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Background: Heated tobacco products (HTPs) have gained global popularity, but their health risks remain unclear. Therefore, the current study aimed to identify plasma metabolites associated with smoking and HTP use in a large Japanese population to improve health risk assessment., Methods: Metabolomics data from 9,922 baseline participants of the Tsuruoka Metabolomics Cohort Study (TMCS) were analyzed to determine the association between smoking habits and plasma metabolites. Moreover, alterations in smoking-related metabolites among HTP users were examined based on data obtained from 3,334 participants involved from April 2018 to June 2019 in a follow-up survey., Results: Our study revealed that cigarette smokers had metabolomics profiles distinct from never smokers, with 22 polar metabolites identified as candidate biomarkers for smoking. These biomarker profiles of HTP users were closer to those of cigarette smokers than those of never smokers. The concentration of glutamate was higher in cigarette smokers, and biomarkers involved in glutamate metabolism were also associated with cigarette smoking and HTP use. Network pathway analysis showed that smoking was associated with the glutamate pathway, which could lead to endothelial dysfunction and atherosclerosis of the vessels., Conclusion: Our study showed that the glutamate pathway is affected by habitual smoking. These changes in the glutamate pathway may partly explain the mechanism by which cigarette smoking causes cardiovascular disease. HTP use was also associated with glutamate metabolism, indicating that HTP use may contribute to the development of cardiovascular disease through mechanisms similar to those in cigarette use.

The Tsuruoka Metabolomics Cohort Study (TMCS) is an ongoing population-based cohort study being conducted in the rural area of Yamagata Prefecture, Japan. This study aimed to enhance the precision prevention of multi-factorial, complex diseases, including non-communicable and aging-associated diseases, by improving risk stratification and prediction measures. At baseline, 11,002 participants aged 35-74 years were recruited in Tsuruoka City, Yamagata Prefecture, Japan, between 2012 and 2015, with an ongoing follow-up survey. Participants underwent various measurements, examinations, tests, and questionnaires on their health, lifestyle, and social factors. This study uses an integrative approach with deep molecular profiling to identify potential biomarkers linked to phenotypes that underpin disease pathophysiology and provide better mechanistic insights into social health determinants. The TMCS incorporates multi-omics data, including genetic and metabolomic analyses of 10,933 participants, and comprehensive data collection ranging from physical, psychological, behavioral, and social to biological data. The metabolome is used as a phenotypic probe because it is sensitive to changes in physiological and external conditions. The TMCS focuses on collecting outcomes for cardiovascular disease, cancer incidence and mortality, disability and functional decline due to aging and disease sequelae, and the variation in health status within the body represented by omics analysis that lies between exposure and disease. It contains several sub-studies on aging, heated tobacco products, and women's health. This study is notable for its robust design, high participation rate (89%), and long-term repeated surveys. Moreover, it contributes to precision prevention in Japan and East Asia as a well-established multi-omics platform.

Purpose: Hypertension (HT), dyslipidemia (DL), and diabetes mellitus (DM) are major risk factors for cardiovascular diseases. Despite the wide availability of medications to reduce this risk, poor adherence to medications remains an issue. The aim of this study is to evaluate medication adherence of prevalent users in these disease medications (HT, DL, DM) using claims data. Factors associated with non-adherence were also examined., Methods: Of 7538 participants of the Tsuruoka Metabolomics Cohort Study, 3693 (HT: 2702, DL: 2112, DM: 661) were identified as prevalent users of these disease medications. Information on lifestyle was collected through a questionnaire. Adherence was assessed by a proportion of days covered (PDC) and participants with PDC ≥0.8 were defined as adherent. Predictors of non-adherence were determined by performing multivariable logistic regression., Results: Medication adherence differed by treatment status. Among those without comorbidities, those with HT-only showed the highest adherence (90.2%), followed by those with DM-only (81.2%) and those with DL-only (80.8%). Factors associated with non-adherence in each medication group were skipping breakfast and poor understanding of medications among those with HT medications, females, having comorbidities, having a history of heart disease, and drinking habit among those with DL medications, and good sleep quality and skipping breakfast among those with DM medications., Conclusion: While participants showed high medication adherence, differences were observed across medication groups. The identified predictors of non-adherence could help target those in need of adherence support., (© 2024 The Author(s). Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Aims: Nonalcoholic fatty liver disease (NAFLD) is known to be associated with atherosclerosis. This study focused on upstream changes in the process by which NAFLD leads to atherosclerosis. The study aimed to confirm the association between NAFLD and the cardio-ankle vascular index (CAVI), an indicator of subclinical atherosclerosis, and explore metabolites involved in both by assessing 94 plasma polar metabolites., Methods: A total of 928 Japanese community-dwellers (306 men and 622 women) were included in this study. The association between NAFLD and CAVI was examined using a multivariable regression model adjusted for confounders. Metabolites commonly associated with NAFLD and CAVI were investigated using linear mixed-effects models in which batch numbers of metabolite measurements were used as a random-effects variable, and false discovery rate-adjusted p-values were calculated. To determine the extent to which these metabolites mediated the association between NAFLD and CAVI, mediation analysis was conducted., Results: NAFLD was positively associated with CAVI (coefficients [95% Confidence intervals (CI)]=0.23 [0.09-0.37]; p=0.001). A total of 10 metabolites were involved in NAFLD and CAVI, namely, branched-chain amino acids (BCAAs; valine, leucine, and isoleucine), aromatic amino acids (AAAs; tyrosine and tryptophan), alanine, proline, glutamic acid, glycerophosphorylcholine, and 4-methyl-2-oxopentanoate. Mediation analysis showed that BCAAs mediated more than 20% of the total effect in the association between NAFLD and CAVI., Conclusions: NAFLD was associated with a marker of atherosclerosis, and several metabolites related to insulin resistance, including BCAAs and AAAs, could be involved in the process by which NAFLD leads to atherosclerosis.

Background: Dehydration, a risk factor for ischemic cerebrovascular diseases, is common in summer; however, the incidence of ischemic diseases is not necessarily higher in summer. Therefore, this study aimed to clarify the relationships between serum osmolarity, hematocrit, daily non-alcohol drink (NAD) intake and factors such as season and age as risk factors for dehydration., Method: Participants (703 women and 306 men) in the follow-up survey, in 2012 and 2013, of the Kobe Orthopedic and Biomedical Epidemiologic (KOBE) Study, consisting of healthy individuals living in Kobe, Japan, were categorized into two groups based on the examination month: the warmer and colder seasons. Multivariate analyses were conducted to examine disparities in serum osmolarity, hematocrit, and NAD intake between these two groups., Results: The colder season was found to be negatively correlated with serum osmolarity and NAD intake, but positively correlated with hematocrit, even after adjusting for relevant factors. Age was independently associated with serum osmolarity, but not with hematocrit and NAD intake., Conclusions: This study suggests that intra-vascular volume depletion is more likely in the colder season despite lower serum osmolarity compared to the warmer season. Age-related increases in serum osmolarity without a corresponding rise in water intake may contribute to this. These findings support the importance of addressing dehydration in the colder season, particularly in older adults.

