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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 Melatonin is a hormone that is primarily produced in the pineal gland and is involved in wide range of biological functions. However, the impact of melatonin on chemotherapy-induced cell death remains to be elucidated in oral squamous cell carcinoma (OSCC) cells. The objective of this study was to clarify the role of melatonin in cisplatin-induced cytotoxicity in CD44high OSCC cells. METHODS CD44high OSCC cells were cultured on fibronectin-coated hydrogel. A lactate dehydrogenase cytotoxicity assay was performed to evaluate cisplatin-induced cell death. The effect of melatonin on cisplatin-induced cell death and Derlin-1 (DERL1) endoplasmic reticulum membrane protein expression was investigated. RESULTS CD44high OSCC cells exhibited mesenchymal-like features when cultured on fibronectin-coated hydrogel. Mesenchymal-like CD44high OSCC cells demonstrated strong resistance to cisplatin-induced cell death compared with epithelial-like CD44high OSCC cells. DERL1 mRNA and DERL1 protein expression levels were significantly higher in mesenchymal-like CD44high cells compared with epithelial-like CD44high cells. Cisplatin-induced cell death was significantly enhanced after DERL1 siRNA knockdown, suggesting that DERL1 is involved in resistance to cisplatin-induced cell death. Melatonin significantly inhibited DERL1 expression and enhanced cisplatin-induced cell death in mesenchymal-like CD44high cells. miR-181c-5p expression was significantly upregulated in the presence of melatonin. Furthermore, melatonin-inhibited DERL1 expression was significantly recovered by miR-181c-5p inhibitor. In addition, melatoninenhanced cisplatin-induced cell death was attenuated by miR-181c-5p inhibitor. These results suggest that melatonin-induced miR-181c-5p enhances cisplatin-induced cell death through inhibition of DERL1 in mesenchymal-like CD44high cells. CONCLUSIONS Melatonin plays a vital role in promoting cisplatin-induced cytotoxicity in mesenchymal-like CD44high OSCC cells.

KY02111 is a widely used small molecule that boosts cardiomyogenesis of the mesoderm cells derived from pluripotent stem cells, yet its molecular mechanism of action remains elusive. The present study resolves the initially perplexing effects of KY02111 on Wnt signaling and subsequently identifies squalene synthase (SQS) as a molecular target of KY02111 and its optimized version, KY-I. By disrupting the interaction of SQS with cardiac ER-membrane protein TMEM43, KY02111 impairs TGFβ signaling, but not Wnt signaling, and thereby recapitulates the clinical mutation of TMEM43 that causes arrhythmogenic right ventricular cardiomyopathy (ARVC), an inherited heart disease that involves a substitution of myocardium with fatty tissue. These findings reveal a heretofore undescribed role of SQS in TGFβ signaling and cardiomyogenesis. KY02111 may find its use in ARVC modeling as well as serve as a chemical tool for studying TGFβ/SMAD signaling.

Giant cell granulomas are a type of giant cell lesions and classified as follows: central giant cell granulomas occurring in the mandible and peripheral giant cell granulomas occurring in the gingiva. Central giant cell granulomas are less frequent than peripheral giant cell granulomas, and it rarely occurs in the mandibular condyle. Mandibular condylectomy is a widely used treatment strategy for lesions in the mandibular condylar region. A commonly indicated treated for mandibular condylectomy is the preauricular approach or the Al-Kayat Bramley method; however, we used the high cervical transmasseteric anteroparotid (HC-TMAP) approach. In recent years, the use of this approach has been reported for open reduction and internal fixation for mandibular condylar fracture cases. In this case report, we describe a technique using the high cervical transmasseteric anteroparotid approach for resecting a mandibular condyle in which a central giant cell granuloma had developed.

