Language：English   Publishing type：Research paper (scientific journal)   Publisher：Stroke  

BACKGROUND: It remains unclear how chronic kidney disease and its underlying pathological conditions, kidney dysfunction, and kidney damage, are associated with cardiovascular outcomes. This study aimed to determine whether kidney dysfunction (ie, decreased estimated glomerular filtration rate), kidney damage (ie, proteinuria), or both are associated with the long-term outcomes after ischemic stroke. METHODS: A total of 12 576 patients (mean age, 73.0±12.6 years; 41.3% women) with ischemic stroke who were registered in a hospital-based multicenter registry, Fukuoka Stroke Registry, between June 2007 and September 2019, were prospectively followed up after stroke onset. Kidney function was assessed by estimated glomerular filtration rate and categorized into G1: ≥60 mL/(min·1.73 m2), G2: 45-59 mL/(min·1.73 m2), and G3: <45 mL/(min·1.73 m2). Kidney damage was evaluated by proteinuria using a urine dipstick test and classified into P1: -, P2: ±/1+, and P3: ≥2+. Hazard ratios and 95% CI for events of interest were estimated by a Cox proportional hazards model. Long-term outcomes included recurrence of stroke and all-cause death. RESULTS: During the median follow-up of 4.3 years (interquartile range, 2.1-7.3 years), 2481 patients had recurrent stroke (48.0/1000 patient-years) and 4032 patients died (67.3/1000 patient-years). Chronic kidney disease was independently associated with increased risks of stroke recurrence and all-cause death even after adjustment for multiple confounding factors, including traditional cardiovascular risk factors. Both estimated glomerular filtration rate and proteinuria were independently associated with increased risks of stroke recurrence (multivariable-adjusted hazard ratio [95% CI], G3: 1.22 [1.09-1.37] versus G1, P3: 1.25 [1.07-1.46] versus P1) and death (G3: 1.45 [1.33-1.57] versus G1, P3: 1.62 [1.45-1.81] versus P1). In subgroup analyses, effect modifications were found in the association of proteinuria with death by age and stroke subtype. CONCLUSIONS: Kidney dysfunction and kidney damage were independently, but differently, associated with increased risks of recurrent stroke and all-cause death.

DOI： 10.1161/STROKEAHA.122.040958

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of the Neurological Sciences  

BACKGROUND AND PURPOSE: This study examined the association between age and clinical outcomes after ischemic stroke, and whether the effect of age on post-stroke outcomes can be modified by various factors. METHODS: We included 12,171 patients with acute ischemic stroke, who were functionally independent before stroke onset, in a multicenter hospital-based study conducted in Fukuoka, Japan. Patients were categorized into six groups according to age: ≤ 45, 46-55, 56-65, 66-75, 76-85, and > 85 years. Logistic regression analysis was performed to estimate an odds ratio for poor functional outcome (modified Rankin scale score of 3-6 at 3 months) for each age group. Interaction effects of age and various factors were analyzed using a multivariable model. RESULTS: The mean age of the patients was 70.3 ± 12.2 years, and 63.9% were men. Neurological deficits at onset were more severe in the older age groups. The odds ratio of poor functional outcome linearly increased (P for trend <0.001), even after adjusting for potential confounders. Sex, body mass index, hypertension, and diabetes mellitus significantly modified the effect of age on the outcome (P < 0.05). The unfavorable effect of older age was greater in female patients and those with low body weight, whereas the protective effect of younger age was smaller in patients with hypertension or diabetes mellitus. CONCLUSIONS: Functional outcome worsened with age in patients with acute ischemic stroke, especially in females and those with low body weight, hypertension, or hyperglycemia.

DOI： 10.1016/j.jns.2023.120589

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PLoS ONE  

BACKGROUND: Very few comparative studies have focused on the differences in the causes of ischemic stroke between young adults and non-young adults. This study was performed to determine what causes of ischemic stroke are more important in young adults than in non-young adults using a large-scale multicenter hospital-based stroke registry in Fukuoka, Japan. METHODS AND RESULTS: We investigated data on 15,860 consecutive patients aged ≥18 years with acute ischemic stroke (mean age: 73.5 ± 12.4 years, 58.2% men) who were hospitalized between 2007 and 2019. In total, 779 patients were categorized as young adults (≤50 years of age). Although vascular risk factors, including hypertension, diabetes mellitus, and dyslipidemia, were less frequent in young adults than in non-young adults, the prevalence of diabetes mellitus and dyslipidemia in young adults aged >40 years were comparable to those of non-young adults. Lifestyle-related risk factors such as smoking, drinking, and obesity were more frequent in young adults than in non-young adults. As young adults became older, the proportions of cardioembolism and stroke of other determined etiologies decreased, but those of large-artery atherosclerosis and small-vessel occlusion increased. Some embolic sources (high-risk sources: arterial myxoma, dilated cardiomyopathy, and intracardiac thrombus; medium-risk sources: atrial septal defect, nonbacterial thrombotic endocarditis, patent foramen ovale, and left ventricular hypokinesis) and uncommon causes (vascular diseases: reversible cerebral vasoconstriction syndrome, moyamoya disease, other vascular causes, arterial dissection, and cerebral venous thrombosis; hematologic diseases: antiphospholipid syndrome and protein S deficiency) were more prevalent in young adults than in non-young adults, and these trends decreased with age. CONCLUSIONS: Certain embolic sources and uncommon causes may be etiologically important causes of ischemic stroke in young adults. However, the contribution of conventional vascular risk factors and lifestyle-related risk factors is not negligible with advancing age, even in young adults.

DOI： 10.1371/journal.pone.0268481

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Stroke  

BACKGROUND AND PURPOSE: This study aimed to determine whether variability of day-by-day blood pressure (BP) during the subacute stage of acute ischemic stroke is predictive of long-term stroke recurrence. METHODS: We analyzed 7665 patients (mean±SD age: 72.9±13.1 years; women: 42.4%) hospitalized for first-ever ischemic stroke in 7 stroke centers in Fukuoka, Japan, from June 2007 to November 2018. BP was measured daily during the subacute stage (4-10 days after onset). Its mean and coefficient of variation (CV) values were calculated and divided into 4 groups according to the quartiles of these BP parameters. Patients were prospectively followed up for recurrent stroke or all-cause death. The cumulative event rate was calculated with the Kaplan-Meier method. We estimated the hazard ratios and 95% confidence intervals of the events of interest after adjusting for potential confounders and mean BP values using Cox proportional hazards models. The Fine-Gray model was also used to account for the competing risk of death. RESULTS: With a mean (±SD) follow-up duration of 3.9±3.2 years, the rates of recurrent stroke and all-cause death were 3.9 and 9.9 per 100 patient-years, respectively. The cumulative event rates of recurrent stroke and all-cause death increased with increasing CVs of systolic BP and diastolic BP. The systolic BP CV was significantly associated with an increased risk of recurrent stroke after adjusting for multiple confounders and mean BP (hazard ratio [95% CI] for fourth quartile versus first quartile, 1.26 [1.05-1.50]); the risk of recurrent stroke also increased with an increasing systolic BP CV for nonfatal strokes (1.26 [1.05-1.51]) and when death was regarded as a competing risk (1.21 [1.02-1.45]). Similar associations were observed for the diastolic BP CV. CONCLUSIONS: Day-by-day variability of BP during the subacute stage of acute ischemic stroke was associated with an increased long-term risk of recurrent stroke.

DOI： 10.1161/STROKEAHA.120.033751

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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&#37; 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&#37;), 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&#37; 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&#37; 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&#37; CI]: 0.62 [0.52-0.74]) and a lower risk of death due to these infections (subdistribution HR [95&#37; 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.

DOI： 10.1212/CPJ.0000000000001087

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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&#37; 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.

DOI： 10.1161/STROKEAHA.120.031392

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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&#37; men) who experienced ESUS without a potential source of embolism and received OAC alone or AP alone. We estimated hazard ratios (HRs) and 95&#37; 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&#37; 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.

