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Abstract Gastrointestinal (GI) bleeding control is critical in elderly patients with atrial fibrillation (AF) receiving oral anticoagulants (OAC). This subgroup analysis aimed to clarify the actual state and significance of GI bleeding in elderly non-valvular AF (NVAF) patients. We evaluated the incidence and risk factors of GI bleeding during the 2-year follow-up and examined the GI bleeding impact on mortality. Of the 32,275 patients in the ANAFIE Registry, 1139 patients (3.5%) experienced GI bleeding (incidence rate, 1.92 events per 100 person-years; mean follow-up, 1.88 years); 339 upper and 760 lower GI bleeding events occurred. GI bleeding risk factors included age ≥ 85 years, body mass index ≥ 25.0 kg/m2, prior major bleeding, hyperuricaemia, heart failure, P-glycoprotein inhibitor use, GI disease, and polypharmacy (≥ 5 drugs). No significant differences in GI bleeding risk were found between direct OAC (DOAC) vs warfarin users (adjusted hazard ratios [95% confidence interval], 1.01 [0.88–1.15]). The 1-year post-GI bleeding mortality rate was numerically higher in patients with upper (19.6%) than lower GI bleeding (8.9%). In elderly Japanese NVAF patients, this large-scale study found no significant difference in GI bleeding risk between DOAC vs. warfarin users or 1-year mortality after upper or lower GI bleeding.

Abstract Aims Atrial fibrillation (AF) and heart failure (HF) often coexist. Older age is strongly associated with stroke, HF, and mortality. The association between coexistence of HF and a risk of clinical outcomes and the effectiveness of anticoagulation therapy including direct oral anticoagulants (DOACs) in elderly patients with AF and HF have not been investigated. We aimed to evaluate 2 years of outcomes and to elucidate the efficacy of DOACs or warfarin in elderly AF patients in the All Nippon AF In the Elderly (ANAFIE) Registry with and without a history of HF. Methods and results The ANAFIE Registry is a multicentre, prospective observational study following elderly non‐valvular AF patients aged ≥75 years for 2 years. Hazard ratios (HRs) were calculated based on the presence or absence of an HF diagnosis and DOAC or warfarin use at enrolment. Among 32 275 eligible patients, 12 116 (37.5%) had been diagnosed with HF. Patients with HF had significantly higher rates of HF hospitalization or cardiovascular death (HR 1.94, P

In this paper, we propose a topological data analysis (TDA) method for the processing of induction motor stator current data, and apply it to the detection and quantification of eccentricity faults. Traditionally, physics-based models and involved signal processing techniques are required to identify and extract the subtle frequency components in current data related to a particular fault. We show that TDA offers an alternative way to extract fault related features, and effectively distinguish data from different fault conditions. We will introduce TDA method and the procedure of extracting topological features from time-domain data, and apply it to induction motor current data measured under different eccentricity fault conditions. We show that while the raw time-domain data are very challenging to distinguish, the extracted topological features from these data are distinct and highly associated with eccentricity fault level. With TDA processed data, we can effectively train machine learning models to predict fault levels with good accuracy, even for new data from eccentricity levels that are not seen in the training data. The proposed method is model-free, and only requires a small segment of time-domain data to make prediction. These advantages make it attractive for a wide range of data-driven fault detection applications.

Abstract Background This ANAFIE Registry sub-analysis investigated 2-year outcomes and oral anticoagulant (OAC) use stratified by glycated hemoglobin (HbA1c) levels among Japanese patients aged ≥ 75 years with non-valvular atrial fibrillation (NVAF) with and without clinical diagnosis of diabetes mellitus (DM). Methods The ANAFIE Registry was a large-scale multicenter, observational study conducted in Japan; this sub-analysis included patients with baseline HbA1c data at baseline. The main endpoints evaluated (stroke/systemic embolic events [SEE], major bleeding, intracranial hemorrhage, cardiovascular death, all-cause death, and net clinical outcome [a composite of stroke/SEE, major bleeding, and all-cause death]) were stratified by HbA1c levels (

Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes are interacting comorbidities of obesity, and increased hepatic de novo lipogenesis (DNL), driven by hyperinsulinemia and carbohydrate overload, contributes to their pathogenesis. Fatty acid synthase (FASN), a key enzyme of hepatic DNL, is upregulated in association with insulin resistance. However, the therapeutic potential of targeting FASN in hepatocytes for obesity-associated metabolic diseases is unknown. Here, we show that hepatic FASN deficiency differentially affects NAFLD and diabetes depending on the etiology of obesity. Hepatocyte-specific ablation of FASN ameliorated NAFLD and diabetes in melanocortin 4 receptor–deficient mice but not in mice with diet-induced obesity. In leptin-deficient mice, FASN ablation alleviated hepatic steatosis and improved glucose tolerance but exacerbated fed hyperglycemia and liver dysfunction. The beneficial effects of hepatic FASN deficiency on NAFLD and glucose metabolism were associated with suppression of DNL and attenuation of gluconeogenesis and fatty acid oxidation, respectively. The exacerbation of fed hyperglycemia by FASN ablation in leptin-deficient mice appeared attributable to impairment of hepatic glucose uptake triggered by glycogen accumulation and citrate-mediated inhibition of glycolysis. Further investigation of the therapeutic potential of hepatic FASN inhibition for NAFLD and diabetes in humans should thus consider the etiology of obesity.

Aggravation of liver steatosis shifts the hepatocellular death mode from apoptosis to necroptosis in acute and chronic liver damage. Here the authors report that the transcription factor ATF3 regulates this shift through the induction of RIPK3, a regulator of necroptosis.

Abstract Background This study evaluated the existence of anti-drug antibodies (ADAs) before and 52 weeks after switching from intravenous infliximab (IFX) to intravenous CT-P13 in patients with rheumatoid arthritis (RA). Methods We performed a prospective observational study. Twenty-eight patients (7 males and 21 females) received intravenous CT-P13 after intravenous IFX, and the clinical data were collected from medical records. Rheumatoid factor (RF) and anti-CCP antibody were examined at baseline. At baseline and 52 weeks after the start of CT-P13 treatment, the Disease Activity Score based on the 28-joint count and the levels of C-reactive protein, matrix metalloproteinase-3, and ADA, as well as the erythrocyte sedimentation rate were evaluated. ADAs were measured using an enzyme-linked immunosorbent assay kit. Results Seven (25%) and 6 (21.4%) cases were positive for ADAs at baseline and 52 weeks after, respectively. One case became newly positive for ADAs at week 52. Two of the ADA-positive cases became ADA-negative 52 weeks after. The ADA-positive group showed significantly higher RF values at baseline than the ADA-negative group (p = 0.03). No difference was observed between the ADA-positive group and the ADA-negative group regarding other clinical parameters. Conclusions The positive rate of ADAs did not increase after switching from intravenous IFX to intravenous CT-P13. Among the patients with ADAs, a high level of RF was observed at baseline.

