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Background: The “1-3-6-12-day rule” for starting direct oral anticoagulants (DOACs) in patients with nonvalvular atrial fibrillation after acute ischemic stroke or transient ischemic attack recommends timings that may be later than used in clinical practice. We investigated more practical optimal timing of DOAC initiation according to stroke severity. Methods: The combined data of prospective registries in Japan, Stroke Acute Management with Urgent Risk-factor Assessment and Improvement-nonvalvular atrial fibrillation (September 2011 to March 2014) and RELAXED (February 2014 to April 2016) were used. Patients were divided into transient ischemic attack and 3 stroke subgroups by the National Institutes of Health Stroke Scale score: mild (0–7), moderate (8–15), and severe (≥16). The early treatment group was defined as patients starting DOACs earlier than the median initiation day in each subgroup. Outcomes included a composite of recurrent stroke or systemic embolism, ischemic stroke, and severe bleeding within 90 days. Six European prospective registries were used for validation. Results: In the 1797 derivation cohort patients, DOACs were started at median 2 days after transient ischemic attack and 3, 4, and 5 days after mild, moderate, and severe strokes, respectively. Stroke or systemic embolism was less common in Early Group (n=785)—initiating DOACS within 1, 2, 3, and 4 days, respectively—than Late Group (n=1012) (1.9% versus 3.9%; adjusted hazard ratio, 0.50 [95% CI, 0.27–0.89]), as was ischemic stroke (1.7% versus 3.2%, 0.54 [0.27–0.999]). Major bleeding was similarly common in the 2 groups (0.8% versus 1.0%). On validation, both ischemic stroke (2.4% versus 2.2%) and intracranial hemorrhage (0.2% versus 0.6%) were similarly common in Early (n=547) and Late (n=1483) Groups defined using derivation data. Conclusions: In Japanese and European populations, early DOAC initiation within 1, 2, 3, or 4 days according to stroke severity seemed to be feasible to decrease the risk of recurrent stroke or systemic embolism and no increase in major bleeding. These findings support ongoing randomized trials to better establish the optimal timing of DOAC initiation.

Background and Purpose— Disease management is a healthcare strategy that includes self-management education and treatment coordination. We conducted a randomized controlled trial to determine whether a disease management program intervention could improve risk factor profiles and, thus, reduce the recurrence of stroke and other cardiovascular diseases. Methods— This study is a prospective randomized, open-label, parallel group study involving outpatients with a history of stroke. Between September 2010 and November 2012, we enrolled patients aged between 40 and 80 years who experienced their last ischemic stroke event or transient ischemic attack within 1 year. After stratifying by the ischemic stroke subtype, 321 subjects (67.5±8.5 years, 95 female) were randomly assigned to either the disease management program intervention group (n=156) or the usual care group (n=165). The primary end point of this study was the difference in the Framingham risk score (general cardiovascular disease 10-year risk) from baseline. The secondary end points of this study included stroke recurrence, onset of cardiovascular disease, all-cause mortality, and all vascular events. Results— Regarding the primary end point, there was no significant difference in the changes in the Framingham risk score at any follow-up time between the groups. The incidence of stroke recurrence tended to be lower in the disease management program intervention group, although no significant difference was found (hazard ratio, 0.49; 95% CI, 0.19–1.29). Conclusions— We were unable to demonstrate a clear benefit of disease management program intervention. Clinical Trial Registration— URL: https://www.clinicaltrials.gov . Unique identifier: NCT02121327.

