Association of cardiovascular disease prevalence with BMD and fracture in men with T2DM.

BACKGROUND: Patients with type 2 diabetes mellitus (T2DM) are predisposed to cardiovascular disease (CVD). Bone mineral density (BMD) is linked to CVD, but most studies focused on women. Our analysis aims to explore the association of BMD and fracture with the prevalence of CVD in men with T2DM. METHODS: In this retrospective cross-sectional study, 856 men with T2DM were enrolled. BMDs at the lumbar spine (L2-4), femoral neck (FN), and total hip (TH) were measured by dual-energy X-ray absorptiometry (DXA). The CVD outcome was determined as the sum of the following conditions: congestive heart failure, coronary heart disease, angina pectoris, myocardial infarction, the requirement for coronary artery revascularization, and stroke. The relationship between BMDs and CVD was investigated by restricted cubic spline curves and logistic regression models. RESULTS: A total of 163 (19.0%) patients developed CVD. The restricted cubic spline curve revealed a linear and negative association between FN-BMD, TH-BMD, and CVD. After full adjustments for confounding covariates, the odds ratios were 1.34 (95% confidence interval [CI] [1.11-1.61], p < .05), 1.3 (95% CI [1.05-1.60], p < .05), and 1.26 (95% CI [1.02-1.55], p < .05) for each 1-SD decrease in BMDs of L2-4, FN and TH, respectively. T-scores of < -1 for BMD of L2-4 and FN were independently associated with CVD (p < .05). Subgroup analyses further supported our findings. CONCLUSIONS: The prevalence of CVD was inversely correlated with BMD levels in men with T2DM, particularly at the FN. We hypothesized that monitoring FN-BMD and early intervention would help reduce CVD risk in men with T2DM, especially those with hypertension.

Modeling an evaluation of the efficacy of the novel neuroanalgesic drug mirogabalin for diabetic peripheral neuropathic pain and postherpetic neuralgia therapy.

Diabetic peripheral neuropathic pain (DPNP) and postherpetic neuralgia (PHN) are challenging and often intractable complex medical conditions, with a substantial impact on the quality of life. Mirogabalin, a novel voltage-gated Ca2+ channel α2δ ligand, was approved for the indication of DPNP and PHN. However, the time course of effects has not yet been clarified.We aimed to establish pharmacodynamic and placebo effect models of mirogabalin and pregabalin in DPNP and PHN, and to quantitatively compare the efficacy characteristics (maximum efficacy, onset time, and other pharmacodynamic parameters) and safety of mirogabalin and pregabalin. Public databases were comprehensively searched for randomized placebo-controlled clinical trials. A model-based meta-analysis (MBMA) was developed to describe the time course of drug efficacy and placebo effects. Adverse events were compared using a fixed-effects meta-analysis. Sixteen studies including 5,147 participants were eligible for this study. The placebo effect was relatively high and gradually increased with time, and it required at least eight weeks to reach a plateau. The pharmacodynamic model revealed that the maximum pure efficacy for mirogabalin and pregabalin was approximately -7.85% and -8.86%, respectively; the efficacy of mirogabalin to relieve DPNP and PHN was not superior to that of pregabalin, and both drugs had similar safety. While the rate constant of the onset rate of pregabalin was approximately thrice as high as that of mirogabalin. In addition, the baseline level of pain was an important factor affecting pregabalin efficacy. These findings are helpful in evaluating the clinical extension value of mirogabalin. They suggest that the high placebo effect and the baseline level of pain should be considered when grouping patients in future research and development of voltage-gated Ca2+ channel neuroanalgesic.

Embolization of a Non-Galenic Pial Arteriovenous Fistula with Assistance of a SolitaireTM Stent: Case Report.

