Clinical characteristics, in-hospital management, and outcomes among patients hospitalized for acute ischemic stroke in rural vs. urban hospitals in China: a nationwide hospital-based study.

BACKGROUND: Efforts to improve rural stroke care have intensified in China. However, high-quality comprehensive data on the differences in care and outcomes between urban and rural hospitals are limited. METHODS: We analyzed data on patients with acute ischemic stroke hospitalized in the China Stroke Center Alliance hospitals from 2015 to 2022. The in-hospital management measures assessed included nine acute and five discharge management measures. Outcomes evaluated included death or discharge against medical advice (DAMA), major adverse cardiovascular events (MACE), disability at discharge, and in-hospital complications. RESULTS: We enrolled 1,583,271 patients with acute ischemic stroke from 1,930 hospitals, comprising 1 086 (56.3%) rural sites with 735 452 patients and 844 (43.7%) urban sites with 847 891 patients. Patients in rural hospitals demonstrate suboptimal management measures compared to those in urban hospitals, including lower rates of intravenous recombinant tissue plasminogen activator within 4.5 h (26.0% vs. 28.3%; difference, -2.3% [-2.5% to -2.0%]), endovascular treatment (0.6% vs. 1.9%; difference, -1.3% [-1.3% to -1.2%]), vessel assessment (88.5% vs. 92.0%; difference, -3.5% [95% CI, -3.6% to -3.4%]), and anticoagulants for atrial fibrillation at discharge (42.9% vs. 47.7%; difference, -4.8% [95% CI, -5.4% to -4.2%]). Overall, the rural-urban disparity in in-hospital outcomes was small. Rural patients had a slightly higher rate of in-hospital death/DAMA (9.0% vs. 8.0%; aOR, 1.22 [95% CI, 1.20-1.23]; aRD, 1.3% [95% CI, 1.2%-1.4%]) and a slightly lower rate of complications (10.9% vs. 13.0%; aOR, 0.83 [95% CI, 0.82-0.84]; aRD, -1.3% [95% CI, -1.3%-1.3%]). No notable rural-urban differences were observed in MACE and disability at discharge. CONCLUSIONS: Patients in rural hospitals demonstrated suboptimal management measures and had higher rates of in-hospital death/DAMA compared to those in urban hospitals. Prioritizing the allocation of health resources to rural hospitals is essential to improve healthcare quality and outcomes. DATA ACCESS STATEMENT: The data supporting the findings of this study are available from the corresponding author upon reasonable request.

Association between PPARγ polymorphisms and neurological functional disability of ischemic stroke.

Peroxisome proliferator-activated receptor-γ (PPARγ) plays a protective role against brain injury after stroke in mice. However, the relationship between PPARγ gene polymorphisms and the functional outcome of acute ischemic stroke (AIS) remains unknown. 8822 patients from The Third China National Stroke Registry (CNSR-III) after whole-genome sequencing, two functional single nucleotide polymorphisms(SNPs) in PPARγ, rs1801282 C > G and rs3856806 C > T, were further analysed. The primary outcome was neurological functional disability at three months. Of the 8822 patients, 968 (11.0%) and 3497 (39.6%) were carriers of rs1801282 and rs3856806, respectively. Carriers of rs3856806 showed reduced risks for three-month neurological functional disability (OR, 0.84; 95% CI, 0.73-0.98; p = 0.02) and reduced risks for higher infarct volume (OR 0.90, 95% CI, 0.81-0.99, p = 0.04). They also had a reduced risk of neurological functional disability only in case of lower baseline IL-6 levels (OR 0.64, 95% CI 0.48-0.84, Pinteraction = 0.01). Carriers of rs1801282 had a reduced risk for three-month neurological functional disability (OR 0.77, 95% CI, 0.61-0.99, p = 0.04). Our study suggested that PPARγ polymorphisms are associated with a reduced risk for neurological functional disability and higher infarct volume in AIS. Therefore, PPARγ can be a potential therapeutic target in AIS.