Background: The current study aimed to investigate the determinants of high double product (DP) by evaluating the association between resting DP, which is calculated as systolic blood pressure (SBP) multiplied by heart rate (HR), and blood test results and lifestyle factors., Methods: This research included 973 participants in the baseline survey of the KOBE study, which included a cohort of urban residents. The possible DP determinants were identified by examining the association between lifestyle factors and laboratory findings and DP by analyzing covariance adjusted for sex and age. Logistic regression analysis was performed with high DP (SBP × HR ≥ 9145 mmHg beats/min or quintile according to sex) as outcome and DP determinants as independent variables., Results: Age, hematocrit, and gamma-glutamyl transferase (log) level were positively associated with a high DP in both men and women. In addition, a high DP was positively associated with Homeostatic Model Assessment for Insulin Resistance score in women alone. Meanwhile, the amount of exercise was negatively associated with a high DP in men alone., Conclusions: High DP values at rest were associated with insulin resistance, gamma-glutamyl transferase, and the amount of exercise in participants without underlying disease.

Objectives: To date, the association between accumulated unhealthy behaviours and insomnia in individuals stratified according to the presence or absence of major cardiovascular risk factors is unclear. This study aimed to examine the effect of accumulated unhealthy behaviours on insomnia in Japanese dwellers., Design: Cross-sectional study., Setting: Baseline data between April 2012 and March 2015., Participants: Our study used cross-sectional data among Japanese aged 35-74 years in a rural community (N=9565), the attendees of annual municipal or work site health check-up programmes., Main Outcome Measures: Insomnia was assessed by Athens Insomnia Scale, which was set at 6 points and greater; other scales were given. Participants were categorised into three groups by their number of unhealthy behaviours (no exercise habit, smoking, alcohol drinking, skipping breakfast and obesity): 0-1, 2-3, 4 or more. The association between accumulated unhealthy behaviours and insomnia was estimated by logistic regression analysis. Further analysis was done after stratification of cardiovascular risk factors assessed by anthropometrics and clinical biochemistry measurements., Results: The overall prevalence of insomnia was 13.3% for men and 19.3% for women. Men with unhealthy behaviour factors were more likely to have insomnia after adjusting for potential confounders, compared with the least unhealthy group (trend p=0.013). Women with four or more unhealthy behaviour factors were more likely to have insomnia, compared with the lowest groups (OR 1.175, 95% CI 1.077 to 1.282). Insomnia has an association with the unhealthy behaviours among men without cardiovascular risk factors (lowest groups: OR 1.133, 95% CI 1.037 to 1.238, trend p=0.026). Women without hypertension were more likely to have suspected insomnia, compared with the lowest group (OR 1.215, 95% CI 1.101 to 1.341)., Conclusion: The results showed accumulated unhealthy behaviours were associated with increased risk of insomnia in Japanese dwellers. For healthy population without cardiovascular risk factors, unhealthy behaviours should be considered as background conditions for insomnia., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Heated tobacco product (HTP) use in Japan has rapidly increased. Despite this rapid spread, little is known about the health effects of HTP use. We conducted a longitudinal cohort study to investigate the change in smoking habits following the spread of HTP use and its effect on forced expiratory volume in 1 second (FEV 1 ) decline., Methods: Participants consisted of a resident population (n = 2,612; mean age, 67.7 years) with FEV 1 measurement in 2012-2014 and 2018-2019, and a worksite population (n = 722; mean age 49.3 years) without FEV 1 data. Participants were categorized as combustible cigarette-only smokers, HTP-only users, dual users, past smokers, and never smokers. The association between smoking group and the change in smoking consumption over a mean 5.6 years was examined. Differences in annual FEV 1 change between smoking groups were examined in the resident population., Results: Prevalence of HTP-only and dual users in 2018-2019 was 0.8% and 0.6% in the resident population, and 5.0% and 1.9% in the worksite population, respectively. The overall number of tobacco products smoked/used increased in dual users compared to baseline, but not in others. Annual FEV 1 decline in dual users tended to be greater than that in cigarette-only smokers (16; 95% confidence interval, -34 to 2 mL/year after full adjustment). Participants switching to HTP-only use 1.7 years before had a similar FEV 1 decline as cigarette-only smokers., Conclusions: HTP use, including dual use, is prevalent even in a rural region of Japan. Dual users appear to smoke/use tobacco products more and have a greater FEV 1 decline. Tobacco policy should consider dual use as high-risk.

Aim: This study investigated the relationship between birth physique and cardiovascular risk factors in Japanese urban residents aged 40 years and more., Methods: A self-administered questionnaire on birth physique was performed among 624 individuals (165 men and 459 women) who participated in the KOBE study. We examined whether self-reported birth physique and available recorded birth weights matched for 72 participants. Then the association between birth physique and risk factors for all participants was examined by gender. Body size at birth in the questionnaire (large, medium, small) was set as an exposure and laboratory values from the baseline survey (2010-2011) were used as outcomes., Results: Mean (standard deviation) recorded birth weight of 72 participants was 3665 (318), 3051 (300), and 2653 (199) g, in the large, medium, and small group, respectively. In the analysis for all participants, odds ratio for having both hypertension and impaired glucose tolerance were significantly higher in the small versus large birth weight group, which was 7.42 (95% CI 1.75-31.50) for men and 4.44 (95% CI 1.14-17.30) for women after adjusting for age, body mass index, smoking/alcohol/exercise habits, and menstrual status in women. Similar results were observed in participants with recorded birth weight., Conclusions: The present study indicates that individuals with small physique at birth might be at higher risk for hypertension and impaired glucose tolerance in middle age compared to those with large birth weight.

Background: Emerging evidence has shown that charged metabolites, such as amino acids, may play an important role in the pathogenesis of various metabolic disorders, many of which women in the postmenopausal period are at high risk of developing. This study examined the metabolic profile of middle-aged Japanese women to investigate alterations in charged metabolites induced by menopausal transition., Methods: The participants were 1193 female residents aged 40-60 at the baseline survey of the Tsuruoka Metabolomics Cohort Study. We investigated the cross-sectional association of menopausal status with 94 metabolomic biomarkers assayed in fasting plasma samples via capillary electrophoresis time-of-flight mass spectrometry using linear regression analysis., Results: Among the participants, 529 were premenopausal, 132 were in menopausal transition (MT), and 532 were postmenopausal. Significant differences were found in age, blood pressure, glucose and lipid levels, and smoking and drinking habits among the three groups. The concentrations of 5 metabolites in the MT group and 15 metabolites in the postmenopausal group were significantly higher than those in the premenopausal group after adjusting for confounding factors. When classified into pathways, these metabolites were related to the tricarboxylic cycle, urea cycle, and homocysteine metabolism, some of which are linked to arteriosclerosis., Conclusion: Multiple charged metabolites were associated with women's menopausal status, showing a gradual increase as women shifted from pre-, to peri-, to postmenopause. These findings might reflect the early changes behind the increased risk of dyslipidemia, diabetes, cardiovascular disease, and osteoporosis in later life., (Copyright © 2021. Published by Elsevier B.V.)