Nuclear pore complexes (NPCs) on the nuclear membrane surface have a crucial function in controlling the movement of small molecules and macromolecules between the cell nucleus and cytoplasm through their intricate core channel resembling a spiderweb with several layers. Currently, there are few methods available to accurately measure the dynamics of nuclear pores on the nuclear membranes at the nanoscale. The limitation of traditional optical imaging is due to diffraction, which prevents achieving the required resolution for observing a diverse array of organelles and proteins within cells. Super-resolution techniques have effectively addressed this constraint by enabling the observation of subcellular components on the nanoscale. Nevertheless, it is crucial to acknowledge that these methods often need the use of fixed samples. This also raises the question of how closely a static image represents the real intracellular dynamic system. High-speed atomic force microscopy (HS-AFM) is a unique technique used in the field of dynamic structural biology, enabling the study of individual molecules in motion close to their native states. Establishing a reliable and repeatable technique for imaging mammalian tissue at the nanoscale using HS-AFM remains challenging due to inadequate sample preparation. This study presents the rapid strainer microfiltration (RSM) protocol for directly preparing high-quality nuclei from the mouse brain. Subsequently, we promptly utilize HS-AFM real-time imaging and cinematography approaches to record the spatiotemporal of nuclear pore nano-dynamics from the mouse brain.

Background: We previously reported that standard deviation (SD) of systolic blood pressure (SBP), an index of BP variability, and SBP-time in target range (TTR), an index of BP consistency, were significantly associated with adverse events in patients with non-valvular atrial fibrillation (NVAF). Thus, this study aimed to compare predictive ability for adverse events among visit-to-visit BP variability/consistency indices using data from the J-RHYTHM Registry. Methods: Of 7406 outpatients with NVAF, 7226 (age, 69.7 ± 9.9 years; men, 70.7%), in whom BP was measured 4 times or more (14.6 ± 5.0 times) during the 2-year follow-up period or until occurrence of an event, were included. As BP consistency for target SBP between 110 and 130 mmHg, SBP-TTR by the Rosendaal method and SBP-frequency in range (FIR) were calculated. Predictive ability was expressed by the area under receiver-operating-characteristic curve (AUC). AUCs of SBP-TTR and SBP-FIR for adverse events were compared with those of SBP-SD by the DeLong’s test. Results: SBP-SD, SBP-TTR, and SBP-FIR were 11.0 ± 4.2 mmHg, 49.5 ± 28.3%, and 52.3 ± 23.0%, respectively. AUCs of these indices for thromboembolism, major hemorrhage, and all-cause death were 0.62, 0.64, and 0.63 for SBP-SD; 0.56, 0.55, and 0.56 for SBP-TTR; and 0.55, 0.56, and 0.58 for SBP-FIR; respectively. AUCs of SBP-SD were significantly larger than those of SBP-TTR for major hemorrhage (P = 0.010) and all-cause death (P = 0.014), and SBP-FIR for major hemorrhage (P = 0.016). Conclusion: Among visit-to-visit BP variability/consistency indices, predictive ability of SBP-SD for major hemorrhage and all-cause death was superior to that of SBP-TTR and SBP-FIR in patients with NVAF.

Abstract Metabolic regulation in skeletal muscle is essential for blood glucose homeostasis. Obesity causes insulin resistance in skeletal muscle, leading to hyperglycemia and type 2 diabetes. In this study, we performed multiomic analysis of the skeletal muscle of wild-type (WT) and leptin-deficient obese (ob/ob) mice, and constructed regulatory transomic networks for metabolism after oral glucose administration. Our network revealed that metabolic regulation by glucose-responsive metabolites had a major effect on WT mice, especially carbohydrate metabolic pathways. By contrast, in ob/ob mice, much of the metabolic regulation by glucose-responsive metabolites was lost and metabolic regulation by glucose-responsive genes was largely increased, especially in carbohydrate and lipid metabolic pathways. We present some characteristic metabolic regulatory pathways found in central carbon, branched amino acids, and ketone body metabolism. Our transomic analysis will provide insights into how skeletal muscle responds to changes in blood glucose and how it fails to respond in obesity.

Hypothalamic neurons regulate body homeostasis by sensing and integrating changes in the levels of key hormones and primary nutrients (amino acids, glucose, and lipids). However, the molecular mechanisms that enable hypothalamic neurons to detect primary nutrients remain elusive. Here, we identified l-type amino acid transporter 1 (LAT1) in hypothalamic leptin receptor–expressing (LepR-expressing) neurons as being important for systemic energy and bone homeostasis. We observed LAT1-dependent amino acid uptake in the hypothalamus, which was compromised in a mouse model of obesity and diabetes. Mice lacking LAT1 (encoded by solute carrier transporter 7a5, Slc7a5) in LepR-expressing neurons exhibited obesity-related phenotypes and higher bone mass. Slc7a5 deficiency caused sympathetic dysfunction and leptin insensitivity in LepR-expressing neurons before obesity onset. Importantly, restoring Slc7a5 expression selectively in LepR-expressing ventromedial hypothalamus neurons rescued energy and bone homeostasis in mice deficient for Slc7a5 in LepR-expressing cells. Mechanistic target of rapamycin complex-1 (mTORC1) was found to be a crucial mediator of LAT1-dependent regulation of energy and bone homeostasis. These results suggest that the LAT1/mTORC1 axis in LepR-expressing neurons controls energy and bone homeostasis by fine-tuning sympathetic outflow, thus providing in vivo evidence of the implications of amino acid sensing by hypothalamic neurons in body homeostasis.

To understand the mechanism of simultaneous drainage event related to supraglacial lakes on a debris-covered glacier, we investigated water-level variations of supraglacial lakes on the southern Inylchek Glacier in Kyrgyzstan. To examine these variations, we used daily aerial images for 2017–2019 from an uncrewed aerial vehicle that were converted to 15 cm-digital surface models and ortho-images. Our main results are as follows: (1) When one lake drained, the water levels of other lakes simultaneously increased, indicating that drainage water is shared with several lakes through a main englacial conduit. In one drainage event, a branched off englacial conduit clearly connected to a main englacial conduit. (2) Sometimes several lakes discharged simultaneously, indicating that several lakes had connected to a main englacial conduit that had opened. Such cases can cause larger-scale drainage than that from the opening of a branched off englacial conduit. (3) Simultaneous drainage occurred twice in the same year, each time through a different conduit, indicating that the main englacial conduit can be abandoned and reused. (4) In some lakes, the water level on the hydraulic gradient line increased gradually with nearly the same increase rate just before drainage. Such an increase may be an indicator of a possible simultaneous drainage event.