Background and Purpose: Evidence regarding sex differences in clinical outcomes and treatment effect following intracerebral hemorrhage is limited. Using the ATACH-2 trial (Antihypertensive Treatment in Intracerebral Hemorrhage-2) data, we explored whether sex disparities exist in outcomes and response to intensive blood pressure (BP)–lowering therapy. Methods: Eligible intracerebral hemorrhage subjects were randomly assigned to intensive (target systolic BP, 110–139 mm Hg) or standard (140–179 mm Hg) BP-lowering therapy within 4.5 hours after onset. Relative risk of death or disability corresponding to the modified Rankin Scale score of 4 to 6 was calculated, and interaction between sex and treatment was explored. Results: In total, 380 women and 620 men were included. Women were older, more prescribed antihypertensive drugs before onset, and had more lobar intracerebral hemorrhage than men. Hematoma expansion was observed less in women. After multivariable adjustment, the relative risk of death or disability in women was 1.19 (95% CI, 1.02–1.37, P =0.023). The relative risk of death or disability between intensive versus standard BP-lowering therapy was 0.91 (95% CI, 0.74–1.13) in women versus 1.13 (95% CI, 0.92–1.39) in men ( P for interaction=0.11), with inconclusive Gail-Simmon test ( P =0.16). Conclusions: Women had a higher risk of death or disability following intracerebral hemorrhage. The benefit of intensive BP-lowering therapy in women is inconclusive, consistent with the overall results of ATACH-2. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01176565.

Background: The present study aimed to clarify the association between left atrial (LA) size and ischemic events after ischemic stroke or transient ischemic attack (TIA) in patients with nonvalvular atrial fibrillation (NVAF). Methods: Acute ischemic stroke or TIA patients with NVAF were enrolled. LA size was classified into normal LA size, mild LA enlargement (LAE), moderate LAE, and severe LAE. The ischemic event was defined as ischemic stroke, TIA, carotid endarterectomy, carotid artery stenting, acute coronary syndrome or percutaneous coronary intervention, systemic embolism, aortic aneurysm rupture or dissection, peripheral artery disease requiring hospitalization, or venous thromboembolism. Results: A total of 1,043 patients (mean age, 78 years; 450 women) including 1,002 ischemic stroke and 41 TIA were analyzed. Of these, 351 patients (34%) had normal LA size, 298 (29%) had mild LAE, 198 (19%) had moderate LAE, and the remaining 196 (19%) had severe LAE. The median follow-up duration was 2.0 years (interquartile range, 0.9–2.1). During follow-up, 117 patients (11%) developed at least one ischemic event. The incidence rate of total ischemic events increased with increasing LA size. Severe LAE was independently associated with increased risk of ischemic events compared with normal LA size (multivariable-adjusted hazard ratio, 1.75; 95% confidence interval, 1.02–3.00). Conclusion: Severe LAE was associated with increased risk of ischemic events after ischemic stroke or TIA in patients with NVAF.

PurposeIntegrin αvβ3 is an essential molecule for tumor angiogenesis. This study aimed to investigate the anti-tumor effect of MK-0429, an integrin αvβ3 antagonist, on oral squamous cell carcinoma (OSCC) through its inhibitory effect on angiogenesis.MethodsIn this study, we investigated the effect of MK-0429 on cellular function and angiogenesis in vitro with the use of an immortalized human umbilical vein endothelial cell, HUEhT-1, which is immortalized by the electroporatic transfection of hTERT. The effect of MK-0429 on the integrin αvβ3 signaling pathway was examined by FAK and ERK 1/2 phosphorylation. The anti-angiogenic effect of MK-0429 was evaluated by in vitro tube formation assay. The anti-tumor effect on OSCC was assessed by administrating MK-0429 to mouse oral cancer xenografts.ResultsMK-0429 inhibited cell proliferation, migration, and adhesion of HUEhT-1 in a dose-dependent manner. FAK and ERK phosphorylation were significantly blocked by MK-0429 treatment. Tube formation was suppressed by MK-0429 in dose-dependent manner. Tumor progression was significantly suppressed by MK-0429 administration in mouse oral cancer xenografts. Histological study revealed that MK-0429 decreased tumor vascularization.ConclusionThese results indicated integrin αvβ3 as a therapeutic target for OSCC and suggested that MK-0429 might be clinically applicable as an anti-tumor agent with potent antiangiogenic activity.

Highlights • We report the first case of cerebral amyloid angiopathy-related inflammation (CAA-RI) presenting palinopsia initially. • Palinopsia is generally caused by intracranial diseases involving the parietal and occipital areas. • CAA dominantly affects parietal and occipital lobes, therefore palinopsia could be an important phenomenon of the disease.

