Monocyte to high-density lipoprotein ratio as an independent predictor of intracranial atherosclerotic stenosis-related emergency large vessel occlusion.

OBJECTIVE: To evaluate the correlation between the monocyte-to-high-density lipoprotein cholesterol ratio (MHR) and intracranial atherosclerotic stenosis-related emergent large vessel occlusion (ICAS-ELVO) in acute ischemic stroke patients with endovascular thrombectomy. METHODS: Included in this study were 215 patients who underwent endovascular thrombectomy. They were randomly assigned to training and testing datasets. The patients in training dataset (n=128) were divided into ICAS group (n=65) and embolism group (n=63). MHR was compared between the two groups. According to the cut-off value, patients in testing dataset (n=87) were divided into low-MHR group (n=54) and high-MHR group (n=33). MHR was compared between the two groups. RESULTS: In training dataset, the proportion of male patients, diabetic patients and smokers in ICAS group was significantly higher than that in embolism group [(50 (76.9%) vs. 30 (47.6%), P=0.001; 29 (44.6%) vs. 14(22.2%), P=0.007; 37(56.9%) vs. 14 (22.2%), P=0.001; 37 (56.9%) vs. 14 (22.2%), P=0.001], while the mean age and the proportion of patients with coronary heart disease (CHD), stroke and atrial fibrillation were significantly lower [(64.74±9.13 vs. 71.38±13.34, P=0.001; 6 (9.2%) vs. 14 (22.2%), P=0.043; 12 (18.5%) vs. 22 (34.9%), P=0.035; 5 (7.7%)vs. 56 (88.9%), P<0.001)]. The laboratory test results showed that monocyte count was significantly higher and high-density lipoprotein level was significantly lower in ICAS group than those in embolism group (0.61±0.26 vs. 0.45±0.13, P=0.001; 1.17±0.28 vs. 1.37±0.27, P=0.001). MHR in ICAS group was significantly higher than that in embolism group (0.55±0.26 vs. 0.34±0.11, P=0.001). In training set, MHR was found to be an independent predictor for the occurrence of ICAS-ELVO with an adjusted OR of 2.39 (95%CI 1.29-4.48, P=0.006). ROC curve analysis showed that the area under the curve (AUC) of MHR was 0.8 (95% CI, 0.72-0.87, p < 0.001), with a sensitivity of 0.60 and a specificity of 0.873. The optimal cut-off value of the MHR level was 0.46. In testing dataset, the rate of ICAS-ELVO in higher quartile was significantly higher than that in the lower quartile (81.8% vs. 33.3%, P<0.001). Patients with a low MHR had a higher rate of cerebral hemorrhagic than those with a high MHR. CONCLUSION: MHR was associated with ICAS-ELVO in acute ischemic stroke patients with endovascular thrombectomy, and the higher level of MHR does benefit to differentiate ICAS from intracranial embolism, suggesting that MHR may prove to be an independent predictor for ICAS-ELVO.

Thrombectomy alone vs thrombectomy with over 2/3-dose intravenous thrombolysis pretreatment in the DIRECT-MT trial.

BACKGROUND: The DIRECT-MT trial showed that endovascular thrombectomy (EVT) alone was noninferior to EVT preceded by intravenous alteplase. However, the infusion of intravenous alteplase was uncompleted before the initiation of EVT in most cases of this trial. Therefore, the additional benefit and risk of over 2/3-dose intravenous alteplase pretreatment remain to be assessed. METHODS: We assessed patients with acute anterior circulation ischemic stroke who received EVT alone or with over 2/3-dose intravenous alteplase pretreatment from the DIRECT-MT trial. Patients were assigned to the thrombectomy-alone group and the alteplase pretreatment group. The primary outcome was the distribution of modified Rankin Scale (mRS) at 90 days. The interaction of treatment allocation and collateral capacity was assessed. RESULTS: A total of 393 patients (thrombectomy alone: 315; alteplase pretreatment: 78) were identified. The thrombectomy alone was comparable with alteplase pretreatment prior to the thrombectomy on the distribution of mRS at 90 days without significant effect modification by collateral capacity (adjusted common odds ratio (acOR), 1.12; 95% CI, 0.72-1.74; adjusted P for interaction = 0.83). Successful reperfusion before thrombectomy and the number of passes in the thrombectomy alone group differed significantly from the alteplase pretreatment group (2.6% vs. 11.5%; corrected P = 0.02 and 2 vs. 1; corrected P = 0.003). There was no interaction between treatment allocation and collateral capacity on all outcomes. CONCLUSIONS: EVT alone and EVT preceded by over 2/3-dose intravenous alteplase might have equal efficacy and safety for patients with acute anterior circulation large vessel occlusion, except for successful perfusion before thrombectomy and the number of passes.

