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Background: Molecular-targeted drugs and immune checkpoint inhibitors have been developed for various malignant diseases, thereby improving clinical outcomes. However, these drugs are expensive, and few studies have assessed their actual use and costs in Japan. This study aimed to survey the use and costs of first-line chemotherapy for advanced/recurrent gastric cancer (AGC) in real-world settings., Methods: The survey included patients with human epidermal growth factor receptor type2 (HER2)-negative AGC who initiated first-line chemotherapy from January 2022 to December 2022 at the participating 92 institutions in the Japan Clinical Oncology Group. Data on the regimens were collected using Google Forms. A regimen that costs >500 000 Japanese yen (JPY) per month was defined as expensive., Results: Data on chemotherapy regimens were collected from 2173 patients at all 92 institutions between March 2023 and May 2023. We analyzed 2113 patients who underwent the chemotherapy with recommended regimens and conditionally recommended regimens according to the Japanese Gastric Cancer Treatment Guidelines sixth edition. The expensive regimens were triplet chemotherapy with fluoropyrimidine (S-1 or capecitabine or 5-fluorouracil/levofolinate), oxaliplatin, and nivolumab. Their monthly costs ranged from 767 648 to 771 046 JPY. Nivolumab-containing regimens cost more than 20 times the price of conventional chemotherapy with fluoropyrimidine and oxaliplatin. These regimens were used in 1416 (67%) of 2113 patients: in 71% of patients aged ≤74 years and in 59% of patients aged ≥75 years., Conclusion: The regimens with >20-fold cost of conventional chemotherapy were used as first-line chemotherapy in two-thirds of patients and more than half even in the elderly population with HER2-negative AGC. This finding is important for future health economic studies on drug cost-efficacy., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: No efficient treatment has yet been established for epidermolytic ichthyosis (EI), which is caused by pathogenic variants of KRT1 or KRT10. Patients with ichthyosis with confetti (IWC) have multiple normal-appearing spots, caused by the revertant somatic recombination of pathogenic variants that occurs at each spot independently. Additionally, some patients with EI have large areas of normal skin due to revertant postzygotic mosaicism., Objectives: To assess the feasibility of transplanting cultured epidermal autografts (CEAs) produced from revertant epidermal keratinocytes in patients with EI and IWC., Methods: We performed a clinical trial of treatment with CEAs produced from each patient's own revertant epidermal keratinocytes as a proof-of-concept study. This was a single-arm, open, unmasked, uncontrolled, single-assignment, treatment-purpose study. The primary outcome was the percentage area that lacked recurrence of ichthyosis lesions 4 weeks after the final transplant. The secondary outcome was the percentage area lacking recurrence of ichthyosis lesions 24 weeks after the initial transplantation. The trial was registered with the Japan Registry of Clinical Trials (jRCTb041190097)., Results: We successfully produced CEAs from genetically confirmed revertant skin from two patients with mosaic EI and from one patient with IWC and confirmed by amplicon sequencing and droplet digital polymerase chain reaction analysis that the CEAs mainly consisted of revertant wild-type cells. Single-cell RNA sequencing analysis confirmed the normal proliferation and safety profiling of CEAs. CEAs were transplanted onto desquamated lesional sites in the patients. Four weeks post-transplantation, the percentage area lacking recurrence of ichthyosis lesions in the three patients was 40%, 100% and 100% respectively, although recurrence of ichthyosis lesions was seen at the site of CEA transplantation in all three patients at 24 weeks post-transplantation., Conclusions: CEAs from normal skin have the potential to be a safe and local treatment option for EI and IWC., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Study Objectives: Light information crucially influences sleep initiation and continuity. The purpose of this study was to compare daily light exposure between patients with Parkinson's disease (PD) and non-PD older adults and evaluate the association of daily light exposure with objective sleep measures in patients with PD., Methods: In this cross-sectional study of 189 outpatients with PD and 1101 community-dwelling older adults (controls), daily light exposure was measured using wrist light meters during the daytime and light meters set in the bedrooms during the nighttime, and objective sleep quality was measured by wrist actigraphy., Results: The median duration of exposure to ≥ 1000 lux light was significantly shorter in patients with PD than in controls. The median nighttime light intensity was higher in patients with PD than in controls. Among patients with PD, multivariable analysis suggested that the highest quartile of exposure to ≥ 1000 lux light during the daytime was linked to significantly higher sleep efficiency (SE) by 8.0% and shorter wake after sleep onset (WASO) by 36.9 minutes than the lowest quartile. During the nighttime, the highest quartile of mean light intensity had significantly lower SE by 6.8%, longer WASO by 24.1 minutes, longer sleep onset latency, and higher fragmentation index, than the lowest quartile. Importantly, daytime and nighttime light levels were independently associated with objective sleep measures., Conclusions: The present study illustrated that greater daytime light exposure and lower nighttime light exposure are significantly associated with better objective sleep measures in patients with PD., (© The Author(s) 2024. Published by Oxford University Press on behalf of Sleep Research Society.)

