Venous thromboembolism (VTE) is a frequent occurrence in patients with cancer. However, it is not known whether treatment with different classes of anticoagulants impacts the risk of subsequent arterial thromboembolism. We performed a retrospective, population-based cohort study using Surveillance, Epidemiology, and End Results data linked with Medicare claims. Patients were eligible for study inclusion if they had a diagnosis of primary brain, colorectal, gastric, pancreatic, lung, or ovarian cancer between 2007 and 2015, were diagnosed with VTE, and had a prescription claim for a direct oral anticoagulant (DOAC), low-molecular-weight heparin (LMWH), or warfarin. We matched patients by propensity score in a 1:1:1 ratio into anticoagulant treatment groups based on their baseline demographic information, cancer-specific characteristics, and cardiovascular comorbidities. The primary aim of the study was to determine and compare the 6-month cumulative incidence of ischemic stroke across anticoagulant classes. The study comprised 4875 total patients with 1625 in each treatment group. At 6 months, the cumulative incidence of ischemic stroke was 5.6% (95% confidence interval [CI], 5.0-6.3) overall and 6.8% (95% CI, 5.6-8.1) in the DOAC, 4.9% (95% CI, 3.9-6.0) in the LMWH, and 5.2% (95% CI, 4.1-6.2) in the warfarin treatment groups (P = .040). We identified hypertension (odds ratio [OR], 1.75), atrial fibrillation/flutter (OR, 1.37), DOAC use (OR, 1.36), and previous stroke (OR, 3.59) as statistically significant risk factors for ischemic stroke in the multivariable modeling. In conclusion, ischemic stroke is a common occurrence after cancer-associated VTE and may occur more frequently in patients treated with DOACs.

Endovascular therapy for acute ischemic stroke: From a decade of trials to the next frontier.

Thirty years of intravenous thrombolysis for acute ischemic stroke: Historical perspectives, evidence from randomized trials, and emerging directions.

Periodontitis is a chronic inflammatory condition with infectious origin that affects the tissues supporting the teeth. Increasing epidemiological evidence suggests that periodontitis is a risk factor for ischemic stroke with associated adverse outcomes. However, the underlying mechanism of this association remains incompletely elucidated. We used a C57BL/6J mice model of ischemic stroke induced by transitory occlusion of the middle cerebral artery in the presence or absence of ligature-induced periodontitis using Porphyromonas gingivalis-soaked ligatures. Stroke severity was evaluated through infarct volume, sensorimotor deficit, blood-brain barrier (BBB) integrity, and markers of systemic and brain inflammation. The direct effect of P gingivalis on BBB endothelial cells was further explored invitro. Mice with P gingivalis-associated periodontitis showed a significant exacerbation of stroke severity: larger infarct volume, more severe sensorimotor deficit, greater BBB disruption, and increased brain neutrophil infiltration compared with sham. Systemic inflammation was also markedly elevated. Intravenous administration of P gingivalis alone, without gingival injury, before transitory occlusion of the middle cerebral artery was sufficient to amplify brain inflammation and stroke lesions. Invitro P gingivalis, through its gingipain proteases, directly impaired BBB integrity by increasing endothelial permeability and disrupting tight-junction proteins. Our findings demonstrate that P gingivalis-associated periodontitis worsens ischemic stroke outcome both indirectly by enhancing systemic and brain inflammation and directly via BBB disruption. These results highlight periodontitis as a modifiable risk factor and potential therapeutic target for improving stroke prognosis.

Delayed hospital arrival after 4.5 hours of stroke onset excludes patients from intravenous thrombolytic therapy. In the United States, prehospital triage is regulated by each state. Understanding race- and ethnicity-specific prehospital delays in each state could guide targeted interventions. This cross-sectional study examined adult patients treated at the GWTG (Get With The Guidelines)-Stroke participating hospitals from January 2021 to August 2023 for acute ischemic stroke. The outcomes, including onset-to-arrival >4.5 hours, onset-to-911 call >2.5 hours, and 911 call-to-arrival >1 hour by race and ethnicity and state, were examined using multivariable logistic regression analysis adjusting for patient and hospital-level characteristics. The study included 691 689 patients with a median age of 71 years and 48.6% women. Compared with White patients, risk-adjusted odds of onset-to-arrival >4.5 hours were higher in Asian patients (1.24 [95% CI, 1.20-1.28]), Black patients (1.18 [95% CI, 1.16-1.19]), and Hispanic patients (1.10 [95% CI, 1.07-1.12]); onset-to-911 call >2.5 hours was higher among Black patients (1.21 [95% CI, 1.16-1.26]); and 911 call-to-arrival >1 hour was lower among Asian (0.55 [95% CI, 0.49-0.63]), Black patients (0.67 [95% CI, 0.62-0.72]), and Hispanic patients (0.69 [95% CI, 0.63-0.75]). Relative to Texas, which has the highest racial and ethnic diversity index, the odds of onset-to-arrival >4.5 hours were higher in 20 states for non-White patients and 9 states for White patients. Delayed hospital arrivals are more prevalent among Asian, Black, and Hispanic patients, but emergency medicine service transportation times are shorter, suggesting the need for culturally tailored community stroke education. A few states have exceedingly high delayed arrival, highlighting an opportunity to improve state-wide stroke readiness and emergency medicine service triage.

