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Magma differentiation in arc settings has usually been attributed to an interplay of processes (fractional crystallization, assimilation, and magma mixing). Homogeneous fractional crystallization has been widely used to model the magmatic evolution of volcanic systems in arc settings due to its simplicity, even though boundary layer fractionation (BLF) has been proposed as a preponderant process of differentiation in hydrous magmatic systems. Both models produce distinct compositional paths and the application of the wrong model yields erroneous estimates of parameters like pressure–temperature-H2O conditions and primary melt compositions. Melt inclusion (MI) populations corrected for post-entrapment processes have the potential to help discriminate between these two types of fractional crystallization, as their compositions are not affected by crystal accumulation and should capture the magmatic evolution as crystallization occurs. In this study, olivine-hosted MIs are used to assess the differentiation trends of basic arc magmas in northern Japan. Differentiation trends from five arc volcanic systems in northern Japan show that BLF is ubiquitous. Homogeneous fractionation models are unable to explain the liquid lines of descent of minor elements, like TiO2 and P2O5. To reproduce these differentiation trends, the presence of accessory phases like titanomagnetite or apatite are required, which in many cases are not equilibrated by the melt or need to be fractionated in amounts that are incompatible with homogeneous fractionation. The prevalence of BLF in all studied arc magmas of northern Japan indicates that solidification fronts are key environments in the crustal evolution of some hydrous subduction zone magmas. [ABSTRACT FROM AUTHOR]

Study design:A cross-sectional analysis.Objective:To examine whether intramedullary stress is related to the appearance of symptoms in cervical spondylotic myelopathy (CSM).Setting:Japan.Methods:Thirty-three consecutive patients with CSM and 30 consecutive patients without CSM were enrolled. A total of 99 disc levels from C3 to C6 in 33 patients with CSM were divided into two groups: 33 disc levels with high signal intensity (HSI) on T2-weighted magnetic resonance image (HSI group) and 66 disc levels without HSI (Non-HSI group). Ninety disc levels from C3 to C6 in patients without CSM were set up in a control group. Intramedullary stress value at each level was analyzed using the finite element method. Stress was compared among the three groups. A cutoff value of stress to present HSI was investigated from receiver operator characteristics (ROC) curve.Results:In all the patients with CSM, the disc level with HSI presented the highest stress among the three disc levels evaluated. The stress was 3.16±0.86 kPa (mean±s.d.) in the HSI group, 1.81±0.72 kPa in the Non-HSI group and 1.01±0.37 kPa in the control group. The stress differed significantly among the three groups (P<0.0001). The qualified cutoff value derived from the ROC curve was 2.30 kPa (sensitivity 78.8%, specificity 91.9%). None of the disc levels in the control group exceeded 2.30 kPa.Conclusion:HSI was strongly associated with intramedullary stress. Threshold of intramedullary stress to present HSI that related closely to the symptoms of myelopathy was revealed. [ABSTRACT FROM AUTHOR]

It is widely accepted that daily exercise improves the dynamic standing balance of elderly persons. In the current study, 77 community-dwelling Japanese elderly persons (aged 71.1 ± 0.5 years) participated in a daily exercise program to assess its effect on their dynamic standing balance. The daily exercise consisted of walking, stretching, muscle strengthening, and balance exercises. The program ran for 31 months and the dynamic standing balance was assessed at the start of the program and again at 3, 7, 12, 19, 24, and 31 months. In most of the tests of dynamic standing balance, the measured values improved drastically in the first 7 months; thereafter, they either reached a plateau or continued to improve more slowly. These findings can contribute to the future planning of community-based exercise programs; in particular, the length of the program and the timing of changes to the exercise load. [ABSTRACT FROM AUTHOR]

The experiment with polarized deuteron beam was performed at energies 140, 200 and 270 MeV at RIKEN, Japan, in December 2000. The high-momentum structure of the 3He, 3H and deuteron was investigated. For this purpose the angular dependence of the tensor and vector analyzing powers were measured for the reactions d+d→3H+p and d+d→3He+n. In this report the results on the tensor Axx, Ayy and vector Ay analyzing powers at 270 MeV are presented. [ABSTRACT FROM AUTHOR]

Introduction: Pregnancy-induced hypertension (PIH) is associated with increased risk for cardiovascular diseases later in life. Objectives: To assess the prevalence of subsequent hypertension and other life-style diseases five years after delivery in women who experienced pregnancy- induced hypertension. Methods: A total of 1527 women who delivered singletons were registered at the National Center for Child Health and Development and Showa University Hospital Mother and child health center of integrated perinatal period between 2003 and 2005. After five years, these women were invited to participate in this study by mail, and 816 women completed the analysis. The women visited our hospital and underwent a medical examination. Women who were pregnant and nursing at the time when the physical examination was conducted were excluded from this survey. The outcomes assessed included the prevalences of hypertension, diabetes, and dyslipidemia. Results: The number of PIH cases was 27 (3.3%: PIH group), whereas 787 women were used as controls subjects. The mean blood pressure five years after delivery was higher in the PIH group than in the control group (91.6±15.5mmHg vs 82.4±8.8mmHg, respectively; p <0.001), and the prevalence of hypertension five years after labor was 18.5% in the PIH group and 2.9% in the controls (odds ratio UOR Y =6.2; 95% confidence interval (CI)=2.2–17.5; p =0.003). Moreover, regarding high-normal blood pressure (>130/85mmHg), the prevalence was 33.4% in the PIH group and 6.1% in the control subjects (OR=7.2; 95% CI=3.1–16.3; p =0.003). No differences in the prevalences of subsequent diabetes or dyslipidemia were observed. Conclusion: Five years after the index pregnancy, women who experienced PIH exhibit an increased risk for subsequent hypertension. Therefore, the blood pressure of women with history of PIH should be regularly monitored after delivery. [Copyright &y& Elsevier]

Objective: The primary objective of this study is to describe cancer mortality rates and trends among Japanese adolescents and young adults aged 15–29 years for the period 1970–2006. [ABSTRACT FROM PUBLISHER]

