Statin Overuse in Cerebral Ischemia Without Indications: Systematic Review and Annual US Burden of Adverse Events.

BACKGROUND: Statin agents play a major role in secondary prevention after acute cerebral ischemia (ACI) events but are not indicated in all patients with ischemic stroke and transient ischemic attack. National guidelines recommend statins for patients with ACI of large or small vessel atherosclerotic origin and without these stroke mechanisms but coexisting coronary artery disease or primary prevention indications. The potential adverse effect burden of statin overuse in the remaining ACI patients have not been well delineated. METHODS: Per Preferred Reporting Items of Systematic Reviews and Meta-Analyses guidelines, we performed systematic meta-analyses of: (1) statin randomized clinical trials to determine absolute risk increases for 6 major adverse events; (2) large clinical series to determine the proportion of ACI events due to large or small vessel atherosclerotic disease; and (3) the proportion of remaining patients with coronary artery disease/primary prevention statin indications. RESULTS: For adverse effects, data were available from 63 randomized clinical trials enrolling 155 107 patients. Statin therapy was associated with an increased risk of the occurrence of 6 conditions: diabetes, myalgia or muscle weakness, myopathy, liver disease, renal insufficiency, and eye disease. Across 55 large series enrolling 53 501 patients, the rate of ACI due to large and small artery atherosclerosis was 45.0% (large artery atherosclerosis 21.6%, small vessel disease 23.4%), the rate of remaining patients with coronary artery disease/primary prevention statin indications was 31.8%, and the rate of patients without statin indications was 23.2%. Data synthesis indicated that, in the United States, were all patients with ACI without statin indications treated with statins, a total of 5601 patients would develop needless adverse events each year, most commonly diabetes, myopathy, and eye disease. CONCLUSIONS: More than one-fifth of patients with ACI do not have an indication for statins, and statin overuse in these patients could annually lead to over 5600 adverse events each year in the United States, including diabetes, myopathy, and eye disease. These findings emphasize the importance of adhering to guideline indications for the start of statin therapy in ACI.

Efficacy and safety of Ferrous iron on the prevention of Vascular cOgnitive impaiRment among patients with cerebral Infarction/TIA (FAVORITE): rationale and design of a multicentre randomised trial.

BACKGROUND: The incidence of vascular cognitive impairment (VCI) is high in patients suffering from ischaemic stroke or transient ischaemic attack (TIA) or with vascular risk factors. Effective prevention strategies for VCI remain limited. Anaemia or low haemoglobin was found as an independent risk factor for adverse outcomes after acute stroke. Anaemia or low haemoglobin was possibly associated with an increased risk of poststroke cognitive impairment. Whether supplement of ferrous iron to correct anaemia reduces the risk of VCI and improves adverse outcomes in patients with ischaemic cerebrovascular disease remains uncertain. AIM: We aim to introduce the design and rationale of the safety and efficacy of Ferrous iron on the prevention of Vascular cOgnitive impaiRment in patients with cerebral Infarction or TIA (FAVORITE) trial. DESIGN: FAVORITE is a randomised, placebo-controlled, double-blind, multicentre trial that compares supplement of ferrous iron with placebo for recent minor stroke/TIA patients complicated with mild anaemia or iron deficiency: Ferrous succinate sustained-release tablet 0.2 g (corresponding to 70 mg of elemental iron) once daily after or during breakfast for 12 weeks or placebo with much the same colour, smell and size as ferrous iron once daily during or after breakfast for 12 weeks. All paticipants will be followed within the next year. STUDY OUTCOMES: The primary effective outcome is the incidence of VCI at 3 months after randomisation and the primary safety outcome includes any gastrointestinal adverse event during 3 months. DISCUSSION: The FAVORITE trial will clarify whether supplement of ferrous iron to correct low haemoglobin reduces the risk of VCI in patients with recent ischaemic stroke or TIA complicated with mild anaemia or iron deficiency compared with placebo. TRIAL REGISTRATION NUMBER: NCT03891277.

Delta opioid peptide [D-ala2, D-leu5]-Enkephalin's ability to enhance mitophagy via TRPV4 to relieve ischemia/reperfusion injury in brain microvascular endothelial cells.