Uterine fibroids and atherosclerotic cardiovascular disease (ASCVD) share biological pathways, yet whether risk of ASCVD is different among those with fibroids compared with those without remains unexplored in large US cohorts with longitudinal data. This study assessed the association between uterine fibroids and risk of incident ASCVD. A US population-based cohort study was done using Optum's de-identified Clinformatics Data Mart Database (2000-2022). Follow-up continued until an ASCVD event, disenrollment, incident fibroid diagnosis in controls, or June 30, 2022. Individuals with fibroids were exact age-matched (1:5) to individuals without fibroids with an annual gynecologic claim. Incident ASCVD, a composite of coronary artery disease, cerebrovascular disease, and peripheral artery disease, was evaluated, including individual events (eg, myocardial infarction and ischemic stroke). Among 450 177 individuals with fibroids and 2 250 885 controls (mean age: 41 years, SD 6.3), the 1-year and 10-year cumulative incidence (95% CI) of ASCVD was 0.74% (0.71-0.77) and 5.42% (5.18-5.67) for the fibroid group versus 0.30% (0.29-0.31) and 3.00% (2.90-3.11) for controls. Adjusted analyses showed an increased ASCVD risk in the fibroid group (1-year risk ratio: 2.47 [95% CI, 2.32-2.61]; 1-year risk difference, 0.41% [95% CI, 0.40-0.47]; 10-year risk ratio, 1.81 [95% CI, 1.66-1.96]; 10-year risk difference, 2.40% [95% CI, 2.07, 2.77]. The increased risk was consistent for all individual components of ASCVD. Results were consistent across race and ethnicity and age subgroup analyses and sensitivity analyses addressing measurement error. Uterine fibroids are associated with sustained increased ASCVD risks up to 10 years postdiagnosis, supporting targeted ASCVD prevention in this population.

Pediatric hemorrhagic stroke can lead to significant neurologic, cognitive, and behavioral morbidities that often emerge over time and can impede long-term academic, vocational, and socioemotional function. While many of the existing data stem from studies in arterial ischemic stroke, functional outcomes in hemorrhagic stroke, and particularly pediatric intracerebral hemorrhage, remain largely understudied. Extrapolating findings from ischemic stroke can be challenging, as there are notable differences in care and potentially in outcomes for hemorrhagic stroke. The primary goal of this consensus statement by a multidisciplinary group of stroke experts is to provide a review of the current literature on neurologic, cognitive, behavioral, and socioemotional outcomes after hemorrhagic stroke. Neurologically, children with pediatric intracerebral hemorrhage often experience motor deficits, including hemiparesis and coordination issues, as well as cognitive impairments affecting attention, memory, and executive function. Behavioral and emotional problems, such as depression, and social difficulties can also occur. Data on academic attainment are also presented, along with considerations regarding long-term outcomes and the transition to adulthood. We further examine a variety of key determinants predicting outcomes, including medical, demographic, familial, and socioeconomic factors, as well as current research on rehabilitation, with an emphasis on gold-standard guidelines for clinical interventions. Given the complexity of outcome measurement in pediatric hemorrhagic stroke and the lack of uniform tools for assessing outcomes across diverse populations, we propose guiding principles for outcome measurement, along with examples of domain-specific tools. Finally, we discuss the limitations of the current literature and outline goals for future clinical practice and research.

