Argatroban in Patients With Acute Ischemic Stroke With Early Neurological Deterioration: A Randomized Clinical Trial.

Importance: The effect of argatroban in patients with acute ischemic stroke (AIS) and early neurological deterioration (END) is unknown. Objective: To assess the efficacy of argatroban for END in AIS. Design, Setting, and Participants: This open-label, blinded-end point, randomized clinical trial was conducted from April 4, 2020, through July 31, 2022. The date of final follow-up was October 31, 2022. This was a multicenter trial. Eligible patients were adults with AIS who experienced END, which was defined as an increase of 2 or more points on the National Institutes of Health Stroke Scale within 48 hours from symptom onset. Patients who withdrew consent, experienced duplicate randomization, or were lost to follow-up were excluded from the study. Interventions: Patients were randomly assigned to the argatroban group and control group within 48 hours of symptom onset. Both groups received standard therapy based on guidelines, including oral mono or dual antiplatelet therapy. The argatroban group received intravenous argatroban for 7 days (continuous infusion at a dose of 60 mg per day for 2 days, followed by 20 mg per day for 5 days) in addition to standard therapy. Main Outcome and Measure: The primary end point was good functional outcome at 90 days, defined as a modified Rankin Scale score of 0 to 3. Results: A total of 628 patients (mean [SD] age, 65 [11.9] years; 400 male [63.7%]) were included in this study (argatroban group, 314 [50%] and control group, 314 [50%]). Of these, 18 withdrew consent, 1 had duplicate randomization, and 8 were lost to follow-up. A total of 601 patients with stroke were included in the intention-to-treat analysis. Finally, 564 patients were included in the per-protocol analysis as 6 participants in the argatroban group and 31 participants in the control group did not follow the complete protocol. The number of patients with good functional outcome at 90 days was 240 (80.5%) in the argatroban group and 222 (73.3%) in the control group (risk difference, 7.2%; 95% CI, 0.6%-14.0%; risk ratio, 1.10; 95% CI, 1.01-1.20; P = .04). The proportion of symptomatic intracranial hemorrhage was 3 of 317 (0.9%) in the argatroban group and 2 of 272 (0.7%) in the control group (P = .78). Conclusions and Relevance: Among patients with AIS with END, treatment with argatroban and antiplatelet therapy resulted in a better functional outcome at 90 days. This trial provided evidence to support the use of argatroban in reducing disability for patients with END. Trial Registration: ClinicalTrials.gov Identifier: NCT04275180.

Low-density lipoprotein cholesterol, statin therapy, and cerebral microbleeds: The CIRCLE study.

BACKGROUND: Current evidence suggests a potential association between cerebral microbleeds (CMBs), low-density lipoprotein cholesterol (LDL-C) levels, and statin use, but the exact relationship remains unclear. This study aims to prospectively examine these relationships in a stroke-free population. METHODS: From January 2010 to January 2020, we enrolled stroke-free individuals with at least one cerebral small vessel disease imaging marker from the CIRCLE study (ClinicalTrials.gov ID: NCT03542734). Participants underwent baseline and 1-year follow-up susceptibility-weighted imaging (SWI), and baseline LDL-C testing. New CMBs were categorized as strictly lobar and deep CMBs based on location. RESULTS: A total of 209 individuals were included. Baseline serum LDL-C levels were divided into quartiles: Q1 (≤1.76 mmol/L), Q2 (1.77-2.36 mmol/L), Q3 (2.37-2.93 mmol/L), and Q4 (>2.93 mmol/L). The incidence of new deep CMBs was 30.0%, 11.1%, 10.9%, 8.2% in Q1, Q2, Q3, Q4, respectively. Multivariate logistic model revealed that only LDL-C in Q1 was associated with increased incidence of new deep CMBs (OR = 4.256; 95% CI: 1.156-15.666; p = 0.029). In a subset of 169 participants without prior statin use, the use of atorvastatin was associated with reduced occurrence of new deep CMBs (OR = 0.181; 95% CI: 0.035-0.928; p = 0.040), while it was not found with rosuvastatin (OR = 0.808; 95% CI: 0.174-3.741; p = 0.785). CONCLUSIONS: While lower LDL-C levels were associated with higher CMB development, statin therapy did not increase the risk of new CMBs. Atorvastatin even demonstrated a protective effect.

Prevalent stroke, age of its onset, and post-stroke lifestyle in relation to dementia: A prospective cohort study.

