Yong Jiang

Background: Haemorrhagic risk after intravenous thrombolysis (IVT) has been explored in eligible patients with acute ischaemic stroke, but not in minor ischaemic stroke (MIS). The study aimed to investigate the incidence, timing and risk factors for intracranial haemorrhage (ICH) in patients with MIS administered intravenous prourokinase. Materials and methods: Patients with MIS who received IVT within 4.5 hours of symptom onset were included in this post-hoc exploratory analysis of the Prourokinase vs Standard Care for Patients With Mild Ischemic Stroke (PUMICE) trial. ICH was defined as any imaging-identified haemorrhage after prourokinase treatment. The time to ICH was defined as the time from prourokinase administration bolus to documented head CT order time with the first evidence of new haemorrhage. Factors associated with ICH were determined by logistic regression models. A meta-analysis of the incidence of symptomatic ICH (sICH) after thrombolysis in patients with MIS was conducted. Results: Of the 726 patients with MIS enrolled in PUMICE with prourokinase administration, the median age was 65.9 years, and 33.8% were women. 21 (2.9%) developed ICHs after IVT with a delayed timing fashion, of which 5 were sICH (0.7%). The median time to ICH was 24.1 hours. Elevated neutrophil to lymphocyte ratio and impaired renal function were identified as independent risk factors for increased risk of ICH in patients with MIS after thrombolysis. The pooled incidence of sICH was 1.2%. Conclusions: The incidence of sICH and ICH after intravenous prourokinase in patients with MIS is low. Future studies are warranted to identify risk factors and patterns of ICH after other thrombolytic agents’ administration.

Background: Stroke remains a leading cause of mortality and adult disability in China, imposing a substantial disease and socioeconomic burden on society, yet nationally representative epidemiological and real-world inpatient care data remain insufficient. Methods: This study integrated data from the Global Burden of Disease 2023, the Hospital Quality Monitoring System (7536 hospitals) in 2023, and the 2021 National Mortality Surveillance System to systematically assess the epidemiology, disease burden, inpatient care patterns, clinical outcomes and average costs of stroke per hospitalisation in China. Results: In 2023, China reported 4.23 million incident cases, 26.68 million prevalent cases and 2.05 million deaths from stroke. Despite declining age-standardised incidence and mortality, ischaemic stroke (IS) prevalence continued to increase, while haemorrhagic stroke remains the principal contributor to disability-adjusted life years. Real-world inpatient data showed that males and older adults accounted for higher proportions of stroke admissions. Stroke admissions were predominantly concentrated in tertiary public hospitals with marked regional variation. Haemorrhagic stroke has substantially higher in-hospital mortality (intracerebral haemorrhage, ICH: 4.23%; subarachnoid haemorrhage, SAH: 4.08% vs IS: 0.49%) and adverse discharge outcomes than IS. Tertiary hospitals exhibited higher mortality (1.19% vs 0.62%) but lower 0–31-day readmission rates (1.19% vs 1.63%) than secondary hospitals, whereas private hospitals showed longer hospital stays (10.54 vs 9.86 days) and higher readmission rates (1.88% vs 1.34%) than public institutions. The mean hospitalisation cost was RMB13 927 (US$1900) per admission, with substantially higher costs for SAH and ICH than for IS. Conclusions: This nationwide analysis provides comprehensive real-world evidence on the epidemiological burden, inpatient care patterns, clinical outcomes and hospitalisation costs of stroke in China, identifying substantial national, regional and hospital-level variations that may inform future research and quality improvement efforts.

