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Background and Objective: Lymphangioleiomyomatosis (LAM) is a rare neoplastic disease associated with the functional tumour suppressor genes TSC1 and TSC2 and causes structural destruction in the lungs, which could potentially increase the risk of lung cancer. However, this relationship remains unclear because of the rarity of the disease., Methods: We investigated the relative risk of developing lung cancer among patients diagnosed with LAM between 2001 and 2022 at a single high-volume centre in Japan, using data from the Japanese Cancer Registry as the reference population. Next-generation sequencing (NGS) was performed in cases where tumour samples were available., Results: Among 642 patients diagnosed with LAM (sporadic LAM, n = 557; tuberous sclerosis complex-LAM, n = 80; unclassified, n = 5), 13 (2.2%) were diagnosed with lung cancer during a median follow-up period of 5.13 years. All patients were female, 61.5% were never smokers, and the median age at lung cancer diagnosis was 53 years. Eight patients developed lung cancer after LAM diagnosis. The estimated incidence of lung cancer was 301.4 cases per 100,000 person-years, and the standardized incidence ratio was 13.6 (95% confidence interval, 6.2-21.0; p = 0.0008). Actionable genetic alterations were identified in 38.5% of the patients (EGFR: 3, ALK: 1 and ERBB2: 1). No findings suggested loss of TSC gene function in the two patients analysed by NGS., Conclusion: Our study revealed that patients diagnosed with LAM had a significantly increased risk of lung cancer. Further research is warranted to clarify the carcinogenesis of lung cancer in patients with LAM., (© 2024 Asian Pacific Society of Respirology.)

Background: Tissue-based comprehensive genomic profiling (CGP) is increasingly being employed for genotype-directed therapies in patients with advanced cancer. However, tissue availability may limit their potential applications. In Japan, the cost of cancer gene panel tests is covered by public insurance for patients diagnosed with advanced solid tumors once in their lifetime. Therefore, it is essential to improve the success rate (reportability) and accuracy of CGP tests. The purpose of this study was to identify the factors associated with efficient and accurate CGP testing using relevant information obtained from real-world data., Methods: This study included 159 samples analyzed using tumor-only panel FoundationOne® CDx cancer genome profiling (F1CDx) and 85 samples analyzed using matched-pair panel OncoGuide™ NCC Oncopanel system (NCCOP) at St. Marianna University Hospital. Sample characteristics (fixation conditions, storage period, histology, tumor cell ratio, and genomic tumor cell content), CGP performance, and quality control status were evaluated across all 244 tested samples., Results: In 237/244 samples (97.1%), CGP testing results were successfully obtained [F1CDx, 99.4% (158/159) and NCCOP, 92.9% (79/85)]. An increased number of fibroblasts, inflammatory cells, and necrotic tumor cells, long-term storage, and/or prolonged fixation of tissue sections were involved in the unreported results and/or qualified CGP results. In addition, a negative correlation between median insert size values and ΔΔCq was observed in the NCCOP system., Conclusion: We identified various factors associated with efficient and accurate CGP testing using relevant information obtained from real-world data, suggesting that thorough selection and preparation of tissue sections could optimize CGP and maximize useful information., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Background and Aim: While several predictive models for the development of hepatocellular carcinoma (HCC) have been proposed, including those for patients with chronic hepatitis C virus (HCV) infection who have achieved sustained virologic response (SVR), the best model may differ between regions. We compared the ability of six reported models to stratify the risk of post-SVR HCC in Japan, where rigorous surveillance and early detection of HCC is common., Methods: A total of 6048 patients with no history of HCC who achieved SVR by oral direct-acting antiviral drugs were enrolled in this nationwide study. Patients continued HCC surveillance every 6 months after SVR. The incidence of post-SVR HCC was compared between risk groups using the aMAP score, FIB-4 index, Tahata model, GAF4 criteria, GES score, and ADRES score., Results: During the observation period with a median duration of 4.0 years after SVR, post-SVR HCC developed in 332 patients (5.5%). All six models performed significantly at stratifying the incidence of HCC. However, Harrell's C-index was below 0.8 for all models (range, 0.660-0.748), indicating insufficient stratification ability., Conclusion: Although all six proposed models demonstrated a good ability to predict the development of post-SVR HCC, their ability to stratify the risk of post-SVRHCC was unsatisfactory. Further studies are necessary to identify the best model for assessing the risk of post-SVR HCC in regions where early detection of HCC is common., (© 2024 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: Restrictions during the coronavirus disease 2019 (COVID-19) pandemic have decreased physical activity levels, which may result in locomotive syndrome. This study evaluated the change in locomotive syndrome prevalence and associated risk factors among an elderly population before and after a coronavirus outbreak., Methods: This written self-administered cross-sectional survey was conducted in conjunction with the coronavirus disease vaccination program in Habikino City, Japan. Participants who were aged ≥65 years completed the five-question Geriatric Locomotive Function Scale before and during the pandemic. The diagnosis of locomotive syndrome and its stage was based on the Geriatric Locomotive Function Scale score: stage 1 (2-3 points), 2 (4-5 points), and 3 (≥6 points). Data on lifestyle changes, including regular exercise, during the pandemic were collected., Results: This study included 12,197 participants (36.7% of the city's total elderly residents). The prevalence of locomotive syndrome increased from 41.3% to 47.1% after the outbreak. In total, 765 (6.3% of overall population) and 295 (9.5% of the participants who had stages 1-2 before the pandemic) participants developed locomotive syndrome and stage 3 locomotive syndrome, respectively. The multivariate logistic regression analysis indicated that a decrease in exercise was significantly associated with the onset of locomotive syndrome (all stages) (odds ratio = 2.5, p < 0.001) and locomotive syndrome stage 3 (odds ratio = 2.6, p < 0.001)., Conclusions: Extrapolation of the study's findings to the entire population of Japan suggests that approximately 2 million elderly individuals might develop locomotive syndrome after the coronavirus outbreak. Additionally, 10% of the participants with mild-moderate locomotive syndrome before the pandemic may develop severe locomotive syndrome after the outbreak. The greatest risk factor for new-onset or worsening locomotive syndrome was a decrease in daily exercise. Thus, there is an urgent need for adequate exercise guidelines during the coronavirus pandemic, especially for the elderly population., Competing Interests: Declaration of competing interest None., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The place of death and related factor, such as diseases, symptoms, family burden, and cost, has been examined, but social background and lifestyle were not considered in most studies. Here, we assessed factors that are associated with the place of death using the largest cohort study in Japan., Methods: A total of 17,781 deaths from the cohort study were assessed. The study database was created from the Japan Public Health Center-based Prospective Study (JPHC Study), in which demographic data were collected from Japanese Vital Statistics. Adjusted odds ratios for home death were calculated using logistic regression., Results: Multivariate analysis adjusted for various factors showed that unmarried status (odds ratio [OR] 2.4; 95% confidence interval [CI], 2.0-2.9), unemployed male (OR 1.3; 95% CI, 1.1-1.5), and high drinking level in male (OR 1.3; 95% CI, 1.1-1.6) were associated with home death. Regarding the cause of death, cardiovascular disease (OR 3.3; 95% CI, 2.9-3.8), cerebrovascular disease (OR 1.9; 95% CI, 1.6-2.2), and external factors (OR 4.1; 95% CI, 3.5-4.8) were significantly associated with home death, compared with cancer. The risk of death at home was significantly higher among unmarried subjects stratified by cause of death (cardiovascular disease: OR 3.2; 95% CI, 2.2-4.7; cerebrovascular disease: OR :5.1; 95% CI, 2.9-9.1; respiratory disease: OR 3.4; 95% CI, 1.6-7.6; and external factors: OR 2.3; 95% CI, 1.4-3.7), but for cancer, the risk of death at home tended to be higher among married participants., Conclusion: This study found that various factors are associated with home death using the largest cohort study in Japan. There is a high possibility of home deaths in people with fewer social connections and in those with diseases leading to sudden death.