Reperfusion status and postoperative blood pressure in acute stroke patients after endovascular treatment.

Background and purpose: An aggressive lowering of blood pressure (BP) could lead to neurological worsening, particularly of the area that has not been reperfused in acute stroke patients with large vessel occlusion (LVO). We sought to investigate the association of reperfusion status and BP course following mechanical thrombectomy (MT) with outcomes in LVO. Materials and methods: Consecutive patients with LVO treated with MT between Jan 2020 to Jun 2021 were enrolled in a retrospective cohort study. Hourly systolic BP (SBP) and diastolic BP (DBP) were recorded for 72 h following MT and maximum SBP and DBP levels were identified. The Extended Thrombolysis in Cerebral Infarction (eTICI) scale was used to assess reperfusion extent. LVO patients were stratified in 2 groups based on reperfusion status: complete reperfusion (eTICI 3) and incomplete reperfusion (eTICI 2b/c). Three-month functional independence was defined as a modified Rankin Scale score of 0-2. Results: A total of 263 acute ischemic stroke patients with LVO were retrospectively evaluated. Complete reperfusion was achieved in 210 patients (79.8%). Post-MT maximum SBP over 160 mmHg was significantly related to worse functional outcome (38.1% vs. 55.7%, p = 0.006), higher likelihood of in-hospital mortality and 3-month mortality (19.0% vs. 6.9%, p = 0.004, 27.4% vs. 14.3%, p = 0.012). No statistical correlation was found between reperfusion status and blood pressure level (p > 0.05). In patients with complete reperfusion, patients with an average BP 120-140 mmHg tends to have worse functional outcome compared with 100-120 mmHg (OR = 1.77, 95%CI: 0.97-3.23, p = 0.061). Conclusion: High maximum SBP levels following MT are associated with an increased likelihood of 3-month functional dependence and mortality. An average BP of 100-120 mmHg tends to have better functional independence in completely reperfused patients. The effect of intensive BP control on incomplete reperfusion still warrants further investigations.

Thrombus migration in patients with acute ischaemic stroke undergoing endovascular thrombectomy.

OBJECTIVE: The impact of thrombus migration (TM) prior to endovascular thrombectomy (EVT) on clinical outcomes and revascularisation rates remains unknown. We aimed to examine whether preinterventional TM modifies the treatment effects of direct EVT versus bridging EVT in acute large vessel occlusion patients. METHODS: All patients undergoing catheter angiography in the Direct Intra-arterial thrombectomy in order to Revascularise acute ischaemic stroke patients with large vessel occlusion Efficiently in Chinese Tertiary hospitals: A Multicentre randomised clinical Trial were included. TM was determined by radiologists unaware of the study by analysing discrepancies between computed tomographic angiography at baseline and first-run digital subtraction angiography before EVT. The primary outcome was the score on the modified Rankin scale (mRS) assessed at 90 days. RESULTS: Of 627 included patients, the TM rate was 11.3% (71/627). In the multivariable logistic regression model, baseline National Institutes of Health Stroke Scale score (adjusted OR 0.956, 95% CI 0.916 to 0.999; p=0.043) and intravenous thrombolysis (adjusted OR 2.614, 95% CI 1.514 to 4.514; p<0.001) were independently associated with TM. The patients with TM were less likely to be completely recanalised than those without TM (21.27% vs 36.23%, p=0.040). The interaction of TM and the EVT treatment effect did not significantly affect mRS shift analysis (p=0.687) or mRS scores of 0 to 1 (p=0.436). CONCLUSION: Preinterventional TM does not modify the treatment effects of direct versus bridging EVT on functional outcomes in patients with acute ischaemic stroke with anterior large vessel occlusion. TM leads to a lower complete recanalisation rate.

