Association of single nucleotide polymorphisms in ITLN1 gene with ischemic stroke risk in Xi'an population, Shaanxi province.

Background: Ischemic stroke (IS) is the main cause of death and adult disability. However, the pathogenesis of this complicated disease is unknown. The present study aimed to assess the relationship between ITLN1 single nucleotide polymorphisms (SNPs) and the susceptibility to IS in Xi'an population, Shaanxi province. Methods: In this study, we designed polymerase chain reaction (PCR) primers located at -3,308 bp upstream of the transcription initiation site within promoter region of the ITLN1 gene. The target fragment was amplified by PCR and identified by agarose gel electrophoresis. Sanger sequencing was then performed in the samples extracted from a cohort comprising 1,272 participants (636 controls and 636 cases), and the obtained sequences were compared with the reference sequences available on the National Center for Biotechnology Information (NCBI) website to detect SNPs in the ITLN1 gene promoter region. Logistic regression analysis was employed to assess the relationship between ITLN1 polymorphisms and IS risk, with adjustments for age and gender. Significant positive results were tested by false-positive report probability (FPRP) and false discovery rate (FDR). The interaction among noteworthy SNPs and their predictive relationship with IS risk were explored using the Multi-Factor Dimensionality Reduction (MDR) software. Results: The results of Sanger sequencing were compared with the reference sequences on the NCBI website, and we found 14 SNPs in ITLN1 gene promoter satisfied Hardy-Weinberg equilibrium (HWE). Logistic regression analysis showed that ITLN1 was associated with a decreased risk of IS (rs6427553: Homozygous C/C: adjusted OR: 0.69, 95% CI [0.48-0.97]; Log-additive: adjusted OR: 0.83, 95% CI [0.70-0.98]; rs7411035: Homozygous G/G: adjusted OR: 0.66, 95% CI [0.47-0.94]; Dominant G/T-G/G: adjusted OR: 0.78, 95% CI [0.62-0.98]; Log-additive: adjusted OR: 0.81, 95% CI [0.69-0.96]; rs4656958: Heterozygous G/A: adjusted OR: 0.74, 95% CI [0.59-0.94]; Homozygous A/A: adjusted OR: 0.51, 95% CI [0.31-0.84]; Dominant G/A-A/A: adjusted OR: 0.71, 95% CI [0.57-0.89]; Recessive A/A: adjusted OR: 0.59, 95% CI [0.36-0.96]; Log-additive: adjusted OR: 0.73, 95% CI [0.61-0.88]), especially in people aged less than 60 years and males. Conclusions: In short, our study revealed a correlation between ITLN1 variants (rs6427553, rs7411035 and rs4656958) and IS risk in Xi'an population, Shaanxi province, laying a foundation for ITLN1 gene as a potential biomarker for predicting susceptibility to IS.

Predicting 3-month Functional Outcome After Endovascular Thrombectomy in Patients with Anterior Circulation Occlusion with an Arterial Transit Artifact Grading System.

PURPOSE: The objective of this study was to evaluate the relationship between arterial transit artifact (ATA), arterial spin labeling (ASL) perfusion imaging, and the outcome of patients with acute ischemic stroke (AIS) due to occlusion of large vessels in anterior circulation after endovascular thrombectomy (EVT). METHODS: Patients with anterior circulation occlusion treated with EVT between October 2017 and December 2021 were enrolled in this retrospective study, and ATA was quantified by a 4-point scale. A favorable outcome was defined by modified Rankin Scale (mRS) scores of 0-2 at 3 months. To identify independent predictors of favorable outcome, age, sex, risk factors, baseline National Institutes of Health Stroke Scale (NIHSS) score, site of occlusion, cause of stroke, and early reperfusion were evaluated with univariate and multivariate analyses. Predictive accuracy was evaluated by calculating the area under the receiver operating characteristic (ROC) curve (AUC) for the model. RESULTS: In this study 187 patients (age, 65.0 ± 12.5 years; men, 55%) were evaluated. Younger age (odds ratio, OR, 0.95; 95% confidence interval, CI, 0.92-0.98, p = 0.002), lower baseline NIHSS score (OR, 0.88; 95% CI, 0.82-0.94, p < 0.001), and lower ATA score (OR, 1.14; 95% CI, 1.06-1.22, p < 0.001) were independently associated with favorable outcomes in multivariate analysis. The ATA score has moderate to good accuracy in predicting favorable outcomes (AUC, 0.753). CONCLUSION: A high ATA score as a potential predictor, can help identify patients who may benefit from EVT.

