prognosis.Patients and methods We analysed 2,267 patients with sICAS from the Third China National Stroke Registry. High-sensitivity C-reactive protein (hsCRP) ≥ 2 mg/L and UACR ≥ 30 mg/g were exposures, and poor outcome (modified Rankin Scale (mRS) 3–6) at 90 days was the endpoint. Multivariable logistic regression assessed independent associations, and mediation analysis quantified the contribution of UACR to the hsCRP–outcome association. In a 217-patient sICAS-Computational Fluid Dynamics (sICAS-CFD) cohort, patient-specific models examined links between UACR and post-stenotic perfusion.Results Both high-sensitivity C reactive protein (hsCRP) ≥2 mg/L (adjusted OR (aOR) 1.43, 95% CI 1.12 to 1.84) and UACR ≥30 mg/g (aOR 1.91, 95% CI 1.49 to 2.45) were independently associated with 90-day mRS 3–6. In a prespecified mediation framework, UACR accounted for an estimated 22.2% of the association between elevated hsCRP and 90-day poor outcome (p=0.008), with larger indirect effects in patients with elevated systolic blood pressure (proportion mediated (PM) 17.5%) or diabetes (PM 26.4%; p<0.05), consistent with systemic microvascular vulnerability. In the computational fluid dynamics cohort, hypoperfused patients with poststenotic mean arterial pressure ≥70 mm Hg exhibited higher UACR than those with lower pressure (p=0.040).Discussion and conclusion In sICAS, UACR statistically mediated the association between inflammation and functional outcome, and higher UACR was exploratorily associated with poststenotic perfusion measures, providing exploratory haemodynamic context that may help explain variation in perfusion vulnerability.

BACKGROUND:The role of adiponectin (ADPN) in stroke remains debatable, despite its significant impact as a major adipocytokine on cardiovascular (CV) diseases. This study aimed to assess the association between ADPN and 5-year mortality, functional outcome and recurrence in Chinese individuals with first ischaemic stroke (IS). METHODS:This prospective, multicentre study recruited IS patients from 201 hospitals in China between August 2015 and March 2018. Multivariable Cox regression evaluated ADPN's association with mortality/recurrence, while logistic regression analysed poor functional outcomes (modified Rankin Scale score 3-6 and 3-5). RESULTS:Among 8086 patients (median age 62; 31.8% female), there were 710 deaths, 1134 recurrences and 1223 poor functional outcomes (modified Rankin Scale 3-6). Higher baseline ADPN levels were significantly associated with increased risk of 5-year non-CV mortality (adjusted HR Q4 vs Q1=1.47 (95% CI 1.10 to 1.96), p=0.06) after adjustment for age, sex, body mass index and National Institutes of Health Stroke Scale. No independent associations were found between ADPN and CV mortality, stroke recurrence or poor functional outcome. Subgroup analysis revealed a significant association between ADPN and 5-year mortality from various causes among patients with cardioembolism (adjusted HR Q4 vs. Q1=2.39 (95% CI 1.24 to 4.62), p=0.007) and large artery atherosclerosis (adjusted HR Q4 vs Q1=2.16 (95% CI 1.34 to 3.47), p=0.004). CONCLUSIONS:Elevated baseline ADPN levels were independently associated with increased 5-year non-CV mortality in Chinese IS patients, especially among those with mild neurological impairment. These findings suggest ADPN may serve as a prognostic biomarker for systemic vulnerability after stroke.

