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Ischemic stroke is a leading cause of death and disability worldwide, with an increasing trend and tendency for onset at a younger age. China, in particular, bears a high burden of stroke cases. In recent years, the inflammatory response after stroke has become a research hotspot: understanding the role of inflammatory response in tissue damage and repair following ischemic stroke is an important direction for its treatment. This review summarizes several major cells involved in the inflammatory response following ischemic stroke, including microglia, neutrophils, monocytes, lymphocytes, and astrocytes. Additionally, we have also highlighted the recent progress in various treatments for ischemic stroke, particularly in the field of stem cell therapy. Overall, understanding the complex interactions between inflammation and ischemic stroke can provide valuable insights for developing treatment strategies and improving patient outcomes. Stem cell therapy may potentially become an important component of ischemic stroke treatment.

BackgroundTension-type headache (TTH) is among the most common primary headache disorders, characterized by recurrent episodes that are difficult to manage, thus posing a significant public health challenge. Acupuncture, a well-recognized non-pharmacological treatment, is frequently employed for pain management, including TTH. However, the variety of acupuncture techniques and inconsistent treatment outcomes underscore the need for a thorough evaluation. This study aims to update the current evidence on acupuncture and related therapies for TTH, evaluate the efficacy and safety of various acupuncture therapies, and identify the most effective therapeutic strategies, providing valuable guidance for clinical practice.MethodsWe systematically searched randomized controlled trials (RCTs) from four English databases (PubMed, Embase, Cochrane Library, and Web of Science) and four Chinese databases (Wanfang, VIP, CNKI, and SinoMed), including gray literature, up to April 19, 2024. The outcome measures included headache frequency, duration, pain intensity, and responder rate. A Bayesian network meta-analysis was conducted using Stata 17.0 to assess the relative effectiveness and safety of the different acupuncture therapies. This study was registered with the Prospective Register of Systematic Reviews (CRD42024537187).ResultsA total of 42 RCTs, encompassing 4,103 participants and 21 distinct treatment therapies, were included in the analysis. The network meta-analysis yielded the following findings: (1) regarding responder rate, several acupuncture or combined acupuncture and medication approaches, such as electro-acupuncture (EA) + cupping therapy (CT) [odds ratio (OR) = 28.66, 95% CI: 1.68 to 487.35], manual acupuncture (MA) + bloodletting therapy (BT) (OR = 6.07, 95% CI: 1.81 to 20.29), plum blossom needle tapping (PBNT) (OR = 3.76, 95% CI: 1.04 to 13.65), and scalp acupuncture (SPA) (OR = 3.65, 95% CI: 2.29 to 5.83), were significantly more effective than western medicine (WM) alone, with EA + CT (92.1%) being the most effective. (2) In terms of reducing headache frequency, EA (85.9%) was the most effective, followed by MA + PBNT (80.9%) and MA + WM (78.4%). Compared to WM, both MA + PBNT (SMD = −1.76, 95% CI: −3.31 to −0.22) and EA (SMD = −1.75, 95% CI: −3.30 to −0.20) significantly reduced headache frequency. (3) For shortening headache duration, EA (83.9%) emerged as the most effective treatment, followed by MA + WM (73.5%) and laser acupuncture (LA) (68.5%). (4) In terms of pain intensity reduction, the MA + WM combination (89.4%) was superior to other treatments, with SPA + WM (77.7%) being the next most effective. Compared to herbal medicine (HM), both MA + WM (SMD = −2.37, 95% CI: −4.20 to −0.55) and MA alone (SMD = −1.00, 95% CI: −1.75 to −0.24) significantly alleviated pain intensity.ConclusionThis comprehensive analysis of 21 acupuncture and related therapies demonstrates that EA is the most effective in reducing headache frequency and shortening headache duration, while EA + CT and MA + WM are the optimal therapies for enhancing responder rate and reducing pain intensity, respectively. However, clinical decisions should be individualized based on the specific needs of each patient.Systematic review registrationThe study protocol was registered on the PROSPERO database under registration number CRD42024537187 (https://www.crd.york.ac.uk/prospero/#recordDetails).

Background Tenecteplase, a bioengineered variant of alteplase, is a new alternative thrombolytic agent. The ORIGINAL study aims to evaluate the efficacy and safety of tenecteplase versus standard care in Chinese patients with acute ischemic stroke within 4.5 hours of symptom onset. Methods This is a multicenter phase III study that employs a randomized (1:1), active‐controlled, parallel‐group, prospective, open‐label, blinded–end point design. Adult participants (aged ≥18 years) with acute ischemic stroke who are eligible for intravenous thrombolysis within 4.5 hours of symptom onset according to current guideline recommendations are recruited from ≈55 neurology clinics/stroke centers throughout China. Results The primary objective of the ORIGINAL study is to demonstrate the noninferiority of tenecteplase (0.25 mg/kg) to alteplase (0.9 mg/kg) on the basis of the proportion of patients who achieve a modified Rankin Scale score of 0 or 1 on day 90, that is, a favorable functional outcome. The prespecified noninferiority risk ratio margin is 0.937. Secondary end points include other functional outcomes and the following safety end points: adjudicated symptomatic intracerebral hemorrhage (up to 36 hours after the end of study drug administration) based on the European Cooperative Acute Stroke Study III definition; all‐cause death within 90 days; and the proportion of patients with a modified Rankin Scale score of 5 or 6 on day 90. Conclusions It is anticipated that the results of this study will contribute to the growing body of evidence for the noninferiority of tenecteplase to alteplase given within 4.5 hours of acute ischemic stroke symptom onset and support a new indication for tenecteplase in China. Clinical Trial Registration Information NCT04915729 (https://clinicaltrials.gov/study/NCT04915729)

ObjectiveThis study aimed to examine the relationship between lipoprotein (a) (Lp[a]) and other blood lipid indexes and carotid artery atherosclerosis in patients with acute ischemic stroke (AIS).MethodsA total of 2,018 patients were selected from the hospital “acute stroke intervention and secondary prevention registration database” by identifying blood fat indexes (cholesterol, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and Lp[a]). Based on the results of carotid artery ultrasound examinations, the patients were divided into a “no plaque” group, comprising 400 patients, a “plaque and no stenosis” group, comprising 1,122 patients and a “carotid stenosis” group, comprising 496 patients. The relationship between Lp(a) and blood lipid indexes and carotid artery atherosclerosis was then investigated using multi-factor logistics regression analysis.ResultsThere were 400 patients (19.8%) with no carotid plaque, 1,122 patients (55.6%) with plaque and no carotid stenosis and 496 patients (24.6%) with carotid stenosis. As the degree of carotid artery atherosclerosis increased, the Lp(a) level gradually increased; Lp(a) and cholesterol were identified as independent risk factors for carotid atherosclerosis.ConclusionLipoprotein (a) and cholesterol are independent risk factors for patients with AIS with carotid atherosclerosis, and their levels increase with the degree of carotid artery atherosclerosis; therefore, attention should focus on levels of cholesterol and Lp(a) in acute stroke patients to control atherosclerosis effectively.

Inflammation is closely related to stroke prognosis, and high inflammation status leads to poor functional outcome in stroke. DNA methylation is involved in the pathogenesis and prognosis of stroke. However, the effect of DNA methylation on stroke at high levels of inflammation is unclear. In this study, we constructed a hyperinflammatory cerebral ischemia mouse model and investigated the effect of hypomethylation and hypermethylation on the functional outcome. We constructed a mouse model of transient middle cerebral artery occlusion and treated the mice with lipopolysaccharide to induce a hyperinflammatory state. To investigate the effect of DNA methylation on stroke, we used small molecule inhibitors to restrain the function of key DNA methylation and demethylation enzymes. 2,3,5-Triphenyltetrazolium chloride staining, neurological function scores, neurobehavioral tests, enzyme-linked immunosorbent assay, quantitative reverse transcription PCR and western blot assay were used to evaluate the effects after stroke in mice. We assessed changes in the global methylation status by measuring DNA 5-mc and DNA 5-hmc levels in peripheral blood after the use of the inhibitor. In the group treated with the DNA methylation inhibitor, brain tissue 2,3,5-triphenyltetrazolium chloride staining showed an increase in infarct volume, which was accompanied by a decrease in neurological scores and worsening of neurobehavioral performance. The levels of inflammatory factors interleukin 6 and interleukin-1 beta in ischemic brain tissue and plasma were elevated, indicating increased inflammation. Related inflammatory pathway exploration showed significant overactivation of nuclear factor kappa B. These results suggested that inhibiting DNA methylation led to poor functional outcome in mice with high inflammation following stroke. Further, the effects were reversed by inhibition of DNA demethylation. Our findings suggest that DNA methylation regulates the inflammatory response in stroke and has an important role in the functional outcome of hyperinflammatory stroke.