PtxRh1−x (x = 0.76, 0.54, and 0.27) solid solutions were prepared by arc-melting. For these solid solutions, the lattice constant was linearly related to the Pt content. The surface compositions of the solid solutions determined by X-ray photoelectron spectroscopy were quite similar to their bulk compositions estimated by energy dispersive X-ray spectroscopy. The CO-stripping voltammograms demonstrated that the onset potential of CO oxidation current density (Eonset) shifted negatively as the surface Pt content decreased, suggesting an increased CO-poisoning resistance. Linear sweep voltammograms of the solid solution electrodes in an Ar-saturated (1 M ethanol + 0.1 M HClO4) solution exhibited that the onset potentials of ethanol oxidation reaction (EOR) current for all solid solution electrodes were lower than of a Pt electrode, and Pt0.54Rh0.46 gave the highest specific activity (SA) of 312 μA·cm−2, which was about 1.8 and 2.5 times higher than the SAs of Pt and Rh, respectively. In situ infrared reflection-absorption spectra exhibited that the Pt0.54Rh0.46 electrode had the bands due to the linear-bonded CO on Pt and bridge-bonded CO on Rh as EOR intermediates around 0.2 V vs. the reversible hydrogen electrode, but the band due to the linear-bonded CO on Rh was not observed even at 0.6 V, suggesting that the existence of the adjacent Pt-Rh sites and the preferential formation of bridge-bonded CO on Rh accelerated the C-C bond cleavage and improved the EOR activity.

BackgroundAlthough anticoagulants are indicated for many elderly patients with non-valvular atrial fibrillation (NVAF), some patients do not receive anticoagulant therapy, whose characteristics and outcomes are diverse.Methods and resultsIn this sub-analysis of the All Nippon AF In the Elderly (ANAFIE) Registry, the phenotypes of patients who were not receiving anticoagulants at baseline were evaluated by cluster analysis using Ward's linkage hierarchical algorithm. Of 32,275 enrolled patients, 2445 (7.6%) were not receiving anticoagulants. Two clusters were identified: (1) elderly paroxysmal AF (PAF) patients with a high proportion of catheter ablation history (57%) and (2) very elderly patients with a high prevalence of previous major bleeding (43%). Respective mean ages were 80.9 and 84.2 years, mean CHA2DS2-VASc scores were 3.8 and 4.9, PAF prevalences were 100.0% and 31.4%, proportions of patients with catheter ablation history were 21.0% and 7.9%, and proportions of patients with a history of major bleeding were 4.0% and 10.8%. Annual incidence rates were 2.72% and 8.81% for all-cause death, 1.66% and 5.85% for major adverse cardiovascular or neurological events, 1.08% and 3.30% for stroke or systemic embolism, and 0.69% and 1.19% for major bleeding, respectively.ConclusionsIn this cohort of elderly NVAF patients from the ANAFIE Registry who were not receiving anticoagulants, over half had PAF with a high proportion of catheter ablation history and a low incidence of adverse outcomes; for them, non-prescription of anticoagulants may be partially understandable, but they should be carefully monitored regarding AF burden or atrial cardiomyopathy and be adequately anticoagulated when adverse findings are detected. The remaining were very elderly patients with a high prevalence of previous major bleeding and a high incidence of adverse outcomes; for them, non-prescription of anticoagulants is inappropriate because of the high thromboembolic risk.Trial registrationRegistration: http://www.umin.ac.jp/; Unique identifier: UMIN000024006.

Background This subcohort study of All Nippon AF In the Elderly (ANAFIE) Registry based on 33 275 elderly patients (aged ≥75 years) with non-valvular atrial fibrillation (NVAF) investigated the relationship between cognitive function and 2-year clinical outcomes.Methods A total of 2963 (mean age, 81.4 years) patients participated in this subcohort study and were classified as having normal cognition (Mini-Mental State Examination (MMSE) score ≥24/30) or cognitive impairment (score ≤23/30) at baseline. Patients with a decrease of >2 points after 24 months were classified as having cognitive decline.Results At baseline, 586 (19.8%) patients had cognitive impairment. These patients tended to be older and had poorer general conditions than patients with normal cognition. The 2-year probability of stroke/systemic embolic events (SEEs), major bleeding and intracranial haemorrhage was numerically higher; those of cardiovascular death, all-cause death and net clinical outcome (composite of stroke/SEE, major bleeding and all-cause death) were significantly higher (all p

Background: Although heart rate (HR) is reportedly associated with major cardiovascular outcomes in the general population, its impact on adverse events in patients with non-valvular atrial fibrillation (NVAF) remains controversial. Thus, we performed post hoc analyses of data from the J-RHYTHM Registry to clarify this in patients with NVAF. Results: Of 7406 outpatients with NVAF from 158 institutions, 6886 (age, 69.8 ± 9.9 years; men, 70.8%), in whom both baseline HR and HR-end (at the time closest to an event or at the last visit of follow-up) were measured during the two-year follow-up period or until the occurrence of an event, constituted the study group. The baseline HR and HR-end values were 72.5 ± 13.3 bpm and 73.3 ± 13.3 bpm, respectively. Thromboembolism, major hemorrhage, all-cause death, and cardiovascular death occurred in 117 (1.7%), 130 (1.9%), 157 (2.3%), and 58 (0.8%) patients, respectively. Baseline HR was not associated with any adverse event, whereas HR-end (per 1-bpm increase) was significantly associated with an increased incidence of all adverse events. Furthermore, the highest quartile of HR-end (≥80 bpm) was independently associated with the incidence of major hemorrhage (adjusted odds ratio [OR], 2.90; 95% confidence interval [CI], 1.69–4.96; P

Abstract Oral glucose ingestion induces systemic changes of many blood metabolites related not only to glucose, but also other metabolites such as amino acids and lipids through many blood hormones. However, the detailed temporal changes in the concentrations of comprehensive metabolites and hormones over a long time by oral glucose ingestion are uncharacterized. We measured 83 metabolites and 7 hormones in 20 healthy human subjects in response to glucose ingestion. We characterized temporal patterns of blood molecules by four features: (i) the decomposability into “amplitude” and “rate” components, (ii) the similarity of temporal patterns among individuals, (iii) the relation of molecules over time among individuals, and (iv) the similarity of temporal patterns among molecules. Glucose and glucose metabolism-related hormones indicated a rapid increase, and citrulline and lipids, which indicated a rapid decrease, returned to fasting levels faster than amino acids. Compared to glucose metabolism-related molecules and lipids, amino acids showed similar temporal patterns among individuals. The four features of temporal patterns of blood molecules by oral glucose ingestion characterize the differences among individuals and among molecules.

Abstract In the ANAFIE Registry home blood pressure subcohort, we evaluated 5204 patients aged ≥75 years with non‐valvular atrial fibrillation (NVAF) to assess blood pressure (BP) control, prevalence of masked hypertension, and anticoagulant use. Mean clinic (C) and home (H) systolic/diastolic BP(SBP/DBP) was 128.5/71.3 and 127.7/72.6 mm Hg, respectively. Overall, 77.5% of patients had hypertension; of these, 27.7%, 13.4%, 23.4%, and 35.6% had well‐controlled, white coat, masked, and sustained hypertension, respectively. Masked hypertension prevalence increased with diabetes, decreased renal function, age ≥80 years, current smoker status, and chronic obstructive pulmonary disease. By morning/evening average, 59.0% of patients had mean H‐SBP ≥ 125 mm Hg; 48.9% had mean C‐SBP ≥ 130 mm Hg. Early morning hypertension (morning H‐SBP ≥ 125 mm Hg) was found in 65.9% of patients. Although 51.1% of patients had well‐controlled C‐SBP, 52.5% of these had uncontrolled morning H‐SBP. In elderly NVAF patients, morning H‐BP was poorly controlled, and masked uncontrolled morning hypertension remains significant.