DOI： 10.1159/000510773

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Background and Purpose—Smoking is an established risk factor for stroke; however, it is uncertain whether prestroke smoking status affects clinical outcomes of acute ischemic stroke. This study aimed to elucidate the association between smoking status and functional outcomes after acute ischemic stroke. Methods—Using a multicenter hospital-based stroke registry in Japan, we investigated 10 825 patients with acute ischemic stroke hospitalized between July 2007 and December 2017 who had been independent before stroke onset. Smoking status was categorized into those who had never smoked (nonsmokers), former smokers, and current smokers. Clinical outcomes included poor functional outcome (modified Rankin Scale score ≥2) and functional dependence (modified Rankin Scale score 2–5) at 3 months. We adjusted for potential confounding factors using a logistic regression analysis. Results—The mean age of patients was 70.2±12.2 years, and 37.0&#37; were women. There were 4396 (42.7&#37;) nonsmokers, 3328 (32.4&#37;) former smokers, and 2561 (24.9&#37;) current smokers. The odds ratio (95&#37; CI) for poor functional outcome after adjusting for confounders increased in current smokers (1.29 [1.11–1.49] versus nonsmokers) but not in former smokers (1.05 [0.92–1.21] versus nonsmokers). However, among the former smokers, the odds ratio of poor functional outcome was higher in those who quit smoking within 2 years of stroke onset (1.75 [1.15–2.66] versus nonsmokers). The risk of poor functional outcome tended to increase as the number of daily cigarettes increased in current smokers (P for trend=0.002). All these associations were maintained for functional dependence. Conclusions—Current and recent smoking is associated with an increased risk of unfavorable functional outcomes at 3 months after acute ischemic stroke.

DOI： 10.1161/STROKEAHA.119.027230

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Objective In this study, we aimed to determine whether insulin resistance is associated with clinical outcomes after acute ischemic stroke.MethodsWe enrolled 4,655 patients with acute ischemic stroke (aged 70.3 ± 12.5 years, 63.5&#37; 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.ResultsThe HOMA-IR score was associated with neurologic improvement (odds ratio, 0.68 [95&#37; 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.ConclusionsThese 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.

DOI： 10.1212/WNL.0000000000005358

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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&#37; 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&#37; 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 [2.0
_2-3
.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.

DOI： 10.1161/STROKEAHA.117.018132

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DOI： 10.1253/circj.CJ-16-1287

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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&#37; 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.

DOI： 10.1161/STROKEAHA.116.015303

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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&#37; 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 (P_{heterogeneity} = 0.001). Conclusions: High plasma hsCRP is independently associated with unfavorable clinical outcomes after acute ischemic stroke.

DOI： 10.1371/journal.pone.0156790

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DOI： 10.1371/journal.pone.0110444

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DOI： 10.1111/ggi.12205

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DOI： 10.1016/j.jstrokecerebrovasdis.2013.11.011

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DOI： 10.1186/1471-2377-13-32

Language：English   Publisher：Hypertension Research  

The aim of this study was to determine whether pulse pressure (PP), an indicator of arterial stiffness, was independently associated with the risk of acute kidney injury (AKI) following intracerebral hemorrhage (ICH). We enrolled patients with acute ICH from a multicenter stroke registry in Fukuoka, Japan, from June 2007 to September 2019. The mean PP, measured three times on the third day after admission, was categorized into three groups based on tertiles: G1 < 54 mmHg, G2 54–64 mmHg, and G3 ≥ 65 mmHg. AKI was defined as an increase of ≥0.3 mg/dL or ≥150% in serum creatinine levels above baseline during hospitalization. The associations between PP and AKI were evaluated using logistic regression analyses. Overall, 1512 patients with acute ICH (mean age: 69.8 ± 13.5 years; 56.4% men) were included in the analysis. The incidence rates of AKI were 5.6%, 11.0%, and 13.2% in groups G1, G2, and G3, respectively. The odds ratio (95% confidence interval) of AKI was significantly elevated in G2 (1.77 [1.07–2.91]) and G3 (1.82 [1.10–3.03]) compared to G1, even after adjusting for initial systolic blood pressure (SBP) values on admission and subsequent SBP reductions. This significant association was observed in patients with an initial SBP < 200 mmHg (P for heterogeneity, 0.045) and those receiving intravenous antihypertensive therapy in the acute stage (P for heterogeneity, 0.03). High PP should be recognized as a novel potential risk factor for AKI following ICH. (Figure presented.)

DOI： 10.1038/s41440-024-02046-2

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DOI： 10.7759/cureus.59135

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Abstract

Smoking has detrimental effects on the cardiovascular system; however, some studies have reported better clinical outcomes after thrombolysis for ischemic stroke in smokers than in nonsmokers, a phenomenon known as the smoking paradox. Therefore, this study aimed to examine the smoking paradox in patients with ischemic stroke receiving reperfusion therapy. Data were collected from a multicenter hospital-based acute stroke registry in Fukuoka, Japan. The 1148 study patients were categorized into current and noncurrent smokers. The association between smoking and clinical outcomes, including neurological improvement (≥ 4-point decrease in the National Institutes of Health Stroke Scale during hospitalization or 0 points at discharge) and good functional outcomes (modified Rankin Scale score of 0–2) at 3 months, was evaluated using logistic regression analysis and propensity score-matched analysis. Among the participants, 231 (20.1%) were current smokers. The odds ratios (ORs) of favorable outcomes after adjusting for potential confounders were not significantly increased in current smokers (OR 0.85, 95% confidence interval [CI] 0.60–1.22 for neurological improvement; OR 0.95, 95% CI 0.65–1.38 for good functional outcome). No significant association was found in the propensity score-matched cohorts. Smoking cessation is strongly recommended since current smoking was not associated with better outcomes after reperfusion therapy.

DOI： 10.1038/s41598-024-59508-3

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Other Link： https://www.nature.com/articles/s41598-024-59508-3

Language：Others   Publishing type：Research paper (scientific journal)   Publisher：JMIR Publications Inc.  

Background

Although machine learning is a promising tool for making prognoses, the performance of machine learning in predicting outcomes after stroke remains to be examined.

Objective

This study aims to examine how much data-driven models with machine learning improve predictive performance for poststroke outcomes compared with conventional stroke prognostic scores and to elucidate how explanatory variables in machine learning–based models differ from the items of the stroke prognostic scores.

Methods

We used data from 10,513 patients who were registered in a multicenter prospective stroke registry in Japan between 2007 and 2017. The outcomes were poor functional outcome (modified Rankin Scale score &gt;2) and death at 3 months after stroke. Machine learning–based models were developed using all variables with regularization methods, random forests, or boosted trees. We selected 3 stroke prognostic scores, namely, ASTRAL (Acute Stroke Registry and Analysis of Lausanne), PLAN (preadmission comorbidities, level of consciousness, age, neurologic deficit), and iScore (Ischemic Stroke Predictive Risk Score) for comparison. Item-based regression models were developed using the items of these 3 scores. The model performance was assessed in terms of discrimination and calibration. To compare the predictive performance of the data-driven model with that of the item-based model, we performed internal validation after random splits of identical populations into 80% of patients as a training set and 20% of patients as a test set; the models were developed in the training set and were validated in the test set. We evaluated the contribution of each variable to the models and compared the predictors used in the machine learning–based models with the items of the stroke prognostic scores.

Results

The mean age of the study patients was 73.0 (SD 12.5) years, and 59.1% (6209/10,513) of them were men. The area under the receiver operating characteristic curves and the area under the precision-recall curves for predicting poststroke outcomes were higher for machine learning–based models than for item-based models in identical populations after random splits. Machine learning–based models also performed better than item-based models in terms of the Brier score. Machine learning–based models used different explanatory variables, such as laboratory data, from the items of the conventional stroke prognostic scores. Including these data in the machine learning–based models as explanatory variables improved performance in predicting outcomes after stroke, especially poststroke death.

Conclusions

Machine learning–based models performed better in predicting poststroke outcomes than regression models using the items of conventional stroke prognostic scores, although they required additional variables, such as laboratory data, to attain improved performance. Further studies are warranted to validate the usefulness of machine learning in clinical settings.