Background and Purpose: IV alteplase at 0.6 mg/kg for acute wake-up and unclear onset strokes was recommended in Japanese stroke guidelines in March 2019. We determined the safety and effectiveness of this newly recommended thrombolysis in clinical practice. Methods: This is a multicenter observational study, enrolling acute ischemic stroke patients with a time last-known-well >4.5 h who have a mismatch between DWI and FLAIR treated with intravenous alteplase. The safety outcomes are intracranial hemorrhage (ICH) with neurological deterioration within 36 h after thrombolysis, all cause deaths within 90 days, and adverse events. The efficacy outcomes are functionally independence defined as a mRS score of 0-1 at 90 days, and NIHSS change at 24h from baseline. Results: Between 2019 March and 2020 March, 63 patients (33 females; age, 74±11y; premorbid functionally independence, 50 (82%); median NIHSS on admission, 11) were enrolled at 14 hospitals. Of them, 40 patients (63%) recognized stroke symptoms at wake-up time, and median time between last-known-well and admission was 6.5 h. Baseline MRA showed any vessel occlusion in 52 patients (88%). IV alteplase was disrupted in one patient. Two patients (3%) had symptomatic ICH (≥4 increase in NIHSS) within 36 h. NIHSS change was -5.1±8.1. Twenty-one patients (36%) had functionally independence at discharge and there was no death during acute hospitalization. Of the overall 63 patients, 22 also underwent mechanical thrombectomy (36%, 72±9y, median NIHSS 16), showing no symptomatic ICH, mean NIHSS change of -8.9±7.5, and 8 patients (42%) had functionally independence at discharge. Conclusions: In clinical practice, IV alteplase for wake-up and unclear onset stroke patients with DWI-FLAIR mismatch seemed to be safe and effective compared with previous randomized control trials. Mechanical thrombectomy could be combined with alteplase safely and effectively.

Background and purpose: To assess the potential effect of prior antithrombotic medication for thrombolysis using alteplase at 0.6mg/kg in unknown onset stroke. Methods: This was a prespecified sub-analysis of a THAWS trial (an investigator-initiated, multicenter, randomized, open, blinded-endpoint trial). Stroke patients with a time last-known-well >4.5 h who had a mismatch between diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery were randomly assigned (1:1) to receive alteplase at 0.6mg/kg or standard medical treatment (SMT). Patients were dichotomized by taking prior antithrombotic medication. The favorable outcome defined as a modified Rankin Scale score of 0-1 at 90 days and any intracranial hemorrhage within 22-36 h were compared in each group. Results: Of 126 patients (intention-to-treat population), 68 received alteplase and 58 had SMT. Seventeen in the alteplase group and 23 in the SMT group took antithrombotic medication (10 with antiplatelet alone, 5 with anticoagulant alone and 2 with both in the IVT group, and 14, 8 and 1, respectively, in the SMT group) before stroke onset. Antithrombotic therapy was more frequently initiated within 24 hours after randomization in the SMT group than in the alteplase group (86% vs. 12%, p Conclusions: Alteplase at 0.6mg/kg appears more beneficial in patients with prior antithrombotic medication.

Background We aimed to clarify associations between prior anticoagulation and short‐ or long‐term clinical outcomes in ischemic stroke or transient ischemic attack patients with nonvalvular atrial fibrillation. Methods and Results A total of 1189 ischemic stroke or transient ischemic attack patients with nonvalvular atrial fibrillation who were hospitalized within 7 days after onset were analyzed. Of these, 813 patients (68.4%) received no prior anticoagulation, 310 (26.1%) received prior warfarin treatment with an international normalized ratio ( INR ) INR ≥2 on admission, and the remaining 38 (3.2%) received prior direct oral anticoagulant treatment. Prior warfarin treatment was associated with a lower risk of death or disability at 3 months compared with no prior anticoagulation ( INR P =0.001; INR ≥2: adjusted odds ratio: 0.40; 95% CI, 0.16–0.97; P =0.043) but was not associated with a lower risk of death or disability at 2 years. Prior warfarin treatment with an INR ≥2 on admission was associated with a higher risk of ischemic events within 2 years compared with no prior anticoagulation (adjusted hazard ratio: 2.94; 95% CI, 1.20–6.15; P =0.021). Conclusions Prior warfarin treatment was associated with a lower risk of death or disability at 3 months but was not associated with a lower risk of death or disability at 2 years in ischemic stroke or transient ischemic attack patients with nonvalvular atrial fibrillation. Prior warfarin treatment with an INR ≥2 on admission was associated with a higher risk of ischemic events within 2 years. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 01581502.

