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Objective: To examine sex differences in early stroke deaths according to cause of death., Methods: We investigated 30-day deaths in patients with acute ischemic stroke enrolled in a multicenter stroke registry between 2007 and 2019 in Fukuoka, Japan. We estimated the multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of cause-specific deaths for women vs men using Cox proportional hazards models and competing risk models. The risk of acute infections during hospitalization and the associated case fatality rates were also compared between the sexes., Results: Among 17,956 patients with acute ischemic stroke (women: 41.3%), the crude 30-day death rate after stroke was higher in women than men. However, adjusting for age and stroke severity resulted in a lower risk of death among women (HR [95% CI]: 0.76 [0.62-0.92]). Analyses using competing risk models revealed that women were less likely to die of acute infections (subdistribution HR [95% CI]: 0.33 [0.20-0.54]). Further analyses showed that women were associated with a lower risk of acute infections during hospitalization (OR [95% CI]: 0.62 [0.52-0.74]) and a lower risk of death due to these infections (subdistribution HR [95% CI]: 052 [0.33-0.83])., Conclusions: When adjusting for confounders, the female sex was associated with a lower risk of 30-day death after stroke, which could be explained by a female survival advantage in poststroke infections. Sex-specific strategies are needed to reduce early stroke deaths., Classification of Evidence: This is a Class I prognostic study because it is a prospective population-based cohort with objective outcomes. Female sex appears to be protective against early stroke deaths and post stroke infections., (© 2021 American Academy of Neurology.)

Background We aimed to determine whether a regional disparity exists in usage of reperfusion therapy (intravenous recombinant tissue plasminogen activator [IV rt-PA] and endovascular thrombectomy [EVT]) and post-reperfusion 30-day mortality in patients with acute ischemic stroke, and which regional factors are associated with their usage. Methods and Results We retrospectively investigated 69 948 patients (mean age±SD, 74.9±12.0 years; women, 41.4%) with acute ischemic stroke treated with reperfusion therapy between April 2010 and March 2016 in Japan using nationwide claims data. Regional disparity was evaluated using Gini coefficients for age- and sex-adjusted usage of reperfusion therapy and 30-day post-reperfusion in-hospital death ratio in 47 administrative regions. The association between regional factors and reperfusion therapy usage was evaluated with fixed-effects regression models. During the study period, Gini coefficients showed low inequality (0.11-0.15) for use of IV rt-PA monotherapy and IV rt-PA and/or EVT and extreme inequality (0.49) for EVT usage in 2010, which became moderate inequality (0.25) by 2015. The densities of stroke centers and endovascular specialists, as well as market concentration, were associated with increased usage of reperfusion therapy whereas the proportion of rural residents and delayed ambulance transport were negatively associated with usage. Inequality in the standardized death ratio after EVT was extreme (0.86) in 2010 but became moderate (0.29) by 2015; inequality was low to moderate (0.17-0.23) for IV rt-PA monotherapy and IV rt-PA and/or EVT. Conclusions Scrutinizing existing data sources revealed regional disparity in reperfusion therapy for acute ischemic stroke and its associated regional factors in Japan.

The EXPAND Study demonstrated the effectiveness and safety of rivaroxaban in patients with non-valvular atrial fibrillation (NVAF) in routine clinical practice in Japan. This sub-analysis was conducted to reveal the effectiveness and safety of rivaroxaban in Japanese NVAF patients according to baseline creatinine clearance (CrCl) levels and rivaroxaban doses in the EXPAND Study. We examined 6806 patients whose baseline CrCl data were available and classified them into 2 groups: normal renal function group with CrCl ≥ 50 mL/min (n = 5326, 78%) and renal dysfunction group with CrCl < 50 mL/min (n = 1480, 22%). In the normal renal function group, 1609 (30%) received 10 mg/day (under-dose), while in the renal dysfunction group, 108 (7%) received 15 mg/day (over-dose). In the normal renal function group, under-dose of rivaroxaban was associated with higher all-cause mortality, while in the renal dysfunction group, over-dose was associated with higher incidence of major bleeding. In contrast, the incidence of stroke or systemic embolism was not different between the 2 groups regardless of the dose of rivaroxaban. In the propensity score matched analysis to adjust the difference in characteristics according to doses of rivaroxaban, the incidences of clinical outcomes were comparable between the 2 dose groups in both renal function groups. These results indicate that the dose of rivaroxaban should be reduced depending on the renal function, considering the balance between risks of bleeding and ischemia., (© 2021. The Author(s).)

Background and Purpose: Little is known about how β-cell dysfunction affects clinical outcome after ischemic stroke. We examined whether β-cell function is associated with clinical outcome after acute ischemic stroke and if so, whether insulin resistance influences this association in a prospective study of patients with acute stroke., Methods: A total of 3590 nondiabetic patients with acute ischemic stroke (mean age, 71 years) were followed up for 3 months. β-Cell function was assessed using the homeostasis model assessment for β-cell function (HOMA-β). Study outcomes were poor functional outcome (modified Rankin Scale score, 3–6) and stroke recurrence at 3 months after stroke onset and neurological deterioration (≥2-point increase in the National Institutes of Health Stroke Scale score) at discharge. Logistic regression analysis was used to evaluate the association between quintile levels of serum HOMA-β and clinical outcomes., Results: The age- and sex-adjusted odds ratios for poor functional outcome and neurological deterioration increased significantly with decreasing HOMA-β levels (P for trend, <0.001 and 0.001, respectively). These associations became more prominent after adjustment for HOMA-insulin resistance and were substantially unchanged even after further adjustment for other confounders, namely, body mass index, dyslipidemia, hypertension, estimated glomerular filtration rate, stroke subtype, National Institutes of Health Stroke Scale score on admission, and reperfusion therapy (odds ratio [95% CI] for the first versus fifth quintile of HOMA-β, 3.30 [2.15–5.08] for poor functional outcome and 10.69 [4.99–22.90] for neurological deterioration). Such associations were not observed for stroke recurrence. In stratified analysis for the combination of HOMA-β and HOMA-insulin resistance levels, lower HOMA-β and higher HOMA-insulin resistance levels were independently associated with increased risks of poor functional outcome and neurological deterioration., Conclusions: Our findings suggest that β-cell dysfunction is significantly associated with poor short-term clinical outcome independently of insulin resistance in nondiabetic patients with acute ischemic stroke.

Background: Hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) is associated with cardiovascular events and poor renal outcome in patients with chronic kidney disease (CKD). This study aimed to investigate the initial responsiveness to darbepoetin alfa (DA) and its contributing factors using the data from the BRIGHTEN., Methods: Of 1980 patients enrolled at 168 facilities, 1695 were included in this analysis [285 patients were excluded mainly due to lack of hemoglobin (Hb) values]. The initial ESA response index (iEResI) was defined as a ratio of Hb changes over 12 weeks after DA administration per weight-adjusted total DA dose and contributing factors to iEResI were analyzed., Results: The mean age was 70 ± 12 years (male 58.8%; diabetic nephropathy 27.6%). The median creatinine and mean Hb levels at DA initiation were 2.62 mg/dL and 9.8 g/dL, respectively. The most frequent number of DA administration during 12 weeks was 3 times (41.1%), followed by 4 (15.6%) times with a wide distribution of the total DA dose (15-900 μg). Remarkably, 225 patients (13.3%) did not respond to DA. Multivariate analysis showed that male gender, hypoglycemic agent use, iron supplementation, high eGFR, low Hb, low CRP, low NT-proBNP, and low urinary protein-creatinine ratio were independently associated with better initial response to DA (P =  < 0.0001, 0.0108, < 0.0001, 0.0476, < 0.0001, 0.0004, 0.0435, and 0.0009, respectively)., Conclusions: Non-responder to DA accounted for 13.3% of patients with non-dialysis CKD. Iron supplementation, low CRP, low NT-proBNP, and less proteinuria were predictive and modifiable factors associated with better initial response to DA.

Competing Interests: The authors have no conflicts of interest to disclose.

Introduction: Pre-stroke dementia is significantly associated with poor stroke outcome. Cholinesterase inhibitors (ChEIs) might reduce the risk of stroke in patients with dementia. However, the association between pre-stroke ChEI treatment and stroke outcome remains unresolved. Therefore, we aimed to determine this association in patients with acute ischemic stroke and pre-stroke dementia., Methods: We enrolled 805 patients with pre-stroke dementia among 13,167 with ischemic stroke within 7 days of onset who were registered in the Fukuoka Stroke Registry between June 2007 and May 2019 and were independent in basic activities of daily living (ADLs) before admission. Primary and secondary study outcomes were poor functional outcome (modified Rankin Scale [mRS] score: 3-6) at 3 months after stroke onset and neurological deterioration (≥2-point increase in the NIH Stroke Scale [NIHSS] during hospitalization), respectively. Logistic regression analysis was used to evaluate associations between pre-stroke ChEI treatment and study outcomes. To improve covariate imbalance, we further conducted a propensity score (PS)-matched cohort study., Results: Among the participants, 212 (26.3%) had pre-stroke ChEI treatment. Treatment was negatively associated with poor functional outcome (odds ratio: 0.68 [95% confidence interval: 0.46-0.99]) and neurological deterioration (0.52 [0.31-0.88]) after adjusting for potential confounding factors. In the PS-matched cohort study, the same trends were observed between pre-stroke ChEI treatment and poor functional outcome (0.61 [0.40-0.92]) and between the treatment and neurological deterioration (0.47 [0.25-0.86])., Conclusions: Our findings suggest that pre-stroke ChEI treatment is associated with reduced risks for poor functional outcome and neurological deterioration after acute ischemic stroke in patients with pre-stroke dementia who are independent in basic ADLs before the onset of stroke., (© 2021 S. Karger AG, Basel.)