The Functional Prognosis of Rescue Conscious Sedation During Mechanical Thrombectomy on Patients with Acute Anterior Circulation Ischemic Stroke: A Single-Center Retrospective Study.

INTRODUCTION: Based on real-world case data, this study intends to explore and analyze the impact of rescue conscious sedation (CS) on the clinical outcomes of patients with anterior circulation acute ischemic stroke (AIS) receiving mechanical thrombectomy (MT). METHODS: This retrospective study enrolled patients with anterior circulation AIS who received MT and were treated with either single local anesthesia (LA) or rescue CS during MT between January 2018 and October 2021. We used univariate and multivariate logistic regression methods to compare the impact of LA and CS on the clinical outcomes of patients with AIS who received MT, including the mRS at 90 days, the incidence of poststroke pneumonia (PSP), the incidence of symptomatic intracranial cerebral hemorrhage (sICH), and the mortality rate. RESULTS: We reviewed 314 patient cases with AIS who received MT. Of all patients, 164 met our search criteria. Eighty-nine patients received LA, and 75 patients received rescue CS. There was no significant difference between the two groups in the 90-day good prognosis (45.3% vs. 51.7%, p = 0.418) and mortality (17.3% vs. 22.5%, p = 0.414). Compared with the LA group, the incidence of postoperative pneumonia in the rescue CS group (44% vs. 25.8%, p = 0.015) was more significant. Multivariate stepwise logistic regression analysis revealed that intraoperative remedial CS was independently associated with PSP following MT. In a subgroup analysis, rescue CS was found to significantly increase the incidence of PSP in patients with dysphagia (OR = 7.307, 95% CI 2.144-24.906, p = 0.001). As the severity of the National Institutes of Health Stroke Scale (NIHSS) increased, intraoperative rescue CS was found to increase the risk of PSP (OR = 1.155, 95% CI 1.034-1.290, p = 0.011) by 5.1% compared to that of LA (OR = 1.104, 95% CI 1.013-1.204, p = 0.024). CONCLUSION: Compared to LA, rescue CS during MT does not significantly improve the 90 days of good prognosis and reduce the incidence of sICH and mortality in patients with anterior circulation AIS. However, it has a significantly increased risk of poststroke pneumonia (PSP), particularly in patients with dysphagia.

Nomogram to predict unfavorable outcome of endovascular thrombectomy for large ischemic core.

OBJECTIVE: The prognosis for patients presenting with a large ischemic core (LIC) following endovascular thrombectomy is relatively poor. This study aimed to construct and validate a nomogram for predicting 3-month unfavorable outcome in patients with anterior circulation occlusion-related LIC who underwent endovascular thrombectomy. METHODS: A retrospective training cohort and a prospective validation cohort of patients with a large ischemic core were studied. The diffusion weighted imaging related radiomic features and pre-thrombectomy clinical features were collected. After the selection of relevant features, a nomogram predicting modified Rankin Scale score of 3-6 as an unfavorable outcome was established. The discriminatory value of the nomogram was evaluated with a receiver operating characteristic curve. RESULTS: A total of 140 patients (mean age 66.3 ± 13.4 years, 35% female) were included in this study, consisting of a training cohort (n = 95) and a validation cohort (n = 45). The percentage of patients with an mRS scores of 0-2 was 30%, 0-3 was 40.7%, and 32.9% were dead. Age, National Institute of Health Stroke Scale (NIHSS) score, and two radiomic features, Maximum2DDiameterColumn and Maximum2DDiameterSlice, were identified as factors associated with unfavorable outcome in the nomogram. The nomogram demonstrated an area under the curve of 0.892 (95% confidence interval [CI], 0.812-0.947) in the training dataset and 0.872 (95% CI, 0.739-0.953) in the validation dataset. INTERPRETATION: This nomogram, which includes age, NIHSS score, Maximum2DDiameterColumn, and Maximum2DDiameterSlice, may predict the risk of unfavorable outcome in patients with LIC caused by anterior circulation occlusion.

HMGB1, angel or devil, in ischemic stroke.