Background: Atrial fibrillation (AF) is a heterogeneous condition caused by various underlying disorders and comorbidities. A cluster analysis is a statistical technique that attempts to group populations by shared traits. Applied to AF, it could be useful in classifying the variables and complex presentations of AF into phenotypes of coherent, more tractable subpopulations. Objectives: This study aimed to characterize the clinical phenotypes of AF using a national AF patient registry using a cluster analysis. Methods: We used data of an observational cohort that included 7406 patients with non-valvular AF enrolled from 158 sites participating in a nationwide AF registry (J-RHYTHM). The endpoints analyzed were all-cause mortality, thromboembolisms, and major bleeding. Results: The optimal number of clusters was found to be 4 based on 40 characteristics. They were those with (1) a younger age and low rate of comorbidities (n = 1876), (2) a high rate of hypertension (n = 4579), (3) high bleeding risk (n = 302), and (4) prior coronary artery disease and other atherosclerotic comorbidities (n = 649). The patients in the younger/low comorbidity cluster demonstrated the lowest risk for all 3 endpoints. The atherosclerotic comorbidity cluster had significantly higher adjusted risks of total mortality (odds ratio [OR], 3.70; 95% confidence interval [CI], 2.37–5.80) and major bleeding (OR, 5.19; 95% CI, 2.58–10.9) than the younger/low comorbidity cluster. Conclusions: A cluster analysis identified 4 distinct groups of non-valvular AF patients with different clinical characteristics and outcomes. Awareness of these groupings may lead to a differentiated patient management for AF.

Ice cliffs can act as “hot spots” for melt on debris-covered glaciers and promote local glacier mass loss. Repeat high-resolution remote-sensing data are therefore required to monitor the role of ice cliff dynamics in glacier mass loss. Here we analyze high-resolution aerial photogrammetry data acquired during the 2007, 2018, and 2019 post-monsoon seasons to delineate and monitor the morphology, distribution, and temporal changes of the ice cliffs across the debris-covered Trakarding Glacier in the eastern Nepal Himalaya. We generate an ice cliff inventory from the 2018 and 2019 precise terrain data, with ice cliffs accounting for 4.7 and 6.1% of the debris-covered area, respectively. We observe large surface lowering (>2.0 m a−1) where there is a denser distribution of ice cliffs. We also track the survival, formation, and disappearance of ice cliffs from 2018 to 2019, and find that ∼15% of the total ice cliff area is replaced by new ice cliffs. Furthermore, we observe the overall predominance of northwest-facing ice cliffs, although we do observe spatial heterogeneities in the aspect variance of the ice cliffs (ice cliffs face in similar/various directions). Many new ice cliffs formed across the stagnant middle sections of the glacier, coincident with surface water drainage and englacial conduit intake observations. This spatial relationship between ice cliffs and the glacier hydrological system suggests that these englacial and supraglacial hydrological systems play a significant role in ice cliff formation.

Summary: Systemic metabolic homeostasis is regulated by inter-organ metabolic cycles involving multiple organs. Obesity impairs inter-organ metabolic cycles, resulting in metabolic diseases. The systemic landscape of dysregulated inter-organ metabolic cycles in obesity has yet to be explored. Here, we measured the transcriptome, proteome, and metabolome in the liver and skeletal muscle and the metabolome in blood of fasted wild-type and leptin-deficient obese (ob/ob) mice, identifying components with differential abundance and differential regulation in ob/ob mice. By constructing and evaluating the trans-omic network controlling the differences in metabolic reactions between fasted wild-type and ob/ob mice, we provided potential mechanisms of the obesity-associated dysfunctions of metabolic cycles between liver and skeletal muscle involving glucose-alanine, glucose-lactate, and ketone bodies. Our study revealed obesity-associated systemic pathological mechanisms of dysfunction of inter-organ metabolic cycles.

Objective To explore anticoagulant usage patterns stratified by stroke and bleeding risk in elderly patients with non-valvular atrial fibrillation (NVAF).Design Prospective, multicentre, observational cohort study.Setting The real-world All Nippon AF In the Elderly (ANAFIE) registry.Participants Japanese patients aged ≥75 years with NVAF (n=32 726).Outcome measures The distribution of stroke and bleeding risk scores, and the selection of anticoagulant regimen for patients at high stroke and bleeding risk.Results Overall, 18 185 (55.6%) patients had a high risk of stroke (CHADS2 score ≥3). Of these, 12 561 (38.4% of the total ANAFIE population) had a low bleeding risk (HAS-BLED ≤2) and 5624 (17.2%) had a high bleeding risk (HAS-BLED ≥3). Significant differences were noted between the high versus low bleeding risk groups in sex, height, weight, systolic blood pressure and rates of abnormality of lipid metabolism, gastrointestinal disease, cerebrovascular disorders, chronic kidney disease, angina pectoris, respiratory disease, primary malignant tumour, dementia and fall history within the past year (all p

Abstract Background Apixaban, a non‐vitamin K oral anticoagulant (NOAC), was approved in Japan in 2012 for the prevention of thromboembolic events in patients with nonvalvular atrial fibrillation (NVAF). However, the safety and effectiveness of apixaban in clinical practice have not yet been elucidated thoroughly among Japanese NVAF patients. Methods A postmarketing surveillance study was conducted to determine the safety and effectiveness of apixaban. Patients were followed‐up for 104 weeks. Outcome events included adverse drug reactions (ADRs), hemorrhages, and thromboembolic events (ischemic stroke, systemic embolism [SE], and transient ischemic attack [TIA]). Results Among 6306 NVAF patients in the safety analysis set (age, 74.5 ± 10.1 years; women, 41.1%; and CHADS2 score, 2.0 ± 1.4), 3600 patients (57.1%) received the standard dose (5 mg twice daily) and 2694 (42.7%) received a reduced dose (2.5 mg twice daily) of apixaban. ADRs occurred in 604 patients (9.58%), with the most common being epistaxis (0.86%), subcutaneous hemorrhage (0.67%), and hematuria (0.57%). Incidence rate of any hemorrhages and major hemorrhage was 5.52% per year and 2.36% per year, respectively. Incidence rate of ischemic stroke/SE/TIA was 1.00% per year among 6286 patients in the effectiveness analysis set. Among three subgroups (3106 apixaban initiators, 2038 patients switched from warfarin, and 1118 patients switched from other NOACs), incidence rates of major hemorrhage (P = 0.221 for trend) and ischemic stroke/SE/TIA (P = 0.686 for trend) were comparable. Conclusions No new safety signals of apixaban were identified in Japanese NVAF patients. Safety and effectiveness of apixaban were consistent with those in the ARISTOTLE study.