Background and Purpose- Several stroke prognostic scores have been developed to predict clinical outcomes after stroke. This study aimed to develop and validate novel data-driven predictive models for clinical outcomes by referring to previous prognostic scores in patients with acute ischemic stroke in a real-world setting. Methods- We used retrospective data of 4237 patients with acute ischemic stroke who were hospitalized in a single stroke center in Japan between January 2012 and August 2017. We first validated point-based stroke prognostic scores (preadmission comorbidities, level of consciousness, age, and neurological deficit [PLAN] score, ischemic stroke predictive risk score [IScore], and acute stroke registry and analysis of Lausanne [ASTRAL] score in all patients; Houston intraarterial recanalization therapy [HIAT] score, totaled health risks in vascular events [THRIVE] score, and stroke prognostication using age and National Institutes of Health Stroke Scale-100 [SPAN-100] in patients who received reperfusion therapy) in our cohort. We then developed predictive models using all available data by linear regression or decision tree ensembles (random forest and gradient boosting decision tree) and evaluated their area under the receiver operating characteristic curve for clinical outcomes after repeated random splits. Results- The mean (SD) age of the patients was 74.7 (12.9) years and 58.3% were men. Area under the receiver operating characteristic curves (95% CIs) of prognostic scores in our cohort were 0.92 PLAN score (0.90-0.93), 0.86 for IScore (0.85-0.87), 0.85 for ASTRAL score (0.83-0.86), 0.69 for HIAT score (0.62-0.75), 0.70 for THRIVE score (0.64-0.76), and 0.70 for SPAN-100 (0.63-0.76) for poor functional outcomes, and 0.87 for PLAN score (0.85-0.90), 0.88 for IScore (0.86-0.91), and 0.88 ASTRAL score (0.85-0.91) for in-hospital mortality. Internal validation of data-driven prediction models showed that their area under the receiver operating characteristic curves ranged between 0.88 and 0.94 for poor functional outcomes and between 0.84 and 0.88 for in-hospital mortality. Ensemble models of a decision tree tended to outperform linear regression models in predicting poor functional outcomes but not in predicting in-hospital mortality. Conclusions- Stroke prognostic scores perform well in predicting clinical outcomes after stroke. Data-driven models may be an alternative tool for predicting poststroke clinical outcomes in a real-world setting.

Objective: We sought to examine whether the effect of treatment modality and drugs for cerebral vasospasm on clinical outcomes differs between elderly and non-elderly subarachnoid hemorrhage (SAH) patients in Japan., Methods: We analyzed the J-ASPECT Study Diagnosis Procedure Combination database (n = 17,343) that underwent clipping or coiling between 2010 and 2014 in 579 hospitals. We stratified patients into two groups according to their age (elderly [≥75 years old], n = 3,885; non-elderly, n = 13,458). We analyzed the effect of treatment modality and anti-vasospasm agents (fasudil hydrochloride, ozagrel sodium, cilostazol, statin, eicosapentaenoic acid [EPA], and edaravone) on in-hospital poor outcomes (mRS 3-6 at discharge) and mortality using multivariable analysis., Results: The elderly patients were more likely to be female, have impaired levels of consciousness and comorbidity, and less likely to be treated with clipping and anti-vasospasm agents, except for ozagrel sodium and statin. In-hospital mortality and poor outcomes were higher in the elderly (15.8% vs. 8.5%, 71.7% vs. 36.5%). Coiling was associated with higher mortality (odds ratio 1.43, 95% confidence interval 1.2-1.7) despite a lower proportion of poor outcomes (0.84, 0.75-0.94) in the non-elderly, in contrast to no effect on clinical outcomes in the elderly. A comparable effect of anti-vasospasm agents on mortality was observed between non-elderly and elderly for fasudil hydrochloride (non-elderly: 0.20, 0.17-0.24), statin (0.63, 0.50-0.79), ozagrel sodium (0.72, 0.60-0.86), and cilostazol (0.63, 0.51-0.77). Poor outcomes were inversely associated with fasudil hydrochloride (0.59, 0.51-0.68), statin (0.84, 0.75-0.94), and EPA (0.83, 0.72-0.94) use in the non-elderly. No effect of these agents on poor outcomes was observed in the elderly., Conclusions: In contrast to the non-elderly, no effect of treatment modality on clinical outcomes were observed in the elderly. A comparable effect of anti-vasospasm agents was observed on mortality, but not on functional outcomes, between the non-elderly and elderly., Competing Interests: Dr. Iihara reports grants from grants from Otsuka Pharmaceutical Co., Ltd., grants from Kaneka Medix Corporation, grants from Eisai Co., Ltd., grants from Mitsubishi Tanabe Pharma Co., personal fees from Otsuka Pharmaceutical Co., Ltd., personal fees from Daiichi Sankyo Ltd, outside the submitted work; Dr. Kitazono reports grants from Otsuka Pharmaceutical Co., Ltd., Takeda Pharmaceuticals Co., Ltd, Mitsubishi Tanabe Pharma Co., Daiichi Sankyo Co., Ltd, Astellas Pharma Inc., MSD KK., and Shionogi & CO., LTD. Dr. Kamouchi reports personal fe 1 es from Daiichi Sankyo Co., Ltd, Ono pharmaceutical Co., Ltd., Bayer Yakuhin, Ltd., and Pfizer Co., Ltd.. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Introduction: Patients with stroke often experience pneumonia during the acute stage after stroke onset. Oral care may be effective in reducing the risk of stroke-associated pneumonia (SAP). We aimed to determine the changes in oral care, as well as the incidence of SAP, in patients with intracerebral hemorrhage, following implementation of a learning health system in our hospital., Methods: We retrospectively analyzed the data of 1716 patients with intracerebral hemorrhage who were hospitalized at a single stroke center in Japan between January 2012 and December 2018. Data were stratified on the basis of three periods of evolving oral care: period A, during which conventional, empirically driven oral care was provided (n = 725); period B, during which standardized oral care was introduced, with SAP prophylaxis based on known risk factors (n = 469); and period C, during which oral care was risk-appropriate based on learning health system data (n = 522). Logistic regression analysis was performed to evaluate associations between each of the three treatment approaches and the risk of SAP., Results: Among the included patients, the mean age was 71.3 ± 13.6 years; 52.6% of patients were men. During the course of each period, the frequency of oral care within 24 hours of admission increased ( P  < .001), as did the adherence rate to oral care ≥3 times per day ( P  < .001). After adjustment for confounding factors, a change in the risk of SAP was not observed in period B; however, the risk significantly decreased in period C (odds ratio 0.61; 95% confidence interval 0.43-0.87) compared with period A. These associations were maintained for SAP diagnosed using strict clinical criteria or after exclusion of 174 patients who underwent neurosurgical treatment., Conclusions: Risk-appropriate care informed by the use of learning health system data could improve care and potentially reduce the risk of SAP in patients with intracerebral hemorrhage in the acute stage., Competing Interests: The authors declare no conflicts of interest., (© 2020 The Authors. Learning Health Systems published by Wiley Periodicals, Inc. on behalf of the University of Michigan.)

Background: This study aimed to determine whether use of oral anticoagulants (OACs) was associated with a reduced risk of recurrent stroke compared with use of antiplatelets (APs) in patients with embolic stroke of undetermined source (ESUS) having no potential source of embolism., Methods: Of 8,790 patients with acute ischemic stroke registered at 7 centers in the Fukuoka Stroke Registry from June 2007 to May 2017, we included 681 patients (mean age 69.7 [SD 14.1] years, 48.3% men) who experienced ESUS without a potential source of embolism and received OAC alone or AP alone. We estimated hazard ratios (HRs) and 95% confidential intervals (CIs) of recurrent ischemic stroke or any stroke after discharge using a Cox proportional hazards model and Fine and Gray model., Results: During a mean follow-up of 3.4 (SD 1.7) years, event rates of recurrent ischemic stroke were 4.4 per 100 person-years in 489 patients treated with AP and 2.0 per 100 person-years in 192 patients treated with OAC. OAC use was associated with a reduced risk of recurrent ischemic stroke, even after adjusting for potential confounding factors (multivariable-adjusted HR [95% CI], 0.42 [0.23-0.80]) and when additionally considering death as a competing risk (0.45 [0.24-0.85]). The reduced risk of recurrent ischemic stroke was still observed in patients treated with OAC (0.32 [0.15-0.67]) in reference to propensity score-matched patients treated with AP. These associations were maintained for all types of stroke, including ischemic and hemorrhagic stroke., Conclusions: This nonrandomized observational study suggests that anticoagulation therapy might be associated with a reduced risk of recurrent stroke compared with antiplatelet therapy in patients with ESUS in whom no potential source of embolism was identified. Further study should be performed in consideration of a potential source of embolism even in patients with ESUS., (© 2020 S. Karger AG, Basel.)

