Dual Antiplatelet Therapy With Cilostazol for Secondary Prevention in Lacunar Stroke: Subanalysis of the CSPS.com Trial.

BACKGROUND: The effectiveness of long-term dual antiplatelet therapy (DAPT) to prevent recurrent strokes in patients with lacunar stroke remains unclarified. Therefore, this study aimed to compare and to elucidate the safety and effectiveness of DAPT and single antiplatelet therapy (SAPT) in preventing recurrence in chronic lacunar stroke. METHODS: CSPS.com (Cilostazol Stroke Prevention Study for Antiplatelet Combination) was a prospective, multicenter, randomized controlled trial. In this prespecified subanalysis, 925 patients (mean age, 69.5 years; 69.4% men) with lacunar stroke were selected from 1884 patients with high-risk noncardioembolic stroke, enrolled in the CSPS.com trial after 8 to 180 days following stroke. Patients were randomly assigned to receive either SAPT or DAPT using cilostazol and were followed for 0.5 to 3.5 years. The primary efficacy outcome was the first recurrence of ischemic stroke. The safety outcomes were severe or life-threatening bleeding. RESULTS: The DAPT group receiving cilostazol and either aspirin or clopidogrel and SAPT group receiving aspirin or clopidogrel alone comprised 464 (50.2%) and 461 (49.8%) patients, respectively. Ischemic stroke occurred in 12 of 464 patients (1.84 per 100 patient-years) in the DAPT group and 31 of 461 patients (4.42 per 100 patient-years) in the SAPT group, during follow-up. After adjusting for multiple potential confounding factors, ischemic stroke risk was significantly lower in the DAPT group than in the SAPT group (hazard ratio, 0.43 [95% CI, 0.22-0.84]). The rate of severe or life-threatening hemorrhage did not differ significantly between the groups (2 patients [0.31 per 100 patient-years] versus 6 patients [0.86 per 100 patient-years] in the DAPT and SAPT groups, respectively; hazard ratio, 0.36 [95% CI, 0.07-1.81]). CONCLUSIONS: In patients with lacunar stroke, DAPT using cilostazol had significant benefits in reducing recurrent ischemic stroke incidence compared with SAPT without increasing the risk of severe or life-threatening bleeding. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01995370. URL: https://www.umin.ac.jp/ctr; Unique identifier: UMIN000012180.

Angiotensin II receptor blocker and statin combination therapy associated with higher skeletal muscle index in patients with cardiovascular disease: A retrospective study.

WHAT IS KNOWN AND OBJECTIVE: Reduction in skeletal muscle mass is the most important component in diagnosing sarcopenia. Ageing and chronic heart failure due to cardiovascular diseases (CVDs) accelerate the reduction of skeletal muscles. However, there are no currently available drugs that are effective for sarcopenia. The purpose of this study was to explore the association between prescribed medications and skeletal muscle mass in patients with CVD. METHODS: This was a single-centre, retrospective, cross-sectional study. The subjects were 636 inpatients with CVD who took prescribed medicines for at least 4 weeks at the time of admission. Skeletal muscle volume was assessed using a bioelectrical impedance assay. RESULTS AND DISCUSSION: Single regression analysis showed that 10 and 3 medications were positively and negatively associated with skeletal muscle index (SMI), respectively. Stepwise multivariate regression analysis revealed that angiotensin II receptor blocker (ARB)/statin combination, dipeptidyl peptidase-4 inhibitor, and antihyperuricemic agents were positively associated with SMI while diuretics and antiarrhythmic agents were negatively associated with SMI. After adjustment using propensity score matching, the SMI was found to be significantly higher in ARB/statin combination users than in non-users. WHAT IS NEW AND CONCLUSION: Combination use of ARB/statin was associated with a higher SMI in patients with CVD. A future randomised, controlled trial is warranted to determine whether the ARB/statin combination will increase the SMI and prevent sarcopenia in patients with CVD.

Fluid-Attenuated Inversion Recovery May Serve As a Tissue Clock in Patients Treated With Endovascular Thrombectomy.

