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Background: Underlying intracranial stenosis is the most common cause of failed mechanical thrombectomy in acute ischemic stroke patients with large vessel occlusion. Adjunct emergent stenting is sometimes performed to improve or maintain reperfusion, despite limited data regarding its safety or efficacy., Methods: We conducted a prospective multicenter observational international cohort study. Patients were enrolled between January 2022 and December 2023 at 25 thrombectomy capable centers in North America, Europe, and Asia. Consecutive patients treated with mechanical thrombectomy were included if they were identified as having underlying intracranial stenosis, defined as 50-99% residual stenosis of the target vessel or intra-procedural re-occlusion. The primary outcome was functional independence, defined as modified Rankin Scale of 0-2 at 90 days. After applying inverse probability of treatment weighting (IPTW) based on propensity scores, we compared outcomes among patients who underwent adjunct emergent intracranial stenting (stenting) versus those who received mechanical thrombectomy alone., Results: A total of 417 patients were included; 218 patients treated with mechanical thrombectomy alone (168 anterior circulation) and 199 with mechanical thrombectomy plus stenting (144 anterior circulation). Patients in the stenting group were less likely to be non-Hispanic White (51.8% vs 62.4%, p=0.03), and less likely to have diabetes (33.2% vs 43.1%, p=0.037) or hyperlipidemia (43.2% vs 56%, p= 0.009). In addition, there was a lower rate of IV thrombolysis use in the stenting group (18.6% vs 27.5%, p=0.03). There was a higher rate of successful reperfusion (modified Treatment In Cerebral Infarction score ≥ 2B) in the stenting versus mechanical thrombectomy alone group (90.9% vs 77.9%, p<0.001) and a higher rate of a 24-hour infarct volume of <30 mL (n=260, 67.9% vs 50.3%, p=0.005). The overall complication rate was higher in the stenting group (12.6% vs 5%, p=0.006), but there was not a significant difference in the rate of symptomatic hemorrhage (9% vs 5.5%, p=0.162). Functional independence at 90 days was significantly higher in the stenting group (42.2% vs. 28.4%, adjusted odds ratio 2.67; 95% CI, 1.66-4.32)., Conclusions: In patients with underlying stenosis who achieved reperfusion with mechanical thrombectomy, adjunct emergent stenting was associated with better functional outcome without a significantly increased risk of symptomatic hemorrhage., Registration: https://clinicaltrials.gov/study/NCT05403593.

Background: Stroke triggers are factors that may precipitate a stroke within a given time interval and can predict the timing of a stroke. While hypoglycemia has been established as a risk factor for cardiovascular events such as acute ischemic stroke (AIS), there is limited research demonstrating hypoglycemic events as stroke triggers. We hypothesize an association between hypoglycemic events and the occurrence of stroke among patients with diabetes., Methods: We used Medicare inpatient, outpatient, emergency department, and subacute nursing facility data sets from January 1, 2016, to December 31, 2019, and validated using International Classification of Diseases , Tenth Revision , Clinical Modification codes to identify conditions. We used a case-crossover study design, testing whether exposure to a hypoglycemia encounter within progressively longer case periods (up to 30 days before index AIS) was associated with the subsequent occurrence of AIS, compared with control periods of equal length exactly 1 year before the case period. We used conditional logistical regression models to estimate odds ratios and 95% CIs., Results: There were 237 667 index admissions with AIS and diabetes during the study period. There were increased odds of AIS following an encounter with hypoglycemia. The risk was the highest immediately on the first day following the hypoglycemia encounter (odds ratio, 3.694 [95% CI, 2.694-5.065]; P <0.0001) and gradually became lower as the case-control period lengthened. At a 30-day case-control interval, the risk was lowest but still significant (odds ratio, 2.345 [95% CI, 2.179-2.523]; P <0.0001)., Conclusions: We found that hypoglycemic events in patients with diabetes are associated with a more than 3-fold greater risk of AIS in the first day but can trigger AIS in the 30 days following the event. More research is needed to assess the link between the severity of hypoglycemia and stroke occurrence, as well as the severity of the stroke. These results, if confirmed in other studies, emphasize the importance of avoiding hypoglycemic events in patients with diabetes.

Background: We aimed to investigate whether rescue stenting (RS) following failed mechanical thrombectomy (MT) for acute basilar artery occlusion (BAO) results in superior functional outcomes and enhanced safety compared to the natural history of failed mechanical thrombectomy (MT)., Methods: This retrospective cohort study utilized data from the PC-SEARCH registry, encompassing eight high-volume centers in the United States and covering the period from 2015 to 2021. Patients with BAO who experienced failed MT (mTICI score of 0-2a after at least one attempt of clot retrieval) were categorized based on whether they received additional intervention with RS. The primary outcome was a shift analysis of the 90-day mRS. Multivariable logistic regression was employed to assess both efficacy and safety outcomes., Results: Of a total of 444 patients, 119 presented failed MT and were included in the analysis. The RS group comprised 65 (14.6%) patients, while the control group consisted of 54 (12.2%) patients. After adjusting, the RS group showed a favorable shift in the overall 90-day mRS distribution (acOR=4.56; 95% CI 1.67-12.45; p=0.003) and higher rates of 90-day 0-3 mRS (RS: 44.6% vs. control: 18.5%, aOR=7.57; 95% CI 1.91-30.12; p = 0.004) compared to the control group. RS also showed lower rates of 90-day mortality (RS: 43.1% vs. control: 64.8%, aOR=0.27; 95% CI 0.09-0.80; p=0.018) and comparable rates of sICH (RS: 3.1% vs. control: 13%, aOR=0.31; 95% CI 0.05-1.95; p=0.214)., Conclusions: Our study demonstrated that RS is associated with improved functional outcomes and reduced mortality in BAO patients presenting MT failure. Further randomized trials are needed to validate these findings.

Achieving health equity in stroke prevention, treatment, and recovery has continued to be a significant challenge. This article highlights the significance of health equity and the role of community-engaged research in addressing stroke disparities, including concepts around health equity as the fair and just opportunity for everyone to attain their highest level of health and well-being. Social determinants impact stroke incidence, prevalence, morbidity, and mortality, which emphasizes the importance of intersectionality and social risk-informed care. A comprehensive roadmap for achieving health equity in stroke through the integration of community-engaged research is presented, including the necessity of community involvement in all aspects of research. Community is defined beyond geographic boundaries, highlighting the importance of shared identities and values. The process of developing targeted goals with communities toward social justice reform is reviewed, including an evolved community engagement framework, emphasizing the need for training to inform about issues and collaborative leadership models. Several stroke disparities intervention studies are highlighted, demonstrating the successful incorporation of community engagement into intervention design and intervention platforms. For enhanced engagement, the use of community health workers and better integration of community health worker models are essential. There may be a critical need for community engagement to optimize inclusion in clinical trials. Finally, acknowledging the complexities of research around decreasing stroke disparities in prevention, treatment, and recovery, this article delves into a framework for understanding the mechanisms by which interventions affect inequities and the need for multifaceted solutions with the community as a partner. Highlighting the roadmap to health equity, this research argues that community engagement is an integral component at all steps along the road to achieving optimum brain health through equitable stroke treatment, prevention, and recovery.