Tumor Metabolism: A New Field for the Treatment of Glioma.

The clinical treatment of glioma remains relatively immature. Commonly used clinical treatments for gliomas are surgery combined with chemotherapy and radiotherapy, but there is a problem of drug resistance. In addition, immunotherapy and targeted therapies also suffer from the problem of immune evasion. The advent of metabolic therapy holds immense potential for advancing more efficacious and tolerable therapies against this aggressive disease. Metabolic therapy alters the metabolic processes of tumor cells at the molecular level to inhibit tumor growth and spread, and lead to better outcomes for patients with glioma that are insensitive to conventional treatments. Moreover, compared with conventional therapy, it has less impact on normal cells, less toxicity and side effects, and higher safety. The objective of this review is to examine the changes in metabolic characteristics throughout the development of glioma, enumerate the current methodologies employed for studying tumor metabolism, and highlight the metabolic reprogramming pathways of glioma along with their potential molecular mechanisms. Importantly, it seeks to elucidate potential metabolic targets for glioblastoma (GBM) therapy and summarize effective combination treatment strategies based on various studies.

DNMT3A dysfunction promotes neuroinflammation and exacerbates acute ischemic stroke.

Somatic mutations related to clonal hematopoiesis of indeterminate potential (CHIP) are risk factors for stroke. The impact of DNMT3A, the most mutated gene in CHIP, on clinical functional outcomes of acute ischemic stroke (AIS) remains unclear. In a well-characterized cohort of 8524 ischemic stroke patients, we demonstrated that DNMT3A-driven CHIP was significantly associated with neurological disability in these patients. With a stroke mouse model of transient middle cerebral artery occlusion (tMCAO), we demonstrated that DNMT3A protein levels in the brain penumbra increased. The DNMT3A inhibitor RG108 administration amplified neutrophil proliferation in the blood, promoted neutrophil infiltration into the brain penumbra, and exaggerated proinflammatory activation in tMCAO male mice. DNMT3A inhibition also significantly increased infarct volume and worsened neurobehavioral function in tMCAO male mice. In conclusion, DNMT3A somatic mutations are associated with worsened neurological disability in some patients with AIS, potentially through increased neutrophil proliferation and infiltration in the ischemic brain region. These findings suggest a possible mechanism for proinflammatory activation and tissue damage in the affected brain tissue, highlighting the need for further research in this area.

Non-O blood types are associated with a greater risk of large artery atherosclerosis stroke and dysregulation of cholesterol metabolism: an observational study.

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.

Hemodynamic Impairment of Blood Pressure and Stroke Mechanisms in Symptomatic Intracranial Atherosclerotic Stenosis.

BACKGROUND: Hemodynamic impairment of blood pressure may play a crucial role in determining the mechanisms of stroke in symptomatic intracranial atherosclerotic stenosis). We aimed to elucidate this issue and assess the impacts of modifications to blood pressure on hemodynamic impairment. METHODS: From the Third China National Stroke Registry III, computed fluid dynamics modeling was performed using the Newton-Krylov-Schwarz method in 339 patients with symptomatic intracranial atherosclerotic stenosis during 2015 to 2018. The major exposures were translesional systolic blood pressure (SBP) drop and poststenotic mean arterial pressure (MAP), and the major study outcomes were cortex-involved infarcts and borderzone-involved infarcts, respectively. Multivariate logistic regression models and the bootstrap resampling method were utilized, adjusting for demographics and medical histories. RESULTS: In all, 184 (54.3%) cortex-involved infarcts and 70 (20.6%) borderzone-involved infarcts were identified. In multivariate logistic model, the upper quartile of SBP drop correlated with increased cortex-involved infarcts (odds ratio, 1.92 [95% CI, 1.03-3.57]; bootstrap analysis odds ratio, 2.07 [95% CI, 1.09-3.93]), and the lower quartile of poststenotic MAP may correlate with increased borderzone-involved infarcts (odds ratio, 2.07 [95% CI, 0.95-4.51]; bootstrap analysis odds ratio, 2.38 [95% CI, 1.04-5.45]). Restricted cubic spline analysis revealed a consistent upward trajectory of the relationship between translesional SBP drop and cortex-involved infarcts, while a downward trajectory between poststenotic MAP and borderzone-involved infarcts. SBP drop correlated with poststenotic MAP negatively (rs=-0.765; P<0.001). In generating hemodynamic impairment, simulating blood pressure modifications suggested that ensuring adequate blood pressure to maintain sufficient poststenotic MAP appears preferable to the reverse approach, due to the prolonged plateau period in the association between the translesional SBP drop and cortex-involved infarcts and the relatively short plateau period characterizing the correlation between poststenotic MAP and borderzone-involved infarcts. CONCLUSIONS: This research elucidates the role of hemodynamic impairment of blood pressure in symptomatic intracranial atherosclerotic stenosis-related stroke mechanisms, underscoring the necessity to conduct hemodynamic assessments when managing blood pressure in symptomatic intracranial atherosclerotic stenosis.