Abstract Background and purpose Nonvalvular atrial fibrillation (NVAF) is a risk factor for stroke. This study was undertaken to determine the influence of NVAF on the mortality and recurrent stroke after a minor stroke event. Methods Data were derived from the Third China National Stroke Registry (CNSR-III) which enrolled 15,166 subjects during August 2015 through March 2018 in China. Patients with minor stroke (NIHSS ≤ 5) within 24 h after onset were included. Clinical outcomes including all-cause mortality, cardiovascular death, recurrent ischemic stroke, and recurrent hemorrhagic stroke were collected. The Cox proportional hazards models were used to determine the association between NVAF and clinical outcomes. Results A total of 4,753 patients were included in our study. Of them, 222 patients had NVAF (4.7%) (mean age, 71.1 years) and 4,531 patients were without AF (95.3%) (mean age, 61.4 years). NVAF was associated with 12-month cardiovascular mortality in both univariate (hazards ratio [HR], 4.13; 95% confidence interval [CI], 1.84 to 9.31; P

BackgroundData on the association between serum alkaline phosphatase (ALP) levels and clinical outcomes in patients with ischemic stroke (IS) are inconsistent and limited. Therefore, this study aimed to investigate the correlation between ALP and prognosis in patients with IS.MethodsPatients with acute ischemic stroke (AIS) or transient ischemic attack (TIA) from the Third China National Stroke Registry were divided into four groups according to the quartiles of serum ALP levels on admission. Cox proportional hazards and logistic regression models were used to evaluate the correlation between ALP and the risk of all-cause mortality, disability (modified Rankin Scale (mRS) score 3–5), and poor functional outcomes (mRS score 3–6).ResultsA total of 11,405 patients were included in the study. Higher levels of ALP were associated with all-cause mortality at 3 months (adjusted hazard ratio [HR] per standard deviation [SD]: 1.16; 95% confidence interval (CI): 1.07–1.27; p = 0.001) and 1 year (adjusted HR: 1.11; 95% CI: 1.03–1.20; p = 0.010). At the 3-month follow-up, each SD increase of ALP was associated with a 12 and 14% higher risk of disability (adjusted odds ratio (OR): 1.12; 95% CI: 1.06–1.18; p

Background China is one of the countries with the highest burden of stroke. Implementing multidimensional management guidelines will help clinicians practise evidence-based care, improve patient outcomes and alleviate societal burdens. This update of the 2019 edition will provide the latest comprehensive recommendations for the diagnosis and treatment of ischaemic cerebrovascular diseases.Methods We conducted a comprehensive search on MEDLINE (via PubMed) up to 31 August 2023. The writing team established the recommendations through multiple rounds of online and offline discussions. Each recommendation was graded using the evidence grading algorithm developed by the Chinese Stroke Association (CSA). The draft was reviewed and finalised by the CSA Stroke Guidelines Writing Committee.Results This update included revisions of 15 existing recommendations and 136 new recommendations in the following areas of stroke care: emergency assessment and diagnosis of ischaemic cerebrovascular disease, acute-phase reperfusion therapy, evaluation of underlying mechanisms, antithrombotic therapy, prevention and treatment of complications, and risk factor management.Conclusions This guideline updated the recommendations for the clinical management of ischaemic cerebrovascular disease from 2019.

Astrocytes are important cellular centers of cholesterol synthesis and metabolism that help maintain normal physiological function at the organism level. Spinal cord injury results in aberrant cholesterol metabolism by astrocytes and excessive production of oxysterols, which have profound effects on neuropathology. 25-Hydroxycholesterol (25-HC), the main product of the membrane-associated enzyme cholesterol-25-hydroxylase (CH25H), plays important roles in mediating neuroinflammation. However, whether the abnormal astrocyte cholesterol metabolism induced by spinal cord injury contributes to the production of 25-HC, as well as the resulting pathological effects, remain unclear. In the present study, spinal cord injury-induced activation of thrombin was found to increase astrocyte CH25H expression. A protease-activated receptor 1 inhibitor was able to attenuate this effect in vitro and in vivo. In cultured primary astrocytes, thrombin interacted with protease-activated receptor 1, mainly through activation of the mitogen-activated protein kinase/nuclear factor-kappa B signaling pathway. Conditioned culture medium from astrocytes in which ch25h expression had been knocked down by siRNA reduced macrophage migration. Finally, injection of the protease activated receptor 1 inhibitor SCH79797 into rat neural sheaths following spinal cord injury reduced migration of microglia/macrophages to the injured site and largely restored motor function. Our results demonstrate a novel regulatory mechanism for thrombin-regulated cholesterol metabolism in astrocytes that could be used to develop anti-inflammatory drugs to treat patients with spinal cord injury.

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 We aimed to investigate the risk factors of early neurological deterioration (END) after intravenous thrombolysis with recombinant tissue-type plasminogen activator (rt-PA) and the relationship between END and poor 3-month functional outcomes. Methods Patients who accepted intravenous recombinant rt-PA were enrolled continuously. END was defined as an increase in National Institute of Health Stroke (NIHSS) score ≥ 4 points or death within 24 hours after intravenous thrombolysis. The modified Rankin Scale (mRS) score was recorded to evaluate the functional outcome of stroke, and the poor 3-month prognosis was defined as an mRS score ≥ of 3. Univariate and multivariate analyses were used to analyze the risk factors of END. The relation between END and 3-month functional outcome was analyzed by multivariate logistic regression analysis. Results A total of 1107 patients (mean age, 63.42 ± 11.33 years; 673 males) were included in the final analysis, and 81(7.32%) patients had END. In multivariate analysis, the serum glucose level was significantly associated with END; the odds ratio was 1.10 (95% CI 1.03 to 1.18, p = 0.004). The multivariate logistic analysis showed END has a notable association with the poor 3-month functional recovery even after adjusting for confounding factors; the adjusted OR was 8.25 (95% CI 3.77 to 18.03, p

Abstract Objective Contribution of individual and combined inflammatory markers in prognosis after stroke was still undefined. We aimed to investigate the association of systemic and local vascular inflammatory markers and recurrent stroke as well as impact on poor functional outcome. Methods In this pre-specified substudy of the Third China National Stroke Registry (CNSR-III), 10,472 consecutive acute ischemic stroke or TIA patients with available centralized-measured levels of Interleukin-6 (IL-6), high sensitive C-reactive protein (hsCRP), IL-1 receptor antagonist (IL-1Ra), lipoprotein-associated phospholipase A2 mass (Lp-PLA2) and activity (Lp-PLA2-A), and YKL-40 from 171 sites were enrolled. The primary outcomes consisted of stroke recurrence and poor functional outcome defined as modified Rankin Scale (mRS) score of 2–6 within 1 year. Results There were 1026 (9.8%) and 2395 (23.4%) patients with recurrent stroke and poor functional outcome within 1 year. The highest quartiles of IL-6 (adjusted HR, 1.36; 95% CI 1.13–1.64; P = 0.001), hsCRP (adjusted HR, 1.41; 95% CI 1.17–1.69; P = 0.0003) and YKL-40 (adjusted HR, 1.28; 95% CI 1.06–1.56; P = 0.01) were associated with increased risk of recurrent stroke; and the highest quartiles of IL-6 (adjusted OR 1.93; 95% CI 1.64–2.27; P

Abstract Background This study investigated the relationships of neutrophil count (NC), neutrophil-to-lymphocyte ratio (NLR) and systemic immune-inflammation index (SII) with cerebral small vessel disease (CSVD). Methods A total of 3052 community-dwelling residents from the Poly-vasculaR Evaluation for Cognitive Impairment and vaScular Events (PRECISE) study were involved in this cross-sectional study. CSVD burden and imaging markers, including white matter hyperintensity (WMH), lacunes, cerebral microbleeds (CMBs) and enlarged perivascular spaces in basal ganglia (BG-EPVS), were assessed according to total CSVD burden score. The associations of NC, NLR and SII with CSVD and imaging markers were evaluated using logistic regression models. Furthermore, two-sample Mendelian randomization (MR) analysis was performed to investigate the genetically predicted effect of NC on CSVD. The prognostic performances of NC, NLR and SII for the presence of CSVD were assessed. Results At baseline, the mean age was 61.2 ± 6.7 years, and 53.5% of the participants were female. Higher NC was suggestively associated with increased total CSVD burden and modified total CSVD burden (Q4 vs. Q1: common odds ratio (cOR) 1.33, 95% CI 1.05–1.70; cOR 1.28, 95% CI 1.02–1.60) and marginally correlated with the presence of CSVD (OR 1.29, 95% CI 1.00–1.66). Furthermore, elevated NC was linked to a higher risk of lacune (OR 2.13, 95% CI 1.25–3.62) and moderate-to-severe BG-EPVS (OR 1.67, 95% CI 1.14–2.44). A greater NLR was related to moderate-to-severe BG-EPVS (OR 1.68, 95% CI 1.16–2.45). Individuals with a higher SII had an increased risk of modified WMH burden (OR 1.35, 95% CI 1.08–1.69) and moderate-to-severe BG-EPVS (OR 1.70, 95% CI 1.20–2.41). MR analysis showed that genetically predicted higher NC was associated with an increased risk of lacunar stroke (OR 1.20, 95% CI 1.04–1.39) and small vessel stroke (OR 1.21, 95% CI 1.06–1.38). The addition of NC to the basic model with traditional risk factors improved the predictive ability for the presence of CSVD, as validated by the net reclassification index and integrated discrimination index (all p

