Clinical Outcomes On Tubridge Flow Diverter in Treatmenting Intracranial Aneurysms: a Retrospective Multicenter Registry Study.

PURPOSE: In China, the application of nitinol Tubridge flow diverter (TFD) has become popular for treating intracranial aneurysms (IAs). In this study, we investigated the safety outcomes of the application of TFD for treating IAs in real-world scenarios. METHODS: We retrospectively analyzed aneurysms treated with TFD in 235 centers throughout China between April 2018 and April 2020. The primary endpoint was the event-free survival rate at 12 months, defined as the occurrence of morbidity (spontaneous rupture, intraparenchymal hemorrhage (IPH), ischemic stroke, and permanent cranial neuropathy) or death. Univariate and multivariate analyses were performed to assess the risk factors. A good outcome was defined as a modified Rankin Score (mRS) of 0-2. RESULTS: We included 1281 unruptured aneurysms treated with TFD. The overall neurological morbidity and death rates after 12 months were 5.4 and 2.8%, respectively. Ischemic strokes were the most common complication (4.2%, P < 0.001). Cranial neuropathy, IPH, and spontaneous rupture occurred in 0.3%, 0.3%, and 0.5% of aneurysms, respectively. Univariate and multivariate analyses indicated that the male gender, older age, larger aneurysm diameter, and aneurysm located on BA were the independent risk factors for neurologic events. Aneurysm located on BA was the independent risk factor for ischemic strokes. Most patients (1222) had access to the mRS, and 93.2% of them achieved good outcomes. CONCLUSION: Treatment of IAs with TFD was associated with low morbidity and mortality, most of which were ischemic events. Large posterior aneurysms might be associated with a higher complication rate. TRIAL REGISTRATION: Retrospectively registered.

Gekko Coil System for Intracranial Aneurysms Treatment in China (GREAT-China): A Prospective Randomized Controlled Open-Label Noninferiority Trial.

OBJECTIVE: This study aimed to evaluate the safety and efficacy of the Gekko coil system in treating intracranial aneurysms (IAs) in clinical practice. METHODS: A prospective multicenter randomized open-label parallel positive control noninferiority trial was conducted by 11 centers in China. Patients with a target IA were randomized 1:1 to coiling with either Gekko or Axium coils. The primary outcome was successful aneurysm occlusion at 6 months postoperative follow-up, whereas the secondary outcomes included the successful occlusion aneurysm rate in the immediate postoperative period, recanalization rate at the 6 months follow-up, and technical success and security. RESULTS: Between May 2018 and September 2020, 256 patients were enrolled and randomized. Per-protocol analysis showed that the successful aneurysm occlusion rate at 6 months was 96.08% for the Gekko coil group compared with 96.12% in the Axium coil group, with a difference of -0.04% (P = 0.877). The successful immediate aneurysm occlusion rates were 86.00% and 77.45% in the Gekko coil group and the Axium coil group, respectively, showing no significant difference between the 2 groups (P = 0.116), whereas the recanalization rates during the 6 months follow-up were 2.02% and 1.96% in the Gekko and Axium coil groups, respectively, which was not statistically significant (P = 1.000). CONCLUSIONS: This trial showed that the Gekko coil system was noninferior to the Axium coil system in terms of efficacy and safety for IA embolization. In clinical practice, the Gekko coil system can be considered safe and effective for treating patients with IA.

Textbook Outcomes Among Patients with Aneurysmal Subarachnoid Hemorrhage Following Endovascular Treatment.

INTRODUCTION: The case fatality rate among patients with aneurysmal subarachnoid hemorrhage (aSAH) has decreased progressively, with numerous patients subjected to contemporary paradigms that minimize the use of agonizing therapeutic processes. The concept of the "Textbook Outcome" (TO), a composite outcome that highlights numerous favorable outcomes, was developed in the context of gastrointestinal tumor surgeries and expeditiously extended across diverse surgical spheres. The aim of this study was to explore the factors hindering the achievement of optimal prognoses in postinterventional aSAH patients, employ textbook outcomes, and establish predictive models. METHODS: We conducted a retrospective review of data from 1270 aSAH patients who received endovascular treatment between 2012 and 2018. We delineated an exemplary TO within the aSAH domain, characterized by favorable clinical results, minimal complications, and the absence of retreatments. This TO-oriented approach is explained within the manuscript. RESULTS: The findings revealed that preoperative intraventricular hemorrhage (IVH), preoperative Hunt and Hess grade (H&H) ≥ 3, World Federation of Neurosurgical Societies (WFNS) grade ≥ 3, the presence of blebs on the aneurysm, aneurysms situated at branching sites, and non-stent-assisted endovascular intervention were the strongest risk factors for not achieving textbook outcomes (non-"Textbook Outcome" [N-TO]). Decision curve analysis and calibration analyses revealed strong concordance between the predictions of the N-TO nomogram model and the actual observations. CONCLUSIONS: Treatment Outcomes hold significant practical value in clinical studies of aSAH patients receiving endovascular treatment. The likelihood of N-TOs was predicted by IVH, H&H grade ≥ 3, WFNS grade ≥ 2, presence o f bleb on the aneurysm, and aneurysms located at branching sites.

