The impact of SAH finding on CT to the clinical outcome after mechanical thrombectomy for large vessel occlusion.

BACKGROUND AND PURPOSE: Whether subarachnoid haemorrhage (SAH) after mechanical thrombectomy affects the clinical outcomes of patients with acute large-vessel occlusion remains unclear. This study aimed to investigate the clinical impact of SAH on computed tomography (CT) after mechanical thrombectomy. METHODS: The SKIP study was an investigator-initiated, multicentre, randomised, open-label clinical trial. This study was performed in 23 hospital networks in Japan from January 1, 2017, to July 31, 2019. Among the 204 patients, seven were excluded because they did not undergo mechanical thrombectomy (MT) and had a modified Rankin scale (mRS) score > 2. The main outcome was the association between SAH within 36 h after mechanical thrombectomy and the clinical outcome at 90 days. RESULTS: Among 197 patients, the median age was 74 (67-79) years, 62.9% were male. Moreover, 26 (13.2%) patients had SAH (seven isolated SAH) on CT within 36 h. The SAH rate did not differ according to IV rt-PA administration (p = 0.4). The rate of favourable clinical outcomes tended to be lower in patients with SAH rather than patients without SAH (11 [42%] vs. 106 [62%], p = 0.08). Among the seven patients with isolated SAH, 6 showed favourable outcomes at 90 days. In the multivariate regression analysis, the presence of SAH within 36 h from onset was not associated with clinical outcome (Odd ratio, 0.59; 95% confidence interval, 0.18-1.95; p = 0.38). CONCLUSIONS: Among patients with acute stroke treated with MT, SAH, especially isolated SAH findings on CT, were not associated with poor clinical outcomes after 90 days. TRIAL REGISTRATION NUMBER: UMIN000021488.

High-risk patent foramen ovale and elderly in cryptogenic stroke.

BACKGROUND: High-risk patent foramen ovale (PFO) could be pathological in cryptogenic stroke (CS), but its clinical characteristics have not been fully studied, especially in elderly patients. METHODS: Patients with CS were enrolled in the CHALLENGE ESUS/CS registry, a multicenter registry of CS patients undergoing transesophageal echocardiography. Clinical characteristics were compared among three groups: high-risk PFO group, large shunt PFO (≥25 microbubbles) or PFO with atrial septal aneurysm (ASA); right-to-left shunt (RLS) group, RLS including PFO with <25 microbubbles or without ASA; and no-RLS group. RESULTS: In total, 654 patients were analyzed: 91, 221, and 342 in the high-risk PFO, RLS, and no-RLS groups, respectively. In multinomial logistic regression analysis, the male sex (odds ratio [OR] 1.825 [1.067-3.122]) was independently associated with high-risk PFO, but hypertension (OR, 0.562 [0.327-0.967]), multiple infarctions (OR, 0.601 [0.435-0.830]), and other cardioaortic embologenic risks (OR, 0.514 [0.294-0.897]) were inversely associated with high-risk PFO compared with non-RLS. In 517 patients aged ≥60 years, multiple infarctions (OR, 0.549 [0.382-0.788]) and other cardioaortic embologenic risks (OR, 0.523 [0.286-0.959]) were inversely associated with high-risk PFO. CONCLUSIONS: High-risk PFO had specific clinical characteristics and possible mechanistic associations, and this trend was consistent among CS patients aged ≥60 years. CLINICAL TRIAL REGISTRATION INFORMATION: http://www.umin.ac.jp/ctr/ (UMIN000032957).

Ultra-early rt-PA administration should improve patient outcome on mechanical thrombectomy: Post hoc analysis of SKIP.