Melatonin is a hormone that is primarily produced in the pineal gland and is involved in wide range of biological functions. However, the impact of melatonin on chemotherapy-induced cell death remains to be elucidated in oral squamous cell carcinoma (OSCC) cells. The objective of this study was to clarify the role of melatonin in cisplatin-induced cytotoxicity in CD44CD44CD44Melatonin plays a vital role in promoting cisplatin-induced cytotoxicity in mesenchymal-like CD44

The rapid increase in the development of machine learning systems in companies today presents new challenges that have not been faced in the development of traditional IT systems. Machine learning systems for human operations have a different set of challenges in comparison with Porter's connected smart products. The methodology for planning and developing such products has not yet been established, and it is mainly based on experience and intuition. In this paper, we define “exploitation” as the process of enhancing machine learning systems and summarize the issues in exploitation pattern based on several case studies. In the latter half of the paper, we propose a development process that minimizes machine learning problems on the exploitation of the systems. This is done by defining multiple uncertainties and proposing multiple development methods that are required for those uncertainties.

This study investigated the fabrication and performance of highly responsive photodetectors, constructed of turbostratic stacked graphene produced via chemical vapor deposition (CVD) and using the photogating effect. This effect was induced by situating photosensitizers around a graphene channel such that these materials coupled with incident light and generated large electrical changes. The responsivity of such devices correlates with the carrier mobility of the graphene, and so improved mobility is critical. This work assessed the feasibility of using turbostratic stacked CVD graphene to improve mobility since, theoretically, multilayers of this material may exhibit linear band dispersion, similar to monolayer graphene. This form of graphene also exhibits higher carrier mobility and greater conductivity than monolayer CVD graphene. The turbostratic stacking can be accomplished simply by the repeated transfer of graphene monolayers produced by CVD. Furthermore, it is relatively easy to fabricate CVD graphene layers having sizes suitable for the mass production of electronic devices. Unwanted carrier scattering that can be caused by the substrate is also suppressed by the lower graphene layers when turbostratic stacked graphene is applied. The infrared response properties of the multilayer devices fabricated in the present work were found to be approximately tripled compared with those of a monolayer graphene photodetector. It is evident that turbostratic stacked CVD graphene, which can be produced on a large scale, serves to increase the responsivity of photodetectors in which it is included. The results of this study are expected to contribute to the realization of low-cost, mass-producible, high-responsivity, graphene-based infrared sensors.

There is a growing interest in low-cost small-format infrared array sensors. In this study, we demonstrate the properties of small-format graphene infrared array sensors. The devices consisted of 9 x 9 pixels, which were composed of graphene field-effect transistors (FETs) and graphene/semiconductor Schottky barrier diodes (SBDs). The photoresponses of these devices were evaluated under middle-wavelength infrared (MWIR) light irradiation. The graphene FETs exhibited ultrahigh responsivity owing to modulation of the field-effect and surface carriers caused by photocarriers generated in photosensitizers. The MWIR photoresponse of the graphene FETs was enhanced by photogating. Compared to the FETs, the SBDs showed improved dark current characteristics. The photocarriers injected into the graphene were amplified by the photogating effect induced in the graphene/insulator region. Line-scan MWIR images and profiles were obtained; the devices were mounted in ceramic image sensor packages and vacuum-cooled. They were then exposed to a scanning blackbody light source, and the MWIR photoresponse was evaluated. The photocurrent linearly increased with the step shift of the blackbody source. The results obtained in this study will contribute to the development of high-performance graphene-based IR image sensors.

Graphene—atomically thin carbon sheets with a two-dimensional hexagonal lattice structure—exhibits unusual electronic and optical properties. Photodetectors are a good prospective application of graphene because they should ideally exhibit a broadband photoresponse from the ultraviolet to terahertz regions and high-speed operation, as well as be inexpensive to produce. Numerous methods have been proposed in order to enhance the responsivity of graphene-based photodetectors. Among these methods, photogating is most promising because it can realize the highest performance. Photogating requires photosensitive layers at the vicinity of graphene in order to produce a voltage change. Various photosensitive layers, including quantum dots, Si, InSb, and LiNbO3, are used in the visible to near-, mid-, and long-wavelength IR (NIR, MWIR, and LWIR) regions, respectively. However, the operating wavelength region is determined by the photosensitive layer, which undermines the advantage of broadband operation of the graphene. In this work, graphene nanoribbon (GNR) was used as a photosensitive layer. Graphene transistors were prepared using Si substrates with a SiO2 layer and source and drain electrodes. Single-layer graphene fabricated by chemical vapor deposition was transferred onto this substrate and formed a channel, and GNR was formed on the graphene channel using a solution dispersion method. The photoresponse was measured in the mid- and long-wavelength infrared regions. The photoresponse was found to be enhanced by GNR photogating compared with the photoresponse of devices without GNR. These results are expected to contribute to the development of high-performance broadband IR photodetectors.