Background and Purpose: We investigated whether the signal change on fluid-attenuated inversion recovery (FLAIR) can serve as a tissue clock that predicts the clinical outcome after endovascular thrombectomy (EVT), independently of the onset-to-admission time. Methods: Consecutive patients with acute stroke treated with EVT between September 2014 and December 2018 were enrolled. Based on the parenchymal signal change on FLAIR, patients were classified into FLAIR-negative and FLAIR-positive groups. The clinical characteristics, imaging findings, EVT parameters, and the intracranial hemorrhage defined as Heidelberg Bleeding Classification ≥1c hemorrhage (parenchymal hemorrhage, intraventricular hemorrhage, subarachnoid hemorrhage, and/or subdural hemorrhage) were compared between the 2 groups. A modified Rankin Scale score 0 to 1 at 3 months was considered to represent a good outcome. Results: Of the 227 patients with EVT during the study period, 140 patients (62%) were classified into the FLAIR-negative group and 87 (38%) were classified into the FLAIR-positive group. In the FLAIR-negative group, the patients were older (P=0.011), the onset-to-image time was shorter (P<0.001), the frequency of cardioembolic stroke was higher (P=0.006), and the rate of intravenous thrombolysis was higher (P<0.001) in comparison to the FLAIR-positive group. Although the rate of complete recanalization after EVT did not differ between the 2 groups (P=0.173), the frequency of both any-intracranial hemorrhage and Heidelberg Bleeding Classification ≥1c hemorrhage were higher in the FLAIR-positive group (P=0.004 and 0.011). At 3 months, the percentage of patients with a good outcome (FLAIR-negative, 41%; FLAIR-positive, 27%) was significantly related to the FLAIR signal change (P=0.047), while the onset-to-image time was not significant (P=0.271). A multivariate regression analysis showed that a FLAIR-negative status was independently associated with a good outcome (odds ratio, 2.10 [95% CI, 1.02­4.31], P=0.044). Conclusions: A FLAIR-negative status may predict the clinical outcome more accurately than the onset-to-admission time, which may support the role of FLAIR as a tissue clock.

The Effect of Aging and Small-Vessel Disease Burden on Hematoma Location in Patients with Acute Intracerebral Hemorrhage.

INTRODUCTION: Intracerebral hemorrhage (ICH) is a devastating hemorrhagic event and is associated with high mortality or severe neurological sequelae. Age-associated differences in hematoma location for nonlobar ICH are not well known. The aims of the present study were to elucidate the relationship between age and hematoma location and to assess the differences in small-vessel disease (SVD) burden as a potential surrogate marker for longstanding hypertension among various hematoma locations. METHODS: From September 2014 through July 2019, consecutive patients with acute, spontaneous ICH were retrospectively enrolled from a prospective registry. Magnetic resonance imaging was performed during admission, and the total SVD burden score (including microbleeds, lacunes, enlarged perivascular spaces, and white matter hyperintensities) was calculated. The relationships of hematoma location with aging and SVD burden were assessed by using multivariate logistic regression analyses. RESULTS: A total of 444 patients (156 women [35%]; median age 69 [interquartile range 59-79] years; National Institutes of Health Stroke Scale score 9 [17][3-17]) were enrolled in the present study. Multivariate logistic regression analyses showed that advanced age was independently associated with thalamic (odds ratio [OR]: 1.48, 95% confidence interval [CI]: 1.19-1.84, p < 0.001 for 10-year increment) and lobar hemorrhage (OR: 1.58, 95% CI: 1.19-2.09, p = 0.002) and was independently and negatively related to putaminal hemorrhage (OR: 0.55, 95% CI: 0.44-0.68, p < 0.001). The total SVD burden score was independently and positively associated with thalamic hemorrhage (OR: 1.27, 95% CI: 1.01-1.59, p = 0.045) and negatively with lobar hemorrhage (OR: 0.74, 95% CI: 0.55-0.99, p = 0.042), even after adjusting by age, but not with putaminal hemorrhage (OR: 0.91, 95% CI: 0.73-1.14, p = 0.395). CONCLUSION: Putaminal, thalamic, and lobar hemorrhages are prone to occur in specific ages and SVD states: putaminal in young patients, thalamic in old and high SVD burden patients, and lobar hemorrhages in old and low SVD burden patients. Susceptibility to bleeding with aging or severe SVD accumulation seems to differ considerably among brain locations.

Pre-stroke cognitive impairment in acute ischemic stroke patients predicts poor functional outcome after mechanical thrombectomy.