BACKGROUND: To investigate whether ultra-early recombinant tissue-plasminogen activator (rt-PA) administration can improve patient outcomes on mechanical thrombectomy (MT) in patients with large vessel occlusion (LVO). METHODS: Participants comprised rt-PA-eligible 204 patients with internal carotid artery or middle cerebral artery occlusion in the SKIP trial, who were randomly assigned to receive mechanical thrombectomy alone or combined intravenous thrombolysis (rt-PA: alteplase at 0.6 mg/kg) plus mechanical thrombectomy. We assessed associations between onset-to-puncture time and onset-to-rt-PA administration time and frequency of favorable outcome at 90 days and any intracerebral hemorrhage (ICH) at 36 h after onset. RESULTS: As a cut-off onset-to-puncture time for favorable outcome, receiver operating characteristic curves defined 2.5 h (57% sensitivity, 62% specificity). For onset-to-puncture times ≤2.5 h and > 2.5 h, frequencies of favorable outcomes were 72% and 63% (p = 0.402) in patients with rt-PA therapy and 44% and 58% (p = 0.212) in patients without rt-PA therapy, respectively. In terms of onset-to-rt-PA administration time, frequencies of favorable outcomes among patients with ultra-early rt-PA administration at ≤100, >100 min after onset, and without rt-PA therapy with onset-to-puncture time ≤ 2.5 h, and with and without rt-PA therapy with onset-to-puncture time > 2.5 h were 84% and 64%, 63%, and 44% and 58%, respectively (p = 0.025). Frequencies of any ICH among those patients were 37% and 32%, 32%, and 63% and 40%, respectively (p = 0.006). CONCLUSION: Ultra-early rt-PA administration should improve patient outcomes on mechanical thrombectomy among patients with LVO. Relatively late rt-PA administration might increase the frequency of any ICH.

Aneurysm Isolation is Associated with Complete Occlusion of Aneurysms After Flow Diverter Treatment.

PURPOSE: Some aneurysms remain patent after treatment with flow diverters (FD) due to residual blood flow in the aneurysm. Several studies have proposed that branches and residual flow are associated with delayed aneurysm occlusion. We propose that aneurysm isolation (i.e., the complete disconnection of the aneurysm from surrounding vessels) might be a possible factor facilitating aneurysm occlusion. This study aimed to determine if aneurysm isolation was a factor associated with aneurysm occlusion after FD treatment. METHODS: We reviewed 80 internal carotid artery (ICA) aneurysms treated with FDs between October 2014 and April 2021. Aneurysm isolation was assessed in high-resolution cone-beam computed tomograms at the end of each treatment. Aneurysms with incorporated branches and those with connections to other branches due to stent malapposition were deemed to be nonisolated. Other factors, such as patient age, sex, anticoagulant use, aneurysm size, adjunct coil use, and the presence of incorporated branches, were considered. The degree of aneurysm occlusion (complete or incomplete) was assessed by follow-up angiograms 12 months after treatment. RESULTS: Complete occlusion was achieved in 57 of 80 aneurysms (71%). Completely occluded aneurysms had a significantly higher ratio of isolation compared to incompletely occluded aneurysms (91.2% vs. 69.6%, P = 0.032). Multivariate logistic regression analysis showed that aneurysm isolation was the sole significant predictor of complete aneurysm occlusion (odds ratio, OR 19.38; 95% confidence interval, CI 2.280-164.657; P = 0.007). CONCLUSION: Aneurysm isolation is a significant factor contributing to complete occlusion after FD treatment.

Detection of Atrial Fibrillation Using Insertable Cardiac Monitors in Patients With Cryptogenic Stroke in Japan (the LOOK Study): Protocol for a Prospective Multicenter Observational Study.