Background FOLFOX and CAPOX are standard adjuvant chemotherapy for resected stage III colon cancer. MOSAIC and XELOXA trials were performed outside of Japan, thus, we conducted a phase II study (NORTH/HGCSG1003) to assess the efficacy and safety of FOLFOX as adjuvant chemotherapy for Japanese patients(pts) with resected stage III colon cancer (UMIN ID: 000004590). Methods This phase II study enrolled patients with resected stage III colon cancer. Patients received 12 cycles of FOLFOX4 or mFOLFOX6. Sample size was determined to be 243 pts. Primary endpoint was disease-free survival (DFS). We assumed an expected 3-year DFS rate of 81.2% in this study. Secondary endpoints included overall survival (OS) and safety. In this meeting, we present for the 5-year OS rate. Results From Sep 2010 to Mar 2013, 273 pts were enrolled at 28 institutions. Full analysis included 265 patients who received FOLFOX. Patients characteristics were as follows: median age; 65(33-84), Male/female; 131/134, PS 0/1; 258/7, stage IIIA/IIIB/IIIC; 37/197/31, colon/rectosigmoid: 214/51. The most common grade 3-4 adverse events were neutrophil count decreased (48.1%), peripheral sensory neuropathy (6.4%), platelet count decreased (2.3%), and allergic reaction (1.5%). The median number of cycles of FOLFOX was 12, and the completion treatment rate was 80.4%. There was no treatment-related death. The 3-year/5-year DFS rate was 76.0%(95%C.I. 70.3- 80.7)/70.6%(95%C.I. 64.7-75.7). The 3-year/5-year 0S rate was 95.8%(95%C.I. 92.5- 97.7)/88.1%(95%C.I. 83.5-91.5). Conclusions In Japanese patients with resected stage III colon cancer, FOLFOX is a well-tolerable regimen as adjuvant chemotherapy. In this trial, the 3-year DFS rate of primary endpoint was not meet the expectation. However, the 3-year DFS and 5-year OS rate in this trial were similar to several pivotal trials. Clinical trial identification UMIN ID: 000004590. Legal entity responsible for the study Non-Political Organization: Hokkaido Gastrointestinal Cancer Study Group. Funding Non-Political Organization: Hokkaido Gastrointestinal Cancer Study Group. Disclosure S. Yuki: Honoraria (self): Yakult Honsha Co. Ltd. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background: It is still unclear whether body mass index (BMI) affects bleeding and cardiovascular events in patients requiring oral anticoagulants (OAC) for atrial fibrillation (AF) and antiplatelet agents after percutaneous coronary intervention (PCI) for coronary artery disease (CAD). The aim of this study was to evaluate the relationship between BMI and clinical events in patients who underwent PCI under OAC therapy for AF., Method: This was a multicenter, observational cohort study conducted at 15 institutions in Japan. AF patients who underwent PCI with drug-eluting stents for CAD were retrospectively and prospectively included. Patients were divided into the Group 1 (BMI <21.3 kg/m2) and the Group 2 (BMI ≥21.3 kg/m2) according to the first-quartile value of BMI. The primary endpoint was net adverse clinical events (NACE), a composite of major adverse cardiovascular events (MACE) and major bleeding events within one year after index PCI procedure., Results: In the 720 patients, 180 patients (25.0%) had BMI value <21.3 kg/m2. While the rates of NACE and MACE were significantly higher in the Group 1 than the counterpart (21.1% vs. 11.9%, p = 0.003 and 17.2% vs. 8.9%, p = 0.004), that of major bleeding did not differ significantly between the 2 groups (5.6% vs. 4.3%, p = 0.54). The cumulative rate of NACE and MACE was significantly higher in the Group 1 than the Group 2 (both log-rank p = 0.002), although that of major bleeding events was equivalent between the 2 groups (log-rank p = 0.41). In multivariable Cox regression analyses, while BMI value <21.3 kg/m2 was not associated with major bleeding events, that cut-off value was an independent predictor for increased NACE and MACE., Conclusions: Among the patients undergoing PCI for CAD and requiring OAC for AF, BMI value was a useful indicator to predict major adverse clinical events., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Yamazaki et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background and Aim: New nomenclature of steatotic liver disease (SLD) including metabolic dysfunction-associated SLD (MASLD), MASLD and increased alcohol intake (MetALD), and alcohol-associated liver disease (ALD) has recently been proposed. We investigated clustering analyses to decipher the complex landscape of SLD pathologies including the former nomenclature of nonalcoholic fatty liver disease (NAFLD) and metabolic dysfunction-associated fatty liver disease (MAFLD)., Methods: Japanese individuals who received annual health checkups including abdominal ultrasonography (n = 15 788, men/women: 10 250/5538, mean age: 49 years) were recruited., Results: The numbers of individuals with SLD, MASLD, MetALD, ALD, NAFLD, and MAFLD were 5603 (35.5%), 4227 (26.8%), 795 (5.0%), 324 (2.1%), 3982 (25.8%), and 4946 (31.3%), respectively. Clustering analyses using t-distributed stochastic neighbor embedding and K-means to visually represent interconnections in SLDs uncovered five cluster formations. MASLD and NAFLD mainly shared three clusters including (i) low alcohol intake with relatively low-grade obesity; (ii) obesity with dyslipidemia; and (iii) dysfunction of glucose metabolism. Both MetALD and ALD displayed one distinct cluster intertwined with alcohol consumption. MAFLD widely shared all of the five clusters. In machine learning-based analyses using algorithms of random forest and extreme gradient boosting and receiver operating characteristic curve analyses, fatty liver index (FLI), calculated by body mass index, waist circumference, and levels of γ-glutamyl transferase and triglycerides, was selected as a useful feature for SLDs., Conclusions: The new nomenclature of SLDs is useful for obtaining a better understanding of liver pathologies and for providing valuable insights into predictive factors and the dynamic interplay of diseases. FLI may be a noninvasive predictive marker for detection of SLDs., (© 2024 The Authors. Journal of Gastroenterology and Hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Purpose: To evaluate the effectiveness and safety of pre-emptive transcatheter arterial embolization (P-TAE) for aortic side branches (ASBs) to prevent Type 2 endoleaks (EL2) before endovascular aneurysm repair (EVAR) using the Excluder stent-graft system (Excluder)., Materials and Methods: In this prospective, multicenter study, 80 patients (mean age, 79.1 years [SD ± 6.7]; 85.0% were men; mean aneurysmal sac diameter, 48.4 mm [SD ± 7.4]) meeting the eligibility criteria were prospectively enrolled from 9 hospitals. Before EVAR, P-TAE was performed to embolize the patent ASBs originating from the abdominal aortic aneurysm. Contrast-enhanced computed tomography (CT) was performed at 1 month and 6 months after EVAR. The primary endpoint was EL2 incidence at 6 months, and the secondary endpoints were aneurysmal sac diameter changes at 6 and 12 months, P-TAE outcomes, adverse events related to P-TAE, reintervention, and aneurysm-related mortality., Results: All patients successfully underwent P-TAE without serious. Coil embolization was successful in 81.6% of ASBs. EL2 incidence at 6 months was identified in 18 of 70 (25.7%) patients. Aneurysmal sac diameter shrinkage (≥5 mm) was observed in 30.0% of patients at 6 months and in 40.9% at 12 months. Only 1 patient required reintervention for EL2 within 1 year of EVAR; aneurysm-related deaths were not observed., Conclusions: P-TAE for ASBs before EVAR using Excluder is a safe and effective strategy. It aids in achieving early aneurysmal sac shrinkage and reduces EL2 reintervention at 1 year after EVAR., (Copyright © 2024 SIR. Published by Elsevier Inc. All rights reserved.)

Background: Convalescent plasma is a potential therapeutic option for patients with coronavirus disease 2019 (COVID-19). Despite its use for treating several viral infections, we lack comprehensive data on its efficacy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)., Methods: We conducted a multicenter, open-label, randomized controlled trial of convalescent plasma therapy with high neutralizing activity against SARS-CoV-2 in high-risk patients within five days after the onset of COVID-19 symptoms. The primary endpoint was the time-weighted average change in the SARS-CoV-2 viral load in nasopharyngeal swabs from days 0-5., Results: Between February 24, 2021, and November 30, 2021, 25 patients were randomly assigned to either convalescent plasma (n = 14) or standard of care (n = 11) groups. Four patients discontinued their allocated convalescent plasma, and 21 were included in the modified intention-to-treat analysis. The median interval between the symptom onset and plasma administration was 4.5 days (interquartile range, 3-5 days). The primary outcome of the time-weighted average change in the SARS-CoV-2 viral load in nasopharyngeal swabs did not significantly differ between days 0-5 (1.2 log 10 copies/mL in the convalescent plasma vs. 1.2 log 10 copies/mL in the standard of care (effect estimate, 0.0 [95% confidence interval, -0.8-0.7]; P = 0.94)). No deaths were observed in either group., Conclusions: The early administration of convalescent plasma with high neutralizing activity did not contribute to a decrease in the viral load within five days compared with the standard of care alone., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2023 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Background: Japan became the world's first country to cover Helicobacter pylori eradication for chronic gastritis under its National Health Insurance (NHI) system in February 2013. Thereafter, H. pylori eradication dramatically increased and gastric cancer deaths began to decrease in Japan. However, the details of gastric cancer deaths and its prevention in the very elderly have not been fully elucidated., Methods: We analyzed the temporal trend of gastric cancer deaths referencing data from Ministry of Health, Labour and Welfare reports and "Cancer Statistics in Japan-2021" and assessed the numbers of H. pylori test and gastric cancer screening using a national database and a report of cancer screening in Shimane Prefecture, respectively., Results: Although gastric cancer deaths in total population have clearly decreased since 2013, those in people aged 80 years and older are still increasing. People aged 80 years and older represent 9% of the total population and accounted for half of all gastric cancer deaths in 2020. The numbers of H. pylori eradication and gastric cancer screening in people aged 80 years and older were 25% and 25% of those in other generations, respectively., Conclusion: In spite of a dramatic increase in H. pylori eradication and a clear decrease in gastric cancer deaths in Japan, gastric cancer deaths in people aged 80 years and older are increasing. This might be due to fewer H. pylori eradication in the elderly than in other generations, indicating the difficulty of gastric cancer prevention in the very elderly., (© 2023 The Authors. Helicobacter published by John Wiley & Sons Ltd.)

Covert hepatic encephalopathy (CHE) impairs patient quality of life and occurs in approximately 30% of liver cirrhosis (LC) cases. Japanese clinical practice guidelines recommend rifaximin to treat overt HE (OHE). However, the usefulness of rifaximin against CHE is not thoroughly investigated in Japanese patients. We aimed to investigate the efficacy of rifaximin against hyperammonemia and CHE in Japan. We observed 102 patients with HE showing hyperammonemia secondary to LC and examined various biochemical and behavioral parameters following rifaximin treatment. CHE was diagnosed when the patients exhibited two or more abnormal neuropsychological test (NPT) scores but did not indicate OHE symptoms. In the 102 cases, a significant therapeutic effect of rifaximin on hyperammonemia was observed from 2 to 48 weeks after starting treatment. Excluding 10 patients diagnosed with OHE upon starting rifaximin treatment, 12 of the 92 remaining patients (11.8%) transitioned to OHE within 1 year. The 1 year cumulative OHE transition rate was 14.5%. Among the 24 patients with CHE diagnosed by the NPT for whom NPT results could be evaluated at 4 and 12 weeks after starting treatment, 10 (41.6%) had recovered from CHE at 12 weeks. When the factors contributing to recovery from CHE were examined by multivariate analysis, an ammonia level <129 μg/dL was a significant factor. Rifaximin was thus significantly effective against both hyperammonemia and CHE in Japanese patients., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests:Professor Naoya Sakamoto received lecture fees from Bristol Myers Squibb and Pharmaceutical K.K., grants and endowments from MSD K.K. and Chugai Pharmaceutical Co. Ltd, and a research grant from Gilead Sciences Inc. Dr. Goki Suda received research grants from Bristol Myers Squibb. The other authors have no relevant financial or non-financial interests to disclose. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Self-efficacy is crucial in improving medical students' communication skills. This study aims to clarify where medical students' self-efficacy is greatest following an interview with a simulated patient and subsequent feedback., Methods: A total of 162 medical students (109 men, 53 women) in their fourth or fifth year at a university in Japan participated in this study. The degree of self-efficacy in medical interviewing was measured before and after a medical interview with a simulated patient, and after the subsequent feedback session., Results: ANOVA analysis revealed that self-efficacy for medical interviews was higher after both the interview and the feedback session than before the interview. Among all three time points, self-efficacy was highest after the feedback session., Conclusions: Feedback following a simulated interview with a simulated patient is important to improve the self-efficacy of medical students when learning medical interviewing skills., (© 2022. The Author(s).)