Background: In ischemic cerebral small vessel diseases (cSVD), recurrent ischemic stroke is rare (2%-3% per year). Because acute ischemia may not always lead to stroke in cSVD due to the small size of lesions, acute stroke may not reliably reflect ischemic activity or the risk of further clinical worsening, as both incident lacunes and incidental diffusion-weighted imaging-positive lesions can occur without stroke symptoms. We aimed to evaluate the total ischemic activity by measuring the incidence of magnetic resonance imaging (MRI)-proven incident ischemia, independent of the presence of stroke symptoms in a large cohort of cSVD., Methods: DHU-LAC is an ongoing French multicenter cohort study of MRI-proven ischemic stroke presumably due to cSVD. We report data on patients recruited between June 2018 and October 2023. In DHU-LAC, patients are enrolled within 15 days of stroke onset and are cared for according to current guidelines. During the first 6 months, patients are systematically reassessed clinically and by brain MRI: (1) at any time if stroke symptoms occur and (2) at the end of the period. We defined MRI-proven incident ischemia as either recurrent ischemic stroke or at least 1 incident lacune or incidental diffusion-weighted imaging-positive lesion on brain MRI at 6 months., Results: Two hundred forty-nine patients were included, of whom 172 had available data at both inclusion and after 6 months. They were aged 63±6 years, 28% were women, and 65% had hypertension. Six (3%) had a recurrent ischemic stroke, but 25 more (15%) had at least 1 incident lacune or incidental diffusion-weighted imaging-positive lesion on brain MRI. MRI-proven ischemia occurs about 5× more frequently than ischemic stroke in cSVD., Conclusions: As data confirming the detrimental clinical effect of both incident lacunes and incidental diffusion-weighted imaging-positive lesions accumulate, MRI-proven incident ischemia may become a plausible outcome for future clinical trials in cSVD., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03552926.

Background: A third of endovascularly treated stroke patients experience incomplete reperfusion (expanded Thrombolysis in Cerebral Infarction, eTICI<3) and the natural evolution of this incomplete reperfusion remains unknown. We systematically reviewed literature and performed a meta-analysis on the natural evolution of incomplete reperfusion after endovascular therapy., Methods: A systematic review of MEDLINE, Embase and PubMed up until March 1, 2024 using a predefined strategy. Only full-text English written articles reporting rates of either favorable (i.e., delayed reperfusion or no new infarct) or unfavorable progression (i.e., persistent perfusion deficit or new infarct) of incompletely reperfused tissue were included. Primary outcome was the rate of delayed reperfusion and its association with functional independence (modified Rankin Scale, mRS 0-2) at 90 days post-intervention. Pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated using a random-effects model., Results: Six studies involving 950 patients (50.7% female; median age 71, IQR 60-79) were included. Four studies assessed the evolution of incomplete reperfusion on MRI perfusion imaging, while two studies used DWI and NCCT imaging, where new infarct was used to denote unfavorable progression. Five studies defined incomplete reperfusion as eTICI2b50 or 2c. Delayed reperfusion occurred in 41% (IQR 33%-51%) of cases 24h post-intervention. Achieving delayed reperfusion was associated with higher likelihood of functional independence at 90 days (OR 2.5, 95%CI 1.9-3.4)., Conclusions: Nearly half of eTICI<3 patients achieve delayed reperfusion, leading to favorable clinical outcome. This subgroup may derive limited or potentially harmful effects from pursuing additional reperfusion strategies (e.g., intra-arterial lytics or secondary thrombectomy). Accurately predicting the evolution of incomplete reperfusion could optimize patient selection for adjunctive reperfusion strategies at the end of an intervention.

Background: The EXCELLENT registry aimed to evaluate the effectiveness of the EMBOTRAP Revascularization Device in an all-comer population in a real-world setting, with a focus on the composition of retrieved clots., Methods: EXCELLENT is a prospective, global registry of patients with acute ischemic stroke treated with EMBOTRAP as the first-line mechanical thrombectomy device conducted at 34 sites (25 sites contributing clot) from September 2018 to March 2021, utilizing core imaging and central histology laboratories blinded to clinical data, independent 90-day modified Rankin Scale assessment and Clinical Events Committee., Results: After screening 3799 patients, a total of 997 subjects (mean age, 70.0±14.2 years; 51.8% women; 19.7% non-White) were included. The first-pass modified Treatment in Cerebral Infarction (mTICI) ≥2b rate was 64.5% (623/966), first-pass mTICI ≥2c was 39.1% (378/966), and final mTICI ≥2b was 94.5% (931/985). A total of 427/912 (46.8%) patients achieved a 90-day modified Rankin Scale of 0 to 2 or ≤baseline. Embolization to a new territory occurred in 0.2% (2/984), and symptomatic intracranial hemorrhage at 24 hours in 1.6% (16/997). The 90-day mortality was 19.1% (175/918). Device- and/or procedure-related serious adverse events occurred in 5.9% (54/912) through 90 days. The mean RBC percentage of retrieved clots was 45.62±21.372. Among patients who achieved mTICI ≥2b with the first pass, 15.7% (52/331) and 9.7% (32/331), respectively, had RBC-poor (<25%) and RBC-rich (>75%) clots. Patients with no clot retrieved in any procedural pass had a lower percentage of hyperdense or susceptibility vessel sign on baseline imaging (58.9% versus 74.7%; P <0.001), pointing to a potential preprocedure indicator of challenging clot., Conclusions: The EXCELLENT registry informs real-world practices in mechanical thrombectomy and sheds light on the range of clots effectively retrieved by current technology. This is the first report of detailed patient characteristics where mechanical thrombectomy maneuvers failed to remove any clot material. Although the composition of nonretrievable clots cannot be assessed histologically, the results support the notion that no retrieval may be correlated with imaging findings suggesting clots lower in RBC., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03685578.

As awareness of dementia increases, more individuals with minor cognitive complaints are requesting clinical assessment. Neuroimaging studies frequently identify incidental white matter hyperintensities, raising patient concerns about their brain health and future risk for dementia. Moreover, current US demographics indicate that ≈50% of these individuals will be from diverse backgrounds by 2060. Racial and ethnic minority populations bear a disproportionate burden of vascular risk factors magnifying dementia risk. Despite established associations between white matter hyperintensities and cognitive impairment, including dementia, no study has comprehensively and prospectively examined the impact of individual and combined magnetic resonance imaging measures of white matter injury, their risk factors, and comorbidities on cognitive performance among a diverse, nondemented, stroke-free population with cognitive complaints over an extended period of observation. The Diverse VCID (Diverse Vascular Cognitive Impairment and Dementia) study is designed to fill this knowledge gap through 3 assessments of clinical, behavioral, and risk factors; neurocognitive and magnetic resonance imaging measures; fluid biomarkers of Alzheimer disease, vascular inflammation, angiogenesis, and endothelial dysfunction; and measures of genetic risk collected prospectively over a minimum of 3 years in a cohort of 2250 individuals evenly distributed among Americans of Black/African, Latino/Hispanic, and non-Hispanic White backgrounds. The goal of this study is to investigate the basic mechanisms of small vessel cerebrovascular injury, emphasizing clinically relevant assessment tools and developing a risk score that will accurately identify at-risk individuals for possible treatment or clinical therapeutic trials, particularly individuals of diverse backgrounds where vascular risk factors and disease are more prevalent.

Cerebral ischemic injury occurs when blood flow drops below a critical level, resulting in an energy failure. The progressive transformation of hypoperfused viable tissue, the ischemic penumbra, into infarction is a mechanism shared by patients with ischemic stroke if timely reperfusion is not achieved. Yet, the pace at which this transformation occurs, known as the infarct growth rate (IGR), exhibits remarkable heterogeneity among patients, brain regions, and over time, reflecting differences in compensatory collateral flow and ischemic tolerance. We review (1) the pathophysiology of infarct growth, (2) the advantages and pitfalls of different approaches of IGR measurement, (3) research gaps for future studies, and (4) the clinical implications of stroke progressor phenotypes. The estimated average IGR in patients with acute large vessel occlusion stroke is 5.4 mL/h although there is wide variability based on ischemic stroke subtype, occlusion location, presence of collaterals, and patient baseline status. The IGR can be calculated using various pragmatic strategies, mostly either quantifying the extension of the infarct at a particular time and dividing this measure by the time that elapsed from symptom onset to imaging assessment or by using collateral blood flow status as a radiological surrogate marker. The IGR defines a spectrum of clinical stroke phenotypes, often dichotomized into fast and slow progressors. An IGR ≥10 mL/h and the perfusion metric hypoperfusion intensity ratio ≥0.5 are commonly used definitions of fast progressors. A nuanced understanding of the IGR and stroke progressor phenotypes could have clinical implications, including informing prognostication, acute decision-making in peripheral-to-comprehensive transfer patients eligible for thrombectomy, and selection for adjuvant neuroprotective agents.