INTRODUCTION: The association of age at stroke onset with dementia and the role of post-stroke lifestyle on dementia risk remains unclear. METHODS: We leveraged data of 496,251 dementia-free participants from UK Biobank and explored the relationship between age at stroke onset and incident dementia. Among 8328 participants with stroke history, we further investigated the association of a healthy lifestyle with risk of dementia. RESULTS: Participants with stroke history had a higher risk of dementia (hazard ratio [HR], 2.02). The association was stronger among participants with stroke onset at a younger age (≤50: HR, 2.63) compared with those at the age > 50 years (50-60: HR, 2.17; ≥60: HR, 1.58). Among participants with stroke history, a favorable lifestyle was associated with a lower risk of incident dementia. DISCUSSION: Stroke onset in earlier life stage predicted a higher risk for dementia, but a favorable post-stroke lifestyle may protect against dementia.

Association of Proton Pump Inhibitor Prophylaxis on Clinical Outcome in Acute Ischemic Stroke in China: A Multicenter Retrospective Cohort Study.

BACKGROUND: Overtreatment with proton pump inhibitors (PPIs) in acute ischemic stroke (AIS) patients continues to grow. We aimed to investigate the frequency of PPI prophylaxis without an appropriate indication in AIS patients in China and clarify the association between PPI prophylaxis and long-term prognosis. METHODS: Based on a multicenter stroke registry database, neurological outcomes, stroke events, recurrent ischemic strokes, and all-cause death were compared between patients with and without PPI prophylaxis. RESULTS: A total of 4542 AIS were included, and 3335 (73.4%) received PPI prophylaxis. Patients with PPI prophylaxis were more likely to have a poor outcome at 1 year than those without PPI prophylaxis (33.3% vs. 25.8%, OR 1.321; 95% CI 1.102-1.584; p = 0.003). No significant differences were found in all-cause death, stroke event, or recurrent ischemic stroke at 1 year between the two groups. After propensity score matching, PPI prophylaxis was still independently associated with a higher rate of poor outcome (30.9% vs. 25.8%, OR 1.432; 95% CI 1.151-1.780; p = 0.001). Sensitivity analysis also showed that PPI prophylaxis increased the rate of a poor outcome in minor strokes or at different durations of PPI prophylaxis. CONCLUSIONS: Approximately 3/4 of AIS patients were given PPI prophylaxis during hospitalization, which was associated with a poor long-term outcome.

Endovascular Treatment for Minor Acute Ischemic Strokes With Large Vessel Occlusion.

Background It remains uncertain whether patients with minor acute ischemic stroke with large vessel occlusion benefit from endovascular treatment (EVT). We aim to evaluate the outcomes of EVT in minor acute ischemic stroke with anterior circulation large vessel occlusion. Methods and Results Based on a nationwide prospective stroke registry, patients with minor acute ischemic stroke with anterior circulation large vessel occlusion within 24 hours of onset were divided into groups receiving standard medical treatment plus EVT or standard medical treatment alone. Primary outcome was excellent functional outcome defined as modified Rankin Scale score 0 to 1 at 90 days. In addition, a multivariable logistic regression model was used to analyze the effect of EVT guided by perfusion imaging. A total of 572 patients with median age 68 years (interquartile range=60-77) and median National Institutes of Health Stroke score 3 (interquartile range =2-4) were identified and 123 patients were treated with standard medical treatment plus EVT. EVT was not associated with excellent functional outcome (unadjusted odds ratio [OR], 0.771 [95% CI, 0.516-1.151]; adjusted OR, 0.793 [95% CI, 0.515-1.219]; P=0.290). However, therapy selection guided by perfusion imaging was a modifier of EVT effect on outcomes, as EVT was significantly associated with excellent functional outcome (60.0% versus 50.8%, unadjusted OR, 1.451 [95% CI, 0.643-3.272]; adjusted OR, 2.849 [95% CI, 1.006-8.067]; P=0.049) but not with symptomatic intracerebral hemorrhage in the imaging-guided group. Conclusions Although functional outcomes in minor acute ischemic stroke caused by anterior circulation large vessel occlusion were not improved from the routine use of EVT, our results suggested that EVT guided by perfusion imaging could be beneficial for those patients. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04487340.

Associations of lipid profiles with the risk of ischemic and hemorrhagic stroke: A systematic review and meta-analysis of prospective cohort studies.

