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Retinal artery occlusion (RAO) results in severe visual impairment and may indicate cerebral infarction and extracranial carotid artery stenosis at onset. RAO-related genetic factors remain understudied. We investigated the association between RAO and RNF213 p.Arg4810Lys (c.14429G > A), a genetic variant recently identified as a susceptibility factor for moyamoya disease, a risk factor for stroke. Patients diagnosed with non-arteritic (NA)-RAO at our department between May 2020 and April 2021 underwent magnetic resonance imaging and computed tomography angiography. Sanger sequencing revealed that RNF213 p.Arg4810Lys was significantly more frequent in the NA-RAO group (10.7%) than in the control group (1.1%). We conducted a logistic regression analysis adjusted for age and sex to compare the NA-RAO (n = 28) and healthy control groups (n = 1,202), which indicated a significant association between RNF213 p.Arg4810Lys and NA-RAO ( P  = 0.001, odds ratio 13.52, 95% confidence interval [3.09–59.18]). Among patients with NA-RAO, 50%, 76%, and 40% had simultaneous strokes, hypertension, and diabetes, respectively. There were no significant differences between groups in medical history, biomarkers, imaging characteristics, or ophthalmic artery diameter. RNF213 p.Arg4810Lys was significantly associated with NA-RAO, indicating genetic susceptibility to systemic vascular diseases. Further studies can elucidate broader implications of RNF213 p.Arg4810Lys in vascular disease pathogenesis, particularly in East Asian populations.

The efficacy of early anticoagulation in acute stroke with nonvalvular atrial fibrillation (NVAF) remains unclear. We performed a study to evaluate the risk of recurrent ischemic stroke (IS) and major bleeding in acute IS patients with NVAF who started rivaroxaban. This observational study evaluated patients with NVAF and acute IS/transient ischemic attack (TIA) in the middle cerebral arterial territory who started rivaroxaban within 30 days after the index IS/TIA. The primary endpoints were recurrent IS and major bleeding within 90 days after the index IS/TIA. The relationship between the endpoints and the time to start rivaroxaban was evaluated by correlation analysis using cerebral infarct volume, determined by diffusion-weighted magnetic resonance images within 48 hours of onset of the index IS/TIA. Of 1309 patients analyzed, recurrent IS occurred in 30 (2.3%) and major bleeding in 11 (0.8%) patients. Among patients with known infarct size (N = 1207), those with small (<4.0 cm3), medium (≥4.0 and <22.5 cm3), and large (≥22.5 cm3) infarcts started rivaroxaban a median of 2.9, 2.9, and 5.8 days, respectively, after the index IS/TIA. Recurrent IS was significantly less frequent when starting rivaroxaban ≤14 days versus ≥15 days after IS (2.0% versus 6.8%, P = 0.0034). Incidences of recurrent IS and major bleeding in whom rivaroxaban was started <3 days (N = 584) after IS were also low: 1.5% and 0.7%, respectively. Initiation of rivaroxaban administration in acute IS or TIA was associated with a low recurrence of IS (2.3%), and a low incidence of major bleeding events (0.8%) for 90 days after the index stroke. For the prevention of recurrent attacks in acute IS patients with NVAF, it is feasible to start the administration of rivaroxaban within 14 days of onset. Rivaroxaban started within 3 days of onset may be a feasible treatment option for patients with a small or medium-sized infarction.

The optimal timing of initiating oral anticoagulants after reperfusion therapy for ischemic stroke is unknown. Factors related to early initiation of rivaroxaban and differences in clinical outcomes of stroke patients with nonvalvular atrial fibrillation (NVAF) who underwent reperfusion therapy was investigated. From data of 1,333 NVAF patients with ischemic stroke or transient ischemic attack (TIA) in a prospective multicenter study, patients who started rivaroxaban after intravenous thrombolysis and/or mechanical thrombectomy were included. The clinical outcomes included the composite of ischemic events (recurrent ischemic stroke, TIA, or systemic embolism) and major bleeding at 3 months. Among the 424 patients, the median time from index stroke to starting rivaroxaban was 3.2 days. On multivariable logistic regression analysis, infarct size (odds ratio [OR], 0.99; 95%CI, 0.99-1.00) was inversely and successful reperfusion (OR, 2.13; 95%CI, 1.24-3.72) was positively associated with initiation of rivaroxaban within 72 hours. 205 patients were assigned to the early group (< 72 hours) and 219 patients (≥ 72 hours) to the late group. Multivariable Cox regression models showed comparable hazard ratios between the two groups at 3 months for ischemic events (hazard ratio [HR], 0.18; 95%CI, 0.03-1.32) and major bleeding (HR, 1.80; 95%CI, 0.24-13.54). Infarct size and results of reperfusion therapy were associated with the timing of starting rivaroxaban. There were no significant differences in the rates of ischemic events and major bleeding between patients after reperfusion therapy who started rivaroxaban < 72 hours and ≥ 72 hours after the index stroke. Unique identifier: NCT02129920; URL: https://www.clinicaltrials.gov.