INTRODUCTION: High-mobility group box 1 protein (HMGB1) is extensively involved in causing ischemic stroke, pathological damage of ischemic brain injury, and neural tissue repair after ischemic brain injury. However, the precise role of HMGB1 in ischemic stroke remains to be elucidated. METHODS: Comprehensive literature search and narrative review to summarize the current field of HMGB1 in cerebral ischemic based on the basic structure, structural modification, and functional roles of HMGB1 described in the literature. RESULTS: Studies have exhibited the crucial roles of HMGB1 in cell death, immunity and inflammation, thrombosis, and remodeling and repair. HMGB1 released after cerebral infarction is extensively involved in the pathological injury process in the early stage of cerebral infarction, whereas it is involved in the promotion of brain tissue repair and remodeling in the late stage of cerebral infarction. HMGB1 plays a neurotrophic role in acute white matter stroke, whereas it causes sustained activation of inflammation and plays a damaging role in chronic white matter ischemia. CONCLUSIONS: HMGB1 plays a complex role in cerebral infarction, which is related to not only the modification of HMGB1 and bound receptors but also different stages and subtypes of cerebral infarction. future studies on HMGB1 should investigate the spatial and temporal dynamics of HMGB1 after cerebral infarction. Moreover, future studies on HMGB1 should attempt to integrate different stages and infarct subtypes of cerebral infarction.

Association of Tirofiban With Functional Outcomes After Thrombectomy in Acute Ischemic Stroke Due to Intracranial Atherosclerotic Disease.

BACKGROUND AND OBJECTIVE: To investigate the efficacy and safety of IV infusion of tirofiban before endovascular thrombectomy for patients with large vessel occlusion due to intracranial atherosclerotic disease. The secondary objective was to identify potential mediators for the clinical effect of tirofiban. METHODS: Post hoc exploratory analysis of the Endovascular Treatment With versus Without Tirofiban for Patients with Large Vessel Occlusion Stroke (RESCUE BT) trial, which was a randomized, double-blinded, placebo-controlled trial at 55 centers in China from October 2018 to October 2021. Patients with occlusion of the internal carotid artery or middle cerebral artery due to intracranial atherosclerosis were included. The primary efficacy outcome was the proportion of patients achieving functional independence (defined as modified Rankin scale 0-2) at 90 days. Binary logistic regression and causal mediation analyses were used to estimate the treatment effect of tirofiban and the potential mediators. RESULTS: This study included 435 patients, of whom 71.5% were men. The median age was 65 (interquartile range [IQR] 56-72) years, with a median NIH Stroke Scale of 14 (IQR 10-19). Patients in the tirofiban group had higher rates of functional independence at 90 days than patients in the placebo group (adjusted odds ratio 1.68; 95% CI 1.11-2.56, p = 0.02) without an increased risk of mortality or symptomatic intracranial hemorrhage. Tirofiban was associated with fewer thrombectomy passes (median [IQR] 1 [1-2] vs 1 [1-2], p = 0.004), which was an independent predictor of functional independence. Mediation analysis showed tirofiban-reduced thrombectomy passes explained 20.0% (95% CI 4.1%-76.0%) of the effect of tirofiban on functional independence. DISCUSSION: In this post hoc analysis of the RESCUE BT trial, tirofiban was an effective and well-tolerated adjuvant medication of endovascular thrombectomy for patients with large vessel occlusion due to intracranial atherosclerosis. These findings need to be confirmed in future trials. TRIAL REGISTRATION INFORMATION: The RESCUE BT trial was registered on the Chinese Clinical Trial Registry: chictr.org.cn, ChiCTR-INR-17014167. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that tirofiban plus endovascular therapy improves 90-day outcome for patients with large vessel occlusion due to intracranial atherosclerosis.

The Relationship Between MMP17 Variants and Ischemic Stroke Risk in the Population from Shaanxi Province in China.

Background: Ischemic stroke (IS) was a multifactorial disease, which was the main cause of death and adult disability. Genetic factors cannot be ignored. Objective: The present study discussed the relationship between MMP17 variants and the susceptibility of IS. Methods: Based on the Agena MassARRAY platform, we genotyped single nucleotide polymorphisms (SNPs) on the MMP17 gene in 1345 participants (670 controls and 675 cases). We used logistic regression analysis to analyze the association of MMP17 SNPs with the risk of IS in the Chinese population, with odds ratio (OR) and 95% confidence intervals (CIs). False-positive report probability (FPRP) detected false positives on the significant results. Besides, we detected the SNP-SNP interaction to predict IS risk by multi-factor dimensionality reduction (MDR) analysis. Results: In the total analysis, MMP17 rs7975920 conferred an increased susceptibility to IS. After a stratified analysis by age and gender, the significant association between rs7975920 and IS risk was displayed in the subjects aged >55 years old and females. After stratified analysis by smoking and drinking, MMP17 rs6598163 was related to the risk of IS in smokers and rs7975920 was associated with the risk of IS in smokers and was in correlation with IS risk in drinkers. Conclusion: In short, we first observed that MMP17 rs7975920 and rs6598163 were related to the risk of IS. The above results provided a theoretical basis for the elaboration of the role of MMP17 in IS in the Chinese population.

