Trial of Thrombectomy 6 to 24 Hours after Stroke Due to Basilar-Artery Occlusion.

BACKGROUND: The effects and risks of endovascular thrombectomy 6 to 24 hours after stroke onset due to basilar-artery occlusion have not been extensively studied. METHODS: In a trial conducted over a 5-year period in China, we randomly assigned, in a 1:1 ratio, patients with basilar-artery stroke who presented between 6 to 24 hours after symptom onset to receive either medical therapy plus thrombectomy or medical therapy only (control). The original primary outcome, a score of 0 to 4 on the modified Rankin scale (range, 0 to 6, with a score of 0 indicating no disability, 4 moderately severe disability, and 6 death) at 90 days, was changed to a good functional status (a modified Rankin scale score of 0 to 3, with a score of 3 indicating moderate disability). Primary safety outcomes were symptomatic intracranial hemorrhage at 24 hours and 90-day mortality. RESULTS: A total of 217 patients (110 in the thrombectomy group and 107 in the control group) were included in the analysis; randomization occurred at a median of 663 minutes after symptom onset. Enrollment was halted at a prespecified interim analysis because of the superiority of thrombectomy. Thrombolysis was used in 14% of the patients in the thrombectomy group and in 21% of those in the control group. A modified Rankin scale score of 0 to 3 (primary outcome) occurred in 51 patients (46%) in the thrombectomy group and in 26 (24%) in the control group (adjusted rate ratio, 1.81; 95% confidence interval [CI], 1.26 to 2.60; P<0.001). The results for the original primary outcome of a modified Rankin scale score of 0 to 4 were 55% and 43%, respectively (adjusted rate ratio, 1.21; 95% CI, 0.95 to 1.54). Symptomatic intracranial hemorrhage occurred in 6 of 102 patients (6%) in the thrombectomy group and in 1 of 88 (1%) in the control group (risk ratio, 5.18; 95% CI, 0.64 to 42.18). Mortality at 90 days was 31% in the thrombectomy group and 42% in the control group (adjusted risk ratio, 0.75; 95% CI, 0.54 to 1.04). Procedural complications occurred in 11% of the patients who underwent thrombectomy. CONCLUSIONS: Among patients with stroke due to basilar-artery occlusion who presented 6 to 24 hours after symptom onset, thrombectomy led to a higher percentage with good functional status at 90 days than medical therapy but was associated with procedural complications and more cerebral hemorrhages. (Funded by the Chinese National Ministry of Science and Technology; BAOCHE ClinicalTrials.gov number, NCT02737189.).

Value of intravenous thrombolysis in endovascular treatment for large-vessel anterior circulation stroke: individual participant data meta-analysis of six randomised trials.

BACKGROUND: Intravenous thrombolysis is recommended before endovascular treatment, but its value has been questioned in patients who are admitted directly to centres capable of endovascular treatment. Existing randomised controlled trials have indicated non-inferiority of endovascular treatment alone or have been statistically inconclusive. We formed the Improving Reperfusion Strategies in Acute Ischaemic Stroke collaboration to assess non-inferiority of endovascular treatment alone versus intravenous thrombolysis plus endovascular treatment. METHODS: We conducted a systematic review and individual participant data meta-analysis to establish non-inferiority of endovascular treatment alone versus intravenous thrombolysis plus endovascular treatment. We searched PubMed and MEDLINE with the terms "stroke", "endovascular treatment", "intravenous thrombolysis", and synonyms for articles published from database inception to March 9, 2023. We included randomised controlled trials on the topic of interest, without language restrictions. Authors of the identified trials agreed to take part, and individual participant data were provided by the principal investigators of the respective trials and collated centrally by the collaborators. Our primary outcome was the 90-day modified Rankin Scale (mRS) score. Non-inferiority of endovascular treatment alone was assessed using a lower boundary of 0·82 for the 95% CI around the adjusted common odds ratio (acOR) for shift towards improved outcome (analogous to 5% absolute difference in functional independence) with ordinal regression. We used mixed-effects models for all analyses. This study is registered with PROSPERO, CRD42023411986. FINDINGS: We identified 1081 studies, and six studies (n=2313; 1153 participants randomly assigned to receive endovascular treatment alone and 1160 randomly assigned to receive intravenous thrombolysis and endovascular treatment) were eligible for analysis. The risk of bias of the included studies was low to moderate. Variability between studies was small, and mainly related to the choice and dose of the thrombolytic drug and country of execution. The median mRS score at 90 days was 3 (IQR 1-5) for participants who received endovascular treatment alone and 2 (1-4) for participants who received intravenous thrombolysis plus endovascular treatment (acOR 0·89, 95% CI 0·76-1·04). Any intracranial haemorrhage (0·82, 0·68-0·99) occurred less frequently with endovascular treatment alone than with intravenous thrombolysis plus endovascular treatment. Symptomatic intracranial haemorrhage and mortality rates did not differ significantly. INTERPRETATION: We did not establish non-inferiority of endovascular treatment alone compared with intravenous thrombolysis plus endovascular treatment in patients presenting directly at endovascular treatment centres. Further research could focus on cost-effectiveness analysis and on individualised decisions when patient characteristics, medication shortages, or delays are expected to offset a potential benefit of administering intravenous thrombolysis before endovascular treatment. FUNDING: Stryker and Amsterdam University Medical Centers, University of Amsterdam.