Background The Naples Prognostic Score (NPS), a novel inflammatory and nutritional score, has attracted widespread attention in the prognosis of various diseases but remains unclear in acute ischemic stroke or transient ischemic attack. We aimed to investigate the association between NPS and poor functional outcomes and test whether PhenoAge acceleration (PAA) mediates or jointly contributes to the relationships. Methods This prospective cohort study included patients with acute ischemic stroke or transient ischemic attack from the CNSR‐III (Third China National Stroke Registry). The NPS (range, 0–4) was calculated based on serum albumin, total cholesterol, neutrophil/lymphocyte ratio, and lymphocyte/monocyte ratio, and categorized as low (0), medium (1 or 2), or high (3 or 4). Logistic regression was used to assess the association between NPS and poor functional outcomes (modified Rankin Scale [mRS] score, 2–6/3–6). Mediation analyses were performed to explore the role of PAA. Results A total of 7932 patients from the CNSR‐III were included in the analysis. High NPS was significantly associated with poor functional outcomes at 3 months (adjusted odds ratio [OR], 1.69 [95% CI, 1.13–2.52], P=0.010 for mRS 3–6; adjusted OR, 1.31 [95% CI, 1.00–1.71], P=0.048 for mRS 2–6). PAA partially mediated the observed association, with mediation proportions of 13.90% and 12.82% for mRS 3 to 6 and 2 to 6 at 3 months, respectively. Patients with both high NPS and PAA ≥0 had the highest risks of poor outcomes (adjusted OR, 2.16 [95% CI, 1.73–2.70] for mRS 3–6; adjusted OR, 1.51 [95% CI, 1.25–1.84] for mRS 2–6). Similar results were observed at 1 year. Incorporating combined NPS and PAA into the basic model improved predictive performance for short‐ and long‐term poor functional outcomes. Conclusions High NPS was associated with increased risk of poor functional outcomes at 3‐month and 1‐year follow‐ups in patients with acute ischemic stroke or transient ischemic attack. This association was partially mediated and jointly influenced by PAA.

The high-sensitivity C-reactive protein-triglyceride glucose index (hsCTI) is an integrated biomarker reflecting systemic inflammation and insulin resistance. This study aimed to evaluate the association between hsCTI levels and the risk of stroke recurrence in a large, real-world cohort. We analyzed data from the China National Stroke Registry-III, including patients with acute ischemic stroke or transient ischemic attack (TIA). The hsCTI was calculated as 0.412 × ln(hsCRP [mg/L]) + ln(TG [mg/dL] × FPG [mg/dL]/2). Outcomes included stroke recurrence, ischemic stroke recurrence, and composite vascular events. Kaplan-Meier curves and Cox proportional hazards models were employed to evaluate the association between hsCTI and clinical outcomes, stratified by sex, age, and glycemic status. The area under the curve (AUC), net reclassification improvement (NRI), and integrated discrimination improvement (IDI) were calculated to evaluate the incremental risk prediction capabilities of hsCTI and TyG index beyond traditional risk factors. Among 4,969 included patients (67.8

BACKGROUND:The effect of the difference between cystatin C- and creatinine-based estimated glomerular filtration rates (eGFRdiff) on stroke outcomes is unclear. This study investigated the association between eGFRdiff and stroke prognosis. METHODS:Participants with ischaemic stroke or transient ischaemic attack were recruited from the Third China National Stroke Registry, a multicenter, prospective cohort. eGFRdiff was calculated using the absolute difference (eGFRabdiff defined as cystatin C-based (eGFRcys) minus creatinine-based (eGFRcr)) and the ratio (eGFRrediff) between eGFRcys and eGFRcr estimates. eGFRabdiff (< -15, -15-15, ≥ 15 mL/min/1.73 m2) and eGFRrediff (< 0.6, ≥ 0.6) were analyzed. Time-updated eGFRdiff (ΔeGFRdiff) was defined as the change from baseline to 1-year blood re-examination and tertiled. Outcomes included 5-year all-cause mortality, stroke disability, and stroke recurrence. RESULTS:Among 10,293 participants, 35.2% had an eGFRabdiff < -15 mL/min/1.73 m2, and 3.5% had an eGFRrediff < 0.6. Compared with midrange eGFRabdiff, participants with eGFRabdiff < -15 mL/min/1.73 m2 had an odds ratio (OR) of 1.19 (95% confidence interval (CI), 1.05-1.35) for disability and a hazard ratio (HR) of 1.28 (95% CI, 1.12-1.46) for mortality. eGFRrediff < 0.6 was associated with a higher risk for disability (OR, 1.66; 95% CI, 1.25-2.19) and mortality (HR, 1.49; 95% CI, 1.17-1.90). Participants with the largest ΔeGFRdiff declines had higher mortality (OR, 1.44; 95% CI, 1.14-1.82) and borderline disability risk significance (HR, 1.25; 95% CI, 0.96-1.61). CONCLUSIONS:Significant and widening eGFRdiff were independently associated with increased risks of post-stroke disability and mortality, highlighting the importance of monitoring eGFRcys and eGFRcr in stroke management.