Background and purpose: The associations of lipid profiles with the risk of ischemic stroke (IS) or hemorrhagic stroke (HS) are controversial. In this study, we aimed to illustrate the optimal level for lipid levels in the risk of IS and HS. Materials and methods: We searched the electronic database of PubMed, Embase, and the Cochrane library from inception until November 2020. Prospective cohort studies published in English for the associations of lipid profiles (TC, TG, LDL-C, HDL-C, and non-HDL-C) with the risk of IS and HS were eligible for this study, and the publication status was not restricted. We calculated the pooled effect estimates using the random-effects model. We tested the associations of lipid profiles with IS and HS and compared their differences. Results: We retrieved 50 prospective cohort studies containing 3,301,613 individuals. An increase in total cholesterol (TC) is associated with an increased IS risk (P < 0.001) and a reduced HS risk (P < 0.001). Similarly, an increase in triglyceride links with a greater IS risk (P < 0.001) but with a lower HS risk (P = 0.014). On the opposite, high-density lipoprotein cholesterol (HDL-C) correlates with a reduced IS risk (P = 0.004) but has no significant association with the HS risk (P = 0.571). Moreover, an increase in low-density lipoprotein cholesterol (LDL-C) or non-high-density lipoprotein cholesterol has no statistically significant effect on both IS and HS. The pooled effect estimates on the risk of IS and HS revealed that TC and LDL-C levels should be controlled under 6.0 and 3.5 mmol/L, respectively, to reduce worsening effects on the IS risk while maintaining potential beneficial effects on reducing the HS risk. Conclusion: We revealed comprehensive relationships between lipid profiles and the risk of stroke, suggesting controlling the TC and LDL-C levels under 6.0 and 3.5 mmol/L, respectively, to balance both the IS and HS risk.

Evaluation of a multicomponent intervention to shorten thrombolytic door-to-needle time in stroke patients in China (MISSION): A cluster-randomized controlled trial.

BACKGROUND: Rapid intravenous thrombolysis (IVT) for acute ischemic stroke (AIS) is crucial for improving outcomes. However, few randomized trials of interventions aimed at reducing in-hospital delay have been carried out in China. We aimed to evaluate the effect of a multicomponent intervention on thrombolytic door-to-needle time (DNT) of AIS patients via video teleconference based on the Behavior Change Wheel (BCW) method. METHODS AND FINDINGS: This cluster-randomized trial, conducted between January 1, 2019 and December 31, 2019, randomly allocated 22 hospitals equally to PEITEM (Persuasion Environment reconstruction Incentivization Training Education Modeling) intervention or routine care plus stroke registry and subsequently enrolled 1,634 AIS patients receiving IVT within 4.5 hours upon stroke onset from participant hospitals. The PEITEM group received a 1-year PEITEM 6-component intervention based on the behavioral theory monthly via video teleconference. The primary outcome was the proportion of patients with a DNT of 60 minutes or less. A total of 987 patients participated in the PEITEM group (mean age, 69 years; female, 411 [41.6%]) and 647 patients in the control group (mean age, 70 years; female, 238 [36.8%]). Of all participants, the proportion of DNT ≤60 minutes in the PEITEM group was higher than in the control group (82.0% versus 73.3%; adjusted odds ratio, 1.77; 95% confidence interval (CI), 1.17 to 2.70; ICC, 0.04; P = 0.007). Among secondary outcomes, the average DNT was 43 minutes in the PEITEM group and 50 minutes in the control group (adjusted mean difference: -8.83; 95% CI, -14.03 to -3.64; ICC, 0.12; P = 0.001). Favorable functional outcome (score of 0 to 1 on the modified Rankin scale (mRS)) was achieved in 55.6% patients of the PEITEM group and 50.4% of the control group (adjusted odds ratio, 1.38; 95% CI, 1.00 to 1.90; ICC, 0.01; P = 0.049). Main study limitations include non-blinding of clinicians, and that specific interventions component responsible for the observed changes could not be determined. CONCLUSIONS: The teleconference-delivered PEITEM intervention resulted in a moderate but clinically relevant shorter DNT and better functional outcome in AIS patients receiving IVT. TRIAL REGISTRATION: Clinicaltrials.gov NCT03317639.

Evaluation of a Multilevel Program to Improve Clinician Adherence to Management Guidelines for Acute Ischemic Stroke.