Background: We aim to assess the efficacy of rapid local ischemic postconditioning (RL-IPostC) following successful reperfusion in patients with acute ischemic stroke with anterior circulation large vessel occlusion who underwent endovascular thrombectomy., Methods: We conducted an ambidirectional cohort study with 78 prospectively enrolled patients with RL-IPostC and endovascular thrombectomy and 129 retrospectively enrolled patients with endovascular thrombectomy. The RL-IPostC procedure involved 5 cycles of 15-s balloon inflation and deflation in the ipsilateral internal carotid artery. The primary outcome was functional independence, defined as a modified Rankin Scale score of 0 to 2. Secondary outcomes included excellent outcomes (modified Rankin Scale score, 0-1) and early therapeutic response. Imaging outcomes involved infarct volume changes and cerebral edema measurements. Outcomes were compared with postpropensity score matching (1:1) and assessed using univariable and multivariable regression models., Results: In the matched cohort of 136 patients (mean age, 71±14 years; 70 men [51%]), RL-IPostC was associated with a higher rate of functional independence (adjusted odds ratio, 2.47 [95% CI, 1.10-5.68]; P =0.030). The RL-IPostC group exhibited significantly reduced infarct volumes at 24 hours (difference, -12.2 [95% CI, -23.9 to -0.53]; P =0.041) and less infarct growth (difference, -12.2 [95% CI, -23.9 to -0.45]; P =0.042). Furthermore, RL-IPostC correlated with lower increases in net water uptake (difference, -0.04 [95% CI, -0.07 to -0.01]; P =0.018), lower decrease cerebrospinal fluid volume (difference, -7.75 [95% CI, -11.7 to -3.84]; P <0.001), and reduced midline shift at 24 hours (difference, -1.39 [95% CI, -2.48 to -0.30]; P =0.013)., Conclusions: RL-IPostC tends to promote functional independence and reduces infarct growth and cerebral edema in patients with acute ischemic stroke post-reperfusion.

In recent years, stroke incidence in older adults has declined strikingly, but stroke in younger women has become more common. Abnormalities of menstruation, the shedding of the uterine lining at the beginning of each menstrual cycle, may offer clues about stroke risk in young and midlife women. Endometrial and structural uterine abnormalities are associated with anemia and may be associated with hypercoagulability, possibly increasing stroke risk. Patient factors that influence both menstruation and stroke risk include coagulopathies, polycystic ovarian syndrome, endometriosis, migraine, and other systemic disorders, in addition to menopause. Environmental and iatrogenic factors that influence both menstruation and stroke risk include hormonal contraceptives, nicotine, xenoestrogens, phytoestrogens, oophorectomy, and hysterectomy. Importantly, secondary stroke prevention can affect menstruation. Our current review presents literature supporting the idea that abnormal menstruation may indicate elevated stroke risk in premenopausal women.

Currently, most acute ischemic stroke patients presenting with a large vessel occlusion are first evaluated at a nonthrombectomy-capable center before transfer to a comprehensive stroke center that performs thrombectomy. Interfacility transfer is a complex process that requires extensive coordination between the referring, transporting, and receiving facilities. As a result, long delays are common, contributing to poor clinical outcomes. In this review, we summarize the accumulating literature about the clinical as well as radiological-infarct growth, collateral change, arterial recanalization, and hemorrhagic transformation-changes during interfacility transfer for thrombectomy. Recent evidence shows that clinical/radiological changes during transfer are heterogeneous across patients and impact long-term functional outcomes, highlighting the urgent need to optimize care during this time window. We review some of the most promising therapeutic strategies-for example, penumbral protection to reduce infarct growth-that may improve clinical outcome in patients being transferred to thrombectomy-capable centers. Finally, we discuss key methodological considerations for designing clinical trials aimed at reducing infarct growth during transfer.

Background: Patients with premorbid dementia have been generally excluded from trials of stroke therapies, and their dementia diagnosis may affect the care received. There are few data on the quality of stroke care and outcomes in these patients., Methods: We compared the quality of care and outcomes for acute ischemic stroke patients with versus without premorbid dementia using national data from the Get With The Guidelines-Stroke registry between July 1, 2020, and December 31, 2021. Process outcomes included receiving intravenous thrombolysis, endovascular thrombectomy, and additional national quality measures. Clinical outcomes included ambulatory status at discharge, discharge destination, and mortality. The analyses were adjusted for patient and hospital characteristics., Results: Among 609 350 patients with acute ischemic stroke, 29 751 of 546 407 (5.4%) had documented prestroke dementia (median age, 84 [interquartile range, 78-89]; 62.8% female). Patients with versus without premorbid dementia were more likely to arrive via emergency medical services (70.5% versus 46.8%) and had more severe strokes (median National Institutes of Health Stroke Scale score, 7 [interquartile range, 3-15] versus 3 [interquartile range, 1-8]). They were less likely to be admitted to a comprehensive stroke center (17.9% versus 22.7%; P <0.0001), to receive intravenous thrombolysis (9.6% versus 11.1%; adjusted odds ratio [aOR], 0.91 [95% CI, 0.87-0.95]) or endovascular thrombectomy (4.5% versus 7.4%; aOR, 0.62 [95% CI, 0.56-0.68]), attain each of the Get With The Guidelines-Stroke Achievement Measures and Quality Measures, or attain defect-free stroke care (92.0% versus 95.0%; aOR, 0.75 [95% CI, 0.71-0.78]). Patients with premorbid dementia had longer door-to-needle times (adjusted difference, 3.17 minutes [95% CI, 1.34-5.01]), lower odds of being discharged home (43.8% versus 60.1%; aOR, 0.96 [95% CI, 0.93-1.00]), and higher odds of being nonambulatory at discharge (25.8% versus 9.3%; aOR, 1.62 [95% CI, 1.54-1.69]), and of in-hospital mortality or hospice admission (23.3% versus 8.6%; aOR, 1.38 [95% CI, 1.32-1.43]). Symptomatic intracranial hemorrhage after intravenous thrombolysis/endovascular thrombectomy did not differ (5.3% versus 3.7%; aOR, 1.13 [95% CI, 0.97-1.31])., Conclusions: Patients with premorbid dementia experienced slightly poorer quality of stroke care across multiple measures, were less likely to receive acute stroke interventions, and had worse poststroke outcomes than patients without dementia in a large nationwide registry. Our findings underscore the need for concerted efforts to further improve care quality and outcomes in this population.