Introduction:Ginkgo biloba leaf extracts belong to the most popular herbal medicines for the treatment of neurological disorders, including Alzheimer's disease (AD) or stroke. EGb 761, a proprietary ginkgo leaf extract, has been shown to improve brain cell energy supply, to enhance neurogenesis and neuroplasticity, to decrease blood viscosity and improve brain perfusion. Thereby it improves cognitive performance, neuropsychiatric symptoms and activities of daily living in patients with dementia or mild cognitive impairment. It has further been shown to be beneficial for patients after ischaemic stroke. Therefore, the aim of this meta-analysis was to evaluate the treatment effects of EGb 761 in patients who had developed dementia following a cerebral infarction. Methods:We performed a meta-analysis of pooled data from clinical trials with EGb 761 in mild to moderate dementia in the subgroup of patients who had a cerebral infarction. Four randomised, placebo-controlled trials with homogeneous patient selection and design were included. Previous stroke was diagnosed by neuroimaging. The analysis focused on the comparison of treatment effects in the domains of cognition, activities of daily living and global assessment. Results:The meta-analysis included data from 488 patients. Significant treatment effects of 240 mg EGb 761 daily versus placebo were found for cognition (p = 0.0467), activities of daily living (p = 0.0230), and global clinical impression (p = 0.0371). The rates of adverse events and adverse drug reactions in the EGb 761 group were like those in the placebo group. Conclusion:The results of our meta-analysis of patients with mild to moderate dementia who had previously had a cerebral infarction verified by neuroimaging showed statistically significant and clinically relevant benefits of EGb 761. The drug was shown to be safe and well tolerated and is a promising treatment option for patients developing dementia after cerebral infarction. Further dedicated clinical trials are needed to confirm these results.

Haematoma expansion (HE) is a significant factor in poor outcomes following intracerebral haemorrhage (ICH). Studies have suggested that acute intensive antihypertensive treatment could reduce HE. However, the impact of early intensive blood pressure reduction on patients with ICH at high risk of HE remains unclear. Therefore, screening ICH patients for high risk of HE upon admission and initiating early intensive blood pressure reduction could improve their prognosis. In this study we utilise a five-point scoring system integrating a deep learning system based on non-contrast CT imaging and clinical predictors to identify ICH patients at high risk of HE. This study aims to compare the efficacy, safety, and feasibility of early intensive antihypertensive treatment versus standard antihypertensive treatment for patients identified as being at high risk of HE. The early intensive antihypertensive treatment in high-risk population of intracerebral haemorrhage expansion predicted by artificial intelligence (ARCHES), is a multicentre, prospective, randomised, open-label, blinded-endpoints clinical trial that will include an estimated 680 participants. ICH patients within 6 h of symptom onset, and at high risk of haematoma expansion with ≥ 3 points on the artificial intelligence-based haematoma expansion 5-point prediction score, will be randomly assigned to receive either intensive antihypertensive treatment (targeting systolic blood pressure control between 130 and 140 mmHg within the first hour of treatment, and maintaining this level for 7 days) or standard antihypertensive treatment (targeting systolic blood pressure control between 140 and 180 mmHg, and maintaining for 7 days). The primary outcome is death or severe disability at 90 days. The ARCHES study aims to verify the hypothesis that early intensive blood pressure lowering leads to reduced HE and improved functional outcomes with good safety in ICH patients at high risk of HE. This study was registered at the Clinical Trials under registry number NCT06242938. Registered on Feb 2, 2024. https://clinicaltrials.gov/study/NCT06242938.