OBJECTIVE: Several studies have investigated the predictors of functional outcome in patients with ischemic stroke after mechanical thrombectomy (MT). However, it is not clear whether pre-stroke cognitive (PSC) impairment is associated with the functional outcome of patients treated with MT. METHODS: We enrolled 113 patients treated with MT from December 2016 to November 2018. PSC was evaluated using the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Poor outcome was defined as a modified Rankin Scale score of 3-6. We compared the clinical characteristics between the groups with poor outcome (n = 61) and good outcome (n = 52) to determine if PSC could be a predictor of poor outcome. RESULTS: IQCODE was significantly higher in the group with poor outcome than good outcome (3.34 vs. 3.13, P = 0.017). Moreover, the following metrics differed between those two groups: age (75.9 vs. 71.6 years old, P = 0.010), the percentage of females (39.9% vs. 17.3%, P = 0.009), the percentage with hypertension (72.1% vs. 44.2%, P = 0.003), National Institutes of Health Stroke Scale (NIHSS) score on admission (20 vs. 11, P < 0.001), and no successful recanalization (24.5% vs. 7.7%; P = 0.025). Multivariable logistic regression analysis demonstrated that PSC (OR: 5.59; 95% CI: 1.55-23.47), history of hypertension (OR: 3.33; 95% CI: 1.29-9.11), no successful recanalization (OR: 5.51; 95% CI: 1.49-25.03), and NIHSS score on admission (OR: 1.14; 95% CI: 1.07-1.22) were associated with poor outcome 3 months after stroke onset. CONCLUSIONS: PSC was significantly and independently associated with poor functional outcome in patients treated with MT.

Effect of Mechanical Thrombectomy Without vs With Intravenous Thrombolysis on Functional Outcome Among Patients With Acute Ischemic Stroke: The SKIP Randomized Clinical Trial.

IMPORTANCE: Whether intravenous thrombolysis is needed in combination with mechanical thrombectomy in patients with acute large vessel occlusion stroke is unclear. OBJECTIVE: To examine whether mechanical thrombectomy alone is noninferior to combined intravenous thrombolysis plus mechanical thrombectomy for favorable poststroke outcome. DESIGN, SETTING, AND PARTICIPANTS: Investigator-initiated, multicenter, randomized, open-label, noninferiority clinical trial in 204 patients with acute ischemic stroke due to large vessel occlusion enrolled at 23 hospital networks in Japan from January 1, 2017, to July 31, 2019, with final follow-up on October 31, 2019. INTERVENTIONS: Patients were randomly assigned to mechanical thrombectomy alone (n = 101) or combined intravenous thrombolysis (alteplase at a 0.6-mg/kg dose) plus mechanical thrombectomy (n = 103). MAIN OUTCOMES AND MEASURES: The primary efficacy end point was a favorable outcome defined as a modified Rankin Scale score (range, 0 [no symptoms] to 6 [death]) of 0 to 2 at 90 days, with a noninferiority margin odds ratio of 0.74, assessed using a 1-sided significance threshold of .025 (97.5% CI). There were 7 prespecified secondary efficacy end points, including mortality by day 90. There were 4 prespecified safety end points, including any intracerebral hemorrhage and symptomatic intracerebral hemorrhage within 36 hours. RESULTS: Among 204 patients (median age, 74 years; 62.7% men; median National Institutes of Health Stroke Scale score, 18), all patients completed the trial. Favorable outcome occurred in 60 patients (59.4%) in the mechanical thrombectomy alone group and 59 patients (57.3%) in the combined intravenous thrombolysis plus mechanical thrombectomy group, with no significant between-group difference (difference, 2.1% [1-sided 97.5% CI, -11.4% to ∞]; odds ratio, 1.09 [1-sided 97.5% CI, 0.63 to ∞]; P = .18 for noninferiority). Among the 7 secondary efficacy end points and 4 safety end points, 10 were not significantly different, including mortality at 90 days (8 [7.9%] vs 9 [8.7%]; difference, -0.8% [95% CI, -9.5% to 7.8%]; odds ratio, 0.90 [95% CI, 0.33 to 2.43]; P > .99). Any intracerebral hemorrhage was observed less frequently in the mechanical thrombectomy alone group than in the combined group (34 [33.7%] vs 52 [50.5%]; difference, -16.8% [95% CI, -32.1% to -1.6%]; odds ratio, 0.50 [95% CI, 0.28 to 0.88]; P = .02). Symptomatic intracerebral hemorrhage was not significantly different between groups (6 [5.9%] vs 8 [7.7%]; difference, -1.8% [95% CI, -9.7% to 6.1%]; odds ratio, 0.75 [95% CI, 0.25 to 2.24]; P = .78). CONCLUSIONS AND RELEVANCE: Among patients with acute large vessel occlusion stroke, mechanical thrombectomy alone, compared with combined intravenous thrombolysis plus mechanical thrombectomy, failed to demonstrate noninferiority regarding favorable functional outcome. However, the wide confidence intervals around the effect estimate also did not allow a conclusion of inferiority. TRIAL REGISTRATION: umin.ac.jp/ctr Identifier: UMIN000021488.

Cholesterol Crystal in Thrombus Removed by Mechanical Thrombectomy Should be a Strong Marker for Aortogenic Embolic Stroke.