Exploring the potential molecular intersection of stroke and major depression disorder.

Stroke and major depression disorder are common neurological diseases, and a large number of clinical studies have shown that there is a close relationship between the two diseases, but whether the two diseases are linked at the genetic level needs to be further explored. The purpose of this study was to explore the comorbidity mechanism of stroke and major depression by using bioinformatics technology and animal experiments. From the GEO database, we gathered transcriptome data of stroke and depression mice (GSE104036, GSE131712, GSE81672, and GSE146845) and identified comorbid gene set through edgR and WGCNA analyses. Further analysis revealed that these genes were enriched in pathways associated with cell death. Programmed cell death gene sets (PCDGs) are generated from genes related to apoptosis, necroptosis, pyroptosis and autophagy. The intersection of PCDGs and comorbid gene set resulted in two hub genes, Mlkl and Nlrp3. Single-cell sequencing analysis indicated that Mlkl and Nlrp3 are mainly influential on endothelial cells and microglia, suggesting that the impairment of these two cell types may be a factor in the relationship between stroke and major depression. This was experimentally confirmed by RT-PCR and immunofluorescence staining. Our research revealed that two specific genes, namely, Mlkl and Nlrp3, play crucial roles in the complex mechanism that links stroke and major depression. Additionally, we have predicted six possible therapeutic agents and the outcomes of docking simulations of target proteins and drug molecules.

The impact of stress hyperglycemia ratio on short-term and long-term outcomes for acute basilar artery occlusion underwent endovascular treatment.

BACKGROUND: Stress hyperglycemia ratio (SHR) reflects a true acute hyperglycemic state during acute basilar artery occlusion (ABAO). We aimed to investigate the association between SHR and short-term and long-term outcomes in patients with ABAO receiving endovascular treatment (EVT). METHODS: We selected patients treated with EVT from the BASILAR study, a nationwide prospective registry. A total 250 patients with documented glucose and glycated hemoglobin (HbA1C) values at admission were included. SHR was calculated as the ratio of glucose/HbA1C. All 250 patients completed 90 days of follow-up and 234 patients (93.6%) completed 1 year of follow-up. The primary outcome was the favorable outcome defined as modified Rankin Scale (mRS) score ≤ 3 at 90 days. Safety outcomes included mortality at 90 days and 1 year, and intracranial hemorrhage. RESULTS: Among the 250 patients included, patients with higher tertiles of SHR were associated with decreased odds of a favorable functional outcome at 90 days (adjusted OR, 0.26; 95% CI, 0.12-0.56; P = 0.001 and adjusted OR, 0.37; 95% CI, 0.18-0.80; P = 0.01; respectively) and 1 year (adjusted OR, 0.34; 95% CI, 0.16-0.73; P = 0.006 and adjusted OR, 0.38; 95% CI, 0.18-0.82; P = 0.01; respectively) after adjusting for confounding covariates. The mortality was comparable across tertiles of SHR groups at 90 days and 1 year. CONCLUSIONS: Our study showed that SHR was associated with a decreased probability of favorable functional outcome both at 90 days and 1 year after EVT in patients with ABAO. The relationship was more pronounced in non-diabetes patients. TRIAL REGISTRATION: Clinical Trial Registry Identifier: ChiCTR1800014759 (November 12, 2013).

Methylprednisolone as Adjunct to Endovascular Thrombectomy for Large-Vessel Occlusion Stroke: The MARVEL Randomized Clinical Trial.