Aims: This retrospective study compared the survival between elderly and non-elderly patients., Methods: A total of 5545 treatment-naive patients with hepatocellular carcinoma (HCC) who visited 7 different hospitals from January 2000 to December 2018 were included. Patients ≥80 years old were defined as elderly patients. We divided the patients into three groups based on the timing of the initial treatment: Early, middle, and late periods defined as 2000 to 2005, 2006 to 2012, and 2013 to 2018, respectively., Results: There were 132 (8.9%), 405 (17.5%), and 388 (22.2%) elderly patients in the early, middle, and late period, respectively, showing a significant increase over time (p < 0.001). In both elderly and non-elderly patients, the median albumin-bilirubin score significantly improved over time and the diagnosis of HCC was made slightly earlier over time. The median overall survival (OS) in elderly patients was 52.8, 42.0, and 45.6 months in the early, middle, and late period, respectively, without a significant improvement (p = 0.17) whereas the OS in non-elderly patients was significantly improved (p < 0.001). The percentage of elderly patients receiving curative treatments did not significantly increase (p = 0.43), while that of non-elderly patients did (p = 0.017). Non-liver-related death in elderly patients significantly differed among periods (p = 0.023), while liver-related death did not (p = 0.050). Liver- and non-liver-related death in non-elderly patients significantly differed among periods (p < 0.001, p = 0.005)., Conclusions: Survival in elderly patients was not improved despite an improvement in their liver function. Curative treatments should be conducted when appropriate after evaluating each elderly patient., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

In the emergency admission due to worsening heart failure (HF) in patients on maintenance hemodialysis, emergent dialysis may be indicated, which increases personnel expenses. To clarify the characteristics and in-hospital management of the patients, we conducted a multicenter retrospective study including 142 patients on maintenance hemodialysis emergently admitted for worsening HF (71.6 ± 9.2 years, 69.0% male, 44.4% HF with preserved [≥50%] ejection fraction). The interval between last hemodialysis and admission was long (median 55 h), suggesting that fluid accumulation triggered HF events. Although most patients (73.9%) were admitted in the nighttime (5 p.m. to 9 a.m.), only 17.9% of them needed nighttime dialysis and were managed medically until the first in-hospital dialysis, with the use of noninvasive positive pressure ventilation in 45.1% and oxygen supplementation in 95.8%. While patients on hemodialysis with worsening HF were frequently admitted in the nighttime, nighttime dialysis was indicated in a limited population., (© 2021 International Society for Apheresis, Japanese Society for Apheresis, and Japanese Society for Dialysis Therapy.)

Background/aim: With the development of systemic treatment methods for unresectable hepatocellular carcinoma (uHCC), the concept of unsuitable for transcatheter arterial chemoembolization (TACE) has become important. This study aimed to establish a simple predictive scoring system for determining TACE unsuitable status., Materials/methods: From 1998 to 2015, 196 patients with intermediate-stage uHCC with Child-Pugh A (score 5:6 = 108:88) and given TACE as the initial treatment were enrolled. At the baseline, tumor burden (Milan criteria-out, up-to-7 in/out, and up-to-11 in/out: 0-2 points) and modified albumin-bilirubin grade 1/2a or 2b (0-1 point) were added to determine the score for TACE unsuitable (CITRUS-MICAN score; low <2 and high ≥2). In addition, a previously reported tumor marker (TM) score, in which alpha-fetoprotein (AFP) was ≥100 ng/mL, fucosylated AFP ≥10%, and des-gamma-carboxy prothrombin ≥100 mAU/mL (each 1 point) (total 0, 1, or ≥2 points), was used for additionally evaluating tumor malignancy potential. Prognosis was retrospectively evaluated based on those scores., Results: Median survival time (MST) was better for low compared to high CITRUS-MICAN score (42.0 vs. 26.4 months) (p = 0.002). A 2-step evaluation using the combination of CITRUS-MICAN and TM scores showed an MST of 43.2 months for low CITRUS-MICAN/TM score 0/1 (rank-A) and 39.6 months for low CITRUS-MICAN/TM score ≥2 (rank-B2), while it was 46.8 months for high CITRUS-MICAN/TM score 0 (rank-B1), 28.8 months for high CITRUS-MICAN/TM score 1 (rank-B2), and 22.8 months for high CITRUS-MICAN/TM score ≥2 (rank-C). For rank-A cases (n = 51), MST was 43.2 months, while it was 46.8 months for rank-B1 (n = 12), 31.2 months for rank-B2 (n = 82), and 22.8 months for rank-C (n = 51) (p = 0.001)., Conclusion: The results showed that rank-C indicates absolute TACE unsuitable status. For rank-A patients, good prognosis with TACE can be expected, while TACE refractoriness status during the clinical course should be carefully evaluated so as to anticipate the appropriate timing for switching to systemic treatment in rank-B1 and -B2 patients., (© 2021 The Author(s). Published by S. Karger AG, Basel.)

Few studies have investigated the relationship between blood type and trauma outcomes according to the type of injury. We conducted a retrospective multicenter observational study in twelve emergency hospitals in Japan. Patients with isolated severe abdominal injury (abbreviated injury scale for the abdomen ≥ 3 and that for other organs < 3) that occurred between 2008 and 2018 were divided into four groups according to blood type. The association between blood type and mortality, ventilator-free days (VFD), and total transfusion volume were evaluated using univariate and multivariate regression models. A total of 920 patients were included, and were divided based on their blood type: O, 288 (31%); A, 345 (38%); B, 186 (20%); and AB, 101 (11%). Patients with type O had a higher in-hospital mortality rate than those of other blood types (22% vs. 13%, p < 0.001). This association was observed in multivariate analysis (adjusted odds ratio [95% confidence interval] = 1.48 [1.25-2.26], p = 0.012). Furthermore, type O was associated with significantly higher cause-specific mortalities, fewer VFD, and larger transfusion volumes. Blood type O was associated with significantly higher mortality and larger transfusion volumes in patients with isolated severe abdominal trauma., (© 2021. The Author(s).)

Aim/background: Transarterial chemoembolization (TACE) is recommended for patients with intermediate-stage hepatocellular carcinoma (HCC). In this study, we investigated the impact of early lenvatinib administration in patients with intermediate-stage HCC, especially those with tumors beyond the up-to-7 criteria., Materials/methods: A total of 208 patients with intermediate-stage HCC whose initial treatment was early lenvatinib administration or TACE were enrolled. Multivariate overall survival analysis was performed in this cohort. In addition, the impact of early lenvatinib administration on survival in patients with HCC beyond the up-to-7 criteria was clarified using inverse probability weighting (IPW) analysis., Results: The overall cumulative survival rates at 6, 12, 18, and 24 months were 94.4, 79.9, 65.8, and 50.1%, respectively. Multivariate analysis with Cox proportional hazards modeling showed that HCC treatment with lenvatinib (hazard ratio [HR], 0.199; 95% confidence interval [CI], 0.077-0.517; p < 0.001), α-fetoprotein ≥100 ng/mL (HR, 1.687), Child-Pugh class B disease (HR, 1.825), and beyond the up-to-7 criteria (HR, 2.016) were independently associated with overall survival. The 6-, 12-, 18-, and 24-month cumulative survival rates were 96.0, 90.4, 65.7, and 65.7%, respectively, in patients treated with lenvatinib, and 94.1, 78.5, 65.3, and 48.4%, respectively, in patients who received TACE (p < 0.001). In addition, univariate analysis with Cox proportional hazards modeling adjusted by IPW showed that lenvatinib therapy was significantly associated with overall survival in patients with HCC beyond the up-to-7 criteria (HR, 0.230; 95% CI, 0.059-0.904; p = 0.035)., Conclusions: Lenvatinib may be a suitable first-line treatment for patients with intermediate-stage HCC beyond the up-to-7 criteria., (© 2021 S. Karger AG, Basel.)

As a new absolute quantitation method for low-molecular compounds, quantitative NMR (qNMR) has emerged. In the Japanese Pharmacopoeia (JP), 15 compounds evaluated by qNMR are listed as reagents used as the HPLC reference standards in the assay of crude drug section of the JP. In a previous study, we revealed that humidity affects purity values of hygroscopic reagents and that (i) humidity control before and during weighing is important for a reproducible preparation and (ii) indication of the absolute amount (not purity value), which is not affected by water content, is important for hygroscopic products determined by qNMR. In this study, typical and optimal conditions that affect the determination of the purity of ginsenoside Rb 1 (GRB1), saikosaponin a (SSA), and barbaloin (BB) (i.e., hygroscopic reagents) by qNMR were examined. First, the effect of humidity before and during weighing on the purity of commercial GRB1, with a purity value determined by qNMR, was examined. The results showed the importance afore-mentioned. The results of SSA, which is relatively unstable in the dissolved state, suggested that the standardization of humidity control before and during weighing for a specific time provides a practical approach for hygroscopic products. In regard to BB, its humidity control for a specific time, only before weighing, is enough for a reproducible purity determination.