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.

Cost-effectiveness of thrombectomy alone versus alteplase before thrombectomy in acute ischemic stroke: results from the DIRECT-MT.

OBJECTIVE: The use of thrombectomy alone (endovascular thrombectomy [EVT]) was found to be noninferior to combination therapy (EVT plus intravenous thrombolysis [IVT] with alteplase before thrombectomy [EVT+IVT]) in the DIRECT-MT (Direct Intra-Arterial Thrombectomy in Order to Revascularize AIS Patients With Large Vessel Occlusion Efficiently in Chinese Tertiary Hospitals: A Multicenter Randomized Clinical Trial), yet the economic value of omitting alteplase was unclear. Thus, in this paper the authors assessed the cost-effectiveness of EVT alone versus EVT+IVT in the DIRECT-MT. METHODS: In the context of the Chinese healthcare system, the authors conducted a post hoc economic analysis of the DIRECT-MT based on an intention-to-treat approach. Index stroke costs were collected at the individual level, while costs after discharge were complemented with published literature and government websites. Utility weights assessed at 90 days using the 5-Level EQ-5D questionnaire were prospectively collected. For long-term modeled cost-effectiveness analysis, a Markov model with 7 health states corresponding to the 7 modified Rankin Scale scores was used. Deterministic and probabilistic sensitivity analyses were performed. All costs are expressed in 2019 US dollars, discounted using the annual Consumer Price Index in China. RESULTS: During the index hospitalization, the mean medication cost in the EVT-alone group was $487 lower than that in the EVT+IVT group ($2453 [95% CI $2205-$2701] vs $2940 [95% CI $2703-$3178], p = 0.01), but the mean overall costs were similar between the groups ($15,565 [95% CI $14,876-$16,254] vs $15,472 [95% CI $14,714-$16,230], p = 0.73). Within 90 days of the trial, there were no significant differences in total costs (difference -$222 [95% CI -$603 to $161], p = 0.06, bootstrapping) or utility values (median 0.84 [IQR 0.48-0.95] vs median 0.85 [IQR 0.26-1.00]; beta coefficient < 0.01 [95% CI -0.06 to 0.07]) between EVT alone and EVT+IVT. Over the lifetime horizon, EVT alone and EVT+IVT yielded comparable lifetime QALYs (2.02 QALYs [95% CI -0.07 to 4.55 QALYs] vs 1.90 QALYs [95% CI -0.09 to 4.55 QALYs]) and costs ($26,795 [95% CI $15,281-$54,463] vs $27,632 [95% CI $14,558-$52,251]). CONCLUSIONS: In this economic analysis based on a trial conducted in China, the authors found that EVT alone was not associated with economic dominance over EVT+IVT in patients with anterior circulation large-vessel occlusion.

Deposition and dissipation of difenoconazole in pepper and soil and its reduced application to control pepper anthracnose.

The initial deposition amount, dissipation dynamics, retention rate, and field control efficacy of difenoconazole in pepper-soil system were studied with different application dosages, planting regions and patterns. The initial deposition amount of difenoconazole under the same application dosage showed the following order: fruits < cultivated soils < lower stems < upper stems < lower leaves < upper leaves, open field < greenhouse, and Changjiang < Cixi < Hefei < Langfang, respectively, which increased with increasing application dosage. The dissipation rates in leaves, stems, fruits and cultivated soils exhibited an initially fast and then slow trend, while the retention rates displayed a tendency of first increasing and then stabilizing with increasing application dosages. After 7 d of difenoconazole application, the retention rates at five concentrations were 10.3%- 39.1%, and the field efficacy mostly reached the minimum effective dose. These results suggested that difenoconazole could be reduced by 25% based on the minimum recommended dose meeting the requirements of field control efficacy for controlling pepper anthracnose.