Background: There is growing concern that screen time and media use in school-age children can negatively affect children's sleep. These negative effects are explained by three main underlying mechanisms: reduced sleep, time allocated for more media consumption; increased mental, emotional, or psychological stimulation by media content; and the effects of light emitted by digital devices on circadian rhythms and sleep physiology and arousal. In this study, we focused not only on sleep duration, but also on sleep problems. We conducted a large-scale survey to examine the relationship between excessive use of digital devices, Internet addictive behaviour, sleep duration, and sleep problems., Methods: We conducted a cross-sectional study of children enrolled in 20 public primary schools in Nagoya City, Japan. Children's parents/guardians completed a questionnaire including the brief sleep questionnaire for Japanese children which is a shortened version of the 'Children's Sleep Habits Questionnaire'. Logistic regression analyses were used to identify associations between sleep problems and grade, sex, weekday sleep time, weekend sleep time, ownership of digital devices, frequent checking of digital devices, use of digital devices for more than 4 hours per day, and Internet addiction., Results: In total, 8172 responses were received (91.6% response rate). After excluding incomplete responses, we analysed complete datasets for 6893 children with a mean age of 9.0 years. When adjusted for sex, grade, sleep duration on weekdays, and sleep duration on weekends, failure to control (odds ratio [OR] = 1.48; 95% confidence interval [CI]: 1.29-1.70; p < .001), more use than intended (OR = 1.27; 95% CI: 1.12-1.44; p < .001), and use to escape a dysphoric mood (OR = 1.30; 95% CI: 1.03-1.64; p = .027) were associated with children's sleep problems. A shorter weekday and a longer weekend sleep duration indicated a higher likelihood of sleep problems., Conclusions: After adjusting for sleep duration, a relationship was found between the three Internet addictive behaviours and sleep problems, but not ownership of digital devices. Parents and teachers may need to address screen media-related sleep problems in children, as these problems may be influenced by psychological factors., (© 2022. The Author(s).)

Background: The Asian Working Group for Sarcopenia 2019 (AWGS 2019) is the gold standard diagnostic criteria for sarcopenia in Asian populations. The calf circumference (CalF), the strength, assistance in walking, rising from a chair, climbing stairs, and falls (SARC-F) and the SARC-CalF questionnaires for sarcopenia screening have been used by AWGS 2019. The aim of this study was to assess accuracy of these three sarcopenia screening tools in patients with interstitial lung disease., Methods: In this cross-sectional study, stable patients with interstitial lung disease were enrolled. The SARC-F, SARC-CalF, and CalF, used in patients with interstitial lung disease, were compared to the diagnostic criteria proposed by AWGS 2019. The accuracy of screening tools was compared using sensitivity and specificity. Moreover, areas under the receiver operating characteristic curves (AUC) were computed., Results: Seventy eight patients were analyzed, and sarcopenia was identified in 25 (32.1%) patients with interstitial lung disease by the AWGS 2019 criteria. The sensitivity of the CalF was highest (96%) of the three screening tools, while the specificity was 60%. The sensitivity of SARC-F and SARC-CalF were 24% and 68%, while the specificity were 92% and 66%, respectively. The AUCs of CalF, SARC-F, and SARC-CalF in all patients were 0.78, 0.58, and 0.67, respectively., Conclusions: The CalF is most suitable for screening sarcopenia in patients with interstitial lung disease, while SARC-F and SARC-CalF are not., (© 2022. The Author(s).)

Background: The attainment of drug resistance in gastric cancer (GC) is a problematic issue. Although many studies have shown that cancer stem cells (CSCs) play an important role in the acquisition of drug resistance, there is no clinically available biomarker for predicting oxaliplatin (L-OHP) resistance in relation to CSCs. Organoid technology, a novel 3D cell culture system, allows harboring of patient-derived cancer cells containing abundant CSCs using niche factors in a dish., Methods: In this study, we established L-OHP-resistant gastric cancer organoids (GCOs) and evaluated their gene expression profile using microarray analysis. We validated the upregulated genes in the L-OHP-resistant GCOs compared to their parental GCOs to find a gene responsible for L-OHP resistance by qRT-PCR, immunohistochemistry, in vitro, and in vivo experiments., Results: We found myoferlin (MYOF) to be a candidate gene through microarray analysis. The results from cell viability assays and qRT-PCR showed that high expression of MYOF correlated significantly with the IC50 of L-OHP in GCOs. Immunohistochemistry of MYOF in GC tissue samples revealed that high expression of MYOF was significantly associated with poor prognosis, T grade, N grade, and lymphatic invasion, and showed MYOF to be an independent prognostic indicator, especially in the GC patients treated with platinum-based chemotherapy. The knockdown of MYOF repressed L-OHP resistance, cell growth, stem cell features, migration, invasion, and in vivo tumor growth., Conclusions: Our results suggest that MYOF is highly involved in L-OHP resistance and tumor progression in GC. MYOF could be a promising biomarker and therapeutic target for L-OHP-resistant GC cases., (© 2021. The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)

Purpose: Pneumonia is a major cause of respiratory-related hospitalization and an important prognostic factor in patients with chronic interstitial lung disease (ILD). However, the relationship between the incidence of pneumonia and human leukocyte antigen (HLA) serotype has not been fully elucidated. Therefore, this study aimed to determine if there is a relationship between HLA serotype and the incidence of pneumonia in Japanese patients with ILD., Methods: The medical records of patients with ILD treated at any of three centers in Japan were reviewed to determine their HLA-A and HLA-B serotypes. The characteristics of patients with and without pneumonia were compared. Cox regression analysis was performed to identify risk factors for pneumonia and death in these patients., Results: One hundred and forty-four patients with ILD (pneumonia group, n = 27; non-pneumonia group, n = 117) and complete HLA serology data available were included. HLA-B54 positivity was significantly more common in the pneumonia group than in the non-pneumonia group (37.0% vs. 15.4%, p = 0.010). HLA-B54 positivity was also a significant risk factor for pneumonia (hazard ratio [HR] 4.166, 95% confidence interval [CI] 1.862-9.320, p = 0.001) and death (HR 4.050, 95% CI 1.581-10.374, p = 0.004) in patients with ILD. Furthermore, HLA-B54 positivity was a significant risk factor for pneumonia (HR 3.964, 95% CI 1.392-11.090, p = 0.010) and death (HR 8.131, 95% CI 1.763-37.494, p = 0.007) in patients with idiopathic pulmonary fibrosis., Conclusion: HLA-B54 positivity was a significant risk factor for pneumonia and death in patients with ILD, including those with idiopathic pulmonary fibrosis., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Sessile serrated lesion (SSL) is a colorectal polyp that has malignant potential. However, the dysplastic components within an SSL can be difficult to diagnose with conventional endoscopy, because most SSLs with dysplasia/carcinoma have subtle mucosal features. Many studies have indicated that narrow-band imaging (NBI) observations of colorectal polyps are very useful, accurate predictors of histology. We aimed to verify the usefulness of the Japan NBI Expert Team (JNET) classification system for the diagnosis of SSLs with dysplasia/carcinoma., Methods: We examined 709 endoscopically or surgically resected lesions that were pathologically diagnosed as SSL, including 647 with no dysplasia, 37 with low-grade dysplasia, 15 with high-grade dysplasia, and 10 with submucosal invasive carcinoma. We retrospectively evaluated their clinicopathologic characteristics and conventional endoscopic and magnifying NBI endoscopic findings using the JNET system., Results: Cases in all groups were more frequently located in the proximal colon. Submucosal invasive carcinomas were significantly larger than no dysplasia and low-grade dysplasia lesions. Almost all studied lesions (96.3%) were covered with a mucus cap. Five hundred and eighty (81.8%) lesions exhibited dark spots inside the crypts, which are NBI findings' characteristic of SSL. As for the JNET classification of magnifying NBI endoscopic findings, all 709 lesions showed Type 1. Six hundred and eighteen (95.5%) SSLs with no dysplasia lesions exhibited Type 1 only, whereas 52 (83.9%) SSLs with dysplasia/carcinoma had a combination of Type 1 and Type 2A, 2B, or 3, corresponding to SSL and dysplasia/carcinoma, respectively. The JNET classification had high sensitivity (83.9%), specificity (95.5%), and overall diagnostic accuracy (94.5%) for diagnosing SSLs with dysplasia/carcinoma., Conclusions: Use of magnifying NBI endoscopy with the JNET classification might be useful for diagnosing SSLs with dysplasia/carcinoma. This increased awareness may also improve the recognition of SSLs with dysplasia/carcinoma.