Aims: The categories in the comprehensive lipid and risk management guidelines were proposed by the Japan Atherosclerosis Society (JAS Guidelines 2017), which adopted the estimated 10 year absolute risk of coronary artery disease (CAD) incidence in the Suita score. We examined whether those categories were concordant with the degree of arterial stiffness., Methods: In 2014, the cardio-ankle vascular index (CAVI), an arterial stiffness parameter, was measured in 1,972 Japanese participants aged 35-74 years in Tsuruoka City, Yamagata Prefecture, Japan. We examined the mean CAVI and the proportion and odds ratios (ORs) of CAVI ≥ 9.0 on the basis of the following three management classifications using the analysis of variance and logistic regression: "Category I (Low risk)," "Category II (Middle risk)," and "Category III (High risk).", Results: The mean CAVI and proportion of CAVI ≥ 9.0 were 8.6 and 34.8% among males and 8.1 and 18.3% among females, respectively. The mean CAVI and proportion of CAVI ≥ 9.0 were associated with an estimated 10 year absolute risk for CAD among males and females, excluding High risk for females. These results were similar to the management classification by the guideline: the multivariable-adjusted ORs (95% confidence intervals) of CAVI ≥ 9.0 among Category II and Category III compared with those among Category I were 2.96 (1.61-5.43) and 7.33 (4.03-13.3) for males and 3.99 (2.55-6.24) and 3.34 (2.16-5.16) for females, respectively., Conclusions: The risk stratification, which was proposed in the JAS Guidelines 2017, is concordant with the arterial stiffness parameter.

We examined 7 cutaneous mixed tumors in 2 wild-captured Japanese giant salamanders Andrias japonicus. The tumors were either already present and/or increased in size, or newly occurred during capativity. We sampled the 7 tumors from these animals and 3 verrucose protrusions from 3 unaffected animals, as controls, and examined them pathologically and virologically. The tumors (5 mm to 4 cm in size) were papillary protrusions or pendulated on the skin surface. The cut surface of the tumors was white, lobulated, partially hard, and contained mucus. All tumors presented similar histological characteristics of a hyaline structure and exhibited biphasic proliferation, with neoplastic epithelial cells partially composing the pseudo-ductal structure and staining positive for cytokeratin AE1/AE3. Vimentin 3B4-positive blast-like mesenchymal cells proliferated to fill the gaps in the epithelial components. Transition from unique mucous gland to neoplastic tissue was observed. The hyaline structure was stained blue by AZAN stain, Alcian blue-periodic acid-Schiff (PAS) double stain, and toluidine blue (TB) stain of pH 7.0, but was unstained by TB with pH values of 4.1 and 2.5. The mucus in the neoplastic tissue and in the mucous gland in verrucose protrusions was stained blue by Alcian blue-PAS double stain; TB staining at pH 7.0, 4.1, and 2.5 revealed metachromasy. No virus was detected in the tumors. The 7 tumors were diagnosed as cutaneous mixed tumors, and it was confirmed that the neoplastic cells originated from the mucous gland in the dermis. The biological behavior and pathological development of tumors should be elucidated because the tumors have the potential to negatively affect A. japonicus.

Background: Although self-reported questionnaires are widely employed in epidemiologic studies, their validity has not been sufficiently assessed. The aim of this study was to evaluate the validity of a self-reported questionnaire on medication use by comparison with health insurance claims and to identify individual determinants of discordance in the Tsuruoka Metabolomics Cohort Study., Methods: Participants were 2,472 community-dwellers aged 37 to 78 years from the Tsuruoka Metabolomics Cohort Study. Information on lifestyle and medications was collected through a questionnaire. Sensitivity and specificity were determined using health insurance claims from November 2014 to March 2016, which were used as a standard. Potential determinants of discordance were assessed using multivariable logistic regression., Results: The self-reported questionnaire on medication use showed high validity. Sensitivity and specificity were 0.95 (95% CI, 0.93-0.96) and 0.97 (95% CI, 0.96-0.98) for antihypertensive medications, 0.94 (95% CI, 0.91-0.97) and 0.98 (95% CI, 0.98-0.99) for diabetes medications, and 0.84 (95% CI, 0.82-0.87) and 0.98 (95% CI, 0.97-0.99) for dyslipidemia medications, respectively. Males without high education and those who currently smoke cigarettes were found to be associated with discordant reporting which affected sensitivity, especially those with medication use for dyslipidemia., Conclusions: In this population-based cohort study, we found that the self-reported questionnaire on medication use was a valid measure to capture regular medication users. Sensitivity for dyslipidemia medications was lower than those for the other medications. Type of medication, sex, education years, and smoking status influenced discordance, which affected sensitivity in self-reporting.

Objective To consider effective measures against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in medical institutions, this study estimated the SARS-CoV-2 infection rate among healthcare workers (HCWs) in Tokyo, Japan, and determined the specific findings for mild coronavirus disease 2019 (COVID-19) cases. Methods This study analyzed the results of serologic tests to detect immunoglobulin G antibodies against SARS-CoV-2 and evaluated the demographic and clinical characteristics of the faculty and HCWs at a Tokyo medical institution in August 2020. The demographic and clinical characteristics of participants with antibody-positive results were compared to those of participants with antibody-negative results. Materials This study recruited 2,341 faculty and HCWs at a Tokyo medical institution, 21 of whom had a COVID-19 history. Results Of the 2,320 participants without a COVID-19 history, 20 (0.862%) had positive serologic test results. A fever and dysgeusia or dysosmia occurred with greater frequency among the participants with positive test results than in those with negative results [odds ratio (OR), 5.475; 95% confidence interval (CI), 1.960-15.293 and OR, 24.158; 95% CI, 2.693-216.720, respectively]. No significant difference was observed in the positivity rate between HCWs providing medical care for COVID-19 patients using adequate protection and other HCWs (OR, 2.514; 95% CI, 0.959-6.588). Conclusion To reduce the risk of COVID-19 spread in medical institutions, faculty and HCWs should follow standard and necessary transmission-based precautions, and those with a fever and dysgeusia or dysosmia should excuse themselves from work as soon as possible.

Currently, large-scale cohort studies for metabolome analysis have been launched globally. However, only a few studies have evaluated the reliability of urinary metabolome analysis. This study aimed to establish the reliability of urinary metabolomic profiling in cohort studies. In the Tsuruoka Metabolomics Cohort Study, 123 charged metabolites were identified and routinely quantified using capillary electrophoresis-mass spectrometry (CE-MS). We evaluated approximately 750 quality control (QC) samples and 6,720 participants' spot urine samples. We calculated inter- and intra-batch coefficients of variation in the QC and participant samples and technical intraclass correlation coefficients (ICC). A correlation of metabolite concentrations between spot and 24-h urine samples obtained from 32 sub-cohort participants was also evaluated. The coefficient of variation (CV) was less than 20% for 87 metabolites (70.7%) and 20-30% for 19 metabolites (15.4%) in the QC samples. There was less than 20% inter-batch CV for 106 metabolites (86.2%). Most urinary metabolites would have reliability for measurement. The 96 metabolites (78.0%) was above 0.75 for the estimated ICC, and those might be useful for epidemiological analysis. Among individuals, the Pearson correlation coefficient of 24-h and spot urine was more than 70% for 59 of the 99 metabolites. These results show that the profiling of charged metabolites using CE-MS in morning spot human urine is suitable for epidemiological metabolomics studies.