Imaging mismatch between Alberta Stroke Program Early CT Score and perfusion imaging may be a good variable for endovascular treatment.

OBJECTIVE: Some patients with acute large vessel occlusion (LVO) presented imaging mismatch, low Alberta Stroke Program Early CT Score (ASPECTS) with small ischemic core, or high ASPECTS with large ischemic core. The study was designed to explore whether patients with imaging mismatch could benefit from endovascular treatment (EVT). METHODS: We retrospectively reviewed patients with LVO treated with EVT in our center from March 2018 to Jul 2020. Patients were divided into three groups, imaging mismatch, small ischemic core, and large ischemic core groups. Pooled analyses based on stroke onset to treatment time were done. Multivariate regression analysis was performed to explore the factors for good outcomes. RESULTS: Sixty-eight of 419 patients with LVO presented with imaging mismatch, and 35 of those (51%) achieved good outcomes after EVT at 90-day. No significant differences were noted in good outcomes and symptomatic intracranial hemorrhage (sICH) between patients with imaging mismatch and small ischemic core. Compared with large ischemic core, patients with imaging mismatch presented lower risk of sICH (95% confidence interval (CI) 0.04-0.75, p = 0.011) within 6 h and higher proportion of good outcomes (95% CI 0.37-0.82, p = 0.002) at 6 to 24 h. Baseline NIHSS (odds ratio (OR) = 0.91, 95% CI 0.88-0.95)), ASPECTS (OR = 1.14, 95% CI 1.01-1.29), ischemic core (OR = 0.99, 95% CI 0.98-1.00), and sICH (OR = 61.61, 95% CI 8.09-461.32) were associated with good outcomes. CONCLUSIONS: Patients with imaging mismatch treated within 24 h could benefit from EVT and without increasing the risk of sICH. KEY POINTS: • Patients with imaging mismatch between ASPECTS and ischemic core could achieve good outcomes after endovascular treatment. • Compared with large ischemic core, patients with imaging mismatch presented lower risk of symptomatic hemorrhage within 6 h and higher proportion of good outcomes within 6-24 h. • Baseline NIHSS score, ASPECTS, ischemic core, and symptomatic intracranial hemorrhage were associated with good outcomes.

The second randomized controlled ENhanced Control of Hypertension ANd Thrombectomy strokE stuDy (ENCHANTED2): Protocol and progress.

BACKGROUND: Uncertainty exists over the optimal level of blood pressure (BP) after mechanical thrombectomy (MT) for acute ischemic stroke (AIS). OBJECTIVES: We aim to determine the effectiveness and safety of intensive BP-lowering following MT reperfusion of large-vessel occlusion (LVO)-related AIS. DESIGN: The second ENhanced Control of Hypertension ANd Thrombolysis strokE stuDy (ENCHANTED2) is an investigator-initiated, multicenter, prospective, randomized, open, blinded-endpoint (PROBE) trial of intensive systolic BP (SBP) control in reperfused (extended treatment in cerebral infarction (eTICI) classification 2b/2c/3) LVO-AIS patients with persistent hypertension (SBP ⩾ 140 mmHg) at 60+ sites in China, and Australia and the United Kingdom. Eligible patients are centrally randomly allocated to more- (target SBP ⩽ 120 mmHg within 1 h) or less-intensive (target SBP 140-180 mmHg) BP management, to be maintained for 72 h. Primary outcome is an ordinal shift analysis of scores on the modified Rankin scale (mRS) at 90 days. Sample size of 2257 patients provides 90% power to detect a 6.5% absolute reduction in poor outcome from more-intensive BP-lowering using ordinal logistic regression. PROGRESS: Recruitment started in China in July 2020. At a meeting of the independent Data and Safety Monitoring Board in March 2022 to review primary outcome data available for 347 patients, they recommended suspension of recruitment due to safety concerns in the more-intensive group; which was implemented by the Trial Steering Committee (TSC) with 817 randomized patients only in China. The TSC then stopped recruitment after the safety concerns persisted on further review of the data in June 2022. The TSC will make a decision on restarting the trial with modification of the protocol when the results are made public. DISCUSSION: ENCHANTED2 will provide further randomized evidence on the role of intensive BP-lowering after reperfusion in MT-treated AIS patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT04140110; registered 25 October 2019.