BACKGROUND: Local brain tissue can suffer from ischaemia/reperfusion (I/R) injury, which lead to vascular endothelial damage. The peptide δ opioid receptor (δOR) agonist [D-ala2, D-leu5]-Enkephalin (DADLE) can reduce apoptosis caused by acute I/R injury in brain microvascular endothelial cells (BMECs). OBJECTIVE: This study aims to explore the mechanism by which DADLE enhances the level of mitophagy in BMECs by upregulating the expression of transient receptor potential vanilloid subtype 4 (TRPV4). METHODS: BMECs were extracted and made to undergo oxygen-glucose deprivation/reoxygenation (OGD/R) accompanied by DADLE. RNA-seq analysis revealed that DADLE induced increased TRPV4 expression. The CCK-8 method was used to assess the cellular viability; quantitative PCR (qPCR) was used to determine the mRNA expression of Drp1; western blot was used to determine the expression of TRPV4 and autophagy-related proteins; and calcium imaging was used to detect the calcium influx. Autophagosomes in in the cells' mitochondria were observed by using transmission electron microscopy. ELISA was used to measure ATP content, and a JC-1 fluorescent probe was used to detect mitochondrial membrane potential. RESULTS: When compared with the OGD/R group, OGD/R+DADLE group showed significantly enhanced cellular viability; increased expression of TRPV4, Beclin-1, LC3-II/I, PINK1 and Parkin; decreased p62 expression; a marked rise in calcium influx; further increases in mitophagy, an increase in ATP synthesis and an elevation of mitochondrial membrane potential. These protective effects of DADLE can be blocked by a TRPV4 inhibitor HC067047 or RNAi of TRPV4. CONCLUSION: DADLE can promote mitophagy in BMECs through TRPV4, improving mitochondrial function and relieving I/R injury.

Ninety-Day Stroke Recurrence in Minor Stroke: Systematic Review and Meta-Analysis of Trials and Observational Studies.

BACKGROUND: Risk of recurrence after minor ischemic stroke is usually reported with transient ischemic attack. No previous meta-analysis has focused on minor ischemic stroke alone. The objective was to evaluate the pooled proportion of 90-day stroke recurrence for minor ischemic stroke, defined as a National Institutes of Health Stroke Scale severity score of ≤5. METHODS AND RESULTS: Published papers found on PubMed from 2000 to January 12, 2021, reference lists of relevant articles, and experts in the field were involved in identifying relevant studies. Randomized controlled trials and observational studies describing minor stroke cohort with reported 90-day stroke recurrence were selected by 2 independent reviewers. Altogether 14 of 432 (3.2%) studies met inclusion criteria. Multilevel random-effects meta-analysis was performed. A total of 6 randomized controlled trials and 8 observational studies totaling 45 462 patients were included. The pooled 90-day stroke recurrence was 8.6% (95% CI, 6.5-10.7), reducing by 0.60% (95% CI, 0.09-1.1; P=0.02) with each subsequent year of publication. Recurrence was lowest in dual antiplatelet trial arms (6.3%, 95% CI, 4.5-8.0) when compared with non-dual antiplatelet trial arms (7.2%, 95% CI, 4.7-9.6) and observational studies 10.6% (95% CI, 7.0-14.2). Age, hypertension, diabetes, ischemic heart disease, or known atrial fibrillation had no significant association with outcome. Defining minor stroke with a lower National Institutes of Health Stroke Scale threshold made no difference - score ≤3: 8.6% (95% CI, 6.0-11.1), score ≤4: 8.4% (95% CI, 6.1-10.6), as did excluding studies with n<500%-7.3% (95% CI, 5.5-9.0). CONCLUSIONS: The risk of recurrence after minor ischemic stroke is declining over time but remains important.

Subtype-Specific Association of Mitochondrial DNA Copy Number With Poststroke/TIA Outcomes in 10†241 Patients in China.