DOI： 10.2196/46840

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Language：Japanese   Publisher：Fukuoka Medical Association  

Database research for stroke have contributed to the development of evidence and the establishment of guidelines for stroke management. In Japan, the Fukuoka stroke registry, a regional cohort̶which provides highly accurate data̶and the Japan stroke data bank̶which includes nationwide comprehensive data̶have been collected through individual questionnaires (as revealed by a conventional epidemiological study). Recently, studies using existing data, such as insurance claims data, have become popular (as revealed by a data-driven epidemiological study). The nationwide survey of acute stroke care capacity for proper designation of comprehensive stroke center in Japan (J-ASPECT study) is assessing the quality of stroke care to close the gap between guidelines and clinical practice using data from the Diagnosis Procedure Combination, developed as a measurement tool to standardize, evaluate, and improve the quality of healthcare in Japan and to clarify the content of acute-phase hospital care. The National Database of Health Insurance Claims and Specific Health Checkups is the largest database globally that facilitates the visualization of stroke care in Japan. Large-scale real-world databases̶such as the Registry of the Canadian Stroke Network and Riks-Stroke̶have been constructed worldwide. In both cases, data are collected without obtaining consent and are linked to existing data, such as administrative data. However, the environment for database research has not been sufficiently developed from the perspective of personal information protection and research ethics in Japan. In this era of medical big data, extensive medical information is automatically recorded electronically. Medical DX (digital transformation) aims to enable the appropriate use of such medical information and linking it with existing data̶such as insurance claims data and administrative data. A large database research utilizing electronic information can change the future of stroke care.

DOI： 10.15017/7164781

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Cerebrovascular Diseases  

INTRODUCTION: Data on sex differences in poststroke functional status for a period longer than 1 year based on large cohorts are sparse. This study aimed to determine whether there are sex differences in long-term functional decline after ischemic stroke. METHODS: We tracked functional status for 5 years among 3-month survivors of acute ischemic stroke and compared outcomes between women and men using a large-scale hospital-based stroke registry in Fukuoka, Japan. Functional status was assessed using the modified Rankin Scale (mRS). Functional dependency was defined as an mRS score of 3, 4, or 5. Logistic regression analysis was used to estimate odds ratios (ORs) and 95% confidence intervals of outcomes after adjusting for possible confounders. RESULTS: A total of 8,446 patients (71.9 ± 12.5 years, 3,377 (40.0%) female patients) were enrolled in this study. Female sex was associated with a higher risk of functional dependency at 5 years poststroke even when adjusting for age, 3-month mRS score, and other confounding factors (multivariable-adjusted OR vs. men, 1.56 [95% confidence interval, 1.26-1.93]). This significant association of female sex with higher dependency at 5 years was also found among patients who were independent at 3 months poststroke. Subgroup analysis showed that increased risk of functional dependency in female patients was more marked in patients aged ≥75 years than in those aged <75 years (p for heterogeneity = 0.02). Conversely, female sex was associated with a lower risk of death. No sex difference was observed in stroke recurrence during 5 years poststroke. DISCUSSION/CONCLUSION: This longitudinal observational study suggests that female sex was independently associated with an increased risk of functional decline in the chronic phase of stroke, especially in older patients. There was no sex difference in 5-year stroke recurrence, and thus, other factors might be involved in more significant deterioration of functional status in female survivors of ischemic stroke. Further studies are needed to elucidate underlying causes of sex differences in long-term functional decline after stroke.

DOI： 10.1159/000526940

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Cytotherapy  

BACKGROUND AIMS: This prospective clinical study aimed to determine the efficacy and prognostic factors of adoptive activated αβT lymphocyte immunotherapy for various refractory cancers. The primary endpoint was overall survival (OS), and the secondary endpoint was radiological response. METHODS: The authors treated 96 patients. Activated αβT lymphocytes were infused every 2 weeks for a total of six times. Prognostic factors were identified by analyzing clinical and laboratory data obtained before therapy. RESULTS: Median survival time (MST) was 150 days (95% confidence interval, 105-191), and approximately 20% of patients achieved disease control (complete response + partial response + stable disease). According to the multivariate Cox proportional hazards model with Akaike information criterion-best subset selection, sex, concurrent therapy, neutrophil/lymphocyte ratio, albumin, lactate dehydrogenase, CD4:CD8 ratio and T helper (Th)1:Th2 ratio were strong prognostic factors. Using parameter estimates of the Cox analysis, the authors developed a response scoring system. The authors then determined the threshold of the response score between responders and non-responders. This threshold was able to significantly differentiate OS of responders from that of non-responders. MST of responders was longer than that of non-responders (317.5 days versus 74 days). The validity of this response scoring system was then confirmed by internal validation. CONCLUSIONS: Adoptive activated αβT lymphocyte immunotherapy has clinical efficacy in certain patients. The authors' scoring system is the first prognostic model reported for this therapy, and it is useful for selecting patients who might obtain a better prognosis through this modality.

DOI： 10.1016/j.jcyt.2022.09.007

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Stroke  

BACKGROUND: Quality indicators (QIs) are an accepted tool for measuring a hospital's performance in routine care. We examined national trends in adherence to the QIs developed by the Close The Gap-Stroke program by combining data from the health insurance claims database and electronic medical records, and the association between adherence to these QIs and early outcomes in patients with acute ischemic stroke in Japan. METHODS: In the present study, patients with acute ischemic stroke who received acute reperfusion therapy in 351 Close The Gap-Stroke-participating hospitals were analyzed retrospectively. The primary outcomes were changes in trends for adherence to the defined QIs by difference-in-difference analysis and the effects of adherence to distinct QIs on in-hospital outcomes at the individual level. A mixed logistic regression model was adjusted for patient and hospital characteristics (eg, age, sex, number of beds) and hospital units as random effects. RESULTS: Between 2013 and 2017, 21 651 patients (median age, 77 years; 43.0% female) were assessed. Of the 25 defined measures, marked and sustainable improvement in the adherence rates was observed for door-to-needle time, door-to-puncture time, proper use of endovascular thrombectomy, and successful revascularization. The in-hospital mortality rate was 11.6%. Adherence to 14 QIs lowered the odds of in-hospital mortality (odds ratio [95% CI], door-to-needle <60 min, 0.80 [0.69-0.93], door-to-puncture <90 min, 0.80 [0.67-0.96], successful revascularization, 0.40 [0.34-0.48]), and adherence to 11 QIs increased the odds of functional independence (modified Rankin Scale score 0-2) at discharge. CONCLUSIONS: We demonstrated national marked and sustainable improvement in adherence to door-to-needle time, door-to-puncture time, and successful reperfusion from 2013 to 2017 in Japan in patients with acute ischemic stroke. Adhering to the key QIs substantially affected in-hospital outcomes, underlining the importance of monitoring the quality of care using evidence-based QIs and the nationwide Close The Gap-Stroke program.

DOI： 10.1161/STROKEAHA.121.038483

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of NeuroInterventional Surgery  

BACKGROUND: The efficacy of combined stent retriever (SR) and aspiration catheter (AC; combined technique: CBT) use for acute ischemic stroke (AIS) is unclear. We investigated the safety and efficacy of single-unit CBT (SCBT)-retrieving the thrombus as a single unit with SR and AC into the guide catheter-compared with single use of either SR or contact aspiration (CA). METHODS: We analysed 763 consecutive patients who underwent mechanical thrombectomy for AIS between January 2013 and January 2020, at six comprehensive stroke centers. Patients were divided into SCBT and single device (SR/CA) groups. The successful recanalization with first pass (SRFP) and other procedural outcomes were compared between groups. RESULTS: Overall, 240 SCBT and 301 SR/CA (SR 128, CA 173) patients were analyzed. SRFP (modified Thrombolysis In Cerebral Infarction (mTICI) ≥2c, 43.3% vs 27.9%, p<0.001; mTICI 3, 35.8% vs 25.5%, p=0.009) and final mTICI ≥2b recanalization (89.1% vs 82.0%, p=0.020) rates were significantly higher, puncture-to-reperfusion time was shorter (median (IQR) 43 (31.5-69) vs 55 (38-82.2) min, p<0.001), and the number of passes were fewer (mean±SD 1.72±0.92 vs 1.99±1.01, p<0.001) in the SCBT group. Procedural complications were similar between the groups. In subgroup analysis, SCBT was more effective in women, cardioembolic stroke patients, and internal carotid artery and M2 occlusions. CONCLUSIONS: SCBT increases the SRFP rate and shortens the puncture-to-reperfusion time without increasing procedural complications.