This study aimed to describe a novel endovascular strategy to help control blood flow used successfully to treat an infant with highflow pial arteriovenous fistula (AVF). Here, a single-hole high-flow nongalenic pial AVF was diagnosed in a 2.5 year-old infant is presented. After coil packing failure despite temporal balloon occlusion, we deployed a SolitaireTM stent in the fistula. By twisting with detachable coils, we achieved satisfactory blood flow control, and obliteration of the fistula was achieved with Onyx injection. In conclusion, SolitaireTM stent deployment in the high-flow pial AVF can help stabilize the coils in the fistula, leading to satisfactory blood control. This strategy may be a valuable addition to currently available options.

Trachelogenin alleviates osteoarthritis by inhibiting osteoclastogenesis and enhancing chondrocyte survival.

BACKGROUND: Osteoarthritis (OA) is a prevalent global health concern associated with the loss of articular cartilage and subchondral bone. The lack of disease-modifying drugs for OA necessitates the exploration of novel therapeutic options. Our previous study has demonstrated that traditional Chinese medical herb Trachelospermum jasminoides (Lindl.) Lem. extract suppressed osteoclastogenesis and identified trachelogenin (TCG) as a representative compound. Here, we delved into TCG's potential to alleviate OA. METHODS: We initially validated the in vivo efficacy of TCG in alleviating OA using a rat OA model. Subsequently, we isolated primary bone marrow-derived macrophages in vitro to investigate TCG's impact on osteoclastogenesis. We further employed a small molecule pull-down assay to verify TCG's binding target within osteoclasts. Finally, we isolated primary mouse chondrocytes in vitro to study TCG's regulatory effects and mechanisms on chondrocyte survival. RESULTS: TCG preserved subchondral bone integrity and protected articular cartilage in a rat OA model. Subsequently, in vitro experiments unveiled TCG's capability to inhibit osteoclastogenesis and function through binding to Ras association proximate 1 (Rap1) and inhibiting its activation. Further study demonstrated that TCG inhibited Rap1/integrin αvß3/c-Src/Pyk2 signaling cascade, and consequently led to failed F-actin ring formation. Besides, TCG promoted the proliferation of mouse primary chondrocytes while suppressing apoptosis in vitro. This is attributed to TCG's ability to upregulate HIF1α, thereby promoting glycolysis. CONCLUSION: TCG exerted inhibitory effects on osteoclastogenesis through binding to Rap1 and inhibiting Rap1 activation, consequently preventing subchondral bone loss. Moreover, TCG enhanced chondrocyte survival by upregulating HIF1α and promoting glycolysis. These dual mechanisms collectively provide a novel approach to prevented against cartilage degradation.

Outcome and Risk of Poststroke Pneumonia in Patients with Acute Ischemic Stroke After Endovascular Thrombectomy: A Post Hoc Analysis of the DIRECT-MT Trial.

BACKGROUND: In this study, we aimed to investigate the risk factors and impact of poststroke pneumonia (PSP) on mortality and functional outcome in patients with acute ischemic stroke (AIS) after endovascular thrombectomy (EVT). METHODS: This was a post hoc analysis of a prospective randomized trial (Direct intraarterial thrombectomy in order to revascularize AIS patients with large-vessel occlusion efficiently in Chinese tertiary hospitals: a multicenter randomized clinical trial). Patients with AIS who completed EVT were evaluated for the occurrence of PSP during the hospitalization period and their modified Rankin Scale (mRS) scores at 90 days after AIS. Logistic regression analysis was conducted to investigate the independent predictors of PSP. Propensity score matching was conducted for the PSP and non-PSP groups by using the covariates resulting from the logistic regression analysis. The associations between PSP and outcomes were analyzed. The outcomes included 90-day poor functional outcome (mRS scores > 2), 90-day mortality, and early 2-week mortality. RESULTS: A total of 639 patients were enrolled, of whom 29.58% (189) developed PSP. Logistic regression analysis revealed that history of chronic heart failure (unadjusted odds ratio [OR] 2.011, 95% confidence interval [CI] 1.026-3.941; P = 0.042), prethrombectomy reperfusion on initial digital subtraction angiography (OR 0.394, 95% CI 0.161-0.964; P = 0.041), creatinine levels at admission (OR 1.008, 95% CI 1.000-1.016; P = 0.049), and National Institutes of Health Stroke Scale at 24 h (OR 1.023, 95% CI 1.007-1.039; P = 0.004) were independent risk factors for PSP. With propensity scoring matching, poor functional outcome (mRS > 2) was more common in patients with PSP than in patients without PSP (81.03% vs. 71.83%, P = 0.043) at 90 days after EVT. The early 2-week mortality of patients with PSP was lower (5.74% vs. 12.07%, P = 0.038). But there was no statistically significant difference in 90-day mortality between the PSP group and non-PSP group (22.41% vs. 14.94%, P = 0.074). The survivorship curve also shows no statistical significance (P = 0.088) between the two groups. CONCLUSIONS: Nearly one third of patients with AIS and EVT developed PSP. Heart failure, higher creatinine levels, prethrombectomy reperfusion, and National Institutes of Health Stroke Scale at 24 h were associated with PSP in these patients. PSP was associated with poor 90-day functional outcomes in patients with AIS treated with EVT.