Abstract Aims/Introduction Non‐alcoholic steatohepatitis (NASH), which occurs in association with insulin resistance and hepatic fat accumulation, is characterized by chronic liver injury and fibrosis. NASH onset and progression is closely related to hepatic inflammation, which is partly regulated by the vagus nerve through the α7 nicotinic acetylcholine receptor (α7nAchR). Hepatic α7nAchR action is impeded in obesity and insulin resistance. In the present study, using α7nAchR knockout (α7KO) mice, we elucidated the effect of α7nAchR deficiency on NASH‐related inflammation and fibrosis. Materials and Methods α7KO mice were fed an atherogenic high‐fat diet (AD) for 32 weeks or methionine/choline‐deficient diet (MCD) for 6 weeks, both of which induce NASH. Mice were then examined for the degree of NASH‐related inflammation and fibrosis by hepatic gene expression analysis and Sirius red histological staining. Results Hepatic triglyceride accumulation and elevated plasma transaminase levels were observed in both AD and MCD mice, but the plasma transaminase level increase was higher in α7KO mice than in control mice. α7KO mice fed an AD showed significant upregulation of the Col1a1 gene encoding alpha‐1 type I collagen, which is involved in liver fibrosis, and the Ccl2 gene encoding C‐C motif chemokine ligand 2, a pro‐inflammatory chemokine; α7KO mice fed an MCD had significant upregulation of the Col1a1 gene and the Tnf gene, an inflammatory cytokine. Histological analysis showed that AD and MCD exacerbated liver fibrosis in α7KO mice. Conclusions The results of this study suggest that α7nAchR deficiency exacerbates hepatic inflammation and fibrosis in a diet‐induced mouse model of NASH.

Abstract Introduction Following approval of dabigatran and other antithrombotics in Japan, few studies have specifically evaluated the clinical characteristics of patients prescribed these antithrombotics for nonvalvular atrial fibrillation (NVAF) in real-world practice. Methods We conducted a descriptive analysis of data from two real-world studies [J-dabigatran surveillance and Japanese study on current Anticoagulation therapies for Patients with nonvalvular Atrial Fibrillation (JAPAF); conducted at sites common to both studies] to determine the characteristics of patients with NVAF initiated on dabigatran etexilate [110 mg twice daily (BID; DE110) or 150 mg BID (DE150)], warfarin, rivaroxaban, or antiplatelets as their first antithrombotic treatment. Inferential statistical analyses were not performed, and no statistical hypothesis was tested. Results Data for 1270 and 3011 eligible patients from the J-dabigatran surveillance (DE110, 976; DE150, 273) and JAPAF study (warfarin, 82.5%; rivaroxaban, 10.3%; antiplatelets, 21%), respectively, were extracted. In the J-dabigatran surveillance, 31.8% (full cohort, 28.1%) of patients had been switched from warfarin to dabigatran. Among patients prescribed DE110/DE150, 41.4%/57.5% and 41.5%/18.7% of patients had low-to-intermediate risk for ischemic stroke (CHADS2 score of 0 or 1) and high risk for bleeding (HAS-BLED score ≥ 3), respectively. Similarly, 33.7%/41.3%/40.2% and 48.7%/42.6%/75.7% of patients taking warfarin/rivaroxaban/antiplatelets had a CHADS2 score of 0 or 1 and HAS-BLED score ≥ 3, respectively. Dabigatran was favored in patients with creatinine clearance > 50 ml/min. Conclusions In Japan, physicians who attempt stroke prevention in patients with atrial fibrillation choose appropriate anticoagulant treatment, taking into consideration the individual patient backgrounds as well as the features of each antithrombotic agent. Trial Registration ClinicalTrials.gov Identifier, NCT01491178 and University Hospital Medical Information Network (UMIN) Clinical Trial Registry Identifier, UMIN000009644. Funding Nippon Boehringer Ingelheim Co., Ltd. Plain Language Summary Plain language summary available for this article.

Background: Based on the results of the PACIFIC study, chemoradiotherapy followed by 1-year consolidation therapy with durvalumab was established as the standard of care for unresectable, locally advanced non-small-cell lung cancer (LA-NSCLC). However, some topics not foreseen in that design can be explored, including progression-free survival (PFS) and overall survival (OS) after the start of chemoradiotherapy, the proportion of patients who proceeded to consolidation therapy with durvalumab, and the optimal chemotherapeutic regimens. In Japan, the combination regimen of S-1 + cisplatin (SP), for which the results of multiple clinical studies have suggested a good balance of efficacy and tolerability, is frequently selected in clinical settings. However, the efficacy and safety of consolidation therapy with durvalumab following this SP regimen have not been evaluated. We therefore planned a multicenter, prospective, single-arm, phase II study. Methods: In treatment-naïve LA-NSCLC, two cycles of combination chemotherapy with S-1 (80–120 mg/body, Days 1–14) + cisplatin (60 mg/m 2 , Day 1) will be administered at an interval of 4 weeks, with concurrent thoracic radiotherapy (60 Gy). Responders will then receive durvalumab every 2 weeks for up to 1 year. The primary endpoint is 1-year PFS rate. Discussion: Compared with the conventional standard regimen in Japan, the SP regimen is expected to be associated with lower incidences of pneumonitis, esophagitis, and febrile neutropenia, which complicate the initiation of consolidation therapy with durvalumab, and have higher antitumor efficacy during chemoradiotherapy. Therefore, SP-based chemoradiotherapy is expected to be successfully followed by consolidation therapy with durvalumab in more patients, resulting in prolonged PFS and OS. Toxicity and efficacy results of the SP regimen in this study will also provide information important to the future establishment of the concurrent combination of chemoradiotherapy and durvalumab. Trial registration: Japan Registry of Clinical Trials, jRCTs031190127, registered 1 November 2019, https://jrct.niph.go.jp/latest-detail/jRCTs031190127

Loss-of-function mutation of the MILDEW RESISTANCE LOCUS O (Mlo) gene confers durable and broad-spectrum resistance to powdery mildew fungi in various plants, including barley. In combination with the intracellular nucleotide-binding domain and leucine-rich repeat receptor (NLR) genes, which confer the race-specific resistance, the mlo alleles have long been used in barley breeding as genetic resources that confer robust non-race-specific resistance. However, a Japanese Blumeria graminis f. sp. hordei isolate, RACE1, has been reported to have the potential to overcome partially the mlo-mediated penetration resistance, although this is yet uncertain because the putative effects of NLR genes in the tested accessions have not been ruled out. In this study, we examined the reproducibility of the earlier report and found that the infectious ability of RACE1, which partially overcomes the mlo-mediated resistance, is only exerted in the absence of NLR genes recognizing RACE1. Furthermore, using the transient-induced gene silencing technique, we demonstrated that RACE1 can partially overcome the resistance in the host cells with suppressed MLO expression but not in plants possessing the null mutant allele mlo-5.