DOI： 10.1136/neurintsurg-2021-017837

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Language：English   Publisher：Psychiatry and Clinical Neurosciences Reports  

Aim: Few studies have investigated the health-related quality of life (HRQoL) in long-stay inpatients with chronic schizophrenia in Japan. This study aimed to clarify the factors associated with HRQoL among these patients. Methods: Out of 238 patients with chronic schizophrenia admitted to three hospitals, 101 inpatients provided informed consent to participate in the study. The patients' HRQoL was assessed using two instruments: the EuroQol 5 dimensions (EQ-5D) as a generic index and the Subjective Well-being Under Neuroleptic Treatment Scale, Japanese Version (SWNS-J) as a disease-specific index. We examined the factors associated with these HRQoL indices using multiple linear regression models. Results: The patients' mean age was 62.9 years, and 51.5% were female. The mean (standard deviation) EQ-5D score and SWNS-J total score were 0.776 (0.177) and 83.5 (16.5), respectively. Multiple linear regression analysis indicated that the EQ-5D score was significantly and negatively associated with the female sex, benzodiazepine use, and Drug-Induced Extrapyramidal Symptoms Scale scores. In contrast, the SWNS-J total score was significantly and negatively associated with first-generation antipsychotics use, Brief Psychiatric Rating Scale scores, Drug-Induced Extrapyramidal Symptoms Scale scores, and Global Assessment of Functioning scale scores. Conclusion: This study identified the factors associated with two HRQoL indices among long-stay inpatients with chronic schizophrenia in Japan. Although the analyses showed differences in the associated factors between the generic EQ-5D and the disease-specific SWNS-J, extrapyramidal symptoms as adverse effects of antipsychotic treatment were found to be associated with both indices.

DOI： 10.1002/pcn5.42

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Language：English   Publisher：John Wiley & Sons Australia, Ltd  

長期入院中の慢性統合失調症(SZ)患者を対象とした質問紙調査を実施し、二つの健康関連QoL(HRQoL)指標の関連要因について検討した。3病院に入院中の慢性SZ患者101例(平均62.9歳、女性51.5%)を対象とした。評価項目は人口統計学的特徴および臨床的特徴、EuroQol 5 dimensions(EQ-5D)、Subjective Well-being Under Neuroleptic Treatment Scale Japanese Version(SWNS-J)、Brief Psychiatric Rating Scale(BPRS)、Drug Induced Extrapyramidal Symptoms Scale(DI EPSS)、機能の全体的評定尺度などとした。その結果、EQ-5Dスコアの平均値は0.776±0.177、SWNS-J総スコアは83.5±16.5であった。重回帰分析の結果、EQ-5Dスコアは、女性、ベンゾジアゼピンの使用、DI EPSSと有意かつ負の相関があることが示された。SWNS-Jの総得点は第1世代抗精神病薬の使用、BPRS、DI EPSS、機能の全体的評定尺度と有意かつ負の相関が認められた。以上のように、錐体外路症状はEQ-5DおよびSWNS-Jの両方におけるHRQoL低下と関連していた。

DOI： 10.1161/str.53.suppl_1.TMP66

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Language：English   Publishing type：Research paper (scientific journal)  

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&#37;) 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.

DOI： 10.1161/JAHA.121.021853

Language：English   Publishing type：Research paper (scientific journal)  

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&#37;) had pre-stroke ChEI treatment. Treatment was negatively associated with poor functional outcome (odds ratio: 0.68 [95&#37; 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.

DOI： 10.1159/000514368

Language：English   Publishing type：Research paper (scientific journal)  

This study aimed to elucidate nationwide trends in reperfusion therapy utilization and subsequent 30-day mortality in acute ischemic stroke patients in Japan. The analysis focused on intravenous recombinant tissue plasminogen activator (IV rt-PA) and endovascular thrombectomy (EVT). Using health insurance claims data, we calculated the age- and sex-adjusted monthly number of acute ischemic stroke patients who received IV rt-PA and/or EVT in Japan from April 2010 to March 2016, and investigated the 30-day all-cause mortality rates after undergoing these therapies. Through an interrupted time-series analysis, we examined the: (1).. trends prior to extension of the IV rt-PA therapeutic time window from 3 hours to 4.5 hours in September 2012, (2).. changes that occurred immediately after the extension, and (3).. differences in trends between the pre- and post-extension periods. During the study period, 69,920 patients with acute ischemic stroke (mean age ± standard deviation: 74.9 ± 12.0 years; 41.4&#37; women) received IV rt-PA and/or EVT. The age- and sex-adjusted number of patients receiving IV rt-PA monotherapy increased immediately after the time window extension (<rk-italic > P < .001), but did not change during the pre- (P = .90) and post-extension (P = .58) periods. In contrast, the number of patients receiving EVT with or without IV rt-PA continuously increased during the pre-extension period (P < .001), and further increased during the post-extension period (P <.001); however, this number decreased immediately after the extension (P < .001). There were no significant changes in 30-day all-cause mortality during the pre- (P = .40) and post-extension (P = .64) periods, as well as immediately after the extension (P = .53). The extension of the IV rt-PA therapeutic time window and progressively widespread use of EVT in Japan have increased the number of acute ischemic stroke patients eligible for reperfusion therapy. These trends were not accompanied by a higher risk of post-reperfusion mortality.

DOI： 10.1097/MD.0000000000024145

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: In Japan there is no consensus on how to efficiently measure quality indicators (QIs), defined as a standard of care, for acute ischemic stroke (AIS). Using information from a health insurance claims database and electronic medical records, we evaluated the feasibility and validity of measuring QIs for AIS patients who received intravenous recombinant tissue plasminogen activator (IV rt-PA) or endovascular therapy (EVT).Methods and Results:AIS patients receiving rt-PA or EVT between 2013 and 2015 were identified. We selected 17 AIS QI measures for primary stroke centers (PSCs) and 8 for comprehensive stroke centers (CSCs). Defined QIs were calculated for each hospital and then averaged. In total, the data of 8,206 patients (rt-PA 83.7&#37;, EVT 34.9&#37;) from 172 hospitals were obtained. Median National Institute of Health Stroke Scale score at admission was 14, and 37.7&#37; of the patients were functionally independent at discharge. All target QIs were successfully measured with fewer missing values, and the accuracy of preset data was about 90&#37;. Adherence rates were low (<50&#37;) in 5 QI measures among PSCs, including door-to-needle time ≤1 h, and in 1 QI measure among CSCs (door-to-brain and vascular imaging time ≤30 min). CONCLUSIONS: Measuring QIs for AIS by this novel approach was feasible and reliable in the provision of a national benchmark.

DOI： 10.1253/circj.CJ-20-0639

Language：English   Publishing type：Research paper (scientific journal)  

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&#37; vs. 8.5&#37;, 71.7&#37; vs. 36.5&#37;). Coiling was associated with higher mortality (odds ratio 1.43, 95&#37; 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 nonelderly 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.

DOI： 10.1371/journal.pone.0230953

Language：English   Publishing type：Research paper (scientific journal)  

Background: We aimed to develop quality indicators (QIs) related to primary and comprehensive stroke care and examine the feasibility of their measurement using the existing Diagnosis Procedure Combination (DPC) database. Methods and Results: We conducted a systematic review of domestic and international studies using the modified Delphi method. Feasibility of measuring the QI adherence rates was examined using a DPC-based nationwide stroke database (396,350 patients admitted during 2013–2015 to 558 hospitals participating in the J-ASPECT study). Associations between adherence rates of these QIs and hospital characteristics were analyzed using hierarchical logistic regression analysis. We developed 17 and 12 measures as QIs for primary and comprehensive stroke care, respectively. We found that measurement of the adherence rates of the developed QIs using the existing DPC database was feasible for the 6 QIs (primary stroke care: early and discharge antithrombotic drugs, mean 54.6&#37; and 58.7&#37;; discharge anticoagulation for atrial fibrillation, 64.4&#37;; discharge antihypertensive agents, 51.7&#37;; comprehensive stroke care: fasudil hydrochloride or ozagrel sodium for vasospasm prevention, 86.9&#37;; death complications of diagnostic neuroangiography, 0.4&#37;). We found wide inter-hospital variation in QI adherence rates based on hospital characteristics. Conclusions: We developed QIs for primary and comprehensive stroke care. The DPC database may allow efficient data collection at low cost and decreased burden to evaluate the developed QIs.