OBJECTIVE:Takayasu arteritis (TAK)-related stroke and large-artery atherosclerosis (LAA)-related stroke share overlapping clinical features but differ fundamentally in pathophysiology and treatment strategies. Differentiating these two aetiologies remains a diagnostic challenge with critical therapeutic implications. We aimed to compare the clinical profiles, imaging characteristics and outcomes of TAK- versus LAA-related stroke to provide insights for diagnosis and management. PATIENTS AND METHODS:We conducted a multicentre comparative study using nationwide prospective registry cohorts in China. Among 926 patients with TAK, 80 patients with stroke were included. In addition, 372 patients with LAA-related stroke were selected from the China National Stroke Registry-III cohort (n=14 146). Clinical and imaging characteristics, traditional stroke risk factors and outcomes were analysed and compared. Subgroup analyses were performed according to the presence of atherosclerosis in TAK. Propensity score weighting was performed as a sensitivity analysis. RESULTS:Compared with LAA-related stroke, TAK-related stroke was younger, with a strong female predominance and lower prevalence of vascular risk factors and appeared to have a higher proportion of favourable functional outcomes (modified Rankin Scale 0-2: 93.2% vs 72.6%, p=0.0002), although direct comparison was limited by differences in follow-up structure and assessment timing. Furthermore, patients with TAK tended to show distinct imaging features, including predominant extracranial artery involvement and anterior circulation infarctions located in the subcortical/deep white matter. Among patients with TAK-related stroke, those with coexisting atherosclerosis were older, had longer disease duration and had a greater risk of supra-aortic complications and a higher rate of endovascular interventions. CONCLUSIONS:This study highlights distinct clinical and imaging profiles between TAK- and LAA-related strokes. It also provides a comparative analysis of TAK-related stroke with and without atherosclerosis, revealing differences in risk factors, vascular characteristics and intervention needs. These findings provide a descriptive framework that may assist aetiological differentiation and hypothesis generation for future studies.

BACKGROUND AND OBJECTIVES:Previous studies have shown a beneficial effect of clopidogrel-aspirin and intensive statin therapy in acute ischemic stroke; however, the synergistic effect of the 2 treatments is still unclear. The aim of this study was to investigate the effect of combining clopidogrel-aspirin and immediate intensive statin in patients with acute mild ischemic stroke or transient ischemic attack (TIA). METHODS:We performed a multicenter, randomized, double-blind, placebo-controlled trial with a 2-by-2 factorial design across 222 hospitals in China. Eligible participants were patients with acute mild ischemic stroke or TIA of a presumed atherosclerotic cause within 72 hours of symptom onset. Patients were randomly assigned to receive clopidogrel plus aspirin or aspirin alone and an immediate or delayed intensive statin. The primary efficacy outcome was a new stroke (ischemic or hemorrhagic) within 90 days, and the primary safety outcome was moderate-to-severe bleeding. RESULTS:Between September 17, 2018, and October 15, 2022, 6,100 patients were enrolled (median age, 65 years; 64.2% male), of whom 1,525 each were assigned to the 4 groups. New stroke within 90 days occurred in 116 patients (7.6%) in the clopidogrel-aspirin plus immediate intensive statin group (hazard ratio [HR] 0.76, 95% CI 0.60-0.97), in 106 patients (7.0%) in the clopidogrel-aspirin plus delayed statin group (HR 0.69, 95% Cl 0.54-0.89), and in 129 patients (8.5%) in the aspirin plus immediate statin group (HR 0.85, 95% Cl 0.67 to 1.07), compared with 150 patients (9.9%) in the aspirin plus delayed intensive statin group. Moderate-to-severe bleeding occurred in 17 (1.1%) in the clopidogrel-aspirin plus immediate statin group (p = 0.047), 10 (0.7%) in the clopidogrel-aspirin plus delayed statin group (p = 0.46), and 6 (0.4%) in the aspirin plus immediate statin group (p = 0.80), compared with 7 (0.5%) in the aspirin plus delayed statin group. DISCUSSION:Among patients with mild ischemic stroke or TIA of presumed atherosclerotic cause, the combination of clopidogrel-aspirin and delayed intensive statin was superior to aspirin plus delayed intensive statin in reducing the risk of new stroke, an effect that was mainly driven by clopidogrel-aspirin and not significantly different from that of clopidogrel-aspirin plus immediate statin. The combination treatment had a low but increased risk of moderate-to-severe bleeding. TRIAL REGISTRATION INFORMATION:ClinicalTrials.gov identifier: NCT03635749. CLASSIFICATION OF EVIDENCE:This study provides Class I evidence that in patients with mild ischemic stroke or TIA of presumed atherosclerotic cause, the combination of clopidogrel-aspirin plus delayed intensive statin was superior to aspirin plus delayed intensive statin in reducing the 90-day risk of new stroke.