Background and Aim: The presence of cirrhosis is an important factor for the management of patients with hepatitis C virus (HCV) infection and it determines the duration of treatment for HCV with the direct-acting antiviral (DAA) regimen of glecaprevir (GLE) and pibrentasvir (PIB), that is, 8 or 12 weeks, if patients do not have a history of DAA failure. However, in real-world settings, determination of cirrhosis depends on the discretion of the attending hepatologists, and it is unclear whether compensated cirrhosis was homogenously diagnosed or not. In this study, we investigated the real-world diagnosis of cirrhosis by characterizing DAA-naïve patients who underwent a 12-week GLE/PIB regimen in whom cirrhosis was diagnosed, comparing their characteristics with those of patients who underwent an 8-week regimen in whom cirrhosis was absent., Methods: In a large, multicenter cohort study, we compared background characteristics and treatment outcomes among DAA-naïve patients who underwent an 8-week versus a 12-week GLE/PIB regimen., Results: Among 977 patients enrolled, 296 (30.3%) were determined to have cirrhosis and underwent a 12-week regimen. Some patient characteristics largely overlapped between the two groups, including liver fibrosis indices. Sustained viral response rates were similar between groups after adjusting liver fibrosis index with propensity score matching., Conclusion: Although adequately diagnosed, the determination of cirrhosis varied widely among institutions or by hepatologists in real-world settings, and the severity of liver fibrosis overlapped significantly between patients in whom compensated cirrhosis was determined to be present and patients in whom cirrhosis was absent. Virologic efficacy was similar after adjusting for the degree of liver fibrosis., (© 2020 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: In clinical trials, a pangenotype direct-acting antiviral (DAA) regimen consisting of glecaprevir (GLE) and pibrentasvir (PIB) exhibited high virologic efficacy and tolerability in patients with hepatitis C virus (HCV) infection. This study sought to confirm these findings in real-world settings, focusing on patients with cirrhosis, history of DAA failure, or HCV genotype 3 who were treated with a 12-week regimen in a large multicenter study from Japan., Methods: In a nationwide multicenter prospective cohort study, we analyzed background characteristics, tolerability, and treatment outcome of patients who underwent a 12-week GLE/PIB regimen., Results: Of 1190 patients, 509 (42.8%) underwent the 12-week regimen, and the remaining patients underwent an 8-week regimen. The rate of sustained virologic response (SVR) of patients treated with the 12-week regimen was 99.0%, comparable with that of patients treated with the 8-week regimen. The adverse events were observed in 29.1% of patients. The main adverse event was pruritus, which was observed in 14.7%. Ten patients (2.0%) discontinued therapy during treatment period., Conclusion: The 12-week GLE/PIB regimen was well-tolerated with high virologic efficacy in patients with cirrhosis, experience of DAA, or HCV genotype 3; tolerability and SVR rate were comparable with those of DAA-naïve, non-cirrhotic, non-genotype 3 patients who underwent 8-week regimen., (© 2019 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Bleeding manifestations in primary immune thrombocytopenia (ITP) range from skin petechiae to life-threatening intracranial hemorrhage (ICH). However, the relation between these various bleeding manifestations and the platelet count in ITP remains poorly characterized. Using a nationwide database of patients with ITP during the years 2005 to 2014 (10 years) in Japan, we analyzed 19 415 adult patients newly diagnosed with ITP, including 222 with ICH. The frequency of skin purpura was 64.8%, and this increased linearly with thrombocytopenia without a specific platelet count threshold. In contrast, mucosal bleeding (epistaxis and gingival bleeding) and organ bleeding (melena, hematuria, and ICH) increased exponentially with thrombocytopenia at a platelet count threshold of 10 to 15 × 109/L. Age showed a much weaker correlation than platelet count with skin and mucosal bleeding. However, the incidence of organ bleeding increased exponentially above 60 years of age. Multivariate analysis showed that the presence of mucosal bleeding was a risk factor for occurrence of melena and hematuria but not for ICH. The frequency of ICH was 1.1% and risk factors for ICH were age ≥60 years (odds ratio [OR], 3.09; 95% confidence interval [CI], 2.13-4.47; P < .001), platelet count <10 × 109/L (OR, 2.96; 95% CI, 2.11-4.15; P < .001), and the presence of hematuria (OR, 1.56; 95% CI, 1.04-2.35; P = .033). The relation between ICH and platelet count varied with age. This large-scale analysis of risk factors for bleeding in ITP has revealed distinct characteristics of skin, mucosal, and organ bleeding in adult patients with newly diagnosed ITP, thus indicating those who are at a high risk of severe organ bleeding., (© 2020 by The American Society of Hematology.)

Background: Direct-acting anti-virals (DAAs) have markedly improved the effectiveness of anti-viral therapy for chronic hepatitis C (CHC) patients. In a phase III trial in Japan, treatment with the NS3/4A protease inhibitor glecaprevir and the NS5A inhibitor pibrentasvir (G/P) resulted in a small number of patients with refractory factors. We aimed to evaluate the effectiveness and safety of G/P, especially among patients with these refractory factors, and the influence of these factors on treatment., Methods: In a prospective, multicenter study involving 33 medical institutions, 1439 patients were treated with G/P, and their efficacy, safety, and most frequent adverse effects (AEs) were analyzed., Results: Overall SVR12 rates were 99.1% (1397/1410) in the per-protocol-analysis, and genotype sustained virologic response SVR12 rates were: genotype 1, 99.4% (707/711); genotype 2, 99.4% (670/674); genotype 3, 80.0% (16/20). DAA-naïve patients (p = 0.008) with HCV genotype except 3 (genotype 1 vs. 3, p = 2.68 × 10 -5 ; genotype 2 vs. 3, p = 3.28 × 10 -5 ) had significantly higher SVR12 rates. No significant difference was observed between CKD stage 1-3 (99.1% [1209/1220]) and chronic kidney disease (CKD) stage 4-5 (98.9% [188/190]) patients, or between cirrhotic (99.0% [398/402]) and non-cirrhotic (99.1% [999/1008]) patients. Multiple logistic regression analysis revealed that genotype 3 [OR 33.404, 95% CI (7.512-148.550), p value (p = 4.06 × 10 -5 )] and past experience of IFN-free DAAs [OR 3.977, 95% CI (1.153-13.725), p value (p = 0.029)] were both significantly independent predictors of non-SVR12. AEs were reported in 28.2% of patients, and 1.6% discontinued treatment owing to drug-related AEs. AEs were significantly higher in CKD stage 4-5 (41.6% [79/190]) than CKD stage 1-3 (26.1% [319/1220]) patients (p = 2.00 × 10 -5 ). AEs were also significantly higher in cirrhotic (38.6% [155/402]) than in non-cirrhotic (24.1% [243/1008]) (p = 2.91 × 10 -18 ) patients., Conclusions: G/P regimen is highly effective and safe to treat CHC patients even with refractory factors such as CKD and advanced liver fibrosis. However, patients with past experience of IFN-free DAA treatment and genotype 3, CKD stage 4 or 5, and advanced liver fibrosis should be more closely observed.

Quantitative NMR (qNMR) has been developed as an absolute quantitation method to determine the purity or content of organic compounds including marker compounds in crude drugs. The "qNMR test" has been introduced into the crude-drug section of the Japanese Pharmacopoeia (JP) for determining the purity of reagents used for the assay in the JP. In Supplement II to the JP 17th edition published in June 2019, fifteen compounds adopted qNMR test were listed as the reagents for the assay. To establish the "qNMR test" in the crude drug section of the JP, there were several problems to be solved. Previously, we reported that the handling impurity signals from reference substances and targeted marker compounds, chemical shifts of reference substances, and peak unity of signals of targeted marker compounds are important factors to conduct qNMR measurements with intended accuracy. In this study, we investigated that the hygroscopicity of reagents could cause the changes in the compounds' purity depending on increasing their water content. Twenty-one standard products used for the crude-drug test in JP were examined by water sorption-desorption analysis, and ginsenosides and saikosaponins were found to be hygroscopic. To prepare a sample solution of saikosaponin b 2 for qNMR analysis, samples need to be maintained for 18 h at 25°C and 76% relative humidity; further, samples need to be weighed at the same humidity for the qNMR analysis.

Based on high efficacy and safety demonstrated in clinical trials, treatment with glecaprevir/pibrentasvir (G/P) for 8 weeks is recommended for hepatitis C virus (HCV)-infected patients who are direct-acting antiviral (DAA) naïve, genotype 1 or 2, and noncirrhotic. The aim of this study was to validate real-world experience with 8-week G/P treatment in Japan. We conducted a prospective observational cohort study in 554 patients who underwent 8-week treatment from among 1,022 patients who initiated G/P therapy. The majority (54.5%) were male, with a median age of 66 years, and HCV genotype distribution was genotype 1, 43.8%; genotype 2, 55.3%; and mixed subtype, 0.9%. Overall, the sustained virologic response rate at 12 weeks (SVR12) was 92.8% (530/571) in the intention-to-treat population and 99.3% (526/530) in the per-protocol population. The SVR12 rates by subgroups were as follows: subtype 1a, 100% (6/6); 1b, 100% (189/189); 2a, 99.3% (150/151); 2b, 99.0% (103/104); and mixed subtype, 50% (2/4). Among four patients with virologic failure following 8-week treatment with G/P, none had baseline polymorphisms or treatment-emergent amino acid substitutions in NS3. However, 2 of 4 patients with virologic failure had treatment-emergent amino acid substitutions in NS5A. Adverse events (AEs) were reported in 21.5% of patients and 1.2% of patients discontinued due to drug-related AEs. In conclusion, G/P treatment for 8 weeks was safe and effective for DAA-naïve noncirrhotic genotype 1 or 2 patients in a real-world clinical setting in Japan., (© 2019 John Wiley & Sons Ltd.)