DOI： 10.1253/circj.CJ-19-0089

Language：English   Publishing type：Research paper (scientific journal)  

Background This study aimed at determining whether diabetes or glucose metabolism is associated with ischemic stroke in the posterior circulation. MethodsWe included 10,245 patients with acute ischemic stroke (mean age 72.7 ± 12.5 years, men 59.5&#37;) 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.ResultsDiabetes was significantly associated with PCIS even after adjusting for multiple confounding factors (odds ratio - OR [95&#37; 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.ConclusionsPoor glycemic control may be associated with an increased risk of thrombotic infarction that occurs preferentially in the posterior circulation of the brain.

DOI： 10.1212/CPJ.0000000000000608

Language：English  

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&#37;) 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.

DOI： 10.1177/1747493018765263

Language：English  

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&#37; 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&#37; male) and 2163 patients with ESUS (mean [SD] age, 72.4 [12.6] years, 57.1&#37; 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&#37; CI, 1.52-8.54 vs CE) but decreased in PE (0.33; 95&#37; 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.

DOI： 10.1001/jamanetworkopen.2018.2953

Language：English  

Background: Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome, is the most common phenotype of mitochondrial disease. It often develops in childhood or adolescence, usually before the age of 40, in a maternally-inherited manner. Mutations in mitochondrial DNA (mtDNA) are frequently responsible for MELAS. Case presentation: A 55-year-old man, who had no family or past history of mitochondrial disorders, suddenly developed bilateral visual field constriction and repeated stroke-like episodes. He ultimately presented with cortical blindness, recurrent epilepsy and severe cognitive impairment approximately 6 months after the first episode. Genetic analysis of biopsied biceps brachii muscle, but not of peripheral white blood cells, revealed a T10158C mutation in the mtDNA-encoded gene of NADH dehydrogenase subunit 3 (ND3), which has previously been thought to be associated with severe or fatal mitochondrial disorders that develop during the neonatal period or in infancy. Conclusion: A T10158C mutation in the ND3 gene can cause atypical adult-onset stroke-like episodes in a sporadic manner.

DOI： 10.1186/s12883-017-1001-4

Language：English  

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&#37; 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&#37; 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&#37; 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.

DOI： 10.1161/JAHA.117.006402

Language：English  

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&#37;) 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&#37;, p < 0.01; poor functional outcome, 63.7 vs. 27.1&#37;, p < 0.01). Multivariable analysis showed that pre-stroke dementia was significantly associated with neurological deterioration (OR 1.67; 95&#37; CI 1.14-2.41; p < 0.01) and poor functional outcome (OR 2.91; 95&#37; 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&#37; CI 1.17-5.78; p < 0.01) and between the dementia and poor functional outcome (OR 3.62; 95&#37; 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.

DOI： 10.1159/000453625

Language：English  

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&#37;) 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&#37;) than in those without the treatment (58.3&#37;, p < 0.01). Multivariable analysis showed that pre-stroke statin treatment was significantly associated with mild neurological symptoms (OR 1.31; 95&#37; 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&#37; CI 0.99-1.62; p = 0.06). In contrast, the frequency of favorable functional outcome was not different between patients with (67.0&#37;) and without (65.3&#37;) 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&#37; 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&#37; 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.

DOI： 10.1159/000447718

Language：English   Publishing type：Research paper (scientific journal)  

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&#37;). However, it had not been detected before or on admission, but identified later during hospitalization in 270 patients (21&#37;). Of the patients who had atrial fibrillation on admission but had not been diagnosed as having it, 108 (8&#37;) had not received any medication before onset of stroke and 220 (17&#37;) had received medications other than OACs. OACs had been administered to 415 (59&#37;) of the patients with known atrial fibrillation. The proportion of pre-stroke CHADS₂ or CHA₂DS₂-VASc scores ≥1 ranged from 93 to 99&#37; 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&#37;) 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.

DOI： 10.1159/000445723

Language：English   Publishing type：Research paper (scientific journal)  

Rheumatoid meningoencephalitis (RM) is a rare complication of rheumatoid arthritis (RA). This report describes a 63-year-old man with complaints of high-grade fever, headache, and vomiting for several days before admission. Both his serum and cerebrospinal fluid were positive for anti-cyclic citrullinated peptide (CCP) antibody and rheumatoid factor, and contrast-enhanced fluid-attenuated inversion recovery magnetic resonance imaging (MRI) showed abnormal gadolinium enhancement of the meninges and high-intensity lesions in the subarachnoid spaces. The patient was diagnosed with RM despite lack of signs suggesting RA. His symptoms drastically improved with intravenous infusion of high-dose methylprednisolone. Two months later, he developed RA. The findings in this patient suggest that RM could develop prior to the onset of RA. Anti-CCP antibody and MRI findings may be useful for the diagnosis of RM, regardless of RA history.

DOI： 10.1159/000447627

Language：English  

A 62-year-old man complained of gait disturbance, bladder and bowel dysfunction and paresthesia of both legs one month before admission. His symptoms were suggestive of cauda equina syndrome. After admission, he developed rapid progressive numbness and weakness of both legs and a disturbance of consciousness. A random skin biopsy was performed and a histological diagnosis of intravascular large B cell lymphoma (IVLBCL) was reached. His symptoms were improved after rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) therapy.

Language：English   Publishing type：Research paper (scientific journal)  

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 3-7. days 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.

DOI： 10.1016/j.expneurol.2014.12.007

Language：English  

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&#37;) 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&#37; 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.

DOI： 10.1161/STROKEAHA.114.006739

Language：English  

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&#37;) under the condition that 66&#37; 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&#37; of the cases; causes included peptic ulceration (28&#37;) and malignancies (12&#37;), and other or unidentified causes accounted for 60&#37;. 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&#37;). After adjustment for confounding factors, GI bleeding was independently associated with neurologic deterioration (OR 3.9, 95&#37; CI 2.3-6.6, p < 0.001), in-hospital death (OR 6.1, 95&#37; CI 3.1-12.1, p < 0.001), and poor outcome at 3 months (OR 6.8, 95&#37; 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.

DOI： 10.1159/000365245

Language：English   Publishing type：Research paper (scientific journal)  

Background Ischemic stroke is accompanied by an inflammatory response, which exacerbates brain injury and deteriorates functional outcome. S100A12 is expressed abundantly in granulocytes, and has been implicated to play an important role on inflammatory reactions in various disease states. We aimed to determine the association between plasma S100A12 levels and a functional outcome in patients with acute ischemic stroke. Methods We prospectively included 171 patients with acute ischemic stroke within 24 h after onset in this study. Plasma samples were collected for the measurement of S100A12 levels. Poor functional outcome was defined as a modified Rankin Scale of 2-6 at day 90 after stroke onset. Results Of 171 patients, 74 (43.3&#37;) had a poor functional outcome at day 90 after stroke onset. Plasma S100A12 levels on admission were significantly higher in patients with a poor functional outcome (2.1 [1.2-5.1] ng/mL, median [interquartile]) than in those with a favorable outcome (1.1 [0.5-2.0] ng/mL; p < 0.001). Multivariate analysis showed that the highest quartile of plasma S100A12 levels on admission showed a significantly higher risk for a poor functional outcome (odds ratio, 4.01; 95&#37; confidence interval, 1.09-16.10; p = 0.03) than the lowest quartile. Conclusions High plasma S100A12 levels on admission are associated with a poor functional outcome in patients with acute ischemic stroke.

DOI： 10.1016/j.jns.2014.02.031

Language：English   Publishing type：Research paper (scientific journal)  

A 60-year-old man was admitted to our hospital complaining of fever, headache and vertigo. Neurological examination on admission showed mild ataxic gait. Brain magnetic resonance imaging showed linear high intensity in the left parietal lobe on diffusion-weighted imaging (DWI) and laboratory data revealed elevated serum lactate dehydrogenase and soluble interleukin-2 receptor. Although intravascular lymphoma was suspected from these findings, bone marrow and skin biopsies were negative. Two months later, he presented with sensory disturbance of the left upper limb, and new lesions in the right frontal and bilateral parietal lobes were detected on DWI. A systemic evaluation showed multiple low-density lesions in the bilateral kidneys on computed tomography. Based on the results of a renal biopsy, we made a histological diagnosis of intravascular large B-cell lymphoma (IVLBCL). As IVLBCL is quite rare and often has a poor prognosis, a systemic evaluation to determine the proper biopsy site is needed for early diagnosis.