Importance: It is uncertain whether intravenous methylprednisolone improves outcomes for patients with acute ischemic stroke due to large-vessel occlusion (LVO) undergoing endovascular thrombectomy. Objective: To assess the efficacy and adverse events of adjunctive intravenous low-dose methylprednisolone to endovascular thrombectomy for acute ischemic stroke secondary to LVO. Design, Setting, and Participants: This investigator-initiated, randomized, double-blind, placebo-controlled trial was implemented at 82 hospitals in China, enrolling 1680 patients with stroke and proximal intracranial LVO presenting within 24 hours of time last known to be well. Recruitment took place between February 9, 2022, and June 30, 2023, with a final follow-up on September 30, 2023. Interventions: Eligible patients were randomly assigned to intravenous methylprednisolone (n = 839) at 2 mg/kg/d or placebo (n = 841) for 3 days adjunctive to endovascular thrombectomy. Main Outcomes and Measures: The primary efficacy outcome was disability level at 90 days as measured by the overall distribution of the modified Rankin Scale scores (range, 0 [no symptoms] to 6 [death]). The primary safety outcomes included mortality at 90 days and the incidence of symptomatic intracranial hemorrhage within 48 hours. Results: Among 1680 patients randomized (median age, 69 years; 727 female [43.3%]), 1673 (99.6%) completed the trial. The median 90-day modified Rankin Scale score was 3 (IQR, 1-5) in the methylprednisolone group vs 3 (IQR, 1-6) in the placebo group (adjusted generalized odds ratio for a lower level of disability, 1.10 [95% CI, 0.96-1.25]; P = .17). In the methylprednisolone group, there was a lower mortality rate (23.2% vs 28.5%; adjusted risk ratio, 0.84 [95% CI, 0.71-0.98]; P = .03) and a lower rate of symptomatic intracranial hemorrhage (8.6% vs 11.7%; adjusted risk ratio, 0.74 [95% CI, 0.55-0.99]; P = .04) compared with placebo. Conclusions and Relevance: Among patients with acute ischemic stroke due to LVO undergoing endovascular thrombectomy, adjunctive methylprednisolone added to endovascular thrombectomy did not significantly improve the degree of overall disability. Trial Registration: ChiCTR.org.cn Identifier: ChiCTR2100051729.

Efficacy and safety of tirofiban combined with endovascular therapy for basilar artery occlusion stroke due to large artery atherosclerosis.

BACKGROUND: This study aimed to evaluate the efficacy and safety of adjuvant tirofiban in patients with acute basilar artery occlusion due to large-artery atherosclerotic (LAA) receiving endovascular therapy (EVT). METHODS: This was a non-randomized, multicenter study using data from the Endovascular Treatment for Acute BASILAR Artery Occlusion (BASILAR) registry. Patients with acute basilar artery occlusion due to LAA within 24h of symptom onset who underwent EVT were included. Patients were divided into tirofiban and non-tirofiban groups according to whether tirofiban was used. The primary outcome was the ordinal modified Rankin scale score at 90 days. Safety outcomes were mortality within 90 days and symptomatic intracranial hemorrhage (sICH) within 48 h. RESULTS: A total of 417 patients were included, of whom 275 patients were in the tirofiban group and 142 patients in the non-tirofiban group. Compared with patients in the non-tirofiban group, patients in the tirofiban group were associated with a favorable shift in functional outcome at 90 days (6[4-6] vs 5 [2-6]; adjusted common OR, 2.51; 95 % CI, 1.64-3.83). The mortality was lower in the tirofiban group than the non-tirofiban group (40.7 % vs 58.5 %; adjusted OR, 0.35; 95 % CI, 0.21-0.56). The rate of sICH was 12.2 % in the non-tirofiban group and 5.2 % in the tirofiban group (adjusted OR, 0.37; 95 % CI, 0.17-0.80; P = 0.012). CONCLUSION: Tirofiban plus EVT might improve functional outcomes with a good safety for patients with acute basilar artery occlusion due to LAA. The results need to be confirmed in a randomized trial.

Effect of Imaging Selection Paradigms on Endovascular Thrombectomy Outcomes in Patients With Acute Ischemic Stroke.

BACKGROUND: The effect of imaging selection paradigms on endovascular thrombectomy outcomes in patients with acute ischemic stroke with large vessel occlusion remains uncertain. The study aimed to assess the effect of basic imaging (noncontrast computed tomography with or without computed tomographic angiography) versus advanced imaging (magnetic resonance imaging or computed tomography perfusion) on clinical outcomes following thrombectomy in patients with stroke with large vessel occlusion in the early and extended windows using a pooled analysis of patient-level data from 2 pivotal randomized clinical trials done in China. METHODS: This post hoc analysis used data from 1182 patients included in 2 multicenter, randomized controlled trials in China that evaluated adjunct therapies to endovascular treatment for acute ischemic stroke (Direct Endovascular Treatment for Large Artery Anterior Circulation Stroke performed from May 20, 2018, through May 2, 2020, and Intravenous Tirofiban Before Endovascular Treatment in Stroke from October 10, 2018, through October 31, 2021). Patients with occlusion of the intracranial internal carotid artery or proximal middle cerebral artery (M1/M2 segments) were categorized according to baseline imaging modality (basic versus advanced) as well as treatment time window (early, 0-6 hours versus extended, 6-24 hours from last known well to puncture). The primary outcome was the proportion of patients with functional independence (modified Rankin Scale score of 0-2) at 90 days. Multivariable Poisson regression analysis was performed to determine the association between imaging selection modality and outcomes after endovascular treatment at each time windows. RESULTS: A total of 1182 patients were included in this cohort analysis, with 648 in the early (471 with basic imaging versus 177 advanced imaging) and 534 in the extended (222 basic imaging versus 312 advanced imaging) time window. There were no differences in 90-day functional independence between the advanced and basic imaging groups in either time windows (early window: adjusted relative risk, 0.99 [95% CI, 0.84-1.16]; P=0.91; extended window: adjusted relative risk, 1.00 [95% CI, 0.84-1.20]; P=0.97). CONCLUSIONS: In this post hoc analysis of 2 randomized clinical trial pooled data involving patients with large vessel occlusion stroke, an association between imaging selection modality and clinical or safety outcomes for patients undergoing thrombectomy in either the early or extended windows was not detected. Our study adds to the growing body of literature on simpler imaging paradigms to assess thrombectomy eligibility across both the early and extended time windows. REGISTRATION: URL: http://www.chictr.org.cn; Unique identifiers: ChiCTR-IOR-17013568 and ChiCTR-INR-17014167.

