Real-World Patent Foramen Ovale (PFO) Closure in Japan　- 30-Day Clinical Outcomes From the AmplatzerTM PFO Occluder Japan Post-Marketing Surveillance Study.

BACKGROUND: The AmplatzerTM PFO Occluder was approved for marketing in Japan in May 2019, and the Amplatzer PFO Occluder Japan Post-marketing Surveillance (PFO Japan PMS) study was initiated in December 2019. This analysis presents 30-day clinical outcomes for PFO Japan PMS study patients.Methods and Results: PFO Japan PMS is a prospective single-arm non-randomized multicenter clinical study. Eligible patients were indicated for patent foramen ovale (PFO) closure and underwent an implant attempt with the AmplatzerTM PFO Occluder. Technical success was defined as successful delivery and release of the occluder; procedural success was defined as technical success with no serious adverse events (SAEs) within 1 day of the procedure. The primary safety endpoint includes predefined device- and/or procedure-related SAEs through 30 days after the procedure. From December 2019 to July 2021, 500 patients were enrolled across 53 Japanese sites. The mean (±SD) patient age was 52.7±15.4 years, and 29.8% of patients were aged >60 years. Technical and procedural success rates were both high (99.8% and 98.8%, respectively). Further, there was only one primary safety endpoint event (0.2%): an episode of asymptomatic paroxysmal atrial fibrillation that occurred 26 days after the procedure. CONCLUSIONS: In this real-world Japanese study with almost one-third of patients aged >60 years, PFO closure with the AmplatzerTM PFO Occluder was performed successfully and safely, with a low incidence of procedure-related atrial arrhythmias.

[Cilostazol was effective for capsular warning syndrome during anticoagulant therapy: a case report].

An 88-year-old woman with atrial fibrillation was admitted to our hospital due to the right hemiplegia and aphasia. MRA shows the left middle cerebral artery M2 occlusion. After intravenous rt-PA, her symptoms improved. She was diagnosed with cardioembolic stroke, and was treated with direct oral anticoagulation therapy. However, she had repeated stereotypical transient right hemiparesis a week after index stroke. Her symptoms were considered capsular warning syndrome (CWS). After cilostazol was administered, no further transient neurological deteriorations occurred. CWS can coexist with acute cardioembolic stroke, and cilostazol was effective.

Cerebral Small Vessel Disease Burden for Bleeding Risk during Antithrombotic Therapy: Bleeding with Antithrombotic Therapy 2 Study.

OBJECTIVE: This study was undertaken to determine the excess risk of antithrombotic-related bleeding due to cerebral small vessel disease (SVD) burden. METHODS: In this observational, prospective cohort study, patients with cerebrovascular or cardiovascular diseases taking oral antithrombotic agents were enrolled from 52 hospitals across Japan between 2016 and 2019. Baseline multimodal magnetic resonance imaging acquired under prespecified conditions was assessed by a central diagnostic radiology committee to calculate total SVD score. The primary outcome was major bleeding. Secondary outcomes included bleeding at each site and ischemic events. RESULTS: Of the analyzed 5,250 patients (1,736 women; median age = 73 years, 9,933 patient-years of follow-up), antiplatelets and anticoagulants were administered at baseline in 3,948 and 1,565, respectively. Median SVD score was 2 (interquartile range = 1-3). Incidence rate of major bleeding was 0.39 (per 100 patinet-years) in score 0, 0.56 in score 1, 0.91 in score 2, 1.35 in score 3, and 2.24 in score 4 (adjusted hazard ratio [aHR] for score 4 vs 0 = 5.47, 95% confidence interval [CI] = 2.26-13.23), that of intracranial hemorrhage was 0.11, 0.33, 0.58, 0.99, and 1.06, respectively (aHR = 9.29, 95% CI = 1.99-43.35), and that of ischemic event was 1.82, 2.27, 3.04, 3.91, and 4.07, respectively (aHR = 1.76, 95% CI = 1.08-2.86). In addition, extracranial major bleeding (aHR = 3.43, 95% CI = 1.13-10.38) and gastrointestinal bleeding (aHR = 2.54, 95% CI = 1.02-6.35) significantly increased in SVD score 4 compared to score 0. INTERPRETATION: Total SVD score was predictive for intracranial hemorrhage and probably for extracranial bleeding, suggesting the broader clinical relevance of cerebral SVD as a marker for safe implementation of antithrombotic therapy. ANN NEUROL 2024;95:774-787.