Abstract Background The danger-associated molecular patterns (DAMPs) are critical contributors to the progressive neuropathology and thereafter affect the functional outcomes following spinal cord injury (SCI). Up to now, the regulatory mechanisms on their inducible production from the living cells remain elusive, aside from their passive release from the necrotic cells. Thrombin is immediately activated by the damaged or stressed central nervous system (CNS), which potently mediates inflammatory astrocytic responses through proteolytic cleavage of protease-activated receptors (PARs). Therefore, SCI-activated thrombin is conceived to induce the production of DAMPs from astrocytes at lesion site. Methods Rat SCI model was established by the cord contusion at T8–T10. The expression of thrombin and macrophage migration inhibitory factor (MIF) was determined by ELISA and Western blot. The PAR1, PAR3, and PAR4 receptors of thrombin were examined by PCR and immunohistochemistry. Primary astrocytes were isolated and purified from the spinal cord, followed by stimulation with different concentrations of thrombin either for transcriptome sequencing or for analysis of thrombin-mediated expression of MIF and related signal pathways in the presence or absence of various inhibitors. The post-injury locomotor functions were assessed using the Basso, Beattie, and Bresnahan (BBB) locomotor scale. Results MIF protein levels were significantly elevated in parallel with those of thrombin induced by SCI. Immunostaining demonstrated that PAR1 receptor, together with MIF, was abundantly expressed in astrocytes. By transcriptome sequencing and bioinformatical analysis of thrombin-stimulated primary astrocytes, MIF was identified to be dynamically regulated by the serine protease. Investigation of the underlying mechanism using various inhibitors revealed that thrombin-activated PAR1 was responsible for the MIF production of astrocytes through modulation of JNK/NFκB pathway. Administration of PAR1 inhibitor at lesion sites following SCI significantly reduced the protein levels of MIF and ameliorated functional deficits of rat locomotion. Conclusion SCI-activated thrombin is a robust inducer of MIF production from astrocytes. Exploring the roles of thrombin in promoting the production of DAMPs from astrocytes at lesion site will provide an alternative strategy for the clinical therapy of CNS inflammation.

Abstract Backgroud and purpose Triglyceride-glucose (TyG) index has been considered a surrogate marker of insulin resistance. We investigated the association between TyG index and stroke recurrence and compared the effectiveness of TyG index with homeostasis model assessment of insulin resistance (HOMA-IR) in predicting stroke recurrence and death in nondiabetic acute ischemic stroke patients. Methods Nondiabetic acute ischemic stroke patients from the ACROSS-China (Abnormal Glucose Regulation in Patients with Acute Stroke across China) registry were included. TyG index was performed and classified into four groups by quartiles. The outcomes were stroke recurrence and death within 1 year. The association between TyG index and the risk of stroke recurrence and death were analyzed by Cox regression models. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the prediction of TyG index and HOMA-IR for stroke recurrence and death. Delong test was used for comparing the differences between area under the curve (AUC) of TyG index and HOMA-IR. Results Among the 1226 patients included, the median (interquartile range) of TyG index was 5.8 (5.5–6.2). Both the third and fourth quartiles of TyG index were associated with an increased risk of stroke recurrence (adjusted hazard ratio 2.04, 95% confidence interval 1.26–3.31; adjusted hazard ratio 1.86, 95% confidence interval 1.13–3.06). Patients with fourth quartiles of TyG index were associated with a higher mortality risk (adjusted hazard ratio, 2.91; 95% confidence interval, 1.62–2.53). Regarding stroke recurrence within 1 year, the AUC (95% confidence interval) of the ROC curve for the TyG index was similar to that of the HOMA-IR[0.56 (0.52–0.61) vs 0.57 (0.52–0.61); P = 0.93]. Regarding death within 1 year, the AUCs (95% confidence interval) of the ROC curve for the TyG index and HOMA-IR were 0.55 (0.50–0.61) and 0.59 (0.53–0.64), respectively (P = 0.32). Conclusions Elevated TyG index was associated with an increased risk of stroke recurrence and death. However, neither of TyG nor HOMA-IR can be a qualified predictor of stroke recurrence and death in nondiabetic acute ischemic stroke patients.

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 The association of lipoprotein(a) [Lp(a)] and stroke functional outcomes was conflicting. The aim of the study was to clarify whether high Lp(a) is associated with unfavorable functional outcomes in patients with ischemic stroke. Methods A total of 9709 individuals from the third China National Stroke Registry cohort were recruited. Plasma level of Lp(a) at admission was measured with enzyme-linked immunosorbent assay. The cut-off was set at the median for Lp(a). Functional outcome was assessed using the modified Rankin scale (mRS) at 3 months and 1 year after ischemic stroke. The association between Lp(a) and functional outcomes was evaluated using a logistic regression model. Results The median age was 63.0 years, and 31.1% participants were women. Patients in higher Lp(a) group had higher incidences of unfavorable functional outcomes at 3 months. In logistic regression model, elevated Lp(a) levels were associated with unfavorable functional outcomes at 3 months (Q4 vs. Q1: odds ratio 1.33, 95% confidence interval 1.11–1.61). Subgroup analysis showed that in the lower Lp-PLA2 group, Lp(a) level was not associated with functional outcomes, but in the higher Lp-PLA2 group, Lp(a) level was significantly associated with functional outcomes. After grouped by different levels of Lp(a) and Lp-PLA2, the Lp(a) high/ Lp-PLA2 high group showed the highest incidence of unfavorable functional outcomes at 3 months and 1 year. Conclusions Elevated Lp(a) level is associated with unfavorable functional outcomes in patients with ischemic stroke. The increment in both Lp(a) and Lp-PLA2 are associated with unfavorable functional outcomes at 3 months and 1 year after ischemic stroke.

Abstract Background The prognostic value of serum bilirubin in stroke is controversial, since bilirubin has both neuroprotective and neurotoxic properties. We aimed to investigate the association between serum bilirubin, including total bilirubin (TBIL), direct bilirubin (DBIL) and indirect bilirubin (IBIL) and poor functional outcomes in patients with acute ischemic stroke (AIS) or transient ischemic attack (TIA). Methods All patients with AIS or TIA were recruited from the Third China National Stroke Registry. The poor functional outcomes included modified Rankin Scale (mRS) score 2–6 and 3–6 at 3 months and 1 year. Multivariable logistic regression was used to investigate the associations of TBIL, DBIL, and IBIL with poor functional outcomes. Results Among 11,121 enrolled patients, the median (interquartile range) of TBIL, DBIL, and IBIL was 13.30 (9.90–17.70), 3.80 (2.70–5.30), and 9.30 (6.70–12.80) µmol/L. After adjustment for conventional confounding factors, patients in the highest TBIL quartile had the highest proportion of mRS score 2–6 at 3 months (odds ratio [OR], 1.37; 95 % confidence interval [CI], 1.19–1.59) and 1 year (OR, 1.31; 95 % CI, 1.13–1.52), and mRS score 3–6 at 3 months (OR, 1.33; 95 % CI, 1.11–1.59) and 1 year (OR, 1.28; 95 % CI, 1.07–1.53), when compared to patients in the lowest TBIL quartile. Similar results were observed for DBIL and IBIL. We also found J-shaped associations between serum bilirubin levels and each outcome. Conclusions Elevated levels of serum bilirubin were significantly associated with poor functional outcomes in patients with AIS or TIA at 3 months and 1 year.