BACKGROUND: Paroxysmal atrial fibrillation (AF) is a probable cause of cryptogenic stroke (CS), and its detection and treatment are important for the secondary prevention of stroke. Insertable cardiac monitors (ICMs) are clinically effective in screening for AF and are superior to conventional short-term cardiac monitoring. Japanese guidelines for determining clinical indications for ICMs in CS are stricter than those in Western countries. Differences between Japanese and Western guidelines may impact the detection rate and prediction of AF via ICMs in patients with CS. Available data on Japanese patients are limited to small retrospective studies. Furthermore, additional information about AF detection, including the number of episodes, cumulative episode duration, anticoagulation initiation (type and dose of regimen and time of initiation), rate of catheter ablation, role of atrial cardiomyopathy, and stroke recurrence (time of recurrence and cause of the recurrent event), was not provided in the vast majority of previously published studies. OBJECTIVE: In this study, we aim to identify the proportion and timing of AF detection and risk stratification criteria in patients with CS in real-world settings in Japan. METHODS: This is a multicenter, prospective, observational study that aims to use ICMs to evaluate the proportion, timing, and characteristics of AF detection in patients diagnosed with CS. We will investigate the first detection of AF within the initial 6, 12, and 24 months of follow-up after ICM implantation. Patient characteristics, laboratory data, atrial cardiomyopathy markers, serial magnetic resonance imaging findings at baseline, 6, 12, and 24 months after ICM implantation, electrocardiogram readings, transesophageal echocardiography findings, cognitive status, stroke recurrence, and functional outcomes will be compared between patients with AF and patients without AF. Furthermore, we will obtain additional information regarding the number of AF episodes, duration of cumulative AF episodes, and time of anticoagulation initiation. RESULTS: Study recruitment began in February 2020, and thus far, 213 patients have provided written informed consent and are currently in the follow-up phase. The last recruited participant (May 2021) will have completed the 24-month follow-up in May 2023. The main results are expected to be submitted for publication in 2023. CONCLUSIONS: The findings of this study will help identify AF markers and generate a risk scoring system with a novel and superior screening algorithm for occult AF detection while identifying candidates for ICM implantation and aiding the development of diagnostic criteria for CS in Japan. TRIAL REGISTRATION: UMIN Clinical Trial Registry UMIN000039809; https://tinyurl.com/3jaewe6a. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/39307.

Evaluating the Potential Pathology and Short-Term Outcomes of Cryptogenic Stroke Using the Etiological Classification System.

AIM: Various embolic sources and pathogenetic mechanisms underlie cryptogenic stroke (CS). We investigated the association of etiological diversity with short-term outcomes in patients with CS using a modified atherosclerosis (A), small-vessel disease (S), cardiac pathology (C), other causes (O), and dissection (D) (ASCOD) system. METHODS: Patients with CS who underwent transesophageal echocardiography were registered in this multicenter, observational study. In the modified classification system, O and D were inapplicable and thus excluded. Instead, atherosclerosis, small-vessel disease, cardiac pathology-CS classification was specifically constructed for the etiological diagnosis of CS. We utilized this system to explore the mechanism of CS by grading each pathology and evaluated its association with poorer modified Rankin Scale scores of 3-6 at hospital discharge. RESULTS: A total of 672 patients (68.7±12.8 years, 220 females) were analyzed. In the multiple logistic regression model, female sex (odds ratio [OR], 1.87 [1.15-3.04]; P =0.012), body mass index (OR, 0.93 [0.88-0.99]; P =0.025), National Institute of Health Stroke Scale score (OR, 1.16 [1.12-1.21]; P＜0.001), CHADS2 score (OR, 1.56 [1.30-1.86]; P＜0.001), D-dimer (OR, 1.04 [1.01-1.08]; P =0.015), diffusion-weighted image (DWI) lesion size (OR, 1.44 [1.10-1.89]; P =0.009), and S＋C score (OR, 1.26 [1.03-1.56]; P =0.029) were associated with poor functional outcome at discharge whereas the S＋C score was marginally associated with poor functional outcome after excluding 137 patients with a premorbid modified Rankin Scale score of ≥ 3. CONCLUSIONS: The coexistence of small-vessel disease and cardiac pathology might be associated with poor in-hospital functional outcome in CS.

Ventral Clival Branch of the Ascending Pharyngeal Artery as a Transosseous Feeder of an Arteriovenous Fistula Surrounding the Clival Lesions.