Gait speed at the acute phase predicted health-related quality of life at 3 and 12 months after stroke: a prospective cohort study.

OBJECTIVE: To investigate the association between acute-phase gait speed and health-related quality of life (HRQoL) at 3 and 12 months post-stroke. DESIGN: Prospective cohort study. SUBJECTS/PATIENTS: 1,475 patients with first-ever ischaemic stroke. METHODS: The patients were divided into 3 groups according to tertiles of gait speed, namely ≤0.8, 0.8-1.1, ≥1.1 m/s. Gait speed was assessed by the 10-m walking test within 2 weeks of hospitalization for acute stroke and before the rehabilitation programme. HRQoL measurements include the 3-level EuroQol five dimensions (EQ-5D-3L) index and EuroQoL visual analogue scale (EQ-VAS) scores. Linear and logistic regression analyses were used to identify associations between gait speed and HRQoL. RESULTS: Adjusted for all covariates, the highest gait speed tertile group were associated with higher EQ-5D-3L index (B = 0.0303 and B = 0.0228, respectively, p < 0.001), and higher EQ-VAS (B = 3.3038 and B = 3.8877, respectively, p < 0.001), and lower odds of having problems with mobility (OR = 2.55 [95% CI: 0.141-0.458] and 0.485 [0.289-0.812], respectively, p < 0.01), self-care (OR = 0.328 [95% CI: 0.167-0.646] and 0.412 [0.217-0.784], respectively, p < 0.01), and usual activities (OR = 0.353 [95% CI: 0.211-0.590] and 0.325 [0.198-0.536], respectively, p < 0.0001) at 3 and 12 months, and pain/discomfort at 12 months (OR = 0.558 [95% CI:0.335-0.930], p < 0.05). CONCLUSION: Acute-phase gait speed was predictive of post-stroke HRQoL at 3 and 12 months, especially when associated with domain-specific EQ-5D-3L.

Inflammatory marker profiles and in-hospital neurological deterioration in patients with acute minor ischemic stroke.

AIM: The aim of the study was to analyze the association between inflammatory marker profiles and in-hospital neurological deterioration (ND) in acute ischemic stroke (AIS) patients. METHODS: Data from patients with minor AIS from the Third China National Stroke Registry were analyzed. Inflammatory cytokine levels within 24 h of admission were measured. The primary outcome was in-hospital ND (an increase in National Institutes of Health Stroke Scale score ≥4 from admission to discharge). Associations were evaluated using odds ratios (ORs) and 95% confidence intervals (CIs) derived from logistic regression models. Net reclassification improvement (NRI) and integrated discrimination improvement (IDI) were used to evaluate incremental predictive values. RESULTS: A total of 4031 patients (1246 women, 30.9%) with a median age of 62 years were included. In-hospital ND occurred in 121 patients (3%). Each standard-deviation increase in interleukin (IL)-6 (OR, 1.17 [95% CI, 1.06-1.31]) and high-sensitivity C-reactive protein (hsCRP) (OR, 1.43 [95% CI, 1.24-1.66]) levels was associated with increased in-hospital ND risk. Incremental predictive values for adding IL-6 (IDI, 0.012; NRI, 0.329) but not hsCRP levels to the conventional risk factors were found. CONCLUSION: In minor AIS, hsCRP and IL-6 levels were associated with in-hospital ND, including IL-6 levels in prognostic models improved risk classification.