Background: Epilepsy is highly heritable, with numerous known genetic risk loci. However, the genetic predisposition's role in poststroke epilepsy (PSE) remains understudied. This study assesses whether a higher genetic predisposition to epilepsy raises poststroke survivor's risk of PSE., Methods: We conducted a case-control genetic association study nested within the UK Biobank, a large UK-based prospective cohort. Our exposures of interest were 2 distinct polygenic risk scores-generalized and focal epilepsy-modeled as deciles and constructed using genetic variants identified in the latest International League Against Epilepsy genome-wide association study meta-analysis. We aimed to evaluate the association between these polygenic risk scores and their corresponding subtype of PSE-generalized and focal. In sensitivity analyses, we evaluated participants of European ancestry separately and considered focal and generalized epilepsy outcomes in participants without a history of stroke. In secondary analyses, we evaluated the polygenic risk of PSE by stroke subtype (ischemic, hemorrhagic, or any stroke). Multivariable logistic regression models were fitted, adjusting for age, sex, genetic ancestry, and the first 5 principal genetic components., Results: Among 17 549 UK Biobank stroke survivors with available genetic information (mean age, 61; 43% female), 185 (1%) developed generalized PSE, while 124 (0.7%) developed focal PSE. Multivariable logistic regression results showed that, when compared against the lowest decile, participants within the highest PRS decile for generalized PSE had 5-fold higher odds of developing generalized PSE (OR, 5.05 [95% CI, 2.37-12.5]; P trend<0.001). Similarly, when compared against the lowest decile, participants within the highest polygenic risk score decile for focal PSE had 3-fold higher odds of developing focal PSE (OR, 3.20; [5% CI, 1.25-9.82]; P trend=0.024). Sensitivity analyses among participants of European ancestry yielded similar results., Conclusions: Our findings suggest that, like other forms of epilepsy, genetic predisposition plays an essential role in PSE. These results underscore the need for future studies to elucidate the mechanisms underlying PSE development and to identify novel therapeutic avenues.

Background: An increasing number of monogenic conditions underlying stroke are being identified. We explored the possibilities of increasing the diagnostic yield of monogenic stroke in a population under 56 years of age., Methods: Fifty probands ≤55 years at their first stroke episode were characterized clinically and investigated by whole genome sequencing. Probands had one or more of: (1) one or more first to second degree relatives with stroke under 60 years or same stroke-causing condition/disease; (2) no hypertension, hypercholesterolemia, diabetes, heart disease, or smoking; or (3) either multiple stroke episodes or multiple arterial dissections. Variants with minor allele frequency under 0.01, identified by using our stroke gene panels, were assessed. The stroke subtypes, including large artery atherosclerotic, large artery nonatherosclerotic (tortuosity, dolichoectasia, aneurysm, nonatherosclerotic dissection, or occlusion), cerebral small vessel disease, cardioembolic (arrhythmia, heart defect, or cardiomyopathy), coagulation dysfunctions (venous thrombosis, arterial thrombosis, or bleeding tendency), intracerebral hemorrhage, vascular malformations (cavernoma or arteriovenous malformations), metabolic disorders, or cryptogenic embolic, were used for genotype-phenotype correlation. In a final step, we combined genetic and clinical information to determine if the genetic variant likely was the cause of stroke in the patients., Results: Whole genome sequencing of younger patients with stroke identified 17 clinically matching genetic variants in 15 of 50 (30%) patients, while a stronger clinical correlation with stroke was established in only 6 (12%) of them. Stroke-related genetic variants were identified in 4 of 5 (80%) patients with cardioembolic stroke subtype, 3 of 4 (75%) with intracerebral hemorrhage, 7 of 18 (39%) with cryptogenic embolic stroke, 1 of 6 (17%) with small vessel disease, and 3 of 15 (20%) of patients with nonatherosclerotic large artery stroke, including 1 of 11 (9%) with cervical dissection stroke., Conclusions: Careful clinical interpretation of whole genome data using stroke gene panels can detect monogenic causes of early stroke, allowing individualized follow-up and opening new possibilities for potential treatment.

While the majority of stroke researchers use frequentist statistics to analyze and present their data, Bayesian statistics are becoming more and more prevalent in stroke research. As opposed to frequentist approaches, which are based on the probability that data equal specific values given underlying unknown parameters, Bayesian approaches are based on the probability that parameters equal specific values given observed data and prior beliefs. The Bayesian paradigm allows researchers to update their beliefs with observed data to provide probabilistic interpretations of key parameters, for example, the probability that a treatment is effective. In this review, we outline the basic concepts of Bayesian statistics as they apply to stroke trials, compare them to the frequentist approach using exemplary data from a randomized trial, and explain how a Bayesian analysis is conducted and interpreted., Competing Interests: Dr Ospel is a consultant for Nicolab. Dr Goyal is a consultant for Mentice, Medtronic, MicroVention, and Stryker. Dr Brown reports compensation from MicroVention, Inc, for consultant services and compensation from the Faculty of Arts, University of Calgary, for consultant services. Dr Rinkel reports grants from the Niels Stensen Fellowship. Dr Ganesh reports compensation from Figure 1 for consultant services; grants from the Heart and Stroke Foundation of Canada; compensation from Atheneum for consultant services; grants from the Canadian Cardiovascular Society; compensation from Creative Research Designs for consultant services; grants from Campus Alberta Neuroscience; grants from the Government of Canada; stock options in TheRounds.com; compensation from DeepBench for consultant services; grants from the Alzheimer Society of Canada; grants from Rhodes Scholarships; grants from the Canadian Institutes of Health Research; compensation from the Canadian Association of Neuroscience Nurses for consultant services; grants from Alberta Innovates; stock holdings in Collavidence, Inc; grants from Wellcome Trust; travel support from the American Academy of Neurology; travel support from the American Heart Association; travel support from the University of Calgary; service as an editorial board member for the journal Stroke for American Heart Association; stock options in SnapDx, Inc; grants from MicroVention, Inc; service as a review editor for Stroke for Frontiers in Neurology; compensation from Alexion Pharmaceuticals for other services; grants from Panmure House; compensation from Biogen for other services; compensation from MD Analytics for consultant services; compensation from MyMedicalPanel for consultant services; compensation from CTC Communications Corporation for consultant services; service as an editorial board member for the journals Neurology and Neurology: Clinical Practice for the American Academy of Neurology; grants from the Fondation Brain Canada; and grants from the Sunnybrook Research Institute. Dr Hill reports grants from Boehringer Ingelheim, Medtronic, MicroVention, Inc, the Canadian Institutes of Health Research, NoNO, Inc, and Medtronic; compensation from Merck for end point review committee services; grants from Stryker Corporation; a patent issued for Systems and Methods for Assisting in Decision-Making and Triaging for Acute Stroke Patients licensed to Circle NVI; compensation from Brainsgate Ltd for consultant services; grants from Biogen, Inc, and Medtronic; and employment by the University of Calgary. The other authors report no conflicts.