Treatment strategies for oesophagogastric junction adenocarcinoma have not been standardized despite its poor prognosis due to differences in the incidence rates between Western countries and Asia. This randomized Phase II/III trial was initiated in June 2023 to determine which neoadjuvant chemotherapy regimen, docetaxel, oxaliplatin and S-1 or fluorouracil, oxaliplatin and docetaxel, is a more promising treatment in Phase II and confirm the superiority of neoadjuvant chemotherapy with docetaxel, oxaliplatin and S-1 or fluorouracil, oxaliplatin and docetaxel followed by surgery and postoperative chemotherapy over upfront surgery and postoperative chemotherapy in terms of overall survival in patients with Clinical Stage III or IVA oesophagogastric junction adenocarcinoma in Phase III. A total of 460 patients, including 150 patients in Phase II and 310 patients in Phase III, are planned to be enrolled from 85 hospitals in Japan over 5 years. This trial has been registered in the Japan Registry of Clinical Trials as jRCTs031230182 (https://jrct.niph.go.jp/latest-detail/jRCTs031230182)., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Genetic modification of specific genes is emerging as a useful tool to enhance the functions of antitumor T cells in adoptive immunotherapy. Current advances in CRISPR/Cas9 technology enable gene knockout during in vitro preparation of infused T-cell products through transient transfection of a Cas9-guide RNA (gRNA) ribonucleoprotein complex. However, selecting optimal gRNAs remains a major challenge for efficient gene ablation. Although multiple in silico tools to predict the targeting efficiency have been developed, their performance has not been validated in cultured human T cells. Here, we explored a strategy to select optimal gRNAs using our pooled data on CRISPR/Cas9-mediated gene knockout in human T cells. The currently available prediction tools alone were insufficient to accurately predict the indel percentage in T cells. We used data on the epigenetic profiles of cultured T cells obtained from transposase-accessible chromatin with high-throughput sequencing (ATAC-seq). Combining the epigenetic information with sequence-based prediction tools significantly improved the gene-editing efficiency. We further demonstrate that epigenetically closed regions can be targeted by designing two gRNAs in adjacent regions. Finally, we demonstrate that the gene-editing efficiency of unstimulated T cells can be enhanced through pretreatment with IL-7. These findings enable more efficient gene editing in human T cells., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Translocation of gut bacteria into the pancreas promotes the development of severe acute pancreatitis (SAP). Recent clinical studies have also highlighted the association between fungal infections and SAP. The sensing of gut bacteria by pattern recognition receptors promotes the development of SAP via the production of proinflammatory cytokines; however, the mechanism by which gut fungi mediate SAP remains largely unknown. Leucine-rich repeat kinase 2 (LRRK2) is a multifunctional protein that regulates innate immunity against fungi via Dectin-1 activation. Here, we investigated the role of LRRK2 in SAP development and observed that administration of LRRK2 inhibitors attenuated SAP development. The degree of SAP was greater in Lrrk2 transgenic (Tg) mice than in control mice and was accompanied by an increased production of nuclear factor-kappaB-dependent proinflammatory cytokines. Ablation of the fungal mycobiome by anti-fungal drugs inhibited SAP development in Lrrk2 Tg mice, whereas the degree of SAP was comparable in Lrrk2 Tg mice with or without gut sterilization by a broad range of antibiotics. Pancreatic mononuclear cells from Lrrk2 Tg mice produced large amounts of IL-6 and TNF-α upon stimulation with Dectin-1 ligands, and inhibition of the Dectin-1 pathway by a spleen tyrosine kinase inhibitor protected Lrrk2 Tg mice from SAP. These data indicate that LRRK2 activation is involved in the development of SAP through proinflammatory cytokine responses upon fungal exposure., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Immunology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Mpox virus (MPXV) is a zoonotic orthopoxvirus and caused an outbreak in 2022. Although tecovirimat and brincidofovir are approved as anti-smallpox drugs, their effects in mpox patients have not been well documented. In this study, by a drug repurposing approach, we identified potential drug candidates for treating mpox and predicted their clinical impacts by mathematical modeling., Methods: We screened 132 approved drugs using an MPXV infection cell system. We quantified antiviral activities of potential drug candidates by measuring intracellular viral DNA and analyzed the modes of action by time-of-addition assay and electron microscopic analysis. We further predicted the efficacy of drugs under clinical concentrations by mathematical simulation and examined combination treatment., Results: Atovaquone, mefloquine, and molnupiravir exhibited anti-MPXV activity, with 50% inhibitory concentrations of 0.51-5.2 μM, which was more potent than cidofovir. Whereas mefloquine was suggested to inhibit viral entry, atovaquone and molnupiravir targeted postentry processes. Atovaquone was suggested to exert its activity through inhibiting dihydroorotate dehydrogenase. Combining atovaquone with tecovirimat enhanced the anti-MPXV effect of tecovirimat. Quantitative mathematical simulations predicted that atovaquone can promote viral clearance in patients by 7 days at clinically relevant drug concentrations., Conclusions: These data suggest that atovaquone would be a potential candidate for treating mpox., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Endogenous DNA is released into the bloodstream as cell-free DNA (cfDNA) following cell death and is associated with various pathological conditions. However, their association with therapeutic drugs against rheumatoid arthritis (RA) remains unknown. Therefore, we investigated the significance of cfDNA in RA treated with tocilizumab and tumour necrosis factor inhibitor (TNF-I). Biological DMARDs (bDMARDs), including tocilizumab and TNF-I, were administered to 77 and 59 RA patients, respectively. Plasma cfDNA levels were measured at weeks 0, 4, and 12 by quantitative polymerase chain reaction. Disease activity was evaluated at the same time point using DAS28ESR. cfDNA levels from RA synovial cells treated with tocilizumab or etanercept for 24 h were measured. Human toll-like receptor 9 (hTLR9)-expressing HEK293 cells, which release secreted embryonic alkaline phosphatase (SEAP) upon NF-κB activation, were stimulated by cfDNA from RA patients, and subsequently, SEAP levels were determined. NF-κB translocation was evaluated by immunofluorescence staining with or without tocilizumab. The DAS28ESR significantly improved in both bDMARD groups at week 12. However, plasma cfDNA levels significantly decreased in the tocilizumab group at week 12 compared to that in week 0. cfDNA levels correlated with DAS28ESR in biological treatment-naïve patients administered tocilizumab. cfDNA levels in synovial cells were significantly suppressed by tocilizumab treatment and unaltered with etanercept. HEK293 cells released SEAP upon cfDNA stimulation, and the observed NF-κB nuclear translocation was suppressed by tocilizumab. Tocilizumab suppressed inflammation via the TLR9 pathway by decreasing cfDNA levels. Regulation of cfDNA may be a therapeutic target for RA., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Immunology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor expressed in hematopoietic and non-hematopoietic cells. Activation of the AhR by xenobiotics, microbial metabolites, and natural substances induces immunoregulatory responses. Autoimmune pancreatitis (AIP) is a chronic fibroinflammatory disorder of the pancreas driven by autoimmunity. Although AhR activation generally suppresses pathogenic autoimmune responses, the roles played by the AhR in AIP have been poorly defined. In this study, we examined how AhR activation affected the development of experimental AIP caused by the activation of plasmacytoid dendritic cells producing IFN-α and IL-33. Experimental AIP was induced in MRL/MpJ mice by repeated injections of polyinosinic-polycytidylic acid. Activation of the AhR by indole-3-pyruvic acid and indigo naturalis, which were supplemented in the diet, inhibited the development of experimental AIP, and these effects were independent of the activation of plasmacytoid dendritic cells producing IFN-α and IL-33. Interaction of indole-3-pyruvic acid and indigo naturalis with AhRs robustly augmented the production of IL-22 by pancreatic islet α cells. The blockade of IL-22 signaling pathways completely canceled the beneficial effects of AhR ligands on experimental AIP. Serum IL-22 concentrations were elevated in patients with type 1 AIP after the induction of remission with prednisolone. These data suggest that AhR activation suppresses chronic fibroinflammatory reactions that characterize AIP via IL-22 produced by pancreatic islet α cells., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Immunology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aims: Available predictive models for sudden cardiac death (SCD) in heart failure (HF) patients remain suboptimal. We assessed whether the electrocardiography (ECG)-based artificial intelligence (AI) could better predict SCD, and also whether the combination of the ECG-AI index and conventional predictors of SCD would improve the SCD stratification among HF patients., Methods and Results: In a prospective observational study, 4 tertiary care hospitals in Tokyo enrolled 2559 patients hospitalized for HF who were successfully discharged after acute decompensation. The ECG data during the index hospitalization were extracted from the hospitals' electronic medical record systems. The association of the ECG-AI index and SCD was evaluated with adjustment for left ventricular ejection fraction (LVEF), New York Heart Association (NYHA) class, and competing risk of non-SCD. The ECG-AI index plus classical predictive guidelines (i.e. LVEF ≤35%, NYHA Class II and III) significantly improved the discriminative value of SCD [receiver operating characteristic area under the curve (ROC-AUC), 0.66 vs. 0.59; P = 0.017; Delong's test] with good calibration (P = 0.11; Hosmer-Lemeshow test) and improved net reclassification [36%; 95% confidence interval (CI), 9-64%; P = 0.009]. The Fine-Gray model considering the competing risk of non-SCD demonstrated that the ECG-AI index was independently associated with SCD (adjusted sub-distributional hazard ratio, 1.25; 95% CI, 1.04-1.49; P = 0.015). An increased proportional risk of SCD vs. non-SCD with an increasing ECG-AI index was also observed (low, 16.7%; intermediate, 18.5%; high, 28.7%; P for trend = 0.023). Similar findings were observed in patients aged ≤75 years with a non-ischaemic aetiology and an LVEF of >35%., Conclusion: To improve risk stratification of SCD, ECG-based AI may provide additional values in the management of patients with HF., Competing Interests: Conflict of interest: Y.S. received honoraria from Otsuka Pharmaceuticals Co., Ltd and Ono Pharmaceuticals Co., Ltd. S.K. received an unrestricted research grant from the Department of Cardiology, Keio University School of Medicine, Bayer Pharmaceuticals Co., Ltd, Daiichi Sankyo Co., Ltd, and Novartis Pharma Co., Ltd. The authors declare no conflicts of interest. The authors declare no patents, products in development, or marketed products., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Objective: First-line pembrolizumab with/without chemotherapy versus chemotherapy was evaluated in programmed death ligand 1 combined positive score ≥1, locally advanced/unresectable or metastatic gastric cancer/gastrooesophageal junction cancer in the KEYNOTE-062 study. We present results for patients enrolled in Asia., Methods: Eligible patients were randomly assigned 1:1:1 to pembrolizumab 200 mg, pembrolizumab plus chemotherapy (cisplatin + 5-fluorouracil or capecitabine) or placebo plus chemotherapy Q3W. End points included overall survival (primary) in combined positive score ≥1 and combined positive score ≥10 populations and safety and tolerability (secondary)., Results: A total of 187 patients were enrolled in Asia (pembrolizumab, n = 62; pembrolizumab plus chemotherapy, n = 64; chemotherapy, n = 61). Compared with the global population, higher proportions of patients had Eastern Cooperative Oncology Group performance status 0 and a diagnosis of stomach cancer. In the programmed death ligand 1 combined positive score ≥1 population, median overall survival was numerically longer with pembrolizumab versus chemotherapy (22.7 vs 13.8 months; hazard ratio, 0.54; 95% confidence interval, 0.35-0.82) and pembrolizumab plus chemotherapy versus chemotherapy (16.5 vs 13.8 months; hazard ratio, 0.78; 95% confidence interval, 0.53-1.16). In the programmed death ligand 1 combined positive score ≥10 population, median overall survival was also numerically longer with pembrolizumab versus chemotherapy (28.5 vs 14.8 months; hazard ratio, 0.43; 95% confidence interval, 0.21-0.89) and pembrolizumab plus chemotherapy versus chemotherapy (17.5 vs 14.8 months; hazard ratio, 0.86; 95% confidence interval, 0.45-1.64). The grade 3-5 treatment-related adverse event rate was 19.4%, 75.8% and 64.9% for patients receiving pembrolizumab, pembrolizumab plus chemotherapy and chemotherapy, respectively., Conclusions: This post hoc analysis showed pembrolizumab monotherapy was associated with numerically improved overall survival and a favourable tolerability profile versus chemotherapy in Asians with programmed death ligand 1-positive advanced gastric cancer/gastrooesophageal junction cancer.This study is registered with ClinicalTrials.gov, NCT02494583., (© The Author(s) 2022. Published by Oxford University Press.)