Preliminary experience with recanalization of large vessel occlusion due to underlying long-segment dissection using a standby microwire technique.

Purpose: This study aimed at investigating a novel standby microwire technique to facilitate revascularization of large vessel occlusion due to underlying long-segment dissection. Methods: Patients with acute ischemic stroke with emergent large vessel occlusion (ELVO) due to underlying long-segment dissection were screened from the prospectively established database between January 2021 and May 2022. The clinical and radiological data of eligible patients who underwent endovascular treatment by using a standby microwire technique were investigated. Results: Of the 165 acute ischemic stroke patients who underwent mechanical thrombectomy, the standby microwire technique was used in five patients aged 33-55 years old with occlusion due to underlying long-segment dissection. Of them, three patients were diagnosed with tandem lesions and three were located at the anterior circulation. A 300 cm exchange microwire was used as the standby microwire. Stent deployment was performed in all five patients. Groin puncture to reperfusion time ranged from 10-68 min. Technical success and favorable clinical outcomes were achieved in all five patients (100%). No technique-related complication was observed. Conclusion: Our preliminary experience showed that the standby microwire technique was a useful ancillary approach to facilitate the revascularization of large vessel occlusion due to underlying long-segment dissection.

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.

Fine-tuning of microglia polarization prevents diabetes-associated cerebral atherosclerosis.

Diabetes increases the occurrence and severity of atherosclerosis. When plaques form in brain vessels, cerebral atherosclerosis causes thickness, rigidity, and unstableness of cerebral artery walls, leading to severe complications like stroke and contributing to cognitive impairment. So far, the molecular mechanism underlying cerebral atherosclerosis is not determined. Moreover, effective intervention strategies are lacking. In this study, we showed that polarization of microglia, the resident macrophage in the central nervous system, appeared to play a critical role in the pathological progression of cerebral atherosclerosis. Microglia likely underwent an M2c-like polarization in an environment long exposed to high glucose. Experimental suppression of microglia M2c polarization was achieved through transduction of microglia with an adeno-associated virus (serotype AAV-PHP.B) carrying siRNA for interleukin-10 (IL-10) under the control of a microglia-specific TMEM119 promoter, which significantly attenuated diabetes-associated cerebral atherosclerosis in a mouse model. Thus, our study suggests a novel translational strategy to prevent diabetes-associated cerebral atherosclerosis through in vivo control of microglia polarization.

AKG Attenuates Cerebral Ischemia-Reperfusion Injury through c-Fos/IL-10/Stat3 Signaling Pathway.