DOI： 10.5692/clinicalneurol.54.484

Language：English   Publishing type：Research paper (scientific journal)  

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&#37; 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.

DOI： 10.1016/j.metabol.2014.04.012

Language：English  

Background: Pericytes are multifunctional cells surrounding capillaries and postcapillary venules. In brain microvasculature, pericytes play a pivotal role under physiological and pathological conditions by producing reactive oxygen species (ROS). The aims of this study were to elucidate the source of ROS and its regulation in human brain pericytes. Methods: The expression of Nox enzymes in the cells was evaluated using RT-PCR and western blot. Superoxide production was determined by superoxide dismutase-inhibitable chemiluminescence. Silencing of Nox4 was performed using RNAi, and cell proliferation was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. Results: Nox4 was predominant among the Nox family in human brain pericytes. Membrane fractions of cells produced superoxide in the presence of NAD(P)H. Superoxide production was almost abolished with diphenileneiodonium, a Nox inhibitor; however, inhibitors of other possible superoxide-producing enzymes had no effect on NAD(P)H-dependent superoxide production. Pericytes expressed angiotensin II (Ang II) receptors, and Ang II upregulated Nox4 expression. Hypoxic conditions also increased the Nox4 expression. Silencing of Nox4 significantly reduced ROS production and attenuated cell proliferation. Conclusion: Our study showed that Nox4 is a major superoxide-producing enzyme and that its expression is regulated by Ang II and hypoxic stress in human brain pericytes. In addition, Nox4 may promote cell growth.

DOI： 10.1159/000369930

Language：English   Publishing type：Research paper (scientific journal)  

The mechanism of cerebral decompression sickness (DCS) is still unclear. We report 2 cases of breath-hold divers with cerebral DCS in whom magnetic resonance imaging (MRI) demonstrated distinctive characteristics. One case presented right hemiparesthesia, diplopia, and gait disturbance after breath-hold diving into the sea at a depth of 20 m. Brain MRI with fluid-attenuated inversion recovery (FLAIR) sequence revealed multiple hyperintense lesions in the right frontal lobe, bilateral thalamus, pons, and right cerebellar hemisphere. The second case presented visual and gait disturbance after repetitive breath-hold diving into the sea. FLAIR imaging showed hyperintense areas in the bilateral occipito-parietal lobes. In both cases, diffusion-weighted imaging and apparent diffusion coefficient mapping revealed hyperintense areas in the lesions identified by FLAIR. Moreover, follow-up MRI showed attenuation of the FLAIR signal abnormalities. These findings are suggestive of transient hyperpermeability in the microvasculature as a possible cause of cerebral DCS.

DOI： 10.1159/000357169

Language：English   Publishing type：Research paper (scientific journal)  

The relationship between the poststroke blood pressure (BP) and functional outcomes in patients with acute ischemic stroke is still controversial. The aim of the present study was to elucidate the impact of the poststroke BP on the clinical outcomes of acute ischemic stroke. Among the patients in the Fukuoka Stroke Registry, 1874 patients with first-ever acute ischemic stroke (within 24 hours of onset) who had been functionally independent before onset were prospectively enrolled in the present study. The poststroke BP levels were defined as the average values during the 48 hours after onset. The study outcomes were a good neurological recovery, neurological deterioration, and a poor functional outcome. The higher poststroke BP levels were significantly associated with a lower probability of a good neurological recovery and elevated risks of neurological deterioration and a poor functional outcome after adjusting for potential confounding factors. The multivariate-adjusted odds ratios (95&#37; confidence interval) in the highest quintile of systolic BP (versus the lowest quintile as a reference) were 0.51 (0.37-0.71) for a good neurological recovery, 1.92 (1.15-3.27) for neurological deterioration, and 2.51 (1.69-3.74) for a poor functional outcome. Similar associations were observed when we applied the poststroke diastolic BP or pulse pressure. No evidence of the J-curve phenomenon was observed for each association. These results suggest that a high poststroke BP was significantly associated with unfavorable clinical outcomes in patients with acute ischemic stroke. There was no evidence of the J-curve phenomenon between the poststroke BP levels and the clinical outcomes.

DOI： 10.1161/HYPERTENSIONAHA.113.02189

Language：English   Publishing type：Research paper (scientific journal)  

Background and purpose: The findings of recent clinical trials suggest that treatment with high-dose statins reduces the risk of stroke recurrence. However, the doses approved in Japan are much lower than those in the previous studies. This study aimed to elucidate whether prescribed doses of statins reduce the risks of cerebrovascular events (CVEs: stroke recurrence or transient ischemic attack) and all-cause mortality in a cohort of Japanese patients with first-ever ischemic stroke. Methods: The 2822 eligible patients registered in the Fukuoka Stroke Registry with first-ever acute ischemic stroke from June 2007 to February 2011 were classified into statin users (n=993) and non-users (n=1829) at discharge, and followed up until March 2012. We assessed the cumulative risks of CVE and all-cause mortality by the Kaplan-Meier method, and calculated hazard ratios (HRs) and 95&#37; confidential intervals (CIs) using the Cox proportional hazards model. Results: During the follow-up time (median, 2.0 years), 305 patients had CVEs and 345 died. The cumulative risks of CVE and death after 4 years were significantly lower in statin users than in non-users (13.8&#37; versus 19.5&#37;, P=0.005 for CVE; 11.8&#37; versus 21.7&#37;, P<0.001 for death). After adjusting for multiple confounding factors, statin treatment significantly reduced the risks of CVE (HR, 0.70; 95&#37; CI, 0.53 to 0.92; P=0.011) and all-cause mortality (HR, 0.67; 95&#37; CI, 0.50 to 0.89; P=0.006). Conclusions: Our findings suggest that low-dose statin may reduce the risks of CVE and death in Japanese patients with acute ischemic stroke.

DOI： 10.1016/j.atherosclerosis.2013.09.017

Language：English   Publishing type：Research paper (scientific journal)  

Background and Purpose: The relationship between the intensity of anticoagulation at the onset of acute cardioembolic stroke and clinical outcome after stroke is unclear. Here, we elucidated the relationship between prothrombin time-international normalized ratio (PT-INR) values on admission and clinical outcomes in patients with acute cardioembolic stroke. Methods: A total of 602 patients from the Fukuoka Stroke Registry in Japan who had been treated with warfarin but developed cardioembolic stroke were enrolled. The patients were classified into 3 groups according to their PT-INR values on admission: PT-INR <1.50, 411 patients; PT-INR 1.50 to 1.99, 146 patients; and PT-INR ≥2.00, 45 patients. The associations between PT-INR categories and severe neurological deficits (National Institutes of Health Stroke Scale ≥10) on admission and poor functional outcome (modified Rankin scale 4-6) at discharge were investigated using a logistic regression analysis. Results: Neurological deficits on admission were less severe, and functional outcome at discharge was more favorable as the PT-INR level on admission increased. The multivariate analysis revealed that severe neurological deficits were inversely associated with PT-INR on admission (PT-INR 1.50-1.99: odds ratio, 0.66;95&#37; confidence interval, 0.43-1.00; PT-INR ≥2.00: odds ratio, 0.41;95&#37; confidence interval, 0.20-0.83; compared with a reference group of PT-INR <1.50). Poor functional outcome was less likely in patients with PT-INR ≥2.00 (odds ratio, 0.20;95&#37; confidence interval, 0.06-0.55) after adjustment for confounders. Conclusions: Prestroke PT-INR ≥2.0 is associated with favorable clinical outcomes after acute cardioembolic stroke.