Accurate preoperative evaluation of lymph node (LN) metastasis is important for determining the treatment strategy for superficial esophageal cancer. Blood biomarkers, such as the neutrophil-lymphocyte, platelet-lymphocyte, and lymphocyte-monocyte ratios (NLR, PLR, and LMR, respectively), have clinical applications as predictors of LN metastasis for different cancers. Here, we investigated the use of these ratios as predictors of pathological LN metastasis and prognosis in patients with clinical stage T1N0M0 esophageal squamous cell carcinoma (ESCC). Patients (n = 185) with cT1N0M0 ESCC who underwent esophagectomy with R0 resection between April 2003 and August 2021 were enrolled. We investigated the ability of pretreatment NLR, PLR, and LMR to predict pathological LN metastasis. The optimal cutoff values of NLR, PLR, and LMR to predict pathological LN metastasis were 2.1, 122, and 4.8, respectively. Univariate and multivariate analyses revealed that the primary tumor length, depth of invasion, and NLR were significant predictors of LN metastasis. Furthermore, similar to the 5-year overall survival, the 5-year relapse-free survival was significantly better in the low NLR group than in the high NLR group. The NLR was the most useful predictor of pathological LN metastasis. Patients diagnosed with clinical stage I ESCC and with a high NLR require adequate LN dissection and may be good candidates for preoperative adjuvant therapy., (© The Author(s) 2022. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Cellular inhibitors of apoptosis proteins 1 (cIAP1) and 2 (cIAP2) are involved in signaling pathways mediated by Toll-like receptors (TLRs) and tumor necrosis factor (TNF)-α. Excessive activation of TLRs and TNF-α underlies the immunopathogenesis of Crohn's disease (CD) and ulcerative colitis (UC). However, the roles played by cIAP1 and cIAP2 in the development of CD and UC remain poorly understood. In this study, we attempted to clarify the molecular link between cIAP1/cIAP2 and colonic inflammation. Human monocyte-derived dendritic cells (DCs) treated with siRNAs specific for cIAP1 or cIAP2 exhibited reduced pro-inflammatory cytokine responses upon stimulation with TLR ligands. Expression of cIAP1 and cIAP2 in human DCs was suppressed in the presence of interferon regulatory factor 4 (IRF4). This effect was associated with inhibition of cIAP1 and cIAP2 polyubiquitination. To verify these in vitro findings, we created mice overexpressing IRF4 in DCs and showed that these mice were resistant to trinitrobenzene sulfonic acid-induced colitis as compared with wild-type mice; these effects were accompanied by reduced expression levels of cIAP1 and cIAP2. Pro-inflammatory cytokine production by mesenteric lymph node cells upon stimulation with TLR ligands was reduced in mice with DC-specific IRF4 overexpression as compared with that in wild-type mice. Finally, in clinical samples of the colonic mucosa from patients with CD, there was a negative relationship between the percentage of IRF4+ DCs and percentages of cIAP1+ or cIAP2+ lamina propria mononuclear cells. These data suggest that the colitogenic roles of cIAP1 and cIAP2 are negatively regulated by IRF4., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Immunology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Esophagogastric junction cancer is defined as adenocarcinoma with the epicenter within 5 cm of the esophagogastric junction in the West according to the Siewert classification. In contrast, it is defined as cancer of any histological type with the epicenter located within 2 cm proximal or distal to the esophagogastric junction in Japan according to the Nishi classification. Recently, the incidence of esophagogastric junction cancer has been rapidly rising all over the world, leading to much attention. Esophagogastric junction cancer was previously treated like gastric cancer or esophageal cancer because it is a less frequently occurring tumor. Esophagogastric junction cancer is considered to have worse prognosis than gastric cancer. Therefore, in recent years, esophagogastric junction cancer has been recognized as an independent malignant disease with poor prognosis, and thus development of treatment strategies focused on esophagogastric junction cancer is needed. The mapping of frequent metastasis in the mediastinal and abdominal lymph nodes has revealed the lymphatic flow from esophagogastric junction cancer specifically, establishing the optimal lymph node dissection area and surgical approach. The development of multimodal treatment that includes chemotherapy, radiotherapy and immunotherapy has been applied to improve the survival of esophagogastric junction cancer. In this review, we summarize clinical trials with important evidence on surgical and multimodal perioperative treatments for esophagogastric junction cancer., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: The short-term efficacy of virtual-assisted lung mapping (VAL-MAP), a preoperative bronchoscopic multi-spot lung-marking technique, has been confirmed in 2 prospective multicentre studies. The objectives of this study were to analyse the local recurrence and survival of patients enrolled in these studies, long-term., Methods: Of the 663 patients enrolled in the 2 studies, 559 patients' follow-up data were collected. After excluding those who did not undergo VAL-MAP, whose resection was not for curative intent, who underwent concurrent resection without VAL-MAP, or who eventually underwent lobectomy instead of sublobar resection (i.e. wedge resection or segmentectomy), 422 patients were further analysed., Results: Among 264 patients with primary lung cancer, the 5-year local recurrence-free rate was 98.4%, and the 5-year overall survival (OS) rate was 94.5%. Limited to stage IA2 or less (≤2 cm in diameter; n = 238, 90.1%), the 5-year local recurrence-free and OS rates were 98.7% and 94.8%, respectively. Among 102 patients with metastatic lung tumours, the 5-year local recurrence-free rate was 93.8% and the 5-year OS rate was 81.8%. Limited to the most common (colorectal) cancer (n = 53), the 5-year local recurrence-free and OS rates were 94.9% and 82.3%, respectively., Conclusions: VAL-MAP, which is beneficial in localizing small barely palpable pulmonary lesions and determining the appropriate resection lines, was associated with reasonable long-term outcomes., Subj Collection: 152, 1542., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Oryza sativa L. ssp. japonica cv. Nipponbare produces a nonproteinogenic amino acid (3R)-β-tyrosine from l-tyrosine by tyrosine aminomutase (OsTAM1). However, physiological and ecological function(s) of β-tyrosine have remained obscure. Often an improved understanding of metabolite localization and transport can aid in design of experiments to test physiological functions. In the current study, we investigated the distribution pattern of β-tyrosine in rice seedlings and found that β-tyrosine is most abundant in the youngest leaves. Based upon observations of high TAM1 activity in mature leaves, we hypothesized that β-tyrosine is transported from mature leaves to young leaves. Patterns of predominant mature synthesis and young leaf accumulation were supported by stable isotope studies using labeled β-tyrosine and the removal of mature leaves. Stem exudate analyses was also consistent with β-tyrosine transport through phloem. Thus, we identify young leaves as a key target in efforts to understand the biological function(s) of β-tyrosine in rice., (© The Author(s) 2022. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry.)