Antioxidants and the risk of stroke: results from NHANES and two-sample Mendelian randomization study.

BACKGROUND: Stroke is the second leading cause of death worldwide, and observational studies have suggested a correlation between antioxidants and reduced stroke risk. However, it remains unclear whether causal relationships exist. METHODS: This study first performed a cross-sectional study of the association between the Composite Dietary Antioxidant Index (CDAI) and stroke using data from the National Health and Nutrition Examination Survey (NHANES) 2007-2018. Second, a two-sample univariable Mendelian Randomization (MR) was performed to analyze the causal effect of circulating levels of antioxidants on different subtypes of stroke. RESULTS: The cross-sectional study included a total of 24,892 participants representing more than 200 million US non-institutionalized residents, a multivariable logistic regression model revealed that the risk of stroke decreased by 3.4% for each unit increase in CDAI (P = 0.017), with a non-linear association found, indicating a reduction in stroke risk before an inflection point of 3.078. MR analysis revealed that genetically determined levels of retinol had a suggestive protective effect on subarachnoid hemorrhage (SAH) (OR = 0.348, P = 0.025), and genetically determined levels of selenium had a suggestive protective effect against SAH (OR = 0.826, P = 0.007). However, no causal relationship was found between antioxidants and ischemic stroke or intracranial hemorrhage risk. CONCLUSIONS: Evidence suggests that diet-derived antioxidants may reduce the risk of stroke, as indicated by the protective effects of retinol and selenium against SAH. However, more research is needed to fully understand how antioxidants prevent stroke.

Activation of BMP4-pSmad1/5 pathway impairs the function of VSMCs in intracranial aneurysms.

Intracranial aneurysms (IAs) are characterized by abnormal dilatation of the cerebral vessels. Vascular smooth muscle cells (VSMCs) are implicated in maintaining vascular homeostasis. Disordered VSMCs are one of the most common causes for occurrence and development of IAs. The bone morphogenetic protein 4 (BMP4) signalling pathway is involved in regulating cell proliferation, apoptosis, and differentiation. This study aimed to investigate the effects of BMP4 on VSMCs and its underlying mechanisms. BMP4 was upregulated in the VSMCs of IAs and caused apoptosis of VSMCs through Smad1/5 phosphorylation. In addition, BMP4 overexpression significantly promoted the proliferation and migration of VSMCs and induced a phenotypic transformation from contractile to inflammatory. Our findings facilitate further understanding of the occurrence and development of IAs and provide a potential therapeutic target.

Smart Liposomal Nanocarrier Enhanced the Treatment of Ischemic Stroke through Neutrophil Extracellular Traps and Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase-Stimulator of Interferon Genes (cGAS-STING) Pathway Inhibition of Ischemic Penumbra.

Brain inflammation is regarded as one of the leading causes that aggravates secondary brain injury and hinders the prognosis of ischemic stroke. After ischemic stroke, high quantities of peripheral neutrophils are recruited to brain lesions and release neutrophil extracellular traps (NETs), leading to the aggravation of blood-brain barrier (BBB) damage, activation of microglia, and ultimate neuronal death. Herein, a smart multifunctional delivery system has been developed to regulate immune disorders in the ischemic brain. Briefly, Cl-amidine, an inhibitor of peptidylarginine deiminase 4 (PAD4), is encapsulated into self-assembled liposomal nanocarriers (C-Lipo/CA) that are modified by reactive oxygen species (ROS)-responsive polymers and fibrin-binding peptide to achieve targeting ischemic lesions and stimuli-responsive release of a drug. In the mouse model of cerebral artery occlusion/reperfusion (MCAO), C-Lipo/CA can suppress the NETs release process (NETosis) and further inhibit the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) pathway in an ischemic brain. In addition, MCAO mice treated with C-Lipo/CA significantly mitigated ischemic and reperfusion injury, with a reduction in the area of cerebral infarction to 12.1%, compared with the saline group of about 46.7%. These results demonstrated that C-Lipo/CA, which integrated microglia regulation, BBB protection, and neuron survival, exerts a potential therapy strategy to maximize ameliorating the mortality of ischemic stroke.

Association between blood pressure and different antihypertensive drugs with outcome after ischemic stroke: A Mendelian randomization study.