Aortogenic embolic stroke (AES) is an important stroke mechanism. However, as many stroke patients have aortic atheromatous lesions, it is unclear whether these lesions are the cause of these strokes. Cholesterol crystals are the solid, crystalline form of cholesterol that is found in atherosclerosis, but not in cardiac diseases such as atrial fibrillation, valvular diseases, and cardiomyopathy. Therefore, if a cholesterol crystal is found in a thrombus removed by mechanical thrombectomy (MT), this makes it possible to diagnose a patient as having an atheromatous lesion. Here, we report an AES case with a cholesterol crystal found in a thrombus removed by MT. A 67-year-old man was admitted due to consciousness disturbance, aphasia, and right hemiplegia. Diffusion-weighted imaging (DWI) showed a hyperintense area in the left frontal lobe, and magnetic resonance angiography demonstrated a branch occlusion of the left middle cerebral artery (MCA). MT was performed 1.5 h after stroke onset, with the thrombus removed and a left occluded MCA completely recanalized. Carotid duplex ultrasonography did not reveal any plaque in the carotid artery. Echocardiography did not show any abnormal function or findings, including thrombus. Transesophageal echocardiography showed a 4.9 mm atheromatous lesion at the aortic arch. Therefore, we suspected this patient as having an AES due to the embolic source of atheromatous lesion at the aortic arch. Pathological examination of the embolus revealed a cholesterol crystal cleft in the thrombus. Therefore, we diagnosed this patient as having AES caused by an atheromatous lesion at the aortic arch.

Early Cognitive Impairment after Minor Stroke: Associated Factors and Functional Outcome.

OBJECTIVES: Evaluation of cognitive status is not performed routinely in the acute stroke setting. This study aimed to evaluate the frequency of early cognitive impairment in patients with minor ischemic stroke, analyze the factors associated with early cognitive impairment, and assess functional outcomes. METHODS: In this prospective study, 112 consecutive patients with acute minor ischemic stroke were enrolled. Neuroimages were assessed for semiquantitative evaluation of brain atrophy and small vessel disease (SVD) markers. Cognitive performance was measured within 5 days of onset using Montreal Cognitive Assessment (MoCA) scores. Functional outcome analyses were adjusted for demographic variables, premorbid cognitive status, education level, vascular risk factors, neuroimaging characteristics, stroke severity, and MoCA scores. RESULTS: The median MoCA score was 22, and 63% of patients had cognitive impairment. Factors independently associated with cognitive impairment were education (odds ratios [OR], .79; confidence intervals [CI], .63-.99), smoking (OR, .26; 95%CI, .073-.89), and temporal horn atrophy (OR, 4.73; 95% CI, 1.66-13.49). Factors independently associated with poor functional outcome were total MoCA score (OR, .78; 95%CI, .62-.95) and the sum of 4 MoCA subscores (visuospatial/executive, attention, language, and orientation; OR, .72; 95%CI, .53-.92). The cutoff value of the sum of 4 MoCA subscores for predicting poor outcome was 13 points with 76.5% sensitivity and 81.1% specificity. CONCLUSIONS: Early cognitive impairment was common after minor ischemic stroke and was associated with preexisting temporal horn atrophy but not SVD markers. The sum of 4 MoCA subscores was useful in predicting the functional outcome.

Early Cognitive Assessment Following Acute Stroke: Feasibility and Comparison between Mini-Mental State Examination and Montreal Cognitive Assessment.

OBJECTIVES: Cognitive assessment is not performed routinely in the acute stroke setting. We investigated factors associated with cognitive impairment and the differences between the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) scores in patients with acute stroke. METHODS: In this prospective study, 881 consecutive patients (median age, 73 years) with acute stroke were enrolled. Clinical characteristics, such as education, vascular risk factors, premorbid cognitive status using the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), and stroke severity, were assessed. Cognitive performance was measured using MMSE and MoCA within 5 days of stroke onset. RESULTS: Both MMSE and MoCA were feasible in 621 (70.5%) patients. Factors independently associated with nonfeasibility were age (odds ratio [OR]: 1.05; 95% confidence interval [CI]: 1.02-1.08), IQCODE score (OR: 1.02; 95%CI: 1.00-1.04), and National Institutes of Health Stroke Scale (NIHSS) score (OR, 1.16; 95%CI, 1.12-1.20). Impaired MoCA (with a cut-off <26/30) performance was observed in 544 of 621 (87.6%) patients. Factors independently associated with cognitive impairment were age (OR: 1.06; 95%CI: 1.03-1.10) and NIHSS score (OR: 1.34; 95%CI: 1.14-1.57). Eighty percent of patients with normal MMSE scores had an impaired MoCA score (MMSE-MoCA mismatch). The differences were highest in the visuospatial (94.8% versus 65.3%; P < .0001), recall (76.6% versus 35.6%; P < .0001), abstraction (82.5% versus 49.8%; P < .0001), and language (72.3% versus 65.9%; P < .0001) domains between the normal MMSE and MoCA group and MMSE-MoCA mismatch group. CONCLUSIONS: The MoCA can be particularly useful in patients with cognitive deficits undetectable on the MMSE in the acute stroke phase.