Effect of low-temperature degradation on the fatigue performance of dental strength-gradient multilayered zirconia restorations.

OBJECTIVES: Fatigue and low-temperature degradation (LTD) are the main factors contributing to zirconia restoration failure. This study evaluated the effect of LTD on the fatigue performance of the novel "strength & shade-gradient" multilayered zirconia restorations. METHODS: Discs (15 mm × 1.2 mm) of each yttria content layer from a newly developed strength-gradient multilayered zirconia were fabricated and under accelerated aging in an autoclave at 134℃ for 0 h, 32 h, and 64 h. Then, the phase transformation, microstructure, and mechanical properties after LTD were assessed. In addition, the crown samples, including the multi-Zir, 3Y-Zir, and 5Y-Zir were fabricated, and their monotonic and fatigue load before and after LTD, percentage of fatigue degradation (Sd) and the fracture morphology were investigated. Statistical analyses were performed using paired samples t-test (α' = α/3 = 0.017), one-way ANOVA and Weibull analysis. RESULTS: After LTD, the phase transformation, surface roughness, depth of transformed zone, and residual stress were increased and inversely associated with the yttria content. The indentation elastic modulus and hardness after LTD decreased; however, there was no significant difference between the different yttria content layers. The monotonic and fatigue load of multi-Zir restorations decreased, but their Weibull modulus increased, and Sd decreased, similar to 3Y-Zir. The crack origin was associated with the cervical region. CONCLUSION: These results show that although LTD reduces the absolute fatigue strength of strength-gradient multilayered zirconia restorations, it also reduces the effect of cyclic fatigue itself on the strength of zirconia (relative to monotonic strength), which might be due to the increase of residual stress. CLINICAL SIGNIFICANCE: The novel "strength & shade-gradient" multilayered zirconia restorations show a promising performance during in vitro LTD and fatigue test and their reliability to some extent is comparable to 3Y-Zir. Yet, further in vivo longitudinal studies are warranted to confirm their precise performance.

Association between clonal hematopoiesis-related gene mutations and unfavorable functional outcome in patients with large-artery atherosclerotic stroke.

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, pinteraction = 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, pinteraction = 0.02), and especially in LAA patients with CHIP (OR 0.1, 95%CI 0.02-0.42, p = 0.002; pinteraction = 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.

Associations between admission levels of multiple biomarkers and subsequent worse outcomes in acute ischemic stroke patients.

The modified Rankin Scale change score (ΔmRS) is useful for evaluating acute poststroke functional improvement or deterioration. We investigated the relationship between multiple biomarkers and ΔmRS by analyzing data on 6931 patients with acute ischemic stroke (average age 62.3 ± 11.3 years, 2174 (31.4%) female) enrolled from the Third China National Stroke Registry (CNSR-III) and 15 available biomarkers. Worse outcomes at 3 months were defined as ΔmRS3m-discharge ≥1 (ΔmRS3m-discharge = mRS3m-mRSdischarge). Adjusted odds ratios (aORs) and their 95% confidence intervals (CIs) were calculated from logistic regression models. At 3-months poststroke, 1026 (14.8%) patients experienced worse outcomes. The highest quartiles of white blood cells (WBCs) (aOR [95%CI],1.37 [1.12-1.66]), high-sensitivity C-reactive protein (hs-CRP) (1.37 [1.12-1.67]), interleukin-6 (IL-6) (1.43 [1.16-1.76]), interleukin-1 receptor antagonist (IL-1Ra) (1.46 [1.20-1.78]) and YKL-40 (1.31 [1.06-1.63]) were associated with an increased risk of worse outcomes at 3 months. Results remained stable except for YKL-40 when simultaneously adding multiple biomarkers to the basic traditional-risk-factor model. Similar results were observed at 6 and 12 months after stroke. This study indicated that WBCs, hs-CRP, IL-6, IL-1Ra, and YKL-40 were significantly associated with worse outcomes in acute ischemic stroke patients, and all inflammatory biomarkers except YKL-40 were independent predictors of worse outcomes at 3 months.