Introduction: Worldwide, 2 million patients aged 18-50 years suffer a stroke each year, and this number is increasing. Knowledge about global distribution of risk factors and aetiologies, and information about prognosis and optimal secondary prevention in young stroke patients are limited. This limits evidence-based treatment and hampers the provision of appropriate information regarding the causes of stroke, risk factors and prognosis of young stroke patients., Methods and Analysis: The Global Outcome Assessment Life-long after stroke in young adults (GOAL) initiative aims to perform a global individual patient data meta-analysis with existing data from young stroke cohorts worldwide. All patients aged 18-50 years with ischaemic stroke or intracerebral haemorrhage will be included. Outcomes will be the distribution of stroke aetiology and (vascular) risk factors, functional outcome after stroke, risk of recurrent vascular events and death and finally the use of secondary prevention. Subgroup analyses will be made based on age, gender, aetiology, ethnicity and climate of residence., Ethics and Dissemination: Ethical approval for the GOAL study has already been obtained from the Medical Review Ethics Committee region Arnhem-Nijmegen. Additionally and when necessary, approval will also be obtained from national or local institutional review boards in the participating centres. When needed, a standardised data transfer agreement will be provided for participating centres. We plan dissemination of our results in peer-reviewed international scientific journals and through conference presentations. We expect that the results of this unique study will lead to better understanding of worldwide differences in risk factors, causes and outcome of young stroke patients., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Recent large placebo-controlled trials of sodium glucose co-transporter 2 (SGLT2) inhibitors revealed desirable effects on heart failure (HF) and renal dysfunction; however, the mechanisms underlying these effects are unknown. The characteristic changes in the early stage of diabetic cardiomyopathy (DCM) are myocardial and interstitial fibrosis, resulting in diastolic and subsequent systolic dysfunction, which leads to clinical HF. Pericytes are considered to play crucial roles in myocardial and interstitial fibrosis. In both DCM and diabetic retinopathy (DR), microaneurysm formation and a decrease in capillaries occur, triggered by pericyte loss. Furthermore, tubulointerstitial fibrosis develops in early diabetic nephropathy (DN), in which pericytes and mesangial cells are thought to play important roles. Previous reports indicate that pericytes and mesangial cells play key roles in the pathogenesis of DCM, DR and DN. SGLT2 is reported to be functionally expressed in pericytes and mesangial cells, and excessive glucose and Na + entry through SGLT2 causes cellular dysfunction in a diabetic state. Since SGLT2 inhibitors can attenuate the high glucose-induced dysfunction of pericytes and mesangial cells, the desirable effects of SGLT2 inhibitors on HF and renal dysfunction might be explained by their direct actions on these cells in the heart and kidney microvasculature.

For Japanese patients with non-valvular atrial fibrillation (NVAF), the risk of stroke and major bleeding events was assessed by using the CHADS 2, CHA 2 DS 2 -VASc, and HAS-BLED scores. The risk factors for embolism and major bleeding under DOAC may be different from current reports. We analyzed the data set of the EXPAND Study to determine the risk factors for events among Japanese NVAF patients in the era of direct oral anticoagulant. Using the data of EXPAND Study, the validity for predictability of the CHADS 2 , CHA 2 DS 2 -VASc, and HAS-BLED scores was identified using the receiver operating characteristic curve analysis. Multivariate analysis was performed with the Cox proportional hazard model to determine the independent risk factors for stroke/systemic embolism and major bleeding among NVAF patients receiving rivaroxaban. Explanatory variables were selected based on the univariate analysis. A total of 7141 patients (mean age 71.6 ± 9.4 years, women 32.3%, and rivaroxaban 15 mg per day 56.5%) were included. Incidence rates of stroke/systemic embolism and major bleeding were 1.0%/year and 1.2%/year, respectively. The multivariate analysis revealed that only history of stroke was associated with stroke/systemic embolism (hazard ratio 3.4, 95% confidence interval 2.5-4.7, p < 0.0001). By contrast, age (1.7, 1.1-2.6, p = 0.0263), creatinine clearance (CrCl) 30-49 mL/min (1.6, 1.2-2.2, p = 0.0011), liver dysfunction (1.7, 1.1-2.8, p = 0.0320), history/disposition of bleeding (1.8, 1.0-3.0, p = 0.0348), and concomitant use of antiplatelet agents (1.6, 1.2-2.3, p = 0.0030) were associated with major bleeding. This sub-analysis showed that some components of the HAS-BLED score were independently associated with major bleeding in Japanese NVAF patients receiving anticoagulation therapy by rivaroxaban. Additionally, CrCl value of 30-49 mL/min was an independent predictor of major bleeding in patients receiving rivaroxaban.

Background: This study aimed at determining whether diabetes or glucose metabolism is associated with ischemic stroke in the posterior circulation., Methods: We included 10,245 patients with acute ischemic stroke (mean age 72.7 ± 12.5 years, men 59.5%) who were enrolled in a multicenter hospital-based stroke registry in Fukuoka, Japan, between June 2007 and August 2016. Posterior circulation ischemic stroke (PCIS) was defined as brain infarction in the territory of the posterior cerebral artery and vertebro-basilar arteries. We investigated the associations between diabetes or glycemic parameters, including plasma glucose concentrations, hemoglobin A1c, and the homeostatic model assessment of insulin resistance (HOMA-IR), and PCIS using logistic regression analysis. To improve covariate imbalance, we further evaluated associations after propensity score matching using 1:1 nearest neighbor matching and inverse probability weighting., Results: Diabetes was significantly associated with PCIS even after adjusting for multiple confounding factors (odds ratio-OR [95% confidence interval], 1.37 [1.25-1.50]). Similarly, fasting (1.07 [1.02-1.12]/SD), casual plasma glucose (1.16 [1.11-1.20]/SD) concentrations, and hemoglobin A1c (1.12 [1.08-1.17]/SD), but not HOMA-IR (1.02 [0.97-1.07]/SD), were associated with PCIS. These associations were maintained in patients with ischemic stroke because of thrombotic etiology and were unchanged even after the propensity score matching methods. In patients with diabetes, the ORs of PCIS further increased with an increase in hemoglobin A1c and the presence of microvascular complications., Conclusions: Poor glycemic control may be associated with an increased risk of thrombotic infarction that occurs preferentially in the posterior circulation of the brain.

The EXPAND Study examined the real-world efficacy and safety of rivaroxaban for the prevention of stroke and systemic embolism (SE) in Japanese patients with non-valvular atrial fibrillation (NVAF). In this sub-analysis, we compared the differences in efficacy and safety between patients with and those without history of stroke or transient ischemic attack (TIA). This multicenter, prospective, non-interventional, observational, cohort study was conducted at 684 medical centers in Japan. A total of 7141 NVAF patients aged ≥ 20 years [mean age 71.6 ± 9.4 (SD) years] who were being or planned to be treated with rivaroxaban (10 mg/day, 43.5%; 15 mg/day, 56.5%) were followed for a mean period of 897.1 ± 206.8 days with a high follow-up rate (99.7%). The primary prevention group comprised patients without history of ischemic stroke or TIA (n = 5546, 77.7%), and the secondary prevention group comprised those with history of ischemic stroke or TIA (n = 1595, 22.3%). In the primary and secondary prevention groups, the incidence rate of stroke or SE (primary efficacy endpoint) was 0.7 and 2.2%/year, respectively (P < 0.001), and the incidence rate of major bleeding (primary safety endpoint) was 1.2 and 1.5%/year, respectively (P = 0.132). For major bleeding events, the incidence rate of intracranial bleeding was 0.4 and 0.8%/year (P = 0.002) in the primary and secondary prevention groups, respectively. This sub-analysis of the EXPAND Study showed that the Japan-specific dosages of rivaroxaban were effective and safe in Japanese NVAF patients with and those without ischemic stroke or TIA in routine clinical practice.

Background The safety of antithrombotic therapy for patients with acute ischemic stroke harboring unruptured intracranial aneurysms remains unclear. Aims This study was performed to determine whether treatment with antiplatelets, anticoagulants, or intravenous thrombolytic agents is safe for patients with acute ischemic stroke and unruptured intracranial aneurysms. Methods Among 9149 patients with acute ischemic stroke enrolled in the Fukuoka Stroke Registry from June 2007 to December 2014, 8857 patients with data on cerebrovascular imaging and three-month outcomes were included in this study. The frequency of adverse events, including intracranial hemorrhage, symptomatic intracranial hemorrhage, and in-hospital mortality, was compared between patients with and without unruptured intracranial aneurysms. The risk of a poor functional outcome (modified Rankin scale score of ≥3) at three months after stroke onset was estimated after adjusting for confounding factors by logistic regression analysis. Results Unruptured intracranial aneurysms were identified in 412 (4.7%) patients, and the mean diameter was 4.1 ± 3.2 mm. There was no significant difference in the frequency of any adverse events between patients with and without unruptured intracranial aneurysms among the overall patients or patients receiving antiplatelets, anticoagulants, or intravenous thrombolytic agents. The odds ratios of a poor functional outcome were not significantly higher in the presence of unruptured intracranial aneurysms, even in patients undergoing antiplatelet therapy, anticoagulation therapy, or intravenous thrombolysis. Conclusions These findings suggest that unruptured intracranial aneurysms are not associated with increased risks of adverse events or poor functional outcomes even after antithrombotic therapy for acute ischemic stroke. However, accumulation of cases is required to verify these findings.