Safety of Anticoagulant Therapy Including Direct Oral Anticoagulants in Patients With Acute Spontaneous Intracerebral Hemorrhage.

BACKGROUND: Because the efficacy and safety of anticoagulant therapy in patients with acute intracerebral hemorrhage (ICH) are not fully known, present study aimed to elucidate the current status and the safety of anticoagulant therapy, mainly direct oral anticoagulants (DOACs), for acute ICH and anticoagulant-indicated patients. Methods and Results: From September 2014 through March 2017, consecutive patients with acute (<7 days from onset), spontaneous ICH were retrospectively enrolled from a prospective registry. Whether to start anticoagulation was at the attending physicians' discretion, and thromboembolic or hemorrhagic events during hospitalization were analyzed. A total of 236 patients (80 women [34%]; median age 69 [interquartile range 61-79] years; National Institutes of Health stroke scale score 7 [3-16]) were enrolled. Of them, 47 patients (20%) had an indication for anticoagulant therapy (33 had atrial fibrillation, 14 developed deep vein thrombosis), and 41 of 47 patients (87%) were actually treated with anticoagulant therapy (DOACs were used in 34 patients) after a median of 7 days from ICH onset. There was neither hematoma expansion nor excessive hemorrhagic complications during hospitalization after starting anticoagulant therapy. CONCLUSIONS: Anticoagulant therapy was conducted for approximately 90% of anticoagulation-indicated patients after a median of 7 days from ICH onset. The predominant anticoagulant medications were DOACs. Anticoagulant therapy started from the acute phase of ICH should be safe.

Characteristics of Acute Spontaneous Intracerebral Hemorrhage in Patients Receiving Oral Anticoagulants.

OBJECTIVE: We investigated the precise clinical and radiologic characteristics of intracerebral hemorrhage associated with direct oral anticoagulant use. METHODS: Patients with acute spontaneous intracerebral hemorrhage admitted to our department from September 2014 to November 2017 were retrospectively analyzed. Clinical and neuroradiological characteristics of patients with direct oral anticoagulant-related intracerebral hemorrhage, and effects of prior treatment on the severity at admission and on outcome at discharge were assessed. RESULTS: Of the 301 enrolled patients (103 women; median age 68 years), 261 received no oral anticoagulants (86.8%), 20 received warfarin (6.6%), and 20 received direct oral anticoagulants (DOACs) (6.6%). Median initial National Institutes of Health Stroke Scale scores differed significantly among the groups (P = .0283). Systolic blood pressure (P = .0031) and estimated glomerular filtration rate (P = .0019) were significantly lower in the oral anticoagulant-related intracerebral hemorrhage group than in other groups. Total small vessel disease scores were significantly higher in the oral anticoagulant-related intracerebral hemorrhage group than in the warfarin group (P = .0413). Multivariate analysis revealed that prior oral anticoagulant treatment (odds ratio: 0.21, 95% confidence interval: 0.05-0.96, P = .0445) was independently negatively associated with moderate-to-severe neurological severity (stroke scale score ≥10) after adjusting for intracerebral hemorrhage location and various risk factors. There were significant differences in hematoma volume in the basal ganglia (P = .0366). CONCLUSIONS: DOAC-related intracerebral hemorrhage may occur particularly in patients with a high risk of bleeding; however, they had a milder initial neurological severity than those with warfarin-related intracerebral hemorrhage, possibly due to relatively smaller hematoma volume, especially in the basal ganglia.

Emergent Large Vessel Occlusion Screen Is an Ideal Prehospital Scale to Avoid Missing Endovascular Therapy in Acute Stroke.