Minimal Imaging Requirements.

The minimal requirements for imaging studies prior to endovascular treatment (EVT) of acute ischemic stroke are those that can provide the information necessary to determine the indication for treatment (treatment triage) and procedural strategies without being time-consuming. An important notion is to determine whether the patient can benefit from EVT. We should recognize that the perfect diagnostic imaging technique does not yet exist, and each has advantages and disadvantages. Generally, stroke imaging protocols to triage for EVT include the following three options: 1) non-contrast CT and CTA, 2) CT perfusion and CTA, and 3) MRI and MRA. It is not known if perfusion imaging or MRI is mandatory for patients with stroke presenting within 6 hours of onset, although non-contrast CT alone has less power to obtain the necessary information. Dual-energy CT can distinguish between post-EVT hemorrhage and contrast agent leakage immediately after EVT.

Rhomboid protease RHBDL4/RHBDD1 cleaves SREBP-1c at endoplasmic reticulum monitoring and regulating fatty acids.

The endoplasmic reticulum (ER)-embedded transcription factors, sterol regulatory element-binding proteins (SREBPs), master regulators of lipid biosynthesis, are transported to the Golgi for proteolytic activation to tune cellular cholesterol levels and regulate lipogenesis. However, mechanisms by which the cell responds to the levels of saturated or unsaturated fatty acids remain underexplored. Here, we show that RHBDL4/RHBDD1, a rhomboid family protease, directly cleaves SREBP-1c at the ER. The p97/VCP, AAA-ATPase complex then acts as an auxiliary segregase to extract the remaining ER-embedded fragment of SREBP-1c. Importantly, the enzymatic activity of RHBDL4 is enhanced by saturated fatty acids (SFAs) but inhibited by polyunsaturated fatty acids (PUFAs). Genetic deletion of RHBDL4 in mice fed on a Western diet enriched in SFAs and cholesterol prevented SREBP-1c from inducing genes for lipogenesis, particularly for synthesis and incorporation of PUFAs, and secretion of lipoproteins. The RHBDL4-SREBP-1c pathway reveals a regulatory system for monitoring fatty acid composition and maintaining cellular lipid homeostasis.

Hypothyroidism With ACTH Deficiency During Pembrolizumab Therapy for Lung Cancer: Case Report and Literature Review.

BACKGROUND/AIM: Immune-checkpoint inhibitors have recently shown great promise in treating various cancers, but often cause immune-related adverse events (irAEs). Simultaneous drug-induced hypothyroidism and isolated adrenocorticotropic hormone (ACTH) deficiency are rare irAEs. This combination of irAEs is associated with paradoxical endocrine dysfunction characterized by large amounts of thyroid-stimulating hormone (TSH) and small amounts of ACTH in the anterior lobe of the pituitary. We herein report a case of hypothyroidism with isolated ACTH deficiency during pembrolizumab therapy for recurrent lung cancer. CASE REPORT: Our patient was a 66-year-old man with recurrence of squamous cell lung carcinoma. Four months after chemotherapy that included pembrolizumab, the patient presented with general fatigue and laboratory tests showed high concentrations of TSH with low concentrations of free-T4. He was diagnosed with hypothyroidism and levothyroxine was prescribed. His ACTH concentration was found to be low 1 week later when he developed an acute adrenal crisis with associated hyponatraemia. We then changed his diagnosis to concurrent hypothyroidism with isolated ACTH deficiency. His condition improved after 3 weeks of administration of cortisol. CONCLUSION: It is difficult to diagnose a concurrent paradoxical endocrine disorder, such as hypothyroidism with isolated ACTH deficiency, as in the present case. Physicians should pay attention to symptoms and laboratory data to identify various types of endocrine disorders as irAEs.