Regulation of depressive-like behaviours by palmitoylation: Role of AKAP150 in the basolateral amygdala.

BACKGROUND AND PURPOSE: Protein palmitoylation is involved in learning and memory, and in emotional disorders. Yet, the underlying mechanisms in these processes remain unclear. Herein, we describe that A-kinase anchoring protein 150 (AKAP150) is essential and sufficient for depressive-like behaviours in mice via a palmitoylation-dependent mechanism. EXPERIMENTAL APPROACH: Depressive-like behaviours in mice were induced by chronic restraint stress (CRS) and chronic unpredictable mild stress (CUMS). Palmitoylated proteins in the basolateral amygdala (BLA) were assessed by an acyl-biotin exchange assay. Genetic and pharmacological approaches were used to investigate the role of the DHHC2-mediated AKAP150 palmitoylation signalling pathway in depressive-like behaviours. Electrophysiological recording, western blotting and co-immunoprecipitation were performed to define the mechanistic pathway. KEY RESULTS: Chronic stress successfully induced depressive-like behaviours in mice and enhanced AKAP150 palmitoylation in the BLA, and a palmitoylation inhibitor was enough to reverse these changes. Blocking the AKAP150-PKA interaction with the peptide Ht-31 abolished the CRS-induced AKAP150 palmitoylation signalling pathway. DHHC2 expression and palmitoylation levels were both increased after chronic stress. DHHC2 knockdown prevented CRS-induced depressive-like behaviours, as well as attenuating AKAP150 signalling and synaptic transmission in the BLA in CRS-treated mice. CONCLUSION AND IMPLICATIONS: These results delineate that DHHC2 modulates chronic stress-induced depressive-like behaviours and synaptic transmission in the BLA via the AKAP150 palmitoylation signalling pathway, and this pathway may be considered as a promising novel therapeutic target for major depressive disorder.

S100A4 modulates cell proliferation, apoptosis and fibrosis in the hyperplastic prostate.

Benign prostatic hyperplasia (BPH) is one of the most common diseases in elderly men worldwide that may result in lower urinary tract symptoms (LUTS). At present, the specific pathophysiological mechanism for BPH/LUTS LUTS remains unclear. S100 calcium binding protein A4 (S100A4), a member of the calcium binding protein family, regulates a variety of biological processes including cell proliferation, apoptosis and fibrosis. The aim of the current study was to explore and clarify the possible role of S100A4 in BPH/LUTS. The human prostate stromal cell line (WPMY-1), rat prostate epithelial cells, human prostate tissues and two BPH rat models were employed in this study. The expression and localization of S100A4 were detected by quantitative real time PCR (qRT-PCR), immunofluorescence microscopy, Western blotting and immunohistochemistry analysis. Also, S100A4 knockdown or overexpression cell models were constructed and a BPH rat model was induced with testosterone propionate (T) or phenylephrine (PE). The BPH animals were treated with Niclosamide, a S100A4 transcription inhibitor. Results demonstrated that S100A4 was mainly localized in human prostatic stroma and rat prostatic epithelium, and showed a higher expression in BPH. Knockdown of S100A4 induced cell apoptosis, cell proliferation arrest and a reduction of tissue fibrosis markers. Overexpression of S100A4 reversed the aforementioned changes. We also demonstrated that S100A4 regulated proliferation and apoptosis mainly through the ERK pathway and modulated fibrosis via Wnt/ß-catenin signaling. In conclusion, our novel data demonstrate that S100A4 could play a crucial role in BPH development and may be explored as a new therapeutic target of BPH.