Background and Purpose- The strong evidence of endovascular therapy in acute ischemic stroke patients with large vessel occlusion (LVO) is revealed. Such patients are required to direct transport to the hospital capable of endovascular therapy. There are several prehospital scales available for paramedics to predict LVO. However, they are time consuming, and several of them include factors caused by other types than LVO. Therefore, we need a fast, simple, and reliable prehospital scale for LVO. Methods- We developed a new prehospital stroke scale, emergent large vessel occlusion (ELVO) screen, for paramedics to predict LVO. The study was prospectively performed by multistroke centers. When paramedics referred to stroke center to accept suspected stroke patients, we obtain the following information over the telephone. ELVO screen was designed focusing on cortical symptoms: 1 observation; presence of eye deviation and 2 questions; paramedics show glasses, what is this? and paramedics show 4 fingers, how many fingers are there? If the presence of eye deviation or ≥1 of the 2 items were incorrect, ELVO screen was identified as positive. We evaluated between results of ELVO screen and presence of LVO on magnetic resonance angiography at hospital arrival. Results- A total of 413 patients (age, 74±13 years; men, 234 [57%]) were enrolled. Diagnosis was ischemic stroke, 271 (66%); brain hemorrhage 73 (18%); subarachnoid hemorrhage, 7 (2%); and not stroke, 62 (15%). One hundred fourteen patients had LVO (internal carotid artery, 33 [29%]; M1, 52 [46%]; M2, 21 [18%]; basilar artery, 5 [4%]; P1, 3 [3%]). Sensitively, specificity, positive predictive value, negative predictive value, and accuracy for ELVO screen to predict LVO were 85%, 72%, 54%, 93% and 76%, respectively. Among 233 patients with negative ELVO screen, only 17 (7%) had LVO, which indicated to be an ideal scale to avoid missing endovascular therapy. Conclusions- The ELVO screen is a simple, fast, and reliable prehospital scale for paramedics to identify stroke patients with LVO for whom endovascular therapy is an effective treatment.

Anticoagulants, Reperfusion Therapy, and Outcomes in Ischemic Stroke Patients With Non-Valvular Atrial Fibrillation　- A Single-Center, 6-Year Experience of 546 Consecutive Patients.

BACKGROUND: This study investigated changes in anticoagulant use, treatment, and functional outcomes in acute ischemic stroke (AIS) patients with non-valvular atrial fibrillation (NVAF) over a 6-year period. Methods and Results: Patients with AIS and NVAF admitted to our department from April 2011 to March 2017 were analyzed retrospectively. Patients were divided into 3 groups based on the time of the initial visit (Periods 1-3, corresponding to April 2011-March 2013, April 2013-March 2015, and April 2015-March 2017, respectively). Associations between prescribed medication prior to event and stroke severity, reperfusion therapy, and outcomes were assessed. There was no significant change in the rate of insufficient warfarin and inappropriately lowered doses of direct oral anticoagulant (DOAC) treatment over time. The number of patients receiving prior DOAC treatment increased, but neurological severity on admission was milder than in the other 2 groups. The rate of reperfusion therapy increased from 19.9% (Period 1) to 42.7% (Period 3) for moderate-to-severe stroke patients. Multivariate logistic regression analysis revealed that reperfusion therapy was independently positively associated with good functional outcomes, but negatively associated with mortality (odds ratios [95% confidence intervals] 7.14 [3.34-15.29] and 0.13 [0.008-0.69], respectively). CONCLUSIONS: Inappropriate anticoagulant use for stroke patients with NVAF did not decrease over time. An increase in reperfusion therapy was a strong factor in improved functional outcomes and mortality.

Insufficient Warfarin Therapy Is Associated With Higher Severity of Stroke Than No Anticoagulation in Patients With Atrial Fibrillation and Acute Anterior-Circulation Stroke.

BACKGROUND: Insufficient anticoagulant intensity on admission is common in stroke patients with atrial fibrillation (AF) on vitamin K antagonist (VKA) therapy. Nevertheless, the effects of VKA under-treatment on stroke severity or arterial occlusion are not well known. The aim of the present study was to investigate the relationship between insufficient VKA therapy and stroke severity, or the site of arterial occlusion in patients with acute ischemic stroke (AIS) and AF.Methods and Results:From March 2011 through July 2016, 446 consecutive patients with AF and AIS were recruited. Of the 446 patients, 364 (167 women; median age, 79 years; IQR, 71-86 years) with anterior-circulation stroke were assessed to investigate the effects of insufficient VKA. Of these, 281 were on no anticoagulant, 53 were undertreated with a VKA, and 30 were sufficiently treated with VKA on admission (PT-INR ≥2.0 for patients <70 years and PT-INR ≥1.6 for ≥70 years old). On multivariate analysis, insufficient VKA was independently associated with severe stroke (i.e., initial NIHSS score ≥10; OR, 2.70, P=0.022) and higher prevalence of proximal artery occlusion (OR, 1.91; P=0.039) compared with no anticoagulant therapy. CONCLUSIONS: Insufficient VKA therapy on admission was associated with higher severity of stroke and higher prevalence of proximal artery occlusion in patients with AF and acute anterior-circulation stroke compared with no anticoagulant medication.