PurposePretreatment ischemic core volume is conceptually equal to follow-up infarct volume (FIV) in patients with successful recanalization. However, there is sometimes an absolute volume difference (AD) between pretreatment core volume and FIV. The aim was to compare the AD values between the Bayesian and the singular value decomposition (SVD) methods with time from onset-to-imaging in acute ischemic stroke (AIS) patients undergoing mechanical thrombectomy.MethodsConsecutive AIS patients were included if they had the following: (1) anterior large vessel occlusion (internal carotid or middle cerebral artery); (2) within 24 h of onset; (3) pretreatment CT perfusion (CTP); (4) successful recanalization (mTICI ≥ 2b); and (5) 24-h diffusion-weighted imaging (DWI). FIV was measured on 24-h DWI. The AD value between FIV and the pretreatment core volume was calculated for Bayesian and SVD methods. Spearman’s rank correlation coefficient (rho) was calculated as appropriate.ResultsIn the 47 patients enrolled (25 men; median age 78 years; median baseline National Institutes of Health Stroke Scale, 22), the median time from onset-to-imaging and onset-to-recanalization was 136 and 220 min, respectively. Shorter onset-to-imaging time was correlated with a larger AD value, and more trend was seen in the SVD method (rho =  − 0.28, p = 0.05) compared with the Bayesian method (rho =  − 0.08). A larger pretreatment core volume was correlated with a larger AD value, and this tendency was slightly stronger for the SVD (rho = 0.63, p < 0.01) than for the Bayesian (rho = 0.32, p = 0.03) method.ConclusionsThe Bayesian method might be more correlated with FIV than the SVD method in patients with a large ischemic lesion immediately after stroke onset, but not perfect.

We present the discovery and characterization of a new multi-planetary system around the Sun-like star K2-360 (EPIC 201595106). K2-360 was first identified in K2 photometry as the host of an ultra-short-period (USP) planet candidate with a period of 0.88 d. We obtained follow-up transit photometry, confirming the star as the host of the signal. High precision radial velocity measurements from HARPS and HARPS-N confirm the transiting USP planet and reveal the existence of an outer (non-transiting) planet with an orbital period of ∼ 10 d. We measure a mass of 7.67 ± 0.75   M ⊕ and a radius of 1.57 ± 0.08   R ⊕ for the transiting planet, yielding a high mean density of 11 ± 2  g  cm - 3 , making it the densest well-characterized USP super-Earth discovered to date. We measure a minimum mass of 15.2 ± 1.8   M ⊕ for the outer planet, and explore a migration formation pathway via the von Zeipel–Kozai–Lidov (ZKL) mechanism and tidal dissipation.

This study elucidates the genotypic and phenotypic spectrum and histopathological findings related to cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) in Japan. For this single-center retrospective observational study, we enrolled 215 patients who were clinically suspected of having CADASIL and were examined at Kumamoto University from 1997 to 2014, and we diagnosed CADASIL in 70 patients. We found 19 different NOTCH3 mutations in the patients, with the NOTCH3 Arg133Cys mutation being found most frequently. We also found the Arg75Pro mutation, a cysteine-sparing NOTCH3 mutation. CADASIL patients with this Arg75Pro mutation were frequently found throughout Japan, and fewer patients with the Arg75Pro mutation showed MRI hyperintensity in the anterior temporal pole compared with patients with other NOTCH3 mutations. Significantly more CADASIL patients with the NOTCH3 Arg133Cys mutation had hyperintensity in the external capsule compared with CADASIL patients with the other mutations not including the NOTCH3 Arg75Pro mutation. We also showed postmortem pathological findings of the first Japanese CADASIL case with the NOTCH3 Arg133Cys mutation, and histopathological findings of fresh frozen skin biopsy specimens of CADASIL patients. In conclusions, the spectrum of NOTCH3 mutations in Japanese CADASIL patients may be partially explained by founder effects. Genotype–phenotype correlations may exist in CADASIL, which should be considered so as to make an accurate diagnosis of CADASIL in each population. Fresh frozen skin biopsy specimens may aid detection of Notch3 deposits on vascular walls for an improved diagnosis of CADASIL.