BACKGROUND: Mitochondrial DNA copy number (mtDNA-CN) is associated with the severity and mortality in patients with stroke, but the associations in different stroke subtypes remain unexplored. METHODS: We conducted an observational prospective cohort analysis on patients with ischemic stroke or transient ischemic attack enrolled in the Third China National Stroke Registry. We applied logistic models to assess the association of mtDNA-CN with functional outcome (modified Rankin Scale score, 3-6 versus 0-2) and Cox proportional hazard models to assess the association with stroke recurrence (treating mortality as a competing risk) and mortality during a 12-month follow-up, adjusting for sex, age, physical activity, National Institutes of Health Stroke Scale at admission, history of stroke and peripheral artery disease, small artery occlusion, and interleukin-6. Subgroup analyses stratified by age and stroke subtypes were conducted. RESULTS: The Third China National Stroke Registry enrolled 15 166 patients, of which 10 241 with whole-genome sequencing data were retained (mean age, 62.2 [SD, 11.2] years; 68.8% men). The associations between mtDNA-CN and poststroke/transient ischemic attack outcomes were specific to patients aged ≤65 years, with lower mtDNA-CN significantly associated with stroke recurrence in 12 months (subdistribution hazard ratio, 1.15 per SD lower mtDNA-CN [95% CI, 1.04-1.27]; P=5.2×10-3) and higher all-cause mortality in 3 months (hazard ratio, 2.19 [95% CI, 1.41-3.39]; P=5.0×10-4). Across subtypes, the associations of mtDNA-CN with stroke recurrence were specific to stroke of undetermined cause (subdistribution hazard ratio, 1.28 [95% CI, 1.11-1.48]; P=6.6×10-4). In particular, lower mtDNA-CN was associated with poorer functional outcomes in stroke of undetermined cause patients diagnosed with embolic stroke of undetermined source (odds ratio, 1.53 [95% CI, 1.20-1.94]; P=5.4×10-4), which remained significant after excluding patients with recurrent stroke (odds ratio, 1.49 [95% CI, 1.14-1.94]; P=3.0×10-3). CONCLUSIONS: Lower mtDNA-CN is associated with higher stroke recurrence rate and all-cause mortality, as well as poorer functional outcome at follow-up, among stroke of undetermined cause, embolic stroke of undetermined source, and younger patients.

Low-intensity focused ultrasound stimulation promotes stroke recovery via astrocytic HMGB1 and CAMK2N1 in mice.

BACKGROUND: Low-intensity focused ultrasound stimulation (LIFUS) has been developed to enhance neurological repair and remodelling during the late acute stage of ischaemic stroke in rodents. However, the cellular and molecular mechanisms of neurological repair and remodelling after LIFUS in ischaemic stroke are unclear. METHODS: Ultrasound stimulation was treated in adult male mice 7 days after transient middle cerebral artery occlusion. Angiogenesis was measured by laser speckle imaging and histological analyses. Electromyography and fibre photometry records were used for synaptogenesis. Brain atrophy volume and neurobehaviour were assessed 0-14 days after ischaemia. iTRAQ proteomic analysis was performed to explore the differentially expressed protein. scRNA-seq was used for subcluster analysis of astrocytes. Fluorescence in situ hybridisation and Western blot detected the expression of HMGB1 and CAMK2N1. RESULTS: Optimal ultrasound stimulation increased cerebral blood flow, and improved neurobehavioural outcomes in ischaemic mice (p<0.05). iTRAQ proteomic analysis revealed that the expression of HMGB1 increased and CAMK2N1 decreased in the ipsilateral hemisphere of the brain at 14 days after focal cerebral ischaemia with ultrasound treatment (p<0.05). scRNA-seq revealed that this expression pattern belonged to a subcluster of astrocytes after LIFUS in the ischaemic brain. LIFUS upregulated HMGB1 expression, accompanied by VEGFA elevation compared with the control group (p<0.05). Inhibition of HMGB1 expression in astrocytes decreased microvessels counts and cerebral blood flow (p<0.05). LIFUS reduced CAMK2N1 expression level, accompanied by increased extracellular calcium ions and glutamatergic synapses (p<0.05). CAMK2N1 overexpression in astrocytes decreased dendritic spines, and aggravated neurobehavioural outcomes (p<0.05). CONCLUSION: Our results demonstrated that LIFUS promoted angiogenesis and synaptogenesis after focal cerebral ischaemia by upregulating HMGB1 and downregulating CAMK2N1 in a subcluster of astrocytes, suggesting that LIFUS activated specific astrocyte subcluster could be a key target for ischaemic brain therapy.

Baseline Stroke Risk and Efficacy of Dual-Antiplatelet Therapy: A Post Hoc Analysis of the POINT Trial.