Revisiting the Smoking Paradox in Acute Ischemic Stroke Patients: Findings From the Chinese Stroke Center Alliance Study.

Background Smoking is a well-established risk factor for the development of acute ischemic stroke (AIS). However, the "smoker's paradox" suggests that it is associated with favorable clinical outcomes following stroke. We aimed to reevaluate the association between smoking and in-hospital outcomes in patients with AIS in contemporary practice. Methods and Results A total of 649 610 inpatients with AIS from 1476 participating hospitals in the Chinese Stroke Center Alliance were included. In-hospital outcomes measurement included all-cause mortality, discharge against medical advice, and complications. Multivariable logistic regression models adjusting for baseline characteristics, clinical profiles at presentation, and in-hospital management were used to evaluate the association between smoking and in-hospital outcomes. A propensity score-matched analysis was also conducted. Of these patients with AIS, 36.8% (n=238 912) were smokers. Smokers were younger, had fewer comorbidities, and had slightly lower rates of adverse in-hospital outcomes than nonsmokers (all-cause death or discharge against medical advice: 6.0% versus 6.1%; in-hospital complications: 14.5% versus 15.1%). Multivariable analysis revealed that smoking was associated with higher risk of adverse in-hospital outcomes (all-cause death or discharge against medical advice: odds ratio [OR], 1.05 [95% CI, 1.02-1.08]; P<0.001; complications: OR, 1.06 [95% CI, 1.04-1.08]; P<0.001). The excess risk of adverse in-hospital outcomes remained in smoking patients with AIS after propensity score-matching analysis (all-cause death or discharge against medical advice: OR, 1.04 [95% CI, 1.00-1.08]; P=0.034; complications: OR, 1.05 [95% CI, 1.03-1.08]; P<0.001). Conclusions Smoking was associated with increased risk of adverse in-hospital outcomes among patients with AIS in contemporary practice, reinforcing the importance of smoking cessation in patients with AIS.

Moderate elevation of serum uric acid levels improves short-term functional outcomes of ischemic stroke in patients with type 2 diabetes mellitus.

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 ([Formula: see text]SUA) with the functional outcome of ischemic stroke (IS) is still unclear. Accordingly, this study aimed to assess the correlation between [Formula: see text]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. [Formula: see text]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 [Formula: see text]SUA ([Formula: see text]SUA > 0) and reduced [Formula: see text]SUA ([Formula: see text]SUA [Formula: see text] 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 [Formula: see text]SUA had a lower incidence of poor functional outcomes at 3 months. Compared with reduced [Formula: see text]SUA, elevated [Formula: see text]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 [Formula: see text]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.

Association Between CYP2B6 Polymorphisms and Efficacy of Clopidogrel in Minor Stroke or Transient Ischemic Attack.

