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Abstract Background The benefits of intravenous thrombolysis in patients with acute minor stroke remain controversial. For the aim of providing a better therapeutic strategy, high-quality trials are required to validate the efficacy of thrombolytic medicine other than intravenous recombinant tissue plasminogen and tenecteplase. In the trial, we evaluate the efficacy and safety of urokinase (UK) in acute minor stroke. Methods This multicenter, open-label, blinded-endpoint, randomized controlled clinical trial enrolled patients with minor stroke within 6 h of symptom onset, with a NIHSS score ≤ 5. The trial was conducted at 25 hospitals in China between October 2020 and February 2023. Eligible patients were randomized to the UK group (1,000,000 U) or the best medicine treatment group. The responsible investigator recommended and implemented the best medicine treatment based on guidelines. The primary endpoint was an excellent functional outcome, defined as a modified Rankin scale (mRS) score of 0–1 at 90 days. The primary safety outcome was symptomatic intracranial hemorrhage (sICH) within 36 h. Results A total of 999 patients were enrolled in the trial, the median age was 64 years, 371 (36.9%) were women; the median (IQR) NIHSS score was 3 (2–4). At 90 days, the primary endpoint was observed in 427 patients (84.9%) in the UK group and 425 patients (85.7%) in the control group (adjusted risk ratio [RR] 1.00, 95% CI 0.96–1.05, p = 0.87). A total of 3 patients in the UK-treated (0.6%) group experienced sICH compared to 1 patient (0.2%) in the control group (RR 1.83, 95% CI 0.16–20.27, p = 0.62). Conclusions For patients with acute minor stroke treated within 6 h of symptom onset, UK intravenous thrombolysis treatment was not found to be beneficial in terms of excellent functional outcome at 90 days, whereas it was safe. Trial registration ClinicalTrials.gov Identifier: NCT04420351.

Abstract Background The prognosis, recurrence rates, and secondary prevention strategies varied significantly among different subtypes of acute ischemic stroke (AIS). Machine learning (ML) techniques can uncover intricate, non-linear relationships within medical data, enabling the identification of factors associated with etiological classification. However, there is currently a lack of research utilizing ML algorithms for predicting AIS etiology. Objective We aimed to use interpretable ML algorithms to develop AIS etiology prediction models, identify critical factors in etiology classification, and enhance existing clinical categorization. Methods This study involved patients with the Third China National Stroke Registry (CNSR-III). Nine models, which included Natural Gradient Boosting (NGBoost), Categorical Boosting (CatBoost), Extreme Gradient Boosting (XGBoost), Random Forest (RF), Light Gradient Boosting Machine (LGBM), Gradient Boosting Decision Tree (GBDT), Adaptive Boosting (AdaBoost), Support Vector Machine (SVM), and logistic regression (LR), were employed to predict large artery atherosclerosis (LAA), small vessel occlusion (SVO), and cardioembolism (CE) using an 80:20 randomly split training and test set. We designed an SFS-XGB with 10-fold cross-validation for feature selection. The primary evaluation metrics for the models included the area under the receiver operating characteristic curve (AUC) for discrimination and the Brier score (or calibration plots) for calibration. Results A total of 5,213 patients were included, comprising 2,471 (47.4%) with LAA, 2,153 (41.3%) with SVO, and 589 (11.3%) with CE. In both LAA and SVO models, the AUC values of the ML models were significantly higher than that of the LR model (P

Abstract Background Previous research on ABO blood types and stroke has been controversial, predominantly suggesting heightened risk of stroke in non-O blood types. Nonetheless, investigations into the correlation and underlying mechanisms between ABO blood groups and stroke subtypes, especially within Chinese cohorts, remain limited. Methods The ABO blood types of 9,542 ischaemic stroke (IS) patients were inferred using two ABO gene loci (c.261G > del; c.802G > A). The healthy population was derived from the 1000 Genomes Project. Patients were classified by the causative classification system (CCS). Volcano plot and gene ontology (GO) analysis were employed to explore protein differential expression among blood types. Additionally, HT29 and SW480 cell lines with downregulated ABO expression were generated to evaluate its impact on cholesterol uptake and efflux. Results A greater proportion of stroke patients had non-O blood types (70.46%) than did healthy individuals (61.54%). Notable differences in blood type distributions were observed among stroke subtypes, with non-O blood type patients mainly classified as having large artery atherosclerosis (LAA). Clinical baseline characteristics, such as the low-density lipoprotein cholesterol level, activated partial thromboplastin time and thrombin time, varied significantly among blood types. A volcano plot revealed 17 upregulated and 42 downregulated proteins in the O blood type. GO term analysis indicated that downregulated proteins were primarily associated with lipid metabolism pathways. In vitro experiments revealed that reducing ABO gene expression decreased cholesterol uptake and increased cholesterol efflux. Conclusions This study revealed that the non-O blood type increased the risk of LAA stroke through cholesterol metabolism.