Abstract Background Two activation states of reactive astrocytes termed A1 and A2 subtypes emerge at the lesion sites following spinal cord injury (SCI). A1 astrocytes are known to be neurotoxic that participate in neuropathogenesis, whereas A2 astrocytes have been assigned the neuroprotective activity. Heat shock transcription factor 1 (HSF1) plays roles in protecting cells from stress-induced apoptosis and in controlling inflammatory activation. It is unknown whether HSF1 is involved in suppressing the conversion of A1 astrocytes following SCI. Methods A contusion model of the rat spinal cord was established, and the correlations between HSF1 expression and onset of A1 and A2 astrocytes were assayed by Western blot and immunohistochemistry. 17-AAG, the agonist of HSF1, was employed to treat the primary cultured astrocytes following a challenge by an A1-astrocyte-conditioned medium (ACM) containing 3 ng/ml of IL-1α, 30 ng/ml of TNF-α, and 400 ng/ml of C1q for induction of the A1 subtype. The effects of 17-AAG on the phenotype conversion of astrocytes, as well as underlying signal pathways, were examined by Western blot or immunohistochemistry. Results The protein levels of HSF1 were significantly increased at 4 days and 7 days following rat SCI, showing colocalization with astrocytes. Meanwhile, C3-positive A1 astrocytes were observed to accumulate at lesion sites with a peak at 1 day and 4 days. Distinctively, the S100A10-positive A2 subtype reached its peak at 4 days and 7 days. Incubation of the primary astrocytes with ACM markedly induced the conversion of the A1 phenotype, whereas an addition of 17-AAG significantly suppressed such inducible effects without conversion of the A2 subtype. Activation of HSF1 remarkably inhibited the activities of MAPKs and NFκB, which was responsible for the regulation of C3 expression. Administration of 17-AAG at the lesion sites of rats was able to reduce the accumulation of A1 astrocytes. Conclusion Collectively, these data reveal a novel mechanism of astrocyte phenotype conversion following SCI, and HSF1 plays key roles in suppressing excessive increase of neurotoxic A1 astrocytes.

Abstract Background and objective The effect of atrial fibrillation (AF) on outcomes of endovascular treatment (EVT) for acute ischemic stroke (AIS) is controversial. This study aimed to investigate the association of AF with outcomes after EVT in AIS patients. Methods Subjects were selected from ANGEL-ACT registry (Endovascular Treatment Key Technique and Emergency Work Flow Improvement of Acute Ischemic Stroke) - a prospective consecutive cohort of AIS patients undergoing EVT at 111 hospitals in China between November 2017 and March 2019, and then grouped according to having a history of AF or not. After 1:1 propensity score matching, the outcome measures including the 90-day modified Rankin Scale (mRS) score, successful recanalization after final attempt, symptomatic intracranial hemorrhage (ICH) within 24 h, and death within 90 days were compared. Results A total of 1755 patients, 550 with AF and 1205 without AF, were included. Among 407 pairs of patients identified after matching, no significant differences were found in the mRS score (median: 3 vs. 3 points; P = 0.29), successful recanalization (87.2 vs. 85.3%; P = 0.42), symptomatic ICH (9. 4 vs. 9.1%; P = 0.86) and death (16.3 vs. 18.4%; P = 0.44) between patients with and without AF. Conclusion The findings of this matched-control study show comparable outcomes of EVT in Chinese AIS patients with and without AF, which do not support withholding EVT in patients with both AIS and AF. Trial registration NCT03370939 First registration date: 28/09/2017 First posted date: 13/12/2017

Background Reperfusion therapy is the most effective treatment for acute ischaemic stroke (AIS) but remains underutilised in China. There is an urgent need to develop tailored strategies to increase adherence to intravenous thrombolysis (IVT) and endovascular thrombectomy (EVT) within the guideline-recommended time window for eligible patients.Aims This study aims to investigate the efficacy of a comprehensive quality improvement intervention on adherence to guideline-recommended reperfusion therapy for patients with AIS in China.Design The Improve Acute Reperfusion Treatment Quality for Stroke in China (IMPROVE Stroke Care in China) trial is designed as a stepped wedge cluster randomised trial within 51 hospitals. We developed the comprehensive intervention ‘STEP’ (Strategies, Toolkit, Exploration, Paradigm) to promote the reconstruction of workflow in stroke centres and shorten in-hospital delay of reperfusion treatment for patients with AIS. The participating hospitals (clusters) were randomised to three groups (cohorts) for different predefined steps to intervention implementation. The primary outcome was the adherent rate of IVT or EVT for eligible patients within the time window. The sample size was estimated to be 7644, and was determined by the number of cases to be enrolled in five study periods to detect a relative increase of 30% (from 19% to 25%) with 90% power and intraclass correlation coefficient of 0.03. All efficacy analyses will be conducted based on the intention-to-treat principle. The primary outcome will be analysed using a mixed-effects logistic regression with a random effect for the cluster (hospital), and a fixed effect for the strategy and period.Conclusions If the efficacy is well established, this targeted comprehensive intervention STEP will inform national strategies to increase adherence to guideline-recommended performance on reperfusion therapy.Trial registration number clinicaltrials.gov Identifier: NCT003578107

ObjectiveThe aim of this study was to investigate the pattern of volume changes in neurofunctional hippocampal subfields in patients with insomnia and their associations with risk of development of insomnia.MethodsA total of 120 patients with insomnia (78 females, 42 males; mean age ± standard deviation, 43.74 ± 13.02 years) and 120 good sleepers (67 females, 53 males; mean age, 42.69 ± 12.24 years) were recruited. The left hippocampus was segmented into anterior (L1), middle (L2), and posterior (L3) subregions. The right hippocampus was segmented into top anterior (R1), second top anterior (R2), middle (R3), posterior (R4), and last posterior (R5) subregions. Multivariate logistic regression was used to evaluate the associations of hippocampal volume (HV) of each subfield with the risk of the development of insomnia. Mediation analyses were performed to evaluate mediated associations among post-insomnia negative emotion, insomnia severity, and HV atrophy. A visual easy-to-deploy risk nomogram was used for individual prediction of risk of development of insomnia.ResultsHippocampal volume atrophy was identified in the L1, R1, and R2 subregions. L1 and R2 volume atrophy each predisposed to an ~3-fold higher risk of insomnia (L1, odds ratio: 2.90, 95% confidence intervals: [1.24, 6.76], p = 0.014; R2, 2.72 [1.19, 6.20], p = 0.018). Anxiety fully mediates the causal path of insomnia severity leading to R1 volume atrophy with a positive effect. We developed a practical and visual competing risk-nomogram tool for individual prediction of insomnia risk, which stratifies individuals into different levels of insomnia risk with the highest prediction accuracy of 97.4% and an average C-statistic of 0.83.ConclusionHippocampal atrophy in specific neurofunctional subfields was not only found to be associated with insomnia but also a significant risk factor predicting development of insomnia.

Background and purposeStudies showed that patients with hemorrhagic stroke are at a higher risk of developing deep vein thrombosis (DVT) than those with ischemic stroke. We aimed to develop a risk score (intracerebral hemorrhage-associated deep vein thrombosis score, ICH-DVT) for predicting in-hospital DVT after ICH.MethodsThe ICH-DVT was developed based on the Beijing Registration of Intracerebral Hemorrhage, in which eligible patients were randomly divided into derivation (60%) and internal validation cohorts (40%). External validation was performed using the iMCAS study (In-hospital Medical Complication after Acute Stroke). Independent predictors of in-hospital DVT after ICH were obtained using multivariable logistic regression, and β-coefficients were used to generate a scoring system of the ICH-DVT. The area under the receiver operating characteristic curve (AUROC) and the Hosmer–Lemeshow goodness-of-fit test were used to assess model discrimination and calibration, respectively.ResultsThe overall in-hospital DVT after ICH was 6.3%, 6.0%, and 5.7% in the derivation (n = 1,309), internal validation (n = 655), and external validation (n = 314) cohorts, respectively. A 31-point ICH-DVT was developed from the set of independent predictors including age, hematoma volume, subarachnoid extension, pneumonia, gastrointestinal bleeding, and length of hospitalization. The ICH-DVT showed good discrimination (AUROC) in the derivation (0.81; 95%CI = 0.79–0.83), internal validation (0.83, 95%CI = 0.80–0.86), and external validation (0.88; 95%CI = 0.84–0.92) cohorts. The ICH-DVT was well calibrated (Hosmer–Lemeshow test) in the derivation (P = 0.53), internal validation (P = 0.38), and external validation (P = 0.06) cohorts.ConclusionThe ICH-DVT is a valid grading scale for predicting in-hospital DVT after ICH. Further studies on the effect of the ICH-DVT on clinical outcomes after ICH are warranted.