The low-affinity nerve growth factor receptor p75 is a stratified epithelial stem/progenitor marker of human epithelia. We found OM-1, a human squamous cell carcinoma (SCC) cell line, showed distinct cells with p75 cluster, especially located at the center of a growing colony in a monolayer culture. A cell with p75 cluster was surrounded by cytokeratin 14- and cytokeratin 13-expressing cells that settled at the outer margin of the colony. OM-1 cells were also capable of forming tumor spheres in a cell suspension culture, an ability which was attenuated by the inhibition of p75-signaling. Intriguingly, we also found a p75-negative cell population from a growing culture of OM-1 that re-committed to become p75-clustering cells. These results indicated the possibility that SCC with epithelial multi-layering capacity can exploit the p75-dependent stratified epithelial progenitor property for the cancer stemness., Highlights • Squamous cell carcinoma cell line OM-1 maintained cell population with p75 cluster in the cell. • Single cell-derived OM-1 colonies with the cell at centre maintained hierarchical stratified epithelial linages. • OM-1 cells have p75-dependent epithelial progenitor and stemness properties.

Background Noninvasive management by closed reduction is a desirable treatment for temporomandibular joint dislocation. However, reduction of long-standing temporomandibular joint dislocation is often difficult. Various conservative treatments have been attempted, but these often render poor outcomes. This article reports the case of long-standing temporomandibular joint dislocation that was successfully closed using intraoral condylectomy. Case presentation A 69-year-old Japanese man who sustained an injury in a car collision was unable to close his mouth. Owing to the diagnosis of long-standing temporomandibular joint dislocation, intraoral condylectomy was performed. In the case of temporomandibular joint dislocation, it is convenient to reach the condyle from the oral cavity because sufficient opening is maintained. The condyle can be clearly visualized using an approach similar to sagittal split ramus osteotomy, and the operation using surgical instruments can be facilitated by resecting the coronoid process. By separating the surrounding soft tissue and pulling the cut condyle with sufficient visual field, the condyle can be resected while addressing the hemostasis. During the 12-month postoperative follow-up period, no temporomandibular joint dislocation recurred and the occlusion remained stable. Conclusions The limited intraoral incision of this surgical technique provides sufficient access for condylectomy. The results of this case report suggest that condylectomy by intraoral approach could become the treatment of choice for long-standing temporomandibular joint dislocation.

Background and Purpose: High blood pressure increases bleeding risk during treatment with antithrombotic medication. The association between blood pressure levels and the risk of recurrent stroke during long-term secondary stroke prevention with thienopyridines (particularly prasugrel) has not been well studied. Methods: This was a post hoc analysis of the randomized, double-blind, multicenter PRASTRO-I trial (Comparison of Prasugrel and Clopidogrel in Japanese Patients With Ischemic Stroke-I). Patients with noncardioembolic stroke were randomly assigned (1:1) to receive prasugrel 3.75 mg/day or clopidogrel 75 mg/day for 96 to 104 weeks. Risks of any ischemic or hemorrhagic stroke, combined ischemic events, and combined bleeding events were determined based on the mean level and visit-to-visit variability, including successive variation, of systolic blood pressure (SBP) throughout the observational period. These risks were also compared between quartiles of mean SBP level and successive variation of SBP. Results: A total of 3747 patients (age 62.1±8.5 years, 797 women), with a median average SBP level during the observational period of 132.5 mm Hg, were studied. All the risks of any stroke (146 events; hazard ratio, 1.318 [95% CI, 1.094–1.583] per 10-mm Hg increase), ischemic stroke (133 events, 1.219 [1.010–1.466]), hemorrhagic stroke (13 events, 3.247 [1.660–6.296]), ischemic events (142 events, 1.219 [1.020–1.466]), and bleeding events (47 events, 1.629 [1.172–2.261]) correlated with increasing mean SBP overall. Similarly, an increased risk of these events correlated with increasing successive variation of SBP (hazard ratio, 3.078 [95% CI, 2.220–4.225] per 10-mm Hg increase; 3.051 [2.179–4.262]; 3.276 [1.172–9.092]; 2.865 [2.042–4.011]; 2.764 [1.524–5.016], respectively). Event rates did not differ between the clopidogrel and prasugrel groups within each quartile of SBP or successive variation of SBP. Conclusions: Both high mean SBP level and high visit-to-visit variability in SBP were significantly associated with the risk of recurrent stroke during long-term medication with either prasugrel or clopidogrel after stroke. Control of hypertension would be important regardless of the type of antiplatelet drugs. Registration: URL: https://www.clinicaltrials.jp ; Unique identifier: JapicCTI-111582.