Importance: Promotion of clinician adherence to stroke guidelines can improve stroke outcomes. Objective: To investigate the outcomes of a multilevel system program on clinician adherence to guidelines for treatment of patients with acute ischemic stroke (AIS). Design, Setting, and Participants: This quality improvement study used a prospective interrupted time series (ITS) and difference-in-difference (DID) design, from August 1, 2018, to January 31, 2020, divided into preprogram term and short and long postprogram terms; each term had 6 months. Data were collected during hospitalization and at discharge with an automated medical record data capture system in 58 public hospitals in Zhejiang province, China. Data were analyzed from August 2018 to January 2020. Exposures: The multilevel system program included a modularized standard template for medical records, centrally supported continuing education, continuous monitoring and feedback, and collaborative workshops. Main Outcomes and Measures: The primary outcome was adherence to 12 key performance indicators (KPIs), expressed as (1) percentage of patient-applicable KPIs achieved in each participant and (2) percentage of participants among whom all applicable KPIs were achieved (dichotomous all-or-none measure). The secondary outcome was severe disability or death (modified Rankin Scale 5-6) at discharge. Results: Among 45 091 patients (mean [SD] age, 69 [12] years; 18 347 female [40.7%]), 28 721 from 30 hospitals received the program and 16 370 from 28 hospitals continued routine care. In adjusted DID analysis, the program was associated with an increase in the absolute percentage of KPIs achieved per patient (6.46%; 95% CI, 5.49% to 7.43%), absolute rate of all-or-none success (8.29%; 95% CI, 6.99% to 9.60%), and decreased rate of severe disability or death at discharge (-1.68%; 95% CI, -2.99% to -0.38%). The ITS result showed the program was associated with an increase in KPIs achieved per patient per week (slope change in short-term period, 0.36%; 95% CI, 0.20% to 0.52%; level change in long-term period, (9.64%; 95% CI, 4.58% to 14.69%) and in all-or-none success (slope change in short-term period 0.34%; 95% CI, 0.23% to 0.46%; level change in long-term period 5.89%; 95% CI, 0.19% to 11.59%). Conclusions and Relevance: The centrally supported program was associated with increases in clinician adherence to guidelines and reduced the proportion of severely disabled or deceased patients with AIS at discharge, providing support for its wider implementation.

Causative Classification of Ischemic Stroke by the Machine Learning Algorithm Random Forests.

Background: Prognosis, recurrence rate, and secondary prevention strategies differ by different etiologies in acute ischemic stroke. However, identifying its cause is challenging. Objective: This study aimed to develop a model to identify the cause of stroke using machine learning (ML) methods and test its accuracy. Methods: We retrospectively reviewed the data of patients who had determined etiology defined by the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) from CASE-II (NCT04487340) to train and evaluate six ML models, namely, Random Forests (RF), Logistic Regression (LR), Extreme Gradient Boosting (XGBoost), K-Nearest Neighbor (KNN), Ada Boosting, Gradient Boosting Machine (GBM), for the detection of cardioembolism (CE), large-artery atherosclerosis (LAA), and small-artery occlusion (SAO). Between October 2016 and April 2020, patients were enrolled consecutively for algorithm development (phase one). Between June 2020 and December 2020, patients were enrolled consecutively in a test set for algorithm test (phase two). Area under the curve (AUC), precision, recall, accuracy, and F1 score were calculated for the prediction model. Results: Finally, a total of 18,209 patients were enrolled in phase one, including 13,590 patients (i.e., 6,089 CE, 4,539 LAA, and 2,962 SAO) in the model, and a total of 3,688 patients were enrolled in phase two, including 3,070 patients (i.e., 1,103 CE, 1,269 LAA, and 698 SAO) in the model. Among the six models, the best models were RF, XGBoost, and GBM, and we chose the RF model as our final model. Based on the test set, the AUC values of the RF model to predict CE, LAA, and SAO were 0.981 (95%CI, 0.978-0.986), 0.919 (95%CI, 0.911-0.928), and 0.918 (95%CI, 0.908-0.927), respectively. The most important items to identify CE, LAA, and SAO were atrial fibrillation and degree of stenosis of intracranial arteries. Conclusion: The proposed RF model could be a useful diagnostic tool to help neurologists categorize etiologies of stroke. Clinical Trial Registration: [www.ClinicalTrials.gov], identifier [NCT01274117].

Undertreatment of Anticoagulant Therapy in Hospitalized Acute Ischemic Stroke Patients With Atrial Fibrillation.