Edaravone dexborneol, a novel neuroprotective agent with combined antioxidant and anti-inflammatory properties, has demonstrated significant improvement in 90-day functional outcomes for patients with acute ischemic stroke. This study aimed to evaluate the outcomes of edaravone dexborneol in patients with acute ischemic stroke with large infarct core. This prospective, multicenter, parallel-group, real-world cohort study was conducted between December 2022 and October 2023 across 72 centers in China. Participants were categorized into an exposed group (receiving edaravone dexborneol 37.5 mg/dose every 12 hours for 14 days) and an unexposed group (not receiving edaravone dexborneol). Propensity score matching (1:1) was used to balance baseline characteristics, and clinical outcomes were compared between the groups. The primary efficacy outcome was the proportion of patients achieving a modified Rankin Scale score of ≤2 at 90 days. After matching, the 90-day modified Rankin Scale ordinal shift was significantly better in the edaravone dexborneol group compared with the unexposed group (median: 2 [interquartile range, 1-4.5] versus 3 [interquartile range, 1-5]; unadjusted odds ratio [OR], 1.90 [95% CI, 1.04-3.46]; P=0.04). Patients in the edaravone dexborneol group had a higher rate of functional independence (58.8% versus 36.8%; unadjusted OR, 2.46 [95% CI, 1.23-4.90]; P=0.01) and a lower 90-day mortality rate (11.8% versus 19.1%; unadjusted OR, 0.56 [95% CI, 0.22-1.46]; P=0.24). In patients with acute ischemic stroke with large infarct core, edaravone dexborneol improved the likelihood of achieving favorable functional outcomes at 90 days. URL: https://www.clinicaltrials.gov; Unique Identifier: NCT05644223.

Intravenous thrombolysis for acute ischemic stroke (AIS) is a proven effective treatment. Whether thrombolysis in patients with AIS with recent direct oral anticoagulant (DOAC) use is safe and efficacious is not well established. We aimed to compare outcomes of patients with AIS and recent DOAC use who received thrombolysis to those otherwise eligible but excluded due to recent DOAC use. This study included patients for the GWTG (Get With The Guidelines) registry with a diagnosis of AIS within 4.5 hours from last known normal, on a DOAC, and either (1) received intravenous thrombolysis, or (2) were excluded from thrombolysis with coagulopathy being the only reason for exclusion. We used univariate and adjusted binary logistic regression models with clustering by site to compare the 2 groups' functional status (ambulation on discharge and discharge disposition) and reported rates of safety outcomes in the thrombolysis group. The study sample included 48 907 patients with AIS using a DOAC; 4702 received thrombolysis and 44 205 did not. In adjusted logistic regression models, patients with recent DOAC use receiving thrombolysis had increased odds of independent ambulation at discharge (odds ratio [OR], 1.35[ 95% CI, 1.21-1.50]) and home discharge (OR, 1.33 [95% CI, 1.22-1.46]). The rate of symptomatic intracranial hemorrhage with intravenous thrombolysis in patients with recent DOAC use was 3.5% (95% CI, 3.0%-4.1%). In this study, intravenous thrombolysis was associated with improved functional outcomes in patients with recent DOAC use and appeared safe. Given the study limitations, findings require validation by prospective trials.

Atrial electrophysiological abnormalities (AEA) are associated with cognitive dysfunction. We evaluated the associations of AEA with longitudinal cognitive decline and incident dementia and investigated underlying mechanisms. In subjects without atrial fibrillation followed prospectively for 5 years, 12-lead ECGs were evaluated for AEA, defined as the presence of sinus node dysfunction (SND), frequent premature atrial complexes, advanced interatrial block (a-IAB), or P-terminal force in V1 (>40 mm*ms). Rate of decline in global cognition (Z-score averaged from 6 cognitive domains), Clinical Dementia Rating-Sum of Boxes score, and associations with cerebrovascular disease on neuroimaging and circulating biomarkers of neurodegenerative disease were determined. Among 358 subjects (age 73.3±7.6 years, 55% female, 47% dementia), 188 (53%) had AEA (94 SND, 6 frequent premature atrial complexes, 52 a-IAB, 92 P-terminal force in V1 >40 mm*ms). Compared with non-AEA, AEA was associated with accelerated decline in both global cognition and Clinical Dementia Rating-Sum of Boxes score (Pinteraction<0.05), 2 timesincreased risk of dementia in competing risk analyses, and increased burden of cortical infarcts, lacunes, and cerebral microinfarcts (P<0.05). Among AEA subtypes, SND (versus non-SND) and a-IAB (versus non-a-IAB) both associated with accelerated decline in global cognition and Clinical Dementia Rating-Sum of Boxes score (Pinteraction<0.05). a-IAB was associated with 3 times increased risk of incident ischemic stroke and P-terminal force in V1 with increased burden of lacunes. SND was associated with increased burden of cerebral microinfarcts and cerebral microbleeds, incident cerebral microbleeds, higher circulating pTau-181 levels, and increased odds of Alzheimer disease among subjects with preexisting dementia (P<0.05). AEA is associated with worse cognitive trajectories and increased cerebrovascular disease burden. These associations may be underpinned by AEA-subtype-specific mechanisms.