Ferroptosis mediated by TNFSF9 interferes in acute ischaemic stroke reperfusion injury with the progression of acute ischaemic stroke.

In this study, we investigated the potential involvement of TNFSF9 in reperfusion injury associated with ferroptosis in acute ischaemic stroke patients, mouse models and BV2 microglia. We first examined TNFSF9 changes in peripheral blood from stroke patients with successful reperfusion, and constructed oxygen-glucose deprivation-reperfusion (OGD-R) on BV2 microglia, oxygen-glucose deprivation for 6 h followed by reoxygenation and re-glucose for 24 h, and appropriate over-expression or knockdown of TNFSF9 manipulation on BV2 cells and found that in the case of BV2 cells encountering OGD-R over-expression of TNFSF9 resulted in increased BV2 apoptosis. Still, the knockdown of TNFSF9 ameliorated apoptosis and ferroptosis. In an in vivo experiment, we constructed TNFSF9 over-expression or knockout mice by intracerebral injection of TNFSF9-OE or sh-TNFSF9 adenovirus. We performed the middle cerebral artery occlusion (MCAO) model on day four, 24 h after ligation of the proximal artery, for half an hour to recanalize. As luck would have it, over-expression of TNFSF9 resulted in increased brain infarct volumes, neurological function scores and abnormalities in TNFSF9-related TRAF1 and ferroptosis-related pathways, but knockdown of TNFSF9 improved brain infarcts in mice as well as reversing TNFSF9-related signalling pathways. In conclusion, our data provide the first evidence that TNFSF9 triggers microglia activation by activating the ferroptosis signalling pathway following ischaemic stroke, leading to brain injury and neurological deficits.

Time to Treatment With Intravenous Thrombolysis Before Thrombectomy and Functional Outcomes in Acute Ischemic Stroke: A Meta-Analysis.

Importance: The benefit of intravenous thrombolysis (IVT) for acute ischemic stroke declines with longer time from symptom onset, but it is not known whether a similar time dependency exists for IVT followed by thrombectomy. Objective: To determine whether the benefit associated with IVT plus thrombectomy vs thrombectomy alone decreases with treatment time from symptom onset. Design, Setting, and Participants: Individual participant data meta-analysis from 6 randomized clinical trials comparing IVT plus thrombectomy vs thrombectomy alone. Enrollment was between January 2017 and July 2021 at 190 sites in 15 countries. All participants were eligible for IVT and thrombectomy and presented directly at thrombectomy-capable stroke centers (n = 2334). For this meta-analysis, only patients with an anterior circulation large-vessel occlusion were included (n = 2313). Exposure: Interval from stroke symptom onset to expected administration of IVT and treatment with IVT plus thrombectomy vs thrombectomy alone. Main Outcomes and Measures: The primary outcome analysis tested whether the association between the allocated treatment (IVT plus thrombectomy vs thrombectomy alone) and disability at 90 days (7-level modified Rankin Scale [mRS] score range, 0 [no symptoms] to 6 [death]; minimal clinically important difference for the rates of mRS scores of 0-2: 1.3%) varied with times from symptom onset to expected administration of IVT. Results: In 2313 participants (1160 in IVT plus thrombectomy group vs 1153 in thrombectomy alone group; median age, 71 [IQR, 62 to 78] years; 44.3% were female), the median time from symptom onset to expected administration of IVT was 2 hours 28 minutes (IQR, 1 hour 46 minutes to 3 hours 17 minutes). There was a statistically significant interaction between the time from symptom onset to expected administration of IVT and the association of allocated treatment with functional outcomes (ratio of adjusted common odds ratio [OR] per 1-hour delay, 0.84 [95% CI, 0.72 to 0.97], P = .02 for interaction). The benefit of IVT plus thrombectomy decreased with longer times from symptom onset to expected administration of IVT (adjusted common OR for a 1-step mRS score shift toward improvement, 1.49 [95% CI, 1.13 to 1.96] at 1 hour, 1.25 [95% CI, 1.04 to 1.49] at 2 hours, and 1.04 [95% CI, 0.88 to 1.23] at 3 hours). For a mRS score of 0, 1, or 2, the predicted absolute risk difference was 9% (95% CI, 3% to 16%) at 1 hour, 5% (95% CI, 1% to 9%) at 2 hours, and 1% (95% CI, -3% to 5%) at 3 hours. After 2 hours 20 minutes, the benefit associated with IVT plus thrombectomy was not statistically significant and the point estimate crossed the null association at 3 hours 14 minutes. Conclusions and Relevance: In patients presenting at thrombectomy-capable stroke centers, the benefit associated with IVT plus thrombectomy vs thrombectomy alone was time dependent and statistically significant only if the time from symptom onset to expected administration of IVT was short.