Background: Novel composite inflammatory markers' role in stroke prognosis is understudied, and the best predictor is unclear, requiring further exploration. Objectives: This study aimed to systematically evaluate the associations of 6 novel composite inflammatory markers on stroke prognosis. Methods: Based on the Third China National Stroke Registry (CNSR‐III), we analyzed 14,476 participants aged ≥ 18 years with ischemic stroke or transient ischemic attack. Novel composite inflammatory markers were calculated, including neutrophil‐to‐lymphocyte ratio (NLR), platelet‐to‐lymphocyte ratio (PLR), monocyte‐to‐lymphocyte ratio (MLR), systemic immune‐inflammation index (SII), systemic inflammatory response index (SIRI), and pan‐immune inflammation value (PIV). Outcomes at 1 year included stroke recurrence (primary outcome) and ischemic stroke, composite vascular events, mortality, and poor functional outcome (mRS 2–6) as secondary outcomes. Multivariable Cox or logistic regression analyses were performed to estimate the association of composite inflammatory markers with these outcomes. XGBoost, IDI, and NRI were utilized to evaluate predictive performance. Additionally, subgroup analyses and sensitivity tests were conducted to assess the robustness of the findings. Results: There were 1403 (9.7%), 1300 (9.0%), 1484 (10.3), 483 (3.3%) and 2865 (21.7%) patients with recurrent stroke, ischemic stroke, composite vascular events, mortality, and poor functional outcome within 1 year. SII, PIV, PLR, NLR, SIRI, and MLR were positively associated with stroke recurrence, with hazard ratios (95% CIs) of highest‐quartile vs. lowest‐quartile 1.39 (1.20, 1.61), 1.40 (1.21, 1.62), 1.16 (1.00, 1.34), 1.42 (1.22, 1.66), 1.38 (1.18, 1.61) and 1.18 (1.02, 1.37), respectively. A graded increase in stroke risk across quartiles was observed (Log‐rank p < 0.05). All six markers were positively associated with ischemic stroke, composite vascular events, mortality, and poor functional outcome. SIRI demonstrated better predictive performance [IDI: 0.004 (0.002, 0.007); NRI: 0.082 (0.052, 0.107)] than the other five composite inflammatory markers for stroke recurrence. Among eight XGBoost models, the AUC increased from 0.598 (base) to 0.610 (adding NIHSS/mRS), and further to 0.624 with the addition of SIRI, which was the highest. Conclusions: Novel composite inflammatory markers were significantly associated with an increased risk of adverse outcomes in stroke patients. When accounting for the influence of inflammatory markers, SIRI demonstrated stronger predictive ability for stroke recurrence than the other markers.

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: This study aimed to investigate the heterogeneity of topographic and connectomic mechanisms underlying diverse functional outcomes in patients with acute ischaemic stroke. Methods and results: In 7891 patients from the Third China National Stroke Registry, arterial territory maps, structural disconnection (SDC) maps and functional disconnection (FDC) maps were generated based on their ischaemic lesions. Strategic brain components, associated with functional outcomes, assessed using the modified Rankin Scale scores, were identified using multiperturbation Shapley value analysis. Exploratory subgroup analysis revealed that the strategic components identified in the arterial territory maps and the FDC maps varied by sex and age, but remained consistent in the SDC maps. Conclusion: Specific topographic distributions and disconnections associated with adverse functional outcomes were identified, revealing individual heterogeneity related to age and sex. These findings may serve as imaging biomarkers and help generate testable hypotheses for potential neuromodulation targets.

Background: The role of renal function in patients with acute ischaemic stroke (AIS) receiving blood pressure (BP) lowering therapy remains incompletely understood. In this prespecified subgroup analysis of the CATIS-2 trial, we tested the hypothesis that baseline estimated glomerular filtration rate (eGFR) affects the relationship between early antihypertensive therapy and outcomes in AIS. Methods: In the CATIS-2 trial, AIS patients were randomly assigned to early treatment (initiating BP-lowering agents within 24–48 hours of stroke onset) or delayed treatment (withholding such agents until day 8). The composite of functional dependence or death (modified Rankin Scale score ≥3) at day 90 was defined as the primary outcome. The treatment effect was analysed between different baseline eGFR values (<90 versus ≥90 mL/min per 1.73 m²). Results: 4685 patients were finally enrolled. Among 1061 patients with eGFR<90, the risk of the primary outcome was higher in early treatment compared with delayed treatment (15.3% vs 10.5%; OR (OR) 1.55, 95% CI 1.07–2.23; p=0.02). In 3624 patients with eGFR≥90, no such difference was observed (10.7% vs 10.2%; OR 1.05, 95% CI 0.85 to 1.30; p=0.63). The interaction was marginally significant (p=0.07). Conclusions: The modification effect of renal function on different antihypertensive timing for AIS was not observed. Further, adequately powered studies were warranted. Trial registration number: NCT03479554 .