BACKGROUND: High-risk transient ischemic attacks and minor ischemic strokes are followed by a variable risk of ischemic stroke. We aimed to determine how baseline stroke risk modified the efficacy of clopidogrel-aspirin (referred to here as dual-antiplatelet therapy [DAPT]) for transient ischemic attack and minor ischemic stroke. METHODS: We performed an unplanned secondary analysis of the POINT trial (Platelet-Oriented Inhibition in New Transient Ischemic Attack and Minor Ischemic Stroke). We first evaluated the associations of the CHA2DS2-VASc and stroke prognosis instrument II (SPI-II) scores with the risk of incident ischemic stroke and major hemorrhage (intracranial hemorrhage or major systemic hemorrhage). We then tested for heterogeneity of the relative and absolute treatment effect of DAPT relative to aspirin across low- and high-risk patient subgroups. RESULTS: A total of 4841 trial participants were included in this analysis, with 2400 participants assigned to treatment with short-term DAPT and 2430 participants to treatment with aspirin and placebo. The dichotomized SPI-II score, but not the CHA2DS2-VASc score (P=0.18), was associated with the risk of incident ischemic stroke. A high-risk SPI-II score (>3) was associated with greater risk of incident ischemic stroke (hazard ratio of incident ischemic stroke relative to low-risk SPI-II score of 1.84 [95% CI, 1.44-2.35]; P<0.001) and numerically greater risk of major hemorrhage though not meeting statistical significance (hazard ratio, 1.80 [95% CI, 0.90-3.57]; P=0.10). The relative risk reduction with DAPT was similar across SPI-II strata (Pinteraction=0.31). The absolute risk reduction for ischemic stroke with DAPT compared with aspirin was nearly 4-fold higher (2.80% versus 0.76%; number needed to treat, 31 versus 131) in the high-risk SPI-II stratum relative to the low-risk stratum. The absolute risk increase for major hemorrhage with DAPT compared with aspirin was 3-fold higher (0.84% versus 0.30%; number needed to harm, 119 versus 331) in the high-risk SPI-II stratum relative to the low-risk stratum. CONCLUSIONS: Stratification by baseline stroke risk identifies a patient subgroup that derives greater absolute benefit from treatment with DAPT. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00991029.

Real-world analysis of two ischaemic stroke and TIA systolic blood pressure goals on 12-month mortality and recurrent vascular events.

INTRODUCTION: Whether obtaining the more intensive goal systolic blood pressure (SBP) of <130 mm Hg, rather than a less intensive SBP goal of <140 mm Hg poststroke/transient ischaemic attack (TIA) is associated with incremental mortality and recurrent vascular event benefit is largely unexplored using real-world data. Lowering SBP excessively may result in poorer outcomes. METHODS: This is a retrospective cohort study of 26 368 Veterans presenting to a Veterans Administration Medical Center (VAMC) with a stroke/TIA between October 2015 and July 2018. Patients were excluded from the study if they had missing or extreme BP values, receiving dialysis or palliative care, left against medical advice had a cancer diagnosis, were cared for in a VAMC enrolled in a stroke/TIA quality improvement initiative, died or had a cerebrovascular or cardiovascular event within 90 days after their index stroke/TIA. The analytical sample included 12 337 patients. Average SBP during 90 days after discharge was assessed in categories (≤105 mm Hg, 106-115 mm Hg, 116-130 mm Hg, 131-140 mm Hg and >140 mm Hg). Separate multivariable Cox proportional hazard regressions were used to examine the relationship between average SBP groups and time to: (1) mortality and (2) any recurrent vascular event, from 90 days to up to 365 days after discharge from the index emergency department visit or inpatient admission. RESULTS: Compared with those with SBP>140 mm Hg, patients with SBP between 116 and 130 mm Hg had a significantly lower risk of recurrent stroke/TIA (HR 0.77, 95% CI 0.60 to 0.99) but not cardiovascular events. Patients with SBP lower than 105 mm Hg, compared with those with >140 mm Hg demonstrated a statistically significant higher risk of death (HR 2.07, 95% CI 1.43 to 3.00), but no statistical differences were found in other SBP groups. DISCUSSION: Data support a more intensive SBP goal to prevent recurrent cerebrovascular events among stroke/TIA patients by 90 days poststroke/TIA compared with less intensive goal. Very low SBPs were associated with increased mortality risk.

Outcomes associated to the time to treatment with intravenous tenecteplase for acute ischaemic stroke: subgroup analysis of the TRACE-2 randomised controlled clinical trial.