BACKGROUND: CYP2B6 (cytochrome P450 subfamily IIB polypeptide 6), encoded by the CYP2B6 gene, is a critical enzyme involved in clopidogrel metabolism. However, the association between CYP2B6 polymorphisms and the efficacy of clopidogrel in minor stroke or transient ischemic attack for secondary stroke prevention remains unclear. METHODS: Based on CHANCE (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events) randomized clinical trial of aspirin plus clopidogrel versus aspirin alone, we investigated the role of CYP2B6 polymorphisms and the efficacy of clopidogrel in patients with minor stroke or transient ischemic attack in China from October 2009 to July 2012. A total of 2853 patients were successfully genotyped for CYP2B6-516G>T, rs3745274 and CYP2B6-1456 T>C, rs2054675. The primary efficacy and safety outcomes were new stroke and any bleeding within 90 days. RESULTS: Among the 2853 patients, 32.8% were identified as the carriers of the CYP2B6-516 GT/TT or -1456 TC/CC genotype. The incidences of 90-day new stroke in aspirin plus clopidogrel and aspirin alone groups were 7.1% versus 11.3% among noncarriers, respectively; and 9.7% versus 12.2% among carriers, respectively. The efficacy of aspirin plus clopidogrel versus aspirin alone was not significantly different (P interaction=0.29) in noncarriers (adjusted hazard ratio, 0.61 [95% CI, 0.45-0.83]) compared to carriers (adjusted hazard ratio, 0.80 [95% CI, 0.54-1.18]). The incidence (n=51) of 90-day any bleeding in aspirin plus clopidogrel and aspirin alone groups were 2.2% (21 bleeds) versus 1.9% (18 bleeds) among noncarriers (adjusted hazard ratio, 1.11 [95% CI, 0.59-2.09]) and 1.9% (9 bleeds) versus 0.7% (3 bleeds) among carriers (adjusted hazard ratio, 3.23 [95% CI, 0.86-12.12]). Similar findings were observed during the 1-year follow-up. CONCLUSIONS: In this post hoc analysis of the CHANCE trial, we did not observe a significant difference in the efficacy of aspirin plus clopidogrel compared with aspirin in carriers versus noncarriers of CYP2B6-516 GT/TT or -1456 TC/CC genotype. Our results suggest that both carriers and noncarriers suffering from a minor stroke are likely to benefit from aspirin plus clopidogrel treatment over aspirin monotherapy for secondary prevention. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT00979589.

U-shaped association between low-density lipoprotein cholesterol levels and risk of all-cause mortality mediated by post-stroke infection in acute ischemic stroke.

During the acute stage of ischemic stroke, it remains unclear how to interpret the low low-density lipoprotein cholesterol (LDL-C) level. We aimed to evaluate the association between LDL-C levels, post-stroke infection, and all-cause mortality. 804,855 ischemic stroke patients were included. Associations between LDL-C levels, infection, and mortality risk were estimated by multivariate logistic regression models and displayed by restricted cubic spline curves. Mediation analysis was performed under counterfactual framework to elucidate the mediation effect of post-stroke infection. The association between LDL-C and mortality risk was U-shaped. The nadir in LDL-C level with the lowest mortality risk was 2.67 mmol/L. Compared with the group with LDL-C = 2.50-2.99 mmol/L, the multivariable-adjusted odds ratio for mortality was 2.22 (95% confidence intervals (CI): 1.77-2.79) for LDL-C <1.0 mmol/L and 1.22 (95% CI: 0.98-1.50) for LDL-C ≥5.0 mmol/L. The association between LDL-C and all-cause mortality was 38.20% (95% CI: 5.96-70.45, P = 0.020) mediated by infection. After stepwise excluding patients with increasing numbers of cardiovascular risk factors, the U-shaped association between LDL-C and all-cause mortality and the mediation effects of infection remained consistent with the primary analysis, but the LDL-C interval with the lowest mortality risk increased progressively. The mediation effects of infection were largely consistent with the primary analysis in subgroups of age ≥65 years, female, body mass index <25 kg/m2, and National Institutes of Health Stroke Scale ≥16. During the acute stage of ischemic stroke, there is a U-shaped association between LDL-C level and all-cause mortality, where post-stroke infection is an important mediating mechanism.