Endovascular recanalization in patients with severely disabling non-acute ischemic stroke.

BACKGROUND: It is unclear whether patients with severely disabling ischemic stroke (SDIS-that is, modified Rankin scale (mRS) scores of 3-5) benefit from non-acute endovascular recanalization (ER). OBJECTIVE: To determine the effect of non-acute ER or medical treatment in severely disabled patients with non-acute ischemic stroke (mRS scores of 3-5). METHODS: Between January 2018 and August 2021, non-acute patients with SDIS and large vessel occlusion were collected from two regional stroke centers. Patients who met the inclusion and exclusion criteria were assigned to two groups based on whether they underwent ER (ER group) or not (medical group). The primary functional outcome was the mRS score at 90 days. The primary safety outcomes were the recurrence of stroke and mortality. RESULTS: Of the 325 patients with hypoperfusion cerebral infarction caused by large vessel occlusion, 63 met the inclusion criteria (32 patients in the ER group, 31 patients in the medical group). A favorable outcome (mRS score ≤2) occurred more often in the ER group than in the medical group (59.4% vs 22.6%, respectively; OR=0.12, 95% CI 0.02 to 0.58; P<0.01). There were no significant differences in new-onset ischemic stroke (6.3% vs 3.2%, respectively; P=1.000), symptomatic intracerebral hemorrhage (12.5% vs 0%, respectively; P=0.113), or mortality within 90 days (6.3% vs 6.5%, respectively; P=1.000) between the two groups. Preoperative mRS scores (OR=7.34, 95% CI 1.56 to 34.5; P=0.02) and ER (OR=0.12, 95% CI 0.02 to 0.58; P<0.01) were significantly associated with outcome. CONCLUSION: Our data suggest that patients with SDIS (mRS score 3-5) with smaller infarct cores and better collateral circulation can benefit from non-acute ER, with no additional perioperative complications or mortality.

The relationship between vertebrobasilar artery calcification and intracranial atherosclerosis-related occlusion in thrombectomy.

Background and purpose: Distinguishing between intracranial atherosclerosis-related occlusion (ICAS-O) and non-ICAS-O can benefit strategies of identifying the need for surgical plans prior to thrombectomy. We investigated the association between vertebrobasilar artery calcification (VBAC) and ICAS-O in acute ischemic stroke patients undergoing thrombectomy. Methods: Patients were recruited from a prospective single-center registration study who had undergone thrombectomy between October 2017 and October 2021. The enrolled patients were divided into ICAS-O and non-ICAS-O, as determined by the intraarterial therapy process. The occurrences of VBAC were recorded on intracranial non-contrast computed tomography (NCCT) scans before thrombectomy. The association between VBAC and ICAS-O was assessed using binary logistic regression. Results: A total of 2732 patients who had undergone digital subtraction angiography were reviewed, and 314 thrombectomy patients (mean age: 65.4 years, 36.6% female) with NCCT were enrolled in this study. VBAC was detected before thrombectomy in 113 (36%) out of 314 patients. Age, hypertension, and diabetes were associated with VBAC, and a higher frequency of VBAC was identified in patients presenting posterior circulation. ICAS-O accounts for 43% (135/314) in eligible patients. From multivariable analyses, VBAC was identified as an independent predictor of ICAS-O (adjusted odds ratio, 6.16 [95% CI, 2.673-14.217], P < 0.001). Meanwhile, the (VBAC[+] atrial fibrillation[-]) group displayed higher rates of ICAS-O than the (VBAC[-] atrial fibrillation [-]) group (P < 0.001). Conclusions: We demonstrated that VBAC is an independent risk factor for ICAS-O in patients who underwent thrombectomy. Patients free of atrial fibrillation with VBAC have more trend to be ICAS-O.

The roles of MMP8/MMP10 polymorphisms in ischemic stroke susceptibility.