Single-cell RNA sequencing of peripheral blood reveals that monocytes with high cathepsin S expression aggravate cerebral ischemia-reperfusion injury.

BACKGROUND: Stroke is a major cause of morbidity and mortality worldwide. After cerebral ischemia, peripheral immune cells infiltrate the brain and elicit an inflammatory response. However, it is not clear when and how these peripheral immune cells affect the central inflammatory response, and whether interventions that target these processes can alleviate ischemia-reperfusion (I/R) injury. METHODS: Single-cell transcriptomic sequencing and bioinformatics analysis were performed on peripheral blood of mice at different times after I/R to analyze the key molecule of cell subsets. Then, the expression pattern of this molecule was determined through various biological experiments, including quantitative RT-PCR, western blot, ELISA, and in situ hybridization. Next, the function of this molecule was assessed using knockout mice and the corresponding inhibitor. RESULTS: Single-cell transcriptomic sequencing revealed that peripheral monocyte subpopulations increased significantly after I/R. Cathepsin S (Ctss)was identified as a key molecule regulating monocyte activation by pseudotime trajectory analysis and gene function analysis. Next, Cathepsin S was confirmed to be expressed in monocytes with the highest expression level 3 days after I/R. Infarct size (p < 0.05), neurological function scores (p < 0.05), and apoptosis and vascular leakage rates were significantly reduced after Ctss knockout. In addition, CTSS destroyed the blood-brain barrier (BBB) by binding to junctional adhesion molecule (JAM) family proteins to cause their degradation. CONCLUSIONS: Cathepsin S inhibition attenuated cerebral I/R injury; therefore, cathepsin S can be used as a novel target for drug intervention after stroke.

Clinical Predictors for Early Mortality of Patients with Acute Basilar Artery Occlusion.

BACKGROUND: Acute ischemic stroke due to basilar artery occlusion (BAO) is associated with the highest mortality in patients with large vessel occlusion. This study aimed to identify modifiable risk factors of early mortality in patients with BAO. METHODS AND RESULTS: This was a cohort study of consecutive patients with BAO admitted to 47 stroke centers in China between January 2014 and May 2019. The primary outcome was all-cause mortality within 7 days after hospitalization. Of 829 patients, 164 died (0-3 days: 115; 4-7 days: 49) within 7 days after hospitalization. Among pre- and periprocedural variables, higher admission National Institutes of Health Stroke Scale (NIHSS, adjusted OR, 1.06, 95% CI: 1.04-1.09; p < 0.001), lower admission posterior circulation-Alberta Stroke Program Early Computed Tomography Score (pc-ASPECTS, adjusted OR, 0.88, 95% CI: 0.79-0.98; p = 0.02), lower Basilar Artery on Computed Tomography Angiography score (BATMAN, adjusted OR, 0.84, 95% CI: 0.76-0.93; p = 0.001), and recanalization failure (adjusted OR, 2.99, 95% CI: 2.04-4.38; p < 0.001) were independently associated with a higher risk of early mortality. Herniation (adjusted OR, 2.84, 95% CI: 1.52-5.30; p = 0.001) is an independent postprocedural predictor of early mortality. In patients dying ≤3 days, higher NIHSS (p < 0.001), lower pc-ASPECTS (p = 0.01), lower BATMAN (p = 0.004), recanalization failure (p < 0.001), herniation (p = 0.001), gastrointestinal hemorrhage (p = 0.046), and absence of pneumonia (p < 0.001) were independent predictors of early mortality. Higher NIHSS (p = 0.01), recanalization failure (p < 0.001), and pneumonia (p = 0.03) were independently associated with early mortality between 4 and 7 days. CONCLUSIONS: Recanalization failure, herniation, gastrointestinal hemorrhage, and pneumonia are potentially modifiable risk factors for early mortality in basilar artery occlusion.