Background Blood pressure (BP) variability has reportedly been a risk factor for various clinical events. To clarify the influence of BP visit‐to‐visit variability on adverse events in patients with nonvalvular atrial fibrillation, a post hoc analysis of the J‐RHYTHM Registry was performed. Methods and Results Of 7406 outpatients with nonvalvular atrial fibrillation from 158 institutions, 7226 (age, 69.7±9.9 years; men, 70.7%), in whom BP was measured 4 times or more (14.6±5.0 times) during the 2‐year follow‐up period or until occurrence of an event, constituted the study group. SD and coefficient of variation of BP values were calculated as BP variability. Thromboembolism, major hemorrhage, and all‐cause death occurred in 110 (1.5%), 121 (1.7%), and 168 (2.3%) patients, respectively. When patients were divided into quartiles of systolic BP‐SD (

Background: The association between right ventricular function and exercise capacity in patients with chronic heart failure remains uncertain. Several studies very recently mentioned the association between right ventricular reserve and exercise capacity, whereas the implication of tricuspid annular plane systolic excursion (TAPSE) remains uninvestigated. We aimed to assess the impact of TAPSE on exercise capacity in cardiac rehabilitation candidates. Methods: Data from patients with chronic heart failure who received cardiopulmonary exercise tests and transthoracic echocardiography prior to cardiac rehabilitation were retrospectively collected, and their association was investigated. Results: A total of 169 patients with chronic heart failure (70.3 ± 11.7 years old, 74.6% men) were included. Tertiled tricuspid annular plane systolic excursion significantly stratified anaerobic threshold (10.2 ± 2.2, 11.4 ± 2.2, and 12.2 ± 2.8 mm; p < 0.01) and peak oxygen consumption (15.9 ± 4.5, 18.3 ± 5.3, and 19.8 ± 5.6 mm; p < 0.01). In the multivariate logistic regression analyses, TAPSE was an independent factor associated with anaerobic threshold and peak oxygen consumption (p < 0.05 for both). Conclusions: Right ventricular impairment was associated with reduced exercise capacity in patients with chronic heart failure. Such knowledge would be useful to estimate patients’ exercise capacity and prescribe cardiac rehabilitation. Its longitudinal association and clinical implication need further studies.

Background: Renal impairment is a risk factor for various adverse events, especially for death. In general, creatinine clearance (CrCl) is used for dose-adjustments of many drugs including oral anticoagulants, and estimated glomerular filtration rate (eGFR) is adopted for the diagnosis of chronic kidney disease. Predictive ability of CrCl versus eGFR for outcomes in patients with non-valvular atrial fibrillation (NVAF) remains controversial; therefore, this was compared using data from the J-RHYTHM Registry. Methods: Out of 7406 outpatients with NVAF from 158 institutions, 6004 (age, 69.7 ± 9.9 years; men, 71.2%) having data of CrCl (mL/min, by the Cockcroft-Gault formula), eGFR (mL/min/1.73 m2, by the equations of the Japanese Society of Nephrology), and body surface area (BSA) were analyzed. C-statistics (area under the receiver-operating characteristic curve) of CrCl and eGFR for events were compared by DeLong's test. Results: Thromboembolism, major hemorrhage, and all-cause death occurred in 107 (1.8%), 117 (1.9%), and 154 (2.6%) patients during the 2-year follow-up period. C-statistics of CrCl for each event were 0.609 (95% confidence interval, 0.559–0.658), 0.599 (0.548–0.657), and 0.746 (0.706–0.786); and those of eGFR were 0.542 (0.487–0.597), 0.573 (0.519–0.626), and 0.677 (0.631–0.723), respectively. C-statistics of CrCl for thromboembolism and all-cause death were significantly higher than those of eGFR (P

Cryptococcus is a mycosis founded in immunocompromised patients. Cryptococcus in the oral cavity is rare and skeletal infection is uncommon.We report the case of a 31-year-old man in whom cellulitis developed due to infection after tooth extraction complicated by acute myeloid leukemia (AML). Cellulitis of the left mandible did not improve after conservative therapy, including antimicrobial therapy, because of AML and chemotherapy, and gas was generated in the left cervical and supraclavicular regions. We considered the infection symptoms to be life-threatening, and surgery was performed for the infection of the head and neck under poor general conditions. As histopathological examination of the removed tissue revealed cryptococcus, antifungal agents were administered for cryptococcal infection. The surgical site healed after the operation.Surgical treatment, including debridement and drainage, should be avoided for patients with a poor general condition caused by AML and chemotherapy. However, the detection of Cryptococcus in the surgical site in such a condition is important. Keywords: Cryptococcus, Acute myeloid leukemia, Skeletal infection

The real-world status of proton pump inhibitor (PPI) use in patients with atrial fibrillation (AF) receiving antithrombotic treatment is largely unknown. The All Nippon AF In the Elderly (ANAFIE) Registry, a prospective, multicenter, observational study, aimed to determine treatment patterns, risk factors, and outcomes among elderly (aged ≥75 years) Japanese non-valvular AF (NVAF) patients in the real-world clinical setting. The present subanalysis of the ANAFIE Registry determined the PPI prescription status of 32,490 elderly Japanese NVAF patients. Patients were stratified by PPI use (PPI+) or no PPI use (PPI-). Risk scores for stroke (CHADS2, CHA2DS2-VASc) and bleeding (HAS-BLED), anticoagulant use, time in therapeutic range (TTR) for warfarin, and anticoagulant/antiplatelet combination use were evaluated. PPIs were used in 11,981 (36.9%) patients. Compared with the PPI- group, the PPI+ group included a greater proportion of female patients (45.2% vs 41.3%; P

Hemoptysis is sometimes observed in lung cancer patients and can be life-threatening. We present a case with severe hemoptysis that was resolved by bronchial artery embolization (BAE) followed by surgery. The presence of necrotic tissue in the majority of the resected tumor and only few cancer cells was presumed to be from loss of bronchial artery blood flow. Although BAE is not a standard therapy for lung cancer, it can be useful and may be considered by physicians as one of the treatment options prior to surgical resection in cases with hemoptysis.

During diabetes, postprandial hyperglycemia is caused by impaired glucose uptake. Here, Watanabe and colleagues show that impaired hepatic glucose uptake during obesity is caused by a reduction in Sirt2 activity, which promotes glucokinase regulatory protein acetylation and its dissociation from glucokinase.

Background: Smoking is a risk factor for cardiovascular diseases, but it is unclear whether smoking status, including environmental tobacco smoke, increases stroke risk in patients with atrial fibrillation (AF). Abnormalities of the left atrium (LA) and aortic atherosclerosis, as detected by transesophageal echocardiography (TEE), are risk factors for stroke and thromboembolism in AF patients. We investigated the impact of smoking status on thromboembolic risk by TEE in patients with nonvalvular AF. Methods: In 122 patients with AF (mean age, 63 years; chronic AF 50%) who underwent TEE before catheter ablation of AF or for detection of the potential cardioembolic source, urinary concentrations of cotinine and clinical variables including smoking status and the CHA2DS2-VASc score were determined. Results: Severe aortic atherosclerosis and increased aortic wall thickness were more frequently detected by TEE in current smokers than in non-smokers (p

Nicotinamide mononucleotide (NMN), a precursor of nicotinamide adenine dinucleotide (NAD), induces disease resistance to the Fusarium head blight fungus Fusarium graminearum in Arabidopsis and barley, but it is unknown at which stage of the infection it acts. Since the rate of haustorial formation of an obligate biotrophic barley powdery mildew fungus Blumeria graminis f. sp. hordei (Bgh) was significantly reduced in NMN-treated coleoptile epidermal cells, the possibility that NMN induces resistance to the biotrophic stage of F. graminearum was investigated. The results show that NMN treatment caused the wandering of hyphal growth and suppressed the formation of appressoria-like structures. Furthermore, we developed an experimental system to monitor the early stage of infection in real-time and analyzed the infection behavior. We observed that the hyphae elongated windingly by NMN treatment. These results suggest that NMN potentiates resistance to the biotrophic invasion of F. graminearum as well as Bgh.