Background: This study aimed to investigate the prevalence and factors associated with the initiation of oral anticoagulation among patients with acute ischemic stroke (AIS) and concurrent atrial fibrillation (AF) at discharge in China. Methods: We continuously included hospitalized patients with AIS with an AF diagnosis registered in the computer-based Online Database of Acute Stroke Patients for Stroke Management Quality Evaluation (CASE II) from January 2016 to December 2020 and divided them into a and non-anticoagulant groups according to the medications at discharge. Binary logistic regression was used to determine the factors associated with the prescription of anticoagulants in patients with AF. Results: A total of 16,162 patients were enrolled. The mean age was 77 ± 9 years, 8,596 (53.2%) were males, and the median baseline National Institute of Health Stroke Scale score was 5 (2-12). Of the 14,838 patients without contraindications of antithrombotic therapy, 6,335 (42.7%) patients were initiated with anticoagulation treatment at discharge. Prior history of hemorrhagic stroke (OR 0.647, p < 0.001) and gastrointestinal bleeding (OR 0.607, p = 0.003) were associated with a lower rate of anticoagulation at discharge. Patients with any intracranial hemorrhage (OR 0.268, p < 0.001), gastrointestinal bleeding (OR 0.353, p < 0.001), or pneumonia during hospitalization (OR 0.601, p < 0.001) were less likely to receive anticoagulants at discharge. Among 7,807 patients with previously diagnosed AF and high risk of stroke (CHA2DS2-VASc ≥2), only 1,585 (20.3%) had been receiving anticoagulation treatment prior to the onset of stroke. However, the mean international normalized ratio (INR) was 1.5 on the first test during hospitalization in patients receiving warfarin. Patients complicated with a previous history of ischemic stroke/transient ischemic attack (TIA; OR 2.303, p < 0.001) and peripheral artery disease (OR 1.456, p = 0.003) were more common to start anticoagulants. Conclusions: Less than half of patients with AIS and concurrent AF initiated guideline-recommended oral anticoagulation at discharge, while only 20% of patients with previously diagnosed AF with a high risk of stroke had been using anticoagulants prior to the onset of stroke, which highlights a large care gap in hospitalized stroke patients and the importance of AF management.

Effect of Imaging Markers on Reperfusion Therapy in Basilar Artery Occlusion.

OBJECTIVE: We aimed to investigate the effectiveness of endovascular therapy (EVT) versus intravenous thrombolysis (IVT) in patients with basilar artery occlusion (BAO), based on the information of advanced imaging. METHODS: We analyzed data of stroke patients with radiologically confirmed BAO within 24 hours. BAO subjects were categorized into "top-of-the-basilar" syndrome (TOBS) and other types. An initial infarct size of <70ml and a ratio of ischemic tissue to infarct volume of ≥1.8 was defined as "target mismatch." The primary outcome was a good outcome, defined as a modified Rankin Scale score of 0 to 3 at 3 months. Propensity score adjustment and inverse probability of treatment weighting (IPTW) propensity score methods were used. RESULTS: Among 474 BAO patients, 93 (19.6%) were treated with IVT prior to EVT, 91 (19.2%) were treated with IVT alone, 95 (20.0%) were treated with EVT alone, and 195 (41.1%) were treated with antithrombotic therapy. In IPTW analyses, we found no benefit of EVT over IVT for good outcome in either TOBS patients (odds ratio = 1.08, 95% confidence interval [CI] = 0.88-1.31) or those with other types (odds ratio = 1.13, 95% CI = 0.94-1.36). However, in patients with other types, if there existed a target mismatch, EVT was independently related to good outcome (odds ratio = 1.46, 95% CI = 1.17-1.81). INTERPRETATION: The "target mismatch profile" seems to be a possible candidate selection standard of EVT for those with other types of BAO. Future studies should separate TOBS from other types of BAO, and try to use advanced imaging. ANN NEUROL 2022;92:97-106.

Prediction of large vessel occlusion for ischaemic stroke by using the machine learning model random forests.