A20/Nrdp1 interaction alters the inflammatory signaling profile by mediating K48- and K63-linked polyubiquitination of effectors MyD88 and TBK1.

A20 is a potent anti-inflammatory protein that mediates both inflammation and ubiquitination in mammals, but the related mechanisms are not clear. In this study, we performed mass spectrometry (MS) screening, gene ontology (GO) analysis, and coimmunoprecipitation (co-IP) in a lipopolysaccharide (LPS)-induced inflammatory cell model to identify novel A20-interacting proteins. We confirmed that the E3 ubiquitin ligase Nrdp1, also known as ring finger protein 41 (RNF41), interacted with A20 in LPS-stimulated cells. Further co-IP analysis demonstrated that when A20 was knocked out, degradation-inducing K48-linked ubiquitination of inflammatory effector MyD88 was decreased, but protein interaction-mediating K63-linked ubiquitination of another inflammatory effector TBK1 was increased. Moreover, western blot experiments showed that A20 inhibition induced an increase in levels of MyD88 and phosphorylation of downstream effector proteins as well as of TBK1 and a downstream effector, while Nrdp1 inhibition induced an increase in MyD88 but a decrease in TBK1 levels. When A20 and Nrdp1 were coinhibited, no further change in MyD88 was observed, but TBK1 levels were significantly decreased compared with those upon A20 inhibition alone. Gain- and loss-of-function analyses revealed that the ZnF4 domain of A20 is required for Nrdp1 polyubiquitination. Upon LPS stimulation, the inhibition of Nrdp1 alone increased the secretion of IL-6 and TNF-α but decreased IFN-ß secretion, as observed in other studies, suggesting that Nrdp1 preferentially promotes the production of IFN-ß. Taken together, these results demonstrated that A20/Nrdp1 interaction is important for A20 anti-inflammation, thus revealing a novel mechanism for the anti-inflammatory effects of A20.

One-Year Outcome After Endovascular Treatment for Acute Basilar Artery Occlusion.

BACKGROUND AND PURPOSE: The BASILAR registry, a nationwide prospective nonrandomized study conducted in China, enrolled consecutive patients with acute basilar artery occlusion receiving endovascular treatment or conventional-treatment from January 2014 to May 2019. This article aimed to report the results of clinical follow-up at one year among these patients. METHODS: The primary outcome was the modified Rankin Scale at one year, assessed as a common odds ratio using ordinal logistic regression analysis adjusted for prespecified prognostic factors. Secondary outcomes included the modified Rankin Scale-based outcome group at one year (0-1, 0-2, or 0-3) and all-cause death. RESULTS: Of the 829 patients enrolled in the original BASILAR registry, one-year data were available for 785 patients (94.7%). The distribution of outcomes on the modified Rankin Scale favored endovascular treatment over conventional-treatment (adjusted common odds ratio, 4.50 [95% CI, 2.81-7.29]; P<0.001). The cumulative one-year mortality rate was 54.6% in the endovascular treatment group versus 83.5% in the conventional-treatment group (adjusted odds ratio, 4.36 [95% CI, 2.69-7.29]; P<0.001). CONCLUSIONS: The beneficial effect of endovascular treatment on functional outcome at one year in patients with acute basilar artery occlusion is similar to that reported at 90 days in the original study. REGISTRATION: URL: http://www.chictr.org.cn; Unique identifier: ChiCTR1800014759.

Pericytes Regulate Cerebral Perfusion through VEGFR1 in Ischemic Stroke.

Neurons in the penumbra (the area surrounding ischemic tissue that consists of still viable tissue but with reduced blood flow and oxygen transport) may be rescued following stroke if adequate perfusion is restored in time. It has been speculated that post-stroke angiogenesis in the penumbra can reduce damage caused by ischemia. However, the mechanism for neovasculature formation in the brain remains unclear and vascular-targeted therapies for brain ischemia remain suboptimal. Here, we show that VEGFR1 was highly upregulated in pericytes after stroke. Knockdown of VEGFR1 in pericytes led to increased infarct area and compromised post-ischemia vessel formation. Furthermore, in vitro studies confirmed a critical role for pericyte-derived VEGFR1 in both endothelial tube formation and pericyte migration. Interestingly, our results show that pericyte-derived VEGFR1 has opposite effects on Akt activity in endothelial cells and pericytes. Collectively, these results indicate that pericyte-specific expression of VEGFR1 modulates ischemia-induced vessel formation and vascular integrity in the brain.