BACKGROUND: Ischemic stroke (IS), a multifactorial and polygenic disease, is the most common cause of death. This study aimed to determine the roles of MMP8/MMP10 polymorphisms in IS susceptibility in the Chinese Han population. METHODS: MMP8 rs1940475 and rs3765620, and MMP10 rs17860949 from 700 IS patients and 700 controls were genotyped by the MassARRAY iPLEX platform. The impact of polymorphisms on IS risk was evaluated by logistic regression analysis. RESULTS: Our study indicated that rs17860949 in MMP10 was significantly associated with a reduced risk of IS (OR = 0.632, p = .002). Precisely, stratification analysis showed that rs17860949 was relate to a decreased susceptibility to IS in patients aged > 55 years (OR = 0.472, p < .001), males (OR = 0.632, p = .012), nonsmokers (OR = 0.610, p = .017), and nondrinkers (OR = 0.559, p = .006). All these significant findings were verified by false-positive report probability test. Furthermore, GG genotype and AG genotype in MMP8 rs3765620 polymorphism were related to a reduced triglycerides concentration (p = .018). CONCLUSION: Our study suggests that rs17860949 in MMP10 may play a protective role in IS in the Chinese Han population.

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.).

Impact of MMP2 rs243849 and rs14070 genetic polymorphisms on the ischemic stroke susceptibility in Chinese Shaanxi population.

Background: Ischemic stroke (IS) is a complex neurological disease affected by genetics and environment. Matrix metalloproteinase-2 (MMP2) is involved in extracellular matrix (ECM) degradation, inflammation and angiogenesis to regulate the development and recovery of IS. Purposes: The aim of this study was to explore the association of rs1053605, rs243849 and rs14070 in MMP2 with the risk of IS in Chinese Shaanxi population. Methods: In this study, 677 IS patients and 681 normal controls were recruited. Rs1053605, rs243849 and rs14070 in MMP2 were genotyped. Logistic regression analysis was applied to evaluate the association of rs1053605, rs243849 and rs14070 in MMP2 with IS susceptibility and the association of environmental factors with MMP2 genetic susceptibility to IS. Results: The results of the overall analysis demonstrated that rs14070 in MMP2 significantly reduced the risk of IS in Chinese Shaanxi population (OR = 0.767, 95% CI = 0.619-0.952, P = 0.016). Subgroup analysis illustrated that rs243849 in MMP2 evidently increased the risk of IS among drinkers, while rs14070 in MMP2 apparently reduced IS susceptibility among females, participants with aged >55, smokers and drinkers. Conclusions: Collectively, rs243849 and rs14070 in MMP2 were significantly associated with the risk of IS in Chinese Shaanxi population, and the effect of MMP2 to IS may be associated with its genetic susceptibility.

Effect of Intravenous Tirofiban vs Placebo Before Endovascular Thrombectomy on Functional Outcomes in Large Vessel Occlusion Stroke: The RESCUE BT Randomized Clinical Trial.

Importance: Tirofiban is a highly selective nonpeptide antagonist of glycoprotein IIb/IIIa receptor, which reversibly inhibits platelet aggregation. It remains uncertain whether intravenous tirofiban is effective to improve functional outcomes for patients with large vessel occlusion ischemic stroke undergoing endovascular thrombectomy. Objective: To assess the efficacy and adverse events of intravenous tirofiban before endovascular thrombectomy for acute ischemic stroke secondary to large vessel occlusion. Design, Setting, and Participants: This investigator-initiated, randomized, double-blind, placebo-controlled trial was implemented at 55 hospitals in China, enrolling 948 patients with stroke and proximal intracranial large vessel occlusion presenting within 24 hours of time last known well. Recruitment took place between October 10, 2018, and October 31, 2021, with final follow-up on January 15, 2022. Interventions: Participants received intravenous tirofiban (n = 463) or placebo (n = 485) prior to endovascular thrombectomy. Main Outcomes and Measures: The primary outcome was disability level at 90 days as measured by overall distribution of the modified Rankin Scale scores from 0 (no symptoms) to 6 (death). The primary safety outcome was the incidence of symptomatic intracranial hemorrhage within 48 hours. Results: Among 948 patients randomized (mean age, 67 years; 391 [41.2%] women), 948 (100%) completed the trial. The median (IQR) 90-day modified Rankin Scale score in the tirofiban group vs placebo group was 3 (1-4) vs 3 (1-4). The adjusted common odds ratio for a lower level of disability with tirofiban vs placebo was 1.08 (95% CI, 0.86-1.36). Incidence of symptomatic intracranial hemorrhage was 9.7% in the tirofiban group vs 6.4% in the placebo group (difference, 3.3% [95% CI, -0.2% to 6.8%]). Conclusions and Relevance: Among patients with large vessel occlusion acute ischemic stroke undergoing endovascular thrombectomy, treatment with intravenous tirofiban, compared with placebo, before endovascular therapy resulted in no significant difference in disability severity at 90 days. The findings do not support use of intravenous tirofiban before endovascular thrombectomy for acute ischemic stroke. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR-IOR-17014167.