OBJECTIVE:To assess the efficacy and safety of edaravone dexborneol, a multitarget brain cytoprotectant composed of antioxidant and anti-inflammatory ingredients, in improving functional outcomes among patients with acute ischaemic stroke undergoing endovascular thrombectomy. DESIGN:Multicentre, double blind, randomised, placebo controlled trial. SETTING:106 hospitals in China between March 2022 and May 2023. PARTICIPANTS:1362 patients with clinically diagnosed acute ischaemic stroke within 24 hours of symptom onset, aged 18-80 years, with a National Institutes of Health Stroke Scale (NIHSS) score of 6-25 and an Alberta Stroke Program Early Computed Tomography Score (ASPECTS) of 6-10, confirmed large vessel occlusion in the anterior circulation, and planned endovascular thrombectomy. INTERVENTIONS:Patients were randomly allocated in a 1:1 ratio to receive edaravone dexborneol 37.5 mg (edaravone, 30 mg; (+)-dexborneol, 7.5 mg; 690 patients) or placebo (672 patients) before endovascular thrombectomy and continued the regimen twice daily for a consecutive period of 10-14 days. MAIN OUTCOME MEASURES:Functional independence at 90 days, defined as a modified Rankin Scale score (range 0 (no symptoms) to 6 (death)) of 0-2, and serious adverse events. RESULTS:One patient from each group was lost to follow-up at 90 days. Of the 1360 patients included in the intention-to-treat analysis, 379 (55.0%) of 689 patients in the edaravone dexborneol group and 333 (49.6%) of 671 patients in the placebo group achieved functional independence on day 90 (risk ratio 1.11, 95% confidence interval (CI) 1.00 to 1.23; P=0.05; risk difference 5.4%, 95% CI 0.1% to 10.7%). Patients with mismatch at admission (defined as NIHSS score ≥10 and ASPECTS ≥9 or NIHSS score ≥20 and ≥7) were more likely to achieve functional independence in the subgroup analysis (55.5% (178/321) versus 42.9% (134/312); risk ratio 1.29, 1.10 to 1.52; risk difference 13.0%, 5.6% to 20.3%; P for interaction=0.003). The rates of serious adverse events were similar in the two groups (27.2% (188/690) versus 25.7% (173/672); risk ratio 1.06, 0.89 to 1.26; risk difference 1.5%, -3.2% to 6.2%: P=0.53). CONCLUSIONS:Among patients with acute ischaemic stroke within 24 hours of symptom onset who underwent endovascular thrombectomy, those treated with edaravone dexborneol, compared with placebo, were more likely to achieve functional independence at 90 days without increased safety concerns. This effect seemed to be primarily driven by the subgroup with mismatch present at admission, suggesting that dedicated trials in this population may be warranted. TRIAL REGISTRATION:ClinicalTrials.gov NCT05249920.