Ambient particulate matter 2.5) has been extensively associated with morbidity and mortality of stroke. However, most previous findings were derived from separate clinical phase analyses and have not focused on the specific components of PM_2.5. Using a national cohort study based on multistate analysis, we aimed to evaluate the associations of PM_2.5 and its specific components with several different clinical progression phases of stroke. We analyzed data from first-ever stroke patients in the Third China National Stroke Registry, and follow-up was conducted through March 2023. Ambient PM_2.5 and its components were assessed using one-year average concentrations before the end point or the latest follow-up, obtained from Tracking Air Pollution in China. Outcomes were verified through hospital records and official registries. We used multistate models to estimate the associations and applied P-splines to assess potential nonlinear associations of PM_2.5 and its components. We also conducted subgroup analyses to explore potential effect modification. We included a total of 11,491 participants with a mean age of 61.5 ± 11.5 years, of whom 7,821 (68.1%) were male. We observed positive associations of PM_2.5 mass concentrations and all 5 chemical components with each stage of ischemic stroke progression. For PM_2.5 mass concentration, the adjusted hazard ratios per 12.5 μg/m³ increase were as follows: 2.82 (95% CI 2.69-2.94) for the transition from first stroke to recurrence, 2.85 (95% CI 2.40-3.37) from first stroke to poststroke cardiovascular diseases (PCVDs), 2.50 (95% CI 2.28-2.73) from first stroke to death, 2.23 (95% CI 1.97-2.53) from stroke recurrence to death, and 1.93 (95% CI 1.33-2.80) from PCVDs to death. All 5 chemical components also showed strong associations across each transition stage. The exposure-response relationships followed J-shaped curves (p for nonlinearity 2.5 and its specific components was positively associated with the risk of recurrent stroke, and secondary morbidity and mortality. Exposure assessment relied on residential addresses rather than personal measurements, which should be noted as a limitation.

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.

Genotype imputation is essential for medical genomics studies. Herein, we present the STROMICS imputation reference panel, constructed from high-depth whole-genome sequencing (WGS) data of 10,241 Chinese individuals. It includes 53,061,655 single-nucleotide variants and insertion-deletions, spanning 22 autosomes and the X chromosome. Imputation performance of the STROMICS and seven other reference panels was compared using WGS data from 159 individuals. STROMICS panel outperformed others in imputation quality, and in genome-wide population- and individual-level accuracy. Validation using 301 Chinese individuals from the 1000 Genomes Project demonstrated STROMICS achieving high imputation accuracy. Among the three Chinese subgroups, the STROMICS reference panel yielded the highest accuracy in Han Chinese in Beijing samples. Notably, STROMICS outperformed all the other panels for the insertion-deletion imputation. When imputing stroke-risk variants and their closely linked variants with STROMICS, only a small statistically significant difference in sensitivity was observed between diseased and healthy individuals for variants closely linked to stroke-risk variants. Furthermore, calculated using pruned variants, the genetic distances between diseased and healthy groups remained largely unchanged before and after imputation. Collectively, these findings indicate that the source material used to construct the STROMICS reference panel has minimal impact on its imputation performance. Finally, we demonstrated high accuracy of STROMICS for genotype imputation in the X-unique region. In conclusion, the STROMICS panel provides a high-quality reference for imputing genotypes across autosomes and the X chromosome in the Chinese population.