Effect of prior anticoagulation therapy on stroke severity and in-hospital outcomes in patients with acute ischemic stroke and atrial fibrillation.

BACKGROUND: We aimed to assess the prevalence of prior anticoagulation therapy (warfarin or non-vitamin K antagonist oral anticoagulants [NOACs]) among patients with acute ischemic stroke (AIS) and atrial fibrillation (AF) in China and investigate the associations between prior anticoagulation therapy and initial stroke severity and in-hospital outcomes. METHODS: We included consecutive patients with AIS and known history of AF admitted to hospitals in the China Stroke Center Alliance (CSCA) program from January 2019 to July 2019. Multivariate logistic regression analyses were performed to determine the associations between prior anticoagulation therapy and initial stroke severity and in-hospital outcomes. RESULTS: Of 7181 patients (median [IQR] age, 75.0 [68.0-81.0] years; 48.7% men), 700 (9.7%), 129 (1.8%), and 255 (3.6%) patients received prior subtherapeutic warfarin (international normalized ratio [INR] <2.0), therapeutic warfarin (INR ≥2.0), and NOACs therapy, respectively. A total of 6499 patients had a preadmission CHA2DS2-VASc score ≥ 2, among whom 94.6% were not adequately anticoagulated. Compared with no prior anticoagulation therapy, prior NOACs therapy was associated with reduced risk of moderate or severe stroke at admission (odds ratio [95% CI], 0.64 [0.43-0.94], P = 0.023) and in-hospital mortality or discharge against medical advice (DAMA) (0.46 [0.24-0.86], P = 0.015). However, no significant association was observed between prior therapeutic warfarin therapy and stroke severity or in-hospital mortality or DAMA. CONCLUSIONS: Among patients with AIS and AF in China, the proportion of patients with inadequate anticoagulation prior to stroke remained substantially high. Prior NOACs therapy was associated with reduced stroke severity and less in-hospital mortality or DAMA.

Telomere length and stroke recurrence after ischemic stroke and TIA.

BACKGROUND AND OBJECTIVE: Shortening telomere length (TL), as an indicator of aging, has been associated with increased risk of cardiovascular disease and incident stroke. However, there are limited data relating to the association between TL and recurrent stroke. METHODS: Patients from the Third China National Stroke Registry who had whole genome sequencing (WGS) were selected. TL was estimated using TelSeq based on binary sequence alignment/map files derived from WGS data. Cox proportional hazards regression models were performed to assess the association of TL with recurrent stroke. RESULTS: A total of 8041 patients with ischemic stroke (IS) or transient ischemic attack (TIA) were included. Mean TL was 2.14 ± 0.82 kb. Patients in the lowest tertile of TL had higher incidence of stroke recurrence compared to those in the middle and highest tertile (6.4% vs 5.9% vs 5.2%), but the difference was not longer significant after adjusting for age, sex, cardiovascular risk factors and stroke severity. Similarly, when analyzing TL as a continuous variable, the HR per 1000 bp increase in TL was significant 0.88 (0.79-0.98), but after adjusting for co-variates, was no longer significant (0.91; 95% confidence interval (CI), 0.81-1.02). In patients aged > 65 years, but not in younger patients, after adjusting for co-variates, TL was significantly associated with stroke recurrence. Compared to the lowest tertile, HRs (95% CI) after adjustment for all co-variates for the middle and highest tertiles were 0.78 (0.55-1.10) and 0.67 (0.46-0.98), respectively, with p for trend of 0.03. In analyses using TL as a continuous variable, adjusted HR (95% CI) per 1000 bp increase in TL was 0.80 (0.66-0.96). However, there was no significant interaction between TL and age on risk of stroke recurrence (p for interaction = 0.09). CONCLUSIONS: In Chinese IS or TIA patients, no independent association was found between TL and risk of stroke recurrence after adjusting for co-variates. We found a possible association in older patients but this needs replicating.