BACKGROUND: Observational studies suggest an association between blood pressure (BP) and functional outcomes in ischemic stroke patients but whether this is causal or due to confounding is uncertain. We used Mendelian randomization (MR) to assess causality, and also explore whether particular classes of anti-hypertensives were associated with a better outcome after ischemic stroke. METHODS: We selected genetic variants associated with systolic and diastolic BP and BP-lowering variants in genes encoding antihypertensive drugs from genome-wide association studies (GWAS) on 757,601 individuals. The primary outcome was 3-month dependence or death defined as a modified Rankin Scale (mRS) of 3-6. The secondary outcome was disability or death after 90 days defined as mRS 2-6. Cochran's Q statistic in the inverse variance weighted (IVW) model, the weighted median, MR-Egger regression, leave-one-single-nucleotide polymorphism (SNP)-out analysis, MR-Pleiotropy Residual Sum and Outlier methods were adopted as sensitivity analyses. To validate our primary results, we performed independent repeat analyses and Bi-directional MR analyses. RESULTS: Genetic predisposition to higher systolic and diastolic BP was associated with disability or death after ischemic stroke in univariable IVW MR analysis (odds ratio (OR) 1.29, 95% confidence interval (CI): 1.05-1.59, p = 0.014; OR 1.27, 95% CI: 1.07-1.51, p = 0.006, respectively). Pulse pressure was associated with both dependence or death and disability or death after ischemic stroke (OR = 1.05, 95% CI: 1.02-1.08, p = 0.002; OR = 1.04, 95% CI = 1.01-1.07, p = 0.009, respectively). Angiotensin-converting enzyme inhibitor (ACEI) and calcium channel blocker (CCB) were significantly associated with improved functional outcomes (dependence or death, OR 0.76, 95% CI: 0.62-0.94, p = 0.009; OR 0.89, 95% CI: 0.83-0.97, p = 0.005). Proxies for ß-blockers, angiotensin receptor blockers (ARB), and thiazides failed to show associations with functional outcomes (p > 0.05). CONCLUSION: We provide evidence for an association of genetic predisposition to higher BP with a higher risk of 3-month functional dependence after ischemic stroke. Our findings support ACEI and CCB as promising antihypertensive drugs for improving functional outcomes in ischemic stroke.

Predictors of recurrence and complications for the endovascular treatment of unruptured middle cerebral artery aneurysm: A high-volume center experience over 12 years.

OBJECT: To assess the safety and efficacy of endovascular treatment (EVT) of unruptured middle cerebral artery (MCA) aneurysms in a retrospective cohort in a high-volume center. Predictors of complications and recurrence were determined. METHODS: Retrospectively reviewed our database of prospectively collected information for all patients with unruptured MCA aneurysms that were treated by endovascular approach from March 2008 to December 2020. A multivariate analysis was conducted to identify predictors of complications and recurrence. RESULTS: Three hundred and fifty-one patients with 370 unruptured MCA aneurysms underwent EVT were included in this study. Seventy-three aneurysms (19.7%) were treated by coiling without stent, 297 (80.3%) with stent-assisted coiling. The procedures were performed with a technical success rate of 100%. Procedure-related neurological complications occurred in 15 patients (4.1%), including 1 patient died from post-procedural stent thrombosis. Age ≥ 65 years (P = 0.039; OR = 3.400; 95% CI, 1.065-10.860) and aneurysm size ≥ 5 mm (P = 0.009; OR = 15.524; 95% CI, 1.988-121.228) were significantly associated with ischemic complications of EVT. Three hundred and six aneurysms were (87.2%) completed image follow-up (235 DSA and 71 CE-MRA). The median angiographic follow-up time were 7.0 ± 4.3 months (range from 1 to 88 months). Follow-up angiograms showed that 249 aneurysms (81.4%) were completed occluded, 29 aneurysms (9.5%) were improved, 17 aneurysms (5.6%) were stable, and 11 aneurysms (3.6%) were recanalized and 10 of them accepted retreatments. Aneurysm size ≥ 10 mm was a predictor of recanalization (P = 0.004; OR = 11.213; 95% CI, 2.127-59.098) and stent-assisted coiling can significantly reduce recanalization (P = 0.004; OR = 0.105; 95% CI, 0.023-0.479). CONCLUSIONS: EVT is a safe and effective therapeutics for unruptured MCA aneurysms management, and provides durable aneurysm occlusion rate during follow-up. Large MCA aneurysms have higher recurrence and ischemic complications risk after EVT. Stent-assisted coiling can significantly reduce the recurrence rate without increasing the risk of complications.

Comparison of staged-stent and stent-assisted coiling technique for ruptured saccular wide-necked intracranial aneurysms: Safety and efficacy based on a propensity score-matched cohort study.