PURPOSE: Arteriovenous fistulas (AVFs) adjacent to the clivus, such as cavernous sinus dural AVFs (CSDAVFs) and condylar AVFs, sometimes have an intraosseous shunted pouch and recruit blood supply from transosseous feeders. Precise analysis of transosseous feeders regarding the clival lesion has not yet been performed. Therefore, this study aimed to clarify the characteristics and identity of transosseous feeders in clival lesions. METHODS: Patients with CSDAVFs and condylar AVFs, who underwent high-resolution cone-beam computed tomography or three-dimensional rotational angiography in our institute, were included. The frequency, type of branch, penetrating point, and termination of intraosseous feeders were retrospectively evaluated. RESULTS: A total of 31 patients with 36 lesions in CSDAVFs and 8 patients with 8 lesions in condylar AVFs underwent angiography. For CSDAVFs, 38 transosseous feeders were detected in 23 out of 31 patients, including 22 in the pharyngeal branch of the ascending pharyngeal artery (APhA), 6 in the hypoglossal branch of the APhA, 6 in the accessory meningeal artery, 3 in the meningohypophyseal trunk (MHT), and 1 in the anterior branch of the middle meningeal artery. For condylar AVFs, 24 transosseous feeders were detected in all 8 patients, including 11 in the pharyngeal branches of the APhA, 7 in the hypoglossal branch of the APhA, 6 in the segmental artery from the vertebral artery, and 2 in the MHT. CONCLUSION: Transosseous feeders of AVFs around the clivus, which are frequently seen in AVFs of this area, mainly arise from ventral clival branches and from pharyngeal branches of the APhA.

An Initial High National Institutes of Health Stroke Scale Score and Any Intracranial Hemorrhage Are Independent Factors for a Poor Outcome in Nonagenarians Treated with Thrombectomy for Acute Large Vessel Occlusion: The Tokyo/Tama-REgistry of Acute Endovascular Thrombectomy (TREAT) Study.

BACKGROUND: Mechanical thrombectomy (MT) is effective in acute ischemic stroke patients ≥80 years old with large vessel occlusion (LVO). However, data for patients ≥90 years old remain very limited, and factors influencing functional outcomes are unclear. This study aimed to investigate factors influencing functional outcomes in patients ≥90 years old treated with MT for acute LVO. METHODS: This retrospective observational study used prospectively collected data from the Tokyo/tama-REgistry of Acute endovascular Thrombectomy (TREAT) study. Inclusion criteria were as follows: 1) patients ≥90 years old treated with MT for LVO and 2) prestroke modified Rankin Scale (mRS) score, 0-3. The functional outcome was defined based on the mRS score at 90 days after the procedure: good functional outcome, mRS score 0-3 and poor functional outcome, mRS score 4-6. RESULTS: Data were analyzed for 104 patients ≥90 years old. The good functional outcome was observed in 25 patients (24.0%), and the poor functional outcome was observed in the remaining 79 patients. Significant differences were identified in initial National Institutes of Health Stroke Scale (NIHSS) score, modified Thrombolysis in Cerebral Infarction grade 2b-3, modified Thrombolysis in Cerebral Infarction grade 3, and any intracranial hemorrhage and hemorrhagic infarction in univariate analyses. Multivariable analysis confirmed the initial NIHSS score (odds ratio, 1.08; 95% confidence interval, 1.01-1.17; P = 0.045) and any intracranial hemorrhage (odds ratio, 11.6; 95% confidence interval, 1.43-95.0; P = 0.022) as independent factors for the functional outcome. CONCLUSIONS: An initial high NIHSS score and any intracranial hemorrhage are independent factors for the poor functional outcome in acute ischemic stroke patients ≥90 years old treated with MT.

Reperfusion Therapy Brings Apixaban Administration Forward in Patients with Nonvalvular Arterial Fibrillation with Anterior Circulation Large Vessel Occlusion or Stenosis.