Purpose of review The global incidence of small papillary thyroid carcinoma (PTC) is increasing remarkably, mostly due to the increased use of imaging studies worldwide. The issue of how to manage low-risk small PTC has become urgent. In this review, we focus on how to treat low-risk papillary thyroid microcarcinomas (PMCs; i.e., PTCs measuring ≤10 mm). Recent findings Studies of large numbers of patients with low-risk PMC clarified that most of the PMCs did not grow or grew very slowly and were harmless. Active observations of these patients discriminated rare progressive cases from the majority. Surgery performed after the detection of progression signs was not too late, and surgery immediately after the detection and diagnosis of low-risk PMC may be overtreatment for most patients. Interestingly, low-risk PMCs in elderly patients were most unlikely to progress, in sharp contrast to clinical PTC. The reason for this phenomenon remains unknown. Summary Active observation without immediate surgery can be a leading alternative to the classical surgical treatment in the majority of the patients with low-risk PMC. It is not too late to perform surgery after the detection of progression signs for these patients. Video abstract http://links.lww.com/COON/A10

Background and purpose: The discrimination between paroxysmal and persistent atrial fibrillations (AF) has not been considered to guide secondary stroke prevention, because it remains unclear whether patients with persistent AF are at higher risk compared with paroxysmal AF, particularly in secondary prevention. We aimed to assess the differences in clinical outcomes between mostly anticoagulated patients with persistent vs. paroxysmal AF who had ischemic stroke or TIA. Methods: Using interim data of 1192 nonvalvular AF (NVAF) patients with acute ischemic stroke or TIA who were registered in the SAMURAI-NVAF study (an ongoing prospective, multicenter, observational study) to determine choice of anticoagulantion therapy and clinical outcomes, we divided patients into those with paroxysmal AF and those with persistent AF. We compared clinical outcomes between the 2 groups. Results: The median follow-up period was 1.0 year (IQR 0.3-2.0). Of the 1192 patients, 434 (191 women, 77.3±10.0 y.o.) and 758 (336, 77.9±9.9) were assigned to the paroxysmal AF group and persistent AF group, respectively. Of each group, 220 (50.7%) and 442 (58.3%) were anticoagulated with warfarin and 199 (45.9%) and 276 (36.4%) were so with non-vitamin K antagonist oral anticoagulant (NOAC) (p=0.004). As for primary outcomes, 30 (6.2%/person-year) and 78 (9.9) ischemic events, respectively [hazard ratio adjusted for sex, age, initial NIHSS, CHADS2 score, creatinine clearance, anticoagulation with warfarin (vs. NOAC) (HR) 0.65; 95% CI 0.42-0.98], and 18 (4.9%/person-year) and 31 (3.8) hemorrhagic events, respectively (HR 0.97, 0.52-1.75), occurred during follow-up. As for secondary outcomes, the person-year rate of ischemic stroke or TIA was 3.9% and 8.4%, respectively (HR 0.46, 0.27-0.76), that of intracranial hemorrhage was 1.6% and 1.7%, respectively (HR 0.97, 0.36-2.37), and that of death was 11.1% and 15.7%, respectively (HR 0.90, 0.64-1.26). Conclusions: Among patients with prior ischemic stroke or TIA, those with persistent AF had a higher risk of ischemic events, and ischemic stroke or TIA compared with those with paroxysmal AF. The prevention of progress to persistent AF from paroxysmal AF may be beneficial for secondary prevention in patients with NVAF.

Objective— Transgenic mice overexpressing angiopoietin-related growth factor (AGF) exhibit enhanced angiogenesis, suggesting that AGF may be a useful drug target in ischemic disease. Our goal was to determine whether AGF enhances blood flow in a mouse hind-limb ischemia model and to define molecular mechanisms underlying AGF signaling in endothelial cells. Methods and Results— Intramuscular injection of adenovirus harboring AGF into the ischemic limb increased AGF production, which increased blood flow through induction of angiogenesis and arteriogenesis, thereby reducing the necessity for limb amputation. In vitro analysis showed that exposing human umbilical venous endothelial cells to AGF increased nitric oxide (NO) production through activation of an ERK1/2-endothelial NO synthetase (eNOS) signaling pathway. AGF-stimulated eNOS phosphorylation, NO production, and endothelial cell migration were all abolished by specific MEK1/2 inhibitors. Moreover, AGF did not restore blood flow to ischemic hind-limbs of either mice receiving NOS inhibitor L-NAME or eNOS knockout mice. Conclusion— Activation of an ERK1/2-eNOS-NO pathway is a crucial signaling mechanism by which AGF increases blood flow through induction of angiogenesis and arteriogenesis. Further investigation of the regulation underlying AGF signaling pathway may contribute to develop a new clinical strategy for ischemic vascular diseases.