Lactone-vitamin D3 is a major metabolite of vitamin D3, a lipophilic vitamin biosynthesized in numerous life forms by sunlight exposure. Although lactone-vitamin D3 was discovered 40 years ago, its biological role remains largely unknown. Chemical biological analysis of its photoaffinity probe identified the hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha (HADHA), a mitochondrial enzyme that catalyzes β-oxidation of long-chain fatty acids, as its selective binding protein. Intriguingly, the interaction of lactone-vitamin D3 with HADHA does not affect the HADHA enzymatic activity but instead limits biosynthesis of carnitine, an endogenous metabolite required for the transport of fatty acids into the mitochondria for β-oxidation. Lactone-vitamin D3 dissociates the protein-protein interaction of HADHA with trimethyllysine dioxygenase (TMLD), thereby impairing the TMLD enzyme activity essential in carnitine biosynthesis. These findings suggest a heretofore undescribed role of lactone-vitamin D3 in lipid β-oxidation and carnitine biosynthesis, and possibly in sunlight-dependent shifts of lipid metabolism in animals.

Background Various wearable devices for objectively evaluating motor symptoms of patients with Parkinson’s disease (PD) have been developed. Importantly, previous studies have suggested protective effects of physical activity in PD. However, the relationships between conventional clinical ratings for PD and three-axis accelerometer measures of physical activity (e.g., daily physical activity levels [PAL] or metabolic equivalents of task [METs]) are still unclear, particularly for METs. In the current study, we sought to elucidate these relationships on a daily basis, and to clarify optimal predictors for clinical states on a 30-min basis. Methods Patients who were hospitalized for adjustment of drugs or deep brain stimulation were enrolled. Using waist-worn three-axis accelerometers, PAL and METs parameter data were obtained and compared with UPDRS-3[On] and symptom diary data. We extracted data from the patients’ best and worst days, defined by the best and worst UPDRS-3[On] scores, respectively. Thus, 22 data sets from 11 patients were extracted. We examined the correlations and produced scatter plots to represent the relationships, then investigated which METs parameters and activity patterns were the best predictors for “On” and “dyskinesia”. Results The parameter “mean METs value within the 95–92.5 percentile range on a day (95–92.5 percentile value)” exhibited the strongest correlation with conventional daily clinical ratings (Rho: − 0.799 for UPDRS-3[On], 0.803 for On hours [p Conclusions This study suggested feasible activity patterns and METs parameters for objective evaluation of motor symptoms on a 30-min or daily basis. Three-axis accelerometer measures focusing on higher METs may be appropriate for evaluating physical activity. Further larger-scale studies are necessary to clarify the validity, reliability, and clinical utility of these objective measures.

The photoresponse mechanism of graphene/InSb heterojunction middle-wavelength infrared (MWIR) photodetectors was investigated. The devices comprised a graphene/InSb heterojunction as a carrier-injection region and an insulator region of graphene on tetraethyl orthosilicate (TEOS) for photogating. The MWIR photoresponse was significantly amplified with an increase in the graphene/TEOS cross-sectional area by covering the entire detector with graphene. The graphene-channel dependence of the MWIR photoresponse indicated that the graphene carrier density was modulated by photocarrier accumulation at the TEOS/InSb boundary, resulting in photogating. The dark current of the devices was suppressed by a decrease in the graphene/InSb carrier-injection region and the formation of the heterojunction using an n-type InSb substrate. The results indicate that photocarrier transportation was dominated by the formation of a Schottky barrier at the interface of the graphene/InSb heterojunction and a Fermi-level shift under bias application. The high-responsivity and low-dark-current photoresponse mechanism was attributed to the graphene/InSb heterojunction diode behavior and the photogating effect. The devices combining the aforementioned features had a noise equivalent power of 0.43 pW / Hz1/2. The results obtained in our study will contribute to the development of high-performance graphene-based IR image sensors.