Stroke in Patients With Common Noncancerous Gynecologic Diseases: A Multicenter Study in Japan.

Background and Objectives: Gynecologic diseases such as uterine fibroids, endometriosis, and adenomyosis are common in women of reproductive age. Case reports and small case series have reported ischemic stroke in women with such common noncancerous gynecologic diseases, and their cause of stroke is frequently attributed to cryptogenic stroke or unconventional mechanisms related to hypercoagulability. However, stroke etiology and prognosis are not well known. We assessed the prevalence of and stroke mechanisms related to common noncancerous gynecologic diseases using hospital-based clinical data. Methods: We retrospectively identified consecutive female patients with common noncancerous gynecologic diseases (uterine fibroids, endometriosis, and adenomyosis) diagnosed with ischemic stroke/transient ischemic attack (TIA) between the ages of 20 and 59 years admitted to 10 stroke centers in Japan by reviewing prospectively collected data between 2017 and 2019. The clinical, laboratory, and neuroimaging features were evaluated and compared between patients with conventional stroke mechanisms (CSMs) (large artery atherosclerosis, small vessel occlusion, cardioembolism, and other determined etiology) and non-CSMs (cryptogenic stroke and causes related to hypercoagulability such as nonbacterial thrombotic endocarditis and paradoxical embolism) according to the Trial of Org 10172 in Acute Stroke Treatment criteria. Results: Of the 470 female patients with ischemic stroke/TIA, 39 (8%) (37 ischemic stroke and 2 TIA) had common noncancerous gynecologic diseases. The most common gynecologic diseases were uterine fibroids in 24 (62%) patients, followed by endometriosis in 9 (23%) and adenomyosis in 6 (15%). Twenty patients (51%) were assigned to the non-CSMs group, and 19 patients (49%) were assigned to the CSMs group. Adenomyosis and endometriosis were more frequent in the non-CSMs group than in the CSMs group. CA125 and D-dimer levels were higher in the non-CSMs group than in the CSMs group. Multiple vascular territory infarcts were frequent in patients with adenomyosis (60%) and endometriosis (43%) in the non-CSMs group. No stroke recurrence or death was observed within 3 months after discharge in both the CSMs and non-CSMs groups. Outcomes at 3 months after discharge were similar in both groups. Discussion: In patients with common noncancerous gynecologic diseases, hypercoagulopathy may play a role in the pathogenesis of ischemic stroke/TIA without CSMs.

Correlation between pretreatment and follow-up infarct volume using CT perfusion imaging: the Bayesian versus singular value decomposition method.

PURPOSE: Pretreatment 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. METHODS: Consecutive 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. RESULTS: In 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. CONCLUSIONS: The 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.

Apposition compound-eye image scanner by glass plate optics.

We propose a design approach for a thin image scanner using the concept of an apposition compound eye comprising many imaging units that take only one pixel image. Although light shielding between adjacent imaging units is always one of the main issues for an artificial compound eye, a simple plane structure using three aperture array layers on two glued glass plates prevents such stray light. Our prototyped scanner, with only 6.8-mm thickness as a packaged module, has 632 microlenses with 200-dpi resolution, resulting in a field of view of 80 mm. The evaluated images show no ghost images.

Post-Treatment Plasma D-Dimer Levels Are Associated With Short-Term Outcomes in Patients With Cancer-Associated Stroke.