Safety and efficacy of three enteral feeding strategies in patients with severe stroke in China (OPENS): a multicentre, prospective, randomised, open-label, blinded-endpoint trial.

BACKGROUND: Early enteral nutrition is crucial for preventing malnutrition and improving outcomes in patients with severe stroke, but previous trials have provided conflicting results regarding the optimal nutritional strategy. We aimed to compare the efficacy and safety of three enteral feeding strategies in patients with severe stroke. METHODS: The Optimizing Early Enteral Nutrition in Severe Stroke (OPENS) study was a multicentre, investigator-initiated, prospective, open-label, randomised controlled trial, with blinded outcome assessment, in 16 tertiary and district general hospitals in the west of China. Adult patients with acute severe ischaemic or haemorrhagic stroke (Glasgow Coma Scale score ≤12 or National Institutes of Health Stroke Scale score ≥11 on admission) who were expected to receive enteral nutrition for more than 7 days were randomly assigned (1:1:1) to full enteral nutrition (70-100% of estimated caloric requirements), modified full enteral nutrition (full enteral nutrition plus prokinetic agents), or hypocaloric enteral nutrition (40-60% of estimated caloric requirements) via a centralised web-based randomisation system. The assigned nutrition was initiated within 24 h after enrolment and continued for 7 days. The computer-generated randomisation sequence was prepared by a statistician not involved with the rest of the study. Randomisation was done with an automated permuted block size of six. The allocation was unblinded to participants and investigators. The primary efficacy outcome was the proportion of participants with poor outcome (modified Rankin Scale score ≥3) at day 90 and the prespecified primary safety outcome was mortality at day 90, assessed in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, NCT02982668. FINDINGS: Between Jan 15, 2017, and Sept 23, 2020, 321 patients were randomly assigned (107 in each group) and 315 patients (175 [56%] men, median age 71 years, IQR 60-78) were included in the final analysis. The study was terminated ahead of schedule on Sept 23, 2020, because a significant difference between groups was detected in mortality. The proportion of participants with poor outcomes at 90 days did not differ (modified full enteral nutrition 86 [82%] of 105 patients vs full enteral nutrition 85 [80%] of 106 patients, adjusted odds ratio [OR] 0·87, 95% CI 0·41-1·86, p=0·721; hypocaloric enteral nutrition 76 [73%] of 104 patients vs full enteral nutrition 0·61, 0·30-1·27, p=0·186; hypocaloric enteral nutrition vs modified full enteral nutrition 0·70, 0·34-1·46, p=0·340). Hypocaloric enteral nutrition showed significantly higher 90-day mortality than did modified full enteral nutrition (35 [34%] of 104 patients vs 18 [17%] of 105 patients, adjusted OR 2·89, 95% CI 1·46-5·72; p=0·0023), whereas the difference was not significant between hypocaloric enteral nutrition and full enteral nutrition (24 [23%] of 106 patients; adjusted OR 1·92, 95% CI 1·00-3·69; p=0·049), and between modified full enteral nutrition and full enteral nutrition (adjusted OR 0·61, 0·29-1·28; p=0·187). The most common adverse event was pneumonia, the incidence of which showed no significant difference among groups (full enteral nutrition 82 [78%] of 105 patients, modified full enteral nutrition 83 [81%] of 103 patients, hypocaloric enteral nutrition 78 [75%] of 104 patients; p=0·625). INTERPRETATION: In the early phase of severe stroke, modified full enteral nutrition or hypocaloric enteral nutrition did not significantly reduce the risk of a poor outcomes compared with full enteral nutrition over a 90-day period. Hypocaloric enteral nutrition might be associated with increased mortality compared with modified full enteral nutrition. Further studies are needed to investigate whether modified full enteral nutrition might be the optimal strategy. FUNDING: Shaanxi province Key Research and Development Project.

Hyperattenuated Lesions on Immediate Non-contrast CT After Endovascular Therapy Predict Intracranial Hemorrhage in Patients With Acute Ischemic Stroke: A Retrospective Propensity Matched Study.