IntroductionSoluble C-type lectin-like receptor 2 (sCLEC-2) is a new biomarker for platelet activation, which can be easily measured by usual blood collection. We conducted the CLECSTRO, a prospective, observational cohort study, to evaluate the clinical implications of sCLEC-2 in patients with acute ischaemic stroke (AIS) and transient ischaemic attack (TIA).Methods and analysisThe participants are patients with AIS/TIA and control patients required for differentiation from AIS/TIA. The target population is 600, including the patients and controls, who would be recruited from eight stroke centres across Japan. The inclusion criteria are AIS within 24 hours of onset and a modified Rankin Scale (mRS) score of 0–2, TIA within 7 days of onset, and contemporary patients required for differentiation from AIS/TIA. Plasma sCLEC-2 will be measured by high-sensitive chemiluminescent enzyme immunoassay using residual blood samples from routine laboratory examinations at the first visit in all patients and 7 days later or at discharge in patients with AIS/TIA. The outcomes include plasma levels of sCLEC-2 in patients with AIS/TIA and controls, sCLEC-2/D-dimer ratio in non-cardioembolic and cardioembolic AIS/TIA, correlation of sCLEC-2 with recurrence or worsening of stroke, severity of stroke, infarct size, ABCD2 score in TIA and outcome (mRS) at 7 days and 3 months.Ethics and disseminationThis study was approved by the Ethical Committee of the University of Yamanashi as the central ethical committee in agreement with the ethical committees of all collaborative stroke centres. Informed consent will be obtained by an opt-out form from the patients at each stroke centre according to the Ethical Guidelines for Medical and Biological Research Involving Human Subjects by the Japanese Ministry of Health, Labour and Welfare.Trial registration numbersNCT05579405, UMIN000048954

BackgroundThis study aimed to elucidate the safety and efficacy of mechanical thrombectomy using the Versi Retriever in patients with acute ischemic stroke (AIS).MethodsThis was a prospective, multicenter, single-arm study conducted at 10 institutes in Japan from December 2018 to March 2021 on mechanical thrombectomy using the Versi Retriever in patients with AIS. The primary efficacy outcome was the modified Rankin scale (mRS) 0–2 at 90 days after the procedure. The primary safety outcome was mortality within 90 days after the procedure.ResultsFifty-eight patients with a mean age of 72.7 years were enrolled in the study. The primary efficacy outcome of mRS 0–2 at 90 days was 62.0% (95% CI 47.2–75.3%) in patients within 8 hours of stroke onset. The rate of immediate reperfusion of Thrombolysis in Cerebral Infarction (TICI) grade 2b-3 using the Versi Retriever in three passes was 78.0% (64.0–88.5%). The rate of final reperfusion of TICI 2b-3 was 100% (92.9–100%). The primary safety outcome of mortality within 90 days was 8.0% (2.2–19.2%) in patients within 8 hours of AIS onset. The incidence of intracranial hemorrhage within 24 hours was 12.0% (4.5–24.3%) for symptomatic cases and 32.0% (19.5–46.7%) for asymptomatic cases.ConclusionThe Versi Retriever proved to be a safe and effective option for mechanical thrombectomy in patients with AIS.