Backgound and Purpose: Recently, three non-vitamin K antagonist oral anticoagulants (NOACs) became available for patients with nonvalvular atrial fibrillation (NVAF) in Japan. We aimed to determine 3-month outcomes in ischemic stroke/TIA patients receiving NOACs or warfarin from a multicenter prospective registry (SAMURAI-NVAF registry, NCT01581502). Methods: Among 1,191 acute ischemic stroke /TIA patients enrolled between September 2011 and March 2014, we studied 916 patients (389 women, 77±10 y) who took oral anticoagulants (OACs) after index stroke and completed 3-month follow-up survey. Primary outcome measures were ischemic events, including recurrent stroke/TIA and thromboembolism, and major bleedings events, such as fatal bleeding and/or symptomatic bleeding in a critical area or organ according to the International Society on Thrombosis and Haemostasis statement. We assessed the incidence and clinical factors associated with primary outcomes within 90 days after initiating OACs. Results: NOACs were given for 370 patients (126 women, 74±9 y; dabigatran 168, rivaroxaban 183 and apixaban 19) and warfarin for 546 (263 women, 79±10 y). NOAC users had lower scores of CHADS2 (median 3 in NOAC, 4 in warfarin, p Conclusion: The 3-month incidence of ischemic events in stroke/TIA patients with NVAF was approximately 4% in both NOAC and warfarin users. Intracranial hemorrhage was relatively infrequent in NOAC users.

Background and Purpose: We aimed to assess whether prior antithrombotic therapy affects initial neurological severity and functional outcome in acute ischemic stroke patients with non-valvular atrial fibrillation (NVAF). Methods: Patients with NVAF who were admitted within 7 days after ischemic stroke onset from 2011 to 2014 were enrolled from the register of a prospective, multicenter, observational study (the SAMURAI-NVAF study). Patients receiving novel oral anticoagulants at onset were excluded from the study. They were classified into 3 groups: the non-WF group, patients without prior warfarin; the iWF group, those on warfarin with initial PT-INR below the target range; the sWF group, those on warfarin with initial PT-INR within or above the target range. They were also divided into patients without prior antiplatelet agents (the non-AP group) and those with (the AP group). Initial neurological severity was measured by NIHSS score. Poor functional outcome was defined by mRS 3-6 at 3 months of onset. Results: Of 1000 patients studied, 713, 221 and 66 were assigned to the non-WF group, the iWF group and the sWF group, respectively. Of all, 245 were assigned to the AP group, mainly taking aspirin (202 patients). On multivariate analysis, the sWF group (vs. the non-WF group) (standardized regression coefficient [β], -0.23; p Conclusions: Prior sufficient warfarinization was associated with mild neurological severity and favorable outcome in acute ischemic stroke patients with NVAF, whereas prior insufficient warfarinization and prior antiplatelet therapy were not.

Background and purpose: The impact of albuminuria on clinical outcomes in acute cardioembolic stroke is not fully investigated. We assessed whether high spot urine albumin/creatinine ratio (ACR) was associated with clinical outcomes in acute stroke with non-valvular atrial fibrillation (NVAF). Methods: From 2011 to 2014, we enrolled acute ischemic stroke/TIA patients with NVAF in the SAMURAI-NVAF study, which is a multicenter, observational study. Patients with complete ACR values were included in the analysis. They were divided into the N (normal, ACR < 30mg/g) and the H (high, ACR ≥ 30mg/g) groups. Clinical outcomes were neurological deterioration (an increase of NIHSS ≥1 point during the initial 7 days) and poor outcome (mRS of 4-6 at 3 months). Results: Of 558 patients (328 men, 77±10 y) who were included, 271 and 287 were assigned to the H group and the N group, respectively. As compared with patients in the N group, those in the H group were more frequently female (52 vs 31%, p < 0.001) and older (80±10 vs 75±10 y, p < 0.001). On admission, patients in the H group more frequently had diabetes (28 vs 17%, p = 0.003), less frequently had paroxysmal AF (68 vs 57%, p = 0.009), had higher levels of SBP (157±28 vs 151±24 mmHg, p = 0.003), NIHSS score (11 vs 5, p < 0.001), CHA2DS2-VASc score (6 vs 5, p < 0.001), plasma glucose (141±62 vs 132±41 mg/dL, p = 0.04), and brain natriuretic peptide (348±331 vs 259±309 pg/mL, p = 0.002), and had lower levels of hemoglobin (13±2 vs 14±2 g/dL, p = 0.02), and estimated glomerular filtration ratio (eGFR) (60±24 vs 66±20 mL/min/1.73m2 p = 0.002). On imaging studies, patients in the H group more frequently had large infarct (29 vs 20 %, p = 0.02) and culprit artery occlusion (64 vs 48%, p < 0.001). Neurological deterioration (14 vs 4%, p < 0.001) and poor outcome (49 vs 24%, p < 0.001) were more frequently observed in the H group. On multivariate regression analysis adjusted for significant confounders and reperfusion therapy, the H group was associated with neurological deterioration (OR 2.43; 95% CI 1.14-5.5; p = 0.02) and poor outcome (OR 2.75; 95% CI 1.45-5.2; p = 0.002), although eGFR was not significantly related to either. Conclusion: High ACR, a marker of albuminuria, was independently associated with unfavorable outcomes in acute stroke patients with NVAF.