Background and Purpose: This study aimed to analyze the association between hyperattenuated lesions (HALs) and postoperative intracranial hemorrhage (IH) and predict perioperative IH through quantitative analysis of HALs in acute ischemic stroke (AIS) with anterior large vessel occlusion (LVO) after endovascular therapy (ET). Materials and Methods: This retrospective, propensity-matched study enrolled AIS who received ET from a single-center registry study between August 2017 and May 2020. The enrolled patients were divided into two groups: IH and non-IH, by follow-up postoperative CT. The occurrences of HALs on immediate CT after ET were also recorded. The association between IH and HALs after propensity score matching (PSM) was determined by binary logistic regression models. The receiver operating characteristic (ROC) curve was used to determine the predictive value of the highest CT Hounsfield units (HU) value on immediate CT. Results: Initially, 1,418 patients who underwent digital subtraction angiography were reviewed and 114 AIS patients with immediate postoperative CT and follow-up CT after ET were enrolled. Forty-nine out of the 114 patients developed IH after therapy. After PSM analysis, patients with IH were more likely to have HALs on immediate CT (Odds Ratio, OR 11.9, P = 0.002, and 95% CI: 2.485-57.284). For 80 patients with HALs, ROC analysis of the highest CT value in the HALs territory showed that the cut-off value was 97 HU, the sensitivity was 70.21%, and the specificity was 81.82%. Conclusions: Patients with HALs after ET are more likely to have perioperative IH. The highest CT value in the HALs area might be used to predict IH.

The cytoprotective role of omentin against oxidative stress-induced PC12 apoptosis.

Oxidative stress has been proven to play a critical role in the pathogenesis of neuronal injury. As a novel adipocytokine, omentin is produced by visceral adipose with insulin sensitizing effects and has been revealed to possess anti-inflammatory effects. However, the possible effect of omentin on oxidative stress remains unknown. The present study aimed to detect the potential protective effect of omentin against hydrogen peroxide (H2O2)-induced cytotoxicity of PC12 cells. The results showed that no cytotoxic effect was shown in PC12 cells co-cultured with omentin alone at a concentration of 50-1000 ng/mL. The CCK8 and TUNEL assays suggested that omentin could remarkably attenuate apoptosis induced by 100 µM H2O2. The PCR and western blotting showed that the expression levels of Bax was significantly inhibited by omentin via the upregulation of miR-128-3p at its 3'-UTR. Taken together, these results indicated that omentin protects PC12 cells against H2O2-induced apoptosis, and further studies need to be conducted before utilization in the clinic for the treatment of neurodegenerative diseases.

Reducing Suppressors of Cytokine Signaling-3 (SOCS3) Expression Promotes M2 Macrophage Polarization and Functional Recovery After Intracerebral Hemorrhage.

Intracerebral hemorrhage (ICH) is a fatal subtype of stroke, and effective interventions to improve the functional outcomes are still lacking. Suppressor of cytokine signaling 3 (SOCS3) plays critical roles in the inflammatory response by negatively regulating cytokine-Jak-Stat signaling. However, the role of SOCS3 in the regulation of macrophage polarization is highly controversial and the fine regulation exerted by SOCS3 needs further understanding. In this study, rat ICH models were established by infusion of collagenase into the caudate nucleus. To decrease SOCS3 expression into microglia/macrophages in the hemorrhagic lesion area, we injected lentiviral short hairpin RNA (shSOCS3) (Lenti-shSOCS3) into the hematoma cavity at 24 h following ICH. We found that the number of iNOS-positive cells (M1 phenotype) was significantly reduced, whereas arginase-1-positive cells (M2 phenotype) were markedly elevated in animals that received Lenti-shSOCS3 injections compared with those in the Lenti-EGFP and saline groups. The increase in arginase-1-positive cells was associated with a significantly lower pro-inflammatory microenvironment, which included the downregulation of pro-inflammatory cytokines [interleukin (IL)-1ß, IL-6, and TNF-α] and concurrent upregulation of anti-inflammatory (IL-10) mediators. In addition, this marked shift toward the M2 phenotype was associated with suppressed NF-κB activation. Furthermore, these changes notably enhanced the neuroprotective effects and functional recovery in Lenti-shSOCS3-injected animals. Our findings indicated that reduction in SOCS3 expression caused a marked bias toward the M2 phenotype and ameliorated the inflammatory microenvironment, which enhanced neuroprotective effects and resulted in notable improvement in functional recovery after ICH.

MicroRNA-769-5p Promotes The Growth Of Glioma Cells By Targeting Lysine Methyltransferase 2A.