Inflammation is dominant in the pathogenesis of ischemic stroke (IS). Alpha-ketoglutarate (AKG), according to previous studies, has demonstrated a variety of pharmacological effects such as antioxidation and inhibitive inflammation activities. However, whether AKG ameliorates cerebral ischemic injury, as well as the underlying molecular events, is still unclear. Therefore, the effect and underlying mechanisms of AKG on ischemic brain injury should be identified. The study established a cerebral ischemia-reperfusion (I/R) model in mice as well as an oxygen-glucose deprivation/reperfusion (OGD/R) model in SH-SY5Y cells, respectively. It was observed that AKG markedly suppressed infarction volume and neuronal injuries and improved the neurological score in vivo. Moreover, AKG reduced the inflammatory response and lowered the expression of proinflammatory cytokines. In vitro, AKG treatment strongly inhibited OGD/R-induced neuronal injury and the proinflammatory factors. It was also found that the increased SOD and GSH levels, as well as the lower ROS levels, showed that AKG reduced oxidative stress in OGD/R-treated SY-SY5Y cells. Mechanistically, AKG largely promoted IL-10 expression in ischemic brain injury and OGD/R-induced neuronal injury. Furthermore, IL-10 silencing neutralized the protective effect of AKG on inflammation. Notably, it was discovered that AKG could upregulate IL-10 expression by promoting the translocation of c-Fos from the cytoplasm to the nucleus. The results indicated that AKG demonstrated neuroprotection on cerebral ischemia while inhibiting inflammation through c-Fos/IL-10/stat3 pathway.

Patient-Reported Anxiety/Depression After Endovascular Thrombectomy: A post-hoc Analysis of Direct-MT Trial.

OBJECTIVE: To analyze the effect of endovascular thrombectomy (EVT) alone vs. EVT after an intravenous (IV) alteplase of ischemic stroke on a patient-reported anxiety/depression, and to identify predictors of patient-reported anxiety/depression by analyzing data from Direct Intraarterial Thrombectomy in Order to Revascularize the patients with Acute Ischemic Stroke with a Large Vessel Occlusion Efficiently in Chinese Tertiary Hospitals: a Multicenter Randomized Clinical Trial (DIRECT-MT). METHODS: Patients with acute ischemic stroke (AIS), triggered by a large-vessel occlusion in the anterior circulation, were randomly allocated to undergo an EVT after IV alteplase (combination-therapy group) or an EVT alone (EVT-alone group) at a 1:1 ratio in DIRECT-MT. Patients in both groups were followed up for 90 days (±14 days) after stroke using a structured modified Ranking Scale (mRS), a Barthel Index (BI), and a 5-Dimensional European Quality of Life Scale (EQ-5D-5L). Patients who returned EQ-5D-5L were included. The EQ-5D-5L anxiety/depression dimension was used to analyze the patient-reported anxiety/depression. First, differences in patient-reported anxiety/depression were compared between the combination-therapy group and the EVT-alone group. Then, the baseline and influencing factors between the anxiety/depression group and no anxiety/depression group were analyzed using univariate regression analysis. Finally, variables with p < 0.1 in univariate regression were subjected to multivariable binary regression analysis to screen independent predictors for patient-reported anxiety /depression after ischemic stroke. RESULTS: : Five hundred fifteen patients returned the EQ-5D-5L in Direct-MT. Of these patients, 226 (43.88%) reported a level of anxiety/depression, and about 7% reported a severe or extremely severe anxiety/depression. The patient-reported anxiety/depression in the EVT-alone group was significantly higher than that in the combination-therapy group (48.26% vs. 39.45%, p = 0.04). The clinical outcomes were significantly different between the no Anxiety/Depression Group and the anxiety/depression group (mRS at 90 days:2 vs 3, p < 0.001; BI of 95 or 100 at 90 days: 73.36% vs 42.04%, p < 0.001; EQ-5D-5l utility indexes at 90 days:0.96 vs.57, p < 0.001). Logistic regression analysis showed that allocation to thrombolysis before EVT strategy was inversely associated with anxiety/depression [0.61(0.40, 0.94), p = 0.03], an insular cortex ischemia, and National Institute of Health Strocke Scale (NIHSS) at 7 days were positively associated with anxiety/depression [2.04(1.07, 3.90), p = 0.03; 1.07(1.03, 1.12), p < 0.001]. CONCLUSIONS: Patient-reported anxiety/depression may suggest that there is a benefit to administering intravenous alteplase before EVT. It may also indicate that it is better to provide IV alteplase before EVT, rather than EVT alone according to patient-reported anxiety/depression. Future research should consider not only the motor function impairments but also the patient-reported mental problems as measures of treatment efficacy in patients with stroke (DIRECT-MT ClinicalTrials.gov number, NCT03469206).