BACKGROUND: The benefit of intravenous alteplase in acute ischaemic stroke (AIS) is time-dependent. Tenecteplase is non-inferior to alteplase among patients with AIS. We aimed to delineate the association of the stroke onset to treatment time (OTT) with tenecteplase compared with alteplase on therapeutic benefit and clinical risks. METHODS: This is a post hoc analysis of the Tenecteplase Reperfusion therapy in Acute ischaemic Cerebrovascular Events-2 an open-label, randomised, controlled, non-inferior trial. A total of 1430 AIS within 4.5 hours onset at 53 sites in China from 12 June 2021 to 29 May 2022 were randomly assigned (1:1) to receive either tenecteplase 0.25 mg/kg or alteplase 0.9 mg/kg. The primary efficacy outcome was the proportion of participants with a modified Rankin Scale score of 0-1 at 90 days. A post hoc subgroup analysis was conducted with the OTT divided into three intervals (0-90 min, 91-180 min and 181-270 min). The primary safety outcome was symptomatic intracranial haemorrhage within 36 hours post-thrombolytic treatment. RESULTS: Treatment was initiated within 270 min of stroke onset in 1412 patients who were randomly allocated to either tenecteplase (n=707) or alteplase (n=705). The OR of primary efficacy outcome was similar as OTT increased (p=0.84). Adjusted odds of an excellent functional outcome were 0.99 (95% CI 0.37 to 2.67) for 0-90 min, 1.23 (95% CI 0.88 to 1.71) for 91-180 min and 1.21 (95% CI 0.88 to 1.65) for 181-270 min. All were in favour of the tenecteplase group. Meta-analysis of 2949 patients yielded a pooled risk difference of 5.54 (95% CI -0.18 to 11.26; p=0.82) in favour of tenecteplase for more than 180 min and 1.77 (95% CI -2.66 to 6.20; p=0.58) for 0-180 min. CONCLUSIONS: In AIS patients who were treated with either tenecteplase or alteplase within 4.5 hours onset, there was no difference observed in the efficacy and safety between the two groups at the three different OTT time intervals.

Early anticoagulation in patients with stroke and atrial fibrillation is associated with fewer ischaemic lesions at 1 month: the ATTUNE study.

BACKGROUND: The optimal time to commence anticoagulation in patients with atrial fibrillation (AF) after ischaemic stroke or transient ischaemic attack (TIA) is unclear, with guidelines differing in recommendations. A limitation of previous studies is the focus on clinically overt stroke, rather than radiologically obvious diffusion-weighted imaging ischaemic lesions. We aimed to quantify silent ischaemic lesions and haemorrhages on MRI at 1 month in patients commenced on early (<4 days) vs late (≥4 days) anticoagulation. We hypothesised that there would be fewer ischaemic lesions and more haemorrhages in the early anticoagulant group at 1-month MRI. METHODS: A prospective multicentre, observational cohort study was performed at 11 Australian stroke centres. Clinical and MRI data were collected at baseline and follow-up, with blinded imaging assessment performed by two authors. Timing of commencement of anticoagulation was at the discretion of the treating stroke physician. RESULTS: We recruited 276 patients of whom 208 met the eligibility criteria. The average age was 74.2 years (SD±10.63), and 79 (38%) patients were female. Median National Institute of Health Stroke Scale score was 5 (IQR 1-12). Median baseline ischaemic lesion volume was 5 mL (IQR 2-17). There were a greater number of new ischaemic lesions on follow-up MRI in patients commenced on anticoagulation ≥4 days after index event (17% vs 8%, p=0.04), but no difference in haemorrhage rates (22% vs 32%, p=0.10). Baseline ischaemic lesion volume of ≤5 mL was less likely to have a new haemorrhage at 1 month (p=0.02). There was no difference in haemorrhage rates in patients with an initial ischaemic lesion volume of >5 mL, regardless of anticoagulation timing. CONCLUSION: Commencing anticoagulation <4 days after stroke or TIA is associated with fewer ischaemic lesions at 1 month in AF patients. There is no increased rate of haemorrhage with early anticoagulation. These results suggest that early anticoagulation after mild-to-moderate acute ischaemic stroke associated with AF might be safe, but randomised controlled studies are needed to inform clinical practice.

Atherosclerosis-related biomarker PABPC1 predicts pan-cancer events.

BACKGROUND: Atherosclerosis (AS) and tumours are the leading causes of death worldwide and share common risk factors, detection methods and molecular markers. Therefore, searching for serum markers shared by AS and tumours is beneficial to the early diagnosis of patients. METHODS: The sera of 23 patients with AS-related transient ischaemic attack were screened by serological identification of antigens through recombinant cDNA expression cloning (SEREX), and cDNA clones were identified. Pathway function enrichment analysis was performed on cDNA clones to identify their biological pathways and determine whether they were related to AS or tumours. Subsequently, gene-gene and protein-protein interactions were performed and AS-associated markers would be discovered. The expression of AS biomarkers in human normal organs and pan-cancer tumour tissues were explored. Then, immune infiltration level and tumour mutation burden of various immune cells were evaluated. Survival curves analysis could show the expression of AS markers in pan-cancer. RESULTS: AS-related sera were screened by SEREX, and 83 cDNA clones with high homology were obtained. Through functional enrichment analysis, it was found that their functions were closely related to AS and tumour functions. After multiple biological information interaction screening and the external cohort validating, poly(A) binding protein cytoplasmic 1 (PABPC1) was found to be a potential AS biomarker. To assess whether PABPC1 was related to pan-cancer, its expression in different tumour pathological stages and ages was screened. Since AS-associated proteins were closely related to cancer immune infiltration, we investigated and found that PABPC1 had the same role in pan-cancer. Finally, analysis of Kaplan-Meier survival curves revealed that high PABPC1 expression in pan-cancer was associated with high risk of death. CONCLUSIONS: Through the findings of SEREX and bioinformatics pan-cancer analysis, we concluded that PABPC1 might serve as a potential biomarker for the prediction and diagnosis of AS and pan-cancer.