Background: The Get With The Guidelines-Stroke program is a quality improvement initiative designed to enhance adherence to evidence-based stroke care. Since its inception in 2003, over 2800 hospitals in the United States have participated in the program., Methods: We examined patient characteristics, adherence to performance measures, and in-hospital outcomes in patients hospitalized for acute ischemic stroke, subarachnoid hemorrhage, intracerebral hemorrhage, and transient ischemic attack in The Get With The Guidelines-Stroke hospitals from 2003 through 2022. We quantified temporal changes in performance measure adherence and clinical outcomes over time. Performance measure denominators consisted of patients who were eligible, excluding those with contraindications., Results: Over the 20 years of the program, a total of 7837 849 stroke cases (median age 71 years, 51.0% female; 69.2% ischemic strokes, 3.9% SAHs, 11.5% ICHs, and 15.3% TIAs) were entered into the registry. Except for antithrombotics at discharge, in which the baseline performance was >92%, there was sustained improvement in all performance metrics regardless of type of cerebrovascular event ( P <0.01 for all). In patients with acute ischemic stroke, large improvements were observed for anticoagulation for atrial fibrillation (55.7% in 2003 to 97.2% in 2022), smoking cessation counseling (44.7%-97.8%), dysphagia screening (53.8%-83.5%), thrombolytic treatment for patients arriving by 3.5 hours, treat by 4.5 hours (15.2%-92.9%), door-to-needle time within 60 minutes (19.0%-75.3%), and endovascular door-to-puncture time within 90 minutes (54.7%-62.8%). Similar improvements were also observed for measures relevant to patients with subarachnoid hemorrhage, intracerebral hemorrhage, and transient ischemic attack. Multivariable analysis showed that there was a sustained increase in odds of receiving each performance measure over time, independent of patient and hospital characteristics for each type of cerebrovascular event. After risk adjustment, there were temporal trends that patients were less likely to be discharged to a skilled nursing facility, and, for ischemic stroke only, more likely to be discharged directly home., Conclusions: During the first 20 years, Get With The Guidelines-Stroke participation was associated with sustained improvement in evidence-based care and outcomes for patients with stroke and transient ischemic attack in the United States., Competing Interests: Dr Xian reports research funding from the American Heart Association and the National Institute on Aging (R01AG062770 and R01AG066672);grants from Daiichi Sankyo Company; grants from Genentech; travel support from Boehringer Ingelheim; and grants from Janssen Pharmaceuticals Inc. Dr Smith reports service as an editor for the Stroke journal. Dr Saver reports consulting fees for advising on rigorous and safe clinical trial design and conduct from Abbott, Acticor, Aeromics, Amgen, Argenica, Astrocyte, Bayer, Biogen, Boehringer Ingelheim, BrainsGate, BrainQ, CSL Behring, Filterlex, Genentech, Johnson&Johnson, MindRhythm, Medtronic, NeuroMerit, Neuronics, Novo Nordisk, Occlutech, Phenox, Phillips, QuantalX, Rapid Medical, Roche, and Stream Biomedical; compensation from MIVI Neuroscience for data and safety monitoring services; and stock options in Rapid Medical, Neuronics Medical, and MindRhythm. Dr Sheth reports grant support from National Institutes of Health, American Heart Association, and Hyperfine; consulting from Astrocyte, Rhaeos, Cerevasc, Bexorg, Sense and Philips Data and Safety Monitoring Board; and patent with Alva; and compensation from Certus for consultant services; stock options in BrainQ. Dr Messé reports personal compensation from Novo Nordisk for work on the Clinical Event Committee for ONWARDS and Zeus Trials; Terumo for work on the Subject Selection Committee for the RelayBranch Trial; WL Gore for work on the Data Safety Monitoring Committee for the GORE CARDIOFORM Septal Occluder Post Marketing Trial; and Conformal Medical for work on the Clinical Event Committee for work on the Conformal left atrial appendage closure trial. He also reports equity in Neuralert Technologies. Dr Schwamm reports consulting for Genentech (member of TIMELESS steering committee NCT03785678), LifeImage, Penumbra (DSMB MIND NCT03342664), Medtronic (co-PI Stroke AF NCT02700945, advise on stroke prevention), grant funding from NINDS (PI, U24NS107243; Co-I, R01NS111952) and PCORI (R-1609-35995), and serves as member board of directors for the American Heart Association. Dr Fonarow reports consulting for Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Eli Lilly, Johnson & Johnson, Medtronic, Merck, Novartis, and Pfizer. The other authors report no conflicts.

Background: Neonatal hypoxic-ischemic encephalopathy disproportionately affects low- and middle-income countries, where ≈96% of affected infants reside. The current standard of care, therapeutic hypothermia, is frequently ineffective in this setting, likely because injury may be occurring earlier during labor. Here, we studied the pharmacokinetics, safety, and efficacy of perinatal caffeine administration in near-term lambs following global ischemic injury to support the development of earlier treatment strategies targeting the fetus in utero as well as the infant postnatally., Methods: Ewes were randomly assigned to receive either 1 g IV caffeine citrate or placebo before delivery and placental transport assessed. Near-term lambs (141-143 days) of both sexes were subjected to severe global hypoxia-ischemia utilizing an acute umbilical cord occlusion model. Lambs that received caffeine in utero also received 20 mg/kg IV caffeine citrate following resuscitation and 10 mg/(kg·d) IV for 2 days. An additional cohort received 60 mg/kg followed by 30 mg/(kg·d) (low dose versus high dose) postnatally. Biochemical, histological, and neurological outcome measures in lambs were assessed over a 6-day period., Results: Perinatal caffeine administration demonstrated excellent placental transport kinetics and was well tolerated with lamb plasma levels comparable to those targeted in neonates with apnea of prematurity. Caffeine administration resulted in a systemic immunomodulatory effect, evidenced by significant reductions in proinflammatory IP-10 levels. Treated lambs demonstrated improved neurodevelopmental outcomes, while histological analysis revealed that caffeine reduced gray matter injury and attenuated inflammation in the cingulate and parasagittal cortex. This neuroprotective effect was greater and via a different mode of action than we previously reported for azithromycin. A higher caffeine dosing regimen demonstrated significant toxicity., Conclusions: Perinatal caffeine administration is well tolerated, attenuates systemic and brain inflammation, and contributes to improvements in histological and neurological outcomes in an ovine model of neonatal hypoxic-ischemic encephalopathy., Competing Interests: None.

Background: Benzodiazepines are commonly prescribed for post-acute ischemic stroke for anxiety, insomnia, and agitation. While guidelines discourage use in those aged ≥65 years, little is known about prescription patterns at the national level., Methods: We analyzed a 20% sample of US Medicare claims from April 1, 2013, to September 30, 2021. We selected beneficiaries aged ≥65 years discharged alive following an acute ischemic stroke who had traditional Medicare coverage and 6 months' prior enrollment in Parts A (hospital insurance), B (Medical insurance), and D (drug coverage). We excluded those with prior benzodiazepine prescriptions, self-discharges, or discharge to skilled nursing facilities. We examined demographics, comorbidities, first prescription days' supply, cumulative incidences of benzodiazepine first prescription fills within 90 days after discharge, and geographic and yearly trends., Results: We included 126 050 beneficiaries with a mean age of 78 years (SD, 8); 54% were female and 82% were White. Within 90 days, 6127 (4.9%) initiated a benzodiazepine. Among new prescriptions, lorazepam (40%) and alprazolam (33%) were the most prescribed. Most (76%) of first fills had a day's supply over 7 days and 55% between 15 and 30 days. Female initiation rates were higher (5.5% [95% CI, 5.3-5.7]) than male initiation rates (3.8% [95% CI, 3.6%-3.9%]). Rates were highest in the southeast (5.1% [95% CI, 4.8%-5.3%]) and lowest in the midwest (4.0% [95% CI, 3.8%-4.3%]), with a modest nationwide initiation decline from 2013 to 2021 (cumulative incidence difference, 1.6%)., Conclusions: Despite a gradual decline in benzodiazepine initiation from 2013 to 2021, we noted excessive supplies in prescriptions post-acute ischemic stroke discharge, underscoring the need for improved policies., Competing Interests: Dr Hsu receives support from the National Institutes of Health, the Agency for Healthcare Research and Quality, Brandies University, Altmed, Cambridge Health Alliance, Columbia University, Invitrx, and the University of South Carolina and reports no conflict of interest. Dr Blacker receives support from the National Institute of Neurological Disorders and Stroke and the National Institute on Aging and reports no conflict of interest. Dr Newhouse is the director of the National Committee for Quality Assurance and reports no conflict of interest. Dr Moura receives support from the Epilepsy Foundation of America and reports no conflict of interest. The other authors report no conflicts.