Abstract Background Astrocytes are the predominant glial cell type in the central nervous system (CNS) that can secrete various cytokines and chemokines mediating neuropathology in response to danger signals. D-dopachrome tautomerase (D-DT), a newly described cytokine and a close homolog of macrophage migration inhibitory factor (MIF) protein, has been revealed to share an overlapping function with MIF in some ways. However, its cellular distribution pattern and mediated astrocyte neuropathological function in the CNS remain unclear. Methods A contusion model of the rat spinal cord was established. The protein levels of D-DT and PGE2 synthesis-related proteinase were assayed by Western blot and immunohistochemistry. Primary astrocytes were stimulated by different concentrations of D-DT in the presence or absence of various inhibitors to examine relevant signal pathways. The post-injury locomotor functions were assessed using the Basso, Beattie, and Bresnahan (BBB) locomotor scale. Results D-DT was inducibly expressed within astrocytes and neurons, rather than in microglia following spinal cord contusion. D-DT was able to activate the COX2/PGE2 signal pathway of astrocytes through CD74 receptor, and the intracellular activation of mitogen-activated protein kinases (MAPKs) was involved in the regulation of D-DT action. The selective inhibitor of D-DT was efficient in attenuating D-DT-induced astrocyte production of PGE2 following spinal cord injury, which contributed to the improvement of locomotor functions. Conclusion Collectively, these data reveal a novel inflammatory activator of astrocytes following spinal cord injury, which might be beneficial for the development of anti-inflammation drug in neuropathological CNS.

Abstract Background Cervicocerebral artery dissection is an important cause of ischemic stroke in young and middle-aged individuals. However, very few studies have compared the differential features between internal carotid artery dissection (ICAD) and vertebral artery dissection (VAD), including both cervical and intracranial artery dissections. We conducted a study to investigate the predisposing factors and radiological features in patients with ICAD or VAD. Methods All cases diagnosed with cervicocerebral artery dissection, ICAD, or VAD were identified through a medical records database, between January 2010 and January 2020. Baseline characteristics, predisposing factors, and radiological features of ICAD versus VAD were compared. Results A total of 140 patients with cervicocerebral artery dissection were included in the study, including 84 patients in the ICAD group and 56 in the VAD group. The mean age of patients in the ICAD and VAD groups was 43.37 ± 14.01 and 41.00 ± 12.98 years old, respectively. Patients with ICAD were more likely to be men compared with VAD (85.71% vs. 67.86%, p = 0.012). The frequency of hypertension, diabetes, smoking, drinking, and cervical trauma did not differ between ICAD and VAD. Dissections of ICAD were more frequently at the extracranial portions of the artery compared with those of VAD (70.24% vs. 44.64%, p = 0.003). In contrast, dissections of VAD were more common in the intracranial artery (55.36% vs. 29.76%, p = 0.003). Radiologically, double lumen (36.90% vs. 19.64%, p = 0.029) and intimal flap (11.90% vs. 1.79%, p = 0.029) were more frequently observed in ICAD than in VAD, and dissecting aneurysms were less frequent (13.10% vs. 26.79%, p = 0.041). Conclusions The distributions of cervical and intracranial artery dissections were different between ICAD and VAD. The frequencies of radiological features detected in patients with ICAD and VAD also differed.

Background and ObjectivesCraniocervical artery dissection (CAD) is the most common cause of ischemic stroke in young adults. The etiologies of CAD can be classified into three types, such as spontaneous (sCAD), minor traumatic (mtCAD), and genetic origin. Recent studies indicated that clinical presentations and imaging features could guide management and inform prognosis. This retrospective analysis sought to compare the clinical and imaging features of sCAD vs. mtCAD in providing evidence-based advice on medical treatment, functional rehabilitation, secondary stroke prevention, and prognosis, ultimately formulating clinical guidelines in managing CAD.MethodsIn total, 148 patients with CAD were identified from the medical records database and subdivided into sCAD and mtCAD based on the clinical presentations and imaging features. A retrospective comparative analysis was performed according to their clinical presentations and imaging features.ResultsPatients with mtCAD are significantly younger than sCAD with 120 cases of sCAD average aged 43.61 ± 12.75, while 28 cases of mtCAD average aged 35.68 ± 14.54. Patients with mtCAD had more cases of neck pain compared to sCAD. Patients with mtCAD had more cases of CAD at extracranial locations compared to sCAD. Patients with mtCAD had more cases of multiple site dissection compared to sCAD. Double lumen and intramural haematoma are the most common imaging findings with mtCAD patients having statistical significantly more cases of intramural haematoma and long tapering stenosis.ConclusionPatients with mtCAD were presented at a much younger age with symptoms of neck pain compared to sCAD. Patients with mtCAD predominantly presented at extracranial sites with more prominent features of multiple site dissection, intramural haematoma, and long tapering stenosis. These clinical and imaging features can translate into clinical practice guidelines for patients with CAD to improve the optimal functional outcome and reduce both morbidity and mortality.

Inorganic and organic nitrates are present in vivo and in vitro. Inorganic nitrate is considered a pool of nitric oxide (NO), but it can be converted into nitrite and NO through various mechanisms. It plays an important role in the regulation of complex physiological and biochemical reactions, such as anti-inflammatory processes and the inhibition of platelet aggregation, which are closely related to the pathology and treatment of cerebrovascular disease. Ischemic cerebrovascular disease is characterized by high incidence, recurrence, and disability rates. Nitrate, nitrite, and NO were recently found to be involved in cerebrovascular disease. In this review, we describe the relationship between cerebrovascular disease and nitrate metabolism to provide a basis for further advances in laboratory and clinical medicine.

In acute ischemic stroke patients with large vessel occlusion, the characteristics of the occluding thrombus on neuroimaging may be associated with recanalization after endovascular thrombectomy (EVT); however, the relationship between magnetic susceptibility of thrombus and clinical outcome remains unclear. We utilized quantitative susceptibility mapping (QSM) MRI to assess the magnetic susceptibility of thrombus in acute ischemic stroke patients undergoing EVT, and to evaluate its relationship with recanalization and functional outcomes. Patients with documented intracranial artery occlusion were consecutively recruited from one research center of the RESCUE-RE study (a registration study for Critical Care of Acute Ischemic Stroke After Recanalization). All the recruited patients underwent a 3D multi-echo MRI scan on a 3.0 T scanner for both susceptibility-weighted imaging (SWI) and QSM quantification of the thrombus. Among 61 patients included in the analyses, 51 (75.0 %) patients achieved thrombolysis in cerebral infarction (TICI) 2b/3 and 22 (36.1 %) patients had favorable functional outcomes. Successful recanalization was significantly associated with a higher thrombus magnetic susceptibility mean value (0.27 ± 0.09 vs 0.20 ± 0.09 ppm, p = 0.020) and lower coefficient of variation (0.42 ± 0.12 vs 0.52 ± 0.19, p = 0.024). ROC curve analysis showed the optimal cutoff value for thrombus susceptibility for predicting good clinical outcomes was 0.25 ppm (sensitivity 86.4 %, specificity 69.2 %). In multivariable logistic regression analyses, increased thrombus magnetic susceptibility was independently and significantly associated with good functional outcomes (adjusted odds ratio 15.11 [95 % confidence interval 2.64–86.46], p = 0.002). This study demonstrated that the increased thrombus magnetic susceptibility is associated with successful recanalization and favorable functional outcomes for intracranial artery occluded stroke patients.

Background and Purpose: Although elevated serum lipoprotein (a) [Lp(a)] is considered to be a risk factor of ischemic stroke, the relationship between Lp(a) and cognitive impairment after stroke remains unclear. This study investigated the association between serum Lp(a) and cognitive function after acute ischemic stroke (AIS) or transient ischemic attack (TIA).Methods: The study included 1,017 patients diagnosed with AIS or TIA from the cognition subgroup of the Third China National Stroke Registry (CNSR3). Montreal Cognitive Assessment (MoCA) at 2 weeks or discharge, 3 months, and 1 year was evaluated. The primary outcome was cognitive impairment at 1 year, defined as MoCA ≤ 22. The secondary outcome was cognition improvement at 1 year compared with 2 weeks. The association between Lp(a) levels and cognitive function was analyzed.Results: Among the 1,017 patients included, 326 (32.1%) had cognitive impairment at 1 year. Patients with MoCA ≤ 22 at 1 year were older, received less education, and had higher baseline NIHSS, higher proportion of ischemic stroke history, large artery atherosclerosis (LAA) subtype, and multiple infarctions (P < 0.05 for all). Patients with highest Lp(a) quartile had slightly higher percentage of cognitive impairment at 1 year but without statistical difference. In subgroup analysis of LAA subtype, the patients with highest Lp(a) quartile had higher percentage of cognitive impairment at 1 year (adjusted OR:2.63; 95% CI: 1.05–6.61, P < 0.05). What is more, the patients with highest Lp(a) quartile in LAA subtype had lower percentage of cognition improvement at 1 year. However, similar results were not found in small artery occlusion (SAO) subtype.Conclusion: Higher Lp(a) level was associated with cognitive impairment and less improvement of cognition in patients after AIS or TIA with large-artery atherosclerosis subtype.