Background: Application of stent-assisted coiling and FD in acute phase of ruptured wide-necked aneurysms is relatively contraindicated due to the potential risk of ischemic and hemorrhagic complications. Scheduled stenting after initial coiling has emerged as an alternative paradigm for ruptured wide-necked aneurysms. The objective of this study is to evaluate the safety and efficacy of a strategy of staged stent-assisted coiling in acutely ruptured saccular wide-necked intracranial aneurysms compared with conventional early stent-assisted coiling strategy via propensity score matching in a high-volume center. Methods: A retrospective review of patients with acutely ruptured saccular wide-necked intracranial aneurysms who underwent staged stent-assisted coiling or conventional stent-assisted coiling from November 2014 to November 2019 was performed. Perioperative procedure-related complications and clinical and angiographic follow-up outcomes were compared. Results: A total of 69 patients with staged stent-assisted coiling and 138 patients with conventional stent-assisted coiling were enrolled after 1:2 propensity score matching. The median interval time between previous coiling and later stenting was 4.0 weeks (range 3.5-7.5 weeks). No rebleeding occurred during the intervals. The rate of immediate complete occlusion was lower with initial coiling before scheduled stenting than with conventional stent-assisted coiling (21.7 vs. 60.9%), whereas comparable results were observed at follow-up (82.5 vs. 72.9%; p = 0.357). The clinical follow-up outcomes, overall procedure-related complications and procedure-related mortality between the two groups demonstrated no significant differences (P = 0.232, P = 0.089, P = 0.537, respectively). Multivariate analysis showed that modified Fisher grades (OR = 2.120, P = 0.041) were independent predictors for overall procedure-related complications and no significant predictors for hemorrhagic and ischemic complications. Conclusions: Staged stent-assisted coiling is a safe and effective treatment strategy for acutely ruptured saccular wide-necked intracranial aneurysms, with comparable complete occlusion rates, recurrence rates at follow-up and overall procedure-related complication rates compared with conventional stent-assisted coiling strategy. Staged stent-assisted coiling could be an alternative treatment option for selected ruptured intracranial aneurysms in the future.

Staged stenting strategy of acutely wide-neck ruptured intracranial aneurysms: A meta-analysis and systematic review.

Objective: In the study, we explored the safety and effectiveness of staged stenting strategy for acutely wide-neck ruptured intracranial aneurysms. Methods: Online databases, including PubMed, EMBASE, the Cochrane database, and Web of Science, were retrospectively and systematically searched. The main observation indicators were the procedure-related complication rate, complete occlusion rate, and favorable clinical outcome. Meta-analysis was performed using a random or fixed effect model based on heterogeneity. Results: A total of 5 studies with 143 patients were included. The hemorrhagic complication rate of the initial coiling and staged stenting was 2.8% (4 of 143) and 0, respectively. The ischemic complication rate of the coiling and supplemental stenting was 3.5% (5 of 143) and 2.9% (4 of 139), respectively. There were no deaths due to procedure-related complications in two stages. The aneurysm complete occlusion rate was 25% (95% CI, 0.13-0.03; I2 = 4.4%; P = 0.168) after initial coiling, 54% (95% CI, 0.63-0.64; I2 = 0%; P = 0.872) after staged stenting, and 74% (95% CI, 0.66-0.81; I2 = 56.4%; P = 0.562) at follow-up, respectively. Favorable clinical outcome rate 74% (95% CI, 0.61-0.86; I2 = 50.5%; P = 0.133) after discharge of initial coiling treatment, and 86% (95% CI, 0.80-0.92; I2 = 0; P = 0.410) after discharge from stenting, and 97% (95% CI, 0.93-1.01; I2 = 43.8%; P = 0.130) at follow-up. Conclusion: Staged stenting treatment of wide-neck RIA with coiling in the acute phase followed by delayed regular stent or flow-diverter stent had high aneurysm occlusion rate, favorable clinical outcome rate and low procedure-related complication rate. A more dedicated and well-designed controlled study is warranted for further evaluation of staged stenting treatment compared to SCA in wide-neck RIA.

Maternally Expressed Gene 3 Negatively Regulated Decorin to Supresse Angiogenesis, Proliferation and Migration of Endothelial Cells.