Abstract Background There is substantial evidence to support the use of several methods for preventing deep-vein thrombosis (DVT) following intracerebral hemorrhage (ICH). However, the extent to which these measures are implemented in clinical practice and the factors influencing patients’ receipt of preventive measures remain unclear. Therefore, we aimed to evaluate the rate of the early implementation of DVT prophylaxis and the factors associated with its success in patients with ICH. Methods This study enrolled 49,950 patients with spontaneous ICH from the Chinese Stroke Center Alliance (CSCA) between August 2015 and July 2019. Early DVT prophylaxis implementation was defined as an intervention occurring within 48 h after admission. Univariate and multivariate logistic regression analyses were conducted to identify the rate and factors associated with the implementation of early prophylaxis for DVT in patients with ICH. Results Among the 49,950 ICH patients, the rate of early DVT prophylaxis implementation was 49.9%, the rate of early mobilization implementation was 29.49%, and that of pharmacological prophylaxis was 2.02%. Factors associated with an increased likelihood of early DVT prophylaxis being administered in the multivariable model included receiving early rehabilitation therapy (odds ratio [OR], 2.531); admission to stroke unit (OR 2.231); admission to intensive care unit (OR 1.975); being located in central (OR 1.879) or eastern regions (OR 1.529); having a history of chronic obstructive pulmonary disease (OR 1.292), ischemic stroke (OR 1.245), coronary heart disease or myocardial infarction (OR 1.2); taking antihypertensive drugs (OR 1.136); and having a higher Glasgow Coma Scale (GCS) score (OR 1.045). Conversely, being male (OR 0.936), being hospitalized in tertiary hospitals (OR 0.778), and having a previous intracranial hemorrhage (OR 0.733) were associated with a lower likelihood of early DVT prophylaxis being administered in patients with ICH. Conclusions The implementation rate of early DVT prophylaxis among Chinese patients with ICH was subpar, with pharmacological prophylaxis showing the lowest prevalence. Various controllable factors exerted an impact on the implementation of early DVT prophylaxis in this population.

Abstract Background Clonal hematopoiesis of indeterminate potential (CHIP) is a phenomenon that characterizes individuals with somatic mutations that are related to hematologic malignancy but without hematologic abnormalities. Presence of CHIP is associated with the atherosclerotic cardiovascular disease through the activation of the interleukin 6 (IL-6) pathway; however, its role on unfavorable functional outcomes in different etiologies of ischemic stroke remains unclear. We aimed to investigate the association between CHIP-related gene mutations and unfavorable functional outcomes of ischemic stroke with different etiologies. Methods We prospectively studied a cohort of 3396 stroke patients with identified etiologies, and identified CHIP and the presence of the IL6R variant (IL6R p.Asp358Ala) by whole-genome sequencing. The IL6R p.Asp358Ala coding mutation was used as a genetic inhibition for IL-6 signaling. The primary outcome was unfavorable functional outcome [(Modified Rankin Scale), mRS 2–6] at 3 months. Results Of the 3396 patients, 110 (3.2%) were CHIP carriers and the median age was 62 years (IQR, 54.0–69.0). The CHIP increased the risk of unfavorable functional outcome among patients with hyper-inflammation status of high-sensitivity C-reactive protein (hsCRP) > median levels in patients with large-artery atherosclerosis (LAA) (OR 2.45, 95% CI 1.00–5.98, p = 0.049, p interaction = 0.01). Presence of IL6R variant (IL6R p.Asp358Ala) could attenuate the risk of unfavorable functional outcome only in patients with CHIP (OR 0.30, 95%CI 0.12–0.76, p = 0.01, p interaction = 0.02), and especially in LAA patients with CHIP (OR 0.1, 95%CI 0.02–0.42, p = 0.002; p interaction = 0.001). Conclusion CHIP is associated with unfavorable functional outcomes in patients with LAA stroke and hyper-inflammation. Genetic IL-6 signaling inhibition might attenuate the risk of unfavorable functional outcomes in CHIP carriers, especially in LAA stroke patients.