Aims: A mineralocorticoid receptor antagonist (MRA) is effective in patients with chronic heart failure; however, the effects of the early initiation of an MRA in patients with acute heart failure (AHF) have not been elucidated., Methods and Results: In this multicentre, randomized, double-blind, placebo-controlled, parallel-group study, we focused on the safety and effectiveness of the treatment with eplerenone, a selective MRA in 300 patients with AHF, that is, 149 in the eplerenone group and 151 in the placebo group in 27 Japanese institutions. The key inclusion criteria were (i) patients aged 20 years or older and (ii) those with left ventricular ejection fraction of ≤40%. The primary outcome was a composite of cardiac death or first re-hospitalization due to cardiovascular disease within 6 months. The mean age of the participants was 66.8 years, 27.3% were women, and the median levels of brain natriuretic peptide were 376.0 pg/mL. The incidences of the primary outcome were 19.5% in the eplerenone group and 17.2% in the placebo group [hazard ratio (HR): 1.09, 95% confidence interval (CI): 0.642-1.855]. In prespecified secondary outcomes, HR for the composite endpoint, cardiovascular death, or first re-hospitalization due to heart failure within 6 months was 0.55 (95% CI: 0.213-1.434). The safety profile for eplerenone was as expected., Conclusion: The early initiation of eplerenone in patients with AHF could safely be utilized. The reduction of the incidence of a composite of cardiovascular death or first re-hospitalization for cardiovascular diseases by eplerenone is inconclusive because of inadequate power., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Background: Although cisplatin and 5-chloro-2,4-dihydropyrimidine (dihydropyrimidine dehydrogenase inhibitor contained in S-1) are excreted into the urine, it remains unknown how creatinine clearance (CrCl) affects the safety and efficacy of cisplatin plus S-1 and docetaxel plus cisplatin plus S-1 in patients with advanced gastric cancer., Methods: Among the 741 participants in JCOG1013 comparing cisplatin plus S-1 with docetaxel plus cisplatin plus S-1, 723 with serum creatinine levels ≤1.2 mg/dL were categorized into A1 (CrCl ≥ 80 mL/min), A2 (60 ≤ CrCl <80) and A3 (CrCl < 60) in the cisplatin plus S-1 arm and similarly B1, B2 and B3 in the docetaxel plus cisplatin plus S-1 arm. The initial dose modification by CrCl was pre-specified in the docetaxel plus cisplatin plus S-1 arm but not in the cisplatin plus S-1 arm., Results: The numbers of patients categorized as A1/A2/A3 and B1/B2/B3 were 169/136/57 and 170/138/53, respectively. In the cisplatin plus S-1 arm, a lower CrCl was associated with higher incidences of grade 4 leukopenia (P = 0.006), neutropenia (P = 0.002), and grade 3/4 anorexia (P = 0.004) and febrile neutropenia (P = 0.049), whereas there was no association in the docetaxel plus cisplatin plus S-1 arm. No significant differences were observed according to CrCl in the overall survival [median: 15.4/15.5/15.4 months in A1/A2/A3 (P = 0.886) and 15.3/13.7/13.7 months in B1/B2/B3 (P = 0.719)], progression-free survival [median: 7.1/6.8/6.2 months in A1/A2/A3 (P = 0.884) and 7.5/7.2/7.8 months in B1/B2/B3 (P = 0.851)] and response rates [58.9/57.8/46.9% in A1/A2/A3 (P = 0.311) and 62.0/61.5/51.5% in B1/B2/B3 (P = 0.362)]., Conclusions: Renal impairment was associated with severe adverse events in cisplatin plus S-1 therapy but not with the efficacy in cisplatin plus S-1 and docetaxel plus cisplatin plus S-1 therapy., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: During the Coronavirus disease 2019 (COVID-19) pandemic, social isolation and impaired social interaction could be the factors that cause mental health problems. This study investigated the association between conversation time in daily life and mental health among Japanese employees., Methods: In August 2021, a web-based cross-sectional survey was conducted with 1000 Japanese employees. Weekly conversation time was assessed in four domains (family members, friends, someone in the workplace, and others), and mental health was assessed using the Japanese version of the Kessler Psychological Distress Scale (K6 scale). Weekly total conversation time was calculated, and participants were assigned to one of the four conversation time categories based on quantile values to investigate the associations with poor mental health (K6 ≥ 13)., Results: The logistic regression analyses revealed that participants with short conversation times (<3.5 h per week) had poorer mental health compared to those with long conversation times (> 21.0 h per week), even after adjusting for confounders (OR = 2.48 [95% CI 1.31-4.71]). For the exploratory analyses of conversation time for each domain, the associations of short conversation time in the workplace with poor mental health was most robust (OR =2.02 [95% CI 1.13-3.63])., Conclusions: Japanese employees with conversation time of <3.5 h per week (i.e., 30 min per day) had poor mental health. During the COVID-19 pandemic, people have largely limited opportunities to have conversations with others, but a certain level of conversation time might be required to maintain mental health., (© 2022 The Authors. Journal of Occupational Health published by John Wiley & Sons Australia, Ltd on behalf of The Japan Society for Occupational Health.)

Objectives: Long working hours in Japan is a social concern. This is also true for the working hours of physicians, who often do side work in addition to working at their main hospital. New physician work regulations to be implemented in Japan require work-hour management, including side work. This study examined the association between physicians' overtime and side work hours and their health outcomes., Methods: We conducted a cross-sectional study using data from a survey of working physicians conducted by the Japan Medical Association from 2021 to 2022. Questionnaires completed by 2906 full-time working physicians aged 24-69, excluding junior resident doctors, were analyzed. Depressive symptoms and the presence of thoughts of death or suicide using the Quick Inventory of Depressive Symptomatology - Japanese version was used to assess health outcomes. Logistic regression analysis was performed using overtime at the main place of employment and side work hours as exposure factors., Results: Both depressive symptoms and thoughts of death or suicide increased in the group with longer overtime hours at the main place of work. A similar tendency was observed for side work but adjusting for overtime hours eliminated the association. In other words, total working hours had an impact on health, regardless of whether overtime work at the main place of employment or side work., Conclusions: Despite the existence of multiple hurdles to managing working hours, including side work, the working environment for physicians needs to be improved to protect their health and quality of medical care., (© 2022 The Authors. Journal of Occupational Health published by John Wiley & Sons Australia, Ltd on behalf of The Japan Society for Occupational Health.)

We previously identified quantitative trait loci (QTL) for prepulse inhibition (PPI), an endophenotype of schizophrenia, on mouse chromosome 10 and reported Fabp7 as a candidate gene from an analysis of F2 mice from inbred strains with high (C57BL/6N; B6) and low (C3H/HeN; C3H) PPI levels. Here, we reanalyzed the previously reported QTLs with increased marker density. The highest logarithm of odds score (26.66) peaked at a synonymous coding and splice-site variant, c.753G>A (rs257098870), in the Cdh23 gene on chromosome 10; the c.753G (C3H) allele showed a PPI-lowering effect. Bayesian multiple QTL mapping also supported the same variant with a posterior probability of 1. Thus, we engineered the c.753G (C3H) allele into the B6 genetic background, which led to dampened PPI. We also revealed an e-QTL (expression QTL) effect imparted by the c.753G>A variant for the Cdh23 expression in the brain. In a human study, a homologous variant (c.753G>A; rs769896655) in CDH23 showed a nominally significant enrichment in individuals with schizophrenia. We also identified multiple potentially deleterious CDH23 variants in individuals with schizophrenia. Collectively, the present study reveals a PPI-regulating Cdh23 variant and a possible contribution of CDH23 to schizophrenia susceptibility., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Background: Human herpesvirus 6 (HHV-6) can be genetically transmitted from parent to child as inherited chromosomally integrated HHV-6 (iciHHV-6). HHV-6 reactivation occurs in pregnant women with iciHHV-6. We found no sex differences in the frequency of index cases with iciHHV-6 but inheritance from the father was more common. We evaluated the association between iciHHV-6 status and spontaneous abortion., Methods: iciHHV-6 was confirmed by high viral DNA copy numbers in whole blood and somatic cells. The origin of integrated viral genome, paternal or maternal, was examined using the same method. The pregnancy history of 23 mothers in families with iciHHV-6 and 285 mothers in families without iciHHV-6 was abstracted., Results: Of 23 iciHHV-6 index cases, 8 mothers and 15 fathers had iciHHV-6. Spontaneous abortion rates in mothers with and mothers without/fathers with iciHHV-6 and mothers in families without iciHHV-6 were 27.6%, 10.3%, and 14.8%, respectively (P = .012). Mothers with iciHHV-6 (odds ratio [OR], 6.41; 95% confidence interval [CI], 1.10-37.4) and maternal age at the most recent pregnancy ≥40 years (OR, 3.91; 95% CI, 1.30-11.8) were associated with 2 or more spontaneous abortions., Conclusions: Mothers with iciHHV-6 is a risk factor for spontaneous abortion., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Objectives: To assess oral health-related quality of life (OHRQoL) and changes in OHRQoL in 3 years of patients with Sjögren's symdrome (SS)., Methods: Thirty-five SS patients and 23 non-SS individuals were enrolled. OHRQoL were quantitatively evaluated using the shortened Oral Health Impact Profile (OHIP-14). After 3 years, 22 patients and 14 controls tool the OHIP-14 survey again., Results: The SS group had a significantly higher OHIP-14 score, which indicated a lower OHRQoL, than the non-SS group. Among individual questions in the OHIP-14, scores for 'trouble pronouncing words', 'uncomfortable to eat foods', 'self-conscious', and 'diet unsatisfactory' were markedly higher in the SS group than in the non-SS group. The OHIP-14 score significantly increased in 3 years in the SS group. Furthermore, there was an inverse correlation between the change rate of salivary flow rate and change of OHIP-14 scores in 3 years in patients with SS whose OHIP-14 score increased. Scores for 'irritable with other people', 'difficulty doing usual jobs', 'felt life less satisfying', and 'unable to function' significantly increased in 3 years., Conclusion: In SS, OHRQoL decreased in 3 years, which was associated with a decrease in saliva secretion. Moreover, troubles related to psychosocial aspects in SS patients were found to intensify over time.