In Hyperacute Recanalization Therapy, Early Hospital Arrival Improves Outcome in Patients with Large Artery Occlusion.

BACKGROUND: It is unknown whether the effect of onset---to-door (OTD) time on clinical outcomes differs between -patients with and without large artery occlusion (LAO) who undergo hyperacute recanalization therapy. METHODS: Hyperacute recanalization therapy includes intravenous thrombolysis tissue-plasminogen activator (tPA), and endovascular therapy (EVT). Favorable clinical outcome was defined as modified Rankin Scale of ≤2 at discharge. RESULTS: Among 164 patients, 117 (71%) patients received tPA, 86 (52%) received EVT, and 39 (24%) received tPA and EVT. One hundred and fifteen patients (70%) were classified into the LAO group and 49 (30%) into the non-LAO group. In the total cohort, multivariate regression analysis showed OTD time (OR 0.809 [95% CI 0.693-0.944], p = 0.007) was an independent factor related to the favorable outcome. Similarly, among patients with LAO, OTD was an independent negative factor for the favorable outcome (0.779 [0.646-0.940], p = 0.009). On the contrary, OTD was not associated with the favorable outcome (1.5 [0.7-2.5] vs. 1.7 [1.1-3.2], p = 0.155) in patients without LAO. This was confirmed with multivariate regression analysis, which did not show OTD to be an independent factor for the favorable outcome (0.900 [0.656-1.236], p = 0.516). CONCLUSION: The effect of early hospital arrival on clinical outcome differed between patients with and without LAO.

Decline in Hemoglobin during Hospitalization May Be Associated with Poor Outcome in Acute Stroke Patients.

BACKGROUND AND PURPOSE: Anemia upon hospital admission is a known predictor of poor functional outcomes in patients with acute cerebral infarction. However, it remains unclear whether reductions in hemoglobin levels during hospitalization influence stroke outcomes. We investigated the association between in-hospital decline in hemoglobin and poor outcomes. MATERIALS AND METHODS: We retrospectively analyzed data from 480 consecutive patients who had experienced acute cerebral infarction and presented without anemia between January 2012 and March 2015. Decline in hemoglobin was taken as the difference between hemoglobin levels upon admission and nadir hemoglobin. Poor outcome was defined as a modified Rankin Scale score 3-6. A multivariate analysis of the relationship between decline in hemoglobin and poor outcome at discharge was conducted for various patient characteristics. RESULTS: The mean hemoglobin level at admission was 14.3 ± 1.3 g/dL, whereas the mean nadir hemoglobin value was 13.1 ± 1.9 g/dL, with a mean decline in hemoglobin of 1.3 ± 1.5 g/dL. In patients with poor outcomes, mean decline in hemoglobin was significantly reduced to 3.1 g/dL (P < .001). The optimal cutoff decline in hemoglobin required to distinguish a poor outcome was 1.5 g/dL whereas the sensitivity and specificity were 62% and 82.3%, respectively, with an area under the curve of .77 (P < .0001). A decline in hemoglobin below 1.5 g/dL was found to be an independent predictor of poor outcome (odds ratio: 2.10; confidence interval: 1.10-3.99; P = .023). CONCLUSION: Decline in hemoglobin in patients hospitalized with acute stroke may be associated with poor outcome.

Low Free Triiodothyronine at Admission Predicts Poststroke Infection.

BACKGROUND: Poststroke infection (PSI) is common and is usually associated with a severe prognosis. We investigated the association between PSI and thyroid hormones, which are critical to immune regulation, in patients with acute stroke. METHODS: We retrospectively enrolled 520 consecutive patients with acute ischemic stroke (326 men; age, 71.9 ± 13.2 years) admitted to our department between September 2014 and June 2016. The impact of serum thyroid hormone levels measured at admission (thyroid-stimulating hormone [TSH], free triiodothyronine [FT3], and free thyroxine [FT4]) on the PSI was evaluated using multivariate logistic regression analysis. RESULTS: We diagnosed 107 patients (20.6%; pneumonia, 65; urinary tract infection, 19; others, 23) with PSIs. While age (P <.001), body mass index (P = .0012), preadmission modified Rankin scale score (P = .0001), National Institutes of Health Stroke Scale score on admission (P <.001), admission FT3 level (P <.001), atrial fibrillation (P <.001), and ischemic heart disease (P = .0451) were significantly associated with PSI, we found no relationship among TSH levels, FT4 levels, and PSI occurrence. After multivariate adjustment, patients with PSIs were more frequently in the Q1 quartile (≤2.25 pg/mL) than in the Q2 (2.26-2.55 pg/mL; P = .0251), Q3 (2.56-2.89 pg/mL; P = .0007), or Q4 (≥2.90 pg/mL; P = .0010) quartiles of FT3 levels. Moreover, low FT3 levels (<2.29 pg/mL) were independently associated with PSI occurrence (P = .0013). CONCLUSIONS: Low FT3 levels at admission are independently associated with PSI occurrence.