BACKGROUND: Angiogenesis of tumor cells is highly associated with tumorsecreted factors and matrix proteins. However, the underlying mechanism of tumorsecreted factors and matrix proteins during angiogenesis is rarely discussed. OBJECTIVES: This study investigated the relationship between the maternally expressed gene 3 (MEG3), a tumor-secreted growth factor, and Decorin, a tumor-secreted matrix protein, and evaluated their derivate roles in human endothelial cell development. METHODS: Human endothelial cells were transiently transfected with a plasmid expressing antisense of Decorin mRNA (shDecorin) and silencing mRNA of MEG3 (siMEG3) or MEG3 over-expressive vectors. A series of qPCR and Western blot analysis was applied to characterize the expressions of MEG3 and Decorin in all transfected cells. Moreover, scratch, Transwell, and Matrigel neovascularization assays were performed to examine three key processes of endothelial cells' angiogenesis, including tubulogenesis, proliferation, and migratory levels. In addition, the cell viability was evaluated at each step via the MTT test. RESULTS: The overexpression of MEG3 inhibited angiogenesis and migration of endothelial cells by preventing the expression of Decorin. At the same time, the inhibition of MEG3 via siRNA resulted in an increased expression of Decorin, enhanced tube formation levels, and promoted endothelial cell proliferation and migration. Furthermore, Decorin's knockdown suppressed the angiogenesis and migration of endothelial cells without affecting the expression of MEG3. Importantly, the stimulation of HUVEC cells with exogenous Decorin protein alleviated most phenotypes induced by the upregulation of MEG3. CONCLUSION: Our study demonstrated the anti-growth effects of MEG3 on vasculogenesis and migration of endothelial cells. Thus, by blocking the expression of Decorin in HUVECs, the overexpression of MEG3 repressed their development and might potentially alleviate the ischemic stroke.

A bibliometric analysis of chronic subdural hematoma since the twenty-first century.

BACKGROUND: Chronic subdural hematoma (CSDH) is a common disease that forms between the dura and arachnoid membranes of the brain. With the development of medications and surgery, significant progress has been made in the diagnosis and treatment of CSDH. However, there is no comprehensive analysis available on CSDH-related studies published in the literature. This study aimed to collect and analyze CSDH-related studies published since the twenty-first century using bibliometric analysis and to summarize the current status of research in this field for the sake of providing systematic data for further study of CSDH. METHODS: CSDH-related studies were searched in the Web of Science Core Collection (WoSCC) database using the Medical Subject Heading (MeSH) term 'chronic subdural hematoma'. Data analysis and visualization were performed by R and CiteSpace software. RESULTS: This study retrieved 1424 CSDH-related articles published since the beginning of the twenty-first century. There was a general increase in both the number of published articles and the mean number of citations. The authors, institutions and journals that contributed the most to the field of CSDH were Jianning Zhang, Tianjin Medical University, and world neurosurgery, respectively. The reference co-citation network identified 13 clusters with significant modularity Q scores and silhouette scores (Q = 0.7124, S = 0.8536). The major research categories were (1) evolution of the therapeutic method and (2) the etiology and pathology of CSDH. Keyword analysis revealed that 'middle meningeal artery embolization' was the latest burst keyword. CONCLUSIONS: This study identified the most influential countries, authors, institutions and journals contributing to CSDH research and discussed the hotspots and the latest subjects of CSDH research.

Worldwide productivity and research trends of publications concerning stent application in acutely ruptured intracranial aneurysms: A bibliometric study.

Background: Stenting is a common clinical practice to treat acutely ruptured intracranial aneurysm (RIA). Although multiple studies have demonstrated its long-term safety and effectiveness, there is currently a lack of bibliometric analysis on stent application in acutely RIA. This study sought to summarize the current status of research in this field and lay a foundation for further study. Materials and methods: Related publications were searched in the Web of Science Core Collection (WoSCC) database. Data analysis and visualization were performed by R and CiteSpace software. Results: A total of 275 publications published in English from 1997 to 2022 were included in this study. The growth of publications slowed down. The reference co-citation network identified 13 clusters with a significant network (Q = 0.7692) and convincing clustering (S = 0.9082). The research focus was acutely RIA and the application of stents during interventional procedures. The main trends of research were: (1) development of materials, and (2) safety of stent application in acutely RIA. The United States contributed the most articles, and Jianmin Liu was the most prolific author. Mayo Clinic was the leading institution in this field. Most articles were published in Interventional Neuroradiology. Conclusions: This study analyzed the research trends, hotspots and frontiers of stent application in acutely RIA. It is our hope that the results obtained could provide useful information to researchers to get a clearer picture about their future research directions in this field.

Cerebrovascular disorders associated with agenesis of the internal carotid artery: Findings on digital subtraction angiography.