Importance: It is unknown whether poststroke outcome varies between different potential causes in patients with cryptogenic stroke., Objective: To investigate whether functional outcome differs according to potential embolic sources after cryptogenic stroke., Design, Setting, and Participants: This multicenter, hospital-based, prospective stroke registry cohort study investigated potential embolic sources on admission and assessed 3-month outcome in patients with ischemic stroke hospitalized at 7 stroke centers in the Fukuoka Stroke Registry. This registry enlisted 9866 consecutive patients with acute ischemic stroke who were enrolled from June 11, 2007, to May 31, 2016, in Fukuoka, Japan. Patients with small vessel occlusion (n = 3130), extracranial and intracranial atherosclerosis causing at least 50% luminal stenosis in arteries supplying the area of ischemia (n = 2011), and other specific uncommon causes of stroke identified (n = 301) were excluded. Potential embolic sources were diagnosed in patients with embolic stroke of undetermined source (ESUS) based on the following criteria proposed by the Cryptogenic Stroke/ESUS International Working Group: minor-risk potential cardioembolic sources (MCS) (n = 209), covert paroxysmal atrial fibrillation (CPAF) (n = 43), cancer associated (CA) (n = 79), arteriogenic emboli (AE) (n = 522), paradoxical embolism (PE) (n = 190), and undetermined embolism (unidentified or ≥2 potential embolic sources) (UE) (n = 1120)., Main Outcomes and Measures: The association between potential causes and functional outcome was evaluated in reference to cardioembolic stroke (CE) caused by major-risk cardioembolic sources after adjusting for age, sex, National Institutes of Health Stroke Scale score on admission, and reperfusion therapy using logistic regression analysis. Functional dependency (modified Rankin Scale score, 3-5) was evaluated at 3 months after onset., Results: The study enrolled 2261 patients with CE (mean [SD] age, 78.4 [10.7] years, 51.8% male) and 2163 patients with ESUS (mean [SD] age, 72.4 [12.6] years, 57.1% male). Compared with CE (median National Institutes of Health Stroke Scale score, 8 [interquartile range {IQR}, 3-17]), baseline neurological deficits did not differ in MCS (median, 7 [IQR, 2-18]), CPAF (median, 6 [IQR, 2-18]), and CA (median, 5 [IQR, 2-13]) but were less severe in AE (median, 2 [IQR, 1-4]), PE (median, 2 [IQR, 1-4]), and UE (median, 3 [IQR, 1-7]). Multivariable-adjusted odds ratios of functional dependency significantly increased in CA (3.61; 95% CI, 1.52-8.54 vs CE) but decreased in PE (0.33; 95% CI, 0.16-0.71 vs CE)., Conclusions and Relevance: Potential causes are associated with poststroke outcome in patients with cryptogenic stroke. Embolic sources potentially underlying cryptogenic stroke should be considered significant variables associated with outcome.

Aims: The EXPAND study examined the real-world efficacy and safety of rivaroxaban for the prevention of stroke and systemic embolism (SE) in Japanese patients with non-valvular atrial fibrillation (NVAF)., Methods and Results: This multicenter, prospective, non-interventional, observational, cohort study was conducted at 684 medical centers in Japan. A total of 7141 NVAF patients ≥20 years of age (mean, 71.6 ± 9.4 years) who were being or about to be treated with rivaroxaban (10 mg/day, 43.5%; 15 mg/day, 56.5%) were followed for an average of 897.1 (±206.8) days with a high follow-up rate (99.65%). The mean CHADS 2 score at baseline was 2.1 (1.3) (0-1, 37%; 2, 29%; ≥3, 34%). The total incidence rate of symptomatic stroke and SE (primary efficacy endpoint) was 1.0%/year, and 0.5%, 0.9%, and 1.7%/year for those with CHADS 2 scores of 0-1, 2, and ≥3, respectively. Cumulative incidence rates for major bleeding (primary safety endpoint) and non-major bleeding (secondary safety endpoint) were 1.2%/year and 4.9%/year, respectively. Differences were noted between new and current users only for major bleeding event rate (1.7% vs. 1.1%/year, P = 0.0024). Comparisons with previous studies suggested that rivaroxaban is effective and safe for low-risk patients (0-1 CHADS 2 ), as shown for warfarin in the XANTUS international prospective post-marketing study., Conclusions: The EXPAND study demonstrated that low dosages of rivaroxaban for Japanese NVAF patients in real-world clinical practice, including those with CHADS 2 scores 0-1, resulted in low rates of stroke and SE, and major and non-major bleeding., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: In this study, we aimed to determine whether insulin resistance is associated with clinical outcomes after acute ischemic stroke., Methods: We enrolled 4,655 patients with acute ischemic stroke (aged 70.3 ± 12.5 years, 63.5% men) who had been independent before admission; were hospitalized in 7 stroke centers in Fukuoka, Japan, from April 2009 to March 2015; and received no insulin therapy during hospitalization. The homeostasis model assessment of insulin resistance (HOMA-IR) score was calculated using fasting blood glucose and insulin levels measured 8.3 ± 7.8 days after onset. Study outcomes were neurologic improvement (≥4-point decrease in NIH Stroke Scale score or 0 at discharge), poor functional outcome (modified Rankin Scale score of ≥3 at 3 months), and 3-month prognosis (stroke recurrence and all-cause mortality). Logistic regression analysis was used to evaluate the association of the HOMA-IR score with clinical outcomes., Results: The HOMA-IR score was associated with neurologic improvement (odds ratio, 0.68 [95% confidence interval, 0.56-0.83], top vs bottom quintile) and with poor functional outcome (2.02 [1.52-2.68], top vs bottom quintile) after adjusting for potential confounding factors, including diabetes and body mass index. HOMA-IR was not associated with stroke recurrence or mortality within 3 months of onset. The associations were maintained in nondiabetic or nonobese patients. No heterogeneity was observed according to age, sex, stroke subtype, or stroke severity., Conclusions: These findings suggest that insulin resistance is independently associated with poor functional outcome after acute ischemic stroke apart from the risk of short-term stroke recurrence or mortality., (© 2018 American Academy of Neurology.)

Background: Renal anemia is an important complication in non-dialysis chronic kidney disease (CKD) patients as well as in dialysis patients. Although recombinant human erythropoietin has dramatically improved prognosis and quality of life in these patients, there have been issues among non-dialysis CKD patients who exhibit hyporesponsiveness to erythropoiesis-stimulating agent (ESA). The causes and definition of ESA hyporesponsiveness, as well as the incidence of renal and cardiovascular disease (CVD) events in such patients, are yet to be clarified., Methods: This ongoing trial is a multicenter, prospective, observational study of non-dialysis CKD patients with renal anemia. The primary objective is to survey the current realities of the therapy with ESA in Japan and evaluate the correlation between hyporesponsiveness to darbepoetin alfa and CKD progression. The secondary objective is to investigate relationship between ESA hyporesponsiveness and CVD events based on the clinical situation in Japan, and to explore an ESA response index., Results: The subjects consist of CKD patients with estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73 m 2 who present renal anemia. The target number of registered cases is 2000 patients, based on estimates of incidences of renal and CVD events from past studies. Renal function and CVD events will be observed for 96 weeks after the initiation of darbepoetin alfa administration. Definitions of ESA hyporesponsiveness will also be investigated., Conclusion: By clarifying markers and factors involved in ESA hyporesponsiveness and their relationships with renal and CVD events, this ongoing study aims to improve evidence-based therapies for renal anemia in non-dialysis CKD patients.

Background and purpose Previous studies have suggested that atrial septal aneurysm is a potential risk factor for cerebral embolism. However, the association between the level of atrial septal protrusion and cerebral embolism is still unclear. The purpose of the present study was to assess the association between the maximal distance of atrial septal protrusion and cryptogenic stroke. Methods A total of 588 consecutive acute ischemic stroke patients (70 ± 11 (mean ± SD) years, 401 men) who underwent transesophageal echocardiography were enrolled. The maximal distance of atrial septal protrusion into the right or left atrium was measured. Atrial septal aneurysm was diagnosed when the maximal distance of atrial septal protrusion was >10 mm. Cryptogenic stroke was defined as non-lacunar ischemic stroke without >50% proximal artery stenosis or occlusion, cardioembolic sources, ≥4 mm atherosclerotic plaques in the aortic arch, or carotid or vertebral artery dissection. Results The rate of cryptogenic stroke increased with the increasing maximal distance of atrial septal protrusion. The maximal distance of atrial septal protrusion (multivariate-adjusted odds ratio (OR) per 1 mm, 1.14; 95% confidence interval (CI), 1.04-1.24; P = 0.003) and atrial septal aneurysm (multivariate-adjusted OR, 4.32; 95% CI, 1.22-20.39; P = 0.022) was independently associated with cryptogenic stroke. Conclusions The maximal distance of atrial septal protrusion was independently associated with cryptogenic stroke.