Immunocompetent sisters with chromosomally integrated human herpesvirus 6A (HHV-6A) transiently excreted HHV-6B genome in their saliva. They did not have past histories of exanthema subitum but had antibodies against HHV-6A and HHV-6B. This suggests that endogenous HHV-6A may modify the clinical features of HHV-6B coinfection., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Recently, immune checkpoint inhibitors such as anti-programmed cell death-1 (PD-1) or programmed cell death ligand-1 (PD-L1) monoclonal antibodies have improved the overall survival of various types of cancers including advanced gastric cancer (AGC). Until now, two ant-PD-1 inhibitors were approved for AGC in Japan: nivolumab as third- or later-line treatment for AGC and pembrolizumab for previously treated patients with microsatellite instability-high tumours. However, a limited number of patients achieved clinical benefit, highlighting the importance of the better selection of patients or additional treatment to overcome resistance to PD-1/PD-L1 blockade. This review focused on pivotal clinical trials, biomarkers and novel combination therapy of immune checkpoint inhibitors forAGC., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Structural changes in the corpus callosum have been reported in schizophrenia; however, the underlying molecular mechanism remains unclear. As the corpus callosum is high in lipid content, we analyzed the lipid contents of the corpora callosa from 15 patients with schizophrenia and 15 age- and sex-matched controls using liquid chromatography coupled to tandem mass spectrometry and identified lipid combinations associated with schizophrenia. Real-time quantitative polymerase chain reaction analyses using extended samples (schizophrenia, n = 95; control, n = 91) showed low expression levels of lipid metabolism-related genes and their potential upstream transcription factors in schizophrenia. Subsequent pathway analysis identified a gene regulatory network where nuclear factor of activated T cells 2 (NFATC2) is placed most upstream. We also observed low gene expression levels of microglial markers, inflammatory cytokines, and colony-stimulating factor 1 receptor (CSF1R), which is known to regulate the density of microglia, in the corpus callosum in schizophrenia. The interactions between CSF1R and several genes in the presently identified gene network originating from NFATC2 have been reported. Collectively, this study provides evidence regarding lipid abnormalities in the corpora callosa of patients with schizophrenia and proposes the potential role of impaired "NFATC2-relevant gene network-microglial axis" as its underlying mechanism., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Although increasing evidence demonstrates the association between intestinal dysbiosis and pancreatic diseases such as chronic pancreatitis and pancreatic cancer, it remains largely unknown whether intestinal dysbiosis is involved in the immunopathogenesis of autoimmune pancreatitis (AIP). Recently, we found that intestinal dysbiosis mediates experimental AIP via the activation of plasmacytoid dendritic cells (pDCs), which can produce interferon (IFN)-α and interleukin (IL)-33. However, candidate intestinal bacteria, which promote the development of AIP, have not been identified. Fecal samples were obtained from type 1 AIP patients before and after prednisolone (PSL) treatment and subjected to 16S ribosomal RNA sequencing to evaluate the composition of intestinal bacteria. Induction of remission by PSL was associated with the complete disappearance of Klebsiella species from feces in two of the three analyzed patients with type 1 AIP. To assess the pathogenicity of Klebsiella species, mild experimental AIP was induced in MRL/MpJ mice by repeated injections of 10 μg of polyinosinic-polycytidylic acid [poly(I:C)], in combination with oral administration of heat-killed Klebsiella pneumoniae. The AIP pathology score was significantly higher in MRL/MpJ mice that received both oral administration of heat-killed K. pneumoniae and intraperitoneal injections of poly(I:C) than in those administered either agent alone. Pancreatic accumulation of pDCs capable of producing large amounts of IFN-α and IL-33 was also significantly higher in mice that received both treatments. These data suggest that intestinal colonization by K. pneumoniae may play an intensifying role in the development of type 1 AIP., (© 2020 British Society for Immunology.)

Gastrectomy with omentectomy and D2 lymph node dissection is the current standard procedure for locally advanced gastric cancer. However, some retrospective studies have reported that omentectomy increased post-operative abdominal complications but provided no survival advantage over omentum preservation. Therefore, we plan a randomized controlled phase III trial to confirm the non-inferiority of omentum preservation compared with omentectomy in patients with cT3 (SS) or cT4a (SE) gastric cancer. A total of 1050 patients will be enrolled from 62 institutions over a period of 6.5 years. The primary end point is relapse-free survival, and the secondary end points are overall survival, blood loss, operation time and adverse events. This trial has been registered at the UMIN Clinical Trials Registry as UMIN000036253., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Takotsubo syndrome occasionally occurs in patients with fever due to underlying diseases. However, the impact of body temperature on inhospital prognosis of patients with takotsubo syndrome remains unknown., Methods: Using the patient cohort in the Tokyo Cardiovascular Care Unit Network Registry from 2013 to 2015, we identified 421 eligible patients whose data on body temperature at admission were available and classified them into three groups: high body temperature group (≥37.5°C; n =27), normal body temperature group (36.0-37.4°C; n =319), and low body temperature group (≤35.9°C; n =75). We compared the patient characteristics and inhospital outcomes among the three groups., Results: On admission, the high body temperature group showed a higher proportion of men and preceding physical triggers, higher heart and respiratory rates, and higher C-reactive protein level than the other groups. Inhospital all-cause mortality was significantly higher in the high body temperature group than in the normal or low body temperature group (18.5% vs. 2.2% vs. 4.0%, respectively, P <0.001). Both cardiac mortality (11.1% vs. 1.3% vs. 1.3%, P =0.001) and non-cardiac mortality (7.4% vs. 0.9% vs. 2.7%, P =0.031) were also significantly higher in the high body temperature group. Multivariable logistic regression analysis showed that high body temperature (reference: normal body temperature) was significantly associated with higher inhospital mortality (adjusted odds ratio 4.22; 95% confidence interval 1.15-15.51; P =0.030)., Conclusions: Our findings suggest that high body temperature at admission is a strong predictor of inhospital mortality in patients with takotsubo syndrome. Febrile takotsubo syndrome patients may need to be managed with recognition of life-threatening conditions from the time of diagnosis, no matter what the causes of fever are.