Objective: Agenesis of the internal carotid artery (ICA) is a rare vascular condition that is complicated by intracranial aneurysms and rete mirabile. The altered hemodynamics caused by this distinctive cerebrovascular angioarchitecture can cause ischemic or hemorrhagic accidents. Data on clinical and radiographic features have been limited to describing this vascular pattern. We present five cases of agenesis of the internal carotid artery confirmed by digital subtraction angiography (DSA) and further investigate the influence of altered angioarchitecture on the integrity of intracranial morphology. Methods: Cases of ICA anomalies were screened from the patients who underwent DSA in two hospitals. Clinical manifestation, radiographic features, management, and outcomes were retrospectively reviewed. Results: Five patients [mean age 44 years (range, 30-65 years)] were included. Two patients presented with subarachnoid hemorrhage, one with cognitive impairment, one with dizziness, and one with intermittent headache. DSA demonstrated that three cases were complicated by intracranial aneurysms, one by dural arteriovenous fistula, and one by rete aneurysm. Three patients underwent endovascular treatment and one underwent bypass surgery. No patient died or experienced cerebrovascular accident during short-term follow-up. Conclusions: ICA agenesis can be complicated by disorders such as intracranial aneurysm, rete aneurysm, and dural arteriovenous fistula. This suggests that ICA agenesis is associated with a tendency towards disrupted cerebrovascular homeostasis resulting from altered hemodynamics.

Intensive blood pressure control after endovascular thrombectomy for acute ischaemic stroke (ENCHANTED2/MT): a multicentre, open-label, blinded-endpoint, randomised controlled trial.

BACKGROUND: The optimum systolic blood pressure after endovascular thrombectomy for acute ischaemic stroke is uncertain. We aimed to compare the safety and efficacy of blood pressure lowering treatment according to more intensive versus less intensive treatment targets in patients with elevated blood pressure after reperfusion with endovascular treatment. METHODS: We conducted an open-label, blinded-endpoint, randomised controlled trial at 44 tertiary-level hospitals in China. Eligible patients (aged ≥18 years) had persistently elevated systolic blood pressure (≥140 mm Hg for >10 min) following successful reperfusion with endovascular thrombectomy for acute ischaemic stroke from any intracranial large-vessel occlusion. Patients were randomly assigned (1:1, by a central, web-based program with a minimisation algorithm) to more intensive treatment (systolic blood pressure target <120 mm Hg) or less intensive treatment (target 140-180 mm Hg) to be achieved within 1 h and sustained for 72 h. The primary efficacy outcome was functional recovery, assessed according to the distribution in scores on the modified Rankin scale (range 0 [no symptoms] to 6 [death]) at 90 days. Analyses were done according to the modified intention-to-treat principle. Efficacy analyses were performed with proportional odds logistic regression with adjustment for treatment allocation as a fixed effect, site as a random effect, and baseline prognostic factors, and included all randomly assigned patients who provided consent and had available data for the primary outcome. The safety analysis included all randomly assigned patients. The treatment effects were expressed as odds ratios (ORs). This trial is registered at ClinicalTrials.gov, NCT04140110, and the Chinese Clinical Trial Registry, 1900027785; recruitment has stopped at all participating centres. FINDINGS: Between July 20, 2020, and March 7, 2022, 821 patients were randomly assigned. The trial was stopped after review of the outcome data on June 22, 2022, due to persistent efficacy and safety concerns. 407 participants were assigned to the more intensive treatment group and 409 to the less intensive treatment group, of whom 404 patients in the more intensive treatment group and 406 patients in the less intensive treatment group had primary outcome data available. The likelihood of poor functional outcome was greater in the more intensive treatment group than the less intensive treatment group (common OR 1·37 [95% CI 1·07-1·76]). Compared with the less intensive treatment group, the more intensive treatment group had more early neurological deterioration (common OR 1·53 [95% 1·18-1·97]) and major disability at 90 days (OR 2·07 [95% CI 1·47-2·93]) but there were no significant differences in symptomatic intracerebral haemorrhage. There were no significant differences in serious adverse events or mortality between groups. INTERPRETATION: Intensive control of systolic blood pressure to lower than 120 mm Hg should be avoided to prevent compromising the functional recovery of patients who have received endovascular thrombectomy for acute ischaemic stroke due to intracranial large-vessel occlusion. FUNDING: The Shanghai Hospital Development Center; National Health and Medical Research Council of Australia; Medical Research Futures Fund of Australia; China Stroke Prevention; Shanghai Changhai Hospital, Science and Technology Commission of Shanghai Municipality; Takeda China; Hasten Biopharmaceutic; Genesis Medtech; Penumbra.

Enhanced treatment of cerebral ischemia-Reperfusion injury by intelligent nanocarriers through the regulation of neurovascular units.