Perceptions on basilar artery occlusion management in China versus other countries: Analysis of the after the BEST of BASICS (ABBA) survey.

INTRODUCTION: Uncertainty remains on the optimal management of basilar artery occlusion (BAO). Two large randomized controlled trials (RCTs) in 2019 and 2021 demonstrated neutral results with respect to the use of endovascular therapy (EVT) for BAO. This study aimed to understand regional variation in physicians' perceptions towards the treatment of BAO as stratified by physician respondents from China versus outside China, prior to the publication of studies demonstrating a benefit of EVT for BAO. METHODS: An international online survey was conducted of stroke neurologists and neurointerventionalists from January to March 2022. Survey questions evaluated physician opinions toward the use of EVT in BAO, as well as the clinical and imaging features underlying treatment decisions. Respondents were dichotomized as either from China or from other countries and differences between groups were analyzed. RESULTS: There were 1245 physician respondents across 73 countries of which 295 (23.7%) were from China. Compared to respondents from the rest of the world, respondents from China were more likely to be interventionalists (71.5% vs 35.0%; p < 0.0001). Overall, more than 95% of respondents believed that EVT was superior to medical therapy under certain circumstances. Chinese respondents were more likely to believe that further RCTs were necessary than respondents from other countries (93.6% vs 76.2%; p < 0.0001). Chinese respondents were more likely to use advanced imaging in later time windows and use a premorbid mRS threshold of ≤2 for BAO selection to EVT. CONCLUSION: Most stroke physicians believe EVT is beneficial in selected patients with BAO. Clinical and imaging modality differences were observed in the selection criteria used for EVT. There was greater inclination to enroll all trial eligible patients in a BAO RCT by respondents from China as compared to other parts of the world.

Inhibition of hypoxia-inducible factor-1 by salidroside in an in vitro model of choroidal neovascularization.

PURPOSE: As a characteristic of age-related macular degeneration (AMD), choroidal neovascularization (CNV) causes severe vision loss. The current treatment has limited efficacy. This study was to investigate effects of Salidroside against CNV and explore its underlying mechanisms. METHODS: RF/6A cells were treated with 200 mM cobalt chloride (CoCl2) for 6 hr to mimic hypoxic condition. Cells were then treated with Salidroside at 10, 30, and 100 µM for 24 hr. Cells treated with DMSO were used as negative control. The cell proliferation was assessed using 3-(4,5-dimethylthiazol)-2,5-diphenyltetrazolium-bromid assay. The tube formation was investigated on Matrigel. The cell migration was measured by a Transwell assay. RT-qPCR was used to detect the gene expression. Immuohistochemistry and western blot were used to detect the expression of proteins. RESULTS: Salidroside significantly inhibited the cell migration and tube formation activity of RF/6A cells under hypoxia. Moreover, Salidroside reduced the expression levels of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1 (HIF-1) in RF/6A cells. CONCLUSIONS: Our data suggested that Salidroside could be a potential novel therapeutic agent against CNV.

Values of Baseline Posterior Circulation Acute Stroke Prognosis Early Computed Tomography Score for Treatment Decision of Acute Basilar Artery Occlusion.

BACKGROUND AND PURPOSE: This study aimed to analyze the impact of baseline posterior circulation Acute Stroke Prognosis Early Computed Tomography Score (pc-ASPECTS) on the efficacy and safety of endovascular therapy (EVT) for patients with acute basilar artery occlusion. METHODS: The BASILAR was a nationwide prospective registry of consecutive patients with a symptomatic and radiologically confirmed acute basilar artery occlusion within 24 hours of symptom onset. We estimated the effect of standard medical therapy alone (SMT group) versus SMT plus EVT (EVT group) for patients with documented pc-ASPECTS on noncontrast CT, both as a categorical (0-4 versus 5-7 versus 8-10) and as a continuous variable. The primary outcomes included favorable functional outcomes (modified Rankin Scale ≤3) at 90 days and mortality within 90 days. RESULTS: In total, 823 cases were included: 468 with pc-ASPECTS 8 to 10 (SMT: 71; EVT: 397), 317 with pc-ASPECTS 5 to 7 (SMT: 85; EVT: 232), and 38 with pc-ASPECTS 0 to 4 (SMT: 13; EVT: 25). EVT was associated with higher rate of favorable outcomes (adjusted relative risk with 95% CI, 4.35 [1.30-14.48] and 3.20 [1.68-6.09]; respectively) and lower mortality (60.8% versus 77.6%, P=0.005 and 35.0% versus 66.2%, P<0.001; respectively) than SMT in the pc-ASPECTS 5 to 7 and 8 to 10 subgroups. Continuous benefit curves also showed the superior efficacy and safety of EVT over SMT in patients with pc-ASPECTS ≥5. Furthermore, the prognostic effect of onset to puncture time on favorable outcome with EVT was not significant after adjustment for pc-ASPECTS (adjusted odds ratio, 0.98 [95% CI, 0.94-1.02]). CONCLUSIONS: Patients of basilar artery occlusion with pc-ASPECTS ≥5 could benefit from EVT. The baseline pc-ASPECTS appears more important for decision making and predicting prognosis than time to EVT. Registration: URL: http://www.chictr.org.cn. Unique identifier: ChiCTR1800014759.