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.

Opinions over targets for blood pressure control after mechanical thrombectomy in patients with acute ischemic stroke: baseline survey for the ENCHANTED2/MT trial in China.

BACKGROUND: Although guidelines recommend a target blood pressure 185-180/105-110 mmHg after mechanical thrombectomy for acute ischemic stroke (AIS), there is limited randomized evidence to support this level. We surveyed candidate institutions about the approach to blood pressure management in this patient group in preparation for inviting them to participate in the Enhanced Blood Pressure Control after Endovascular Thrombectomy for the Acute Ischemic Stroke Trial (ENCHANTED2/MT). METHODS: Physicians from a professional network of institutions that met mechanical thrombectomy qualification requirements were invited to participate in an online questionnaire covering basic clinical information as well as questions on blood pressure management. RESULTS: We invited 88 sites to participate with 44 (50%) ultimately joining the trial, and a total of 88 physicians finished the survey. The median number of annual mechanical thrombectomy cases performed per site was 89 [IQR 65-150]. Only 38 (43%) institutions strictly adhere to guidelines when managing the blood pressure of mechanical thrombectomy patients. The most popular blood pressure target for reperfusion patients was 140-160 mmHg (n=47, 53%), and <120 mmHg (n=28, 32%). Fewer hospital stroke beds (40 [21-57] vs. 60 [39-110], p = 0.01) and lower proportion of elevated blood pressure after mechanical thrombectomy (25% [10%-50%] vs. 50% [20%-70%], p = 0.02) were related to a more aggressive blood pressure target (<120 mmHg). Urapidil (n=82, 93%) and calcium channel blockers (CCBs) (n = 87, 99%), were the most widely used antihypertensive drugs, respectively. CONCLUSIONS: According to the survey, unstandardized blood pressure management protocols are performed in mechanical thrombectomy patients at institutions across China, which is different from prior survey from another country. More high-quality studies are needed to guide clinical practice.

Effect of Clot Burden Score on Safety and Efficacy of Intravenous Alteplase Prior to Mechanical Thrombectomy in Acute Ischemic Stroke: A Subgroup Analysis of a Randomized Phase 3 Trial.