Reperfusion injury is one of the major causes of disability and death caused by ischemic stroke, and drug development focuses mainly on single neuron protection. However, different kinds of cells in the neurovascular units (NVUs), including neurons, microglia and vascular endothelial cells, are pathologically changed after cerebral ischemia-reperfusion injury, resulting in an urgent need to develop a drug delivery system to comprehensively protect the kinds of cells involved in the NVU. Herein, we have constructed a c(RGDyK) peptide modified, NF-κB inhibitor caffeic acid phenethyl ester (CAPE)-loaded and reactive nitrogen species (RNS) stimuli-responsive liposomal nanocarrier (R-Lipo-CAPE) to target ischemic lesions and then remodel the NVU to reduce the progression of cerebral ischemia-reperfusion injury. The R-Lipo-CAPE liposomes were approximately 170 nm with a zeta potential of -30.8 ± 0.2 mV. The in vitro CAPE release behavior from R-Lipo-CAPE showed an RNS-dependent pattern. For in vivo studies, transient middle cerebral artery occlusion/reperfusion (MCAO) model mice treated with R-Lipo-CAPE had the least neurological impairment and decreased brain tissue damage, with an infarct area of 13%, compared with those treated with saline of 53% or free CAPE of 38%. Furthermore, microglia in the ischemic brain were polarized to the tissue-repairing M2 phenotype after R-Lipo-CAPE treatment. In addition, R-Lipo-CAPE-treated mice displayed a prominent down-regulated expression of MMP-9 and restored expression of the tight junction protein claudin-5. This proof-of-concept indicates that R-Lipo-CAPE is a promising nanomedicine for the treatment of cerebral ischemia-reperfusion injury through the regulation of neurovascular units. STATEMENT OF SIGNIFICANCE: Based on the complex mechanism and difficulty in treatment of cerebral ischemia-reperfusion injury, the overall regulation of neurovascular unit has become an extremely important target. However, little nanomedicine has been directed to remodel the neurovascular units in targeted cerebral ischemia-reperfusion injury therapy. Here, c(RGDyK) peptide modified reactive nitrogen species (RNS) stimuli-responsive liposomal nanocarrier loaded with a NF-κB inhibitor (CAPE), was designed to simultaneously regulate various cells in the microenvironment of cerebral ischemia-reperfusion injury to remodel the neurovascular units. Our in vitro and in vivo data showed that the intelligent nanocarrier exerted the ability of pathological signal stimuli-responsive drug release, cerebral ischemia-reperfusion injury site targeting and neurovascular units remodeling through reducing neuron apoptosis, regulating microglia polarization and repairing vascular endothelial cell. Overall, the intelligent liposomal drug delivery system was a promising and safe nanomedicine in the perspective of cerebral ischemia-reperfusion injury treatment.

Low profile visualized intraluminal support stent-assisted Hydrocoil embolization for acutely ruptured wide-necked intracranial aneurysms: A propensity score-matched cohort study.

PURPOSE: To compare the safety and efficacy of low profile visualized intraluminal support (LVIS) stent-assisted hydrogel coil embolization and LVIS stent-assisted bare platinum coil embolization for acutely ruptured wide-necked intracranial. METHODS: 89 patients who underwent LVIS stent-assisted hydrogel coil embolization (hydrogel coil group) and 145 patients who underwent LVIS stent-assisted bare platinum coil embolization (platinum coil group) were retrospectively reviewed after 1:2 propensity score matching (PSM). Procedure-related complications, clinical and angiographic follow-up outcomes were compared between the two groups. RESULTS: All baseline characteristics were equivalent between hydrogel coil group and platinum coil group after PSM. There were no statistical differences in immediate postoperative embolization results, clinical and angiographic follow-up outcomes between the two groups (P = 0.514, P = 0.323 and P = 0.949, respectively). Intraprocedural aneurysm rupture, intraprocedural thrombosis and postprocedural thrombosis occurred in 2 patients (2.2%, 2/89), 1 patient (1.1%, 1/89) and 1 patient (1.1%, 1/89) of the hydrogel coil group compared with 1 patient (0.7%, 1/145), 1 patient (0.7%, 1/145) and 2 patients (1.4%, 2/145) of the platinum coil group, respectively (P = 0.559, P = 1.000 and P = 1.000). Nevertheless, the rate of postprocedural aneurysm early rebleeding in the hydrogel coil group was significantly lower than that in the platinum coil group (0.0% vs 4.8%, P = 0.046). CONCLUSION: LVIS stent-assisted hydrogel coil embolization may reduce the risk of aneurysm early rebleeding compared with LVIS stent-assisted bare platinum coil embolization for the treatment of acutely ruptured wide-necked intracranial aneurysms, which implies that hydrogel coil may improve the safety of stent placement for ruptured intracranial aneurysms.

The Diagnostic Value of Whole Blood lncRNA NR_120420 for Acute Ischemic Stroke.