Abstract Background Easier to perform than the conventional procedure, mini-tracheostomy (MT) is widely used in the operating room or intensive care unit to remove sputum or other obstructions of the upper airway. This option, however, does carry the risk of various complications, including malposition, disposition, bleeding, and subcutaneous emphysema. Here, we report a case of endotracheal tube obstruction due to a massive clot resulting from late bleeding around the insertion site of an MT tube. This necessitated removal of the endotracheal tube together with the clot followed tube re-introduction. Case presentation The patient was an 85-year-old man in whom an MT tube had been inserted 6 days earlier following aortic replacement surgery. On re-admittance to our intensive care unit, large amounts of hemosputum and clotting were observed around the insertion site of the tube. The MT tube was subsequently removed and tracheal intubation performed. Ventilation via the endotracheal tube proved impossible, however, and cardiac arrest ensued. Fiberoptic bronchoscopy revealed that the endotracheal tube was completely obstructed by a massive clot. Therefore, we immediately pushed the clot toward the right main bronchus to secure ventilation via the left lung. After many attempts to remove the massive clot, including suction and grasping with basket forceps, it was successfully dislodged by replacing the endotracheal tube with a new one while maintaining oxygenation by one-lung ventilation. Any small fragments of the clot that still remained were then removed by suction under fiberoptic bronchoscopy. Conclusions Here, we report a case of endotracheal tube obstruction due to a clot derived from very late (6 days) bleeding after insertion of an MT tube. The patient was successfully rescued by replacing the clot-bearing endotracheal tube with a new one. This experience suggests that the intensive care physician should be aware of the potential risk of clot retention in endotracheal tubes after the elapse of several days.

GCN5 inhibits hepatic gluconeogenesis through acetylation of PGC-1α. Here the authors show that GCN5 also activates hepatic gluconeogenesis by acetylating histone H3K9, and that the affinity of GCN5 for its different substrates is regulated via phosphorylation at S275 by PKA in a CITED2-dependent manner.

A couple of toluene (TL) and its hydrogenation product, methylcyclohexane (MCH), are promising high-density hydrogen carriers to store and transport large amounts of hydrogen. Electrochemical hydrogenation of TL to MCH can achieve energy savings compared with hydrogenation using molecular hydrogen generated separately, and development of highly active catalysts for electrochemical TL hydrogenation is indispensable. In this study, binary Pt3M (M = Rh, Au, Pd, Ir, Cu and Ni) alloy nanoparticle-loaded carbon catalysts were prepared by a colloidal method, and their activity for electrochemical TL hydrogenation was evaluated by linear sweep voltammetry. Each Pt3M electrode was initially activated by 100 cycles of potential sweep over a potential range of 0–1.2 or 0.8 V vs. reversible hydrogen electrode (RHE). For all activated Pt3M electrodes, the cathodic current density for electrochemical TL hydrogenation was observed above 0 V, that is the standard potential of hydrogen evolution reaction. Both specific activity, cathodic current density per electrochemical surface area, and mass activity, cathodic current density per mass of Pt3M, at 0 V for the Pt3Rh/C electrode were the highest, and about 8- and 1.2-times as high as those of the commercial Pt/C electrode, respectively, which could mainly be attributed to electronic modification of Pt by alloying with Rh. The Tafel slope for each activated Pt3M/C electrode exhibited the alloying of Pt with the second metals did not change the electrochemical TL hydrogenation mechanism.

To further develop barley breeding and genetics, more information on gene functions based on the analysis of the mutants of each gene is needed. However, the mutant resources are not as well developed as the model plants, such as Arabidopsis and rice. Although genome editing techniques have been able to generate mutants, it is not yet an effective method as it can only be used to transform a limited number of cultivars. Here, we developed a mutant population using ‘Mannenboshi’, which produces good quality grains with high yields but is susceptible to disease, to establish a Targeting Induced Local Lesions IN Genomes (TILLING) system that can isolate mutants in a high-throughput manner. To evaluate the availability of the prepared 8043 M3 lines, we investigated the frequency of mutant occurrence using a rapid, visually detectable waxy phenotype as an indicator. Four mutants were isolated and single nucleotide polymorphisms (SNPs) were identified in the Waxy gene as novel alleles. It was confirmed that the mutations could be easily detected using the mismatch endonuclease CELI, revealing that a sufficient number of mutants could be rapidly isolated from our TILLING population.

Background/aim: A post-marketing surveillance (PMS) study is being conducted to investigate the safety and effectiveness of the long-term use of dabigatran etexilate (dabigatran) in Japanese patients with nonvalvular atrial fibrillation (NVAF). Results of an interim analysis of this prospective cohort study including patient characteristics and adverse drug reactions (ADRs) collected up to September 17, 2014 are reported here. Methods: Patients with NVAF who began to receive dabigatran for the first time from December 2011 to November 2013 were enrolled at 1042 study sites in Japan. Clinical parameters included patient characteristics, dabigatran dose strength, concomitant medications and outcome events. All outcome events were collected as serious and non-serious adverse events (AEs). ADRs were evaluated in this report. Pre-defined safety events of special interest for intensive survey were serious and non-serious outcome events such as myocardial infarction, as well as the total number of hemorrhage and gastrointestinal disorders. Results: A total of 6772 patients were registered. The safety analysis set included 6148 patients; mean age was 70.8±9.9 (SD) years: 2323 patients (37.8%) were aged 75 years or older. Males accounted for 66.8% of the patients. Mean CHADS2 score was 1.8±1.3; the CHADS2 score was 0 in 13.6%, 1 in 31.3%, 2 in 25.9%, 3 in 14.9%, and 4 to 6 in 11.1% of the patients. Of the 6148 patients, 1701 patients (27.7%) were switchers from warfarin and 4407 patients (71.7%) were non-switchers (OAC naïve patients). Treatment adherence was assessed for the first 3 months from the start of treatment for this analysis. Total 5656 patients (92.0%) reported taking dabigatran twice daily (bid) every day according to the label recommendation. During the follow up period [mean duration of follow up: 498±259 days (corresponding to 8386 patient-years)], pre-defined safety events of special interest for intensive survey (reported as serious ADRs) were: myocardial infarction, reported in 5 patients (0.06 per 100 patient-years); serious hemorrhage, reported in 46 patients (0.55 per 100 patient-years); and gastrointestinal disorders (non-hemorrhagic), reported in 11 patients (0.13 per 100 patient-years). Fifteen patients had ADRs with fatal outcome. Conclusions: The interim findings from this 6148 patient PMS study further corroborate the favorable safety profile of dabigatran as demonstrated previously in controlled clinical trials. (ClinicalTrials.gov number, NCT01491178.)