Renal dysfunction and sarcopenia are important prognostic factors in patients with chronic liver disease (CLD). Muscle atrophy can cause the overestimation of renal function based on serum creatinine. However, the frequency of overestimated renal function in Japanese patients with CLD and its relationship with sarcopenia are unclear. In present study, we evaluated the frequency of overestimated renal function, defined as a >20% higher eGFR using creatinine than using cystatin C, in 307 patients with CLD as well as its relationship with indicators of sarcopenia. In total, 24.8% of patients had overestimated renal function. In a multivariate regression analysis, liver cirrhosis ( p = 0.004) and psoas muscle mass index ( p = 0.049) were significantly associated with overestimated renal function. Loss of skeletal muscle mass was significantly more frequent in both male and female patients with overestimated renal function than without. In males, the loss of muscle strength and rate of sarcopenia, defined as loss of muscle mass and strength, were significantly higher in patients with than without overestimated renal function. The high frequency of overestimated renal function in Japanese patients suggests that indicators of renal function should be carefully considered; furthermore, monitoring and interventions for both renal function and sarcopenia are needed in patients with CLD.

Introduction: Idiopathic pulmonary fibrosis (IPF) is a fibrotic disease of unknown aetiology with a poor prognosis. Several clinical trials of nintedanib in patients with IPF have reported its inhibitory effect on reduced lung function, incidence of acute exacerbation of IPF and worsened health-related quality of life. Although nintedanib has a manageable safety and tolerability profile over long-term use, it was discontinued in over 20% of patients because of adverse events such as diarrhoea and liver dysfunction. This might explain why nintedanib use in patients with IPF is not widespread, especially among patients with early-stage IPF. In the present study, we aimed to clarify the efficacy, safety and tolerability of nintedanib in patients with stage I/II IPF, based on the Japanese IPF disease severity staging classification system., Methods and Analysis: This is an ongoing, prospective, multicentre observational cohort study of patients with stage I/II IPF who will start receiving nintedanib. Totally, 215 patients at 35 sites in Kyushu and Okinawa, Japan will be enrolled and followed up for 3 years. Nintedanib therapy would be initiated at the discretion of the investigator. The primary endpoint, change in forced vital capacity (FVC) at 156 weeks, will be shown as the mean change in FVC from baseline to week 156 with 95% CIs estimated using the Wald method. The safety endpoint-occurrence of adverse events-will be assessed in each system organ class/preferred term., Ethics and Dissemination: The study protocol and informed consent documents were approved by the Institutional Review Board at Nagasaki University Hospital (approval number 19102146) and each participating site. Written informed consent was obtained from all participants. Patient recruitment has begun. The results will be disseminated through scientific peer-reviewed publications and national and international conferences., Trial Registration Number: UMIN000038192., Competing Interests: Competing interests: NS, NHam, MO, KT, HIch, HIsh, KI and HM received lecture fees from the Nippon Boehringer Ingelheim., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Aim: Endoscopic balloon dilation (EBD) is effective for esophageal stenosis caused by ESD. However, an efficient EBD method has not been established. We, therefore, conducted EBD experiments on porcine esophageal stenosis models., Methods: Study 1: in dilation models (day 22 after ESD), the thickness of the outer muscle layer (as an index of the extension effect) and the area of muscle fiber bundle necrosis in the inner muscle layer (as an index of thermal damage) were evaluated. Study 2: in restenosis models (day 43 after ESD), the thickness of the fibrous plexus (as an index of restenosis) was evaluated. In total, 12 porcine models were created., Results: Study 1: the thickness of the outer muscle layer was 1243 ± 322 μm in surrounding locations and it was 803 ± 145 μm beneath the laceration (p = 0.005). In cases of muscular layer injury, the area of necrosis was 15,500 ± 10400 μm 2 in surrounding locations and it was 40,200 ± 12900 μm 2 at the laceration site (p < 0.001). Study 2: the thickness of the fibrous plexus was 1359 ± 196 μm in surrounding locations and it was 1322 ± 136 μm 2 in the laceration scar site (p = 0.74)., Conclusion: Since thermal damage persists until the completion of stenosis, EBD in the initial stage should be carefully performed. An extension effect was observed only at the laceration site and it later returned to a status similar to that of surrounding locations. Additional intervention would be required for preventing restenosis.

This study examined the association of green tea consumption with influenza among Japanese workers in the Kanto and Tokai areas. We conducted a case-control study in a cohort of 4302 workers. Consumption frequency of green tea in 2011 and physician-diagnosed influenza that occurred over the winter season from November 2011 through April 2012 were ascertained using a self-administered questionnaire. Two controls matched by company, sex, and age (and checkup date in one company) were randomly selected for each case. Odds ratio of influenza were estimated by conditional logistic regression. One hundred and seventy-nine cases and 353 controls with complete data were included in the analysis. Green tea consumption was significantly associated with decreased odds of developing influenza; the multivariable-adjusted odds ratio for green tea consumption of ≥5 cups/week was 0.61 (95% CI 0.39-0.95) compared with <1 cup/week (P for trend = 0.028). When analysis was restricted to cases confirmed using a diagnostic kit, the corresponding value was 0.68 (95% CI 0.39-1.18; P for trend = 0.16). Our data suggest that green tea consumption is associated with a lower risk of influenza. The present findings require confirmation in large-scale prospective studies using diagnostic tool for influenza infection.

Background: Carbapenemase-producing Enterobacterales (CPE) are spreading in hospitals, environment and retail foods in Yangon, Myanmar., Objectives: To investigate whether CPE colonize healthy individuals living in Yangon and whether clinical-related strains are spreading in the community., Methods: CPE was isolated from faecal samples obtained from healthy Japanese residents of Yangon with no history of hospitalization. Isolates were subjected to WGS using short- and long-read sequencers and compared with those previously isolated in Yangon., Results: Six Escherichia coli strains harbouring blaNDM-1 or blaNDM-5 belonging to five different STs-ST10, ST38, ST48, ST410 and ST8453-were isolated from 69 volunteers. The ST38 isolates were related to those previously isolated from retail food in Yangon. The ST410 and ST8453 isolates were highly related to previous Yangon isolates including those of clinical and food origins., Conclusions: The analysis suggested the acquisition of blaNDM-positive E. coli, which are disseminating in a clinical setting and through retail foods, by healthy residents in Yangon., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: The epidemiology of infectious diseases in Japan remains undefined despite the increasing tourism. GeoSentinel, an epidemiological surveillance system for reporting imported infectious diseases, has only two participating facilities in Japan. Although the number of infectious diseases is reported by the National Institute of Infectious Diseases, there is no detailed clinical information about these cases. Therefore, we established J-RIDA (Japan Registry for Infectious Diseases from Abroad) to clarify the status of imported infectious diseases in Japan and provide detailed information., Methods: J-RIDA was started as a registry of imported infectious diseases. Case registration began in October 2017. Between October 2017 and September 2019, 15 medical institutions participated in this clinical study. The registry collected information about the patient's age, sex, nationality, chief complaint, consultation date, date of onset, whether visit was made to a travel clinic before travel, blood test results (if samples were collected), travel history, and final diagnosis., Results: Of the 3046 cases included in this study, 46.7% to Southeast Asia, 13.0% to Africa, 13.7% to East Asia, 11.5% to South Asia, 7.5% to Europe, 3.8% to Central and South America, 4.6% to North America, 3.9% to Oceania, and 2.8% to Central and west Asia. More than 85% of chief complaints were fever and general symptoms, gastrointestinal symptoms, respiratory symptoms, or dermatologic problems. The most common diseases were travelers' diarrhea, animal bite, upper respiratory infection, influenza, and dengue fever., Conclusions: We summarized two-year cases registered in Japan's imported infectious disease registry. These results will significantly contribute to the epidemiology in Japan., Competing Interests: Declaration of competing interest None declared., (Copyright © 2020 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Short-term exposure to ozone and nitrogen dioxide is a risk factor for acute exacerbation (AE) of idiopathic pulmonary fibrosis (AE-IPF). The comprehensive roles of exposure to fine particulate matter in AE-IPF remain unclear. We aim to investigate the association of short-term exposure to fine particulate matter with the incidence of AE-IPF and to determine the exposure-risk time window during 3 months before the diagnosis of AE-IPF., Methods: IPF patients were retrospectively identified from the nationwide registry in Japan. We conducted a case-control study to assess the correlation between AE-IPF incidence and short-term exposure to eight air pollutants, including particulate matter < 2.5 µm (PM 2.5 ). In the time-series data, we compared monthly mean exposure concentrations between months with AE (case months) and those without AE (control months). We used multilevel mixed-effects logistic regression models to consider individual and institutional-level variables, and also adjusted these models for several covariates, including temperature and humidity. An additional analysis with different monthly lag periods was conducted to determine the risk-exposure time window for 3 months before the diagnosis of AE-IPF., Results: Overall, 152 patients with surgically diagnosed IPF were analyzed. AE-IPF was significantly associated with an increased mean exposure level of nitric oxide (NO) and PM 2.5 30 days prior to AE diagnosis. Adjusted odds ratio (OR) with a 10 unit increase in NO was 1.46 [95% confidence interval (CI) 1.11-1.93], and PM 2.5 was 2.56 (95% CI 1.27-5.15). Additional analysis revealed that AE-IPF was associated with exposure to NO during the lag periods lag 1, lag 2, lag 1-2, and lag 1-3, and PM 2.5 during the lag periods lag 1 and lag 1-2., Conclusions: Our results show that PM 2.5 is a risk factor for AE-IPF, and the risk-exposure time window related to AE-IPF may lie within 1-2 months before the AE diagnosis. Further investigation is needed on the novel findings regarding the exposure to NO and AE-IPF.