Background and Objective: Hypercoagulability is associated with increased risks of ischemic stroke and subsequent mortality in patients with active cancer. This study investigated the relationships between plasma D-dimer levels after stroke treatment and short-term outcomes in patients with cancer-associated stroke. Methods: This retrospective, observational, multicenter study analyzed consecutive patients with cancer-associated ischemic stroke. Hypercoagulability was assessed by plasma D-dimer levels before and after stroke treatment. Short-term outcomes were assessed in terms of poor outcomes (a modified Rankin Scale score >3), cumulative rates of recurrent ischemic stroke, and mortality at 30 days after admission. Results: Of 282 patients, 135 (47.9%) showed poor outcomes. Recurrent ischemic stroke was observed in 28 patients (9.9%), and the cumulative mortality rate was 12.4%. Multivariate analysis showed that post-treatment plasma D-dimer levels ≥10 µg/ml were independently associated with both poor outcomes (adjusted odds ratio [OR], 9.61; 95% confidence interval [CI], 3.60-25.70; P < 0.001) and mortality (adjusted OR, 9.38; 95% CI, 3.32-26.44; P < 0.001). Pre-treatment plasma D-dimer levels ≥10 µg/ml were not associated with these outcomes. Patients who received heparin had higher pre-treatment plasma D-dimer levels than those treated with other anticoagulants. Heparin produced a significant reduction in D-dimer levels from pre- to post-treatment without increasing the incidence of hemorrhagic events. Conclusion: A high plasma D-dimer level after stroke treatment was associated with poor short-term outcomes in patients with cancer-associated stroke. Using anticoagulants to reduce D-dimer levels may improve short-term outcomes in these patients.

Increased Cerebral Small Vessel Disease Burden With Renal Dysfunction and Albuminuria in Patients Taking Antithrombotic Agents: The Bleeding With Antithrombotic Therapy 2.

Background The aim of this study was to determine the associations of cerebral small vessel disease (SVD) burden with renal dysfunction and albuminuria in patients taking oral antithrombotic agents. Methods and Results Patients who newly started or continued taking oral antiplatelets or anticoagulants were enrolled in a prospective, multicenter, observational study. Obligatorily acquired multimodal magnetic resonance imaging at registration with prespecified imaging conditions was assessed for cerebral microbleeds, white matter hyperintensities, enlarged basal ganglia perivascular spaces, or lacunes, and an ordinal SVD score was calculated (range, 0-4). Multivariable adjusting covariates were age, sex, hypertension, diabetes, dyslipidemia, current smoking, drinking, and estimated glomerular filtration rate (eGFR). Of 5324 patients (1762 women; median age, 73 years), 4797 (90.1%) patients were taking oral antithrombotic agents for secondary stroke prevention. Cerebral microbleeds were present in 32.7%, confluent white matter hyperintensities in 51.8%, extensive basal ganglia perivascular spaces in 38.9%, and lacunes in 59.4%. Median SVD score was 2. Compared with eGFR category G1 (eGFR ≥90 mL/min per 1.73 m2), adjusted odds ratios for SVD score increment were 1.63 (95% CI, 1.11-2.39) at category G4 (eGFR 15-<30 mL/min per 1.73 m2) and 2.05 (95% CI, 1.33-3.16) at G5 (eGFR <15 mL/min per 1.73 m2). Corresponding odds ratios relative to urinary albumin-to-creatinine ratio (ACR) category A1 (ACR <30 mg/g) were 1.29 (95% CI, 1.12-1.49) for category A2 (ACR 30-<300 mg/g) and 1.37 (95% CI, 1.05-1.77) for A3 (ACR ≥300 mg/g). When combined eGFR and ACR categories were assessed, risks for SVD score increment generally increased as eGFR decreased and ACR increased. Conclusions Both reduced eGFR and albuminuria were independently associated with increased cerebral SVD burden in patients requiring oral antithrombotic medication mainly for secondary stroke prevention. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01581502; URL: https://www.umin.ac.jp/ctr; Unique identifier: UMIN000023669.

Tenecteplase versus alteplase for large vessel occlusion recanalization (T-FLAVOR): Trial protocol.