Aims: Drug-induced liver damage characterized by serum alanine aminotransferase (ALT) elevation often occurs in direct-acting antiviral (DAA) combination therapy for chronic hepatitis C virus (HCV) infection. This study explored single nucleotide polymorphisms (SNPs) at drug metabolism- or transport-related genes that were associated with ALT elevation in asunaprevir plus daclatasvir therapy., Methods: Subjects were 185 Japanese patients with chronic HCV genotype 1b infection who received asunaprevir plus daclatasvir therapy. Tag SNPs at possible metabolizing enzyme and transporter genes, which were involved in the pharmacokinetics of asunaprevir and daclatasvir, were selected., Results: Among the tag SNPs analyzed, CYP3A4 rs4646437 was significantly associated with ALT elevation (p = 0.013): maximum ALT values in patients with genotype CC were higher than those in patients with genotype non-CC (allele T). The proportion of grades 2-4 in genotype CC patients were significantly greater than those in genotype non-CC patients (p = 0.028). No patients with genotype non-CC showed grade ≥2 ALT elevation. In multivariate analysis, rs4646437 genotype CC and cirrhosis were significant, independent factors associated with grade ≥1 ALT elevation (odds ratio, 2.83 and 1.88; p = 0.040 and 0.045, respectively). In exploratory analyses, although serum concentrations of asunaprevir and daclatasvir were not correlated with maximum ALT values or rs4646437 genotypes, asunaprevir concentrations in patients with grade ≥1 ALT elevation were significantly higher than those in patients with grade <1 ALT elevation (P = 0.023)., Conclusions: CYP3A4 rs4646437 was found to be significantly and independently associated with ALT elevation in Japanese patients receiving ASV plus DCV therapy. Notably, none of the patients with rs4646437 genotype non-CC (allele T) had grade ≥2 ALT elevation. SNP genotyping prior to treatment might be useful for carefully monitoring patients to complete treatment safely., Competing Interests: The authors have declared that no competing interests exist.

Background: Vitamin D has promising anti-proliferative and anti-fibrotic properties, but its clinical utility in nonalcoholic fatty liver disease (NAFLD) is unclear., Aims: This study aimed to clarify the association between vitamin D levels, single nucleotide polymorphisms (SNPs) in vitamin D-related genes, and the histopathological severity of disease in patients with biopsy-proven NAFLD., Methods: SNPs in CYP2R1, DHCR7, vitamin D binding protein (GC), CYP27B1, and vitamin D receptor (VDR) were determined for 229 consecutive patients with biopsy-proven NAFLD., Results: In this study, vitamin D deficiency defined as 25-hydroxyvitamin-D 3 levels of ≤20 ng/mL was found in 151 patients (65.9%). Multivariate analysis revealed that cold season, advanced fibrosis, and CYP2R1 rs1993116 genotype non-AA were independent factors significantly associated with vitamin D deficiency. Old age (p = 5.05 × 10 -8 ), high body mass index (p = 2.13 × 10 -2 ), low total-cholesterol (p = 1.46 × 10 -4 ), low serum vitamin D level (p = 7.34 × 10 -3 ), and VDR rs1544410 genotype CC (p = 9.15 × 10 -3 ) were independent factors associated with advanced liver fibrosis., Conclusion: Serum 25-hydroxyvitamin-D 3 levels and the VDR gene SNP were significantly and independently associated with the severity of liver fibrosis in patients with biopsy-proven NAFLD., (Copyright © 2019 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: The aim of this study is to ascertain whether the TLL1 variant at rs17047200 is associated with the development of HCC after achieving sustained virological response (SVR) by interferon (IFN)-free therapy for chronic hepatitis C (CHC)., Methods: A total of 1029 Japanese CHC patients with the following inclusion criteria were enrolled: (i) achieved SVR by IFN-free therapy, (ii) followed up at least 1 year from the end of treatment (EOT) (median 104 weeks), (iii) no history of hepatocellular carcinoma (HCC) by 1 year from the EOT., Results: Nineteen patients developed HCC (HCC group) and 1010 did not (non-HCC group). The proportion of rs17047200 AT/TT was significantly higher in the HCC group than the non-HCC group (47.4% vs. 20.1%, P = 0.008). Multivariate analysis showed that higher levels of α-fetoprotein, FIB-4 and rs17047200 AT/TT were independent risk factors for developing HCC (HR = 3.22, P = 0.021 for α-fetoprotein > 4.6 ng/ml; HR = 3.89, P = 0.036 for FIB-4 > 2.67; HR = 2.80, P = 0.026 for rs17047200 AT/TT). Cumulative incidence of HCC was significantly higher in patients with rs17047200 AT/TT than in those with AA (P = 0.006). Comparing clinical characteristics according to the TLL1 genotypes, patients with rs17047200 AT/TT had significantly lower platelet counts and higher levels of FIB-4 than those with AA (P = 0.011 and 0.032, respectively)., Conclusions: The TLL1 variant was independently associated with HCC development after HCV eradication by IFN-free regimen. It might be involved in hepatic fibrogenesis and thereby carcinogenesis.

Background and Aim: This study aimed to evaluate the efficacy and safety of elbasvir/grazoprevir in genotype 1b chronic hepatitis C Japanese patients with chronic kidney disease (CKD), including those undergoing hemodialysis., Methods: This post hoc analysis of a multicenter, retrospective study included patients who had received elbasvir/grazoprevir. CKD was defined by an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m 2 . The sustained virologic response (SVR) rate and frequency of treatment-emergent adverse events were assessed in patients with CKD., Results: The study population comprised 155 men and 182 women. The median eGFR level at baseline was 69.6 mL/min/1.73 m 2 (range, 3.0-128.5 mL/min/1.73 m 2 ). Among the 337 patients, 109 (32.3%) had CKD: 72, 14, and 23 (including 20 hemodialysis) had CKD stages 3, 4, and 5, respectively. The SVR rates according to the baseline CKD stages were 98.1% (51/52) in stage 1, 98.3% (173/176) in stage 2, 93.9% (46/49) in stage 3a, 100% (23/23) in stage 3b, 100% (14/14) in stage 4, and 100% (23/23) in stage 5. All 20 patients undergoing hemodialysis achieved SVR. There was no significant decrease from baseline in the median eGFR level throughout the treatment period among the patients with CKD. The incidence of treatment-emergent adverse events was 6.4% (7/109) among the patients with CKD and 9.7% (22/228) among the patients without CKD (not significant, P = 0.323)., Conclusions: The present study demonstrated that elbasvir and grazoprevir are highly effective and safe for genotype 1b chronic hepatitis C Japanese patients with CKD, including those undergoing hemodialysis., (© 2018 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: The real-world virological efficacy and safety of an interferon (IFN)-free direct-acting antiviral (DAA) therapy with elbasvir (EBR) and grazoprevir (GZR) were evaluated in Japanese patients chronically infected with hepatitis C virus (HCV) genotype 1., Methods: The rate of sustained virologic response (SVR) and safety were analyzed in patients who started the EBR/GZR regimen between November 2016 and July 2017. SVR rates were compared based on patient baseline characteristics., Results: Overall, 371 of 381 patients (97.4%) achieved SVR. Multivariate analysis identified a history of failure to IFN-free DAA therapy and the presence of double resistance-associated substitutions (RASs) in HCV non-structural protein 5A (NS5A) as factors significantly associated with failure to EBR/GZR treatment. The SVR rates of patients with a history of IFN-free DAA therapy and those with double RASs were 55.6 and 63.6%, respectively. In all other subpopulations, the SVR rates were more than 90%. There were no severe adverse events associated with the treatment., Conclusions: The EBR/GZR regimen yielded high virological efficacy with acceptable safety. Patients with a history of failure to IFN-free DAA therapy or with double RASs in HCV-NS5A remained difficult to treat with this regimen.

When foot-and-mouth disease (FMD) occurs and a "vaccination-to-live" policy is adopted in a country, the country must perform serological surveillance of a nonstructural protein (NSP) of FMD virus. The NCPanaftosa kit is the only kit for detecting antibodies to NSPs that is officially recognized as the reference regent by the World Organization for Animal Health; however, it is only used in South American countries. In this study, the specificity and sensitivity of the NCPanaftosa kit were compared with those of the PrioCHECK kit sold by an international company. Results in this study suggest that the PrioCHECK kit performs similarly to the NCPanaftosa kit in detecting antibodies to the NSP in the cattle population.