DOI： 10.1161/STROKEAHA.113.002523

Language：Japanese  

Hemodynamic brain infarction in bilateral middle cerebellar peduncles and upper pons in a patient with bilateral vertebral artery occlusion

DOI： 10.3995/jstroke.35.337

Language：English   Publishing type：Research paper (scientific journal)  

A 40-year-old man who presented with left hemiparesis was admitted to our hospital. He had tachycardia and a fever. He had a 25-year history of insulin therapy for diabetes mellitus. Brain magnetic resonance (MR) images showed fresh infarction in the right hemisphere, and carotid ultrasonography showed stenosis of the right internal carotid artery (ICA). We determined that atherothrombotic brain infarction had likely occurred. After admission, the right ICA became narrow and finally occluded. Computed tomography revealed the presence of a thrombus in the right ICA, and gadoliniumenhanced MRA showed vasculitis of the ICA. In laboratory tests, his thyroid hormones were elevated. He was diagnosed with hyperthyroidism. After treatment, the tachycardia and high fever were improved. Because of a positive antiglutamic acid decarboxylase antibody test result, he was diagnosed with insulin-dependent diabetes mellitus. We found that he had anti-phospholipid antibody syndrome because he was positive for anti-beta-glycoprotein I antibody. These findings suggested that his condition was autoimmune polyglandular syndrome type 3. He received prednisolone and warfarin. After 3 months, his neurological findings were improved; however, occlusion of the ICA remained. Autoimmunity was considered to be the cause of ICA occlusion. Ischemic stroke with autoimmune polyglandular syndrome is very rare and is associated with progressive carotid lesions in juvenile patients. It is necessary to diagnose and treat this condition as soon as possible.

DOI： 10.5692/clinicalneurol.53.531

Language：English   Publishing type：Research paper (scientific journal)  

We report a Japanese breath-hold diver (Ama) who presented neurological disorders after diving. He repeated diving into 25-30 meters depth in the sea for 6 hours. After diving, he felt dizziness and unsteady gait. Neurological examination showed left quadrant hemianopia, bilateral limb ataxia and ataxic gait. Head CT revealed gas bubbles in the left parietal lobe. In CT scan on 3 days after onset, gas bubbles disappeared and low density areas were observed in the bilateral parietal lobes. Brain imaging (DWI, T²WI and FLAIR) demonstrated high intensity in the parietooccipital lobes. Neither pulmonary barotrauma nor intracardiac shunt was detected. He was diagnosed as having neurological decompression illness and therefore underwent hyperbaric oxygen therapy. The pathogenesis of this case was considered to be microbubbles induced by decompression. The present case suggests that repetitive rapid surfacing from the deep sea causes neurological decompression illness even in the breath-hold diver.

DOI： 10.5692/clinicalneurol.52.757

Language：English  

The central nervous system (CNS) pericytes play an important role in brain microcirculation. Na⁺/H⁺ exchanger isoform 1 (NHE1) has been suggested to regulate the proliferation of nonvascular cells through the regulation of intracellular pH, Na⁺, and cell volume; however, the relationship between NHE1 and intracellular Ca²⁺, an essential signal of cell growth, is still not known. The aim of the present study was to elucidate the role of NHE1 in Ca²⁺ signaling and the proliferation of human CNS pericytes. The intracellular Ca²⁺ concentration was measured by fura 2 in cultured human CNS pericytes. The cells showed spontaneous Ca²⁺ oscillation under quasi-physiological ionic conditions. A decrease in extracellular pH or Na⁺ evoked a transient Ca ²⁺ rise followed by Ca²⁺ oscillation, whereas an increase in pH or Na⁺ did not induce the Ca²⁺ responses. The Ca²⁺ oscillation was inhibited by an inhibitor of NHE in a dose-dependent manner and by knockdown of NHE1 by using RNA interference. The Ca²⁺ oscillation was completely abolished by thapsigargin. The proliferation of pericytes was attenuated by inhibition of NHE1. These results demonstrate that NHE1 regulates Ca²⁺ signaling via the modulation of Ca²⁺ release from the endoplasmic reticulum, thus contributing to the regulation of proliferation in CNS pericytes.

DOI： 10.1152/ajpheart.01203.2007

Language：English  

Background and aims: Central nervous system (CNS) pericytes located at the abluminal side of microvessels, such as arterioles, venules, and particularly capillaries, appear to play an important role in angiogenesis, regulation of blood flow, immune responses, and maintenance of blood-brain barrier (BBB). Na+/H+ exchanger isoform 1 (NHE1) ubiquitously expressed in plasma membrane has been implicated to have a role in proliferation of non-vascular cells through regulation of intracellular pH, Na+ and cell volume; however, the relationship between NHE1 and pericyte growth is not known. Thus, the aim of the present study was to elucidate the role of NHE1 in the proliferation of human CNS pericytes. We have found on intracellular Ca2+ change, an essential signal of cell growth. Methods: Human brain microvascular pericytes were cultured and cytosolic Ca2+ concentration and pH were measured by fluorescent indicators, fura-2 and 2', 7'-bis-2-carboxyethyl-5-(6)-carboxyfluorescein (BCECF), respectively. Reverse transcription and polymerase chain reaction (RT-PCR) was used to examine expression level of each mRNA. Knockdown of NHE1 mRNA was done by RNA interference (RNAi) with the double-strand siRNAs targeting NHE1 specifically. Cell proliferation was evaluated by cell count. Results: Human microvascular pericytes showed spontaneous Ca2+ oscillation in the presence of extracellular Na+ (132mM). A decrease in extracellular Na+ (0-99mM) evoked transient Ca2+ rise followed by Ca2+ plateau or Ca2+ oscillation, whereas increase in extracellular Na+ to 166mM eliminated the Ca2+ responses. A decrease in extracellular pH to 6.5 induced similar cytosolic Ca2+ change as that by low extracellular Na+. Low Na+-induced Ca2+ oscillation was inhibited by hexamethylene amiloride (HMA, an inhibitor of Na+/H+ exchanger) dosedependently (5-50μM). The Ca2+ oscillation was also inhibited by amiloride (50μM) or benzamil (50μM). Nicardipine (1μM), Gd3+ (100μM), La3+ (100μM) or omission of external Ca2+ did not affect the Ca2+ oscillation. KB-R7943 (10μM; a selective inhibitor of Na+/Ca2+ exchanger), carbonyl cyanide p-trifluoro-methoxyphenylhydrazone (1μM; FCCP, the mitochondrial uncoupler), or changes in the external osmolarity did not affect the Ca2+ oscillation. On the other side, the Ca2+ oscillation was completely abolished by pretreatment with thapsigargin (1μM; an inhibitor of sarco/endoplasmic reticulum Ca2+ ATPase), suggesting that Ca2+ oscillation was originated from endoplasmic reticulum. RT-PCR revealed that human CNS pericytes expressed NHE1 and NHE7. Low extracellular Na+ could not induce the Ca2+ oscillation in the cells transfected with specific siRNA targeting NHE1. Proliferation of the pericytes was significantly attenuated by addition of HMA (5μM) to the medium. Knockdown of NHE1 by transfecting mRNA also inhibited the proliferation of pericytes. Conclusions: These results indicate that NHE1 plays an important role in Ca2+ signaling via modulation of endoplasmic reticulum and thereby contributes to the regulation of proliferation in CNS pericytes. This novel role of NHE1 in the pericytes may have pathophysiological relevance to angiogenesis or BBB disruption in the cerebral ischemia.

Language：English   Publishing type：Research paper (scientific journal)  

A 65-year-old woman with poorly controlled diabetes presented bilateral miosis, bilateral abducens nerve palsy, and left hemiparesis. On MRI, cavernous sinus thrombosis, subdural empyema and hemorrhagic infarction in the frontotemporal lobe were detected. Cerebral angiogram revealed filling defect in the cavernous sinus with venous congestion but no involvement of internal carotid artery. Postmortem examination demonstrated hemorrhagic infarction in the right frontotemporal lobe as well as hemorrhagic necrosis of the pituitary gland. It should be noted that venous congestion due to cavernous sinus thrombosis may cause these complications.