BACKGROUND: Accumulating evidence supports the involvement of microRNAs (miRNAs) in the progression of human cancers including glioma. Recently, miR-769-5p has been reported to play a tumor suppressive role in colorectal cancer and lung cancer, whereas it exerts an oncogenic role in melanoma. However, the role of miR-769-5p and its related mechanism are poorly elucidated. METHODS: The levels of miR-769-5p in glioma tissues and adjacent non-tumor tissues were detected by qRT-PCR. In addition, the effects of miR-769-5p on cell proliferation and apoptosis were evaluated by CCK-8, EdU, colony formation and flow cytometric assays, respectively. Meanwhile, the dual-luciferase reporter assay was used to investigate the interaction of miR-769-5p and lysine methyltransferase 2A (KMT2A) in glioma. RESULTS: We found that miR-769-5p expression was strongly upregulated in glioma tissues and cell lines. Glioma tissues with high World Health Organization (WHO) grades had obvious higher levels of miR-769-5p compared to samples with low WHO grades. Interestingly, glioma patients highly expressing miR-769-5p showed prominent poorer survivals. Knockdown of miR-769-5p significantly suppressed cell proliferation and resulted in apoptosis in glioma cells. Additionally, miR-769-5p silencing restrained in vivo growth of glioma cells in mice. Interestingly, KMT2A was identified to be a direct target of miR-769-5p in glioma cells. The expression of KMT2A mRNA was downregulated in glioma tissues and inversely correlated with miR-769-5p level. KMT2A overexpression inhibited cell proliferation and induced the apoptosis of A172 cells. Moreover, siRNA-mediated KMT2A silencing could partially abolish miR-769-5p knockdown-induced suppressive effects on A172 cells. CONCLUSION: In summary, our findings suggest that targeting miR-769-5p/KMT2A axis may be a promising therapeutic target for glioma treatment.

Suppression of SIRT6 by miR-33a facilitates tumor growth of glioma through apoptosis and oxidative stress resistance.

microRNA-33a (miR-33a) belongs to the miR-33 family that is implicated in the progression of various types of cancers. Aberrant expression of miR-33a has been detected in several human cancers, and has been shown to regulate the migration and invasion as well as proliferation and apoptosis of tumor cells. However, the clinical significance and precise mechanisms underlying the dysfunction of miR-33a in glioma have not been well investigated in previous studies. In this study, overexpression of miR-33a was observed in clinical glioma specimens and cell lines. Clinicopathological detection revealed that miR-33a highly expressing patients showed large tumor sized and advanced World Health Organization (WHO) grade as well as reduced overall survival. Furthermore, the results of in vitro experiments confirmed that loss of miR-33a resulted in reduced proliferation and enhanced apoptosis in U251 cells, while miR-33a restoration showed opposite effects in U87 cells. Further studies indicated that miR-33a knockdown restrained tumor growth of glioma in vivo. miR-33a negatively regulated the expression of sirtuin 6 (SIRT6) at both mRNA and protein levels via targeting the 3'UTR of SIRT6 mRNA. SIRT6 was underexpressed and inversely correlated with miR-33a expression in the glioma tissues. Mechanistically, SIRT6 overexpression increased the levels of lactate dehydrogenase (LDH) and reactive oxygen species (ROS) while it reduced cell survival under H2O2 treatment. In addition, SIRT6 restoration led to apoptosis with alterative expression of Bax, Bcl-2, cleaved caspase-8, and inhibition of Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway in glioma. Thus, our studies demonstrated that the deregulation of miR-33a may promote tumor development in human glioma by regulating the expression of its target gene, SIRT6.

Neuroglobin functions as a prognostic marker and promotes the tumor growth of glioma via suppressing apoptosis.

Neuroglobin (Ngb) has been reported to be upregulated by hypoxia and plays an anti-apoptotic function. Previous studies have reported that Ngb is expressed in human glioblastoma cells and up-regulated in hypoxic microregions of glioblastoma tumor xenografts. While, the clinical significance of Ngb and its function in human glioma keep unknown. Ngb expression was analyzed in 86 glioma tissues and 20 normal brain tissues. Results showed that Ngb was significantly overexpressed in glioma tissues compared to normal brain tissues. In addition, increased levels of Ngb also observed in glioma cell lines. Clinicopathological analysis verified that the positive expression of Ngb was associated with histological type and world health organization (WHO) grade of glioma. Moreover, Kaplan-Meier analysis found that Ngb overexpression led to a shorter survival. Multivariate Cox regression analysis demonstrated that Ngb expression was an independent prognostic marker. Further experiments illustrated that Ngb knockdown significantly inhibited proliferation and facilitated apoptosis in U251 cells. In vivo experiments further confirmed that Ngb silencing notably prohibited the tumor growth of glioma in nude mice. While, Ngb overexpression prominently promoted proliferation and suppressed apoptosis in U87 cells. Taken together, this work support the first evidence that Ngb can be potentially used as a promising biomarker and target for novel treatment of human glioma.