Association Between CYP2B6 Polymorphisms and Efficacy of Clopidogrel in Minor Stroke or Transient Ischemic Attack.

BACKGROUND: CYP2B6 (cytochrome P450 subfamily IIB polypeptide 6), encoded by the CYP2B6 gene, is a critical enzyme involved in clopidogrel metabolism. However, the association between CYP2B6 polymorphisms and the efficacy of clopidogrel in minor stroke or transient ischemic attack for secondary stroke prevention remains unclear. METHODS: Based on CHANCE (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events) randomized clinical trial of aspirin plus clopidogrel versus aspirin alone, we investigated the role of CYP2B6 polymorphisms and the efficacy of clopidogrel in patients with minor stroke or transient ischemic attack in China from October 2009 to July 2012. A total of 2853 patients were successfully genotyped for CYP2B6-516G>T, rs3745274 and CYP2B6-1456 T>C, rs2054675. The primary efficacy and safety outcomes were new stroke and any bleeding within 90 days. RESULTS: Among the 2853 patients, 32.8% were identified as the carriers of the CYP2B6-516 GT/TT or -1456 TC/CC genotype. The incidences of 90-day new stroke in aspirin plus clopidogrel and aspirin alone groups were 7.1% versus 11.3% among noncarriers, respectively; and 9.7% versus 12.2% among carriers, respectively. The efficacy of aspirin plus clopidogrel versus aspirin alone was not significantly different (P interaction=0.29) in noncarriers (adjusted hazard ratio, 0.61 [95% CI, 0.45-0.83]) compared to carriers (adjusted hazard ratio, 0.80 [95% CI, 0.54-1.18]). The incidence (n=51) of 90-day any bleeding in aspirin plus clopidogrel and aspirin alone groups were 2.2% (21 bleeds) versus 1.9% (18 bleeds) among noncarriers (adjusted hazard ratio, 1.11 [95% CI, 0.59-2.09]) and 1.9% (9 bleeds) versus 0.7% (3 bleeds) among carriers (adjusted hazard ratio, 3.23 [95% CI, 0.86-12.12]). Similar findings were observed during the 1-year follow-up. CONCLUSIONS: In this post hoc analysis of the CHANCE trial, we did not observe a significant difference in the efficacy of aspirin plus clopidogrel compared with aspirin in carriers versus noncarriers of CYP2B6-516 GT/TT or -1456 TC/CC genotype. Our results suggest that both carriers and noncarriers suffering from a minor stroke are likely to benefit from aspirin plus clopidogrel treatment over aspirin monotherapy for secondary prevention. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT00979589.

Photochemically induced thalamus infarction impairs cognition in a mouse model.

BACKGROUND: Small subcortical infarcts account for up to 25% of ischaemic strokes. Thalamus is one of the subcortical structures that commonly manifest with lacunar infarcts on MRI of the brain. Studies have shown that thalamus infarction is associated with cognitive decline. However, due to the lack of proper animal models, little is known about the mechanism. We aimed to establish a focal thalamus infarction model, characterise the infarct lesion and assess functional effects. METHODS: Male C57BL/6J mice were anaesthetised, and Rose Bengal dye was injected through the tail vein. The right thalamus was illuminated with green laser light by stereotactic implantation of optic fibre. Characteristics of the infarct and lesion evolution were evaluated by histological analysis and 7T MRI at various times. The cognitive and neurological functions were assessed by behavioural tests. Retrograde tracing was performed to analyse neural connections. RESULTS: An ischaemic lesion with small vessel occlusion was observed in the thalamus. It became a small circumscribed infarct with reactive astrocytes accumulated in the infarct periphery on day 21. The mice with thalamic infarction demonstrated impaired learning and memory without significant neurological deficits. Retrogradely labelled neurons in the retrosplenial granular cortex were reduced. CONCLUSION: This study established a mouse model of thalamic lacunar infarction that exhibits cognitive impairment. Neural connection dysfunctions may play a potential role in post-stroke cognitive impairment. This model helps to clarify the pathophysiology of post-stroke cognitive impairment and to develop potential therapies.