Machine-learning (ML) software engineering design patterns encapsulate reusable solutions to commonly occurring problems within the given contexts of ML systems and software design. These ML patterns should help develop and maintain ML systems and software from the design perspective. However, to the best of our knowledge, there is no study on the practitioners’ insights on the use of ML patterns for design of their ML systems and software. Herein we report the preliminary results of a literature review and a questionnaire-based survey on ML system developers’ state-of-practices with concrete ML patterns.

Graphene infrared (IR) photodetectors are promising devices that take advantage of the unique optoelectronic properties of graphene, such as broadband light absorption, rapid response, and high chemical stability. Despite its advantages, graphene has a low absorbance of 2.3%, which limits its photoresponsivity. We have previously reported the responsivity enhancement of graphene middle wavelength IR (MWIR) photodetectors using the photogating effect. The photogating effect is induced by photosensitizers located around the graphene channel that generate a large electrical change. The MWIR photoresponse with the photogating effect was enhanced by 100-fold relative to conventional graphene field-effect transistors (FETs). Although our graphene FETs using photogating exhibited ultrahigh responsivity, the dark current was extremely high, as in the case of conventional graphene FETs, because the normally-OFF operation cannot be realized in graphene. Therefore, reducing the high dark current is essential for applying graphene photodetectors to IR applications. We demonstrate dark current reduction and high responsivity MWIR light detection in graphene MWIR photodetectors. The devices consist of graphene FETs with a carrier injection region. The dark current is reduced by applying a bias voltage. The photocarriers injected into the graphene are amplified by the photogating effect induced in the graphene/insulator region. The dark current of the devices was significantly suppressed compared with that of conventional graphene FETs. The photoresponse characteristics were investigated for devices of different structure sizes. The results obtained in this study will contribute to the development of high-performance graphene-based IR image sensors.

Graphene has unique optoelectronic properties and potential applications in improved infrared (IR) photodetectors. Due to its Dirac cone structure, graphene exhibits broadband light absorption and rapid responsivity. In addition, unlike conventional quantum photomaterials, graphene can be synthesized inexpensively via a non-toxic process. Although graphene has advantages in IR photodetector applications, graphene photodetectors have shown low responsivity due to their minimal IR absorption (just 2.3%) and also require cooling. Therefore, there is considerable interest in enhancing the responsivity of graphene photodetectors operating at room temperature so that their advantages can be employed in IR applications. The present work demonstrates room temperature, high-responsivity, long-wavelength infrared (LWIR) graphene photodetectors. These devices operate on the photogating effect, using a lithium niobate (LiNbO3) substrate with enhancement of the photogating via a pyroelectric effect in the substrate in conjunction with a SiN layer. This effect significantly modulates the back-gate voltage to increase the photoresponse by a factor of approximately 600 compared to that for a conventional graphene photodetector. This work also found a change in the type of charge carrier with variations in temperature, which was attributed to a large shift in the Dirac point owing to the strong photogating effect. The results of this study are expected to contribute to the future realization of high-responsivity, low-cost LWIR photodetectors for applications such as thermal imaging, medical care and gas analysis.

Graphene, an atomically thin carbon sheet, has drawn significant attention in many fields because of its unique electronic and optical properties. Graphene is a potential candidate for plasmonic metamaterial absorbers and emitters because of its optical tunability and extreme thinness. We have previously demonstrated graphene Salisbury screen metasurfaces. Although the absorption wavelength of such metasurfaces can be controlled by varying the graphene patch size, the absorbance is insufficient for practical applications. In this study, therefore, multilayer graphene metamaterial absorbers (MGMAs) were theoretically investigated in the middle- to long-wavelength infrared (IR) region. The MGMAs consist of graphene layers alternating with insulator layers formed on a bottom reflector. The spectral absorbance was calculated using the rigorous coupled-wave analysis method. The calculation results demonstrated that a high absorption of ~100% can be achieved because of the multiple plasmonic resonance between each graphene layer and the bottom reflector. The absorption wavelength can be controlled by regulating the graphene pattern size because of the plasmonic resonance of graphene. Furthermore, the absorption wavelength can be tuned by controlling the chemical potential of graphene, which allows for the development of electrically tunable wavelength-selective IR absorbers and emitters. These results will contribute to the development of high-performance wavelength-tunable graphene-based IR detectors and emitters.