Background and Purpose: The role of early hospital arrival in improving poststroke clinical outcomes in patients without reperfusion treatment remains unclear. This study aimed to determine whether early hospital arrival was associated with favorable outcomes in patients without reperfusion treatment or with minor stroke., Methods: This multicenter, hospital-based study included 6780 consecutive patients (aged, 69.9±12.2 years; 63.9% men) with ischemic stroke who were prospectively registered in Fukuoka, Japan, between July 2007 and December 2014. Onset-to-door time was categorized as T 0-1 , ≤1 hour; T 1-2 , >1 and ≤2 hours; T 2-3 , >2 and ≤3 hours; T 3-6 , >3 and ≤6 hours; T 6-12 , >6 and ≤12 hours; T 12-24 , >12 and ≤24 hours; and T 24- , >24 hours. The main outcomes were neurological improvement (decrease in National Institutes of Health Stroke Scale score of ≥4 during hospitalization or 0 at discharge) and good functional outcome (3-month modified Rankin Scale score of 0-1). Associations between onset-to-door time and main outcomes were evaluated after adjusting for potential confounders using logistic regression analysis., Results: Odds ratios (95% confidence intervals) increased significantly with shorter onset-to-door times within 6 hours, for both neurological improvement ( T 0- 1 , 2.79 [2.28-3.42]; T 1-2 , 2.49 [2.02-3.07]; T 2-3 , 1.52 [1.21-1.92]; T 3-6 , 1.72 [1.44-2.05], with reference to T 24- ) and good functional outcome ( T 0-1 , 2.68 [2.05-3.49], T 1-2 2.10 [1.60-2.77], T 2-3 1.53 [1.15-2.03], T 3-6 1.31 [1.05-1.64], with reference to T 24- ), even after adjusting for potential confounding factors including reperfusion treatment and basal National Institutes of Health Stroke Scale. These associations were maintained in 6216 patients without reperfusion treatment and in 4793 patients with minor stroke (National Institutes of Health Stroke Scale ≤4 on hospital arrival)., Conclusions: Early hospital arrival within 6 hours after stroke onset is associated with favorable outcomes after ischemic stroke, regardless of reperfusion treatment or stroke severity., (© 2017 American Heart Association, Inc.)

Background: Among patients with ischemic stroke and atrial fibrillation, which ones are at high risk of recurrent stroke is unclear. This study aimed to determine whether left atrial size was associated with long-term risk of stroke recurrence in patients with nonvalvular atrial fibrillation., Methods and Results: In this multicenter prospective cohort study, nonvalvular atrial fibrillation patients hospitalized for acute ischemic stroke were enrolled and followed up after discharge. Indexed-left atrial diameter was obtained by dividing left atrial diameter by body surface area. Cause-specific and subdistribution hazard ratios of recurrent stroke were estimated by Cox proportional hazards and Fine-Gray models, respectively. Risk prediction was evaluated by integrated discrimination improvement and net reclassification improvement. In total, 1611 patients (77.8±10.2 [mean±SD] years, 44.5% female) were included. During follow-up for 2.40±1.63 (mean±SD) years, 251 patients had recurrent stroke and 514 patients died. An increased indexed-left atrial diameter (per 1 cm/m 2 ) was significantly associated with elevated risk of stroke recurrence (hazard ratio 1.60, 95% CI 1.30-1.98). The association was maintained when death was regarded as the competing risk and in 1464 patients who were treated with anticoagulants (hazard ratio 1.59, 95% CI 1.27-2.00). Risk prediction for recurrent stroke was significantly improved by adding indexed-left atrial diameter to the baseline model composed of the factors in the CHADS 2 score or those in the CHA 2 DS 2 -VASc score., Conclusion: These findings suggest that left atrial enlargement is associated with an increased risk of recurrent stroke in nonvalvular atrial fibrillation patients with ischemic stroke., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background: Dementia and stroke are major causes of disability in the elderly. However, the association between pre-stroke dementia and functional outcome after stoke remains unresolved. We aimed to determine this association in patients with acute ischemic stroke., Methods: Among patients registered in the Fukuoka Stroke Registry from June 2007 to May 2015, 4,237 patients with ischemic stroke within 24 h of onset, who were functionally independent before the onset, were enrolled in this study. Pre-stroke dementia was defined as any type of dementia that was present prior to the index stroke. Primary and secondary study outcomes were poor functional outcome (modified Rankin Scale 3-6) at 3 months after the stroke onset and neurological deterioration (≥2-point increases on the National Institutes of Health Stroke Scale score during hospitalization), respectively. For propensity score (PS)-matched cohort study to control confounding variables for pre-stroke dementia, 318 pairs of patients with and without pre-stroke dementia were also selected on the basis of 1:1 matching. Multivariable logistic regression models and conditional logistic regression analysis were used to quantify associations between pre-stroke dementia and study outcomes., Results: Of all 4,237 participants, 347 (8.2%) had pre-stroke dementia. The frequencies of neurological deterioration and poor functional outcome were significantly higher in patients with pre-stroke dementia than in those without pre-stroke dementia (neurological deterioration, 16.1 vs. 7.1%, p < 0.01; poor functional outcome, 63.7 vs. 27.1%, p < 0.01). Multivariable analysis showed that pre-stroke dementia was significantly associated with neurological deterioration (OR 1.67; 95% CI 1.14-2.41; p < 0.01) and poor functional outcome (OR 2.91; 95% CI 2.17-3.91; p < 0.01). In the PS-matched cohort study, the same trends were observed between the pre-stroke dementia and neurological deterioration (OR 2.60; 95% CI 1.17-5.78; p < 0.01) and between the dementia and poor functional outcome (OR 3.62; 95% CI 1.89-6.95; p < 0.01)., Conclusions: Pre-stroke dementia was significantly associated with higher risks for poor functional outcome at 3 months after stroke onset as well as for neurological deterioration during hospitalization in patients with acute ischemic stroke., (© 2016 S. Karger AG, Basel.)

The use of rivaroxaban, a factor Xa inhibitor, has been increasing for prevention of ischemic stroke and systemic embolism in patients with non-valvular atrial fibrillation (AF) in Japan. We conducted the nationwide multicenter study, termed as the EXPAND Study, to address its effectiveness and safety in the real-world practice of patients with non-valvular AF in Japan. The EXPAND Study is a prospective, non-interventional, observational cohort study to evaluate the effectiveness and safety of rivaroxaban in non-valvular AF patients in a real-world clinical practice. A total of 7,178 patients with non-valvular AF were enrolled in 684 medical institutes between November 20, 2012 and June 30, 2014. As for the baseline demographic and clinical characteristics of 7,164 patients, the proportion of female patients was 32.2%, and those of patients with creatinine clearance < 50 mL/min and non-paroxysmal (persistent or permanent) AF were 21.8% and 55.1%, respectively. The proportions of patients complicated with hypertension, congestive heart failure, diabetes mellitus, and a history of ischemic stroke were 70.9%, 25.9%, 24.3%, and 20.2%, respectively. The proportions of patients with a CHADS 2 score ≤ 1 and a CHA 2 DS 2 -VASc score ≤ 1 were 37.3% and 13.6%, respectively. They were followed up until March 31, 2016 for a mean follow-up period of approximately 2.5 years. The findings of the EXPAND Study will help to establish an appropriate treatment with rivaroxaban for Japanese patients with non-valvular AF.

Background and Purpose: There is a strong association between ambient concentrations of particulate matter (PM) and cardiovascular disease. However, it remains unclear whether acute exposure to fine PM (PM 2.5 ) triggers ischemic stroke events and whether the timing of exposure is associated with stroke risk. We, therefore, examined the association between ambient PM 2.5 and occurrence of ischemic stroke., Methods: We analyzed data for 6885 ischemic stroke patients from a multicenter hospital-based stroke registry in Japan who were previously independent and hospitalized within 24 hours of stroke onset. Time of symptom onset was confirmed, and the association between PM (suspended PM and PM 2.5 ) and occurrence of ischemic stroke was analyzed by time-stratified case-crossover analysis., Results: Ambient PM 2.5 and suspended PM at lag days 0 to 1 were associated with subsequent occurrence of ischemic stroke (ambient temperature-adjusted odds ratio [95% confidence interval] per 10 μg/m 3 : suspended PM, 1.02 [1.00-1.05]; PM 2.5 , 1.03 [1.00-1.06]). In contrast, ambient suspended PM and PM 2.5 at lag days 2 to 3 or 4 to 6 showed no significant association with stroke occurrence. The association between PM 2.5 at lag days 0 to 1 and ischemic stroke was maintained after adjusting for other air pollutants (nitrogen dioxide, photochemical oxidants, or sulfur dioxide) or influenza epidemics and was evident in the cold season., Conclusions: These findings suggest that short-term exposure to PM 2.5 within 1 day before onset is associated with the subsequent occurrence of ischemic stroke., (© 2016 American Heart Association, Inc.)