The incidence of high myopia is increasing worldwide with myopic maculopathy, a complication of myopia, often progressing to blindness. Our two-stage genome-wide association study of myopic maculopathy identifies a susceptibility locus at rs11873439 in an intron of CCDC102B (P = 1.77 × 10 -12 and P corr  = 1.61 × 10 -10 ). In contrast, this SNP is not significantly associated with myopia itself. The association between rs11873439 and myopic maculopathy is further confirmed in 2317 highly myopic patients (P = 2.40 × 10 -6 and P corr  = 1.72 × 10 -4 ). CCDC102B is strongly expressed in the retinal pigment epithelium and choroids, where atrophic changes initially occur in myopic maculopathy. The development of myopic maculopathy thus likely exhibits a unique background apart from the development of myopia itself; elucidation of the roles of CCDC102B in myopic maculopathy development may thus provide insights into preventive methods for blindness in patients with high myopia.

Objectives: International guidelines recommend the use of long-acting bronchodilators for the treatment of chronic obstructive pulmonary disease (COPD), but the usefulness of short-acting bronchodilator assist use for stable COPD remains uncertain. The purpose of the present study was to objectively demonstrate the effects of assist use of procaterol, a short-acting β2-agonist, on the respiratory mechanics of stable COPD patients treated with a long-acting bronchodilator using forced oscillation technique (FOT) and conventional spirometry. We also confirmed the length of time for which procaterol assist could significantly improve the pulmonary function., Methods: We enrolled 28 outpatients with mild to severe COPD (Global Initiative for Obstructive Lung Disease stages I-III), who had used the same long-acting bronchodilator for longer than 3 months and who were in stable condition. All measures were performed using both FOT and spirometry sequentially from 15 min to 2 h after inhalation., Results: Compared to baseline, inhaled procaterol assist use modestly but significantly improved spirometric and FOT measurements within 2 h after inhalation. These significant effects continued for at least 2 h. -Significant correlations were found between parameters -measured by spirometry and those measured by FOT., Conclusions: Procaterol assist use modestly but significantly improved pulmonary function determined by spirometry and respiratory mechanics in patients with stable COPD treated with long-acting bronchodilators. Thus, inhaled procaterol has the potential for assist use for COPD., (© 2018 The Author(s) Published by S. Karger AG, Basel.)

Background: Hepatitis C virus (HCV) infection is common in hemodialysis patients and worsens their prognosis, while antiviral therapy options are limited. Recently, clinical trial and real-world, small-scale studies have reported excellent responses to direct-acting antivirals in patients with advanced chronic kidney diseases. However, real-world, large-scale data were lacking. This large multicenter analysis included HCV-infected hemodialysis patients receiving combination therapy with a nonstructural protein 5A (NS5A) inhibitor, daclatasvir (DCV), and a protease inhibitor, asunaprevir (ASV)., Methods: Twenty-three centers in Japan participated in this study of 123 hemodialysis patients with genotype 1 HCV infection, who received DCV/ASV combination therapy between November 2014 and March 2016. We collected and analyzed data relating to treatment outcome, baseline clinical information, laboratory measurements (during and after the treatment), and adverse events., Results: Thirty-nine patients (31.7%) had advanced liver fibrosis, 12 (9.8%) had histories of hepatocellular carcinoma (HCC), and 18 (14.6%) had baseline resistance-associated variants (RAVs) of NS5A. The overall sustained virological response (SVR)12 rate was 95.9% (118/123). Notably, all patients with HCC and 94.4% (17/18) of those with NS5A RAVs achieved SVR12. Significant factors associated with non-SVR were advanced fibrosis and the interleukin-28B non-TT genotype at rs8099917. Four patients (3.3%) discontinued therapy because of adverse events including elevated serum alanine transaminase levels (n = 2), rash (n = 1), and HCC (n = 1); all of these achieved SVR12., Conclusions: This real-world, nationwide study revealed that DCV/ASV combination therapy was safe and highly effective for hemodialysis patients with genotype 1 HCV infections. This study was registered at the UMIN Clinical Trials Registry (UMIN000024227).

Purpose: The AI-300 automated infusion device (Sumitomo Heavy Industries, Ltd., Tokyo, Japan) is subject to administration error as a function of smaller volumes of 18 F-FDG dispensed via a three-way cock supplied with a disposable kit. The present study aimed to validate the administration accuracy of the AI-300 using an improved disposable kit for quantitative positron emission tomography (PET) assessment., Methods: We determined administration accuracy between the improved and previous disposable kits by measuring variations in dispensed volumes and radioactive concentrations of 18 F-FDG according to the criteria of the Japanese Society of Nuclear Medicine. A reference value was generated by measuring radioactivity using a standard dose calibrator., Results: The values obtained using the previous kit deviated from the reference values by a maximum of -10.6%, and the deviation depended on dispensed volumes of 18 F-FDG<0.25 mL. In contrast, the values were relatively stable when using the improved kit with dispensed 18 F-FDG volumes < 0.25 mL. Variations in radioactive concentrations were relatively stable using the improved kit, whereas that of the previous kit was slightly unstable at high radioactive concentrations., Conclusion: The administration accuracy of the AI-300 using the previous kit varied considerably according to smaller dispensed volumes, but the improved kit might alleviate this problem. The present results indicated that the improved disposal kit should be immediately implemented to eliminate uncertainty surrounding quantitative PET findings.

The effectiveness of a vaccine preserved for emergency use in Japan was analyzed under experimental conditions using cows and pigs in order to retrospectively evaluate the effectiveness of the emergency vaccination performed in the 2010 epidemic in Japan. Cows and pigs were administered a vaccine preserved for emergency use in Japan at 3 or 30 days before virus infection (dbv) and were subsequently infected with the foot-and-mouth disease virus (FMDV) O/JPN/2010, which was isolated in the 2010 epidemic in Japan. All animals vaccinated at 30 dbv and one of three pigs vaccinated at 3 dbv showed no vesicular lesions during the experimental period. The virus titers and viral RNA loads obtained from clinical samples were lower in the vaccinated cows than in the non-vaccinated cows. The viral excretion periods were shorter in the vaccinated cows than in the non-vaccinated cows. In contrast, in the vaccinated pigs, the virus titers and viral RNA loads obtained from the samples, except for those obtained from sera, were not decreased significantly, and the viral excretion periods were not sufficiently shortened. These results suggest that the vaccine can protect against clinical signs of infection by the FMDV O/JPN/2010 in animals; however, it should be noted that in vaccinated and infected animals, especially pigs, clinical samples, such as saliva and nasal swabs, may contain excreted viruses, even if no clinical signs were exhibited.

Background: The present study explored the treatment outcome of daclatasvir (DCV) and asunaprevir (ASV) therapy combining oral direct-acting antiviral agents (DAAs) for chronic hepatitis C (HCV) including liver cirrhosis according to resistance-associated variants (RAVs) in NS3/NS5A region., Methods: Overall, 641 patients enrolled in Japan with HCV-1b received DCV and ASV for 24 weeks. Baseline drug-resistant mutations L31F/I/M/V, Q54H, P58S, A92K, and Y93H in the HCV NS5A region and V36A, T54A/S, Q80K/L/R, R155K/T/Q, A156S/V/T, and D168A/E/H/T/V in the HCV NS3/4A region were assessed by direct sequencing., Results: Overall, 86.9 % (543/625) of patients had SVR12, which was significantly higher in NS5A 93Y (wild) (88.3 %) compared with NS5A 93H at baseline (48.0 %), indicating the SVR12 rate was significantly lower in patients with 93H mutations. Additionally, 66.7 % (18/27) of patients with prior triple therapy including simeprevir (SMV) failure had virological failure. The virological failure rate of DCV/ASV therapy after SMV failure was significantly higher in those with preexisting NS3/4A 168 substitutions compared with without substitutions at baseline [84.2 % (16/19) vs. 28.6 % (2/7), p = 0.014]. The number of patients with multiple RAVs or deletions in NS5A increased from 0 to 85 % in failed patients. Alanine aminotransferase elevation was a frequent adverse event causing discontinuation of DCV/ASV therapy, although 87.5 % (14/16) patients achieved SVR12, subsequently., Conclusions: History of SMV therapy and pre-existing NS5A Y93H were associated with virological failure of DCV/ASV therapy, resulting in the emergence of multiple RAVs. Patients with RAVs at baseline should be assessed to optimize future DAA therapies.