BACKGROUNDS: The timely identification of large vessel occlusion (LVO) in the prehospital stage is extremely important given the disease morbidity and narrow time window for intervention. The current evaluation strategies still remain challenging. The goal of this study was to develop a machine learning (ML) model to predict LVO using prehospital accessible data. METHODS: Consecutive acute ischaemic stroke patients who underwent CT or MR angiography and received reperfusion therapy within 8 hours from symptom onset in the Computer-based Online Database of Acute Stroke Patients for Stroke Management Quality Evaluation-II dataset from January 2016 to August 2021 were included. We developed eight ML models to integrate National Institutes of Health Stroke Scale (NIHSS) items with demographics, medical history and vascular risk factors to identify LVO and validate its efficiency. RESULTS: Finally, 15 365 patients were included in the training set and 4215 patients were included in the test set. On the test set, random forests (RF), gradient boosting machine and extreme gradient boosting presented area under the curve (AUC) of 0.831 (95% CI 0.819 to 0.843), which were higher than other models, and RF presented the highest specificity (0.827). In addition, the AUC of RF was higher than other scales, and the accuracy of the model was improved by 6.4% compared with NIHSS. We also found the top five items of identifying LVO were total NIHSS score, gaze deviation, level of consciousness (LOC), LOC commands and motor left leg. CONCLUSIONS: Our proposed model could be a useful screening tool to predict LVO based on the prehospital accessible medical data. TRIAL REGISTRATION NUMBER: NCT04487340.

Prediction of Acute Myocardial Infarction in Asian Patients With Acute Ischemic Stroke: The CTRAN Score.

Background: Patients with acute ischemic stroke (AIS) are susceptible to acute myocardial infarction (AMI), which would lead to a dramatic increase of in-hospital mortality. Objectives: The authors established and validated an easy-used model to stratify the risk of in-hospital AMI among patients with AIS. Methods: We consecutively included patients with AIS who were admitted within 7 days from symptom onset in our prospectively maintained database (NCT04487340) from January 2016 to December 2020. In the derivation cohort from 70 centers, we developed a score to predict in-hospital AMI by integrating the bedside-accessible predictors identified via multivariable logistic regression. Then in the validation cohort from 22 centers, we externally evaluated the performance of this score. Results: Overall, 96,367 patients were included. In-hospital AMI occurred in 392 (0.41%) patients. The final model, named CTRAN, incorporated 5 predictors including the history of coronary heart disease, malignant tumor, renal insufficiency, age, and baseline National Institutes of Health Stroke Scale score. The CTRAN score was confirmed in the validation cohort using receiver operating characteristic curve, which yielded an area under the curve of 0.758 (95% CI: 0.718-0.798). Conclusions: The CTRAN score could be a good tool for clinicians to identify patients with AIS at high in-hospital AMI risk.

Inclusive finance, industrial structure upgrading and farmers' income: Empirical analysis based on provincial panel data in China.

This paper empirically studies the relationship among inclusive finance, industrial structure upgrading and farmers' income, using the panel data of 28 provinces in China from 2006 to 2016.The research finds that inclusive finance can significantly promote the increase of farmers' income. Moreover, the Upgrading of Industry Structure (UIS) is the intermediary mechanism of inclusive finance to promote the increase of farmers' income, and this intermediary mechanism is heterogeneous among farmers with different income levels. Finally, the promotion effect of the UIS on farmers' income is affected by the threshold effect of inclusive finance. Compared with the development level of low inclusive finance, the promotion effect of the UIS on farmers' income is stronger under the development level of high inclusive finance. According to the results of empirical analysis, we suggest that the development strategy of inclusive finance should aim at the industrial development in rural areas, promote the organic connection between farmers and modern agricultural industry, and drive farmers to increase their income through the transformation and upgrading of rural industries.

Novel Prehospital Triage Scale for Detecting Large Vessel Occlusion and Its Cause.

Background Patients with large vessel occlusion stroke (LVOS) need to be rapidly identified and transferred to comprehensive stroke centers. However, current prehospital evaluation and strategies still remain challenging. Methods and Results We retrospectively reviewed our prospectively collected database of patients with acute ischemic stroke (AIS). Based on the items of National Institutes of Health Stroke Scale and medical history that had a strong association with LVOS, we designed the 4-item Stroke Scale (4I-SS) and validated it in multi-centers. The 4I-SS incorporated gaze, level of consciousness, arm weakness, and atrial fibrillation. Receiver operating characteristic analysis was used to compare the 4I-SS with previously established prehospital prediction scales. Finally, 1630 and 11 440 patients were included in the derivation and validation cohort, respectively. In the validation cohort, Youden Index, area under the curve, sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the 4I-SS≥4 to predict LVOS were 0.494, 0.800, 0.657, 0.837, 0.600, 0.868, and 0.788, respectively, and that of the 4I-SS≥7 to predict basilar artery occlusion were 0.200, 0.669, 0.229, 0.971, 0.066, 0.974, and 0.899, respectively. Youden Index and area under the curve were higher than previously published scales for predicting LVOS. Further analysis showed that for predicting whether cardiogenic embolism was the cause, its accuracy was 0.922 when the 4I-SS score, including atrial fibrillation, was ≥6, and its accuracy of predicting the occluded vessel was intracranial internal carotid artery or M1 segment of the middle cerebral artery when it was ≥7 was 0.590. Conclusions The 4I-SS is an effective and simple tool that can identify LVOS and its cause. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03317639.