Objective: Skull fractures caused by head trauma can lead to life-threatening complications. Hence, timely and accurate identification of fractures is of great importance. Therefore, this study aims to develop a deep learning system for automated identification of skull fractures from cranial computed tomography (CT) scans.Method: This study retrospectively analyzed CT scans of 4,782 patients (median age, 54 years; 2,583 males, 2,199 females; development set: n = 4,168, test set: n = 614) diagnosed with skull fractures between September 2016 and September 2020. Additional data of 7,856 healthy people were included in the analysis to reduce the probability of false detection. Skull fractures in all the scans were manually labeled by seven experienced neurologists. Two deep learning approaches were developed and tested for the identification of skull fractures. In the first approach, the fracture identification task was treated as an object detected problem, and a YOLOv3 network was trained to identify all the instances of skull fracture. In the second approach, the task was treated as a segmentation problem and a modified attention U-net was trained to segment all the voxels representing skull fracture. The developed models were tested using an external test set of 235 patients (93 with, and 142 without skull fracture).Results: On the test set, the YOLOv3 achieved average fracture detection sensitivity and specificity of 80.64, and 85.92%, respectively. On the same dataset, the modified attention U-Net achieved a fracture detection sensitivity and specificity of 82.80, and 88.73%, respectively.Conclusion: Deep learning methods can identify skull fractures with good sensitivity. The segmentation approach to fracture identification may achieve better results.

Objective: Cystatin C, a marker of atherosclerosis, is encoded by CST3. We aimed to evaluate whether two single-nucleotide polymorphisms (SNPs) of CST3 are correlated with large-artery atherosclerotic stroke (LAAS) and prognosis.Methods: This subgroup analysis of the Third China National Stroke Registry (CNSR-III) enrolled acute ischemic stroke (AIS) patients within 7 days from August 2015 to March 2018 in China. rs13038305 and rs911119 of CST3 were selected based on the strong association with cystatin C concentration.Results: Two loci of CST3 (rs13038305 and rs911119) were analyzed in 3,833 ischemic stroke patients. Carriers of T allele in rs13038305 and C allele in rs911119 tend to have lower serum cystatin C levels (p < 0.05). Compared with C/C as a reference in rs13038305, odds ratio (OR) of T/T was 0.486, 95% CI 0.237–0.994, p = 0.048. Per C allele of rs13038305 also showed an increased level of low-density lipoprotein cholesterol (LDL-C), β (95% CI) was 1.335 (1.008–1.250), p = 0.044. No correlation was found between the selected SNPs and stroke prognosis (functional outcome, recurrence, and mortality).Conclusions: Carriers of the T allele in rs13038305 tend to have a lower proportion of LAAS. rs13038305 and rs911119 polymorphisms were likely to affect cystatin C concentration independently of kidney function.

Objective: We aimed to investigate the distribution of [68Ga]Ga-p14-032, a novel PET ligand that binds to vascular amyloid, in patients diagnosed clinically with probable cerebral amyloid angiopathy (CAA) compared with patients with Alzheimer's disease (AD) and normal controls (NC).Methods: This longitudinal cohort study was composed of 10 subjects (three probable CAA patients, two AD patients, five NC subjects), recruited from a clinic in China. CAA patients had a history of lobar intracerebral hemorrhage (ICH) and met modified Boston criteria for probable CAA. All participants were aged at least 55 years and underwent [68Ga] Ga-p14-032 PET/CT or/and PET/MRI, and the Montreal Cognitive Assessment on initial assessment. Demographics were measured at baseline (diabetes, hypertension, hypercholesterolemia, ischemic stroke, and ICH). Two PET imaging experts reviewed the PET images with cortical standardized uptake value ratio (SUVr) displayed on a color scale and visually classified the images as positive or negative. The mean of SUVr was calculated using the pons as reference.Results: In CAA patients, PET scans were positive in regions with higher numbers of CMBs. No significant signal was seen in AD subjects or controls. The relative [68Ga]Ga-p14-032 retention in the cortex was stronger in patients with CAA than AD and NC (median SUVr 2.68 ± 1.53 vs. 1.77 ± 0.08 and 0.83 ± 0.24).Conclusions: Our results provide early evidence that the [68Ga] Ga-p14-032 PET probe binds preferentially to vascular amyloid and may be a useful tracer for diagnosing CAA.

Background and purpose: This study aimed to examine the association of polyvascular disease and clinical outcomes in patients with lacunar stroke.Methods: Data of patients with recent lacunar stroke were collected from The Third China National Stroke Registry. Polyvascular disease is defined as the existence of atherosclerosis across two or more vascular beds. For the present study, polyvascular disease patients were grouped as follows: coronary heart disease (CHD) and lacunar stroke, peripheral arterial disease (PAD) and lacunar stroke, and CHD/PAD and lacunar stroke. The major clinical outcome was recurrence, and the secondary clinical outcome was major adverse cardiovascular events (MACEs). A Cox proportional multivariable hazards regression model was applied to estimate the association between polyvascular disease and outcomes.Results: Among 3,165 patients with recent lacunar stroke, CHD was present in 375 (11.8%) and peripheral arterial disease in 168 (5.3%). The hazard ratio (HR) for stroke recurrence was 0.98 (95% confidence interval [CI], 0.65–1.46; p = 0.91) for patients with CHD and lacunar stroke, 1.07 (95% CI, 0.61–1.87; p = 0.82) for patients with PAD and lacunar stroke, and 0.95 (95% CI, 0.66–1.35; p = 0.75) for patients with CHD/PAD and lacunar stroke compared with patients with isolated lacunar stroke. The HR for MACEs was 1.01 (95% CI, 0.69–1.49; p = 0.94) for patients with CHD and lacunar stroke, 1.11 (95% CI, 0.65–1.90; p = 0.71) for patients with PAD and lacunar stroke, and 0.99 (95% CI, 0.70–1.40; p = 0.95) for patients with CHD/PAD and lacunar stroke.Conclusion: Polyvascular disease is not associated with recurrence of stroke and MACEs in patients with recent lacunar stroke at 1 year.

Objective: There are limited data regarding the characteristics of intracranial plaques according to stroke mechanism in the posterior circulation. This study aims to compare whether the plaque characteristics and baseline features are different in patients with artery-to-artery (A-to-A) embolism and those with parent artery disease in the intracranial vertebrobasilar atherosclerotic disease.Methods: From September 2014 to January 2017, patients with recent posterior circulation stroke due to intracranial vertebrobasilar atherosclerotic disease were retrospectively analyzed. Patients with the following eligibility criteria were included: (1) age ≥18 years old, (2) ischemic stroke in the vertebrobasilar territory, (3) 70–99% stenosis of the intracranial vertebral artery or basilar artery, and (4) two or more atherosclerotic risk factors. Patients with concomitant ipsilateral or bilateral extracranial vertebral artery >50% stenosis, cardio-embolism, or non-atherosclerotic stenosis were excluded. The plaque characteristics, including intraplaque compositions (intraplaque hemorrhage and intraplaque calcification), intraplaque enhancement, and remodeling index, were evaluated by using 3T high-resolution magnetic resonance imaging (HRMRI). The baseline features including vascular risk factors and the involved artery were collected. Patients were divided into A-to-A embolism and parent artery disease groups based on the diffusion-weighted images, T2-weighted images, or computed tomography. The plaque characteristics and baseline features were compared between the two groups.Results: Among consecutive 298 patients, 51 patients were included. Twenty-nine patients had A-to-A embolism and 22 patients had parent artery disease. Compared with parent artery disease, the occurrence rates of intraplaque enhancement and intracranial vertebral involvement were higher in the A-to-A embolism group (79.3 vs. 36.4%; p = 0.002 and 62.1 vs. 18.2%; p = 0.002, respectively). Multivariable logistic regression analysis showed that intraplaque enhancement and intracranial vertebral artery plaques were also associated with A-to-A embolism (adjusted OR, 7.31; 95% CI 1.58–33.77; p = 0.011 and adjusted OR, 9.42; 95% CI 1.91–46.50; p = 0.006, respectively).Conclusion: Intraplaque enhancement and intracranial vertebral artery plaques seem to be more closely associated with A-to-A embolism than parent artery disease in patients with symptomatic intracranial vertebrobasilar disease.Clinical Trial Registration:http://www.clinicaltrials.gov, identifier: NCT02705599.