We determined the complete nucleotide sequence of a self-transmissible IncL/M plasmid, pKOI-34, from a Klebsiella oxytoca isolate. pKOI-34 possessed the core structure of an IncL/M plasmid found in Erwinia amylovora, pEL60, with two mobile elements inserted, a transposon carrying the arsenic resistance operon and a Tn21-like core module (tnp and mer modules) piggybacking blaIMP-34 as a class 1 integron, In808, where blaIMP-34 confers a resistance to carbapenems in K. oxytoca and Klebsiella pneumoniae., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

A 9-year surveillance for multidrug-resistant (MDR) Pseudomonas aeruginosa in the Hiroshima region showed that the number of isolates harboring the metallo-β-lactamase gene bla(IMP-1) abruptly increased after 2004, recorded the highest peak in 2006, and showed a tendency to decline afterwards, indicating a history of an epidemic. PCR mapping of the variable regions of the integrons showed that this epidemic was caused by the clonal persistence and propagation of an MDR P. aeruginosa strain harboring the bla(IMP-1) gene and an aminoglycoside 6'-N-acetyltransferase gene, aac(6')-Iae in a class I integron (In113), whose integrase gene intl1 was disrupted by an IS26 insertion. Sequence analysis of the representative strain PA058447 resistance element containing the In113-derived gene cassette array showed that the element forms an IS26 transposon embedded in the chromosome. It has a Tn21 backbone and is composed of two segments sandwiched by three IS26s. In Japan, clonal nationwide expansion of an MDR P. aeruginosa NCGM2.S1 harboring chromosomally encoded In113 with intact intl1 is reported. Multilocus sequence typing and genomic comparison strongly suggest that PA058447 and NCGM2.S1 belong to the same clonal lineage. Moreover, the structures of the resistance element in the two strains are very similar, but the sites of insertion into the chromosome are different. Based on tagging information of the IS26 present in both resistance elements, we suggest that the MDR P. aeruginosa clone causing the epidemic in Hiroshima for the past 9 years originated from a common ancestor genome of PA058447 and NCGM2.S1 through an IS26 insertion into intl1 of In113 and through IS26-mediated genomic rearrangements., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Background: We have reported that the total number of peptic ulcers (PUs) had increased 1.5-fold after the Great East Japan Earthquake compared with those of the previous year, and that hemorrhagic ulcers were more prominently increased by 2.2-fold. The aim of this study is to determine the risk factors for bleeding ulcers after the Great East Japan Earthquake., Methods: Clinical data of all peptic ulcer subjects endoscopically detected at the 7 major hospitals in the middle of the stricken area during the 3 months after the earthquake were retrospectively collected. Based on endoscopic and laboratory findings, peptic ulcer cases were divided into 227 bleeding ulcer cases and 102 non-bleeding controls. Other than ordinary risk factors for bleeding ulcers, the refugee shelter was included in the analysis as a unique confounder after the earthquake. Multiple logistic regression analyses were used to adjust for potential confounders., Results: Eighty-seven (27%) of 329 PUs emerged from refuge shelters, and the majority (76 of 87) of PUs occurring in such shelters was the bleeding type. Multivariate regression showed that residence in a shelter was a strong risk factor for ulcer bleeding with OR (95% CI): 4.4 (2.1-9.6, p < 0.0001), independent of the progressiveness of ulcer diseases., Conclusions: Accommodation in a refugee shelter can be a strong risk factor for ulcer bleeding after a large-scale disaster. Since acid-suppressive drugs are supposed to decrease the risk for stress-induced ulcer bleeding, our results will encourage effective use of a limited medical resource in such catastrophic events.

Objectives: This study investigated the relationship between hepatitis C virus (HCV) dynamics and sustained virological response (SVR), as well as the efficacy of an extended treatment with telaprevir-based triple therapy among patients with chronic hepatitis C genotype 1b., Methods: Among 220 patients receiving triple therapy for 24 weeks, the SVR rate was analyzed at each time point at which HCV RNA became undetectable. The SVR rates in the patients who did not achieve a rapid virological response (RVR) were compared with those in 27 patients who received triple therapy for 48 weeks., Results: The SVR rates of interleukin 28B (IL28B) TT and non-TT patients were 100 versus 66.7% after 1 week, 97.6 versus 72.2% after 2 weeks, 95.2 versus 84.2% after 3 weeks, 93.1 versus 72.2% after 4 weeks, 76.9% versus 11.1% after 6 weeks, and 88.9 versus 14.3% after 8 weeks, respectively. All of the IL28B TT patients who showed undetectable HCV RNA levels until week 8 achieved an SVR. In contrast, the SVR rates in the IL28B non-TT patients who did not achieve RVR with 24 and 48 weeks of treatment were 11.8 and 62.5%, respectively (P=0.017)., Conclusion: These results suggest that an SVR can frequently be achieved by IL28B TT patients, even with 24 weeks of treatment, when HCV RNA remains undetectable until week 8, and also that IL28B non-TT patients should have RVR values to achieve an SVR with 24 weeks of treatment. The SVR rate was low in IL28B non-TT patients treated for 24 weeks who did not achieve an RVR; however, it could increase when the treatment duration was extended to 48 weeks.

Genotypes are associated with the natural course of hepatitis C virus (HCV) infection and response to antiviral therapy for HCV. HCV genotype 1b has been the dominant genotype in Japan, where the prevention of HCV transmission through blood transfusion or nosocomial infection has been established since 1990. The distribution of HCV genotype was investigated based on patient's birth year in 5515 HCV-infected Japanese individuals at three institutions from different areas of Japan. At all three institutions, the proportion of HCV genotype 1b decreased and was <50% in individuals born after 1970. By contrast, the percentage of HCV genotype 2b increased in subsequent birth cohorts after 1920-1929. Significant changes in HCV genotype distribution were observed across Japan regardless of area.

Background: Genetic polymorphisms near Interleukin 28B (IL28B) (rs8099917) and a rapid virological response (RVR) have been reported as predictors for a sustained virological response (SVR) to telaprevir (TVR)-based triple combination therapy. However, the association between SVR and viral kinetics earlier than week 4 after initiation of therapy remains unclear. Thus, we evaluated the SVR prediction ability of baseline factors and reduced hepatitis C virus (HCV) RNA levels at week 1 after the initiation of TVR-based therapy in Japanese genotype-1b chronic hepatitis C (CHC) patients., Methods: A total of 156 Japanese CHC patients received a 24-week regimen of TVR-based therapy. Baseline factors and reduction in HCV RNA levels at weeks 1 and 4 after the initiation of therapy were analyzed for SVR prediction., Results: Multiple logistic regression analysis for SVR in TVR-based therapy identified the IL28B TT genotype, a reduction of ≥ 4.7 log10 IU/mL in HCV RNA levels at week 1, RVR, and treatment-naïve/relapse. Whereas the SVR rate was higher than 90 % regardless of the reduction in HCV RNA levels at week 1 in patients with the TT genotype, a reduction of ≥ 4.7 log10 IU/mL in HCV RNA levels at week 1 was the strongest predictor of SVR in patients with the non-TT genotype, as determined by multiple logistic regression analysis (P = 0.0043)., Conclusions: The IL28B TT genotype is the most important baseline factor for predicting SVR, and a ≥ 4.7 log10 IU/mL reduction in HCV RNA at week 1 is a useful very early on-treatment predictor of SVR, especially in the non-TT genotype.

This synopsis outlines the Japanese guideline Version 2.0 for the data acquisition protocol of oncology FDG-PET/CT scans that was created by a joint task force of the Japanese Society of Nuclear Medicine Technology, the Japanese Society of Nuclear Medicine and the Japanese Council of PET Imaging, and was published in Kakuigaku-Gijutsu 2013; 33:377-420 in Japanese. The guideline aims at standardizing the PET image quality among PET centers and different PET camera models by providing criteria for the IEC body phantom image quality as well as for the patient PET image quality based on the noise equivalent count (NEC), NEC density and liver signal-to-noise ratio, so that the appropriate scanning parameters can be determined for each PET camera. This Version 2.0 covers issues that were not focused on in Version 1.0, including the accuracy of the standardized uptake value (SUV), effect of body size together with adjustment of scanning duration, and time-of-flight (TOF) reconstruction technique. Version 2.0 also presents data acquired with new PET camera models that were not tested in Version 1.0. Reference values for physical indicators of phantom image quality have been updated as well.

To determine the incidence of depression and anxiety disorders in patients with high myopia as well as the factors that would predict the development of psychiatric complications and their impact on vision-related quality of life (VR-QoL). Two hundred and five patients with pathologic myopia (axial length ≥26.50 mm) were studied. Incidence of depression and anxiety disorders was determined using the Hospital Anxiety and Depression Scale (HADS). VR-QoL was determined by the 25-item National Eye Institute Visual Function Questionnaire. Incidence of depression was 22.0 % and incidence of anxiety disorder was 25.9 %. Absence of children was the only factor significantly associated with the presence of depression, and a past history of cataract surgery was the only factor significantly associated with the presence of anxiety disorder. Factors which decreased the VR-QoL were in order of importance--anxiety disorder, decreased visual acuity in the best eye, depression, and being female. Responses of the subjects to two HADS statements 'I can laugh and see the funny side of things' and 'I can enjoy a good book or radio or television program' identified 82.2 % of depressed patients, and 'I get sudden feelings of panic' and 'I can sit at ease and feel relaxed' identified 71.7 % of patients with anxiety disorder. Twenty-two to 26 % of highly myopic patients had psychiatric disorders which had a strong negative impact on their VR-QoL. Two statements from the HADS questionnaire can be used to screen highly myopic patients for depression or anxiety disorders.