Testosterone deficiency (TD), or male hypogonadism, affects up to 25% of Canadian men aged 40 to 60. Testosterone replacement therapy (TRT) is widely used to manage symptoms of TD. Despite over seven decades of clinical use, the relationship between TRT and major adverse cardiovascular events (MACE) remains unclear. To investigate the association between TRT and MACE using a large population-based database. A propensity-weighted, retrospective cohort study was conducted using provincial health administrative databases. Men were eligible if they had no prior TRT use or MACE and maintained at least one year of provincial health coverage between April 1, 1995, and December 31, 2018. TRT was defined as having at least two prescriptions filled within one year for testosterone products (capsules, gels, patches, or injections). MACE was defined as the first occurrence of myocardial infarction, coronary revascularization, ischemic stroke, or hospitalization for heart failure. A logistic regression model including age, socioeconomic status, index year, diabetes, hypertension, dyslipidemia, and renal disease generated propensity scores. Stabilized inverse propensity treatment weighting was applied. A Cox proportional hazards model was used to assess time to first MACE. Among 6949 men who received TRT and 415 837 controls, TRT was associated with a 27% increased risk of MACE (HR 1.27, 95% CI: 1.16-1.39) in weighted analyses. Among 7306 men diagnosed with TD and 442 602 matched controls, those with TD also showed a 27% increased risk of MACE (HR 1.27, 95% CI: 1.16-1.39). Median time to MACE was 2828days in the TRT group and 2707days in controls. MACE occurred in 9.95% of TRT users versus 5.56% of controls. Clinicians should be aware that both TRT and underlying TD are associated with increased cardiovascular risk. Assessment of comorbidities and patient-specific cardiovascular risk remains essential when initiating TRT. This study leverages a large, real-world, population-based dataset with robust propensity weighting methodology. However, unmeasured confounding such as obesity, smoking, or physical activity levels may influence outcomes. Diagnostic coding limitations may also affect TD case identification. Both TRT use and TD were associated with a significantly increased risk of MACE. Whether TRT independently drives this risk or merely reflects underlying disease requires further investigation. Risk stratification and shared decision-making should guide the initiation of TRT.

The TICI score determines the reperfusion grade on DSA after endovascular treatment (EVT) in patients with acute ischemic stroke. Despite successful macrovascular reperfusion, almost one-half of patients have poor clinical outcomes. In addition to the large vessels, DSA also depicts the passage of contrast in the capillaries. We aim to study differences in DSA perfusion parameters generated from the time-intensity curves that might differentiate between good and poor clinical outcome in patients who achieved successful reperfusion. Patients from the MR CLEAN Registry with an ICA, M1, and M2 occlusion, and successful reperfusion extended TICI (eTICI ≥2b) were selected. Perfusion parameters of the capillary pixels were computed on post-EVT DSA by deconvolving the time-intensity curve with the arterial input function obtained from the ICA. We extracted 4 perfusion parameters: CBV, CBF, time-to-maximum (Tmax), and mean transit time (MTT). The association between the perfusion parameters and favorable functional outcome at 90 days (0-2 mRS) was analyzed using logistic regression with adjustments for prognostic patient characteristics including eTICI. In total, 743 of 5768 patients were included. There was no association between eTICI scores and favorable functional outcome. In contrast, a shorter MTT and Tmax were associated with favorable functional outcome (adjusted OR, 1.25 [95% CI, 1.03-1.51], 1.39 [95% CI, 1.06-1,82]). DSA-CBV and DSA-CBF were not significantly associated with mRS. Quantifying DSA perfusion parameters provides additional information about reperfusion status and could contribute to differentiating between favorable and unfavorable functional outcomes. The code for producing the quantitative digital subtraction perfusion angiography is publicly available at: https://github.com/RuishengSu/perfDSA.