Disorderly stacked multilayer graphene, called turbostratic graphene, is a promising candidate for highly responsive infrared detectors due to its higher carrier mobility than well-ordered multilayer graphene, and facility to suppress the Coulomb scattering from the substrate. Such properties are expected to enhance photogating for high-responsivity infrared detection. The electronic structure of turbostratic graphene was investigated using first-principles calculations. The turbostratic graphene was modeled by introducing disorder to bilayer graphene in terms of the distance and the rotation angle between the graphene layers. The calculation results show that an increase in these parameters leads to linear band dispersion and a structure similar to monolayer graphene.

Mutations in the valosin-containing protein (VCP) gene are known to cause various neurodegenerative disorders. Here, we report 8 Japanese patients [6 men, 2 women; median age at onset: 49.5 (range, 35–58) years] from 5 unrelated families with VCP missense mutations. Although 7 of 8 patients were diagnosed with either inclusion body myopathy or amyotrophic lateral sclerosis, 1 patient showed demyelinating polyneuropathy, which was confirmed by longitudinal nerve conduction studies. Sural nerve biopsy of the patient revealed intranuclear ubiquitin staining in Schwann cells. Three known pathogenic VCP mutations (p.Arg191Gln, p.Arg155Cys, and p.Ile126Phe) were detected. A novel mutation, c.293 A>T (p.Asp98Val), was also identified in a patient with amyotrophic lateral sclerosis and frontotemporal dementia. This mutation was predicted to be “deleterious” or “disease causing” using in silico mutation analyses. In conclusion, demyelinating polyneuropathy may be a novel phenotype caused by VCP mutations. The p.Asp98Val mutation was found to be a novel pathogenic mutation of VCP proteinopathy. We believe our cases represent a wide clinical spectrum of VCP mutations.

BACKGROUND We determined the 2-year long-term risk-benefit profile in patients with stroke or transient ischemic attack (TIA) receiving warfarin or direct oral anticoagulants (DOACs) for nonvalvular atrial fibrillation (NVAF) using a prospective, multicenter, observational registry in Japan.Methods and Results:NVAF patients within 7 days after onset of ischemic stroke/TIA were enrolled in 18 stroke centers. Outcome measures included ischemic and bleeding events and death in the 2-year follow-up period. We enrolled 1,116 patients taking either warfarin (650 patients) or DOACs (466 patients) at acute hospital discharge. DOAC users were younger and had lower National Institutes of Health Stroke Scale, CHADS2and discharge modified Rankin Scale scores than warfarin users (P

Background: Previous studies have revealed that hematoma growth mainly occurs during the first 6 h after the onset of spontaneous intracerebral hemorrhage (ICH). Early lowering of blood pressure (BP) may be beneficial for preventing hematoma growth. However, relationships between timing of BP lowering and hematoma growth in ICH remain unclear. We investigated associations between timing of BP lowering and hematoma growth for ICH. Methods: The Stroke Acute Management with Urgent Risk-factor Assessment and Improvement (SAMURAI)-ICH Study was a multicenter, prospective, observational study investigating the safety and feasibility of early (within 3 h from onset) reduction of systolic BP (SBP) to < 160 mm Hg with intravenous nicardipine for acute hypertension in cases of spontaneous ICH. The present study was a post hoc analysis of the SAMURAI-ICH study. We examined relationships between time from onset, imaging, and initiation of treatment to target SBP achievement and hematoma growth (absolute growth ≥6 mL) in ICH patients. Target SBP achievement was defined as the time at which SBP first became < 160 mm Hg. Results: Among 211 patients, hematoma growth was seen in 31 patients (14.7%). The time from imaging to target SBP and time from treatment to target SBP were significantly shorter in patients without hematoma growth than in those with (p = 0.043 and p = 0.032 respectively), whereas no significant difference was seen in time from onset to SBP < 160 mm Hg between groups (p = 0.177). Patients in the lower quartiles of time from imaging to target SBP and time from treatment to target SBP showed lower incidences of hematoma growth (p trend = 0.023 and 0.037 respectively). The lowest quartile of time from imaging to target SBP (< 38 min) was negatively associated with hematoma growth on multivariable logistic regression (OR 0.182; 95% CI 0.038–0.867; p = 0.032). Conclusions: Early achievement of target SBP < 160 mm Hg is associated with a lower risk of hematoma growth in ICH.