Background: Dual antiplatelet therapy (DAPT) was noninferior to alteplase in minor nondisabling strokes in the ARAMIS trial (Antiplatelet Versus R-tPA for Acute Mild Ischemic Stroke); however, early neurological deterioration (END) associated with vessel stenosis may benefit from DAPT. We investigated whether the efficacy of DAPT was greater than alteplase in minor strokes with no large vessel occlusion (LVO)., Methods: This study was a prespecified post hoc analysis of the ARAMIS trial and included patients with responsible vessel examination in the as-treated analysis set of the ARAMIS trial who were divided into LVO group and non-LVO group. In each group, patients were further classified into DAPT and intravenous alteplase treatments. Primary outcome was END at 24 hours defined as more than or equal to 4-point National Institutes of Health Stroke Scale score increase compared with baseline, and safety outcomes were symptomatic intracerebral hemorrhage and bleeding events during study. The primary analysis was estimated with a risk difference calculated by a generalized linear model including adjusted different baseline characteristics between treatments., Results: Of 723 patients from the ARAMIS trial, 480 patients were included: 36 were categorized into LVO group and 444 into non-LVO group, of whom 20 patients had END. Compared with intravenous alteplase, a lower proportion of END was found after DAPT treatment in the non-LVO group (adjusted risk difference, -4.8% [95% CI, -6.9% to -2.6%]; P <0.001), but not in the LVO group (adjusted risk difference, 2.3% [95% CI, -17.6% to 22.3%]; P =0.82). The interaction was marginally significant between groups ( P =0.06). In the non-LVO group, a lower proportion of bleeding events was found after DAPT treatment than intravenous alteplase (adjusted risk difference, -6.4% [95% CI, -8.9% to -3.9%]; P <0.001). Other safety outcomes were similar between the 2 treatments., Conclusions: Among minor nondisabling acute ischemic stroke without LVO, DAPT may be superior to intravenous alteplase regarding preventing END with a better safety profile., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03661411., Competing Interests: None.

Competing Interests: Dr Woo reports employment by the University of Cincinnati and grants from the National Institutes of Health. Dr Sansing reports grants from the American Heart Association, employment by Yale University School of Medicine, and grants from the National Institutes of Health. The other authors report no conflicts.

Background: Timely revascularization in acute arterial ischemic stroke (AIS) is paramount for optimal outcomes. However, factors causing treatment delays in pediatric AIS remain understudied. We investigated determinants affecting the time from symptom onset or last-known-well to the start of recanalization treatment in pediatric AIS., Methods: We conducted an ancillary analysis of the French KID-CLOT study (The National Retrospective Study of Recanalization Treatments in Pediatric Arterial Ischemic Stroke), considering patients with pediatric AIS receiving recanalization treatments (IV thrombolysis IVT and mechanical thrombectomy) from 2015 to 2018. The study assessed prehospital triage's impact, direct versus transferred admissions, and unit type (pediatric versus adult) on treatment delay and clinical outcomes using modified Rankin Scale at 1 year., Results: Among 68 patients (median age, 11 [IQR, 4-16]; initial PedNIHSS, 13 [IQR, 7-19]), treatment modalities were IVT (n=31), and mechanical thrombectomy (n=23), and IVT+mechanical thrombectomy (n=14). Prehospital triage significantly reduced last-known-well to treatment delay (overall, 229 versus 270 minutes; P =0.01), most notably for and mechanical thrombectomy ( P <0.001). There was no substantial delay difference between direct and transferred admissions, or between unit types, although a trend favored adult units (370.3 versus 436.73 minutes; P =0.06). Prehospital triage correlated with improved outcomes, with a shift to lower modified Rankin Scale scores ( P =0.021)., Conclusions: For pediatric AIS treated with reperfusion therapy, prehospital triage emerges as a pivotal factor in reducing treatment delays and enhancing outcomes. These findings underscore the need for a dedicated prehospital stroke protocol for children., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03887143., Competing Interests: None.

Competing Interests: None.

Background: Risk models to identify patients at high risk of asymptomatic carotid artery stenosis (ACAS) can help in selecting patients for screening, but long-term outcomes in these patients are unknown. We assessed the diagnostic and prognostic value of the previously published Prevalence of ACAS (PACAS) risk model to detect ACAS at baseline and to predict subsequent risk of stroke and cardiovascular disease (CVD) during follow-up., Methods: We validated the discrimination and calibration of the PACAS risk model to detect severe (≥70% narrowing) ACAS with patients from the Reduction of Atherothrombosis for Continued Health registry. We subsequently calculated the incidence rates of stroke and CVD (fatal and nonfatal stroke or myocardial infarction or vascular death) during follow-up in 4 risk groups (low, medium, high, and very high, corresponding to sum scores of ≤9, 10-13, 14-17, and ≥18, respectively)., Results: Among 26 384 patients, aged between 45 and 80 years, without prior carotid procedures, 1662 (6.3%) had severe baseline ACAS. During ≈70 000 patient-years of follow-up, 1124 strokes and 2484 CVD events occurred. Discrimination of the PACAS model was 0.67 (95% CI, 0.65-0.68), and calibration showed adequate concordance between predicted and observed risks of severe baseline ACAS after recalibration. Significantly higher incidence rates of stroke ( P trend <0.0001) during follow-up were found with increasing PACAS risk groups. Among patients with high PACAS sum score of ≥14 (corresponding to 27.7% of all patients), severe baseline ACAS prevalence was 11.4%. In addition, 56.6% of incident strokes and 64.9% of incident CVD events occurred in this group.P trend <0.0001) during follow-up were found with increasing PACAS risk groups. Among patients with high PACAS sum score of ≥14 (corresponding to 27.7% of all patients), severe baseline ACAS prevalence was 11.4%. In addition, 56.6% of incident strokes and 64.9% of incident CVD events occurred in this group., Conclusions: The PACAS risk model can reliably identify patients at high risk of severe baseline ACAS. Incidence rates of stroke and CVD during follow-up were significantly higher in patients with high PACAS sum scores. Selective screening of patients with high PACAS sum scores may help to prevent future stroke or CVD., Competing Interests: Dr Bhatt discloses the following relationships: advisory board: Angiowave, Bayer, Boehringer Ingelheim, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, and Stasys; board of directors: American Heart Association New York City, Angiowave (stock options), Bristol Myers Squibb (stock), DRS.LINQ (stock options), and High Enroll (stock); consultant: Broadview Ventures, Hims, SFJ, and Youngene; data monitoring committees: Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial [Portopulmonary Hypertension Treatment With Macitentan: A Randomized Clinical Trial], funded by St. Jude Medical, now Abbott), Boston Scientific (chair: the PEITHO trial [Pulmonary Embolism Thrombolysis]), Cleveland Clinic, Contego Medical (chair: PERFORMANCE 2 [Protection Against Emboli During Carotid Artery Stenting Using the Neuroguard IEP System]), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept Medical; for ALLAY-HF [Safety and Efficacy of the Alleviant System for No-Implant Interatrial Shunt Creation in Patients With Chronic Heart Failure], funded by Alleviant Medical), Novartis, Population Health Research Institute, and Rutgers University (for the National Institutes of Health-funded MINT trial [Myocardial Ischemia and Transfusion]); honoraria: American College of Cardiology (senior associate editor: Clinical Trials and News, ACC.org; chair: ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; the RE-DUAL PCI [Evaluation of Dual Therapy With Dabigatran vs Triple Therapy With Warfarin in Patients With AF That Undergo a PCI With Stenting] Clinical Trial Steering Committee funded by Boehringer Ingelheim; AEGIS-II [Study to Investigate CSL112 in Subjects With Acute Coronary Syndrome] Executive Committee funded by CSL Behring), Belvoir Publications (editor-in-chief: Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), CSL Behring (AHA lecture), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial [A Trial Comparing Cardiovascular Safety of Degarelix Versus Leuprolide in Patients With Advanced Prostate Cancer and Cardiovascular Disease], funded by Ferring Pharmaceuticals), HMP Global (editor-in-chief: Journal of Invasive Cardiology), Journal of the American College of Cardiology (guest editor, associate editor), K2P (co-chair: interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (Continuing Medical Education [CME] steering committees), MJH Life Sciences, Oakstone CME (course director: Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS [Cardiovascular Outcomes for People Using Anticoagulation Strategies] Operations Committee, Publications Committee, Steering Committee, and USA national coleader, funded by Bayer), WebMD (CME steering committees), and Wiley (steering committee); other: Clinical Cardiology (deputy editor); patent: Sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women’s Hospital that assigned to Lexicon; neither he nor Brigham and Women’s Hospital receive any income from this patent); research funding: Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Alnylam, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Otsuka, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, and 89Bio; royalties: Elsevier (editor: Braunwald’s Heart Disease); site coinvestigator: Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, and Vascular Solutions; trustee: American College of Cardiology; and unfunded research: FlowCo. Dr Steg discloses the following relationships: employment: Assistance Publique-Hôpitaux de Paris and Université Paris-Cité; research grants: Bayer; consulting: Amarin, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Janssen, Pfizer, PhaseBio, Novartis, NovoNordisk, Regeneron, Sanofi, and Servier; and patent issued as coinventor of use of alirocumab to reduce cardiovascular risk (patent assigned to Sanofi). The other authors report no conflicts.