BACKGROUND AND PURPOSE: Whether thrombus burden in acute ischemic stroke modify the effect of intravenous thrombolysis (IVT) before mechanical thrombectomy (MT) remains uncertain. We aim to investigate the treatment effect of stratified clot burden score (CBS) on the efficacy and safety of direct versus bridging MT. MATERIALS AND METHODS: This is an exploratory subgroup analysis of a randomized trial evaluating the effect of CBS on clinical outcome in the DIRECT-MT trial. CBS was divided into 3 groups (0-3, 4-6, and 7-10) based on preoperative CTA, where higher scores indicated a lower clot burden. We report the adjusted common odds ratio for a shift toward better outcomes on the mRS after thrombectomy alone compared with combination treatment by stratified CBS groups. RESULTS: No modification effect of mRS distribution was observed by CBS subgroups (CBS 0-3: adjusted common ratio odds 1.519 [95% CI, 0.928-2.486]; 4-6: 0.924 [0.635-1.345]; 7-10: 1.040 [0.481-2.247]). Patients with CBS 4-6 had a higher rate of early reperfusion (adjusted OR (aOR), 0.3 [95% CI, 0.1-0.9]), final reperfusion (aOR 0.5 [95% CI, 0.3-0.9]), and fewer thrombectomy attempts (aOR 0.4 [95% CI, 0.1-0.7]). Patients with CBS 7-10 had a higher rate of asymptomatic intracranial hemorrhage (14.9% versus 36.8%, P = .0197) for bridging MT. No significant difference was observed in other safety outcomes by trichotomized CBS. CONCLUSIONS: The subgroup analysis of DIRECT-MT suggested that thrombus burden did not alter the treatment effect of IVT before MT on functional outcomes in CBS subgroups.

The functions of exosomes targeting astrocytes and astrocyte-derived exosomes targeting other cell types.

Astrocytes are the most abundant glial cells in the central nervous system; they participate in crucial biological processes, maintain brain structure, and regulate nervous system function. Exosomes are cell-derived extracellular vesicles containing various bioactive molecules including proteins, peptides, nucleotides, and lipids secreted from their cellular sources. Increasing evidence shows that exosomes participate in a communication network in the nervous system, in which astrocyte-derived exosomes play important roles. In this review, we have summarized the effects of exosomes targeting astrocytes and the astrocyte-derived exosomes targeting other cell types in the central nervous system. We also discuss the potential research directions of the exosome-based communication network in the nervous system. The exosome-based intercellular communication focused on astrocytes is of great significance to the biological and/or pathological processes in different conditions in the brain. New strategies may be developed for the diagnosis and treatment of neurological disorders by focusing on astrocytes as the central cells and utilizing exosomes as communication mediators.

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.

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.

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.

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.

Hemodynamic assessment for intracranial atherosclerosis from angiographic images: a clinical validation study.

BACKGROUND: Intracranial atherosclerotic stenosis (ICAS) is one of the leading causes of ischemic stroke. Conventional anatomical analysis by CT angiography, MRI, or digital subtraction angiography can provide valuable information on the anatomical changes of stenosis; however, they are not sufficient to accurately evaluate the hemodynamic severity of ICAS. The goal of this study was to assess the diagnostic performance of the pressure ratio across intracranial stenoses (termed as fractional flow (FF)) derived from cerebral angiography for the diagnosis of hemodynamically significant ICAS defined by pressure wire-derived FF. METHODS: This retrospective study represents a feasible and reliable method for calculating the FF from cerebral angiography (AccuFFicas). Patients (n=121) who had undergone wire-based measurement of FF and cerebral angiography were recruited. The accuracy of the computed pressure ratio was evaluated using wire-based FF as the reference standard. RESULTS: The mean value of wire-based FF was 0.78±0.19, while the computed AccuFFicas had an average value of 0.79±0.18. Good correlation (Pearson's correlation coefficient r=0.92, P<0.001) between AccuFFicas and FF was observed. Bland-Altman analysis showed that the mean difference between AccuFFicas and FF was -0.01±0.07, indicating good agreement. The area under the curve (AUC) of AccuFFicas in predicting FF≤0.70, FF≤0.75, and FF≤0.80 was 0.984, 0.986, and 0.962, respectively. CONCLUSION: Angiography-based FF computed from cerebral angiographic images could be an effective computational tool for evaluating the hemodynamic significance of ICAS.

The Efficacy and Safety of Tirofiban Use in Endovascular Thrombectomy for Intravenous Thrombolysis Applicable Patients with Large Vessel Occlusion Stroke-a Post Hoc Analysis from the Direct-MT Trial.