Food intake biomarkers can be critical tools that can be used to objectively assess dietary exposure for both epidemiological and clinical nutrition studies. While an accurate estimation of food intake is essential to unravel associations between the intake and specific health conditions, random and systematic errors affect self-reported assessments. This study aimed to clarify how habitual food intake influences the circulating plasma metabolome in a free-living Japanese regional population and to identify potential food intake biomarkers. To achieve this aim, we conducted a cross-sectional analysis as part of a large cohort study. From a baseline survey of the Tsuruoka Metabolome Cohort Study, 7,012 eligible male and female participants aged 40-69 years were chosen for this study. All data on patients' health status and dietary intake were assessed via a food frequency questionnaire, and plasma samples were obtained during an annual physical examination. Ninety-four charged plasma metabolites were measured using capillary electrophoresis mass spectrometry, by a non-targeted approach. Statistical analysis was performed using partial-least-square regression. A total of 21 plasma metabolites were likely to be associated with long-term food intake of nine food groups. In particular, the influential compounds in each food group were hydroxyproline for meat, trimethylamine-N-oxide for fish, choline for eggs, galactarate for dairy, cystine and betaine for soy products, threonate and galactarate for carotenoid-rich vegetables, proline betaine for fruits, quinate and trigonelline for coffee, and pipecolate for alcohol, and these were considered as prominent food intake markers in Japanese eating habits. A set of circulating plasma metabolites was identified as potential food intake biomarkers in the Japanese community-dwelling population. These results will open the way for the application of new reliable dietary assessment tools not by self-reported measurements but through objective quantification of biofluids., Competing Interests: The authors have declared that no competing interests exist.

The Japan Pediatric Helicobacter pylori Study Group published the first guidelines on childhood H. pylori infection in 1997. They were later revised by the Japanese Society for Pediatric Gastroenterology, Hepatology and Nutrition (JSPGHAN). The H. pylori eradication rates, when employing triple therapy with amoxicillin and clarithromycin, currently recommended as the first-line therapy of H. pylori infection in Japan, have substantially decreased, creating an important clinical problem worldwide. In Japanese adults, the "test-and-treat" strategy for H. pylori infection is under consideration as an approach for gastric cancer prevention. However, the combined North American and European pediatric guidelines have rejected such a strategy for asymptomatic children. As risk for gastric cancer development is high in Japan, determining whether the "test-and-treat" strategy can be recommended in children has become an urgent matter. Accordingly, the JSPGHAN has produced a second revision of the H. pylori guidelines, which includes discussion about the issues mentioned above. They consist of 19 clinical questions and 34 statements. An H. pylori culture from gastric biopsies is recommended, not only as a diagnostic test for active infection but for antimicrobial susceptibility testing to optimize eradication therapy. Based upon antimicrobial susceptibility testing of H. pylori strains (especially involving clarithromycin), an eradication regimen including use of the antibiotics to which H. pylori is susceptible is recommended as the first-line therapy against H. pylori-associated diseases. The guidelines recommend against a "test-and-treat" strategy for H. pylori infection for asymptomatic children to protect against the development of gastric cancer because there has been no evidence supporting this strategy., (© 2020 The Authors. Pediatrics International published by John Wiley & Sons Australia, Ltd on behalf of Japan Pediatric Society.)

The effect of the sodium-to-potassium ratio (Na/K) on renal function within the clinically normal range of renal function are limited. We investigated the effects of an estimated 24 h urinary Na/K (e24hUNa/K) on a 6-year renal function decline among 927 urban Japanese community dwellers with no history of cardiovascular diseases and medication for hypertension, diabetes, or dyslipidemia. We partitioned the subjects into quartiles according to the e24hUNa/K. The estimated glomerular filtration rate (eGFR) was calculated using the chronic kidney disease epidemiology collaboration (CKD/EPI) formula and renal function decline was defined as an absolute value at or above the third quartile of the eGFR decline rate. A multivariable logistic regression model was used for estimation. Compared with the first quartile of the e24hUNa/K, multivariable-adjusted odds ratios (ORs) for eGFR decline in the second, third, and fourth quartiles were 0.96 (95% confidence interval: 0.61-1.51), 1.06 (0.67-1.66), and 1.65 (1.06-2.57), respectively. These results were similar when the simple spot urine Na/K ratio was used in place of the e24hUNa/K. Apparently healthy urban residents with an almost within normal range mean baseline eGFR and high e24hUNa/K ratios had an increased risk for a future decline in renal function. Reducing the Na/K ratio may be important in the prevention of chronic kidney disease in its early stage.

This study aimed to investigate the efficacy of guiding sheath delivery with the crossover approach using a newly customized inner dilator for a 0.018-in. guidewire of the Destination ® guiding sheath (Terumo Corporation, Tokyo, Japan) (18-system), compared with that of the conventional-type 0.035-in. guidewires with inner dilators (35-system), and to predict failure of guiding sheath delivery. We conducted a prospective multicenter case series study of the contralateral crossover approach using Destination ® , to determine whether the 18-system could be a rescue system in cases in which the conventional 35-system failed. To evaluate the efficacy of the 18-system, we created an in vitro aortoiliac bifurcation model by using a silicone vessel. We enrolled 172 cases consecutively. The initial crossover approach with the 35-system failed in 37 cases (21.5%), and a second attempt with the 18-system was successful in all failed cases. The bifurcation angles in the 35-system failure cases were significantly steeper than those in the 35-system success cases. A receiver operating characteristic curve analysis demonstrated that an aortoiliac bifurcation angle of 68° was the optimal cut-off value for predicting failure of the crossover procedure. Data from the analysis using the silicone vessel model suggested that the 18-system provided superior results, especially in aortoiliac bifurcation angles steeper than 60°, consistent with the in vivo findings. The results of the initial use of the 18-system with the crossover approach suggest that it may be superior to the conventional 35-system, especially in cases of steeper aortoiliac bifurcation angles.