Abstract Background Estimated glucose disposal rate (eGDR), a simple and noninvasive measure of insulin resistance, has been proven to be an independent risk factor for first-time stroke and all-cause mortality. In this study, we aimed to investigate the associations between eGDR and the stroke outcome in patients with first-time acute ischemic stroke (AIS). Methods We included first-time AIS patients with available data on eGDR in the China National Stroke Registry III (CNSR-III), and divided the subjects into lower eGDR group (eGDR ≤ 6 mg/kg/min) and higher eGDR group (eGDR > 6 mg/kg/min). The primary outcome was excellent functional outcome (modified Rankin Scale score 0–1) at 3 months. Secondary outcomes included stroke recurrence and favorable functional outcome (modified Rankin Scale score 0–2) at 3 months, and functional outcome and combined vascular event at one year. Univariate and multivariate analyses were performed to evaluate the association between eGDR and outcomes. Results A total of 6,271 patients with AIS were included in this study. The median values of eGDR in lower and higher eGDR group were 5.0 mg/kg/min (interquartile range, 4.2–5.6) and 7.6 mg/kg/min (interquartile range, 6.8–9.6), respectively. Patients with higher eGDR were significantly associated with higher incidence of excellent functional outcome (adjusted odds ratio, 1.24; 95% confidence interval, 1.06–1.45; P

Abstract Background Serum uric acid (SUA), an end-product of purine catabolism diffused in the blood, is positively associated with the risk of type 2 diabetes mellitus (T2DM). However, in the T2DM population, the association of SUA fluctuation ( $$\Delta$$ Δ SUA) with the functional outcome of ischemic stroke (IS) is still unclear. Accordingly, this study aimed to assess the correlation between $$\Delta$$ Δ SUA and short-term IS functional outcomes in T2DM patients. Methods All T2DM patients diagnosed with IS in the China National Stroke Registry III were included. $$\Delta$$ Δ SUA, which was defined as the difference between the SUA levels at baseline and 3 months after symptom onset, was classified into two groups, i.e., elevated $$\Delta$$ Δ SUA ( $$\Delta$$ Δ SUA > 0) and reduced $$\Delta$$ Δ SUA ( $$\Delta$$ Δ SUA $$\le$$ ≤ 0). The outcomes measured using the Modified Rankin Scale (mRS) were scored from 0 to 6, and poor functional outcome was defined as an mRS score of 3–6 at 3 months after IS. Results Among the 1255 participants (mean age: 61.6 ± 9.8 years), 64.9% were men. Patients with elevated $$\Delta$$ Δ SUA had a lower incidence of poor functional outcomes at 3 months. Compared with reduced $$\Delta$$ Δ SUA, elevated $$\Delta$$ Δ SUA at 0–50 μmol/L (odds ratio [OR] = 0.46, 95% confidence interval [CI] = 0.28–0.78, p = 0.004) and 50–100 μmol/L (OR = 0.40, 95% CI = 0.21–0.77, p = 0.006) was significantly correlated with a reduced risk of poor functional outcomes at 3 months. Conclusion This study showed that a moderate increase in $$\Delta$$ Δ SUA in the range of 0–100 μmol/L at 3 months after IS might be beneficial in T2DM adults and more studies are warranted to confirm this.

Abstract Background and purpose Mild acute ischemic stroke (AIS) patients with large vessel occlusion (LVO) may benefit from thrombolysis or thrombectomy therapy. However, the predictors for LVO in mild AIS patients have not been extensively explored. We aimed to investigate the predictors for LVO in mild AIS patients. Methods We collected the data of consecutive AIS patients with a National Institutes of Health Stroke Scale (NIHSS) score ≤ 5 from The Third China National Stroke Registry - a prospective nationwide registry of AIS or transient ischemic attack (TIA) patients in China from August 2015 to March 2018. Patients were divided into LVO and non-LVO group based on the vascular imaging during the hospitalization. Multivariable regression analyses involving clinical characteristics and NIHSS subitems was performed to detect the predictors for LVO. Result A total of 7653 mild AIS patients from The Third China National Stroke Registry were included in this study. Among them, 620 patients (8.1%) had LVO. The level of consciousness (adjusted odds ratio, 1.87; 95% confidence interval, 1.08 to 3.23), visual field (adjusted odds ratio, 2.10; 95% confidence interval, 1.43 to 3.06) and sensory (adjusted odds ratio, 0.75; 95% confidence interval, 0.60 to 0.94) were predictors for mild AIS patients with LVO. Conclusions Impaired LOC, visual field and sensory were independently predictors for LVO in mild stroke patients. Further studies are warranted to test these predictors in prehospital setting and in other population.