Purpose: The aim of this study is to determine whether short-term exposure to fine particulate matter (PM 2.5 ) is associated with emergency ambulance dispatches for cardiovascular diseases in Japan., Methods: The nationwide data on emergency dispatches of ambulance for cardiovascular diseases classified as I00-I99 by International Classification of Diseases-10th revision in 30 Japanese prefectures between April 1 and December 31, in 2010 were analyzed. Data on weather variability including PM 2.5 , temperature and relative humidity were acquired from ambient air pollution monitoring stations. Conditional Poisson regression models were used to estimate the prefecture-specific effects of PM 2.5 on morbidity, and adjust for confounding factors. A meta-analysis was then applied to pool estimates at the 30-prefecture level., Results: A total of 160,566 emergency ambulance dispatches for cardiovascular diseases were reported during the study period. The risk of emergency ambulance dispatch for cardiovascular diseases significantly increased with an increase in the exposure to PM 2.5 in Fukuoka and Iwate Prefectures. However, we found no statistically significant associations between PM 2.5 and emergency ambulance dispatches in the pooled analysis (odds ratio 1.00, 95 % confidence interval 0.99-1.00). Heterogeneity was not observed between prefectures (Cochran Q test, p = 0.187, I 2  = 18.4 %)., Conclusions: Exposure to PM 2.5 is not associated with overall emergency ambulance dispatches for cardiovascular diseases in Japan.

Background: Dysphagia is a serious health problem in aging populations. Older persons also experience high rates of chronic illness and hospitalization. Accurate identification of dysphagia at the time of hospital admission is important for providing supportive interventions for effective swallowing and preventing complications of dysphagia., Objectives: This study aimed to estimate the prevalence of potential impairment of swallowing function, the association between self-reported and observed swallowing difficulty, and factors associated with swallowing impairment in hospitalized patients., Methods: Data from 11,963 patients who were admitted to a community hospital from July 2012 to June 2014 were used. Patients responded to a brief self-administered questionnaire (BSAQ) about swallowing difficulties and performed a modified water swallow test (MWST) using a standardized protocol. Sensitivity and specificity of the BSAQ were evaluated against swallowing impairment based on the MWST. Logistic regression analysis was performed to evaluate associations between background characteristics and impaired swallowing as evaluated by the screening tests., Results: Median age of patients was 73 years (interquartile range, 63-81 years), and 5,780 (48.3%) were women. On the BSAQ, a total of 3,026 patients reported severe symptoms in any of 15 dysphagia-related questions (253 per 1,000 patients). The MWST showed that 593 patients were unable to successfully swallow 3 ml of cold water without choking or experiencing wet hoarseness two times within 30 seconds (50 per 1,000 patients). Each item score and the total score of the BSAQ were significantly associated with impaired swallowing as evaluated by the MWST. The sensitivity and specificity of the BSAQ for impaired swallowing as evaluated by the MWST were 72% and 66%, respectively. The prevalence of impaired swallowing as evaluated by both tests increased with age-especially in patients of ages ≥80 years. Age, male gender, and underlying diseases, including neurological and respiratory diseases, were associated with swallowing dysfunction detected by the MWST., Discussion: Impaired swallowing function may frequently be present in older hospitalized patients. The clinical significance of the validated screening tests in nursing practice should be further studied.

Background and Purpose: Although plasma C-reactive protein (CRP) is elevated in response to inflammation caused by brain infarction, the association of CRP with clinical outcomes after acute ischemic stroke remains uncertain. This study examined whether plasma high-sensitivity CRP (hsCRP) levels at onset were associated with clinical outcomes after acute ischemic stroke independent of conventional risk factors and acute infections after stroke., Methods: We prospectively included 3653 patients with first-ever ischemic stroke who had been functionally independent and were hospitalized within 24 h of onset. Plasma hsCRP levels were measured on admission and categorized into quartiles. The association between hsCRP levels and clinical outcomes, including neurological improvement, neurological deterioration, and poor functional outcome (modified Rankin scale ≥3 at 3 months), were investigated using a logistic regression analysis., Results: Higher hsCRP levels were significantly associated with unfavorable outcomes after adjusting for age, sex, baseline National Institutes of Health Stroke Scale score, stroke subtype, conventional risk factors, intravenous thrombolysis and endovascular therapy, and acute infections during hospitalization (multivariate-adjusted odds ratios [95% confidence interval] in the highest quartile versus the lowest quartile as a reference: 0.80 [0.65-0.97] for neurological improvement, 1.72 [1.26-2.34] for neurological deterioration, and 2.03 [1.55-2.67] for a poor functional outcome). These associations were unchanged after excluding patients with infectious diseases occurring during hospitalization, or those with stroke recurrence or death. These trends were similar irrespective of stroke subtypes or baseline stroke severity, but more marked in patients aged <70 years (Pheterogeneity = 0.001)., Conclusions: High plasma hsCRP is independently associated with unfavorable clinical outcomes after acute ischemic stroke.

Background: Oral anticoagulants (OACs) reduce the incidence of embolic events associated with non-valvular atrial fibrillation (NVAF); however, ischemic stroke can still occur in such patients. Although there are various causes of ischemic stroke in patients with NVAF, their medication status at onset has scarcely been studied. This retrospective study aimed to determine the underlying causes of ischemic stroke in patients with NVAF in relation to pre-stroke anticoagulation., Methods: Among Japanese patients with acute ischemic stroke enrolled in the Fukuoka Stroke Registry from June 2007 to May 2013, 1,302 patients with NVAF who had been hospitalized within 24 h of onset were included in this study, and their backgrounds, pre-stroke use of OACs and prothrombin time-international normalized ratio (PT-INR) on admission were investigated. Strokes were regarded as being non-cardioembolic (CE) type when causes other than NVAF had been identified. The sub-therapeutic range (TR) for warfarin was defined according to Japanese guidelines for pharmacotherapy of atrial fibrillation., Results: Atrial fibrillation had been diagnosed prior to onset of stroke in 704 of 1,302 patients (54%). However, it had not been detected before or on admission, but identified later during hospitalization in 270 patients (21%). Of the patients who had atrial fibrillation on admission but had not been diagnosed as having it, 108 (8%) had not received any medication before onset of stroke and 220 (17%) had received medications other than OACs. OACs had been administered to 415 (59%) of the patients with known atrial fibrillation. The proportion of pre-stroke CHADS2 or CHA2DS2-VASc scores ≥1 ranged from 93 to 99% depending on whether atrial fibrillation had been diagnosed or anticoagulation therapy administered before stroke onset. The PT-INR was in the sub-TR on admission in 283 of 399 patients (71%) receiving warfarin. Male sex, smoking and previous stroke were more prevalent in patients with values within or over the TR of PT-INR than in those in the sub-TR. Non-CE stroke was more prevalent in patients with values above the lower therapeutic limit of the recommended PT-INR than in those in the sub-TR (p < 0.001). The number of CE strokes was much smaller in patients with high admission PT-INR values; this was not observed for non-CE ischemic strokes (p < 0.001)., Conclusions: In the clinical setting, under-diagnosis, underuse and sub-therapeutic doses of OACs are major causes of ischemic stroke in patients with NVAF. However, non-CE ischemic strokes may develop in patients receiving therapeutic doses of warfarin., (© 2016 S. Karger AG, Basel.)

Background: Statins have neuroprotective effects against ischemic stroke. However, associations between pre-stroke statin treatment and initial stroke severity and between the treatment and functional outcome remain controversial. This study aimed at determining these associations in ischemic stroke patients., Methods: Among patients registered in the Fukuoka Stroke Registry from June 2007 to October 2014, 3,848 patients with ischemic stroke within 24 h of onset, who had been functionally independent before onset, were enrolled in this study. Ischemic stroke was classified as cardioembolic or non-cardioembolic infarction. Primary and secondary study outcomes were mild neurological symptoms defined as a National Institutes of Health Stroke Scale score of ≤4 on admission and favorable functional outcome defined as a modified Rankin Scale score of ≤2 at discharge, respectively. Multivariable logistic regression models were used to quantify associations between pre-stroke statin treatment and study outcomes., Results: Of all 3,848 participants, 697 (18.1%) were taking statins prior to the stroke. The frequency of mild neurological symptoms was significantly higher in patients with pre-stroke statin treatment (64.1%) than in those without the treatment (58.3%, p < 0.01). Multivariable analysis showed that pre-stroke statin treatment was significantly associated with mild neurological symptoms (OR 1.31; 95% CI 1.04-1.65; p < 0.01). Sensitivity analysis in patients with dyslipidemia (n = 1,998) also showed the same trend between pre-stroke statin treatment and mild neurological symptoms (multivariable-adjusted OR 1.26; 95% CI 0.99-1.62; p = 0.06). In contrast, the frequency of favorable functional outcome was not different between patients with (67.0%) and without (65.3%) the treatment (p = 0.40). Multivariable analysis also showed no significant association between pre-stroke statin treatment and favorable functional outcome (OR 1.21; 95% CI 0.91-1.60; p = 0.19). Continuation of statin treatment, however, was significantly associated with favorable functional outcome among patients with pre-stroke statin treatment (multivariable-adjusted OR 2.17; 95% CI 1.16-4.00; p = 0.02)., Conclusions: Pre-stroke statin treatment in ischemic stroke patients was significantly associated with mild neurological symptoms within 24 h of onset. Pre-stroke statin treatment per se did not significantly influence the short-term functional outcome; however, continuation of statin treatment during the acute stage of stroke seems to relate with favorable functional outcome for patients with pre-stroke statin treatment., (© 2016 S. Karger AG, Basel.)