Background: We aimed to clarify associations between pre-admission risk scores (CHADS2, CHA2DS2-VASc, and HAS-BLED) and 2-year clinical outcomes in ischemic stroke or transient ischemic attack (TIA) patients with non-valvular atrial fibrillation (NVAF) using a prospective, multicenter, observational registry. Methods: From 18 Japanese stroke centers, ischemic stroke or TIA patients with NVAF hospitalized within 7 days after onset were enrolled. Outcome measures were defined as death/disability (modified Rankin Scale score ≥3) at 2 years, 2-year mortality, and ischemic or hemorrhagic events within 2 years. Results: A total of 1,192 patients with NVAF (527 women; mean age, 78 ± 10 years), including 1,141 ischemic stroke and 51 TIA, were analyzed. Rates of death/disability, mortality, and ischemic or hemorrhagic events increased significantly with increasing pre-admission CHADS2 (p for trend p for trend = 0.024 for events), CHA2DS2-VASc (p for trend p for trend = 0.004 for death/disability, p for trend p for trend = 0.024 for events) scores. Pre-admission CHADS2 (OR per 1 point, 1.52; 95% CI 1.35–1.71; p p p = 0.016 for events), CHA2DS2-VASc (1.55, 1.41–1.72, p < 0.001; 1.21, 1.12–1.30, p < 0.001; 1.17, 1.07–1.27, p < 0.001; respectively), and HAS-BLED (1.33, 1.17–1.52, p < 0.001; 1.23, 1.10–1.38, p < 0.001; 1.18, 1.05–1.34, p = 0.008; respectively) scores were independently associated with all outcome measures. Conclusions: In ischemic stroke or TIA patients with NVAF, all pre-admission risk scores were independently associated with death/disability at 2 years and 2-year mortality, as well as ischemic or hemorrhagic events within 2 years.

Irregular menstrual cycles, reduced responses to exogenous hormonal treatments, and altered endocrine profiles (high FSH/high LH/low AMH) are observed in women with increasing age before menopause. In this study, because the granulosa cell-specific Nrg1 knockout mice (gcNrg1KO) presented ovarian and endocrine phenotypes similar to older women, we sought to understand the mechanisms of ovarian aging and to develop anewstrategy for improving fertility in older women prior to menopause. In the ovary of 6-month-old gcNrg1KO mice, follicular development was blocked in bilayer secondary follicles and heterogeneous cells accumulated in ovarian stroma. The heterogeneous cells in ovarian stroma were distinguished as two different types: (i) the LH receptor-positive endocrine cells and (ii) actin-rich fibrotic cells expressing collagen. Both the endocrine and fibrotic cells disappeared following long-term treatment with a GnRH antagonist, indicating that the high levels of serum LH induced the survival of both cell types and the abnormal endocrine profile to reduce fertility. Moreover, follicular development to the antral stages was observed with reduced LH and the disappearance of the abnormal stromal cells. Mice treated with the GnRH antagonist regained normal, recurrent estrous cycles and continuously delivered pups for at least for 3 months. We conclude that endocrine and matrix alternations occur within the ovarian stroma with increasing age and that abolishing these alternations resets the cyclical release of LH. Thus, GnRH antagonist treatments might provide a new, noninvasive strategy for improving fertility in a subset of aging women before menopause., This work was supported in part by The Japan Society for the Promotion of Science (JSPS) KAKENHI, JP24688028, JP 16H05017 (to MS) and JP15J05331 (to TU), by Japan Agency for Medical Research and Development (AMED) 16gk0110015 h0001 (to MS), and by National Institute of Health (NIH)-HD-076980 (to JSR).