Effect of stroke etiology on endovascular thrombectomy with or without intravenous alteplase: a subgroup analysis of DIRECT-MT.

BACKGROUND: Stroke etiology might influence the clinical outcomes in patients with large vessel occlusion receiving endovascular treatment (EVT) with or without thrombolysis. OBJECTIVE: To examine whether stroke etiology resulted in different efficacy and safety in patients treated with EVT-alone or EVT preceded by intravenous alteplase (combined therapy). METHODS: We assessed the efficacy and safety of treatment strategy based on prespecified stroke etiology, cardioembolism (CE), large-artery atherosclerosis (LAA), and undetermined cause (UC) for patients enrolled in the DIRECT-MT trial. The primary outcome was the modified Rankin Scale (mRS) score at 90 days. Multivariate ordinal logistic regression analysis was used to calculate the adjusted common OR for a shift of better mRS score for EVT-alone versus combined therapy. A term was entered to test for interaction. RESULTS: In this study, 656 patients were grouped into three prespecified stroke etiologic subgroups. The adjusted common ORs for improvement in the 90-day ordinal mRS score with EVT-alone were 1.2 (95% CI 0.8 to 1.8) for CE, 1.6 (95% CI 0.8 to 3.3) for LAA, and 0.8 (95% CI 0.5 to 1.3) for UC. Compared with CE, EVT-alone was more likely to result in an mRS score of 0-1 (pinteraction=0.047) and extended Thrombolysis in Cerebral Infarction ≥2b (pinteraction=0.041) in the LAA group. The differences in mortality and symptomatic intracranial hemorrhage within 90 days were not significant between the subgroups (p＞0.05). CONCLUSIONS: The results did not support the hypothesis that a specific treatment strategy based on stroke etiology should be used for patients with large vessel occlusion (NCT03469206).

Endovascular treatment of acute ischemic stroke with a fully radiopaque retriever: A randomized controlled trial.

Objective: The Neurohawk retriever is a new fully radiopaque retriever. A randomized controlled non-inferiority trial was conducted to compare the Neurohawk and the Solitaire FR in terms of safety and efficacy. In order to evaluate the efficacy and safety of endovascular treatment in acute ischemic stroke (AIS) caused by intracranial atherosclerotic disease (ICAD) larger vessel occlusion (LVO), a sub-analysis was performed. Methods: Acute ischemic stroke patients aged 18-80 years with LVO in the anterior circulation were randomly assigned to undergo thrombectomy with either the Neurohawk or the Solitaire FR. The primary efficacy endpoint was successful reperfusion (mTICI 2b-3) rate by the allocated retriever. A relevant non-inferiority margin was 12.5%. Safety outcomes were symptomatic intracranial hemorrhage (sICH) and all-cause mortality within 90 days. Secondary endpoints included first-pass effect (FPE), modified FPE, and favorable outcomes at 90 days. In subgroup analysis, the patients were divided into the ICAD group and non-ICAD group according to etiology, and baseline characteristics, angiographic, and clinical outcomes were compared. Results: A total of 232 patients were involved in this analysis (115 patients in the Neurohawk group and 117 in the Solitaire group). The rates of successful reperfusion with the allocated retriever were 88.70% in the Neurohawk group and 90.60% in the Solitaire group (95%CI of the difference, -9.74% to 5.94%; p = 0.867). There were similar results in FPE and mFPE in both groups. The rate of sICH seemed higher in the Solitaire group (13.16% vs. 7.02%, p = 0.124). All-cause mortality and favorable outcome rates were comparable as well. In subgroup analysis, 58 patients were assigned to the ICAD group and the remaining 174 to the non-ICAD group. The final successful reperfusion and favorable outcome rates showed no statistically significant differences in two groups. Mortality within 90 days was relatively lower in the ICAD group (6.90% vs. 17.24%; p = 0.054). Conclusion: The Neurohawk retriever is non-inferior to the Solitaire FR in the mechanical thrombectomy of large vessel occlusion-acute ischemic stroke (LVO-AIS). The sub-analysis suggested that endovascular treatment including thrombectomy with the retriever and essential rescue angioplasty is effective and safe in AIS patients with intracranial atherosclerotic disease-larger vessel occlusion (ICAD-LVO). Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT04995757, number: NCT04995757.