Objective　Several studies have suggested that high dietary Na/K ratio and body mass index (BMI) increase the prevalence of hypertension. However, there have been a few reports on the combination of these two factors and their relationship with hypertension. This study aimed to examine the association of the combined estimated 24-h urinary Na/K ratio (24h-u-Na/K) (high or low) and BMI (high or low) with the risk of high blood pressure.Method　We performed a cross-sectional study involving 1,112 participants (340 men and 772 women) of the Kobe Orthopedic and Biomedical Epidemiological study (KOBE study) who had no cardiovascular diseases or current anti-hypertensive medications. Sex-specific analyses were performed. The 24h-u-Na/K ratio was calculated from an estimation formula using collected spot urine. Participants were divided into four groups based on their 24h-u-Na/K ratio (low or high) and BMI (low or high), with the cutoff points being the median and 25 kg/m 2 , respectively.　Participants with systolic blood pressure (SBP) ≥130 mmHg or diastolic blood pressure (DBP) ≥80 mmHg were diagnosed with high blood pressure. Odds ratios (ORs) for high blood pressure according to the combined risks of high 24h-u-Na/K and BMI were examined with a logistic regression analysis.Results　The average SBP/DBP for men and women was 122.7/77.9 and 113.3/69.1 mmHg, respectively, and prevalence of high blood pressure among men and women was 47.4% and 21.3%, respectively. The mean BMI was 22.8 kg/m 2 for men and 20.9 kg/m 2 for women. The median 24h-u-Na/K was 3.2 for men and 3.1 for women. The prevalence of high blood pressure (men, women) was the highest in the group in which both 24h-u-Na/K and BMI were high (60.0%, 62.9%; men: P=0.273; women: P<0.001). In the same group, the multivariate-adjusted ORs for high blood pressure were significantly higher for both men (2.59; 95% confidence interval [CI]: 1.15-5.86) and women (10.78; 95% CI: 4.87-23.88) compared to the reference group with both factors classified as low. Women with low BMI but high 24h-u-Na/K also demonstrated a higher risk for high blood pressure (OR: 1.62; 95% CI: 1.10-2.40).Conclusion　The risk of high blood pressure was the highest when both BMI and 24h-u-Na/K were high. The current specific healthcare guidance in Japan is focused on obese individuals. However, in order to prevent hypertension more effectively, additional focus should be placed on the Na/K diet. Increased intake of vegetables and fruits and reduced intake of salt should be strongly recommended.

Objective　To explore health-related and socioeconomic factors that can predict future deterioration in Psychological Distress Scale (K6) scores.Method　We conducted a baseline (2010, 2011) self-administered questionnaire survey of the Kobe Orthopedic and Biomedical Epidemiological study (KOBE study) involving 1,117 participants who had no previous history of cancer or cardiovascular diseases and were not under treatment for hypertension, diabetes, or dyslipidemia. We used the Japanese K6 as an indicator of stress and defined K6≧5 points as a high-stress group and K6<5 points as a low-stress group. A four-year follow-up survey (2014, 2015) was conducted on 1,004 people (follow-up rate of 90%). We excluded 39 participants with missing values, and 185 people whose K6 score was higher than 5 points at baseline. A final total of 780 participants' scores were examined for: gender, age, living situation, physical activity level, average sleep time, as well as the K6 score, the Japanese Hearing Handicap Inventory for Elderly (HHIE-S), and the Japanese Oswestry Disability Index (ODI). We conducted a logistic regression analysis using K6≧5 points at the four-year follow-up survey as the dependent variable and each factor at the baseline survey as the independent variable.Results　Of the 780 subjects analyzed, 132 (16.9%) were highly stressed (K6≧5 points) at the four-year follow-up point. A logistic regression analysis found age (40s/70s) (odds ratio 3.38, 95% confidence interval 1.45-7.86), living situation (single/living together) (odds ratio 1.98, 95% confidence interval 1.07-3.68), and ODI scores (every 1%) (odds ratio 1.05, 95% confidence interval 1.01-1.09), to all be significantly associated with high stress.Conclusion　This study suggests that age, living situation, and ODI scores are related to future stress.

The present study sought to clarify if being conscious of water intake (CWI) is associated with sufficient non-alcohol drink (NAD) intake. We used data of healthy participants without diabetes, aged 40-74 years, in the Kobe Orthopedic and Biomedical Epidemiologic (KOBE) study. The association between being CWI and NAD intake was evaluated by multivariate linear regression analyses after adjusting for age, sex, surveyed months (seasons), alcohol drinking, health-awareness life habits, socioeconomic factors, serum osmolarity, estimated daily salt intake, and reasons for NAD intake. Among 988 (698 women and 290 men) participants eligible for the present analyses, 644 participants (65.2%) were CWI and 344 participants (34.8%) were not CWI (non-CWI). The most popular reason for being CWI was to avoid heat stroke in summer and to prevent ischemic cerebral stroke in winter. The CWI group took more NAD, especially decaffeinated beverages, than the non-CWI group (1846.7 ± 675.1 mL/day vs. 1478.0 ± 636.3 ml/day, p < 0.001). There was a significant association between being CWI and NAD intake in multivariate linear regression analyses ever after adjusting for the relevant variables (β = 318.1, p < 0.001). These findings demonstrated CWI, regardless of the reasons and the seasons, was associated with high NAD intake in Japanese healthy population.

Background: The trend of association between overweight and high serum total cholesterol (TC) among the elderly is unclear. In addition, there is little evidence of risk of underweight for high TC. Therefore, we examined the trend of association of overweight or underweight with high TC among Japanese elderly people using nationwide population-based data., Methods: Data of the National Survey on Circulatory Disorders and National Health and Nutrition Survey for 1980, 1990, 2000, and 2010 were used in the analysis. High TC was defined as 220 mg/dL and above. For participants aged ≥50 years, sex-specific odds ratios (ORs) of overweight or underweight compared with normal body mass index participants for high TC were calculated using a logistic regression model adjusted for age, smoking, drinking, exercise, food, and treatment of hyperlipidemia., Results: A total of 5,734, 4,673, 5,059, and 2,105 participants enrolled in these surveys in 1980, 1990, 2000, and 2010, respectively. Although overweight was positively and significantly associated with high TC in 1980, the association has gradually weakened since (ORs in 1980 and 2010 were 2.44; 95% confidence interval [CI], 1.83-3.24 and 0.92; 95% CI, 0.66-1.27 among men and 1.43; 95% CI, 1.18-1.72 and 1.08; 95% CI, 0.81-1.44 among women, respectively). While underweight was inversely and significantly associated with high TC in 1980, the association also gradually weakened among women (ORs in 1980 and 2010 were 0.28; 95% CI, 0.12-0.60 and 0.37; 95% CI, 0.10-1.28 among men and 0.39; 95% CI, 0.26-0.57 and 0.96; 95% CI, 0.58-1.57 among women, respectively)., Conclusions: These findings provide evidence that high TC prevention efforts must expand the target to not only overweight but also to normal and underweight people.