The disturbed integrity of myelin and white matter, along with dysregulation of the lipid metabolism, may be involved in schizophrenia pathophysiology. Considering the crucial role of sphingolipids in neurodevelopment, particularly in oligodendrocyte differentiation and myelination, we examined the role of sphingolipid dynamics in the pathophysiology of schizophrenia. We performed targeted mass spectrometry-based analysis of sphingolipids from the cortical area and corpus callosum of postmortem brain samples from patients with schizophrenia and controls. We observed lower sphingosine-1-phosphate (S1P) levels, specifically in the corpus callosum of patients with schizophrenia, but not in major depressive disorder or bipolar disorder, when compared with the controls. Patient data and animal studies showed that antipsychotic intake did not contribute to the lowered S1P levels. We also found that lowered S1P levels in the corpus callosum of patients with schizophrenia may stem from the upregulation of genes for S1P-degrading enzymes; higher expression of genes for S1P receptors suggested a potential compensatory mechanism for the lowered S1P levels. A higher ratio of the sum of sphingosine and ceramide to S1P, which can induce apoptosis and cell-cycle arrest, was also observed in the samples of patients with schizophrenia than in controls. These results suggest that an altered S1P metabolism may underlie the deficits in oligodendrocyte differentiation and myelin formation, leading to the structural and molecular abnormalities of white matter reported in schizophrenia. Our findings may pave the way toward a novel therapeutic strategy., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Autism spectrum disorder is a neurodevelopmental disorder characterized by difficulties in social communication and interaction, as well as repetitive and characteristic patterns of behaviour. Although the pathogenesis of autism spectrum disorder is unknown, being overweight or obesity during infancy and low weight at birth are known as risks, suggesting a metabolic aspect. In this study, we investigated adipose tissue development as a pathophysiological factor of autism spectrum disorder by examining the serum levels of adipokines and other metabolic markers in autism spectrum disorder children ( n  = 123) and typically developing children ( n  = 92) at 4-12 years of age. Among multiple measures exhibiting age-dependent trajectories, the leptin levels displayed different trajectory patterns between autism spectrum disorder and typically developing children, supporting an adipose tissue-dependent mechanism of autism spectrum disorder. Of particular interest, the levels of fatty acid binding protein 4 (FABP4) were significantly lower in autism spectrum disorder children than in typically developing subjects, at preschool age (4-6 years old: n  = 21 for autism spectrum disorder and n  = 26 for typically developing). The receiver operating characteristic curve analysis discriminated autism spectrum disorder children from typically developing children with a sensitivity of 94.4% and a specificity of 75.0%. We re-sequenced the exons of the FABP4 gene in a Japanese cohort comprising 659 autism spectrum disorder and 1000 control samples, and identified two rare functional variants in the autism spectrum disorder group. The Trp98Stop, one of the two variants, was transmitted to the proband from his mother with a history of depression. The disruption of the Fabp4 gene in mice evoked autism spectrum disorder-like behavioural phenotypes and increased spine density on apical dendrites of pyramidal neurons, which has been observed in the postmortem brains of autism spectrum disorder subjects. The Fabp4 knockout mice had an altered fatty acid composition in the cortex. Collectively, these results suggest that an 'adipo-brain axis' may underlie the pathophysiology of autism spectrum disorder, with FABP4 as a potential molecule for use as a biomarker., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Perioperative treatment for locally advanced gastric cancer has been inconsistent between Japan and the Western countries. In Japan, D2 gastrectomy followed by adjuvant chemotherapy is regarded as standard treatment, while neoadjuvant or perioperative chemotherapy is considered to be a standard in the Western countries. Stomach Cancer Study Group of Japan Clinical Oncology Group (JCOG) has conducted many perioperative chemotherapy trials. After the publishing of positive results of ACTS-GC trial, stage-specific adjuvant chemotherapy protocols are planned. JCOG1104 was conducted as to demonstrate the non-inferiority of four courses of S-1 to standard eight courses of S-1, because the efficacy of S-1 appears to be sufficient in stage II. The trial failed to demonstrate the non-inferiority of four courses of S-1. S-1 for 1 year is still recognized to be a standard for stage II gastric cancer. For stage III, studies with more intensive treatments were planned as the efficacy of S-1 monotherapy seems to be insufficient. As in the Western countries, JCOG planned the perioperative chemotherapy. However, the clinical staging is a serious issue to select optimal patients for perioperative chemotherapy. JCOG conducted a prospective cohort study to evaluate the validity of clinical staging in JCOG1302A. From the results of this study, cT3-4 and cN1-3 are selected as optimal candidate for perioperative chemotherapy. JCOG1509 was conducted to demonstrate the superiority of perioperative chemotherapy to adjuvant chemotherapy in these cohorts. Perioperative chemotherapy for marginally resectable tumours such as linitis plastica or extensive nodal disease and special type of cancer like HER2 positive are also conducted., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aims: Heart failure (HF) is associated with an increased risk of sudden cardiac death (SCD). This study sought to demonstrate the incidence of SCD within a multicentre Japanese registry of HF patients hospitalized for acute decompensation, and externally validate the Seattle Proportional Risk Model (SPRM)., Methods and Results: We consecutively registered 2240 acute HF patients from academic institutions in Tokyo, Japan. The discrimination and calibration of the SPRM were assessed by the c-statistic, Hosmer-Lemeshow statistic, and visual plotting among non-survivors. Patient-level SPRM predictions and implantable cardioverter-defibrillator (ICD) benefit [ICD estimated hazard ratio (HR), derived from the Cox proportional hazards model in the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT)] was calculated. During the 2-year follow-up, 356 deaths (15.9%) occurred, which included 76 adjudicated SCDs (3.4%) and 280 non-SCDs (12.5%). The SPRM showed acceptable discrimination [c-index = 0.63; 95% confidence interval (CI) 0.56-0.70], similar to that of original SPRM-derivation cohort. The calibration plot showed reasonable conformance. Among HF patients with reduced ejection fraction (EF; < 40%), SPRM showed improved discrimination compared with the ICD eligibility criteria (e.g. New York Heart Association functional Class II-III with EF ≤ 35%): c-index = 0.53 (95% CI 0.42-0.63) vs. 0.65 (95% CI 0.55-0.75) for SPRM. Finally, in the subgroup of 246 patients with both EF ≤ 35% and SPRM-predicted risk of ≥ 42.0% (SCD-HeFT defined ICD benefit threshold), mean ICD estimated HR was 0.70 (30% reduction of all-cause mortality by ICD)., Conclusion: The cumulative incidence of SCD was 3.4% in Japanese HF registry. The SPRM performed reasonably well in Japanese patients and may aid in improving SCD prediction., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Objectives: At the Fukushima Daiichi Nuclear Power Plant, run by the Tokyo Electric Power Company, new procedures were introduced as part of the fitness for duty program in July 2016. These were designed to ensure that treatment and further investigations identified as necessary during health examinations were carried out. This study aimed to assess the effectiveness of the initiative by testing whether workers who needed further health examinations obtained them promptly, and whether the number with unmet health needs decreased and the number of workers being treated increased., Methods: The primary contractors reported aggregated quarterly results of health examinations of both their own and their subcontractors' employees, and follow-up visits to medical institutions were also reported over the next two quarters. The study used data for the period from July 2016 to December 2018. Incident rate ratios were estimated using a multilevel Poisson regression model, including the logarithm of the number of workers who took health examination for each primary contractor company as offset. The linear trend was assessed by treating the number of periods as a continuous variable., Results: The incident rate ratio for workers who needed treatment having a follow-up examination promptly showed a significant decrease over time. The incident rate ratio for those with unmet needs decreased, and those being treated increased over time., Conclusions: The findings showed that the initiative was effective, with the number of early visits for further health examinations increasing and a decrease in the number of people with unmet health needs., (© 2020 The Authors. Journal of Occupational Health published by John Wiley & Sons Australia, Ltd on behalf of The Japan Society for Occupational Health.)

Introduction: Hyponatremia predicts adverse prognosis in patients with heart failure in particular with reduced ejection fraction. In contrast, it has recently been reported that hyponatremia on admission is not a predictor of post-discharge mortality in patients with heart failure with preserved ejection fraction. We investigated the prognostic impact of hyponatremia at discharge in patients with heart failure with preserved ejection fraction and its clinical characteristics., Methods and Results: The Japanese Heart Failure Syndrome with Preserved Ejection Fraction (JASPER) registry is a nationwide, observational, prospective registration of consecutive Japanese patients hospitalised with heart failure with preserved ejection fraction and left ventricular ejection fraction of 50% or greater. Five hundred consecutive patients were enrolled in this analysis. We divided the patients into two groups based on their sodium serum levels at discharge: hyponatremia group (sodium <135 mEq/L, n =50, 10.0%) and control group (sodium ⩾135 mEq/L, n =450, 90.0%). This present analysis had two primary endpoints: all-cause death and all-cause death or rehospitalisation for heart failure. At discharge, the hyponatremia group had lower systolic blood pressure (110.0 mmHg vs. 114.5 mmHg, P =0.014) and higher levels of urea nitrogen (31.9 mg/dL vs. 24.2 mg/dL, P =0.032). In the Kaplan-Meier analysis, more patients in the hyponatremia group reached the primary endpoints than those in the control group (log rank <0.01, respectively). In the Cox proportional hazard analysis, hyponatremia at discharge was a predictor of the two endpoints (all-cause death, hazard ratio 2.708, 95% confidence interval 1.557-4.708, P<0.001; all-cause death or rehospitalisation for heart failure, hazard ratio 1.829, 95% confidence interval 1.203-2.780, P =0.005)., Conclusions: Hyponatremia at discharge is associated with adverse prognosis in hospitalised patients with heart failure with preserved ejection fraction.