Background: A growing body of evidence has indicated a possible association between oral and gastrointestinal (orodigestive) cancers and periodontal disease or tooth loss. However, the evidence remains contradictory. This study investigated whether tooth loss, which is indicative of poor oral health and a potential source of oral infections, is associated with death from orodigestive cancer., Methods: The study included 656 subjects in Fukuoka prefecture, Japan, who were 80 years old at baseline in 1998. All subjects underwent oral clinical examination and answered a questionnaire to determine their background characteristics. Cause of death over the 12-year follow-up was recorded from the registers at the Public Health Centers and classified according to the WHO International Classification of Diseases. Statistical analysis of associations was performed using Kaplan-Meier and Cox multivariate regression analyses., Results: A significant association was observed between tooth loss (continuous variable) and cancer death (hazard ratio (HR): 1.03, 95% confidence interval (CI): 1.00-1.07), after adjustment for potential confounders, including sex and smoking status. However, that association became insignificant in the fully adjusted model. On the other hand, tooth loss was significantly associated with orodigestive cancer (HR: 1.06, 95% CI: 1.01-1.13), even in the fully adjusted model including place of residence as a part of socioeconomic status., Conclusions: This study provides the first evidence in a prospective study in a Japanese population that tooth loss is associated with increased orodigestive cancer mortality, although the causality remains unclear.

Background and Objectives: A 1-year multicenter prospective randomized controlled study was conducted on the effects of vitamin E-bonded polysulfone dialyzers on erythropoiesis-stimulating agent response in hemodialysis patients., Design, Setting, Participants, & Measurements: Major inclusion criteria were use of high-flux polysulfone dialyzers with 50-70 ml/min β2-microglobulin clearance over 3 months, transferrin saturation over 20%, same erythropoiesis-stimulating agent for over 3 months, and hemoglobin at 10-12 g/dl. Hemodialysis patients were placed in four interventional groups: two hemoglobin ranges (10.0-10.9 or 11.0-11.9 g/dl) and two dialyzers. Patients were randomly assigned by central registration to a vitamin E-bonded polysulfone dialyzers or polysulfone control group. Primary end point was relative erythropoiesis resistance index at baseline between groups at 12 months. Erythropoiesis resistance index was defined as total weekly erythropoiesis-stimulating agent dose divided by hemoglobin., Results: There were no statistically significant differences in age or sex. There was no significant difference in relative erythropoiesis resistance index between vitamin E-bonded polysulfone dialyzers and control groups at 12 months (vitamin E-bonded polysulfone dialyzers: 1.1, control: 1.3). The vitamin E-bonded polysulfone dialyzers group showed better relative erythropoiesis resistance index than the control group at 11.0-11.9 g/dl hemoglobin (vitamin E-bonded polysulfone dialyzers: 1.0, control: 1.4 at 12 months, significant difference) but no difference at 10.0-10.9 g/dl hemoglobin., Conclusions: The overall relative erythropoiesis resistance index showed no difference between the vitamin E-bonded polysulfone dialyzers and control groups, although the change in relative erythropoiesis resistance index differed according to hemoglobin level.

Aim: Although the prevalence of Helicobacter pylori (H. pylori) increases with age and the main period of acquisition is childhood, the route of transmission of H. pylori infection remains unclear. This study aims to evaluate the relationship between prevalence of children and grandparents., Methods: A total of 838 consecutive children who attended the Urita clinic and whose blood was taken for work up were enrolled in the present study. They were 449 boys and 389 girls, with a mean age of 12.4 years. H. pylori serology of their family members who were living together in one house was picked up to analyse intra-familial clustering of H. pylori infection. The family members of these children consisted of 448 fathers, 597 mothers, 205 grandfathers, 361 grandmothers and 589 siblings., Results: The seropositive rates of mothers, grandmother and siblings in seropositive children were significantly higher than those in seronegative children. H. pylori infection in mothers and grandmothers was a marked risk factor for infection in the index children. Larger family size was not a risk factor for H. pylori infection. In contrast, having an infected father or grandfather was not an independent predictor for children infection., Conclusions: Our data demonstrate that not only mother-to-child transmission but also grandmother-to-child transmission is an important mechanism for the spread of H. pylori in a three-generation household., (© 2013 The Authors. Journal of Paediatrics and Child Health © 2013 Paediatrics and Child Health Division (Royal Australasian College of Physicians).)

Background: Societal stress derived from an event that affects the whole society, e. g., a natural disaster, provides a unique, indirect way of determining the relationship between psychological stress and peptic ulcer disease in humans. In this study, we investigated the changing patterns of the incidence of peptic ulcers before and after the Great East Japan earthquake, which occurred on 11 March, 2011., Methods: Clinical data of patients with peptic ulcers were retrospectively collected during the 3 months after the earthquake (2011) from 7 major hospitals in the middle of the stricken area, and were compared with the data for the same period of the previous year (2010). The eligible subjects were classified into four groups according to Helicobacter pylori infection status and intake of nonsteroidal anti-inflammatory drugs (NSAIDs)., Results: The incidence of all types of peptic ulcers was 1.5-fold increased after the earthquake, and in particular, the incidence of hemorrhagic ulcers was 2.2-fold increased; the gastric ulcer/duodenal ulcer ratio in hemorrhagic ulcers was also significantly increased (p < 0.05). Regarding the etiology of the peptic ulcers, the proportion of non-H. pylori and non-NSAID ulcers was significantly increased, from 13 % in 2010 to 24 % in 2011 after the earthquake (p < 0.05)., Conclusion: In addition to the increased incidence of peptic ulcers, compositional changes in the disease were observed after the Great East Japan earthquake. The significant increase in the proportion of non-H. pylori and non-NSAID ulcers after the earthquake indicated that psychological stress alone induced peptic ulcers in humans independently of H. pylori infection and NSAID intake.

Ruxolitinib (INC424), a potent and selective oral Janus kinase 1 and 2 inhibitor, was recently approved by the US food and drug administration for the treatment of intermediate or high-risk myelofibrosis. The safety, tolerability, and pharmacokinetics (PK) of ruxolitinib have been extensively evaluated in healthy subjects and patients. The present study is the first to investigate the PK and tolerability of ruxolitinib in the Japanese population. Forty subjects were randomized to receive single (10-100 mg) and multiple (10 and 25 mg every 12 h) doses of ruxolitinib or placebo. Cohorts were sequentially enrolled based on the outcome of safety assessments. Ruxolitinib was rapidly absorbed, and its exposure increased dose proportionally up to 100 mg. The half-life of ruxolitinib was approximately 3 h, and drug accumulation was not observed after repeated dosing at a 12-h dosing interval. Decreasing absolute neutrophil counts were observed in five Japanese subjects treated once (100 mg, n = 1) or twice (10 mg, n = 3; 25 mg, n = 1) daily. These events were manageable and reversible upon drug discontinuation. Orally administered ruxolitinib was well tolerated in healthy Japanese volunteers. There were no apparent differences in the safety or PK of ruxolitinib between Japanese and non-Japanese subjects.

In recent years, many anthocyanin-containing dietary supplements of various dosages and formulations have been sold through advertising their large number of beneficial effects. On the other hand, there is an increased risk of distributing deteriorated supplements to consumers due to lax regulations, because in Japan these supplements are classified as food. Spectrophotometric methods are commonly used to control the quality of supplements. However, these methods have limitations with regard to assessing deterioration. In this study, we evaluated a new index for detection of deteriorated products. The stability of 3 formulations and the quality of 20 supplements were investigated by ultra-high performance liquid chromatography, which is superior to spectrophotometry for identifying and quantifying individual anthocyanins. The stability was not only affected by storage temperature but also by formulation. We defined "Degradation Index" (DI) as an indicator of the deterioration of supplements. Of 20 supplements investigated, the DI of 5 supplements was more than 3-fold the value of Bilberon-25, and the worst one was 12.7-fold. These results suggest that DI could be a useful quality control index for detecting deteriorated supplements., (© 2013 Institute of Food Technologists®)

Background: Prevention of chronic kidney disease (CKD) is a major public health issue. Although several studies have been performed on the association between alcohol consumption and CKD or renal function, it remains controversial. Numerous genetic polymorphisms have been reported to be associated with CKD and kidney function. Mitochondrial DNA cytosine/adenine (Mt5178 C/A) polymorphism is associated with longevity in Japanese. This polymorphism modifies the effects of alcohol consumption on blood pressure, risk of hypertension, serum triglyceride levels, risk of hyper-LDL cholesterolemia and serum uric acid levels. The objective of this study was to investigate whether Mt5178 C/A polymorphism modifies the effects of alcohol consumption on renal function in male Japanese health check-up examinees., Methods: A total of 394 male subjects aged 29-76 years were selected from among individuals visiting the hospital for regular medical check-ups. After Mt5178 C/A genotyping, a cross-sectional study assessing the combined effects of Mt5178 C/A polymorphism and habitual drinking on the risk of mildly decreased estimated glomerular filtration rate (eGFR) (<90 ml/min/1.73 m(2)) was conducted., Results: For Mt5178A genotypic men, habitual drinking may increase eGFR (P for trend = 0.003) or reduce the risk of mildly decreased eGFR (P for trend = 0.003). Daily drinkers had a significantly higher eGFR than non-drinkers (P = 0.005). The crude odds ratio for decreased eGFR was significantly lower in daily drinkers than in non-drinkers (odds ratio = 0.092, 95% confidence interval: 0.012-0.727, P = 0.024). On the other hand, for Mt5178C genotypic men, habitual drinking does not appear to affect eGFR., Conclusion: The present results suggest a joint effect of Mt5178 C/A polymorphism and alcohol consumption on eGFR and the risk of mildly decreased eGFR in male Japanese subjects.