A novel de novo TSC2 nonsense mutation detected in a pediatric patient with tuberous sclerosis complex.

PURPOSE: Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem disorder characterized by hamartomas in multiple organ systems. The TSC1 and TSC2 genes have been identified as the genetic basis of TSC. Two gene tests were used for definitive genetic diagnosis. METHODS: In our study, the case of a Chinese pediatric patient with seizures, hypomelanotic macules, hyperpigmented patches, multiple parenchymal lesions in the ventricle, and developmental retardation is detailed. Whole-genome sequencing (WGS) and multiplex ligation-dependent probe amplification (MLPA) were employed to detect genetic variations and copy number variations of TSC1 and TSC2. RESULTS: A novel heterozygous nonsense mutation in the TSC2 gene (c.3751A>T, p.Lys1251Ter) was identified in a Chinese pediatric patient suffering from TSC, whose unaffected parents did not carry this mutation. The mutation was classified as "pathogenic" according to the American College of Medical Genetics (ACMG) guidelines. CONCLUSION: WGS was carried out to definitively diagnose and detect variations in the exon and noncoding region of the gene and copy number variations in the whole genome simultaneously. For diseases with complex genetic mechanisms, WGS as the first-line test can be efficient and cost-effective for clinical diagnosis.

An observation of the peer-assisted learning (PAL) method in the clinical teaching of vertigo/dizziness-related diseases for standardized residency training (SRT) students in China: a randomized, controlled, multicenter study.

BACKGROUND: Vertigo and dizziness (VD) are among the most frequently seen symptoms in clinics and are important for medical students, especially for those in Chinese standardized residency training (SRT). The aim of our study was to examine the PAL method's feasibility in the clinical teaching of VD-related diseases for SRT students in China. METHODS: This is a randomized, controlled, multicenter study. A total of 228 residents were invited to participate in this study, of which 198 completed the program. The students were randomized into two groups, and VD-related diseases were taught using lecture-based learning (control group) or peer-assisted learning (PAL). An examination paper and a rating scale were used to evaluate students' performance in the mastery of VD-related theoretical knowledge and clinical skills, meanwhile students' perceptions, satisfaction, and risk of burnout were also analyzed using a questionnaire. Independent-samples t-test and chi-square analysis were performed to evaluate statistical significance for continuous variables and categorical variables, respectively, using SPSS 18.0 software. RESULTS: The PAL group performed better in mastering theoretical knowledge and clinical skills than the control group. And more students believed that PAL could help improve their personal qualities such as teamwork skills. However, more students reported that PAL increased the risk of burnout. CONCLUSIONS: PAL was a suitable and effective method in the clinical teaching of some specialized diseases, especially it was recommended for students who had gained initial knowledge and skills, such as Chinese SRT students. However, we should draw attention to the increased risk of burnout if PAL is intended to be widely used in clinical teaching. TRIAL REGISTRATION: ISRCTN registry, ISRCTN53773239 , 05/07/2021, retrospectively registered.

Asymmetric Slow-Spike-Wave Patterns with Maximal Discharges Contralateral to MRI Lesions Predict Better Surgical Prognosis in Symptomatic Lennox-Gastaut Syndrome or Lennox-Gastaut Phenotypes.

INTRODUCTION: Lennox-Gastaut syndrome (LGS) is a severe subtype of childhood-onset epileptic encephalopathy with drug-resistant and poor surgical prognosis. However, electroencephalogram (EEG) patterns of symptomatic LGS or LG phenotypes with structural brain lesions including focal abnormalities or asymmetric slow-spike-wave (SSW) patterns remain largely unknown. Due to the contradictory lateralization difference between MRI lesions and EEG pattern in symptomatic LGS or LG phenotypes, it is difficult to determine the precise lateralization of epileptic lesions, which is crucial to better surgical prognosis. This study is aim to ascertain the clinical characteristics of the EEG patterns, and its relationship with MRI lesions and to evaluate its prognostic value of surgical treatment in symptomatic LGS or LG phenotypes. METHODS: Twenty-four symptomatic LGS cases with asymmetric EEG SSW patterns and contralaterally independent or contralaterally dominant MRI lesions were collected, and their clinical features were analyzed retrospectively. RESULTS: In this cohort, most of lesions were perinatal or acquired during the first 6 months of life. The most common etiology was intracerebral hemorrhage. The LGS patients with both asymmetric SSW and focal sporadic epileptic waves (SEW) patterns showed the best surgical outcome with Engel class I level. Asymmetric SSW patterns with maximal discharges contralateral to MRI lesions were frequently observed in most of symptomatic LGS or LG phenotypes. Predominantly diffuse destructive lesions led to an attenuated voltage of ipsilateral scalp EEG producing an asymmetric SSW pattern in those patients with symptomatic LGS or LG phenotypes. CONCLUSIONS: Our study reveals a special SEW EEG pattern in symptomatic LG patients with asymmetric SSW and MRI lesions contralateral to the dominant EEG patterns. Contradictory lateralization difference between MRI and EEG probably arises from the relative voltage attenuation presenting in EEG ipsilateral to huge destructive lesions from early life. Our study suggests that the independent focal SEW activity remaining ipsilateral to the MRI lesion can potentially predict better surgical prognosis in symptomatic LGS or LG phenotypes.