Objective: Serum cystatin C (CysC) is a sensitive marker of renal function to predict cardiovascular diseases. We aimed to investigate the predictive value of CysC for clinical outcomes independent of renal function in patients with acute ischemic stroke (AIS).Methods: We measured serum CysC levels in 10,256 AIS patients from Third China National Stroke Registry (CNSR-III). The primary outcome was a combination of all-cause mortality and major disability (modified Rankin scale score, 3–6). Secondary outcomes included stroke recurrence and combined vascular events at 1 year. Outcomes were analyzed using logistic regression and Cox proportional hazards models, respectively.Results: The median CysC of included patients was 0.95 mg/l (interquartile range, 0.83–1.10 mg/l). A U-shaped association was observed between CysC and primary outcome (all-cause mortality or major disability) [quartile (Q)1 vs. Q2: adjusted odds ratio (aOR) 1.29, 95% CI 1.06–1.58, p = 0.012; Q3 vs. Q2: aOR 1.12, 95% CI 0.93–1.35, p = 0.242; Q4 vs. Q2: aOR 1.35, 95% CI 1.10–1.65, p = 0.004]. A similar trend also existed in “preserved renal function” patients. Adding CysC to a model containing conventional risk factors improved the model performance with integrated discrimination improvement (IDI) of 0.13% (p = 0.016) and net reclassification index (NRI) of 13.10% (p

Abstract Background Astrocytes have been shown to produce several pro- and anti-inflammatory cytokines to maintain homeostasis of microenvironment in response to vast array of CNS insults. Some inflammation-related cytokines are responsible for regulating such cell events. Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that can be inducibly expressed in the lesioned spinal cord. Unknown is whether MIF can facilitate the production of immunosuppressive factors from astrocytes to tune milieu following spinal cord injury. Methods Following establishment of contusion SCI rat model, correlation of PGE2 synthesis-related protein levels with that of MIF was assayed by Western blot. ELISA assay was used to detect production of PGE2, TNF-α, IL-1β, and IL-6. Immunohistochemistry was performed to observe colocalization of COX2 with GFAP- and S100β-positive astrocytes. The primary astrocytes were treated by various inhibitors to validate relevant signal pathway. Results The protein levels of MIF and COX2, but not of COX1, synchronously increased following spinal cord injury. Treatment of MIF inhibitor 4-IPP to the lesion sites significantly reduced the expression of COX2, mPGES-1, and as a consequence, the production of PGE2. Astrocytes responded robustly to the MIF interference, by which regulated MAPK/COX2/PGE2 signal pathway through coupling with the CD74 membrane receptor. MIF-induced production of PGE2 from astrocytes was able to suppress production of TNF-α, but boosted production of IL-1β and IL-6 in LPS-activated macrophages. Conclusion Collectively, these results reveal a novel function of MIF-mediated astrocytes, which fine-tune inflammatory microenvironment to maintain homeostasis. These suggest an alternative therapeutic strategy for CNS inflammation.

Background and Purpose: The Enterprise stent has been used for treating intracranial atherosclerotic stenosis (ICAS), but its long-term outcome remains unclear. The purpose of this study was to evaluate the long-term clinical efficacy of the Enterprise stent used for patients with symptomatic ICAS due to hypoperfusion.Method: Patients with symptomatic ICAS due to hypoperfusion treated with the Enterprise stents from a high-volume stroke center were evaluated. The successful recanalization was defined as the Modified Thrombolysis In Cerebral Infarction (mTICI) ≥ 2b. The stroke and neurological death that occurred within 72 h after the procedure as well as long-term clinical and imaging outcomes were analyzed.Results: Overall, 130 patients with 130 ICAS treated with the Enterprise stent were included in our study. The successful recanalization rate was 100%. The mean pre- and postprocedural stenosis was 82.9 ± 8.9% vs. 15.1 ± 8.4%. Periprocedural complications occurred in 5 (3.8%) patients within 72 h after the procedure. Clinical follow-up data were available in 125 (96.2%) patients (median, 24 months) and any stroke or neurological death was encountered in 6 (4.8%) patients. Angiographic follow-up data was obtained from 118 (90.8%) patients (median, 13.5 months). In addition, 1-year in-stent restenosis (>70%) was found in 17 (14.4%) patients, and among them, 4 (23.5%) patients were symptomatic.Conclusion: Deployment of Enterprise stent is safe for ICAS. The short-term and long-term outcomes were acceptable, but the efficacy of the Enterprise stent needs to be further evaluated in future studies.

Background: Low heart rate variability (HRV) is known to be associated with increased all-cause, cardiovascular, and cerebrovascular mortality but its association with clinical outcomes in patients with transient ischemic attack (TIA) or minor stroke is unclear.Methods: We selected TIA and minor stroke patients from a prospective registration study. From each continuous electrocardiograph (ECG) record, each QRS complex was detected and normal-to-normal (N-N) intervals were determined. The standard deviation of all N-N intervals (SDNN) and the square root of the mean squared differences of successive N-N intervals (RMSSD) were calculated. Logistic regression analysis and Cox regression analysis were performed to assess the outcomes of patients at 90 days, and the odds and risk ratios (OR/HR) of each index quartile were compared.Results: Compared with SDNN patients in the lowest quartile, neurological disability was significantly reduced in other quartile groups at 90 days, with significant differences [OR of group Q2 was 0.659; 95% confidence interval (CI), 0.482–0.900; p = 0.0088; OR of group Q3 was 0.662; 95% CI, 0.478–0.916; p = 0.0127; OR of group Q4 was 0.441; 95% CI, 0.305–0.639; p

Background: The inverse association between obesity and outcome in stroke patients (known as the obesity paradox) has been widely reported, yet mechanistic details explaining the paradox are limited. The triglyceride glucose (TYG) index has been proposed as a marker of insulin resistance. We sought to explore possible associations of the TYG index, body mass index (BMI), and stroke outcome.Methods: We identified 12,964 ischemic stroke patients without a history of diabetes mellitus from the China National Stroke Registry and classified patients as either low/normal weight, defined as a BMI

Background: High plasma levels of trimethylamine N-oxide (TMAO) and its precursor choline have been linked to stroke; however, their association with cerebral small vessel disease remains unclear. Here we evaluated the association of plasma levels of TMAO and choline with imaging markers of cerebral small vessel disease, including white matter hyperintensities, lacunes, and cerebral microbleeds.Methods: We performed a baseline cross-sectional analysis of a multicenter hospital-based cohort study from 2015 to 2018. The data were collected from 30 hospitals in China and included 1,098 patients with ischemic stroke/transient ischemic attack aged ≥18 years. White matter hyperintensities, lacunes, and cerebral microbleeds were evaluated with the patients' demographic, clinical, and laboratory information removed. White matter hyperintensities were rated using the Fazekas visual grading scale, while the degree of severity of the lacunes and cerebral microbleeds was defined by the number of lesions.Results: Increased TMAO levels were associated with severe white matter hyperintensities [adjusted odds ratio (aOR) for the highest vs. lowest quartile, 1.5; 95% confidence interval (CI), 1.0–2.1, p = 0.04]. High TMAO levels were more strongly associated with severe periventricular white matter hyperintensities (aOR for the highest vs. lowest quartile, 1.6; 95% CI, 1.1–2.3, p = 0.009) than deep white matter hyperintensities (aOR for the highest vs. lowest quartile, 1.3; 95% CI, 0.9–1.9, p = 0.16). No significant association was observed between TMAO and lacunes or cerebral microbleeds. Choline showed trends similar to that of TMAO in the association with cerebral small vessel disease.Conclusions: In patients with ischemic stroke or transient ischemic attack, TMAO and choline appear to be associated with white matter hyperintensities, but not with lacunes or cerebral microbleeds; TMAO and choline were associated with increased risk of a greater periventricular, rather than deep, white matter hyperintensities burden.