Background: Although several epidemiological studies have suggested that high serum uric acid (SUA) levels are related to a decline in kidney function, only a few studies have investigated using cystatin C to calculate estimated glomerular filtration rate (eGFR). We aimed to clarify the relationship between SUA levels and kidney function assessed by cystatin C in a Japanese general community population without chronic kidney disease (CKD)., Methods: We conducted a community-based cross-sectional study that included 1086 healthy participants, aged 40-74 years, without CKD and not undergoing treatment of hyperuricemia, who had participated in the baseline survey of the Kobe Orthopedic and Biomedical Epidemiological (KOBE) study. The preconditions for participation in this study were no past histories of cardiovascular disease or cancer, and not undergoing treatment for diabetes, hypertension, or dyslipidemia. We classified the participants into quartiles stratified by sex according to their SUA level and then examined the relationship with eGFR. The odds ratios for having a low eGFR, defined as the lowest quartile of eGFR (i.e., ≤78.4 mL/min/1. 73m 2 ) was estimated according to SUA quartiles (men, Q1 ≤ 5.0, Q2 5.1-5.9, Q3 6.0-6.6, and Q4 ≥ 6.7; women, Q1 ≤ 3.8, Q2 3.9-4.3, Q3 4.4-4.9, and Q4 ≥ 5.0 mg/dL) after adjustment for age, body mass index, systolic blood pressure, HbA1c, high and low density lipoprotein cholesterol, and smoking and drinking habits. The adjusted mean of each quartile was also calculated., Results: Multivariable-adjusted means of eGFR showed a graded decrease in higher SUA quartiles (men, Q1 90.5, Q2 88.0, Q3 83.5, and Q4 82.0; women, Q1 95.7, Q2 91.3, Q3 89.2, and Q4 86.7). In addition, the multivariable-adjusted odds ratios for having a lower eGFR (95% confidence interval) for each SUA quartile compared with Q1 was Q2 2.29 (0.98, 5.35), Q3 4.94 (2.04, 11.97), and Q4 8.01 (3.20, 20.04) for men, and was Q2 2.20 (1.12, 4.32), Q3 2.68 (1.39, 5.20), and Q4 4.96 (2.62, 9.41) for women., Conclusions: There was a graded inverse relationship between mild elevations in SUA levels and eGFR assessed by cystatin C in an apparently healthy Japanese population without CKD. This association was similar in both men and women.

Background: Cohort studies with metabolomics data are becoming more widespread, however, large-scale studies involving 10,000s of participants are still limited, especially in Asian populations. Therefore, we started the Tsuruoka Metabolomics Cohort Study enrolling 11,002 community-dwelling adults in Japan, and using capillary electrophoresis-mass spectrometry (CE-MS) and liquid chromatography-mass spectrometry. The CE-MS method is highly amenable to absolute quantification of polar metabolites, however, its reliability for large-scale measurement is unclear. The aim of this study is to examine reproducibility and validity of large-scale CE-MS measurements. In addition, the study presents absolute concentrations of polar metabolites in human plasma, which can be used in future as reference ranges in a Japanese population., Methods: Metabolomic profiling of 8,413 fasting plasma samples were completed using CE-MS, and 94 polar metabolites were structurally identified and quantified. Quality control (QC) samples were injected every ten samples and assessed throughout the analysis. Inter- and intra-batch coefficients of variation of QC and participant samples, and technical intraclass correlation coefficients were estimated. Passing-Bablok regression of plasma concentrations by CE-MS on serum concentrations by standard clinical chemistry assays was conducted for creatinine and uric acid., Results and Conclusions: In QC samples, coefficient of variation was less than 20% for 64 metabolites, and less than 30% for 80 metabolites out of the 94 metabolites. Inter-batch coefficient of variation was less than 20% for 81 metabolites. Estimated technical intraclass correlation coefficient was above 0.75 for 67 metabolites. The slope of Passing-Bablok regression was estimated as 0.97 (95% confidence interval: 0.95, 0.98) for creatinine and 0.95 (0.92, 0.96) for uric acid. Compared to published data from other large cohort measurement platforms, reproducibility of metabolites common to the platforms was similar to or better than in the other studies. These results show that our CE-MS platform is suitable for conducting large-scale epidemiological studies.

Background: An increased risk of total death owing to human T-lymphotropic virus type-I (HTLV-I) infection has been reported. However, its etiology and protective factors are unclear. Various studies reported fluctuations in immune-inflammatory status among HTLV-I carriers. We conducted a matched cohort study among the general population in an HTLV-I-endemic region of Japan to investigate the interaction between inflammatory gene polymorphisms and HTLV-I infection for total death, incidence of cancer, and atherosclerosis-related diseases., Method: We selected 2180 sub-cohort subjects aged 35-69 years from the cohort population, after matching for age, sex, and region with HTLV-I seropositives. They were followed up for a maximum of 10 years. Inflammatory gene polymorphisms were selected from TNF-α, IL-10, and NF-κB1. A Cox proportional hazard model was used to estimate the hazard ratio (HR) and the interaction between gene polymorphisms and HTLV-I for risk of total death and incidence of cancer and atherosclerosis-related diseases., Results: HTLV-I seropositivity rate was 6.4% in the cohort population. The interaction between TNF-α 1031T/C and HTLV-I for atherosclerosis-related disease incidence was statistically significant (p = 0.020). No significant interaction was observed between IL-10 819T/C or NF-κB1 94ATTG ins/del and HTLV-I. An increased HR for total death was observed in the Amami island region, after adjustment of various factors with gene polymorphisms (HR 3.03; 95% confidence interval, 1.18-7.77)., Conclusion: The present study found the interaction between TNF-α 1031T/C and HTLV-I to be a risk factor for atherosclerosis-related disease. Further follow-up is warranted to investigate protective factors against developing diseases among susceptible HTLV-I carriers., (Copyright © 2017 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Objective: The aim of the study was to investigate the associations of amino acids and other polar metabolites with metabolic syndrome (MetS) in postmenopausal women in a lean Asian population., Methods: The participants were 1,422 female residents enrolled in a cohort study from April to August 2012. MetS was defined according to the National Cholesterol Education Program Adult Treatment Panel III modified for Japanese women. Associations were examined between MetS and 78 metabolites assayed in fasting plasma samples using capillary electrophoresis-mass spectrometry. Replication analysis was performed to confirm the robustness of the results in a separate population created by random allocation., Results: Analysis was performed for 877 naturally postmenopausal women, including 594 in the original population and 283 in the replication population. The average age, body mass index, and levels of high- and low-density lipoprotein cholesterol of the entire population were 64.6 years, 23.0 kg/m, 72.1 mg/dL, and 126.1 mg/dL, respectively. There was no significant difference in low-density lipoprotein cholesterol levels between women with and without MetS. Thirteen metabolites were significantly related to MetS: multiple plasma amino acids were elevated in women with MetS, including branched-chain amino acids, alanine, glutamate, and proline; and alpha-aminoadipate, which is generated by lysine degradation, was also significantly increased., Conclusions: Our large-scale metabolomic profiling indicates that Japanese postmenopausal women with MetS have abnormal polar metabolites, suggesting altered catabolic pathways. These results may help to understand metabolic disturbance, including in persons with normal body mass index and relatively high levels of high-density lipoprotein cholesterol, and may have clinical utility based on further studies.