OBJECTIVE: The initiation of anticoagulant administration after large vessel occlusion (LVO) or stenosis with nonvalvular arterial fibrillation (NAVF) is controversial. We evaluate the timing of anticoagulation and its relationship with clinical factors. METHODS: We enrolled 595 anterior circulation LVO or stenosis with NAVF cases from 38 stroke centers. Laboratory data; activities of daily living; the Alberta Stroke Program Early CT Score (ASPECTS); the National Institutes of Health Stroke Scale (NIHSS) score; occluded artery; treatment methods; date of the initiation of apixaban administration and outcome were recorded. Multivariate analyses were performed after univariate analysis. RESULTS: The median start of apixaban administration after the stroke was 2 days (interquartile range, 1-5; range, 0-14). Multivariate analysis of variance showed that non-internal carotid artery occlusion (F value 4.60), reperfusion therapy (31.1), high ASPECTS (6.27) before anticoagulant intake, and absence of intracranial hemorrhage (12.9) were significantly correlated with early apixaban administration. Multiple logistic regression analysis for independent living at 90 days after the stroke showed significant factors: aging (odds, 0.94; 95% confidence interval [CI], 0.91-0.97); male (odds, 0.46; 95% CI, 0.26-0.79); prestroke independence (odds, 20.7; 95% CI, 6.48-93.9); number of white blood cells (odds, 0.99; 95% CI, 0.97-1.00); non-internal carotid artery occlusion; NIHSS score at 72 hours after the stroke (odds 0.92; 95% CI, 0.89-0.96); ASPECTS before apixaban intake (odds, 1.15; 95% CI, 1.00-1.31) and initiation of apixaban (odds, 0.91; 95% CI, 0.83-0.99). CONCLUSIONS: Early administration of apixaban is induced by nonsevere infarction, reperfusion therapy or none of intracranial hemorrhage and it correlates with an independent long-term outcome.

Intravenous Alteplase is Associated with First Pass Effect in Stent-retriever but not ADAPT Thrombectomy : Post Hoc Analysis of the SKIP Study.

PURPOSE: To investigate the effect of alteplase, either combined with stent-retriever thrombectomy or a direct aspiration first pass technique (ADAPT), in patients with large-vessel occlusion stroke. METHODS: This was a retrospective post hoc analysis of data from The Direct Mechanical Thrombectomy in Acute LVO Stroke (SKIP) study. Patients were divided into two groups according to the first-line thrombectomy technique: stent-retriever and ADAPT. Each group was further divided into two subgroups, namely MT and MT + alteplase. The procedural outcomes, such as first pass effect (FPE) ratio and number of passes, were evaluated. The clinical outcomes included mRS score at 3 months. RESULTS: A total of 180 patients were included (116 in the stent-retriever group and 64 in the ADAPT group). No interaction was detected between the first-line technique and alteplase administration. In the stent-retriever group, after adjusting for factors associated with FPE, the adjusted odds ratio (95% confidence interval) of FPE of the MT + alteplase subgroup versus the MT subgroup was 3.57 (1.5-8.48) and in the ADAPT group it was 1.35 (0.37-4.91). With alteplase, the number of passes decreased with adjusted odds ratios of 0.59 (0.37-0.93) in the stent-retriever group but not in the ADAPT group. In both first-line technique groups, clinical outcomes did not differ between subgroups. CONCLUSION: In the SKIP study, alteplase administration was associated with increased FPE when combined with stent-retriever thrombectomy, but not with ADAPT. We found no differences in the clinical outcomes.

Distinction in Prevalence of Atherosclerotic Embolic Sources in Cryptogenic Stroke With Cancer Status.

Background Cerebrovascular diseases are common comorbidities in patients with cancer. Although active cancer causes ischemic stroke by multiple pathological conditions, including thromboembolism attributable to Trousseau syndrome, the relationship between stroke and inactive cancer is poorly known. The aim of this study was to elucidate the different underlying pathogeneses of cryptogenic stroke in active and inactive patients with cancer, with detailed investigation by transesophageal echocardiography. Methods and Results CHALLENGE ESUS/CS (Mechanisms of Embolic Stroke Clarified by Transesophageal Echocardiography for Embolic Stroke of Undetermined Source/Cryptogenic Stroke) registry is a multicenter registry including data of patients initially diagnosed as having cryptogenic stroke and undergoing transesophageal echocardiography. Patients were divided into active cancer, inactive cancer, and noncancer groups, and their clinical features were compared. Of the total 667 enrolled patients (age, 68.7±12.8 years; 455 men), 41 (6.1%) had active cancer, and 51 (7.5%) had a history of inactive cancer. On multinomial logistic regression analysis, infarctions in multiple vascular territories (odds ratio [OR], 2.73; 95% CI, 1.39-5.40) and CRP (C-reactive protein) (OR, 1.10; 95% CI, 1.01-1.19) were independently associated with active cancer, whereas age (OR, 1.05; 95% CI, 1.01-1.08), contralateral carotid stenosis from the index stroke lesion (OR, 4.05; 95% CI, 1.60-10.27), calcification of the aortic valve (OR, 2.10; 95% CI, 1.09-4.05), and complicated lesion of the aortic arch (OR, 2.13; 95% CI, 1.11-4.10) were significantly associated with inactive cancer. Conclusions Patients with cancer were not rare in cryptogenic stroke. Although patients with active cancer had more multiple infarctions, patients with inactive cancer had more atherosclerotic embolic sources potentially causing arteriogenic strokes. Registration URL: https://www.umin.ac.jp/ctr/; Unique identifier: UMIN000032957.