Ischemic stroke is one of the leading causes of disability and mortality worldwide. Thrombosis is the main pathological process of stroke and is therefore an important therapeutic target in stroke prevention. In recent years, with the development of endovascular treatment and therefore retrieving the thrombus for further investigation, evidence is accumulating that immune cells are inextricably linked to stroke pathogenesis. Circulating immune cells have been found to induce immunothrombosis, and they actively participate in the formation of the thrombus by promoting platelet recruitment and thrombin activation. Additionally, the formation of thromboinflammation leads to increased instability of atherosclerotic plaques. We review the concepts of stroke immunothrombosis and thromboinflammation and the effect of immune cells on vessel recanalization and patient outcome. In addition, we elaborate on the possible mechanism of immune cells being activated and participating in thrombosis in ischemic stroke.

Background: Inflammation promotes atherogenesis. Randomized controlled trials of anti-inflammatory therapies for prevention after stroke have not yet demonstrated clear benefit. IL-6 (interleukin-6) and hsCRP (high-sensitivity C-reactive protein) are independently associated with major adverse cardiovascular events poststroke and may guide patient selection in future randomized controlled trials. Optimal timing of hsCRP/IL-6 measurement poststroke is unknown, as early blood levels may be confounded by the inflammatory response to brain infarction., Methods: Using individual-participant data from a systematic review, we performed a time-course analysis to investigate the association between hsCRP/IL-6 and recurrent events stratified by timing of sampling. The prespecified coprimary end points after sample measurement were: (1) recurrent major adverse cardiovascular events (first major coronary event, recurrent stroke, or vascular death) and (2) recurrent stroke (ischemic, hemorrhagic, or unspecified). The poststroke dynamics of IL-6/hsCRP were analyzed by plotting their median (interquartile interval) concentrations within each tenth of the sampling timeframe. Acute/postacute phases were defined for each biomarker according to the shape of this relationship., Results: There were data for 9798 patients from 11 studies (19 891 person-years follow-up, 10 observational cohorts, and 1 randomized trial). Each marker was measured once. IL-6 was markedly elevated <24 hours poststroke compared with postacute levels (≥24 hours; 11.6 versus 3.02 pg/mL; P <0.001). HsCRP was elevated for 10 days. IL-6 was associated with recurrent major adverse cardiovascular events in the postacute phase (≥24 hours; risk ratio, 1.30 [CI, 1.19-1.41], per unit log e IL-6), but not in the acute phase (<24 hours; risk ratio, 1.10 [CI, 0.98-1.25]; P interaction unit (risk ratio, 1.16 [CI, 1.05-1.66]) and per quarter increase (risk ratio, 1.55 [CI, 1.19-2.02]; Q4 versus Q1), but not if measured acutely. Similar findings were observed for recurrent stroke. There was no evidence of time-dependent interaction with hsCRP.e unit (risk ratio, 1.16 [CI, 1.05-1.66]) and per quarter increase (risk ratio, 1.55 [CI, 1.19-2.02]; Q4 versus Q1), but not if measured acutely. Similar findings were observed for recurrent stroke. There was no evidence of time-dependent interaction with hsCRP., Conclusions: Timing of sample measurement after stroke modifies the association with recurrent major adverse cardiovascular events for IL-6 but not hsCRP. These data inform future randomized controlled trial designs incorporating biomarker-based selection of patients for anti-inflammatory therapies.

Background: Sex critically determines stroke pathophysiology and recovery. To reveal potential gaps in stroke care, we analyzed sex-specific differences in the stroke patient hospital admission and treatment process., Methods: In this single-center retrospective analysis, we screened all patients referred to our stroke center between 2014 and 2020 with suspicion of stroke (n=7112). Patients with different cerebrovascular events and stroke mimics were included. We collected demographic hospitalization and 90-day follow-up data and stratified results according to sex. In a logistic regression analysis for 90-day functional outcome, we estimated the effect of sex corrected for the clinically most relevant confounders., Results: Of 7102 patients, 56.7% were male and 43.3% female. Women were older (median, 76.3 years; interquartile range (IQR), 64-84, versus 70.7; IQR, 59-79; P <0.001), and lived more often in nursing homes before the event (10.5% versus 3.8%; P <0.001). Among patients with acute ischemic stroke (n=4515), women had more often a large vessel occlusion (38.6% versus 34.8%; P =0.015), a higher stroke severity (National Institutes of Health Stroke Scale score, 4; IQR, 1-12 versus 3; IQR, 1-8; P <0.001), and were treated more often with endovascular treatment (21.4% versus 17.3%; P =0.001). Onset-to-door, onset-to-treatment, and door-to-treatment times were significantly longer in women. A favorable 90-day functional outcome (modified Rankin Scale score 0-2) occurred more often in men (73.9% versus 64.9%; P <0.001). When correcting for confounders in a multivariable logistic regression, age, admission National Institutes of Health Stroke Scale, and prestroke modified Rankin Scale remained highly ( P <0.001), large vessel occlusion and arterial hypertension moderately significant predictors for 90-day functional outcome ( P <0.05), whereas female sex was not. This could be confirmed when analyzing different patient age groups separately in multivariable logistic regression subgroup analyses. An interaction-term analysis revealed no additional association between age and female sex (OR, 0.99; P =0.815)., Conclusions: Although treatment and outcome parameters seem to be in favor of men, most can be explained by older age, poorer prestroke independence, higher stroke severity, and more large vessel occlusion in women. Sex was not independently associated with worse 90-day functional outcome in women.

The quotation, attributed to Confucius many centuries ago, in our opinion, applies to the evolving story of defining a primary surgical treatment for spontaneous intracerebral hemorrhage. The precise quote is: "Keep it simple and focus on what matters. Don't let yourself be overwhelmed." 1 The evidence from multiple trials on intracerebral hemorrhage regarding mortality benefit and potential functional benefit directs us toward the simple task of evacuating the clot, similar to our prime focus on opening the artery in ischemic stroke. We need not be overwhelmed by questions about adjustments to patient selection, comparative techniques, and precision timing, for which we do not have conclusive data. We review the consensus results from the recent MISTIE trial (Minimally Invasive Surgery Plus Alteplase in ICH Evacuation) and ENRICH trial (Early Minimally Invasive Removal of Intracerebral Hemorrhage) and articulate remaining questions where further evidence is needed to challenge equipoise and define future practice.