Effect of renal impairment on the efficacy and safety of intra-arterial treatment: A post-hoc analysis of DIRECT-MT study.

OBJECTIVE: To determine the influence of renal impairment on clinical outcomes in patients presenting emergent anterior circulation occlusion treated with mechanical thrombectomy. METHODS: Consecutive patients with anterior circulation stroke treated with mechanical thrombectomy at 41 academic tertiary care centers were included. renal impairment was defined as glomerular filtration rate <60 mL/min/1.73 m2 at the time of admission. The primary outcome was the distribution of scores on the modified Rankin scale, and safety outcomes were mortality within 90 days and hemorrhagic complications. Binary and ordinal logistic regression was used to evaluate the associations between renal impairment and categorical outcomes. Linear regression was used to assess continuous outcomes. RESULTS: A total of 607 patients (47 renal impairment and 600 non-renal impairment) who underwent mechanical thrombectomy were included in this study. Multivariate regression analysis showed that renal impairment was independently associated with the increase of the modified Rankin scale at 90 days. The proportion of patients with successful reperfusion was 71.7% in the renal impairment group and 83.3% in the non-renal impairment group. Renal impairment was an independent predictor of 90-day mortality. No significant treatment for the ordinal modified Rankin scale or 90-day mortality was observed by renal impairment interaction. The risk of asymptomatic intracranial hemorrhage was higher in the mechanical thrombectomy plus IVT group (53.6%) than in the mechanical thrombectomy alone group (15.8%) for renal impairment, but was similar between the mechanical thrombectomy plus IVT group (34.6%) and the mechanical thrombectomy alone group (36.4%) for non-renal impairment (p = 0.01). CONCLUSION: These results demonstrated that the outcomes of mechanical thrombectomy alone and mechanical thrombectomy plus IVT group did not differ significantly in acute stroke patients with and without renal impairment. Also, renal impairment was an independent predictor of worse functional independence and higher mortality at 90 days.

Endovascular Treatment for Acute Basilar Artery Occlusion: A Comparison of Arteriosclerotic, Embolic and Tandem Lesions.

PURPOSE: To evaluate the safety and efficacy of endovascular treatment (EVT) for patients with acute ischemic stroke (AIS) due to intracranial atherosclerosis-related basilar artery occlusion (ICAS-related BAO) by comparison with embolic and tandem occlusion. METHODS: We retrospectively reviewed consecutive patients with AIS due to BAO who underwent EVT. Patients were assigned to the ICAS-related group and embolic group, and tandem group based on the etiology. Baseline data, procedural details, and clinical outcomes were compared between the three groups. RESULTS: A total of 100 patients (ICAS-related group: 31; embolic group: 41; tandem group: 28) were included. No significant difference was observed in the successful reperfusion (mTICI 2b or 3), but the procedural time differed significantly (60 min vs. 43 min vs. 60 min, P = 0.010). There were no differences in the different intracranial hemorrhage grades among the three groups (P = 0.134). After adjusting for baseline differences, there was no significant difference in pairwise comparisons regarding favorable outcome (mRS 0-2), moderate outcome (mRS 0-3), and mortality. CONCLUSIONS: Endovascular treatment for patients with acute ICAS-related BAO had equal efficacy and safety compared with embolic BAO and tandem BAO. Primary endovascular treatment and rescue modalities were effective treatments for acute ICAS-related BAO.