Central insulin action activates hepatic IL-6/STAT3 signaling, which suppresses the gene expression of hepatic gluconeogenic enzymes. The vagus nerve plays an important role in this centrally mediated hepatic response; however, the precise mechanism underlying this brain-liver interaction is unclear. Here, we present our findings that the vagus nerve suppresses hepatic IL-6/STAT3 signaling via α7-nicotinic acetylcholine receptors (α7-nAchR) on Kupffer cells, and that central insulin action activates hepatic IL-6/STAT3 signaling by suppressing vagal activity. Indeed, central insulin-mediated hepatic IL-6/STAT3 activation and gluconeogenic gene suppression were impeded in mice with hepatic vagotomy, pharmacological cholinergic blockade, or α7-nAchR deficiency. In high-fat diet-induced obese and insulin-resistant mice, control of the vagus nerve by central insulin action was disturbed, inducing a persistent increase of inflammatory cytokines. These findings suggest that dysregulation of the α7-nAchR-mediated control of Kupffer cells by central insulin action may affect the pathogenesis of chronic hepatic inflammation in obesity.

Sigmoid-shaped interventricular septum (SIS) is not uncommon in elderly patients and is considered a normal part of the aging process. However, several patients have been reported to have clinical symptoms due to the narrowing of the left ventricular outflow tract (LVOT). Two patients with SIS presented with recurrent episodes of syncope after drinking or taking sublingual nitroglycerin (NG). In both patients, a head-up tilt test involving provocation with alcohol, NG, or isoproterenol induced the vasovagal reflex along with an increase in the pressure gradient between the apex and LVOT. The patients experienced no further episodes of syncope after initiating bisoprolol treatment. In patients with SIS, induction of the vasovagal reflex via an increase in left ventricular (LV) pressure due to LVOT obstruction concomitant with increased LV construction is a potentially important cause of syncope, which may be effectively prevented by beta-blockers.

High humidity decreases the penetration rate of barley powdery mildew Blumeria graminis f. sp. hordei. However, the mechanism is not well understood. In this study, the morphological and cytochemical analyses revealed that substances containing proteins leaked from the tip of the appressorial germ tube of conidia without the formation of appressorium under a high humidity condition. In addition, exposure to high humidity prior to the formation of appressorium caused the aberrant formation of the appressorial germ tube without appressorium formation, resulting in failure to penetrate the host cell. These findings suggest that the formation and maturation of the appressorium requires a low humidity condition, and will be clues to improve the disease management by humidity control.

A sequence {φn} in a Hilbert space H with inner product is called a generalized Riesz system if there exist an ONB e={en} in H and a densely defined closed operator T in H with densely defined inverse such that {en}⊂D(T)∩D((T-1)⁎) and Ten=φn, n=0,1,⋯, and (e,T) is called a constructing pair for {φn} and T is called a constructing operator for {φn}. The main purpose of this paper is to investigate under what conditions the ordered set Cφ of all constructing operators for a generalized Riesz system {φn} has maximal elements, minimal elements, the largest element, and the smallest element in order to find constructing operators fitting to each of the physical applications.

Pd crystals enclosed by (100) facets were prepared in an aqueous solution containing cetyltrimethylammonium bromide (CTAB) as the capping agent and ascorbic acid as the reducing agent at 30, 40, and 50°C by a modified seed-mediated fabrication technique. Regardless of the reaction temperature, the absorption peak between 300 and 400 nm assigned to PdCl42- decreased with an increase in the reaction time after the addition of ascorbic acid in the PdCl42- aqueous solution containing CTAB because of Pd deposition. The field emission-scanning electron microscopy images showed that the Pd crystals were enclosed by only (100) facets, and their fractions depended on the reaction temperature. The ratios of the peak current at 0.54 and 0.48 V were 0.60, 0.54, and 0.47 for the samples prepared at 30, 40, and 50°C, respectively, suggesting that the proportion of the (100) facet on the Pd surface was higher at lower temperatures.

The consumption of soybean protein has well-known favorable metabolic effects (e.g., reduced body weight, body fat, hyperglycemia, insulin resistance, hepatic steatosis, and lipogenesis). These effects of soy protein have been linked to modulation by the gut microbiota; however, the dynamic interplay among these factors remains unclear. Accordingly, we examined the metabolic phenotype, intestinal BA pool, and the gut microbiome of male C57BL/6 mice that were randomized to receive either a regular high-fat diet (HFD) or HFD that contained soybean protein isolate (SPI) in place of dairy protein. The intake of SPI significantly reduced the HFD-induced weight gain and adipose tissue mass accumulation and attenuated hepatic steatosis. Along with an enhancement in the secretion of intestinal Glucagon-like peptide-1 (GLP-1), an enlarged cecal BA pool with an elevated secondary/primary BA ratio was observed in the mice that consumed SPI, while fecal BA excretion remained unaltered. SPI also elicited dramatic changes in the gut microbiome, characterized by an expansion of taxa that may be involved in the biotransformation of BAs. The observed effects were abolished in germ-free (GF) mice, indicating that they were dependent on the microbiota. These findings collectively indicate that the metabolic benefits of SPI under the HFD regime may arise from a microbiota-driven increase in BA transformation and increase in GLP-1 secretion.

Pd core nanoparticles less than 5 nm in mean size were prepared on carbon black (CB) without any stabilizer by using palladium acetate as a precursor and CO as a reducing agent, and then used for preparing Pd core/Pt shell nanoparticles-loaded CB (Pt/Pd/CB). The mean size of Pd nanoparticles could be controlled by the concentration of palladium acetate and the CO bubbling time. The cyclic voltammograms of two Pd nanoparticles-loaded CB (Pd4.2/CB, Pd3.3/CB) electrodes whose mean size was 4.2 and 3.3 nm, respectively, had characteristics similar to a Pt electrode after the formation of a Pt monolayer shell, suggesting that the Pd core nanoparticles were almost covered with the Pt monolayer shell. The oxygen reduction reaction (ORR) on both Pt/Pd/CB proceeded in 4-electron reduction mechanism. Both Pt/Pd/CB electrodes was ca. 1.5 times higher in ORR activity per electrochemical surface area of Pt (specific activity, SA) than the commercial Pt nanoparticles-loaded CB (Tanaka Kikinzoku Kogyo, Pt/CB-TKK) electrode, and the Pt/Pd3.3/CB electrode had higher SA than the Pt/Pd4.2/CB electrode. The ORR activity per unit mass of Pt for both Pt/Pd/CB electrodes was 5.0 and 5.5 times as high as that for the Pt/CB-TKK electrode, respectively. The durability of both Pt/Pd/CB electrodes was comparable to that of Pt/CB-TKK.