Rationale: Microglia cells as niche homeostasis monitor with rapid responses to acute ischemic stroke (IS). T-cell intracellular antigen 1 (TIA1), a core component of stress granules (SGs), is involved in cellular stress responses such as hypoxia, but its roles and mechanisms in regulating microglial responses during IS remain unclear.Methods: To evaluate the function of microglial TIA1 in IS, we established a mouse model of IS by using photothrombotic method. Furthermore, conditional knockout (CKO) of Tia1 in microglia mice (Tia1Cx3cr1-CKO mice) was generated and then Tia1Cx3cr1-CKO IS mice and their littermate controls (Tia1f/f IS mice) were used as experimental subjects. The behavioral tests, immunostaining, Laser speckle contrast imaging (LSCI), TTC staining, Nissl staining, quantitative real-time PCR (qPCR) and Western blotting were used to assess the effects of microglial Tia1 deletion in IS progression. In vitro, we utilized the microglia cell line (HMC3 cells) and primary cultured microglia to establish an OGD model, and generated stable TIA1-knockdown or TIA1-overexpressing HMC3 cell lines, and employed a co-culture system of HMC3 and N2a cells to further explore the roles of microglial Tia1 signaling in IS. Through RNA sequencing (RNA-seq) of control HMC3 cells and Tia1-knockdown HMC3 cells, we investigated in depth the role and molecular mechanism of TIA1-mediated insulin-like growth factor 2 (IGF2) signaling pathway in microglia during IS progression.Results: Microglial TIA1 was significantly upregulated in mice during the acute phase of IS. Microglial Tia1 knockout suppressed microglial pro-inflammatory responses, enhanced anti-inflammatory responses, promoted phagocytic clearance of infarct debris, alleviated neuronal death, and improved motor deficits in post-IS mice. In vitro, TIA1 promoted pro-inflammatory responses to exacerbate neuronal cell death and inhibited phagocytic ability of microglia cells after OGD. Mechanistically, Tia1 deletion in microglia impaired SG formation, reduced sequestration of Igf2 mRNA into SGs, upregulated IGF2 expression, and IGF2 signaling enhanced anti-inflammatory responses and phagocytic capacity while suppressing pro-inflammatory activation in microglia.Conclusions: These findings identify a previously unrecognized function of microglial TIA1 in modulating microglia homeostasis and sustaining pro-inflammatory responses via SGs-mediated Igf2 mRNA sequestration after IS, providing a novel therapeutic target for IS treatment.

Although recurrent ischemic stroke (IS) is associated with higher rates of mortality and comorbidities as well as an increased economic burden than the first attack, the choice of first-line antihypertensive agent for secondary prevention remains controversial.This study examined the efficacy of various antihypertensive agents for the secondary prevention of recurrent ischemic stroke in a real-world context. Using the National Health Insurance Research Database, patients with first acute IS from 1 January 2000 to 31 December 2020 were enrolled. Using propensity score-based probability of treatment weighting, all participants were divided into other antihypertensive drugs (OHTND), angiotensin-converting-enzyme-inhibitors/angiotensin II-receptor-blockers (ACEI/ARB), and calcium-channel-blockers (CCB) cohorts. Primary outcome was difference in risk of recurrent IS, and secondary outcomes were all-cause mortality, stroke-related death, and major adverse cardiac and cerebrovascular events (MACCEs). Cox proportional hazards models were used to estimate the adjusted hazard ratio and 95% confidence intervals. Compared with the OHTND cohort, individuals in the ACEI/ARB and CCB cohorts had a 14% (p < 0.001) and 15% (p < 0.001) lower risk of recurrent IS, respectively. Individuals in the CCB cohort had a 37% (p = 0.006) higher risk of acute myocardial infarction compared with the OHTND cohort. Compared with ACEI users, ARB users experienced a 22% lower risk of recurrent IS, while ARB users had a 46% lower risk of stroke-related death. The use of ACEI/ARB following acute IS was associated with a lower risk of recurrent IS. Our results not only corresponded to pre-existing randomized controlled trials (RCTs) but also addressed the knowledge gap regarding the choice of first-line antihypertensive agents following acute IS.

Taohong Siwu decoction alleviates cerebral ischemia-reperfusion injury by inhibiting the formation of NETs through STAT1/NLRP3/GSDMD pathway.

Lobetyolin alleviates microglial inflammation by activating CK2α/Opa1-mediated mitochondrial fusion in ischemic stroke.

Interplay between lipid metabolism and macrophage dynamics in ischemic stroke: From mechanistic insights to therapeutic strategies.

Network pharmacology approach and experimental validation of Lamei pills in treating ischemic stroke based on UHPLC-QE-MS.

Naoxintong capsules for secondary prevention of ischemic stroke: Meta-Analyses of clinical and preclinical evidence.

Effects of Arcadlin on dendritic spine morphology of hippocampal granule cells in a mouse model of ischemic stroke.