Objective— Ephrin-B2 plays a key role in vascular development. The purpose of this study was to elucidate the molecular mechanisms of ephrin-B2 signaling through the EphB receptor in endothelial cells and to determine whether ephrin-B2 contributes to in vivo angiogenesis in adult mice. Methods and Results— A chemotaxis assay on a polycarbonate membrane revealed that ephrin-B2/Fc chimeric protein induced migration of human umbilical vein endothelial cells (HUVECs) at a level 98% greater than control ( P Conclusions— Ephrin-B2/Fc induces the migration of HUVECs through the PI3 kinase signaling pathway. Ephrin-B2/Fc promotes in vivo angiogenesis in adult mice, suggesting that it contributes to adult angiogenesis.

Objective: Early anticoagulant therapy is commonly used for acute cardioembolic stroke in Japan, although its usefulness remains undetected. The purpose of this study was to estimate the efficacy and safety of early anticoagulation for the treatment of acute stroke/TIA patients with nonvalvular atrial fibrillation (NVAF). Methods: From September 2011 through June 2013, 697 acute ischemic stroke/TIA patients with NVAF were registered from a multicenter prospective registry (the SAMURAI-NVAF study including 18 Japanese stroke centers, NCT01581502). Of those, the patients who started anticoagulant therapy within 48 hours after the onset were assessed for the incidence of ischemic and hemorrhagic events during the first 30 days. Results: A total of 438 patients (62.8%; 247 men, 77.4±9.8 years old) was evaluated. Of these, 292 patients (66.7%) started anticoagulation with intravenous unfractionated heparin (UFH) mono-therapy, 87 patients (19.9%) with UFH and warfarin, and 2 patients (0.5%) with UFH switched to novel oral anticoagulants (NOACs). As oral anticoagulants mono-therapy, 34 patients (7.8%) started with warfarin, and 23 (5.3%) with NOAC. Ischemic events were developed in 11 patients (2.5%: 11 recurrent ischemic strokes), and hemorrhagic events in 11 patients (2.5%: 6 symptomatic intracranial hemorrhages during the first 7days and 5 extracranial hemorrhages). Patients with major artery occlusion had higher incidence of hemorrhagic events than those without (4.0% versus 0.6%, p=0.02), whereas ischemic events were similar in both groups (2.4% versus 2.7%, p=0.82). In multivariable analysis, major artery occlusion was independently associated with higher rate of major hemorrhagic events (OR 6.19; 95% CI 1.01-119.75) adjusted for age, sex, BMI, HAS-BLED score before index TIA/stroke, and NIHSS on admission. Conclusion: In our cohort, early initiation of anticoagulant therapy is often performed in patients with acute stroke/TIA with NVAF patient, and the frequency of ischemic and hemorrhagic events seems to be low compared with previous reports. Early anticoagulant therapy can be safe for patients without major artery occlusion.