Purpose: The aim of this study was to investigate the prevalence of Lynch syndrome among Japanese patients with surgically resected colorectal cancer at a single institution., Methods: Of 616 colorectal cancer patients who underwent surgical operation in our institution from January 2005 to August 2010, immunohistochemistry analyses for mismatch repair proteins (MLH1, MSH2, MSH6, and PMS2) and microsatellite instability (MSI) testing for surgically resected, formalin-fixed paraffin-embedded colorectal cancer specimens from 138 colorectal cancer patients under 60 years of age were undertaken. Hypermethylation of the MLH1 promoter and BRAF mutation were analyzed where necessary., Results: Seven patients were identified as candidates for genetic testing by mismatch repair protein loss (n = 7) or MSI-H (n = 6). Methylation of MLH1 was detected in one case. Three patients were diagnosed with Lynch syndrome, comprising 2.2 % of the total colorectal cancer patients younger than 60 years of age., Conclusion: The prevalence of Lynch syndrome among hospital-based diagnosed cancer patients may therefore be lower than expected in Japan compared with Western populations.

Objective: Metabolomics is a promising approach to the identification of biomarkers in plasma. Here, we performed a population-based, cross-sectional study to identify potential biomarkers of alcohol intake and alcohol-induced liver injury by metabolomic profiling using capillary electrophoresis-mass spectrometry (CE-MS)., Methods: Fasting plasma samples were collected from 896 Japanese men who participated in the baseline survey of the Tsuruoka Metabolomics Cohort Study, and 115 polar metabolites were identified and absolutely quantified by CE-MS. Information on daily ethanol intake was collected through a standardized, self-administered questionnaire. The associations between ethanol intake and plasma concentration of metabolites were examined. Relationships between metabolite concentrations or their ratios and serum liver enzyme levels in the highest ethanol intake group (>46.0 g/day) were then examined by linear regression analysis. Replication analysis was conducted in 193 samples collected from independent population of this cohort., Results: Nineteen metabolites were identified to have an association with daily alcohol consumption both in the original and replication population. Three of these metabolites (threonine, glutamine, and guanidinosuccinate) were found to associate well with elevated levels of serum liver enzymes in the highest ethanol intake group, but not in the non-drinker group. We also found that the glutamate/glutamine ratio had a much stronger relation to serum γ-glutamyltransferase, aspartate transaminase, and alanine transaminase than glutamate or glutamine alone (standardized beta = 0.678, 0.558, 0.498, respectively)., Conclusions: We found 19 metabolites associated with alcohol intake, and three biomarker candidates (threonine, guanidinosuccinate and glutamine) of alcohol-induced liver injury. Glutamate/glutamine ratio might also be good biomarker.

Background: The number of elderly patients with asthma has been increasing in Japan. Treatment for these patients should be provided based on the condition of individual patients. This study was performed to clarify the relationship between inhalation procedure and sex difference in elderly patients with asthma., Methods: The inhalation procedure was examined in 155 elderly patients with asthma (male: n=66, average age ± standard deviation: 75.5±5.65 years old; female: n=89, average age ± standard deviation: 78.7±6.87 years old) during a medical examination., Results: For the three items that were common to all devices, the percentages of the 155 patients who could/could not perform the actions were examined by separate Fisher's exact tests for males and females. A statistically significant difference (P=0.007) was observed for "breath holding", and more females than males were not able to hold their breath. Although no significant difference was seen in the "accurate number of times of inhalation", females tended to not be able to inhale accurately compared to males (P=0.072)., Conclusion: Our results suggest that elderly female patients with asthma have less understanding of inhaled steroid therapy, compared to elderly male patients. Therefore, it is particularly important to confirm that the correct inhalation procedure is used by elderly female patients with asthma.

Background/objective: Gene-gene interactions in the reverse cholesterol transport system for high-density lipoprotein-cholesterol (HDL-C) are poorly understood. The present study observed gene-gene combination effect and interactions between single nucleotide polymorphisms (SNPs) in ABCA1, APOA1, SR-B1, and CETP in serum HDL-C from a cross-sectional study in the Japanese population., Methods: The study population comprised 1,535 men and 1,515 women aged 35-69 years who were enrolled in the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study. We selected 13 SNPs in the ABCA1, APOA1, CETP, and SR-B1 genes in the reverse cholesterol transport system. The effects of genetic and environmental factors were assessed using general linear and logistic regression models after adjusting for age, sex, and region., Principal Findings: Alcohol consumption and daily activity were positively associated with HDL-C levels, whereas smoking had a negative relationship. The T allele of CETP, rs3764261, was correlated with higher HDL-C levels and had the highest coefficient (2.93 mg/dL/allele) among the 13 SNPs, which was statistically significant after applying the Bonferroni correction (p<0.001). Gene-gene combination analysis revealed that CETP rs3764261 was associated with high HDL-C levels with any combination of SNPs from ABCA1, APOA1, and SR-B1, although no gene-gene interaction was apparent. An increasing trend for serum HDL-C was also observed with an increasing number of alleles (p<0.001)., Conclusions: The present study identified a multiplier effect from a polymorphism in CETP with ABCA1, APOA1, and SR-B1, as well as a dose-dependence according to the number of alleles present.

Quality improvement initiatives in intensive care units (ICUs) have increased survival rates. Changes in functional status following ICU care have been studied, but results are inconclusive because of insufficient consideration of the combinations of critical care procedures used. Using the Japanese administrative database including the Barthel Index (BI) at admission and discharge, we measured the changes in functional status among the adult patients and determined whether longer ICU stay or use of various critical care procedures was associated with functional deterioration. Of the 12 502 528 patients admitted to 1206 hospitals over 5 consecutive years from 2006, we analyzed data from patients aged 15 years or older who survived ICU admission in 320 hospitals. Critical care procedures evaluated were ventilation, blood purification (hemodialysis, hemodiafiltration, or hemadsorption), and cardiac support devices (intra-aortic balloon pump or percutaneous cardiopulmonary support system). Functional outcomes were determined by the difference between BI at admission and at discharge and were divided into improvement, no change, or deterioration. We compared patient characteristics, principal diagnosis, comorbidities, timing of surgical procedure, complications, days in ICU, and use of critical care procedures among the 3 categories. Associations between critical care procedures and functional deterioration were identified using multivariate analysis. Of 234 209 patients with complete BI information, 7137 (3.1%) received blood purification, 27 100 (11.7%) received ventilation, 2888 (1.2%) received blood purification and ventilation, 5613 (2.4%) received a cardiac support device, 247 (0.1%) received a cardiac support device and blood purification, 10 444 (4.5%) received a cardiac support device and ventilation, and 1110 (0.5%) received a cardiac support device, ventilation, and blood purification. Longer use of blood purification or ventilation and a longer ICU stay were associated with functional deterioration. Intensivists should be aware of the effects of critical care procedures on functional deterioration and advance the appropriate use of functional support according to each patient's condition.