Objective : This study identified biomarkers that can be used to assess disease activity and response to therapy in patients with interstitial lung disease complicating anti-melanoma differentiation-associated gene 5 (MDA5) antibody (Ab)-positive clinically amyopathic dermatomyositis (CADM). Methods : In 15 patients with interstitial lung disease complicating anti-MDA5 Ab-positive CADM, anti-MDA5 Ab, neopterin, interleukin (IL)-18, ferritin, and soluble interleukin 2 receptor (sIL-2R) levels were measured in cryopreserved serum specimens before and at multiple times after remission induction therapy, and their correlations were assessed. Results : Anti-MDA5 Ab, neopterin, IL-18, ferritin, and sIL-2R levels did not differ significantly between patients who survived and those who succumbed to the disease. In many cases, serum anti-MDA5 Ab titers were over the upper limit (over 150 index value) before treatment in the usual measuring method, and gradually decreased to the normal range at stable phase. Meanwhile, serum neopterin levels (21.6 [15.3-48.3] nmol/L) were significantly elevated in newly diagnosed patients and fell to 6.8 (5-11.4) nmol/L at 6 months after treatment introduction. Conclusions : Elevated serum neopterin as well as ferritin, sIL-2R, KL-6, and anti-MDA5 Ab titer might help identify patients with interstitial lung disease complicated with DM and might be useful in monitoring response to therapy.

Genome-wide association studies (GWASs) have identified >100 susceptibility loci for schizophrenia (SCZ) and demonstrated that SCZ is a polygenic disorder determined by numerous genetic variants but with small effect size. We conducted a GWAS in the Japanese (JPN) population (a) to detect novel SCZ-susceptibility genes and (b) to examine the shared genetic risk of SCZ across (East Asian [EAS] and European [EUR]) populations and/or that of trans-diseases (SCZ, bipolar disorder [BD], and major depressive disorder [MDD]) within EAS and between EAS and EUR (trans-diseases/populations). Among the discovery GWAS subjects (JPN-SCZ GWAS: 1940 SCZ cases and 7408 controls) and replication dataset (4071 SCZ cases and 54479 controls), both comprising JPN populations, 3 novel susceptibility loci for SCZ were identified: SPHKAP (Pbest = 4.1 × 10-10), SLC38A3 (Pbest = 5.7 × 10-10), and CABP1-ACADS (Pbest = 9.8 × 10-9). Subsequent meta-analysis between our samples and those of the Psychiatric GWAS Consortium (PGC; EUR samples) and another study detected 12 additional susceptibility loci. Polygenic risk score (PRS) prediction revealed a shared genetic risk of SCZ across populations (Pbest = 4.0 × 10-11) and between SCZ and BD in the JPN population (P ~ 10-40); however, a lower variance-explained was noted between JPN-SCZ GWAS and PGC-BD or MDD within/across populations. Genetic correlation analysis supported the PRS results; the genetic correlation between JPN-SCZ and PGC-SCZ was ρ = 0.58, whereas a similar/lower correlation was observed between the trans-diseases (JPN-SCZ vs JPN-BD/EAS-MDD, rg = 0.56/0.29) or trans-diseases/populations (JPN-SCZ vs PGC-BD/MDD, ρ = 0.38/0.12). In conclusion, (a) Fifteen novel loci are possible susceptibility genes for SCZ and (b) SCZ "risk" effect is shared with other psychiatric disorders even across populations., (© The Author(s) 2018. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

IgG4-related disease (IgG4-RD) is a newly defined multi-organ disease proposed by Japanese physicians. IgG4-RD is characterized by elevated serum levels of IgG4 and massive infiltration of IgG4-expressing plasma cells in the affected organs. Recent studies have shown that abnormal adaptive immune responses mediated by T helper type 2 cells, regulatory T cells, follicular helper T cells, cytotoxic CD4 + T cells, and plasmablasts are involved in IgG4-RD immunopathogenesis. In addition to adaptive immune responses, innate immune responses play pathogenic roles in IgG4-RD. Plasmacytoid dendritic cells (pDCs), M2 macrophages, and basophils are activated to produce various kinds of cytokines in IgG4-RD. Recent studies highlight the importance of type I IFN and IL-33 produced by pDCs in IgG4-RD immunopathogenesis.

Background:: Although the typical apical form of Takotsubo syndrome and anterior acute myocardial infarction have similar electrocardiographic and echocardiographic presentations, data on the clinical differences between the two disorders are limited., Methods:: Using the Tokyo Cardiovascular Care Unit network registry, we identified patients hospitalised with apical Takotsubo syndrome ( n=540; 2010-2014) or anterior acute myocardial infarction ( n=2,806; 2013-2014) and created 522 age and sex-matched pairs (mean age 74.1 years; women 78.5%). We compared the clinical characteristics and inhospital outcomes between the two groups., Results:: On admission, patients with apical Takotsubo syndrome showed a lower body mass index, less frequent chest pain/tightness, lower systolic blood pressure, higher heart rate, lower creatine kinase, higher C-reactive protein and brain natriuretic peptide, and less frequent ST-elevation than patients with anterior acute myocardial infarction. Patients with apical Takotsubo syndrome received catecholamine (12.8% vs. 24.5%, P<0.001) and intra-aortic balloon pumping (5.9% vs. 15.1%, P<0.001) less frequently. Despite similar all-cause mortality (5.4% vs. 7.9%, P=0.134), patients with apical Takotsubo syndrome showed lower cardiac mortality (2.1% vs. 6.7%, P<0.001; risk difference -4.6% (95% confidence interval -7.1% to -2.1%)) but higher non-cardiac mortality (3.3% vs. 1.1%, P=0.033; 2.1% (0.3%-3.9%)). In subgroup comparisons, patients with physically triggered Takotsubo syndrome had higher non-cardiac mortality (7.0%) than those with non-physically triggered Takotsubo syndrome (1.2%, P=0.001) or anterior acute myocardial infarction (1.1%, P<0.001)., Conclusions:: This study found that cardiac and non-cardiac mortality risks differed significantly between apical Takotsubo syndrome and anterior acute myocardial infarction. Our findings underscore the importance of differentiating between the two disorders for appropriate management.

The present study describes the hair growth-promoting effects of sodium thiosulfate (STS), a widely used compound, in mice. STS accelerated hair growth in the "telogen model", suggesting that it stimulates telogen hair follicles to reenter the anagen phase of hair growth. In the same model, STS potentiated hair growth in an additive manner with minoxidil (MXD), a drug used for the treatment of androgenic alopecia. Furthermore, in the "anagen model", STS promoted hair growth, probably by promoting hair follicle proliferation. Since STS elevated the skin surface temperature, its hair growth-promoting activity may be partly due to vasorelaxation, similar to MXD. In addition, STS is known to generate a gaseous mediator, H 2 S, which has vasorelaxation and anti-inflammatory/anti-oxidative stress activities. Therefore, STS and/or provisionally its metabolite, H 2 S, may aid the hair growth process. Collectively, these results suggest that salts of thiosulfate may represent a novel and beneficial remedy for hair loss.

Adjuvant chemotherapy with S-1 is a standard treatment for patients with stage II/III gastric cancer after D2 gastrectomy; however, this is not uniformly applicable in older patients. The Stomach Cancer Study Group of the Japan Clinical Oncology Group conducted a questionnaire survey on older patients aged ≥80 years and revealed wide heterogeneity among older patients of similar chronological age. This randomized trial aims to confirm the superiority of modified S-1 treatment (reduced initial dose of S-1 by ≥ 1 level compared with the standard dose) versus surgery alone in vulnerable older (≥80 years old) patients with pathological stage II/III gastric cancer after curative resection. A total of 370 patients will be enrolled from 62 institutions over 4.5 years. The primary endpoint of this study is overall survival. This trial has been registered in the UMIN Clinical Trials Registry with code UMIN000025742 [http://www.umin.ac.jp/ctr/index.htm].