A deteriorated liver functional reserve during systemic therapy for unresectable hepatocellular carcinoma (HCC) causes poor patient outcomes. We aimed to identify predictive factors associated with the deterioration of Child-Pugh score at 8 weeks after lenvatinib initiation. Patients with adequate clinical data and baseline preserved serum samples available were included. Baseline fibroblast growth factor (FGF)19 and 21, angiopoietin (ANG)2, and vascular endothelial growth factor (VEGF) levels were evaluated. Thirty-seven patients were included, and 6, 15, 14, and 2 experienced complete response, partial response, stable disease, and progressive disease, respectively. Twenty-four (65%) and 13 (35%) patients showed a maintained/improved and deteriorated Child-Pugh-score, respectively. While baseline clinical data, treatment response, and laboratory data were similar between these two patient groups, baseline ANG2 and VEGF levels were significantly higher (P = 0.0017) and lower (P = 0.0231), respectively, in patients with deteriorated Child-Pugh score than in those without. Based on receiver operating characteristic curve analysis, cut-off values for ANG2 and VEGF were found to be 3,108 pg/mL and 514.9 pg/mL, respectively. Among patients with low VEGF and high ANG2, 89% (8/9) exhibited a deteriorated Child-Pugh score, whereas none of the patients (0/9) with high VEGF and low ANG2 did. The deterioration of the Child-Pugh score in patients with unresectable HCC who are treated with lenvatinib may be predictable based on combined baseline serum ANG2 and VEGF levels., Competing Interests: Professor Naoya Sakamoto has received lecture fees from Bristol Myers Squibb and Pharmaceutical K.K., grants and endowments from MSD, K.K., and Chugai Pharmaceutical Co., Ltd., and a research grant from Gilead Sciences Inc. and AbbVie GK. Dr. Goki Suda has received research grants from Merck & Co, Gilead Sciences Inc., and Bristol Myers Squibb. The other authors have no conflicts of interest to disclose. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Acute kidney injury usually assessed within 48 h after percutaneous coronary intervention (PCI) is associated with poor clinical outcomes, and persistent kidney damage is also strongly related to long-term mortality. However, little is known about longitudinal renal function change from a very early period to long-term follow-up after PCI. A total of 327 patients with stable coronary artery disease underwent elective PCI. Renal function was assessed with serum creatinine levels and estimated glomerular filtration rate (eGFR) at baseline, 1 day after PCI, at 1 year and at the latest follow-up. Kidney injury was defined as an increase in creatinine levels ≥ 0.3 mg/dl or ≥ 50% from baseline at each timepoint. Major adverse cardiovascular events (MACE) was defined as a composite of death, myocardial infarction, and stroke. eGFR was significantly increased 1 day after PCI, while it was progressively decreased at 1-year and long-term follow-up (median 28 months). Overall, eGFR was declined by - 2.3 ml/min/1.73 m 2 per year. Only one (0.3%) patient developed kidney injury 1 day after PCI, whereas kidney injury at 1-year and long-term follow-up was observed in 15 (4.6%) and 27 (8.3%). During the follow-up period, 23 (7.0%) patients had MACE. The incidence of subsequent MACE was significantly higher in patients with kidney injury at 1 year than those without. In conclusion, kidney injury within 24 h after elective PCI was rarely observed. eGFR was progressively decreased over time, and mid-term kidney injury at 1 year was associated with future MACE.

Background: Polymyositis/dermatomyositis (PM/DM) is an autoimmune disease that is sometimes complicated with rapidly progressive interstitial lung disease (RPILD). However, serum and lung biomarkers that can predict RPILD development remain unclear., Objectives: To determine potential serum and lung biomarkers that can predict RPILD development in patients with PM/DM-ILD., Methods: In total, 49 patients with PM/DM-ILD were enrolled. We measured the serum levels of 41 cytokines/chemokines, ferritin and anti-MDA5 antibody, compared them between the RPILD (n = 23) and non-RPILD (n = 26) groups, and ranked them by their importance through random forest analysis. To distinguish the two groups, we determined biomarker combinations by logistic regression analysis. We also measured the bronchoalveolar lavage fluid (BALF) levels of 41 cytokines/chemokines. Using immunohistochemistry, we examined IL-15 expression in lung tissues. The IL-15 production was also investigated using A549 and BEAS-2B cells., Results: The RPILD group had significantly higher IL-15, IL-1RA, IL-6, CXCL10, VCAM-1, anti-MDA5 antibody and ferritin serum levels than the non-RPILD group, but it had a significantly low CCL22 level. Meanwhile, anti-MDA5 antibody, IL-15, CXCL8, CCL22, IL-1RA and ferritin were the best combination to distinguish the two groups. IL-15 and CCL22 were also predictive marker for RPILD development in anti-MDA5 antibody-positive patients. Additionally, the RPILD group had significantly high IL-15 levels in BALF. The lung tissues expressed IL-15, which increased after cytokine stimulation in the A549 cells., Conclusion: This study identified a combination of biomarkers predicting PM/DM-RPILD progression, and IL-15 is an important cytokine for predicting RPILD development and reflecting ILD severity., (© 2020 The Association for the Publication of the Journal of Internal Medicine.)

Introduction: We reported, in our previous study, a patient with coronavirus disease 2019 (COVID-19) who was successfully treated with extracorporeal membrane oxygenation. Data on clinical courses and outcomes of critically ill patients with COVID-19 in Japan are limited in the literature. This study aimed to describe the clinical courses and outcomes of critically ill patients with COVID-19 in Tokyo, Japan., Methods: This is a single-center case series study. Patients with COVID-19 treated with mechanical ventilation (MV) were reviewed retrospectively. Data on baseline characteristics, in-hospital treatment, and outcomes were collected., Results: Between February 2, 2020, and June 30, 2020, 14 critically ill patients with COVID-19 were treated with MV. Most patients were male and had comorbidities, especially hypertension or diabetes; 35.7% were overweight and 21.4% were obese. The majority of the patients had dyspnea on admission. The median duration of MV was 10.5 days, and the 28-day mortality rate was 35.7%. In the four patients with COVID-19 who died, the cause of death was respiratory failure., Conclusions: As in previous reports from other countries, the mortality rate of patients with COVID-19 requiring intensive care remains high in Tokyo. Further study on the appropriate timing of MV initiation and specific treatments for critically ill patients with COVID-19 is needed., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

We report an unusual case of acute myocardial infarction in a high school girl. The patient was 17 years of age and had multiple coronary risk factors, including marked obesity with a body mass index (BMI) of 42.7 kg/m 2 , dyslipidemia and glucose intolerance. She had been an on and off smoker since she was 13 years of age. Due to the recent Westernization of the lifestyle, the prevalence of metabolic syndrome in the young generation has been increasing in Japan. Cardiovascular disease based on lifestyle-related diseases may become more common in young people.