Central nervous system (CNS) pericytes have been recognized as an indispensable component of the neurovascular unit. The expression of platelet-derived growth factor receptor β (PDGFRβ) is markedly increased in CNS pericytes after brain ischemia. It has been elucidated that PDGFRβ, expressed in pericytes and pericyte-derived fibroblast-like cells, plays important roles in the maintenance of the blood-brain barrier (BBB) and in the repair process in infarct areas. The aim of this study was to uncover how the PDGFRβ expression is regulated in pericytes after brain ischemia. We found that basic fibroblast growth factor (bFGF), but neither hypoxia at 1% O2 nor acidification at pH 6.5, significantly upregulated the PDGFRβ expression in human cultured CNS pericytes. SU5402, an inhibitor of FGF receptor (FGFR), and inhibitors of its downstream effectors Akt and Erk abolished the bFGF-induced upregulation of PDGFRβ. On the other hand, acidification significantly upregulated the expression of bFGF, while hypoxia upregulated the expression of FGFR1 in the pericytes. The expression of bFGF and FGFR1 was markedly induced in the ischemic hemisphere after ischemic insult in a middle cerebral artery occlusion stroke model. Immunofluorescent double labeling demonstrated that the expression of bFGF and FGFR1 was co-localized with PDGFRβ-positive cells in peri-infarct areas. Moreover, treatment with bFGF enhanced cell growth and the PDGF-BB-induced migratory activity of cultured pericytes, which were significantly suppressed by SU5402 or Sunitinib, an inhibitor of PDGFR. These data suggested that increased bFGF upregulates the expression of PDGFRβ and may enhance PDGFRβ-mediated pericyte functions after brain ischemia., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Involvement of central nervous system is very common in Behçet disease, known as neuro-Behçet disease (NBD). However, there have been few reports which evaluated stroke-like cerebral small-vessel disease associated with Behçet disease., Objective: We evaluated cerebral small-vessel lesions by using magnetic resonance imaging in 2 patients with NBD., Clinical Cases: In a 41-year-old woman case, who developed dysarthria and left hemiparesis, diffusion-weighted images (DWI) showed small high-intensity areas in the bilateral internal capsule. The right lesion had a low apparent diffusion coefficient (ADC) value, whereas the left one had a high value. In a 59-year-old woman case, who developed dysarthria and left hemihypesthesia, DWI showed high-intensity areas in the right side of the pons and in the right peduncle of the midbrain. The lesion in the pons had a low ADC value, whereas the lesion in the midbrain had a high value. ADC map may be useful to identify symptomatic lesions in the brain, because only the lesions with low ADC values were symptomatic., Conclusions: NBD should be considered in those who had not had any risk factors for ischemic stroke but experienced cerebral small-vessel disease., (Copyright © 2015 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: The relationship between blood pressure (BP) variability and functional outcome in patients with acute ischemic stroke remains unclear. This study aimed to elucidate whether in-hospital day-by-day BP variability is associated with functional outcome after acute ischemic stroke., Methods: Using the Fukuoka Stroke Registry, we included 2566 patients with a first-ever ischemic stroke who had been functionally independent before the onset and were hospitalized within 24 hours. BP was measured daily, and its variability was assessed by SD, coefficients of variance, and variations independent of mean. Poor functional outcome was assessed by modified Rankin Scale scores ≥3 at 3 months., Results: After adjustment for multiple confounding factors including age, sex, risk factors, stroke features, baseline severity, thrombolytic therapy, antihypertensive agents, and mean BP, day-by-day BP variability during the subacute stage (4-10 days after onset) was independently associated with a poor functional outcome (multivariable-adjusted odds ratios [95% confidence interval] in the top versus bottom quartile of systolic BP variability, 1.51 [1.09-2.08] for SD; 1.63 [1.20-2.22] for coefficients of variance; 1.64 [1.21-2.24] for variations independent of mean). Similar trends were also observed for diastolic BP variability. These trends were unchanged in patients who were not treated with antihypertensive drugs. In contrast, no association was found between indices of BP variability during the acute stage and functional outcome after adjusting for potential confounders., Conclusions: These data suggest that intraindividual day-by-day BP variability during the subacute stage is associated with the 3-month functional outcome after acute ischemic stroke., (© 2015 American Heart Association, Inc.)

Fibrosis is concomitant with repair processes following injuries in the central nervous system (CNS). Pericytes are considered as an origin of fibrosis-forming cells in the CNS. Here, we examined whether platelet-derived growth factor receptor β (PDGFRβ), a well-known indispensable molecule for migration, proliferation, and survival of pericytes, was involved in the production of extracellular matrix proteins, fibronectin and collagen type I, which is crucial for fibrosis after ischemic stroke. Immunohistochemistry demonstrated induction of PDGFRβ expression in vascular cells of peri-infarct areas at 3-7days in a mouse stroke model. The PDGFRβ-expressing cells extended from peri-infarct areas toward the ischemic core after day 7 while expressing fibronectin and collagen type I in the infarct areas. In contrast, desmin and α-smooth muscle actin, markers of pericytes, were only expressed in vascular cells. In PDGFRβ heterozygous knockout mice, the expression of fibronectin and collagen type I was attenuated at both mRNA and protein levels with an enlargement of the infarct volume after ischemic stroke compared with that in wild-type littermates. In cultured brain pericytes, the expression of PDGF-B, PDGFRβ, fibronectin, and collagen type I, but not desmin, was significantly increased by serum depletion (SD). The SD-induced upregulation of fibronectin and collagen type I was suppressed by SU11652, an inhibitor of PDGFRβ, while PDGF-B further increased the SD-induced upregulation. In conclusion, the expression level of PDGFRβ may be a crucial determinant of fibrosis after ischemic stroke. Moreover, PDGFRβ signaling participates in the production of fibronectin and collagen type I after ischemic stroke., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background and Purpose: Variable sex differences in clinical outcomes after stroke have been reported worldwide. This study aimed to elucidate whether sex is an independent risk factor of poor functional outcome after acute ischemic stroke., Methods: Using the database of patients with acute stroke registered in the Fukuoka Stroke Registry in Japan from 1999 to 2013, 6236 previously independent patients with first-ever ischemic stroke who were admitted within 24 hours of onset were included in this study. Baseline characteristics were assessed on admission. Study outcomes included neurological improvement, neurological deterioration, and poor functional outcome (modified Rankin Scale score, 3-6 at discharge). Logistic regression analyses were performed to evaluate the association between sex and clinical outcomes., Results: Overall, 2398 patients (38.5%) were women. Severe stroke (National Institutes of Health Stroke Scale score, ≥8) on admission was more prevalent in women than in men. The frequency of neurological improvement or deterioration during hospitalization was not different between the sexes. After adjusting for possible confounders, including age, stroke subtype and severity, risk factors, and poststroke treatments, it was found that female sex was independently associated with poor functional outcome at discharge (odds ratio, 1.30; 95% confidence interval, 1.08-1.57). There was heterogeneity of the association between sex and poor outcome according to age: women had higher risk of poor outcome than men among patients aged ≥70 years, but no clear sex difference was found in patients aged <70 years., Conclusions: Female sex was associated with the risk of poor functional outcome at discharge after acute ischemic stroke., (© 2014 American Heart Association, Inc.)

We herein report the finding of a 62-year-old male, who developed dysarthria and dysphagia, with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy- (CADASIL-) like cerebral lesions. He also suffered from slowly progressive renal failure with the findings of granular deposits similar to electron-dense granular osmiophilic material in the renal arterioles. We found a novel heterozygous missense mutation of the NOTCH3 gene, c.4039G>C in exon 24, resulting in a p.Gly1347Arg substitution in its extracellular domain. The noncysteine substitution may underlie the pathogenesis of white matter lesions in the brain and of the chronic renal failure in the present case.

Objective: Thiazide diuretics are reported to have antioxidant effects and reduce pulse pressure (PP). The aim of this study was to elucidate whether hydrochlorothiazide additionally exerts such effects in stroke patients under treatment with losartan., Methods: This study was an open-label, randomized, multicenter study. Patients with a history of chronic stroke and treatment with angiotensin receptor blockers or angiotensin-converting enzyme inhibitors for essential hypertension were enrolled. Fifty-five hypertensive patients were randomly assigned to two groups: those further treated with hydrochlorothiazide and those further treated with non-diuretic antihypertensive drugs., Results: Both groups showed a significant decrease in PP over six months (hydrochlorothiazide group: 67±12 mmHg to 58±12, p<0.001; non-diuretic group: 72±12 to 61±12, p<0.001), although no significant differences were observed between the two groups. The malondialdehyde-modified low-density lipoprotein levels did not change significantly after treatment in either group., Conclusion: In this study, hydrochlorothiazide treatment did not provide any additional benefits over non-diuretic antihypertensive drugs in terms of antioxidant effects or reducing PP.