Glymphatic clearance function in patients with cerebral small vessel disease.

Few studies have focused on the connection between glymphatic dysfunction and cerebral small vessel disease (CSVD), partially due to the lack of non-invasive methods to measure glymphatic function. We established modified index for diffusion tensor image analysis along the perivascular space (mALPS-index), which was calculated on diffusion tensor image (DTI), compared it with the classical detection of glymphatic clearance function calculated on Glymphatic MRI after intrathecal administration of gadolinium (study 1), and analyzed the relationship between CSVD imaging markers and mALPS-index in CSVD patients from the CIRCLE study (ClinicalTrials.gov ID: NCT03542734) (study 2). Among 39 patients included in study 1, mALPS-index were significantly related to glymphatic clearance function calculated on Glymphatic MRI ( r  = -0.772~-0.844, p < 0.001). A total of 330 CSVD patients were included in study 2. Severer periventricular and deep white matter hyperintensities (ß = -0.332, p < 0.001; ß = -0.293, p < 0.001), number of lacunas (ß = -0.215, p < 0.001), number of microbleeds (ß = -0.152, p = 0.005), and severer enlarged perivascular spaces in basal ganglia (ß = -0.223, p < 0.001) were related to mALPS-index. Our results indicated that non-invasive mALPS-index might represent glymphatic clearance function, which could be applied in clinic in future. Glymphatic clearance function might play a role in the development of CSVD.

Iodinated Contrast Agents Reduce the Efficacy of Intravenous Recombinant Tissue-Type Plasminogen Activator in Acute Ischemic Stroke Patients: a Multicenter Cohort Study.

This study aimed to investigate whether the application of iodinated contrast agents before intravenous (IV) recombinant tissue plasminogen activator (rt-PA) reduces the efficacy in acute ischemic stroke (AIS) patients. To determine whether the application of iodinated contrast agents before intravenous rt-PA reduces the efficacy in AIS patients. We analyzed our prospectively collected data of consecutive AIS patients receiving IV rt-PA treatment in the MISSION CHINA study. Clinical outcome at 3 months was assessed with modified Rankin Scale (mRS) score and dichotomized into good outcome (0-2) and poor outcome (3-6). Symptomatic intracerebral hemorrhage (sICH) was defined as cerebral hemorrhagic transformation in combination with clinical deterioration of National Institutes of Health Stroke Scale (NIHSS) score ≥ 4 points at 24-h. We performed logistic regression analysis and propensity score matching analysis to investigate the impact of iodinated contrast agents before IV rt-PA on poor outcome and sICH, respectively. A total of 3593 patients were finally included, and iodinated contrast agents were used before IV rt-PA among 859 (23.9%) patients. Patients in the iodinated contrast group were more likely to result in poor outcome (39.9% vs 33.4%, P = 0.001) and sICH (3.4% vs 1.5%, P < 0.001), compared with non-contrast group. Binary logistic regression analysis revealed that the application of iodinated contrast agents was independently associated with poor outcome (OR 1.342; 95% CI 1.103-1.631; P = 0.003) and sICH (OR 1.929; 95% CI 1.153-3.230; P = 0.012), respectively. After propensity score matching, the application of iodinated contrast agents was still independently associated with poor outcome (OR 1.246; 95% CI 1.016-1.531; P = 0.034) and sICH (OR 1.965; 95% CI 1.118-3.456; P = 0.019). Applying iodinated contrast agents before IV rt-PA may reduce the thrombolytic efficacy in AIS patients. Further benefit-risk analysis might be needed when iodinated contrast-used imaging is considered before intravenous thrombolysis.

Antegrade Blood Flow on 4-Dimensional Computed Tomography Angiography Predict Stroke Subtype in Patients With Acute Large Artery Occlusion.