Objectives Osteogenesis imperfecta (OI) is a skeletal dysplasia characterized by recurrent fractures due to congenital bone fragility. The only bisphosphonate approved for OI in Japan is pamidronate (PAM). To investigate whether monthly intravenous alendronate (ALN) infusions can maintain bone strength in OI children following cyclical PAM treatment. Methods A prospective and non-inferiority study was conducted. Eight school-age OI patients aged 8.5±2.0 years who were treated with cyclical PAM for 6.0±2.3 years were enrolled and switched to monthly intravenous ALN (0.030 mg/kg/month). Changes in L1-4 bone mineral density (BMD) Z-scores, fracture rates, and bone turnover markers for 12 months were analyzed. Results Average BMD Z-scores were -3.0±1.9, -2.9±2.0, and -2.2±2.0 in 12 months before enrollment, at enrollment, and after 12 months of ALN treatment, respectively. BMD Z-scores increased significantly during treatment with both PAM and ALN (p=0.012), and the effect of ALN was not inferior to that of PAM (p=0.67). There was no change in fracture rates (p=0.86) and bone turnover markers during the 12 months before and after enrollment. Additionally, ALN showed no remarkable side effects. Conclusions Our results suggest that monthly intravenous ALN can maintain bone strength after primary usage of cyclical PAM. We concluded that monthly intravenous ALN as a maintenance treatment following cyclical PAM administration can be an option for OI children.

Background and Aim: Immune checkpoint inhibitors (ICI) have revolutionized anti-malignancy therapy and thus have been increasingly used. Although ICI may cause immune-related adverse events (irAE) in various organs, including the liver, the prevalence and predictive factors of irAE have not been clarified., Methods: In this retrospective study, consecutive patients who had malignancies and were treated with ICI without other chemotherapeutic agents at Hokkaido University Hospital between 2014 and 2019 were screened. Patients were excluded if they were < 20 years old and had insufficient clinical data., Results: Of the 233 patients screened, 202 patients met the inclusion criteria and were included in the analysis. The patients were aged 25-92 years, and 60.9% were male. The patients received nivolumab (n = 137), pembrolizumab (n = 45), ipilimumab (n = 17), atezolizumab (n = 2), and avelumab (n = 1). The prevalence of any grade and grade ≥ 3 irAE hepatitis was 8.4% (17/202) and 4.0% (8/202), respectively. irAE hepatitis occurred at a median duration of 42 days in any grade and 36 days in grade ≥ 3 after ICI initiation. The clinical course of grade ≥ 3 irAE hepatitis was generally favorable; however, 50% required corticosteroid treatment and two patients required additional mycophenolate mofetil. Female sex and history of ICI treatment were significantly associated with the incidence of grade ≥ 3 irAE hepatitis., Conclusions: Grade ≥ 3 irAE hepatitis was observed in 4.0% of the patients who were treated with ICI. Female sex and history of ICI treatment were significantly associated with the incidence of grade ≥ 3 irAE hepatitis., (© 2020 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Introduction: An ongoing outbreak of a novel coronavirus disease (coronavirus disease 2019, COVID-19) has become a global threat. While clinical reports from China to date demonstrate that the majority of cases remain relatively mild and recover with supportive care, it is also crucial to be well prepared for severe cases warranting intensive care. Initiating appropriate infection control measures may not always be achievable in primary care or in acute-care settings., Case: A 45-year-old man was admitted to the intensive care unit due to severe pneumonia, later confirmed as COVID-19. His initial evaluation in the resuscitation room and treatments in the intensive care unit was performed under droplet and contact precaution with additional airborne protection using the N95 respirator mask. He was successfully treated in the intensive care unit with mechanical ventilation and extracorporeal membrane oxygenation for respiratory support; and antiretroviral treatment with lopinavir/ritonavir. His total intensive care unit stay was 15 days and was discharged on hospital day 24., Conclusions: Strict infection control precautions are not always an easy task, especially under urgent care in an intensive care unit. However, severe cases of COVID-19 pneumonia, or another novel infectious disease, could present at any moment and would be a continuing challenge to pursue appropriate measures. We need to be well prepared to secure healthcare workers from exposure to infectious diseases and nosocomial spread, as well as to provide necessary intensive care., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Objectives: To analyse plasmids carrying bla IMP-6 in Klebsiella pneumoniae isolates obtained from multicentre carbapenem-resistant Enterobacteriaceae surveillance., Methods: Plasmids harbouring bla IMP-6 were characterised by the whole-genome sequencing of four Klebsiella pneumoniae isolates carrying bla IMP-6 , and compared with the pKPI-6 plasmid, which is widespread in western Japan, through pulsed-field gel electrophoresis, Southern blotting, bacterial conjugation, and qPCR., Results: Whole-genome sequencing analysis revealed that three of the four isolates carried approximately 50 kbp plasmids similar to the pKPI-6 plasmid; however, one isolate carried a 250 kbp plasmid harbouring bla IMP-6 (pE196&#95;IMP6). So far, all of the reported plasmids carrying bla IMP-6 were similar to the pKPI-6 plasmid, and this plasmid was a novel bla IMP6 -carrier. The size and transferability of this plasmid was confirmed by Southern hybridisation and conjugation experiments. It was demonstrated that the generation of plasmid pE196&#95;IMP6 was due to an intramolecular transposition mediated by IS26, and a homologous recombination between plasmids pKPI-6 and pE013 that was obtained from another carbapenem-resistant Enterobacteriaceae isolate in this analysis. As a result of co-integration with pE013, pE196&#95;IMP6 acquired six additional pairs of type II toxin-antitoxin systems that pKPI-6 does not carry. Transcription of all of the toxin-antitoxin systems were confirmed in an isolate carrying pE196&#95;IMP6 by qPCR., Conclusions: This study detected a novel plasmid carrying bla IMP-6 , and revealed the origin of this plasmid. Toxin-antitoxin system acquisition could enable pE196&#95;IMP6 maintenance persistently through successions, even without selection pressure by the clinical usage of antimicrobials, generating broad dissemination and longer carbapenem-resistant Enterobacteriaceae colonisation duration in patients., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The efficacy, safety, and pharmacokinetics of the combination of three direct-acting antiviral (DAA) agents (adafosbuvir [also known as AL-335], odalasvir, and simeprevir) were investigated in DAA treatment-naïve Japanese patients with genotype (GT)1 or GT2 chronic hepatitis C virus (HCV) infection, with or without compensated cirrhosis., Methods: In this Phase IIa, open-label, multicenter study-OMEGA-3 (NCT02993250)-patients received JNJ-4178 (adafosbuvir 800 mg once daily [QD], odalasvir 25 mg QD, and simeprevir 75 mg QD) for 8 (non-cirrhotic patients; Cohort 1) or 12 (cirrhotic patients; Cohort 2) weeks. Patients were followed-up to 24 weeks following the end of treatment (EOT). The primary endpoint was safety, including adverse events (AEs)., Results: Overall, 33 patients were enrolled into Cohort 1 (N = 22) or 2 (N = 11) and received combined treatment with JNJ-4178. During the treatment and follow-up phases, a higher percentage of patients in Cohort 2 (81.8%) experienced AEs compared with Cohort 1 (68.2%), but the incidence of treatment-related AEs was similar. Most AEs were mild-to-moderate in severity and no patients discontinued due to an AE. There was one serious AE (cataract) in a patient in Cohort 2, which was not considered related to treatment. All patients achieved sustained virologic response 12 weeks after EOT (SVR12). No incidences of viral relapse were observed during follow-up., Conclusions: In HCV GT1- and GT2-infected Japanese patients, treatment with JNJ-4178 was well tolerated and resulted in 100% of patients achieving SVR12.

Rationale: Acute exacerbation during the course of idiopathic pulmonary fibrosis causes a poor prognosis. Coagulation abnormalities and endothelial damage are involved in its pathogenesis. Thrombomodulin alfa, a recombinant human soluble thrombomodulin, has anticoagulant and antiinflammatory effects. Several clinical studies have shown that thrombomodulin alfa may improve survival of acute exacerbation. Objectives: To determine the efficacy and safety of thrombomodulin alfa compared with placebo in acute exacerbation of idiopathic pulmonary fibrosis. Methods: This randomized, double-blind placebo-controlled phase 3 study conducted at 27 sites in Japan involved patients with an acute exacerbation of idiopathic pulmonary fibrosis. Subjects were randomized 1:1 to receive placebo or thrombomodulin alfa (380 U/kg/d for 14 d by intravenous drip infusion). All subjects were treated with high-dose corticosteroid therapy. The primary endpoint was the survival proportion on Day 90. Measurements and Main Results: Of the 82 randomized subjects, 77 completed the study and were included in the full analysis set (thrombomodulin alfa, n  = 40; placebo, n  = 37). The survival proportions on Day 90 were 72.5% (29 of 40) in the thrombomodulin alfa group and 89.2% (33 of 37) in the placebo group, a difference of -16.7 percentage points (95% confidence interval, -33.8 to 0.4%; P  = 0.0863). In the safety population ( n  = 80), bleeding adverse events occurred in the thrombomodulin alfa group (10 of 42; 23.8%) and the placebo group (4 of 38; 10.5%). Conclusions: Thrombomodulin alfa did not improve the 90-day survival proportion. The present results suggest that the use of thrombomodulin alfa for the treatment of acute exacerbation of idiopathic pulmonary fibrosis not be recommended.Clinical trial registered with www.clinicaltrials.gov (NCT02739165).