PURPOSE: The purpose of the study was to evaluate the efficacy and safety of tirofiban use in endovascular thrombectomy for intravenous thrombolysis applicable patients of large vessel occlusion stroke with data from Direct-MT trial. MATERIALS AND METHODS: Direct-MT was the first randomized controlled trial to prove the non-inferiority of thrombectomy alone to bridging therapy (intravenous thrombolysis before thrombectomy) for large vessel occlusion stroke. Patients who underwent endovascular procedure were included and divided into thrombectomy-alone group and bridging therapy group. The effect of tirofiban use on 90 days MRS distribution, MRS 0-2 and mortality, successful reperfusion, the ASPECTS and outcome lesion volume of index stroke, re-occlusion of the treated vessel, futile recanalization and safety outcomes were further evaluated in both groups after adjustment for relevant confounding factors. The interaction between tirofiban and rt-PA was also assessed. RESULTS: Of 639 patients included in this analysis, 180 patients underwent thrombectomy with tirofiban use (28.2%). Patients with tirofiban use had lower percentage of bridging therapy (41.1% vs 54.3%, P = 0.003), higher proportion of large artery atherosclerosis (P < 0.001) and more emergent stenting (30.56% vs 6.97%, P < 0.001). After adjustment for confounding factors, the 90-day modified Rankin Scale distribution, successful final recanalization rate, outcome lesion volume of index stroke on CT and intracranial hemorrhage risk showed no difference after tirofiban use in thrombectomy-alone group and in bridging therapy group. No interaction effect between tirofiban and rt-PA was detected. CONCLUSION: Based on data from Direct-MT trial, tirofiban is a safe medication for intravenous thrombolysis applicable patients with large vessel occlusion stroke undergoing thrombectomy. LEVEL OF EVIDENCE: Level 3, cohort study of randomized trial.

Genetically determined blood pressure, antihypertensive medications, and risk of intracranial aneurysms and aneurysmal subarachnoid hemorrhage: A Mendelian randomization study.

INTRODUCTION: Observational studies suggest that different classes of antihypertensive drugs may have different effects on the occurrence of intracranial aneurysms (IA) and subarachnoid hemorrhage (SAH). However, the reported results in previous studies are inconsistent, and randomized data are absent. We performed a two-sample Mendelian randomization (MR) analysis to study the causal effects of genetically determined blood pressure (BP) and genetic proxies for antihypertensive drug classes on the risk of IA and SAH. MATERIALS AND METHODS: Genetic instruments and outcome data were obtained from independent genome-wide association studies (GWAS) or published data, which were exclusively restricted to European ancestry. Causal relationships were identified using inverse-variance weighted MR analyses and a series of statistical sensitivity analyses. The FinnGen consortium was used for repeated analysis to verify results obtained from the above GWAS. RESULTS: Two-sample MR analysis showed that genetically determined Systolic BP, Dystolic BP, and Pulse Pressure were related to a higher risk of IA and SAH. Based on identified single nucleotide polymorphisms (SNPs) that influence the effect of calcium channel blockers (CCB, 42 SNPs), beta-blockers (BB, 8 SNPs), angiotensin-converting enzyme inhibitors (ACEI, 2 SNPs), angiotensin receptor blockers (ARB, 1 SNPs), and thiazides (5 SNPs), genetically determined effect of CCBs was associated with a higher risk of IA (OR, 1.07 [95% CI, 1.03-1.10], p = 5.02 × 10-5) and SAH (OR, 1.06 [95% CI, 1.03-1.09], p = 1.84 × 10-3). No associations were found between other antihypertensive drugs and the risk of IA or SAH. The effect of CCBs on SAH was confirmed in FinnGenconsortium samples (OR, 1.04 [95% CI, 1.00-1.08], p = 0.042). DISCUSSION AND CONCLUSION: This MR analysis supports the role of elevated blood pressure in the occurrence of intracranial aneurysms and subarachnoid hemorrhage. However, genetic proxies for calcium channel blockers were associated with an increased risk of intracranial aneurysms and subarachnoid hemorrhage. Further studies are required to confirm these findings and investigate the underlying mechanisms.