Background: Tenecteplase has higher fibrin specificity with a longer half-life and the potential to achieve higher rates of recanalization than alteplase. A critical limitation of tenecteplase is no commercial use in Japan and no experience with its administration to Japanese patients. Hypothesis: Tenecteplase is superior to alteplase in achieving recanalization on the initial angiogram when administered ≤4.5-hour of stroke onset in patients planned for mechanical thrombectomy (MT) in Japan where alteplase at the unique dose of 0.6mg/kg is officially used. Methods: The Tenecteplase versus alteplase For LArge Vessel Occlusion Recanalization (T-FLAVOR) trial is an investigator-initiated, phase II, multicenter, prospective, randomized, open-label, masked-endpoint, superiority study. Eligibility criteria include acute ischemic stroke with pre-stroke modified Rankin Scale score ≤3 and large vessel occlusion (internal carotid artery, middle cerebral artery, or basilar artery) eligible for intravenous thrombolysis ≤4.5-hour and MT ≤6-hour of stroke onset. After completing the safety confirmation phase involving three patients who received non-masked tenecteplase (0.25 mg/kg), 220 patients will be randomized to two groups (1:1), intravenous alteplase (0.6mg/kg, n = 110) or tenecteplase (0.25mg/kg, n = 110), prior to MT. Outcomes: In the safety confirmation phase, the primary outcome is symptomatic intracranial hemorrhage (sICH) ≤24-36-hour. In the randomized, comparative phase, the primary efficacy outcome is substantial angiographic reperfusion (mTICI grade 2b/2c/3) or absence of retrievable thrombus on the initial angiogram. The primary safety outcome is sICH ≤24-36-hour and 90-day mortality. Discussion: T-FLAVOR may help determine if tenecteplase should be recommended as a routine clinical strategy before MT for Japanese stroke patients. Trial registration: jRCTs051210055.

[Cerebral vein/venous sinus thrombosis with thrombocytopenia syndrome after COVID-19 vaccination].

Vaccines are important in managing the COVID-19 pandemic caused by SARS-CoV-2. Despite the very low incidence, severe cases of thrombosis with thrombocytopenia after COVID-19 vaccination termed as Thrombosis with Thrombocytopenia Syndrome (TTS) have been reported. TTS clinically resembles autoimmune heparin-induced thrombocytopenia. TTS can cause disability and even death. It usually presents 4-28 days after vaccination characterized by thrombocytopenia and progressive thrombosis, often causing cerebral vein/venous thrombosis (CVT) and splanchnic venous thrombosis. We should avoid all forms of heparin and platelet transfusion. While awaiting further information on the pathophysiological mechanism and treatment of TTS, clinicians should be aware of TTS with CVT in patients receiving COVID-19 vaccinations. This new syndrome of TTS is an active area of investigation globally. Here, we review the available literature.

Inhibitory synaptic transmission is impaired at higher extracellular Ca2+ concentrations in Scn1a+/- mouse model of Dravet syndrome.

Dravet syndrome (DS) is an intractable form of childhood epilepsy that occurs in infancy. More than 80% of all patients have a heterozygous abnormality in the SCN1A gene, which encodes a subunit of Na+ channels in the brain. However, the detailed pathogenesis of DS remains unclear. This study investigated the synaptic pathogenesis of this disease in terms of excitatory/inhibitory balance using a mouse model of DS. We show that excitatory postsynaptic currents were similar between Scn1a knock-in neurons (Scn1a+/- neurons) and wild-type neurons, but inhibitory postsynaptic currents were significantly lower in Scn1a+/- neurons. Moreover, both the vesicular release probability and the number of inhibitory synapses were significantly lower in Scn1a+/- neurons compared with wild-type neurons. There was no proportional increase in inhibitory postsynaptic current amplitude in response to increased extracellular Ca2+ concentrations. Our study revealed that the number of inhibitory synapses is significantly reduced in Scn1a+/- neurons, while the sensitivity of inhibitory synapses to extracellular Ca2+ concentrations is markedly increased. These data suggest that Ca2+ tethering in inhibitory nerve terminals may be disturbed following the synaptic burst, likely leading to epileptic symptoms.

Tumor Cells Detected in Retrieved Thrombus: Cancer-associated Stroke.

A 51-year-old man with a history of renal cell carcinoma presented with sudden aphasia, right hemiparesis, and dysesthesia. MRA showed left middle cerebral artery occlusion, and he was diagnosed with acute ischemic stroke and treated with intravenous recombinant tissue plasminogen activator and endovascular thrombectomy. The pathological diagnosis of the retrieved thrombus was consistent with the already-known pathological findings of the primary renal cell carcinoma. Therefore, a diagnosis of cerebral embolism caused by tumor cells was made. The pathological findings of the retrieved thrombi were important in determining the cause of ischemic stroke.