Effect of prior antiplatelet therapy on large vessel occlusion in patients with non-valvular atrial fibrillation newly initiated on apixaban.

INTRODUCTION: We evaluated the effect of prior antiplatelet therapy on large vessel occlusion (LVO) in patients with non-valvular atrial fibrillation (NVAF) newly initiated on apixaban. METHODS: Patients with acute LVO with acute stroke due to NVAF or stenosis with NVAF started on apixaban within 14 days of onset were enrolled. We compared incidence of major bleeding, cerebral hemorrhage, ischemic events, cerebral infarction, and all-cause mortality between patients with and without prior antiplatelet therapy for acute LVO. We also compared these events between patients who continued antiplatelet therapy after onset (continued group) and those who discontinued it (discontinued group). Hazard ratios were estimated after adjusting for confounders; interaction was evaluated considering intravenous thrombolysis (IVT) or endovascular treatment (EVT) according to major bleeding. RESULTS: The study comprised 686 eligible patients (excluded [n = 194]; enrolled [n = 492]). The antiplatelet group consisted of older patients (mean: 79 vs. 76 years; p = 0.006) and had a higher cumulative incidence of major bleeding (7.3% vs. 2.9%, p = 0.003). The incidence of ischemic events and all-cause mortality was similar between the groups. Among the 109 patients in the antiplatelet group, the cumulative incidence of major bleeding, ischemic events, and all-cause mortality was comparable between continued group (n = 26) and discontinued group (n = 83). There were no significant differences between groups with and without IVT/EVT. However, major bleeding occured more frequently in the antiplatelet group without IVT. CONCLUSION: Prior antiplatelet therapy for LVO in patients with NVAF newly initiated on apixaban was associated with major bleeding, which was more frequent in the antiplatelet group without IVT.

Cardiac and Echocardiographic Markers in Cryptogenic Stroke with Incidental Patent Foramen Ovale.

OBJECTIVE: Some cardiac abnormalities could be a substrate for potential embolic source in cryptogenic stroke (CS). We evaluated whether cardiac and echocardiographic markers were associated with CS in patients with incidental patent foramen ovale (PFO) as defined using the Risk of Paradoxical Embolism (RoPE) score. MATERIALS AND METHODS: Among 677 patients enrolled in a multicenter observational CS registry, 300 patients (44%) had PFOs detected by transesophageal echocardiography. They were classified into probable PFO-related stroke (RoPE score>6, n = 32) and stroke with incidental PFO (RoPE score≤6, n = 268) groups, and clinical characteristics, laboratory findings, cardiac and echocardiographic markers (i.e. brain natriuretic peptide, left atrial [LA] diameter, ejection fraction, early transmitral flow velocity/early diastolic tissue Doppler imaging velocity [E/e'], LA appendage flow velocity, spontaneous echo contrast, atrial septal aneurysm, substantial PFO, and aortic arch plaques), stroke recurrence, and excellent outcome (modified Rankin scale score <2) at discharge were compared. Risk factors for low RoPE scores were determined using multiple logistic regression analysis. RESULTS: Higher brain natriuretic peptide levels (p = 0.032), LA enlargement (p < 0.001), higher E/e' (p = 0.001), lower LA appendage flow velocity (p < 0.001), non-substantial PFO (p = 0.021), and aortic arch plaques (p = 0.002) were associated with the low RoPE score group. Patients with high RoPE scores had excellent outcomes (58% versus 78%, p = 0.035). LA enlargement (age- and sex-adjusted odds ratio, 1.15; 95 % confidence interval, 1.00-1.32; p = 0.039) was an independent predictor of low RoPE scores. CONCLUSIONS: Abnormal cardiac substrate could be associated with CS occurrence in a subset of patients with PFO. Patients with CS who had incidental PFO may be at risk of cardioembolism.