Objectives: The benefit of intravenous recombinant tissue plasminogen activator (rt-PA) therapy for very old patients with acute ischemic stroke remains unclear. The aim of this study was to elucidate the efficacy and safety of intravenous rt-PA therapy for patients over 80 years old., Methods: Of 13,521 stroke patients registered in the Fukuoka Stroke Registry in Japan from June 1999 to February 2013, 953 ischemic stroke patients who were over 80 years old, hospitalized within 3 h of onset, and not treated with endovascular therapy were included in this study. Among them, 153 patients were treated with intravenous rt-PA (0.6 mg/kg). For propensity score (PS)-matched case-control analysis, 148 patients treated with rt-PA and 148 PS-matched patients without rt-PA therapy were selected by 1:1 matching with propensity for using rt-PA. Clinical outcomes were neurological improvement, good functional outcome at discharge, in-hospital mortality, and hemorrhagic complications (any intracranial hemorrhage [ICH], symptomatic ICH, and gastrointestinal bleeding)., Results: In the full cohort of 953 patients, rt-PA use was associated positively with neurological improvement and good functional outcome, and negatively with in-hospital mortality after adjustment for multiple confounding factors. In PS-matched case-control analysis, patients treated with rt-PA were still at lower risk for unfavorable clinical outcomes than non-treated patients (neurological improvement, odds ratio 2.67, 95% confidence interval 1.61-4.40; good functional outcome, odds ratio 2.23, 95% confidence interval 1.16-4.29; in-hospital mortality, odds ratio 0.30, 95% confidence interval 0.13-0.65). There was no significant association between rt-PA use and risk of hemorrhagic complications in the full and PS-matched cohorts., Conclusions: Intravenous rt-PA therapy was associated with improved clinical outcomes without significant increase in risk of hemorrhagic complications in very old patients (aged>80 years) with acute ischemic stroke.

Aim: The present study aimed to determine the efficacy and safety of thrombolytic therapy with recombinant tissue plasminogen activator (rt-PA) therapy in older patients compared with younger patients., Methods: Using the Fukuoka Stroke Registry, a prospective multicenter study for acute stroke in Japan, we analyzed data of 401 patients with acute ischemic stroke (aged 74.5 ± 13.1 years) treated with thrombolytic therapy using rt-PA. Patients were categorized into two groups according to age: those aged ≥ 75 years (n=240) and <75 years (n=161). Neurological improvement was defined as a decrease in the National Institute of Health Stroke Scale (NIHSS) score of ≥ 4 during hospitalization or an NIHSS score of 0 at discharge. Good functional outcome was defined as a modified Rankin scale score of 0-2 at 3 months after onset., Results: Neurological symptoms at admission were more severe in older patients than in younger patients. Old age (≥ 75 years) was not associated with neurological deterioration (multivariate-adjusted odds ratio [OR] 0.90, 95% confidence interval [CI] 0.46-1.77), neurological improvement (multivariate-adjusted OR 0.91, 95% CI 0.54-1.53) and symptomatic intracranial hemorrhage (multivariate-adjusted OR 1.11, 95% CI 0.19-8.87). Old age was negatively associated with good functional outcome (multivariate-adjusted OR 0.29, 95% CI 0.16-0.52) and positively associated with in-hospital mortality (multivariate-adjusted OR 19.3, 95% CI 2.4-474.9)., Conclusions: In patients treated with rt-PA, old age is associated with poor functional outcome and in-hospital mortality. However, the probability of neurological improvement and symptomatic intracranial hemorrhage in older patients is comparable with that in younger patients., (© 2013 Japan Geriatrics Society.)

Objective: Although adiponectin is a major adipocytokine that affects the pathogenesis of various cardiovascular diseases, its clinical significance in stroke remains controversial. We investigated the clinical significance of plasma adiponectin for the diagnosis, neurological severity and functional outcomes of patients with ischemic stroke., Methods: We prospectively enrolled 171 patients with ischemic stroke and 171 age- and sex-matched healthy controls. Blood samples and clinical information were obtained at day 0, 3, 7, 14 and 90 after stroke onset., Results: Average adiponectin values at day 0 did not significantly differ between the controls and the patients, but were significantly lower and higher in patients with atherothrombotic brain (ATBI) (p=0.047) and cardioembolic (CE) (p=0.008) infarction, respectively, than in the controls. Multivariate logistic regression analyses showed that the adiponectin value at day 0 could predict ATBI (odds ratio, 0.75; 95% confidence interval, 0.58 to 0.91, p=0.009, per 1-μg/mL increase). Adiponectin values at day 0 were positively associated with neurological severity as evaluated by the National Institute of Health Stroke Scale upon admission (r=0.420, p=0.003) and were higher in the groups with poor outcomes (modified Rankin Scale (mRS) ≥ 3 on day 90) than in those with good ones (mRS ≤ 2) in all stroke subtypes, with statistical significance in ATBI (p=0.015)., Conclusions: Plasma adiponectin values may help to classify stroke subtypes and predict neurological severity and functional outcome in ischemic stroke patients., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Gastrointestinal (GI) hemorrhage is a potentially serious complication of acute stroke, but its incidence appears to be decreasing. The aim of this study was to elucidate the etiology of GI bleeding and its impact on clinical outcomes in patients with acute ischemic stroke in recent years., Methods: Using the database of the Fukuoka Stroke Registry, 6,529 patients with acute ischemic stroke registered between June 2007 and December 2012 were included in this study. We recorded clinical data including any previous history of peptic ulcer, prestroke drug history including the use of antiplatelets, anticoagulants, steroids and nonsteroidal anti-inflammatory drugs (NSAIDs), and poststroke treatment with suppressing gastric acidity. GI bleeding was defined as any episode of hematemesis or melena on admission or during hospitalization. The cause and origin of bleeding were diagnosed endoscopically. Logistic regression analysis was used to identify risk factors for GI bleeding and its influence on deteriorating neurologic function, death, and poor outcome., Results: GI bleeding occurred in 89 patients (1.4%) under the condition that 66% of the total patients received acid-suppressing agents after admission. Multivariate analysis revealed that GI bleeding was associated with the absence of dyslipidemia (p = 0.03), a previous history of peptic ulcer (p < 0.001), and the severity of baseline neurologic deficit (p = 0.002) but not with antiplatelet drugs, anticoagulants, and NSAIDs. The source was the upper GI tract in 51% of the cases; causes included peptic ulceration (28%) and malignancies (12%), and other or unidentified causes accounted for 60%. GI bleeding mostly occurred within 1 week after stroke onset. Hemoglobin concentration fell by a median value of 2.5 g/dl in patients with GI bleeding. Among them, 28 patients underwent blood transfusion (31.5%). After adjustment for confounding factors, GI bleeding was independently associated with neurologic deterioration (OR 3.9, 95% CI 2.3-6.6, p < 0.001), in-hospital death (OR 6.1, 95% CI 3.1-12.1, p < 0.001), and poor outcome at 3 months (OR 6.8, 95% CI 3.7-12.7, p < 0.001). These associations were significant irrespective of whether patients underwent red blood cell transfusion., Conclusions: GI bleeding infrequently occurred in patients with acute ischemic stroke, which was mostly due to etiologies other than peptic ulcer. GI bleeding was associated with poor clinical outcomes including neurologic deterioration, in-hospital mortality, and poor functional outcome.

Background: Epidemiologic studies have elucidated that the 1425G/A single-nucleotide polymorphism (rs2230500 single-nucleotide polymorphism) in exon 9 of the protein kinase C eta (PRKCH) gene is an independent risk factor for ischemic stroke: stroke incidence is significantly higher in the subjects with AA than those with AG or GG genotype. However, its impact on stroke recurrence remains unknown. The aim of the present study was to clarify whether the polymorphism is also a risk factor for recurrent stroke in patients with acute ischemic stroke., Methods: We enrolled 2418 consecutive patients with acute and first-ever ischemic stroke and investigated the 1425G/A polymorphism of PRKCH. Patients were followed up for a median of 733 days. The association between the polymorphism and stroke recurrence was investigated using the Cox proportional hazard model., Results: In the enrolled patients, the GG genotype was the most prevalent (63%), followed by AG (32%) and AA genotypes (5%). Recurrent stroke occurred in 302 patients during the follow-up period. Kaplan-Meier analyses revealed no difference in the rate of recurrent stroke after first-ever stroke among the 3 genotypes. The incidence of recurrent stroke was not significantly different in patients with AA (hazard ratio [HR] 1.02, 95% confidence interval .59-1.64, P=.94) or AG (HR .89, 95% confidence interval .69-1.14, P=.36) genotypes compared with those with the GG genotype after adjusting for multiple confounders., Conclusions: The 1425G/A polymorphism in PRKCH is not a significant predictor of stroke recurrence in patients with acute ischemic stroke during a 2-year follow-up period., (Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.)