Retinal microvascular signs and recurrent vascular events in patients with TIA or minor stroke.

BACKGROUND AND PURPOSE: Retinal pathologies are an independent risk factor for ischaemic stroke, but research on the predictive value of retinal abnormalities for recurrent vascular events in patients with prior stroke is inconclusive. We investigated the association of retinal pathologies with subsequent vascular events. METHODS: In a substudy of the Intensified secondary prevention intending a reduction of recurrent events in TIA and minor stroke patients (INSPiRE-TMS) trial, we enrolled patients with recent transient ischaemic attack (TIA) or minor stroke with at least one modifiable risk factor. Primary outcome was the composite of subsequent vascular events. Retinal photographs were taken at baseline and categorised into three different fundus groups by a telemedically linked ophthalmologist. RESULTS: 722 patients participated in the current study and 109 major vascular events occurred. After multivariable adjustments, we did not find a significant association between fundus categories and risk for subsequent vascular events (HRs for moderate vascular retinopathy and vascular retinopathy with vessel rarefaction in comparison to no vascular retinopathy 1.03 (95% CI 0.64 to 1.67), p=0.905 and 1.17 (95% CI 0.62 to 2.20), p=0.626). In a selective post hoc analysis in patients with diabetes mellitus and hypertension, patients with vascular retinopathy with vessel rarefaction had a higher risk for recurrent stroke (HR 24.14 (95% CI 2.74 to 212.50), p=0.004). CONCLUSIONS: Retinal changes did not predict major subsequent vascular events in patients with recent TIA or minor stroke. Further studies are needed to examine the utility of fundus photography in assessing the risk of stroke recurrence in patients with diabetes mellitus and hypertension.

Prospective Validation of Computed Tomography to Identify Patients at High Risk for Stroke After Transient Ischemic Attack or Minor Stroke.

BACKGROUND: Computed tomography (CT) findings of acute and chronic ischemia are associated with subsequent stroke risk in patients with transient ischemic attack. We sought to validate these associations in a large prospective cohort of patients with transient ischemic attack or minor stroke. METHODS: This prospective cohort study enrolled emergency department patients from 13 hospitals with transient ischemic attack who had CT imaging. Primary outcome was stroke within 90 days. Secondary outcomes were stroke within 2 or 7 days. CT findings were abstracted from radiology reports and classified for the presence of acute ischemia, chronic ischemia, or microangiopathy. Multivariable logistic regression was used to test associations with primary and secondary end points. RESULTS: From 8670 prospectively enrolled patients between May 2010 and May 2017, 8382 had a CT within 24 hours. From this total population, 4547 (54%) patients had evidence of acute ischemia, chronic ischemia, or microangiopathy on CT, of whom 175 had a subsequent stroke within 90 days (3.8% subsequent stroke rate; adjusted odds ratio [aOR], 2.33 [95% CI, 1.62-3.36]). This was in comparison to those with CT imaging without ischemia. Findings associated with an increased risk of stroke at 90 days were isolated acute ischemia (6.0%; aOR, 2.42 [95% CI, 1.03-5.66]), acute ischemia with microangiopathy (10.7%; aOR, 3.34 [95% CI, 1.57-7.14]), chronic ischemia with microangiopathy (5.2%; aOR, 1.83 [95% CI, 1.34-2.50]), and acute ischemia with chronic ischemia and microangiopathy (10.9%; aOR, 3.49 [95% CI, 1.54-7.91]). Acute ischemia with chronic ischemia and microangiopathy were most strongly associated with subsequent stroke within 2 days (aOR, 4.36 [95% CI, 1.31-14.54]) and 7 days (aOR, 4.50 [95% CI, 1.73-11.69]). CONCLUSIONS: In patients with transient ischemic attack or minor stroke, CT evidence of acute ischemia with chronic ischemia or microangiopathy significantly increases the risk of subsequent stroke within 90 days of index visit. The combination of all 3 findings results in the greatest early risk.

Stroke Learning Health Systems: A Topical Narrative Review With Case Examples.