OBJECTIVE: Current clinical practice based on CT or multimodal images to diagnose ischemic stroke always led to substantial treatment delay. We perform this study to explore possible circulating lncRNA biomarker to help promptly diagnose the disease. METHODS: We used microarray to identify the differentially expressed lncRNAs in the peripheral whole blood between AIS patients and controls and verified the results by quantitative polymerase chain reaction (qPCR). Multivariate logistic regressions were performed to determinate the lncRNAs independently associated with AIS occurrence. The ROC curve was used to detect the diagnostic accuracy of candidate lncRNAs in AIS and AIS subtypes, which was classified according to the Oxford Community Stroke Project (OCSP) criteria. RESULTS: The microarray analysis screened out 5686 differentially expressed lncRNAs. Among the nine selected lncRNAs verified by qPCR, NR_120420 (OR 1.29, 95% CI 1.02-1.65, P = 0.037) was found independently associated with AIS after balancing patient baseline characteristics. The receiver operating characteristic (ROC) analysis concerning NR_120420 in total anterior circulation infarction subgroup showed that the area under the curve was 0.86 (95% CI: 0.73-0.99, P = 0.003), and at the optimal cutoff point of 1.93, the sensitivity and specificity reached 85.7% and 84.6%, respectively. CONCLUSION: Our study indicated that NR_120420 could predict the total anterior circulation infarction with high sensitivity and specificity and could be potentially used as a biomarker for total anterior circulation infarction in AIS patients.

Bone marrow mesenchymal stem cells-derived exosomal microRNA-124-3p attenuates hypoxic-ischemic brain damage through depressing tumor necrosis factor receptor associated factor 6 in newborn rats.

Mesenchymal stem cells (MSCs)-derived exosomes (Exo) are beneficial in the use of brain damages. Restrictively, the mechanism of Exo expressing miR-124-3p in hypoxic-ischemic brain damage (HIBD) is not completely comprehended. Thereupon, this work was put forward to reveal the action of bone marrow MSCs-derived Exo (BMSCs-Exo) expressing miR-124-3p in the illness. BMSCs were isolated and transfected with miR-124-3p agomir. Then, BMSCs-Exo were extracted and identified. The newborn HIBD rats were injected with miR-124-3p-modified BMSCs-Exo or tumor necrosis factor receptor associated factor 6 (TRAF6)-related vectors. Next, neurological functions, neuron pathological and structural damages, oxidative stress and neuronal apoptosis were observed. miR-124-3p and TRAF6 expression was tested, along with their targeting relationship. miR-124-3p was down-regulated, and TRAF6 was up-regulated in newborn HIBD rats. miR-124-3p targeted TRAF6. BMSCs-Exo improved neurological functions, alleviated neuron pathological and structural damages, suppressed oxidative stress and reduced neuronal apoptosis in newborn HIBD rats, whereas BMSCs-Exo-mediated effects were enhanced by restoring miR-124-3p. Silencing TRAF6 attenuated HIBD in newborn rats, but overexpression of TRAF6 reversed the protective role of miR-124-3p-overexpressing BMSCs-Exo. This work makes it comprehensive that up-regulated exosomal miR-124-3p ameliorates HIBD in newborn rats by targeting TRAF6, which replenishes the potential agents for curing HIBD.

Predictors of unfavorable outcome in stent-assisted coiling for symptomatic unruptured intracranial spontaneous vertebral artery dissecting aneurysms (uis-VADAs): results from a multicenter study.

OBJECTIVE: To evaluate predictors of unfavorable outcome in stent-assisted coiling for symptomatic unruptured intracranial spontaneous vertebral artery dissecting aneurysms (uis-VADAs) based on 608 reconstructed lesions in 30 medical centres. METHODS: A total of 608 patients (male:female=479:129; mean age, 53.26±10.26 years) with 608 symptomatic uis-VADAs underwent reconstructive treatments using stent(s) with coils between January 2009 and December 2015. Treatments and predictors of unfavorable outcomes were retrospectively analyzed. RESULTS: Mainly, three methods were used to treat patients with uis-VADAs, including routine single-stent in 208 patients (such as Enterprise and others), new low-profile LVIS single stent in 107 patients, and multiple stents in 293 patients. During the median 66 months of clinical follow-up, 14 patients died, and 16 of the remaining 594 survivors had unfavorable outcomes (modified Rankin Scale score 3-5). The overall mortality rate was 2.3% (14/608), and the unfavorable outcome (mRS score 3-6) rate was 4.9% (30/608). Multivariate logistic regression analysis indicated that preprocedural ischemic infarctions (OR=3.78; 95% CI 1.52 to 9.40; p<0.01), diabetes mellitus (OR=3.74; 95% CI 1.31 to 10.68; p=0.01), and procedural complications (OR=14.18; 95% CI 5.47 to 36.80; p<0.01) were predictors of unfavorable outcome in the reconstructed VADAs. CONCLUSIONS: This multicenter study indicated that preprocedural ischemic infarctions, diabetes mellitus, and procedural complications were related to unfavorable clinical outcomes in the reconstructed uis-VADAs.