Purpose: Atrial fibrillation (AF) is often detected after embolic events occur, and it is an obstacle to effective preventive anticoagulation. We aimed to determine a percentage of patients with nonvalvular AF (NVAF) unidentified prior to stroke in the overall stroke patients with NVAF, as well as background features, stroke severity and outcome of such occult NVAF patients. Methods: A total of 743 acute ischemic stroke/TIA patients with NVAF (344 women, 78±10 years old) were enrolled between Sep 2011 and Jun 2013 from a multicenter prospective registry (the SAMURAI-NVAF study, NCT01581502). Patients were divided into two groups; those with identified AF before stroke/TIA (Group I) and those with unidentified AF that was documented at emergent visit or later (Group U). Favorable outcome was defined as mRS 0-2 at hospital discharge (for 710 patients, median 23 days) and at 3 months (for 565 patients). Results: 285 patients belonged to the Group U (38%; 138 women, 78±11 years old). Although both median CHADS 2 (2 vs. 2, p2 DS 2 -VASc (3 vs. 4, p2 and 91% according to CHA 2 DS 2 -VASc in the Group U. After multivariate adjustment, paroxysmal AF (OR 1.91, 95% CI 1.24-2.75) was more common and congestive heart failure (0.63, 0.40-0.99) and premorbid use of oral anticoagulants (0.08, 0.04-0.13) were less common in the Group U than the Group I. The median initial NIHSS was higher in the Group U (11 [IQR 4-19]) than in the Group I (6 [2-17], p Conclusion: Two fifth of the stroke/TIA patients with NVAF were not diagnosed as having AF prior to the attack, though their ischemia-risk indices were generally high. Patients with such occult NVAF had severer stroke and worse outcome than those with identified AF.

It is well known that chronic inflammatory conditions involving the bile ducts predispose to the development of bile duct carcinoma, although the relationship between chronic inflammation and malignant transformation is unclear. In this study, by combining immunohistochemistry and computer imaging techniques, we quantified and compared the cyclooxygenase-2 (COX-2) protein expression levels of epithelial cells according with their histopathological backgrounds. This technique revealed that the highest levels of COX-2 were expressed in bile duct carcinoma cells, mainly in cytoplasm, and the expression pattern was homogenous and abundant. Moderate levels of COX-2 protein expression were also observed in noncancerous epithelial cells with inflammatory reaction, but the staining intensity was heterogeneous among the positive cells exhibiting inflammation. In contrast, only scattered weak reactivity of COX-2 protein was observed in the noncancerous bile duct epithelial cells without inflammatory reaction. Moreover, bile duct epithelial cells in primary sclerosing cholangitis (PSC) showed very strong expression of COX-2 protein, that was comparable with carcinoma cells. On the other hand, primary biliary cirrhosis (PBC) epithelial cells showed moderate levels of COX-2 expression. In addition, specific COX-2 inhibitors, JTE-522 and NS-398, directly inhibited the growth of 4 bile duct carcinoma and 1 gall bladder carcinoma cell lines that expressed COX-2 protein, in vitro. These data suggest that COX-2 expression might regulate carcinogenesis of bile duct epithelial cells in inflammatory regions and tumor progression in this cancer. The data also suggest that COX-2 selective inhibitors might have therapeutic effects not only on bile duct carcinoma, but other hepatobiliary carcinomas.

Expression of cell-cycle modulators at the G1-S boundary, retinoblastoma gene product (pRb), p21, p16, p27, p53, cyclin D1, and cyclin E was investigated with 104 hepatocellular carcinomas (HCC), as well as 90 of their adjacent noncancerous lesions and 9 normal liver control specimens. The labeling indices (LI) of pRb, p21, p16, and p27 were higher in HCC lesions than in the adjacent noncancerous lesions and normal controls. Especially, p27 LI in noncancerous lesions was significantly higher than that in normal livers (P =.011). Aberrant p53 expression and cyclin D1 and E overexpression were observed exclusively in HCC lesions. pRb was positive in 85.6% of the HCC cases and was not related to any clinicopathological parameters. The p21 LI was generally low (average, 5.5 +/- 9.8). Although a negative regulator, p21 LI was higher in cases with intrahepatic metastasis (P =.0359). The p16 LI was significantly decreased (P =.0121) in cases with advanced stage. p27 LI was significantly decreased in cases with portal invasion (P =.0409), poor differentiation (P