Abstract Background The triglyceride-glucose (TyG) index was significantly related to clinical outcome in patients with cardiovascular disease (CAD) and cerebrovascular disease (CVD). We aim to investigate the association between TyG index and clinical prognosis of acute ischemic stroke (IS) patients with type-2 diabetes mellitus (T2DM). Methods Among 19,604 patients with acute IS admitted to the China National Stroke Registry II (CNSRII), 3359 IS patients with T2DM were included in the cross-sectional analysis. The TyG index (calculated by ln [fasting triglycerides (mg/dL) × fasting glucose (mg/dL)/2]) was split into four quartiles. The outcomes included recurrent IS, all-cause death and poor outcome at 1 year were analyzed. The association between the TyG index and adverse cerebrovascular outcomes was assessed by proportional hazards regression analysis. Results During 1 year follow-up, recurrent IS, all-cause death and poor outcome occurred in 305 (9.08%), 229 (6.82%) and 443 (47.9%) cases, respectively. Multivariable Cox proportional hazards analyses showed that the risk of incident primary endpoints was associated with a higher TyG quartile. After adjustment for confounding factors, patients with a higher TyG index had an association with IS recurrence (adjusted hazard ratio, 1.41; 95% confidence interval, 0.97–2.03; P = 0.048) and all-cause death (adjusted hazard ratio, 1.70; 95% confidence interval, 1.062–2.74; P = 0.028), compared with those in the first quartile at 1 year time follow-up. In addition, there were interactions between TyG index and age (≥ 65), female, hypertensive agents, anticoagulant agents, statins and antidiabetic agents in subgroup analyses, especially patients without taken anticoagulant drugs were significantly related to IS recurrence, all-cause death and poor outcome (P = 0.003, P = 0.006 and P = 0.001, respectively). Conclusions TyG index is strongly related to the IS recurrence and all-cause death in acute IS patients with T2DM. This finding indicates that the TyG index might be a potential predictor of clinical outcome for acute IS patients with T2DM.

Abstract Background The influence of chronic kidney disease (CKD) on the severity and prognosis of spontaneous intracerebral hemorrhage (ICH) has been scarcely investigated. We aimed to explore the association of admission estimated glomerular filtration rate (eGFR) levels with hemorrhagic stroke severity and outcomes in ICH patients. Materials and methods The patients enrolled in this study were from the China Stroke Center Alliance study (CSCA). Patients were divided into four groups according to differences in eGFR at admission (≥90; 60–89; 45–59;

Abstract Background Persistent critical illness is common in critically ill patients and is associated with vast medical resource use and poor clinical outcomes. This study aimed to define when patients with sepsis would be stabilized and transitioned to persistent critical illness, and whether such transition time varies between latent classes of patients. Methods This was a retrospective cohort study involving sepsis patients in the eICU Collaborative Research Database. Persistent critical illness was defined at the time when acute physiological characteristics were no longer more predictive of in-hospital mortality (i.e., vital status at hospital discharge) than antecedent characteristics. Latent growth mixture modeling was used to identify distinct trajectory classes by using Sequential Organ Failure Assessment score measured during intensive care unit stay as the outcome, and persistent critical illness transition time was explored in each latent class. Results The mortality was 16.7% (3828/22,868) in the study cohort. Acute physiological model was no longer more predictive of in-hospital mortality than antecedent characteristics at 15 days after intensive care unit admission in the overall population. Only a minority of the study subjects (n = 643, 2.8%) developed persistent critical illness, but they accounted for 19% (15,834/83,125) and 10% (19,975/198,833) of the total intensive care unit and hospital bed-days, respectively. Five latent classes were identified. Classes 1 and 2 showed increasing Sequential Organ Failure Assessment score over time and transition to persistent critical illness occurred at 16 and 27 days, respectively. The remaining classes showed a steady decline in Sequential Organ Failure Assessment scores and the transition to persistent critical illness occurred between 6 and 8 days. Elevated urea-to-creatinine ratio was a good biochemical signature of persistent critical illness. Conclusions While persistent critical illness occurred in a minority of patients with sepsis, it consumed vast medical resources. The transition time differs substantially across latent classes, indicating that the allocation of medical resources should be tailored to different classes of patients.