Brain vasculature is an essential structural component of the brain and plays an important role in maintaining neural function. Its morphological alterations are increasingly implicated in physiological aging and neurological diseases. However, due to the lack of automated, reproducible tools for morphological analysis, quantitative characterization of brain vasculature and its pathological changes at a population level remains a major challenge. Here, we present MARVAL (Morphological Analysis of ceRebroVAscuLature), an integrated platform for comprehensive cerebrovascular morphometry comprising a high-quality annotated time-of-flight magnetic resonance angiography (TOF-MRA) dataset, a generalizable automated segmentation pipeline with enhanced recall in small vessels, and a comprehensive toolkit for deep phenotyping and group analysis. Leveraging MARVAL in a large community-based healthy cohort, we established a high-resolution standard template of the brain vasculature in East Asians, revealing key normative characteristics of vascular aging. We also systematically demonstrated, for the first time, the modulating effects of non-imaging phenotypes on brain vascular morphology. Furthermore, in a stroke cohort, we identified novel morphological biomarkers associated with stroke prognosis. Together, our findings provide a foundational reference for cerebrovascular health and establish vascular morphometry as a framework to advance precision neurology.

Background Frailty is a multidimensional geriatric syndrome characterized by reduced physiological reserve and is consistently associated with adverse outcomes in cardiovascular diseases. Frailty has also been linked to poor short‐term prognosis in cerebrovascular disease. However, its association with long‐term functional recovery and stroke recurrence remains insufficiently established in large prospective cohorts. Methods We conducted a cohort study using data from the Impairment of Cognition and Sleep Study of the China National Stroke Registry III. Frailty was assessed at baseline using a deficit accumulation frailty index and categorized as robust, pre‐frail, or frail. Primary outcomes were 1‐year excellent functional outcome (modified Rankin Scale 0–1), favorable functional outcome (modified Rankin Scale 0–2), and stroke recurrence. Secondary outcomes were corresponding outcomes at 3 and 6 months. Associations were evaluated using multivariable logistic and Cox regression models. Results Among 2396 patients, 65.3% were robust, 18.0% pre‐frail, and 16.7% frail. Increasing frailty severity was independently associated with lower odds of 1‐year excellent functional outcome (pre‐frail: odds ratio [OR], 0.6; 95% CI, 0.4–0.8; frail: OR, 0.2; 95% CI, 0.2–0.3; P for trend <0.001). Frail patients also had higher stroke recurrence risk (hazard ratio [HR], 1.90; 95% CI, 1.33–2.71) and lower likelihood of favorable functional outcome. Similar dose–response relationships were observed at 3 and 6 months, with consistent findings in sensitivity and subgroup analyses. Conclusions Frailty is common after acute ischemic stroke and shows a strong, graded association with 1‐year functional recovery, supporting its potential value for long‐term prognostic stratification beyond age and comorbidity burden.