Historically, the management of carotid artery disease has primarily focused on the degree of stenosis as the main indicator for assessing stroke etiology, risk, and need for intervention. However, accumulating evidence suggests that structural and biological features within the arterial wall, such as intraplaque hemorrhage, may have superior diagnostic, prognostic, and therapeutic values. Under current guidelines, unless an atheroma results in ≥50% stenosis, it is not considered the cause of a cerebrovascular event. This results in extensive and often unproductive diagnostic workup, prescription of ineffective medical therapy, and preclusion of patients from receiving revascularization procedures that have been shown to prevent recurrent cerebrovascular events in cases of ≥50% stenosis. A subset of embolic strokes of undetermined source, which account for up to 25% of all ischemic cerebrovascular events, are thought to be due to thromboembolic phenomena from undiagnosed plaque disruptions in nonstenotic arteries (<50% stenosis). Recently, it has been proposed to reclassify this subgroup of patients as symptomatic nonstenotic carotid if the carotid plaque ipsilateral to the cerebrovascular event presents with high-risk features including intraplaque hemorrhage, lipid-rich necrotic core, thinning/rupture of the fibrous cap, and ulceration. In this review, we first provide a historical overview of the chain of events and circumstances that resulted in the present management of carotid artery disease. Second, we embed the contemporary biomarkers of plaque vulnerability in a modern mechanistic paradigm of carotid plaque disruption and thromboembolization. Third, we review the clinically available imaging tools to detect these biomarkers, and how their use has started to shed light on the prevalence and natural history of this underdiagnosed condition. Fourth, we review recent clinical studies employing a contemporary definition of symptomatic nonstenotic carotid and discuss targeted treatments for this condition. Finally, we make a case to generate the much-needed high-level evidence to align the clinical management of patients with symptomatic nonstenotic carotid with a contemporary understanding of plaque disruption and thromboembolization.

Telemedicine for stroke (Telestroke) has been a key component to efficient, widespread acute stroke care for many years. The expansion of reimbursement through the Furthering Access to Stroke Telemedicine Act and rapid deployment of telemedicine resources during the COVID-19 public health emergency have further expanded remote care, with practitioners of varying educational backgrounds, and experience providing acute stroke care via telemedicine (Telestroke). Some Telestroke practitioners have not had fellowship-level vascular neurology training and many are without training specific to virtual modalities. While many vascular neurology fellowship programs incorporate Telestroke training into the curriculum, components of this curriculum are not consistent, extent of involvement is variable, and not all fellows receive hands-on training in remote care. Furthermore, the extent of training and evaluation of Telestroke in American Board of Psychiatry and Neurology training requirements and Accreditation Council for Graduate Medical Education assessments for vascular neurology fellowship are not standardized. We suggest that Telestroke be formally incorporated into vascular neurology fellowship curricula and provide considerations for key components of this training and metrics for evaluation.

Randomized trials in stroke often focus on outcomes beyond a single clinical event. Trials of stroke prevention commonly use composite outcomes that include multiple components (eg, death, stroke, or myocardial infarction). A major limitation is that all events count equally but may differ markedly in terms of clinical severity. Trials in acute stroke often use ordinal outcomes or scale scores. Limitations include the requirement for statistical assumptions and the difficulty of handling the competing risk of death. We introduce the win ratio as an alternative method. It works by placing components of a composite into a hierarchy, whereby clinically more important outcomes take priority over less important ones. We illustrate how it works using data from 2 major stroke trials: the ICSS (International Carotid Stenting Study, a trial in stroke prevention) and the MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands). Potential benefits of the win ratio approach include the possibility to (1) emphasize the clinically most important outcomes, (2) combine components of different outcome types into a composite (eg, a mixture of time-to-event, continuous, and categorical), and (3) naturally handle the competing risk of death in analyses of quantitative outcomes. The win ratio will be used in the upcoming analysis of the ECST-2 (Second European Carotid Surgery Trial), which has a hierarchical primary outcome of (1) time to perioperative death, fatal stroke, or fatal myocardial infarction (most important); (2) time to nonfatal stroke; (3) time to nonfatal myocardial infarction (excluding silent infarcts); and (4) new silent cerebral infarct on brain imaging (least important). The win ratio provides a useful clinically relevant method for analyzing trial outcomes. It has some advantages over conventional methods, and we recommend its wider application in future stroke trials.

Background: Ischemic stroke is a leading cause of death and disability. Society guidelines recommend pharmacotherapies for secondary stroke prevention. However, the role of sex differences in prescription and adherence to guideline-directed medical therapies (GDMT) after ischemic stroke remains understudied. The aim of this study was to examine sex differences in prescription and adherence to GDMT at 1-year after ischemic stroke in a cohort of commercially insured patients. Methods: Using the Truven Health MarketScan database from 2016-2020, we identified patients admitted with ischemic stroke. GDMT was defined as any statin, antihypertensive, and anticoagulant prescription within 30-days after discharge. Medication adherence was estimated using the proportion of days covered (PDC) at 1-year. PDC <0.80 was used to define non-adherence. A multivariable model adjusting for covariates was performed to identify the factors associated with non-adherence at 1-year. This analysis was restricted to new users of GDMT. Results: Among 155220 patients admitted with acute ischemic stroke during the study period, 15,919 met the inclusion criteria. The mean age was 55.7 years, and 7,701 (48.3%) were women. Women were less likely prescribed statins (58.0% vs 71.8%), and antihypertensives (27.7% vs 41.8%). In this subset of patients with atrial flutter/fibrillation, women were also less likely prescribed anticoagulants (41.2% vs 45.0%). Women were more likely to be non-adherent (i.e., PDC <0.80) to statins (47.3% vs 41.6%, P<0.0001), antihypertensives (33.3% vs 32.2%, P=0.005), and the combination of both (49.6% vs 45.0%, P=0.003). On multivariable analysis, women were likely to be non-adherent to GDMT at 1-year (odds ratio 1.23, 95% confidence interval 1.08-1.41). Conclusions: In this real-world analysis of commercially insured patients with ischemic stroke, women were less likely initiated on GDMT within 30 days after discharge. Women were more likely to be non-adherent to statins and antihypertensive agents at 1-year. Future efforts and novel interventions are needed to understand the reasons and minimize these disparities.

Background: Branch atheromatous disease (BAD)-related stroke has emerged as a meaningful subtype of ischemic stroke yet remained understudied. We aimed to investigate the demographic, clinical, therapeutic, and prognostic characteristics of BAD-related stroke., Methods: The BAD-study was a nationwide, multicenter, prospective, observational cohort study in 20 Chinese hospitals from June 2021 to June 2023, enrolling patients aged 18 to 80 years with BAD-related stroke within 72 hours of onset. Eligible single subcortical infarct in the territory of lenticulostriate artery and paramedian pontine artery was included. Clinical, laboratory, and treatment data were collected at baseline. The primary outcome was a proportion of good outcomes (modified Rankin Scale score, 0-2) at 90 days. Main secondary outcomes included early neurological deterioration (END), cerebrovascular event, major bleeding, and excellent outcome (modified Rankin Scale score, 0-1) during 90-day follow-up., Results: We finally enrolled 476 patients, with a median age of 60 (interquartile range, 53-68) years, and 70.2% were male. The median National Institutes of Health Stroke Scale score was 3 (interquartile range, 2-6) at enrollment. Involvement of the lenticulostriate artery was more common than the paramedian pontine artery (60.7% versus 39.3%). END occurred in 14.7% of patients, with a median time from onset of 38 (interquartile range, 22-62) hours. The rates of good and excellent outcomes were 86.5% and 72%, respectively. Its 90-day stroke recurrence rate was 1.9%. Acute-phase therapy (from onset to 7 days of enrollment) showed heterogeneity and was not associated with prognosis. Multivariable logistic regression analysis identified the National Institutes of Health Stroke Scale score ≥4 at admission and END as negative predictors and extracranial artery stenosis as a positive predictor of good outcomes. Age ≥60 years, National Institutes of Health Stroke Scale score ≥4 at admission, and END were negative predictors of excellent outcomes., Conclusions: With distinct demographic, clinical, and prognostic characteristics, along with a high incidence of END and a low risk of stroke recurrence, BAD-related stroke could be categorized as a separate disease entity. Moreover, its acute-phase treatment strategies were undetermined, awaiting further high-quality studies., Competing Interests: None.