Puerarin blocks the aging phenotype in human dermal fibroblasts.

Dermal fibroblast aging contributes to aging-associated functional defects in the skin since dermal fibroblasts maintain skin homeostasis by interacting with the epidermis and extracellular matrix. Here, we found that puerarin, an isoflavone present in Pueraria lobata (Kudzu), can prevent the development of the aging-phenotype in human dermal fibroblasts. Normal human dermal fibroblasts (NHDFs) were subcultivated and high-passage cells were selected as senescent cells, whereas low-passage cells were selected as a young cell control. Puerarin treatment increased cell proliferation and decreased the proportion of senescence-associated beta-galactosidase-positive cells in a high-passage culture of NHDFs. Moreover, puerarin treatment reduced the number of smooth muscle actin (SMA)-positive myofibroblasts and the expression of a reticular fibroblast marker, calponin 1 (CNN1), which were induced in high-passage NHDFs. Fulvestrant, an estrogen receptor antagonist, blocked the puerarin-mediated downregulation of SMA and CNN1. Our results suggest that puerarin may be a useful functional food that alleviates aging-related functional defects in dermal fibroblasts.

[Ischemic Stroke].

CASE: A patient with a history of chronic atrial fibrillation was diagnosed with sudden onset of right hemiparalysis in the hospital. The patient had been normal two hours prior and was referred to the cerebral vascular center. Images: Head CT images showed early ischemic changes in the left frontal lobe, insula, and temporal lobe(Alberta Stroke Program Early CT Score[ASPECTS]: 6 points). A hyperdense internal carotid artery(ICA)sign was found at the top of the left internal carotid artery. MRI DWI-ASPECTS was performed at 6 points. The MRA showed loss of the left internal carotid, anterior cerebral, and middle cerebral arteries. T2*WIs showed a susceptibility vessel sign(SVS)at the top of the left ICA and FLAIR vessel hyperintensity(FVH)in the left ICA to the middle cerebral artery. DIAGNOSIS: The patient was diagnosed with acute cerebral embolism with clinical-DWI mismatch and treated with endovascular therapy. COMMENTARY: Early CT signs are important in determining cerebral ischemic lesions, and hyperdense ICA/MCA signs are useful in identifying occluded vessels. Early ischemic changes can be seen more easily on MRI-DWI, and the location of the occluded vessel can be estimated by evaluating MRA, SVS, and FVH together.

Different aspects of early and late development of atrial fibrillation during hospitalization in cryptogenic stroke.

The detection of underlying atrial fibrillation (AF) has become increasingly possible by insertable cardiac monitoring (ICM). During hospitalization for cryptogenic stroke, factors related to the early and late development of AF have not been studied. CHALLENGE ESUS/CS is a multicenter registry of cryptogenic stroke patients undergoing transesophageal echocardiography. Twelve-lead electrocardiogram, continuous cardiac monitoring, and 24-h Holter electrocardiogram were all used for the detection of AF. Early and late detection of AF was determined with an allocation ratio of 1:1 among patients with AF. A total of 677 patients (68.7 ± 12.8 years; 455 men) were enrolled, and 64 patients developed AF during hospitalization. Four days after admission was identified as the approximate median day to classify early and late phases to detect AF: ≤ 4 days, 37 patients; > 4 days, 27 patients. Multiple logistic regression analysis showed that spontaneous echo contrast (SEC) (OR 5.91; 95% CI 2.19-15.97; p < 0.001) was associated with AF ≤ 4 days, whereas a large infarction > 3 cm in diameter (OR 3.28; 95% CI 1.35-7.97; p = 0.009) was associated with AF > 4 days. SEC and large infarctions were important predictors of in-hospital AF detection, particularly in the early and late stages, respectively; thus, they could serve as indications for recommending ICM.