BACKGROUND:Lp-PLA2 (lipoprotein-associated phospholipase A2) is a sensitive biomarker of vascular inflammation and atherosclerosis. This study evaluated the influence of Lp-PLA2 activity on the efficacy and safety of ticagrelor-aspirin versus clopidogrel-aspirin among patients with minor stroke or transient ischemic attack carrying CYP2C19 loss-of-function alleles. METHODS:The CHANCE-2 trial (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events-II) randomized 6412 patients with minor stroke or transient ischemic attack carrying CYP2C19 loss-of-function alleles to receive ticagrelor-aspirin or clopidogrel-aspirin. This subgroup study included patients with available baseline Lp-PLA2 activity measurements, stratified by the median value of 188.4 nmol/min per milliliter. The primary efficacy and safety outcomes were stroke recurrence and severe or moderate bleeding events within 90 days. Associations between treatment and outcomes were assessed using multivariable Cox proportional hazards models, adjusting for a history of hyperlipidemia. RESULTS:A total of 5919 patients were included (mean age, 64.4 years; 33.9% female). Among patients with low Lp-PLA2 activity, ticagrelor-aspirin reduced the 90-day risk of recurrent stroke compared with clopidogrel-aspirin (5.4% versus 7.4%; adjusted hazard ratio, 0.72 [95% CI, 0.54-0.97]). In patients with high Lp-PLA2 activity, no significant difference was observed (6.9% versus 8.2%; adjusted hazard ratio, 0.84 [95% CI, 0.65-1.09]). The P value was 0.45 for the treatment × Lp-PLA2 activity interaction effect on stroke recurrence. The risk of bleeding associated with ticagrelor-aspirin did not differ across Lp-PLA2 activity levels. CONCLUSIONS:In patients with minor stroke or transient ischemic attack carrying CYP2C19 loss-of-function alleles, elevated Lp-PLA2 activity did not significantly modify the efficacy or safety of dual antiplatelet therapy. Further research is needed to clarify the potential role of Lp-PLA2 in guiding individualized treatment decisions. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT04078737.

Background and Purpose: Single Small Subcortical Infarction (SSSI) is a subtype of ischemic stroke with unique pathophysiology, often leading to poor outcomes. This study investigates the association between admission hematocrit (HCT) levels and the risk of progressive stroke in SSSI patients. Methods: We conducted a retrospective cohort study using data from the China National Stroke Registry III, including 2,457 SSSI patients. Progressive stroke was defined as an increase in the NIHSS score by 2 points during hospitalization. Logistic regression models assessed the association between HCT levels and progressive stroke risk. Results: Among 2,457 SSSI patients, 135 (5.50%) experienced progressive stroke. Higher HCT levels were independently associated with a lower risk of progressive stroke (adjusted OR 0.983, 95% CI 0.973-0.994, P = 0.002), with a potential dose-response relationship. The protective effect was more pronounced in patients with severe sensory deficits (P for interaction = 0.013) and younger age (<65 years) (P for interaction = 0.037). Lower HCT levels were also independently associated with increased mortality risk within 3 months after stroke (adjusted OR 0.937, 95% CI 0.892-0.984, P < 0.001). Conclusions: Higher admission HCT levels are associated with a lower risk of progressive stroke in SSSI patients, particularly those with severe sensory deficits and younger age. Lower HCT levels may also increase early mortality risk. These findings highlight the importance of monitoring and optimizing HCT levels in SSSI management. Further research should explore the underlying mechanisms and therapeutic implications ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement non ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: IRB approval number: KY2015-001-01 I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data are available upon reasonable request.

Background GNB3 C825T polymorphism affects G protein-coupled receptor signaling, influencing platelet function, inflammation, and cardiovascular risk. This study aimed to investigate the unknown effects of the GNB3 C825T polymorphism on recurrent stroke risk in large-artery atherosclerosis and its potential interaction with antiplatelet therapy.Methods Using the CNSR-III (Third China National Stroke Registry) data, we analyzed 1233 patients with large-artery atherosclerotic acute ischemic stroke enrolled within 72 hours of onset. Whole-genome sequencing was performed to identify the GNB3 C825T polymorphism. Cox regression analysis was used to assess its association with 1-year recurrent ischemic stroke after adjusting for vascular risk factors. Associations with antiplatelet regimens and mediating effects of inflammatory biomarkers in the overall cohort were also evaluated.Results Carriers of the GNB3 825T-allele (CT/TT, 72.7%) exhibited a significantly lower risk of 1-year recurrent ischemic stroke than noncarriers (adjusted hazard ratio, 0.67 [95% CI, 0.48-0.93]; P=0.02). In exploratory analyses, the association was observed in the aspirin monotherapy subgroup, but the interaction with aspirin use was not significant. Elevated baseline interleukin-6 partially attenuated this genetic protection in the overall cohort (mediation proportion, -9.82%; P=0.02).Conclusions The GNB3 825T-allele was associated with a reduced risk of recurrent stroke in patients with large-artery atherosclerotic acute ischemic stroke. In exploratory analyses, this association was observed in the aspirin monotherapy subgroup; however, the formal interaction with aspirin use was not statistically significant. These findings support a potential prognostic role of the GNB3 C825T polymorphism and warrant further validation in independent cohorts.