Aims/introduction: We examined the association between hemoglobin A1c (HbA1c) and anemia, which was categorized into three groups according to mean corpuscular volume (MCV), as well as the association between hemoglobin in the non-anemic range and HbA1c., Materials and Methods: We used the 2016 health checkup data from 36,422 workers without diabetes. Anemic people were divided into three groups based on MCV: <80, 80-90 and >90 fL. Non-anemic people were divided into four groups based on their hemoglobin levels. We carried out multiple linear regression models to estimate the means and 95% confidence intervals (CIs) of HbA1c., Results: For men, 0.2% had anemia with MCV <80 fL, 0.5% had anemia with MCV 80-90 fL, 0.9% had anemia with MCV >90 fL and 98.4% had no anemia. For women, the corresponding values were 6.1, 6.4, 2.8 and 84.7%, respectively. The adjusted mean HbA1c (%) values for men with anemia with MCV <80, 80-90 and >90 fL were 5.67 (95% CI 5.60-5.74), 5.58 (95% CI 5.54-5.62) and 5.41 (95% CI 5.37-5.44), respectively. Among men without anemia, HbA1c (%) increased from 5.36 (95% CI 5.34-5.39) in those with hemoglobin ≥17.5 mg/dL to 5.45 (95% CI 5.45-5.46) in those with hemoglobin 13.0 to <14.5 mg/dL (P for trend <0.001). The HbA1c values were higher in men with anemia with MCV <80 fL or MCV 80-90 fL, but lower in men with MCV >90 fL, compared with non-anemic men with hemoglobin 13.0 to <14.5 mg/dL (All P < 0.001). Similar findings were observed in women., Conclusions: We observed elevated HbA1c among anemic people with MCV <80 fL or MCV 80-90 fL, and decreased HbA1c among anemic people with MCV >90 fL, suggesting that different types of anemia might influence HbA1c differently. In addition, non-anemic people with lower hemoglobin levels had higher HbA1c levels, suggesting that hemoglobin levels are in need of consideration when interpreting HbA1c values among non-anemic people., (© 2019 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

For women with gestational diabetes mellitus (GDM), the evaluation of glucose tolerance (GT) in the early postpartum period is universally recommended. Nevertheless, few studies have evaluated the risk factors for T2DM on the basis of GT data obtained during the early postpartum period. We aimed to identify the risk factors for type 2 diabetes mellitus (T2DM) by evaluating GT in the first 12 weeks postpartum (12wPP) in women with GDM and to categorize the risk using a combination of the principal risk factors. This retrospective multicenter observational study included 399 East Asian women with GDM who underwent a 75-g oral glucose tolerance test (OGTT) within 12wPP, which was repeated annually or biennially and used to identify the postpartum development of T2DM. Forty-three women (10.8%) developed T2DM during a median follow-up period of 789 ± 477 days. The independent risk factors for T2DM were pre-pregnancy obesity (BMI ≥25 kg/m 2 ), early postpartum impairment in glucose tolerance (IGT), and an early postpartum glycated hemoglobin (HbA1c) ≥5.7%. The odds ratios (95% confidence intervals) for T2DM were 3.2 (1.3-7.8) in women with either early postpartum IGT or pre-pregnancy obesity, 9.2 (3.0-28.3) in those with early postpartum IGT, pre-pregnancy obesity, and HbA1c <5.7%, and 51.4 (16.1-163.9) in those with early postpartum IGT, pre-pregnancy obesity, and HbA1c ≥5.7%, compared with those without obesity or IGT. T2DM risk in East Asian women with GDM should be stratified according to pre-pregnancy obesity and early postpartum IGT, and these patients should be followed up and receive appropriate care for their risk category.

Background: The incidence of post-ERCP pancreatitis (PEP) has been reported to be significantly higher in patients without main pancreatic duct (MPD) obstruction who undergo transpapillary biliary metal stent (MS) placement than in those with ordinary ERCP setting. Objective: To evaluate the benefit of endoscopic sphincterotomy (ES) prior to MS placement in preventing PEP in patients with distal malignant biliary obstruction (MBO) without MPD obstruction. Materials and methods: In total, 160 patients who underwent initial MS placement for MBO were enrolled. Eighty-two patients underwent ES immediately prior to MS placement, whereas 78 underwent MS placement without ES. An inverse probability of treatment weighting method was adopted to adjust the differences of the patients' characteristics. The primary outcome was the incidence of PEP. The secondary outcomes included the incidence of other adverse events (bleeding, cholangitis, perforation and stent dislocation) and time to recurrent biliary obstruction. Results: The incidence of PEP was 26.8% in the ES and 23.1% in the non-ES (unadjusted odds ratio [OR] [95%CI]: 1.22, [0.60-2.51], adjusted OR [95%CI]: 1.23, [0.53-2.81], p  = .63). Logistic-regression analysis revealed no factors that could be attributed to the occurrence of PEP. The incidence of other adverse events was not different between the groups. The median time to recurrent biliary obstruction was 131 (2-465) days and 200 (4-864) days in the ES and non-ES, respectively ( p  = .215). Conclusions: ES prior to MS placement for patients with distal MBO without MPD obstruction does not reduce the incidence of PEP.

Background: The presence of histologically evident epithelioid granuloma is required for the diagnosis of sarcoidosis worldwide. The Japan Society of Sarcoidosis and Other Granulomatous Disorders 2015 diagnostic criteria (JSSOG 2015 criteria) includes "clinically proven diagnosis" (involvement of at least 2 of 3 systems confirmed solely by clinical assessment) because of the frequency of sarcoidosis with ocular, cardiac, and respiratory involvement in Japan and the difficulty of obtaining specimens. Here, we describe in detail the clinical presentation of clinically diagnosed sarcoidosis., Methods: We enrolled 68 consecutive patients with clinically diagnosed sarcoidosis (12 men, 56 women) based on the JSSOG 2015 criteria who were treated at Jichi Medical University between December 2018 and January 2000. We analyzed age at diagnosis, organ involvement, and laboratory findings., Results: Age at diagnosis was unimodal in women. Ocular, splenic, cardiac, and skin involvement, and hypercalcemia were observed in 95.6%, 8.8%, 7.4%, 5.9%, and 35.0% of patients, respectively. High serum lysozyme and soluble interleukin-2 receptor (sIL-2R) levels, bilateral hilar lymphadenopathy on chest radiography, high-grade atrioventricular block or fatal ventricular arrhythmia, and bundle branch block were found in 18.8%, 48.3%, 95.6%, 5.0%, and 10.0% of patients, respectively., Conclusions: The age-specific distribution of clinically diagnosed sarcoidosis was similar to histologically diagnosed sarcoidosis in women, as previously reported. Rates of elevated serum lysozyme and sIL-2R levels were lower in this study than previously reported in histologically diagnosed patients in Japan., Competing Interests: Declaration of Competing Interest The authors report no conflicts of interest., (Copyright © 2019 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: We aimed to evaluate the association between hyperactivity/anxiety and obesity among elementary school students in Matsuyama City, Japan., Methods: We conducted a cross-sectional study of all 46 elementary school students (24, 296 students) in Matsuyama City. The questionnaire included question items from the Strengths and Difficulties Questionnaire (SDQ), as well as questions about height and weight. The students were classified into two groups according to Rohrer index. After separating the data by gender, we examined the association between (1) obesity and hyperactivity, (2) obesity and anxiety, and (3) obesity and combination of hyperactivity and anxiety, by estimating relative risk using Poisson regression model. We also conducted stratified analyses to examine the effect modification by age groups and unbalance of diet on those associations. Moreover, we calculated relative excess risk due to the interaction (RERI) to examine whether there was an additive interaction between hyperactivity and anxiety., Results: Sixteen thousand forty-eight students were included in the present analysis. The prevalence ratio (PR) of being obese in girls who had both hyperactivity and anxiety was higher compared to girls without those symptoms (PR = 1.80; 95% CI 1.04-3.13). There was no significant difference in the prevalence ratio for obesity in boys, whether they were hyperactive, anxious, or neither. RERI was 0.00 for boys and 0.18 for girls., Conclusion: We found a significant association between obesity and co-existence of hyperactivity and anxiety among elementary school girls. Our findings strengthen the need to further explore the association between childhood obesity, hyperactivity, and anxiety.