Abbreviations ACC American College of Cardiology ACT activated clotting time ADL activities of daily living AF atrial fibrillation AHA American Heart Association BMI body mass index BMS bare metal stent CCI Charlson comorbidity index CCr creatinine clearance CFAE complex fractionated atrial electrogram CKD chronic kidney disease CLBBB complete left bundle branch block CLS closed loop stimulation CMR cardiac magnetic resonance CO cardiac output COPD chronic obstructive pulmonary disease CRT cardiac resynchronization therapy CRT-D cardiac resynchronization therapy defibrillator CRT-P cardiac resynchronization therapy pacemaker CSP conduction system pacing CT computed tomography DBP diastolic blood pressure DDD/DDDR dual chamber pacing, dual chamber sensing, and pacemaker activation or inhibition on a sensed event / rate-modulated pacing DOAC direct oral anticoagulant ECG electrocardiogram eGFR estimated glomerular filtration rate EPS electrophysiological study EV-ICD extra vascular-implantable cardioverter defibrillator FAAM fractionated signal areas in the atrial muscle FDA US Food and Drug Administration FIRM focal impulse and rotor modulation FNNC filamin C FXa factor Xa HBP His bundle pacing HFpEF heart failure with preserved ejection fraction HFrEF heart failure with reduced ejection fraction HRS Heart Rhythm Society ICD implantable cardioverter defibrillator ILAM isochronal late activation map INR international normalized ratio LBBA left bundle branch area LBBAP left bundle branch area pacing LBBB left bundle branch block LGE late gadolinium enhancement LMNA lamin A/C LVA low-voltage areas LVAD left ventricular assist device LVEF left ventricular ejection fraction MMSE mini-mental state examination MRI magnetic resonance imaging MRSA methicillin-resistant Staphylococcus aureus NCDR National Cardiovascular Data Registry NSAIDs non-steroidal anti-inflammatory drugs NSVT non-sustained ventricular tachycardia NYHA New York Heart Association PCI percutaneous coronary intervention PCWP pulmonary capillary wedge pressure PFA pulsed field ablation PLN phospholamban PVC premature ventricular contraction PVI pulmonary vein isolation PVS pulmonary vein stenosis QOL quality of life RBM20 RNA binding motif protein 20 RCT randomized controlled trial RVP right ventricular pacing SBP systolic blood pressure SCD sudden cardiac death S-ICD subcutaneous implantable cardioverter defibrillator SPRM Seattle proportional risk model SUV standard uptake value V6RWPT R wave peak time in lead V6 VDD atrial-synchronized ventricular pacing (ventricle pacing, dual chamber sensing, and pacemaker activation or inhibition on a sensed event) VOM vein of Marshall VOM-EI ethanol injection into the vein of Marshall VF ventricular fibrillation VT ventricular tachycardia VVI/VVIR ventricular demand pacing (ventricle pacing, ventricle sensing, and pacemaker inhibition on a sensed event) / rate-modulated pacing 6MWD 6-minute walking distance 18F-FDG-PET 18F-fluorodeoxyglucose-positron emission tomography TABLE OF CONTENTS Foreword 2 I. Implantable Cardiac Electrical Devices 3 1. The importance of comprehensive management, which includes not only drug therapy but also the identification and intervention of various modifiable risk factors, is now recognized worldwide. Since the publication of the Guidelines for the Nonpharmacologic Treatment of Arrhythmias in 2000, guidelines for catheter ablation, pacemaker and implantable cardioverter-defibrillator (ICD) therapy, and arrhythmia surgery have been revised in 2006 and 2011.4 In addition, the atrial fibrillation catheter ablation technique has become common practice due to remarkable progress in medical engineering technology and the establishment of treatment techniques and surgical procedures, diversifying the nonpharmacological treatment of arrhythmia. Level A Demonstrated in multiple randomized interventional clinical trials or meta-analysis Level B Demonstrated in a single randomized intervention clinical trial or a large non-randomized intervention clinical trial Level C Consensus among experts and/or small clinical trials (including backward-looking studies and registries) Clinical Questions The Japanese Circulation Society guidelines have introduced a format in which clinical questions (CQs) are set, a systematic review is conducted using the GRADE system, and recommendations are clearly indicated. Because this is a focused update, we did not establish a systematic review group independent of the guideline writing committee members, and instead, we developed 2 CQs that occur in daily practice. [...]in promoting shared decision-making, providing information to citizens and patients is crucial, and this focus update guideline includes six topics related to arrhythmia treatment.

Clinical characteristics of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) include migraine, recurrent stroke, white matter lesions, and vascular dementia. CADASIL is one of the most common hereditary cerebral small vessel diseases. Clinical presentation of CADASIL varies and a racial gap may exist between the Asian and Caucasian populations. This is the first nationwide epidemiological survey which aimed to elucidate the clinical features of CADASIL in Japan. Moreover, the registration database of CADASIL was constructed. Subjects included CADASIL patients who visited the hospitals (totally 1,448 hospitals) certified by the Japanese Society of Neurology and/or Japan Stroke Society in 2016. This study consisted of a two-step survey; patients with CADASIL were identified genetically by the first questionnaire, and their clinical features were assessed by the second questionnaire. Selected 6 hospitals registered the data of all CADASIL patients using a Research Electronic Data Capture (REDCap) system for the second questionnaire. Based on the criteria, 88 patients (50 male and 38 female) with CADASIL were enrolled. The mean age of symptom onset was 49.5 years. Sixteen (18.2%) patients had an elderly onset (>60 years). Thirteen patients (13.6%) had history of migraine with aura and 33 patients (37.5%) had vascular risk factor(s). From among the 86 patients who were examined using magnetic resonance imaging, abnormal deep white matter lesions were detected in 85 patients (98.8%), WMLs extending to anterior temporal pole in 73 patients (84.9%), and cerebral microbleeds in 41 patients (47.7%). Anti-platelet therapy was received by 65 patients (73.9%). Thirty-eight patients (43.2%) underwent treatment with lomerizine hydrochloride. Thirty-four different mutations of were found in exons 2, 3, 4, 5, 6, 8, 11, 14, and 19. Most of the mutations existed in exon 4 ( = 44, 60.3%). The prevalence rate of CADASIL was 1.20 to 3.58 per 100,000 adults in Japan. This questionnaire-based study revealed clinical features and treatment status in Japanese CADASIL patient, although it may not be an exhaustive search. We have constructed the REDCap database for these CADASIL patients.