A20 Ameliorates Intracerebral Hemorrhage-Induced Inflammatory Injury by Regulating TRAF6 Polyubiquitination.

Reducing excessive inflammation is beneficial for the recovery from intracerebral hemorrhage (ICH). Here, the roles and mechanisms of A20 (TNFAIP3), an important endogenous anti-inflammatory factor, are examined in ICH. A20 expression in the PBMCs of ICH patients and an ICH mouse model was detected, and the correlation between A20 expression and neurologic deficits was analyzed. A20 expression was increased in PBMCs and was negatively related to the modified Rankin Scale score. A20 expression was also increased in mouse perihematomal tissues. A20-/- and A20-overexpressing mice were generated to further analyze A20 function. Compared with wild-type (WT) mice, A20-/- and A20-overexpressing mice showed significant increases and decreases, respectively, in hematoma volume, neurologic deficit score, mortality, neuronal degeneration, and proinflammatory factors. Moreover, WT-A20-/- parabiosis was established to explore the role of A20 in peripheral blood in ICH injury. ICH-induced damage, including brain edema, neurologic deficit score, proinflammatory factors, and neuronal apoptosis, was reduced in A20-/- parabionts compared with A20-/- mice. Finally, the interactions between TRAF6 and Ubc13 and UbcH5c were increased in A20-/- mice compared with WT mice; the opposite occurred in A20-overexpressing mice. Enhanced IκBα degradation and NF-κB activation were observed in A20-/- mice, but the results were reversed in A20-overexpressing mice. These results suggested that A20 is involved in regulating ICH-induced inflammatory injury in both the central and peripheral system and that A20 reduces ICH-induced inflammation by regulating TRAF6 polyubiquitination. Targeting A20 may thus be a promising therapeutic strategy for ICH.

Genetic Polymorphisms and Clopidogrel Efficacy for Acute Ischemic Stroke or Transient Ischemic Attack: A Systematic Review and Meta-Analysis.

BACKGROUND: The association of genetic polymorphisms and clopidogrel efficacy in patients with ischemic stroke or transient ischemic attack (TIA) remains controversial. We performed a systematic review and meta-analysis to assess the association between genetic polymorphisms, especially CYP2C19 genotype, and clopidogrel efficacy for ischemic stroke or TIA. METHODS: We conducted a comprehensive search of PubMed and EMBASE from their inceptions to June 24, 2016. Studies that reported clopidogrel-treated patients with stroke or TIA and with information on genetic polymorphisms were included. The end points were stroke, composite vascular events, and any bleeding. RESULTS: Among 15 studies of 4762 patients with stroke or TIA treated with clopidogrel, carriers of CYP2C19 loss-of-function alleles (*2, *3, and *8) were at increased risk of stroke in comparison with noncarriers (12.0% versus 5.8%; risk ratio, 1.92, 95% confidence interval, 1.57-2.35; P<0.001). Composite vascular events were also more frequent in carriers of CYP2C19 loss-of-function alleles than in noncarriers (13.7% versus 9.4%; risk ratio, 1.51, 95% confidence interval, 1.10-2.06; P=0.01), whereas bleeding rates were similar (2.4% versus 3.1%; risk ratio, 0.89, 95% confidence interval, 0.58-1.35; P=0.59). There was no evidence of statistical heterogeneity among the included studies for stroke, but there was for composite vascular events. Genetic variants other than CYP2C19 were not associated with clinical outcomes, with the exception that significant associations of PON1, P2Y12, and COX-1 with outcomes were observed in 1 study. CONCLUSIONS: Carriers of CYP2C19 loss-of-function alleles are at greater risk of stroke and composite vascular events than noncarriers among patients with ischemic stroke or TIA treated with clopidogrel.