Background: Polyvascular disease (PolyVD) and interleukin (IL)-6 are associated with poor outcomes in patients with stroke respectively. However, whether combined PolyVD and elevated IL-6 levels would increase the risk of poor outcomes of stroke patients is yet unclear.Methods: Data were obtained from the Third China National Stroke Registry (CNSR-III). PolyVD was defined as acute ischemic stroke (AIS) or transient ischemic attack (TIA) with coronary artery disease (CAD) and/or peripheral artery disease (PAD). Patients were divided into four groups according to the combination of vascular beds number (non-PolyVD or PolyVD) and IL-6 levels (IL-6 < 2.64 pg/mL or IL-6 ≥ 2.64 pg/mL). The primary outcome was a recurrent stroke at 1-year follow-up. Cox proportional hazard models were employed to identify the association of the combined effect of PolyVD and IL-6 with the prognosis of patients.Results: A total of 10,773 patients with IL-6 levels and 1-year follow-up were included. The cumulative incidence of recurrent stroke was 9.87% during the 1-year follow-up. Compared to non-PolyVD and IL-6

Background and Aims: Although noninferior to stent retriever (SR) as first-line approach for endovascular treatment (EVT) of acute large vessel occlusion (LVO) stroke, little is known about the current status of direct aspiration (DA) as first-line thrombectomy in China. This analysis of a prospective, nationwide registry (ANGEL-ACT) aimed to investigate the prevalence and comparative effectiveness of DA-first thrombectomy in a real-world practice in China. Methods: All patients receiving thrombectomy were screened from a prospective cohort of LVO patients undergoing EVT at 111 hospitals in China between November 2017 and March 2019, and divided into two groups based upon which type of thrombectomy was attempted first (“DA-first” and “SR-first”). The following outcome measures were compared using logistic regression models with adjustment: successful recanalization after first-device alone and all procedures, use of rescue treatment, intracranial hemorrhage (ICH) within 24 h, and modified Rankin Scale (mRS) score at 90 days. Results: A total of 1225 patients, 102 (8.3%) in DA-first group and 1123 (91.7%) in SR-first group, were included. Patients receiving DA-first had less often successful recanalization after first-device alone [30.4 versus 66.4%; odds ratio (OR) = 0.23, 95% confidence interval (CI) = 0.15–0.37], more frequent rescue treatment (62.8 versus 27.0%; OR = 4.55, 95% CI = 2.92–7.08) and ICH (35.4 versus 22.1%; OR = 1.78, 95% CI = 1.12–2.83) than those receiving SR-first; however, no significant difference was found in successful recanalization after all procedures (84.3 versus 90.3%; p = 0.18) and 90-day mRS (median: 3 versus 3 points; p = 0.90) between both groups. Conclusion: This real-world registry suggested that DA-first thrombectomy for acute stroke patients lagged behind in China during the study period. Far fewer DA-first than SR-first thrombectomies were performed, and DA-first was associated with lower first-device recanalization, more frequently requiring rescue treatment, and increased ICH risk. Clinical Trial Registration: ClinicalTrials.gov , NCT03370939.

Background and purpose Hyperperfusion (HP) is a devastating complication associated with carotid artery stenting (CAS) or endarterectomy. The efficacy and safety of staged angioplasty (SAP) in patients with CAS at high risk of HP remains unclear. We sought to determine whether SAP is superior to regular CAS in patients with high risk of HP.Methods A randomised, multicentre open-label clinical trial with blinded outcome assessment (STEP) was conducted. Patients with severe carotid stenosis at high risk of HP were randomly assigned (1:1) to the SAP or regular CAS group. The primary endpoint was hyperperfusion syndrome (HPS) and intracerebral haemorrhage (ICH) within 30 days after the procedure.Results From November 2014 to January 2017, a total of 64 patients were enrolled in 11 centres. 33 patients were allocated to the SAP group and 31 to the regular CAS group. At 30 days, the rate of primary endpoint was 0.0% (0/33) in the SAP group and 9.7% (3/31) in the regular CAS group (absolute risk reduction (ARR), 9.7%; 95% CI −20.1% to 0.7%; p=0.11). As one of the secondary endpoints, the incidence of HP phenomenon (HPP) was lower in the SAP group than the regular CAS group (0.0% vs 22.6%, ARR,−22.6%; 95% CI −36.8% to −10.2%; p=0.04).Conclusion The rate of HPS and ICH was not significantly lower in SAP group; the extended secondary endpoint of HPP, however, significantly reduced, which suggested that SAP may be a safe and effective carotid revascularisation procedure to prevent HP.Trial registration number NCT02224209.

Background: We aim to investigate the effects and safety of clopidogrel plus aspirin in patients with different types of single small subcortical infarction (SSSI) in the Clopidogrel in High-risk patients with Acute Non-disabling Cerebrovascular Events (CHANCE) trial.Methods: SSSI was defined as single DWI lesion of ≤2.0 cm. Patients with SSSI were divided into SSSI + PAD (parent artery disease) and SSSI – PAD, according to the stenosis of the parent artery. The efficacy outcome was stroke recurrence during 90-day follow-up. Cox proportional hazards models or logistic regression models were used to assess the interaction of the treatment effects of clopidogrel plus aspirin vs. aspirin alone among patients with and without PAD.Results: Among 338 patients with SSSI included in the subanalysis, 105 were with PAD and 233 without. The efficacy of clopidogrel plus aspirin compared with aspirin alone on any stroke was consistent between patients with [adjusted hazard ratio (HR) 0.84; 95% confidence interval (CI), 0.25–2.75] and without PAD (adjusted HR 1.03; 95% CI, 0.40–2.68, interaction P = 0.83). In patients with SSSI + PAD, the rate of stroke recurrence in those treated with dual antiplatelet therapy and mono antiplatelet therapy was not significantly different (10.9 vs. 13.6%, P = 0.77). The number of bleeding events was similar between the clopidogrel-aspirin group and aspirin group regardless of SSSI + PAD or SSSI – PAD.Conclusions: There was no significant difference in the efficacy of clopidogrel plus aspirin compared with aspirin alone between patients with SSSI + PAD and SSSI – PAD in the CHANCE trial. Studies in other populations and with adequate power are needed to further verify such findings.

Background and Purpose: Our aim was to investigate the frequency of dehydration at admission and associations with in-hospital mortality in patients with intracerebral hemorrhage (ICH).Methods: Data of consecutive patients with ICH between August 2015 and July 2019 from the China Stroke Center Alliance (CSCA) registry were analyzed. The patients were stratified based on the blood urea nitrogen (BUN) to creatinine (CR) ratio (BUN/CR) on admission into dehydrated (BUN/CR ≥ 15) or non-dehydrated (BUN/CR < 15) groups. Data were analyzed with multivariate logistic regression models to investigate admission dehydration status and the risks of death at hospital.Results: A total number of 84,043 patients with ICH were included in the study. The median age of patients on admission was 63.0 years, and 37.5% of them were women. Based on the baseline BUN/CR, 59,153 (70.4%) patients were classified into dehydration group. Patients with admission dehydration (BUN/CR ≥ 15) had 13% lower risks of in-hospital mortality than those without dehydration (BUN/CR < 15, adjusted OR = 0.87, 95%CI 0.78–0.96). In patients aged

Background and Aims: YKL-40, an inflammatory biomarker, has been reported to be involved in the process and progression of atherosclerosis. Several studies have investigated the association between YKL-40 and plaque and suggested YKL-40 might be a potential biomarker for plaque instability. This study aimed to investigate the association between YKL-40 and carotid plaque instability.Methods: Based on a community-based study in Beijing from February 2014 to May 2016, 1,132 participants with carotid plaques were enrolled in this study. Data on demographics and medical history were collected through face-to-face interviews, and fasting blood samples were collected and stored. We used ultrasound to evaluate the presence of carotid plaque and its instability. The level of YKL-40 was measured by enzyme-linked immunosorbent assay (ELISA). Multivariate logistic regression analysis was performed to investigate the association between YKL-40 level and carotid atherosclerotic plaque instability.Results: The mean age of the 1,132 participants was 58.0 (52.0–64.0) years, and 560 (49.5%) were male. Unstable plaques were detected in 855 (75.53%) participants. YKL-40 level was classified into four groups according to its quartile: quartile 1:

Objective: To investigate the safety and efficacy of tirofiban in acute ischemic stroke (AIS) patients with large artery atherosclerosis (LAA) stroke etiology receiving endovascular therapy (EVT).Methods: In this multi-center prospective study, patients who were considered to have an indication received a low dose intra-arterial bolus (0.25–1 mg) of tirofiban. The safety and efficacy outcomes at 90-day follow-ups included symptomatic intracranial hemorrhage (sICH), recanalization rate, functional outcome, and mortality.Results: Among the 649 AIS patients with LAA, those in the tirofiban group (n = 244) showed higher systolic blood pressure (BP) and NIHSS score on admission, puncture-to-recanalization time, lower frequency of intravenous thrombolysis and intra-arterial thrombolysis, higher frequency of antiplatelet, heparinization, mechanical stent retrieval, aspiration, balloon angioplasty, and more retrieval times compared with those in the non-tirofiban group (n = 405) (all P < 0.05). Tirofiban was found to be associated with superior clinical outcomes in anterior circulation stroke and major stroke patients [adjusted odds ratio (OR) = 2.163, 95% confidence interval (CI) = 1.130–4.140, P = 0.02 and adjusted OR = 2.361, 95% CI = 1.326–4.202, P = 0.004, respectively] and a lower risk of mortality at 90-day follow-ups (adjusted OR = 0.159, 95% CI = 0.042–0.599, P = 0.007 and adjusted OR = 0.252, 95% CI = 0.103–0.621, P = 0.003, respectively). There was no significant difference in sICH between the two groups.Conclusions: Tirofiban in AIS patients with LAA undergoing EVT is safe and may benefit the functional outcomes in anterior circulation and major stroke patients and showed a trend for reduced mortality.