Background: Heparin bridging therapy (HBT) is indeed related to a high frequency of bleeding after endoscopic mucosal resection (EMR). In this study, our aim was to investigate clinical impact of management of oral anticoagulants without HBT in bleeding after colonic EMR., Methods: From data for patients who underwent consecutive colonic EMR, the relationships of patient factors and procedural factors with the risk of bleeding were analysed. Our management of antithrombotic agents was based on the shortest cessation as follows: the administration of warfarin was generally continued within the therapeutic range, and direct oral anticoagulants (DOACs) were not administered on the day of the procedure. We calculated bleeding risks after EMR in patients who used antithrombotic agents and evaluated whether perioperative management of anticoagulants without HBT was beneficial for bleeding., Results: A total of 1734 polyps in 825 EMRs were analysed. Bleeding occurred in 4.0% of the patients and 1.9% of the polyps. The odds ratios for bleeding using multivariate logistic regression analysis were 3.67 in patients who used anticoagulants and 4.95 in patients who used both anticoagulants and antiplatelet agents. In patients with one-day skip of DOACs, bleeding occurred in 6.5% of the polyps, and there were no significant differences in bleeding risk between HBT and continuous warfarin or one-day skip DOACs., Conclusions: The use of oral anticoagulants was related to bleeding after colonic EMR, and perioperative management of oral anticoagulants based on the shortest cessation without HBT would be clinically acceptable.

Objective: Few data regarding the incidence of cancer-associated thromboembolism (TE) are available for Asian populations. We investigated the incidence of TE (TEi) and its risk factors among gastric and colorectal cancer (GCC) patients received chemotherapy in a daily practice setting., Design: A retrospective cohort study., Setting: A single-institutional study that used data from Sapporo City General Hospital, Japan, on patients treated between January 2008 and May 2015., Participants: Five hundred Japanese GCC patients who started chemotherapy from January 2008 to May 2015., Primary and Secondary Outcome Measures: TE was diagnosed by reviewing all the reports of contrast-enhanced CT performed during the follow-up period. All types of thrombosis detected by CT or additional imaging tests, such as venous TE, arterial TE and cerebral infarction, were defined as TE. Medical records of all identified patients were reviewed and potential risk factors for TE, including clinicopathological backgrounds, were collected. We defined the following patients as 'active cancer'; patients with unresectable advanced GCC, cancer recurrence during or after completing adjuvant chemotherapy and/or presence of other malignant tumours., Results: Of the 500 patients, 70 patients (14.0%) developed TE during the follow-up period. TEi was 9.2% and 17.3% in GCC patients, 18.1% and 3.5% in active and non-active cancer patients, and 24.0% and 12.9% in multiple and single primary, respectively. Multivariate logistic regression analysis showed that colorectal cancer (CRC) (OR 2.371; 95% CI 1.328 to 4.233), active cancer (OR 7.593; 95% CI 2.950 to 19.543) and multiple primary (OR 2.527; 95% CI 1.189 to 5.370) were independently associated with TEi., Conclusion: TEi was 14.0% among Japanese GCC patients received chemotherapy, and was significantly higher among patients with CRC, active cancer and multiple primary than among those with gastric cancer, non-active cancer and single primary, respectively., Trial Registration Number: UMIN000018912., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Honeycombing on high-resolution computed tomography (HRCT) is a distinguishing feature of usual interstitial pneumonia and predictive of poor outcome in interstitial lung diseases (ILDs). Although fine crackles are common in ILD patients, the relationship between their acoustic features and honeycombing on HRCT has not been well characterized., Methods: Lung sounds were digitally recorded from 71 patients with fine crackles and ILD findings on chest HRCT. Lung sounds were analyzed by fast Fourier analysis using a sound spectrometer (Easy-LSA; Fukuoka, Japan). The relationships between the acoustic features of fine crackles in inspiration phases (onset timing, number, frequency parameters, and time-expanded waveform parameters) and honeycombing in HRCT were investigated using multivariate logistic regression analysis., Results: On analysis, the presence of honeycombing on HRCT was independently associated with onset timing (early vs. not early period; odds ratios [OR] 10.407, 95% confidence interval [95% CI] 1.366-79.298, P = 0.024), F99 value (the percentile frequency below which 99% of the total signal power is accumulated) (unit Hz = 100; OR 5.953, 95% CI 1.221-28.317, P = 0.029), and number of fine crackles in the inspiratory phase (unit number = 5; OR 4.256, 95% CI 1.098-16.507, P = 0.036). In the receiver-operating characteristic curves for number of crackles and F99 value, the cutoff levels for predicting the presence of honeycombing on HRCT were calculated as 13.2 (area under the curve [AUC], 0.913; sensitivity, 95.8%; specificity, 75.6%) and 752 Hz (AUC, 0.911; sensitivity, 91.7%; specificity, 85.2%), respectively. The multivariate logistic regression analysis additionally using these cutoff values revealed an independent association of number of fine crackles in the inspiratory phase, F99 value, and onset timing with the presence of honeycombing (OR 33.907, 95% CI 2.576-446.337, P = 0.007; OR 19.397, 95% CI 2.311-162.813, P = 0.006; and OR 12.383, 95% CI 1.443-106.293, P = 0.022; respectively)., Conclusions: The acoustic properties of fine crackles distinguish the honeycombing from the non-honeycombing group. Furthermore, onset timing, number of crackles in the inspiratory phase, and F99 value of fine crackles were independently associated with the presence of honeycombing on HRCT. Thus, auscultation routinely performed in clinical settings combined with a respiratory sound analysis may be predictive of the presence of honeycombing on HRCT.

Background: Until recently, interferon-free anti-hepatitis C virus (HCV) therapy for genotype 2 (GT2) HCV-infected hemodialysis patients was an unfulfilled medical need. Recent clinical trials of glecaprevir and pibrentasvir (G/P) for hemodialysis patients showed high efficacy and safety; however, the number of GT2 HCV-infected patients, especially Asian patients, was limited and most of them were treated with a 12-week regimen. In this prospective multicenter study, we aimed to investigate the efficacy and safety of G/P in Japanese hemodialysis patients with GT2 HCV infection., Methods: Twenty-seven Japanese hemodialysis patients with GT2 HCV infection who were started on with 8- or 12-week G/P regimen between November 2017 and June 2018 were included and followed up for around 12 weeks after treatment completion., Results: Among the 27 included patients, 13 non-liver cirrhosis (LC) and direct-acting antivirals (DAAs)-naïve patients were treated with 8 weeks of G/P and 14 patients with LC (n = 13) or history of failure of DAAs (n = 1) were treated with a 12-week regimen. The overall sustained virological response at 12 weeks after treatment completion (SVR 12) was 96.3% (26/27). All patients with 8 weeks of treatment achieved SVR12. Two patients discontinued the therapy at 2 and 11 weeks after treatment initiation. The patient who discontinued at 2 weeks due to pruritus alone failed to respond to G/P. No patients experienced lethal adverse events during the therapy, and the most common adverse event was pruritus., Conclusions: An 8- or 12-week G/P regimen is highly effective and safe in GT2 HCV-infected hemodialysis patients.

Aim: To clarify the utility of sepsis evaluation using the Quick Sequential Organ Failure Assessment (qSOFA) tool in addition to the Pneumonia Severity Index (PSI); age, dehydration, respiration, orientation and blood pressure (A-DROP) index; and immunodeficiency, respiration, orientation, age and dehydration (I-ROAD) scoring systems, and risk factor evaluation of potentially drug-resistant (PDR) pathogens are suggested in the 2017 guidelines for pneumonia of the Japanese Respiratory Society in nursing- and healthcare-associated pneumonia patients., Methods: We included 289 hospitalized nursing- and healthcare-associated pneumonia patients between April 2016 and March 2017, and investigated the ability of PSI, A-DROP, I-ROAD and qSOFA to predict pneumonia-related mortality. We also evaluated the associations among the risk factors for PDR pathogens, the detection ratio of PDR pathogens and pneumonia-related mortality., Results: The mortality rate of pneumonia during hospitalization was 6.9% (20/289). The area under the curve for pneumonia-related mortality predicted using PSI, A-DROP, I-ROAD and qSOFA was 0.697 (95% confidence interval [CI] 0.59-0.80), 0.63 (95% CI 0.51-0.76), 0.61 (95% CI 0.52-0.70) and 0.701 (95% CI 0.59-0.81), respectively. In addition, higher areas under the curve were observed for pneumonia-related mortality predicted according to a combination of PSI and hypoalbuminemia (<2.5 g/dL) (0.75, 95% CI 0.64-0.86), and qSOFA and hypoalbuminemia (0.74, 95% CI 0.62-0.86) than for PSI and qSOFA alone. No significant associations were observed among the risk factors for PDR pathogens, the detection ratios of PDR pathogens and pneumonia-related mortality., Conclusions: qSOFA and the combination of qSOFA and hypoalbuminemia might be simple and useful evaluation tools for predicting pneumonia-related mortality in nursing- and healthcare-associated pneumonia patients. Geriatr Gerontol Int 2019; 19: 177-183., (© 2018 Japan Geriatrics Society.)