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.

Atrial Septal Aneurysm may Cause In-Hospital Recurrence of Cryptogenic Stroke.

AIMS: Awareness of potentially embologenic diseases is critical to determining the prognosis of cryptogenic stroke. The clinical significance of atrial septal aneurysm (ASA) in cryptogenic stroke has not been fully studied. Therefore, we explored clinical characteristics and in-hospital recurrence in patients with ASA in cryptogenic stroke. METHODS: A multicenter observational registry of cryptogenic stroke patients was conducted. We obtained baseline characteristics, radiological and laboratory findings, and echocardiographic findings, especially of embolic sources on transesophageal echocardiography. The CHALLENGE ESUS/CS (Mechanisms of Embolic Stroke Clarified by Transesophageal Echocardiography for embolic stroke of undetermined source/cryptogenic stroke) registry was recorded at http://www.umin.ac.jp/ctr/ (UMIN000032957). Patients' clinical characteristics were compared according to the presence of ASA, and factors associated with in-hospital stroke recurrence were assessed. RESULTS: The study included 671 patients (age, 68.7±12.7 years; 450 males; median National Institutes of Health Stroke Scale score, 2). ASA was detected in 92 patients (14%), displaying higher age (72.4±11.0 vs. 68.1 ±12.9 years, p=0.004), reduced frequency of diabetes mellitus (16% vs. 27%, p=0.030), higher frequency of right-to-left shunt (66% vs. 45%, p＜0.001), and in-hospital stroke recurrence (8% vs. 3%, p=0.034). ASA was relatively associated with in-hospital recurrence (odds ratio 2.497, 95% confidence interval 0.959-6.500, p= 0.061). CONCLUSIONS: The CHALLENGE ESUS/CS registry indicated that ASA was not rare in cryptogenic stroke, and ASA's clinical characteristics included higher age, reduced frequency of diabetes mellitus, and increased frequency of concomitant right-to-left shunt. ASA may be related to in-hospital stroke recurrence in cryptogenic stroke.

Safety of Early Administration of Apixaban on Clinical Outcomes in Patients with Acute Large Vessel Occlusion.

Early administration of direct oral anticoagulants in patients with acute large vessel occlusion (LVO) and nonvalvular atrial fibrillation (NVAF) is a concern, as endovascular therapy (EVT) became highly utilized. We conducted a historical and prospective multicenter registry at 38 centers in Japan from July 2016 to February 2018. Patients aged ≥ 20 years with NVAF and acute LVO or stenosis who received apixaban within 14 days from onset were included. We compared patients who received apixaban < 48 h (Early group) and ≥ 48 h (Late group) after onset in terms of the primary outcome (a composite of ischemic events, major bleeding events, and all-cause deaths). The secondary outcomes were each component of the primary outcome. Among the 686 patients, the median time from onset to administration was 2.5 days (range, 0-14; Early 263, Late 423). The Alberta Stroke Program Early CT Score (ASPECTS) and diffusion-weighted imaging (DWI)-ASPECTS) were significantly higher in the Early group than in the Late group. Recombinant tissue plasminogen activator (rt-PA) and EVT were more utilized in the Early group (rt-PA 46% vs. 35%, p = 0.003; EVT 62% vs. 46%, p < 0.0001). The cumulative incidence of primary outcome was similar between groups (ischemic events: Early 1.9% vs. Late 0.5% at 30 days; 3.5% vs. 0.7% at 90 days, major bleeding 3.4% vs. 2.9% at 30 days; 5.0% vs. 3.4% at 90 days). Early administration of apixaban (< 48 h), after onset of acute LVO in patients with NVAF, was generally safe compared with those who received it Late (≥ 48 h). http://www.clinicaltrials.gov . Unique identifier: NCT02818868 (June 30, 2016).