Somatic mutation contributing to clonal haematopoiesis is a risk factor of recurrent stroke in first-ever acute ischaemic stroke: a prospective cohort study.

BACKGROUND: Somatic mutation contributes to clonal haematopoiesis of indeterminate potential (CHIP) is related to age and associated with a higher risk of stroke and atherosclerotic cardiovascular disease. Here, we investigated the prognostic significance of CHIP in a large first-ever acute ischaemic stroke (AIS) cohort and explored the underlying mechanisms. METHODS: We studied a prospective cohort of 6016 patients who had a first-ever AIS in China. Whole-genome sequencing was performed to identify CHIP. High-sensitivity C reactive protein (hs-CRP) levels above 3 mg/L at baseline were defined as hyperinflammation. Recurrent stroke during the 3-month follow-up was the primary outcome. RESULTS: Among the 6016 patients who had a first-ever AIS, with a median age was 62 years (IQR, 54.0‒70.0), 3.70% were identified as CHIP carriers. The most common mutations occurred in the DNMT3A (30.0%) and TET2 (11.4%) genes. During a follow-up of 3 months, the presence of CHIP was associated with recurrent stroke (HR 1.62, 95% CI 1.04 to 2.51, p=0.03), recurrent ischaemic stroke (HR 1.64, 95% CI 1.04 to 2.58, p=0.03) and combined vascular events (HR 1.58, 95% CI 1.02 to 2.44, p=0.04) after adjusting for hsCRP levels at baseline in patients who had a first-ever AIS. Subgroup analysis demonstrated that CHIP was only associated with recurrent stroke when patients under hyperinflammation (OR 3.10, 95% CI 1.92 to 5.00, p<0.001) but not in those without hyperinflammation (OR 0.18, 95% CI 0.03 to 1.04, p=0.06, Pinteraction=0.002). CONCLUSION: Our results suggest that somatic mutations contributing to CHIP increase the risk of short-term recurrent stroke in patients who had a first-ever AIS. Hyperinflammation may be important in the relationship between CHIP and recurrent stroke.

Stroke-associated infection in patients with co-morbid diabetes mellitus is associated with in-hospital mortality.

Background and objective: The association between infection and acute ischemic stroke (AIS) with diabetes mellitus (DM) remains unknown. Therefore, this study aimed to explore the effect of infection on AIS with DM. Materials and methods: The data of patients with AIS and DM were extracted from the Chinese Stroke Center Alliance (CSCA) database from August 2015 to July 2019. The association between infections [pneumonia or urinary tract infection (UTI)] and in-hospital mortality was analyzed. Logistic regression models were used to identify the risk factors for in-hospital mortality of patients with infection. Results: In total, 1,77,923 AIS patients with DM were included in the study. The infection rate during hospitalization was 10.5%, and the mortality rate of infected patients was 3.4%. Stroke-associated infection was an independent risk factor for an early poor functional outcome [odds ratio (OR) = 2.26, 95% confidence interval (CI): 1.97-2.34, P < 0.0001] and in-hospital mortality in AIS patients with DM. The in-hospital mortality after infection was associated with age (OR = 1.02, 95% CI: 1.01-1.03, P < 0.0001), male (OR = 1.39, 95% CI: 1.13-1.71, P = 0.0018), reperfusion therapy (OR = 2.00, 95% CI: 1.56-2.56, P < 0.0001), and fasting plasma glucose at admission (OR = 1.05, 95% CI: 1.03-1.08, P < 0.0001). In contrast, antiplatelet drug therapy (OR = 0.63, 95% CI: 0.50-0.78, P < 0.0001) and hospital stay (OR = 0.96, 95% CI: 0.94-0.97, P < 0.0001) were independent protecting factors against in-hospital mortality of patients with infection. Conclusion: Infection is an independent risk factor of in-hospital mortality for patients with AIS and DM, and those patients require strengthening nursing management to prevent infection.