To our knowledge, the adoption of Learning Health System (LHS) concepts or approaches for improving stroke care, patient outcomes, and value have not previously been summarized. This topical review provides a summary of the published evidence about LHSs applied to stroke, and case examples applied to different aspects of stroke care from high and low-to-middle income countries. Our attempt to systematically identify the relevant literature and obtain real-world examples demonstrated the dissemination gaps, the lack of learning and action for many of the related LHS concepts across the continuum of care but also elucidated the opportunity for continued dialogue on how to study and scale LHS advances. In the field of stroke, we found only a few published examples of LHSs and health systems globally implementing some selected LHS concepts, but the term is not common. A major barrier to identifying relevant LHS examples in stroke may be the lack of an agreed taxonomy or terminology for classification. We acknowledge that health service delivery settings that leverage many of the LHS concepts do so operationally and the lessons learned are not shared in peer-reviewed literature. It is likely that this topical review will further stimulate the stroke community to disseminate related activities and use keywords such as learning health system so that the evidence base can be more readily identified.

Rationale and design of a randomised double-blind 2×2 factorial trial comparing the effect of a 3-month intensive statin and antiplatelet therapy for patients with acute mild ischaemic stroke or high-risk TIA with intracranial or extracranial atherosclerosis (INSPIRES).

BACKGROUND: It remains unclear if intensive antiplatelet and statin treatments begun within 24-72 hours of cerebral ischaemic events from intracranial or extracranial atherosclerosis is effective or safe. METHODS: The Intensive Statin and Antiplatelet Therapy for High-risk Intracranial or Extracranial Atherosclerosis (INSPIRES) trial is a randomised, double-blind, placebo-controlled, multicentre and 2×2 factorial trial. 6100 individuals between the ages of 35 and 80 who have experienced a mild ischaemic stroke or high-risk transient ischaemic attack (TIA) within the previous 72 hours that is attributed to ≥50% atherosclerotic stenosis of a major intracranial or extracranial artery or multiple infarctions of atherosclerotic origin will be enrolled in the trial. Eligible subjects will be randomised 1:1:1:1 to one of four groups: (1) intensive antiplatelet therapy (combined clopidogrel and aspirin for days 1-21, then aspirin placebo and clopidogrel for days 22-90) plus immediate intensive statin therapy(atorvastatin at a dose of 80 mg daily for the first 21 days, then 40 mg daily for days 22-90); (2) intensive antiplatelet therapy plus delayed intensive statin therapy (atorvastatin placebo for days 1-3, followed by 40 mg per day of atorvastatin for days 4-90); (3) standard antiplatelet therapy (combination of clopidogrel placebo with aspirin for 90 days) plus immediate intensive statin therapy and (4) standard antiplatelet therapy plus delayed intensive statin therapy. The primary efficacy endpoint is any new stroke (ischaemic or haemorrhagic) within 90 days after randomisation. The primary safety endpoint is moderate to severe bleeding at 90 days. CONCLUSION: The INSPIRES trial will assess the efficacy and safety of intensive antiplatelet therapy and immediate intensive statin therapy begun within 72 hours of onset in decreasing the recurrent stroke at 90 days in patients with acute mild ischaemic stroke or high-risk TIA of intracranial or extracranial atherosclerosis origin. TRIAL REGISTRATION NUMBER: NCT03635749.

Diagnosis, Workup, Risk Reduction of Transient Ischemic Attack in the Emergency Department Setting: A Scientific Statement From the American Heart Association.

At least 240 000 individuals experience a transient ischemic attack each year in the United States. Transient ischemic attack is a strong predictor of subsequent stroke. The 90-day stroke risk after transient ischemic attack can be as high as 17.8%, with almost half occurring within 2 days of the index event. Diagnosing transient ischemic attack can also be challenging given the transitory nature of symptoms, often reassuring neurological examination at the time of evaluation, and lack of confirmatory testing. Limited resources, such as imaging availability and access to specialists, can further exacerbate this challenge. This scientific statement focuses on the correct clinical diagnosis, risk assessment, and management decisions of patients with suspected transient ischemic attack. Identification of high-risk patients can be achieved through use of comprehensive protocols incorporating acute phase imaging of both the brain and cerebral vasculature, thoughtful use of risk stratification scales, and ancillary testing with the ultimate goal of determining who can be safely discharged home from the emergency department versus admitted to the hospital. We discuss various methods for rapid yet comprehensive evaluations, keeping resource-limited sites in mind. In addition, we discuss strategies for secondary prevention of future cerebrovascular events using maximal medical therapy and patient education.