Low Free Triiodothyronine Predicts 3-Month Poor Outcome After Acute Stroke.

BACKGROUND AND PURPOSE: The association between thyroid hormone levels and long-term clinical outcome in patients with acute stroke has not yet been thoroughly studied. The purpose of the present study was to test the hypothesis that thyroid hormone levels are associated with 3-month functional outcome and mortality after acute stroke. METHODS: We retrospectively analyzed 702 consecutive patients with acute stroke (251 women; median age, 73 years) who were admitted to our department. General blood tests, including thyroid stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine (FT4), were performed on admission. Neurological severity was evaluated using National Institutes of Health Stroke Scale (NIHSS) scores on admission and modified Rankin Scale (mRS) scores at 3 months after stroke onset. Poor outcome was defined as an mRS score of 3-5 or death. The impact of thyroid function on 3-month outcome was evaluated using multiple logistic regression analysis. RESULTS: Poor functional outcome was observed in 295 patients (42.0%). Age (P < .0001), female sex (P < .0001), admission NIHSS score (P < .0001), smoking (P = .0026), arterial fibrillation (P = .0002), preadmission mRS (P < .0001), estimated glomerular filtration rate (P = .0307), and ischemic heart disease (P = .0285) were significantly associated with poor functional outcome, but no relationship between FT4, TSH, and poor functional outcome was found. A multivariate logistic regression analysis showed that low FT3 values (<2.00 pg/mL) were independently associated with poor functional outcome (odds ratio [OR], 3.16; 95% confidence interval [CI], 1.60-6.24) and mortality (OR, 2.55; 95% CI, 1.33-4.91) at 3 months after stroke onset. CONCLUSIONS: Our data suggest that a low FT3 value upon admission is associated with a poor 3-month functional outcome and mortality in patients with acute stroke.

Arene-Inserted Extended Germa[n]pericyclynes: Synthesis, Structure, and Phosphorescence Properties.

This report describes the synthesis and characterization of arene-inserted extended (ArEx) germa[n]pericyclynes composed of germanium and 1,4-diethynylbenzene units. These novel cyclic germanium-π unit materials were synthesized with diethynylbenzene and germanium dichloride. X-ray crystallographic analysis revealed their structures, and the planar conformation of ArEx germa[4]pericyclyne along with the regular aromatic rings. UV/Vis absorption spectra and fluorescence emission spectra showed considerably unique and highly improved character compared to previously reported germa[n]pericyclynes. Even in the absence of transition metal components, phosphorescence emissions were observed, and the emission lifetimes were dramatically improved. ArEx germa[n]pericyclynes showed high photoluminescence quantum yields, whereas low photoluminescence quantum yields were observed for acyclic compounds. Density functional theory calculations show delocalized orbitals between skipped alkyne units through a germanium tether, and an increase in the HOMO energy level, leading to a small HOMO-LUMO energy gap.

Enhanced phasic GABA inhibition during the repair phase of stroke: a novel therapeutic target.

Ischaemic stroke is the leading cause of severe long-term disability yet lacks drug therapies that promote the repair phase of recovery. This repair phase of stroke occurs days to months after stroke onset and involves brain remapping and plasticity within the peri-infarct zone. Elucidating mechanisms that promote this plasticity is critical for the development of new therapeutics with a broad treatment window. Inhibiting tonic (extrasynaptic) GABA signalling during the repair phase was reported to enhance functional recovery in mice suggesting that GABA plays an important function in modulating brain repair. While tonic GABA appears to suppress brain repair after stroke, less is known about the role of phasic (synaptic) GABA during the repair phase. We observed an increase in postsynaptic phasic GABA signalling in mice within the peri-infarct cortex specific to layer 5; we found increased numbers of α1 receptor subunit-containing GABAergic synapses detected using array tomography, and an associated increased efficacy of spontaneous and miniature inhibitory postsynaptic currents in pyramidal neurons. Furthermore, we demonstrate that enhancing phasic GABA signalling using zolpidem, a Food and Drug Administration (FDA)-approved GABA-positive allosteric modulator, during the repair phase improved behavioural recovery. These data identify potentiation of phasic GABA signalling as a novel therapeutic strategy, indicate zolpidem's potential to improve recovery, and underscore the necessity to distinguish the role of tonic and phasic GABA signalling in stroke recovery.