Background The purpose of this study was to determine whether the presence of antegrade blood flow was related to stroke subtype in patients with acute intracranial large artery occlusion. Methods and Results The prospectively collected data for consecutive patients who had occlusion of the unilateral M1 segment of the middle cerebral artery with or without internal carotid artery and received reperfusion therapy were retrospectively reviewed. Stroke causes were determined according to the Trial of ORG 10172 in Acute Stroke Treatment standard. We defined antegrade flow as early opacification at the distal interface of the clot with subsequent distal extension on 4-dimensional computed tomography angiography. A total of 387 large artery occlusion patients were analyzed (229 men and 158 women; mean age, 71±14 years), including 77 (19.9%) with large artery atherosclerosis (LAA), 206 (53.2%) with cardioembolism, and 104 (26.9%) with undetermined causes. Antegrade flow was found in 206 (53.2%) patients, and 181 (46.8%) presented with retrograde flow. The rate of antegrade flow was much higher in patients with LAA than in those with cardioembolism (85.7% versus 42.2%, P<0.001). Multivariable logistic regression revealed that presence of antegrade flow was significantly associated with cuse of LAA after adjusting for confounding factors, when setting cardioembolism as reference (odds ratio, 5.650; 95% confidence interval, 2.451-13.158; P<0.001). The sensitivity, specificity, and positive and negative predictive values of the antegrade flow for predicting LAA were 43.1%, 91.5%, 85.7%, and 57.8%, respectively. Conclusions Using 4-dimensional computed tomography angiography, antegrade flow can be identified in more than half of acute anterior large artery occlusion patients and occurs more frequently in those with LAA as the cause of stroke.

Rationale and design of individualized quality improvement based on the Computer Analysing system to improve Stroke management quality Evaluation (CASE): a multicenter historically controlled study.

BACKGROUND: Guideline-based medical care has been identified to improve outcomes in stroke. However, data acquisition and medical quality management during hospital stay still need to be improved in China. We have developed a computer-based medical data collecting system, together with automated calculation of key performance indicators (KPIs) and regular individualized education, and thus aim to explore whether it can improve the medical care quality of acute ischemic stroke (AIS) during hospital stay in stroke centers. METHODS: The individualized quality improvement based on the Computer Analysing system to improve Stroke management quality Evaluation (CASE) trial is a prospective, multicenter, historical control study among 30 stroke centers in China. In this trial, the data is directly extracted from the saved original medical record of each AIS patient during hospital stay, regardless of different Electronic Medical Record System (EMRS) in each center. Then, the automated calculation of KPIs and the regular education via teleconference per month allow the clinicians to examine the causes of non-compliance of guideline-based care and develop programs to decrease their frequency. DISCUSSION: We compare KPIs between pre-intervention stage and post-intervention stage (without or with education) among stroke centers. If proved effective, this approach might be generalized around China and even worldwide, where a unified EMRS is difficult to be applied and in-patient care needs to be improved. TRIAL REGISTRATION: ClinicalTrials.gov NCT03684629 . Registered on 9 December 2018. Retrospectively registered.

Impairment of the Glymphatic Pathway and Putative Meningeal Lymphatic Vessels in the Aging Human.

OBJECTIVE: Aging is a major risk factor for numerous neurological disorders, and the mechanisms underlying brain aging remain elusive. Recent animal studies demonstrated a tight relationship between impairment of the glymphatic pathway, meningeal lymphatic vessels, and aging. However, the relationship in the human brain remains uncertain. METHODS: In this observational cohort study, patients underwent magnetic resonance imaging before and at multiple time points after intrathecal administration of a contrast agent. Head T1-weighted imaging was performed to assess the function of the glymphatic pathway and head high-resolution T2-fluid attenuated inversion recovery imaging to visualize putative meningeal lymphatic vessels (pMLVs). We measured the signal unit ratio (SUR) of 6 locations in the glymphatic pathway and pMLVs, defined the percentage change in SUR from baseline to 39 hours as the clearance of the glymphatic pathway and pMLVs, and then analyzed their relationships with aging. RESULTS: In all patients (N = 35), the SUR of the glymphatic pathway and pMLVs changed significantly after intrathecal injection of the contrast agent. The clearance of both the glymphatic pathway and pMLVs was related to aging (all p < 0.05). The clearance of pMLVs was significantly related to the clearance of the glymphatic pathway (all p < 0.05), and the clearance of the glymphatic pathway was significantly faster in patients with early filling of pMLVs than those with late filling (all p < 0.05). INTERPRETATION: We revealed that both the glymphatic pathway and pMLVs might be impaired in the aging human brain through the novel, clinically available method to simultaneously visualize their clearance. Our findings also support that in humans, pMLVs are the downstream of the glymphatic pathway. Ann Neurol 2020;87:357-369.