Background: Mental disorders and suicide resulting from overwork or work-related stress have become major occupational health issues worldwide, particularly in Asian countries. However, no studies have reported incidence rates of mental disorders and suicide by sex, age group and industry, using a national database containing all cases involving compensation in Asian countries., Aims: The present study examined incidence rates of occupational mental disorders and suicide by sex, age group and industry using a database containing all cases involving compensation for mental disorders and suicide in Japan over a 5-year period., Methods: Cases involving compensation for mental disorders and suicide in Japan between January 2010 and March 2015 were analysed. Incidence rates over the 5-year study period were calculated by sex, age group and industry., Results: In total, 1990 cases involving compensation for mental disorders and suicide (619 women and 1371 men) between January 2010 and March 2015 were analysed. The incidence rate involving compensation was higher in employees aged between 30 and 39 years. In men, incidence rates were higher in 'accommodation/eating/drinking services', 'information/communication' and 'scientific research, professional and technical services'. In these industries, incidence rates were particularly high for those aged 29 years or younger., Conclusions: Our findings highlight the importance of promoting mental health support for younger employees and increasing awareness of their working conditions. Differences in incidence rates by sex, age and industry should be taken into consideration in the development of a national policy and industry- and age-specific preventive measures for overwork-related mental disorders and suicide.

Objectives: This retrospective cohort study evaluated the impact of the Stress Check Program, a recently introduced national policy and program aimed at reducing psychological distress among Japanese workers., Methods: A baseline survey was conducted from November 2015 to February 2016, the period when Japan began enforcing the Stress Check Program. A one-year follow-up survey was conducted in December 2016. In the follow-up survey, two exposure variables were collected: having taken the annual stress survey, and experiencing an improvement in the psychosocial work environment. Psychological distress was assessed using the Brief Job Stress Questionnaire (BJSQ) at baseline and 1-year follow-up. The two exposure variables were used to define four groups: "Neither", "Stress survey (SS) only", "Psychosocial work environment improvement (WI) only", and "Both". BJSQ results were analyzed using repeated measures general linear modeling (GLM)., Results: The study included 2,492 participants: 1,342 in the "Neither" group, 1,009 in the "SS only" group, 76 in the "WI only" group, and 65 in the "Both" group. Overall time-group interaction effects were not significant. The "Both" group showed significantly greater improvements in psychological distress than the "Neither" group (p = 0.02) at the 1-year follow-up, although the effect size was small (d = -0.14)., Conclusions: Combination of the annual stress survey and improvement in psychosocial work environment may have been effective in reducing psychological distress in workers, although the effect size was small.

Background: Quality of life (QoL) is a key component in decision-making for surgical palliation, but QoL data in association with surgical palliation in advanced gastric cancer are scarce. The aim of this multicentre observational study was to examine the impact of surgical palliation on QoL in advanced gastric cancer., Methods: The study included patients with gastric outlet obstruction caused by incurable advanced primary gastric cancer who had no oral intake or liquid intake only. Patients underwent palliative distal/total gastrectomy or bypass surgery at the physician's discretion. The primary endpoint was change in QoL assessed at baseline, 14 days, 1 month and 3 months following surgical palliation by means of the EuroQoL Five Dimensions (EQ-5D™) questionnaire and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire gastric cancer module (QLQ-STO22). Secondary endpoints were postoperative improvement in oral intake and surgical complications., Results: Some 104 patients (23 distal gastrectomy, 9 total gastrectomy, 70 gastrojejunostomy, 2 exploratory laparotomy) were enrolled from 35 institutions. The mean EQ-5D™ utility index scores remained consistent, with a baseline score of 0·74 and the change from baseline within ± 0·05. Gastric-specific symptoms showed statistically significant improvement from baseline. The majority of patients were able to eat solid food 2 weeks after surgery and tolerated it thereafter. The rate of overall morbidity of grade III or more according to the Clavien-Dindo classification was 9·6 per cent (10 patients) and the 30-day postoperative mortality rate was 1·9 per cent (2 patients)., Conclusion: In patients with gastric outlet obstruction caused by advanced gastric cancer, surgical palliation maintained QoL while improving solid food intake, with acceptable morbidity for at least the first 3 months after surgery. Registration number 000023494 (UMIN Clinical Trials Registry).

In several eudicot species, one copy of each member of the WUSCHEL-RELATED HOMEOBOX (WOX) gene family, WOX1 and WOX3, is redundantly or differentially involved in lateral leaf outgrowth, whereas only the WOX3 gene regulating the lateral domain of leaf development has been reported in grass. In this study, we show that a WOX3 gene, LEAF LATERAL SYMMETRY1 (LSY1), regulates lateral leaf development in a different manner ftom that of other duplicated paralogs of WOX3, NARROW LEAF2 (NAL2)/NAL3, in rice. A loss-of-function mutant of LSY1 exhibited an asymmetrical defect from early leaf development, which is different from a symmetric defect in a double loss-of-function mutant of NAL2/3, whereas the expression of both genes was observed in a similar domain in the margins of leaf primordia. Unlike NAL2/3, overexpression of LSY1 produced malformed leaves whose margins were curled adaxially. Expression domains and the level of adaxial/abaxial marker genes were affected in the LSY1-overexpressing plants, indicating that LSY1 is involved in regulation of adaxial-abaxial patterning at the margins of the leaf primordia. Additive phenotypes in some leaf traits of lsy1 nal2/3 triple mutants and the unchanged level of NAL2/3 expression in the lsy1 background suggested that LSY1 regulates lateral leaf development independently of NAL2/3. Our results indicated that all of the rice WOX3 genes are involved in leaf lateral outgrowth, but the functions of LSY1 and NAL2/3 have diverged. We propose that the function of WOX3 and the regulatory mode of leaf development in rice are comparable with those of WOX1/WOX3 in eudicot species.

Background: This study was conducted to assess the transmissibility of rotavirus vaccine strains after rotavirus vaccination in a neonatal intensive care unit (NICU)., Methods: Pentavalent (RV5) or monovalent (RV1) rotavirus vaccine was administered to infants admitted to the NICU. Nineteen vaccinated infants and 49 unvaccinated infants whose beds were located in close proximity to the vaccinated infants were enrolled in this study. Dissemination and fecal shedding of vaccine viruses within the NICU were examined using real-time reverse transcription-polymerase chain reaction., Results: Shedding of the vaccine strain was detected in all 19 vaccinated infants. RV5 virus shedding started 1 day after the first vaccination and persisted for 8 days after the first vaccination, and viral shedding terminated by day 5 after administration of the second RV5 dose. The kinetics of RV1 virus shedding differed among vaccinated infants. The duration of RV1 virus shedding was longer after the first vaccination than after the second vaccination. In contrast to the vaccinated infants, no vaccine virus genomes were detected in any of the stool samples collected from the 49 unvaccinated infants., Conclusions: This study is direct evidence of no transmission of rotavirus vaccine strains between vaccinated infants and unvaccinated infants in close proximity within a NICU., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Heparan sulphate proteoglycan (HSPG) is present in the glomerular basement membrane (GBM) and is thought to play a major role in the glomerular charge barrier. Reductions and structural alterations of HSPG are observed in different types of kidney diseases accompanied by proteinuria. However, their causal relations remain unknown., Methods: We generated podocyte-specific exostosin-like 3 gene (Extl3) knockout mice (Extl3KO) using a Cre-loxP recombination approach. A reduction of HSPG was expected in the GBM of these mice, because EXTL3 is involved in its synthesis. Mice were separated into three groups, according to the loads on the glomeruli: a high-protein diet group, a high-protein and high-sodium diet group and a hyperglycaemic group induced by streptozotocin treatment in addition to maintenance on a high-protein and high-sodium diet. The urinary albumin:creatinine ratio was measured at 7, 11, 15 and 19 weeks of age. Renal histology was also investigated., Results: Podocyte-specific expression of Cre recombinase was detected by immunohistochemistry. Moreover, immunofluorescent staining demonstrated a significant reduction of HSPG in the GBM. Electron microscopy showed irregularities in the GBM and effacement of the foot processes in Extl3KO. The values of the urinary albumin:creatinine ratio were within the range of microalbuminuria in all groups and did not significantly differ between the control mice and Extl3KO., Conclusions: The reduction of HSPG in the GBM did not augment urinary albumin excretion. HSPG's anionic charge appears to contribute little to the glomerular charge barrier., (© The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)