Background: We investigated the characteristic features and treatment of hemorrhagic peptic ulcers after the Great East Japan Earthquake, which occurred on 11 March 2011., Methods: Clinical data of patients with hemorrhagic peptic ulcers were retrospectively collected during the 3 months after the earthquake from seven major hospitals in the middle of the stricken area, and were compared with those during the same period of the previous year., Results: After the earthquake, the number of hemorrhagic ulcers increased 2.2 fold as compared with the previous year, and gastric ulcers were significantly more frequent compared with duodenal ulcers (p < 0.05) and more often presented multiple forms (p < 0.05). Nonetheless, the proportion of re-bleeding cases after hemostasis treatment (8% in 2010 vs. 5% in 2011) or total mortality rate (2.5% in 2010 vs. 1.2% in 2011) was rather lower after the earthquake compared with that of the previous year., Conclusion: We clarified that post-disaster hemorrhagic ulcers existed frequently in the stomach, often as multiple ulcers at the same time. The Great East Japan Earthquake and Tsunami caused many cases of hemorrhagic ulcer. However, because of the high success rate of endoscopic hemostasis, the mortality remained as low as in the previous year. Our present study provides important information for large-scale disasters which can occur anywhere., (Copyright © 2013 S. Karger AG, Basel.)

Background: Several genetic polymorphisms have been reported to modify the effects of smoking on serum lipid levels. The objective of this study was to investigate whether longevity-associated mitochondrial DNA 5178 (Mt5178) C/A polymorphism modifies the effects of habitual smoking on the risk of dyslipidemia in middle-aged Japanese subjects., Methods: A total of 394 male subjects (age, 53.9 ± 7.9 years; mean ± SD) were selected from among individuals visiting the hospital for regular medical check-ups. After Mt5178 C/A genotyping, a cross-sectional study assessing the joint effect of Mt5178 C/A polymorphism and cigarette smoking on the risk of hypo-high-density lipoprotein (HDL) cholesterolemia, hyper-low-density lipoprotein (LDL) cholesterolemia or hypertriglyceridemia was conducted., Results: For subjects with Mt5178C, the risk of hypo-HDL cholesterolemia increased with the number of cigarettes smoked daily (P for trend = 0.001). On the other hand, the association between Mt5178A genotype and the risk of hypo-HDL cholesterolemia did not appear to depend on the number of cigarettes smoked daily. For those with Mt5178A, the risk of hyper-LDL cholesterolemia or hypertriglyceridemia increased with cigarettes smoked daily (P for trend = 0.017 and P for trend = 0.002, respectively). However, the association between Mt5178C genotype and the risk of hyper-LDL cholesterolemia or hypertriglyceridemia did not depend on the number of cigarettes smoked daily., Conclusions: The present results suggest that Mt5178 C/A polymorphism modulates the effects of habitual smoking on the risk of dyslipidemia in middle-aged Japanese men.

Purpose: To determine the 2-year results of intravitreal bevacizumab in highly myopic eyes with choroidal neovascularization (CNV)., Methods: An open-label, consecutive, interventional case series. Seventy-five eyes of 69 consecutive Japanese patients with either subfoveal or nonsubfoveal myopic CNVs were studied. The eyes were treated with intravitreal bevacizumab and followed-up for at least 2 years. The best-corrected visual acuities at the baseline in eyes with subfoveal CNV were compared with that in eyes with nonsubfoveal CNV at 2 years after the intravitreal bevacizumab., Results: The difference between the mean best-corrected visual acuity at the baseline and that at 2 years in eyes with a subfoveal CNV was not significant. However, the mean best-corrected visual acuity in eyes with nonsubfoveal CNV was significantly improved from 0.53 ± 0.36 logarithm of the minimal angle of resolution units (Snellen 20/66) before intravitreal bevacizumab to 0.29 ± 0.36 logMAR units (Snellen 20/40) (P < 0.001) 2 years after intravitreal bevacizumab. The incidence of chorioretinal atrophy after 2 years was 3 of 49 (6.1%) in eyes with nonsubfoveal CNV and 21 of 26 (80.8%) in eyes with which subfoveal CNV (P < 0.001). Furthermore, the chorioretinal atrophy area with nonsubfoveal CNV was 0.05 ± 0.21 mm, which was also significantly smaller than that of subfoveal CNV at 1.76 ± 1.60 mm (P < 0.001)., Conclusion: Intravitreal bevacizumab is a good treatment for eyes with nonsubfoveal CNV; however, another treatment is necessary for eyes with a subfoveally located CNV.

This study investigated the relationship between eating behavior and childhood overweight among population-based elementary schoolchildren in Japan. Data was collected from fourth graders (9 or 10 years of age) from Ina Town, Saitama Prefecture, Japan from 1999 to 2009. Information about subjects' sex, age, and lifestyle, including eating behaviors (eating until full and chewing thoroughly), was obtained using a self-administered questionnaire, and height and weight were measured directly. Overweight was determined according to the definition established by the International Obesity Task Force. Data from 4027 subjects (2079 boys and 1948 girls) were analyzed. Chewing thoroughly was associated with a significantly decreased odds ratio (OR) for being overweight, whereas eating until full significantly increased the OR for being overweight (OR: 1.50, 95% confidence interval: 1.16-1.94) among boys. However, eating until full was not associated with a significantly increased OR for being overweight among the group that reported chewing thoroughly, whereas it was associated with a significantly increased OR for being overweight (2.02, 1.38-2.94) among boys who did not chew thoroughly. In conclusion, eating until full or not chewing thoroughly was associated with being overweight among elementary schoolchildren. Results of this study suggest that chewing thoroughly may be an avenue to explore childhood overweight prevention efforts.

Although a number of studies have investigated the relationship of sleep duration to overweight and obesity, studies conducted among population-based elementary schoolchildren have been limited in Japan. The aim of the present study was to investigate the relationship between sleep duration and overweight among elementary schoolchildren in Japan. The study subjects were all fourth-grade schoolchildren (9 or 10 years of age) in Ina-town, Saitama Prefecture, Japan from 1999 to 2008. Information concerning each subject's sex, age, and lifestyle was obtained using a self-administered questionnaire, while measurements of his or her height and weight were carried out. Childhood overweight was determined according to the definition established by the International Obesity Task Force. Data from 3,433 children were analyzed. In logistic regression analysis, a statistically significant dose-response relationship was observed between sleep duration and overweight among boys (p for trend = 0.014) but not among girls (p for trend = 0.149). Short sleep duration was associated with childhood overweight, and the sex difference in the association was observed. These findings suggested that it is important to consider sleep duration as part of any program to prevent overweight among elementary schoolchildren, especially among boys.

Background: Monitoring secular trends in blood pressure (BP) among children is important in predicting subsequent hypertension and cardiovascular disease. We investigated secular trends in BP using data from population-based annual screenings of Japanese schoolchildren., Methods: The participants were 10 894 children (all fourth graders between 1994 and 2010 and all seventh graders between 1997 and 2010) living in the town of Ina in Saitama Prefecture, Japan. Body height, weight, and BP were measured, after which children were classified as non-overweight, overweight, or obese. Trends in variables relative to calendar year were analyzed using regression models., Results: Systolic BP was significantly associated with calendar year among fourth- and seventh-grade boys (-0.350 and -0.434 mm Hg/year, respectively) and fourth- and seventh-grade girls (-0.513 and -0.473 mm Hg/year, respectively) (all P < 0.001), respectively, over time. Systolic BP and calendar year were significantly negatively correlated regardless of physique or sex among all fourth graders, but not among obese seventh-grade girls. In addition, diastolic BP and calendar year did not significantly correlate among seventh-grade overweight or obese boys or obese seventh-grade girls., Conclusions: BP decreased among fourth-grade schoolchildren in Ina during the past 17 years, regardless of sex or physique. However, BP and calendar year did not significantly correlate among obese seventh graders.