BACKGROUND:The efficacy and safety of intravenous thrombolysis with tenecteplase within 24 h after stroke onset due to basilar artery occlusion are not well studied. We aimed to assess whether intravenous tenecteplase administered within 24 h after symptom onset improved functional outcome compared with standard medical treatment in patients with basilar artery occlusion. METHODS:TRACE-5 was a prospective, randomised, open-label, blinded-endpoint, superiority, phase 3 trial conducted at 66 stroke centres in China. We included patients aged 18 years or older with stroke due to basilar artery occlusion who were eligible for intravenous thrombolytics within 24 h of stroke onset or the time they were last known to be well and had a pre-stroke modified Rankin scale (mRS) score of 3 or less (scores range from 0 to 6, with higher scores indicating greater disability). Patients were randomly assigned to receive a single intravenous bolus of tenecteplase (0·25 mg/kg; maximum 25 mg) within 24 h after symptom onset or standard medical treatment (which could include intravenous alteplase at 0·9 mg/kg, maximum 90 mg, within 4·5 h of symptom onset; anticoagulation; or antiplatelets), with or without endovascular thrombectomy. The primary outcome was a score of 0-1 on the mRS or return to the baseline mRS score (if the baseline pre-stroke mRS score was 2-3) at 90 days. Safety outcomes were symptomatic intracranial haemorrhage and death. The primary outcome and safety outcomes were assessed in all randomly assigned participants included in their originally assigned groups. This trial is registered with ClinicalTrials.gov, NCT06196320. FINDINGS:Between Jan 24, 2024, and June 20, 2025, 452 patients were enrolled (mean age 66·4 years [SD 11·2], 321 [71%] males, and 131 [29%] females), of whom 222 (49%) subsequently underwent thrombectomy; 221 were randomly assigned to receive tenecteplase and 231 to receive standard medical treatment. Alteplase was used in 80 (35%) of the patients in the standard medical treatment group. An mRS score of 0-1 or return to the baseline mRS score occurred in 83 (38%) patients in the tenecteplase group and 66 (29%) patients in the standard medical treatment group (adjusted relative rate 1·50 [95% CI 1·09-2·08], p=0·014). Symptomatic intracranial haemorrhage within 36 h occurred in four (2%) patients in the tenecteplase group and seven (3%) patients in the standard medical treatment group (adjusted relative rate 0·58 [95% CI 0·17-1·99]). All-cause mortality at 90 days was similar between groups (65 [29%] patients in the tenecteplase group and 71 [31%] patients in the standard medical treatment group; adjusted relative rate 0·87 [95% CI 0·62-1·22]), as was the proportion of patients with an mRS score of 5-6 at 90 days (82 [37%] vs 89 [39%]; 0·87 [0·65-1·18]). INTERPRETATION:In this trial involving Chinese patients with ischaemic stroke due to basilar artery occlusion, tenecteplase within 24 h after stroke onset improved functional outcome compared with standard medical treatment. The incidence of symptomatic intracranial haemorrhage and death was similar. FUNDING:Noncommunicable Chronic Diseases-National Science and Technology Major Project, Beijing Municipal Science Fund for Distinguished Young Scholars, National Natural Science Foundation of China, and China Shijiazhuang Pharmaceutical Company Recomgen Pharmaceutical (Guangzhou).