DOI： 10.2169/internalmedicine.45.1430

Language：English   Publishing type：Research paper (scientific journal)  

Amino acid-starved yeast activates the eIF2α kinase Gcn2p to suppress general translation and to selectively derepress the transcription factor Gcn4p, which induces various biosynthetic genes to elicit general amino acid control (GAAC). Well-fed yeast activates the target of rapamycin (TOR) to stimulate translation via the eIF4F complex. A crosstalk was demonstrated between the pathways for GAAC and TOR signaling: the TOR-specific inhibitor rapamycin activates Gcn2p. Here we demonstrate that, upon TOR-inactivation, the putative TOR-regulated eIF4E-associated protein Eap1p likely functions downstream of Gcn2p to attenuate GCN4 translation via a mechanism independent of eIF4E-binding, thereby constituting another interface between the two pathways.

DOI： 10.1016/j.febslet.2005.03.043

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1159/000071134

Language：English   Publishing type：Research paper (scientific journal)  

Purpose: It has been suggested that intracranial aneurysms could be observed using transcranial color-coded duplex sonography (TCDS). We investigated the sensitivity of TCDS studies for detecting unruptured aneurysms both with and without an echo contrast agent. Methods: We studied 39 patients (44 aneurysms) who were diagnosed as having unruptured intracranial aneurysms by cerebral angiography (36 patients) or MRA (3 patients). We performed TCDS both with and without echo contrast agents in all patients. In 7 patients who underwent endovascular treatment for unruptured intracranial aneurysms, enhanced TCDS studies were done both before and after the treatment. Results: Because of an insufficient transtemporal bone window, intracranial cerebral arteries were not visible with TCDS in 3 patients, despite enhancement by echo contrast agents. Among the 36 patients (38 aneurysms) whose intracranial cerebral arteries could be evaluated by TCDS, 13 cerebral aneurysms were detected (34&#37;) without the aid at echo contrast agents. After echo contrast agents were administered, 9 additional aneurysms were observed by TCDS studies and the sensitivity of the test resulted in 58&#37;. The sensitivity of enhanced TCDS for detecting cerebral aneurysms in the internal carotid artery, middle cerebral artery, anterior cerebral artery or anterior communicating artery, and basilar artery was 46&#37;, 80&#37;, 17&#37;, and 67&#37;, respectively. The frequency of larger aneurysms detection (>5 mm) was significantly higher (78&#37;) than that of smaller ones (<5 mm; 40&#37;). In all the patients who underwent endovascular treatment, cerebral aneurysms that had been observed by enhanced TCDS were not detected after the treatment. Conclusions: TCDS may be suitable for the detection as well as follow-up study of intracranial aneurysms. The sensitivity of this noninvasive study is drastically improved by contrast agents.

DOI： 10.7887/jcns.12.179

Language：English   Publishing type：Research paper (scientific journal)  

Background - We report a case of a 71-year-old woman with cerebral infarction due to occlusion of the internal carotid artery (ICA) caused by a neck tumor. Case Description - In 1998, the patient complained of mild hoarseness, and a diagnostic workup showed a cervical mass that was considered a benign neck tumor. In September 2000, she developed right-sided weakness. Diffusion-weighted MRI showed a high-intensity area in the territory of the left middle cerebral artery. Carotid angiography and ultrasonography revealed occlusion of the left ICA, which was due to compression by the neck tumor. Superficial temporal artery-middle cerebral artery anastomosis was performed to prevent critical reduction of cerebral blood flow in the left ICA territory; this was followed by tumor resection. The occluded ICA recanalized after tumor resection. Microscopic examination showed that the tumor was a vagal neurilemmoma. Conclusions - This is the first case of cerebral infarction due to left ICA occlusion by a cervical neurilemmoma. Even when the neck tumor is benign, it may occlude the ICA and thereby cause cerebral infarction.

DOI： 10.1161/01.STR.0000015241.40071.99

Language：English   Publishing type：Research paper (scientific journal)  

We report a 72-year-old man with hepatocellular carcinoma, which showed spontaneous regression. He was diagnosed as having chronic hepatitis type C five years before admission. In January 1998, a liver mass was found by ultrasonography. In February, computed tomography showed a low-density mass, 3.5cm in diameter in the S5 region. Although liver biopsy was not performed, findings obtained by computed tomography and ultrasonography indicated that the tumor was hepatocellular carcinoma. The levels of α-fetoprotein and PIVKA (protein induced by vitamin K antagonist)-II were increased to 1000ng/mL and 2000mAU/mL, respectively. The patient was admitted to our hospital in March 1998. At the time, the size of liver mass was reduced to 2.5cm in diameter on computed tomography, and the tumor markers, α-fetoprotein and PIVKA-II, spontaneously decreased to the normal range. We considered that hepatocellular carcinoma of this patient regressed spontaneously. Because it was hard to exclude the possibility that the mass contained residual malignant cells, we resected the mass on April 28, 1998. Microscopically, the resected mass did not contain any malignant cells. The parenchyma surrounding tumor necrosis, which is reflected by severe inflammatory infiltration with lymphocytes, indicates spontaneous regression. Although the precise mechanism regarding spontaneous regression of hepatocellular carcinoma is not fully understood, either ischemia due to rapid growth of the tumor or some inflammatory mechanism may be involved in regression of hepatocellular carcinoma.

Language：English   Publishing type：Research paper (scientific journal)  

Isolated arterial dissection, which occurs with the absence of aortic dissection, has been reported in carotid and renal arteries but rarely in visceral arteries. A case of isolated celiac artery dissection is reported here. A healthy 58-year-old man experienced sudden upper abdominal pain, which continued for several days. A body computed tomogram (CT) showed a multiple low-density wedge-shaped area in the spleen, which was diagnosed as splenic infarction, and an aneurysm with thrombus in the celiac artery. A selective angiogram showed dilatation of the celiac artery with wall irregularity, and proximal occlusion of the hepatic artery. The distal hepatic artery was fed by collateral arteries from the superior mesenteric artery. Splenic infarction was probably due to the embolism from the thrombus in the dissected celiac artery. The absence of other vascular lesions and causes or risks for the arterial dissection would suggest the occurrence of spontaneous dissection. The dissection of visceral arteries should be considered in diagnosing acute abdominal pain.

DOI： 10.1177/000331970005100710

Event date： 2019.5

Language：English   Presentation type：Oral presentation (general)  

Venue：Mirano   Country：Italy  

Event date： 2018.10

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Event date： 2015.10

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Event date： 2015.4

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Event date： 2024.5

Language：Japanese   Presentation type：Public lecture, seminar, tutorial, course, or other speech  

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Event date： 2024.5

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Event date： 2024.2

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Event date： 2024.2

Language：Japanese   Presentation type：Public lecture, seminar, tutorial, course, or other speech  

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Event date： 2019.5

Language：English   Presentation type：Oral presentation (general)  

Venue：Mirano   Country：Italy  

Event date： 2018.4

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Venue：Athens   Country：Greece  

Event date： 2016.5

Language：English   Presentation type：Oral presentation (general)  

Venue：Barcelona   Country：Spain  

Event date： 2015.4

Language：English   Presentation type：Oral presentation (general)  

Venue：Glasgow, Scotland   Country：Other  

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Language：Japanese   Presentation type：Public lecture, seminar, tutorial, course, or other speech  

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Language：Japanese  

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Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publisher：(株)日本臨床社  

Language：Japanese   Publisher：(株)日本臨床社  

Type：Peer review 

Number of peer-reviewed articles in foreign language journals：16

Number of peer-reviewed articles in Japanese journals：1

Proceedings of International Conference Number of peer-reviewed papers：0

Proceedings of domestic conference Number of peer-reviewed papers：0

Type：Peer review 

Number of peer-reviewed articles in foreign language journals：15

Number of peer-reviewed articles in Japanese journals：0

Proceedings of International Conference Number of peer-reviewed papers：0

Proceedings of domestic conference Number of peer-reviewed papers：0

Type：Peer review 

Number of peer-reviewed articles in foreign language journals：16

Number of peer-reviewed articles in Japanese journals：0

Proceedings of International Conference Number of peer-reviewed papers：0

Proceedings of domestic conference Number of peer-reviewed papers：0

Type：Competition, symposium, etc. 

Type：Peer review 

Number of peer-reviewed articles in foreign language journals：19

Number of peer-reviewed articles in Japanese journals：0

Proceedings of International Conference Number of peer-reviewed papers：0

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Type：Peer review 

Number of peer-reviewed articles in foreign language journals：7

Number of peer-reviewed articles in Japanese journals：0

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