Aim: This study aimed to investigate the relationship between hospital volume and clinical outcomes of elderly and non-elderly patients with acute biliary diseases using data from a national administrative database., Methods: Overall, 26720 elderly and 33774 non-elderly patients with acute biliary diseases were referred to 820 hospitals in Japan. Hospital volume was categorized into three groups based on the case numbers during the study period: low-volume, medium-volume and high-volume. We compared the risk-adjusted length of stay (LOS) and in-hospital mortality in relation to hospital volume. These analyses were stratified according to the presence of invasive treatments for acute biliary diseases., Results: Multiple linear regression analyses showed that increased hospital volume was significantly associated with shorter LOS in both elderly and non-elderly patients with and without invasive treatments. Increased hospital volume was significantly associated with decreased relative risk of in-hospital mortality in elderly patients. The odds ratio for high-volume hospitals was 0.672 in elderly patients without invasive treatments (95% confidence interval [CI] 0.533-0.847, P=0.001) and 0.715 in those with invasive treatments (95% C, 0.566-0.904, P=0.005). However, no significant differences for in-hospital mortality were seen in non-elderly patients with and without invasive treatments., Conclusion:   This study has highlighted that higher volume hospitals significantly reduced LOS and in-hospital mortality for elderly patients with acute biliary diseases, but not non-elderly patients. The current results are of value for elderly healthcare policy decision-making, and highlight the need for further studies into the quality of care for elderly patients., (© 2012 Japan Geriatrics Society.)

Post-procedure hemodynamic management for aneurysmal subarachnoid hemorrhage is controversial because of the paucity of studied patients. Using a Japanese administrative database, we tested whether increased albumin, catecholamine, and volumes of fluid administered between the procedure and the 4th post-procedure day would be associated with outcomes of mortality, consciousness deterioration at discharge and re-intubation between the 5th and 14th post-procedure days. Across 550 hospitals, 5,400 patients were identified who received clipping, wrapping and endovascular coiling within 48 h after admission in 2010. Patient characteristics and the administration of albumin, catecholamine, and volume of fluid normalized by body weight were analyzed among the groups and categorized according to the presence of albumin and catecholamine administered between the procedure and the 4th post-procedure day. The association of early hemodynamic management with outcomes was measured using logistic regression models, through controlling for the preference of early administration of albumin and catecholamine. For the patients, 9.3 % received albumin only, 14.4 % catecholamine only, and 4.9 % both between the procedure and the 4th post-procedure day, while 16.5 % received albumin or catecholamine on other days. Variation in albumin and catecholamine administration was observed. Higher normalized fluid volume, commenced before the 4th post-procedure day, was associated with increased mortality and re-intubation (although with decreased complications), and vice versa between the 4th and 14th post-procedure days. Catecholamine administration was associated with worsened outcomes. Hypervolemic and hypertensive therapies commenced before the 4th post-procedure day require further research to determine whether their associations with outcomes in this administrative data base are causal or not.

Little information is available on the factors influencing length of stay (LOS) in hospital and medical costs during hospitalization associated with cholecystectomy for acute cholecystitis. We determined the independent factors affecting LOS and medical costs of patients who underwent cholecystectomy for acute cholecystitis based on data from the Diagnosis Procedure Combination (DPC) database. In 2008, a total of 2176 patients with acute cholecystitis were referred for cholecystectomy to 624 hospitals in Japan. We collected patient characteristics and data on treatments for acute cholecystitis using the DPC database and identified independent factors affecting LOS and medical costs during hospitalization using multiple linear regression models. Analysis revealed that early cholecystectomy was significantly associated with a decrease in LOS, whereas longer preoperative antimicrobial therapy was significantly associated with an increase of LOS: the standardized coefficient for early cholecystectomy was -0.372 and that for preoperative antimicrobial therapy was 0.353 (P < 0.001). These procedures were also significant independent factors with regard to medical costs during hospitalization: the standardized coefficient for early cholecystectomy was -0.391 and that for preoperative antimicrobial therapy was 0.335 (P < 0.001). Early cholecystectomy significantly reduces the LOS and medical costs of cholecystectomy for acute cholecystitis, while preoperative antimicrobial therapy increases LOS and medical costs during hospitalization. These results highlight the need for health care implementations such as promotion of early cholecystectomy, appropriate use of antimicrobial drugs, and centralization of patients with cholecystectomy for acute cholecystitis in Japan.

Acute cholecystitis is one of the most frequently encountered conditions in daily practice in Japan. However, there is a shortage of detailed data about treatments that have been performed according to the clinical practice guidelines (CPGs) for acute cholecystitis. We therefore examined the management of acute cholecystitis for adherence to the appropriate CPGs using the Japanese administrative database associated with the Diagnosis Procedure Combination (DPC) system. We collected data from 6,070 patients with acute cholecystitis, examining for the application of four recommended treatments (administration of antimicrobial drugs and nonsteroidal anti-inflammatory drugs (NSAIDs) and performance of early and laparoscopic cholecystectomy). The patients were classified according to the procedures documented for each case: no gallbladder drainage (n = 4,333), gallbladder drainage without supportive care (ventilation or hemodiafiltration or the use of vasopressor) (n = 1,591) and gallbladder drainage and supportive care (n = 146). Multiple logistic regression models revealed that patients with gallbladder drainage without supportive care and those with gallbladder drainage and supportive care significantly higher received administration of antimicrobial drugs and NSAIDs, while these patients underwent less early or laparoscopic cholecystectomy than did patients without gallbladder drainage, after adjusting for potential confounding effects of the clinical variables. This study demonstrated that there were various differences with regard to the performance of recommended treatments between the levels of procedures required for acute cholecystitis. In addition, this administrative database was a feasible tool for the evaluation of care processes and will provide useful information contributing to improved quality of medical care.

Purpose: Little information is available on the influence of diabetes mellitus on the short-term clinical outcomes of patients with bleeding peptic ulcers. The aim of this study is to investigate whether diabetes mellitus influences the short-term clinical outcomes of patients with bleeding peptic ulcers using a Japanese national administrative database., Materials and Methods: A total of 4863 patients treated by endoscopic hemostasis on admission for bleeding peptic ulcers were referred to 586 participating hospitals in Japan. We collected their data to compare the risk-adjusted length of stay (LOS) and in-hospital mortality of patients with and without diabetes mellitus within 30 days. Patients were divided into two groups: patients with diabetes mellitus (n=434) and patients without diabetes mellitus (n=4429)., Results: Mean LOS in patients with diabetes mellitus was significantly longer than those without diabetes mellitus (15.8 days vs. 12.5 days, p<0.001). Also, higher in-hospital mortality within 30 days was observed in patients with diabetes mellitus compared with those without diabetes mellitus (2.7% vs. 1.1%, p=0.004). Multiple linear regression analysis revealed that diabetes mellitus was significantly associated with an increase in risk-adjusted LOS. The standardized coefficient was 0.036 days (p=0.01). Furthermore, the analysis revealed that diabetes mellitus significantly increased the risk of in-hospital mortality within 30 days (odds ratio=2.285, 95% CI=1.161-4.497, p=0.017)., Conclusion: This study demonstrated that presence of diabetes mellitus significantly influences the short-term clinical outcomes of patients with bleeding peptic ulcers.

Objective: Public health emergencies like earthquakes and tsunamis underscore the need for an evidence-based approach to disaster preparedness. Using the Japanese administrative database and the geographical information system (GIS), the interruption of hospital-based mechanical ventilation administration by a hypothetical disaster in three areas of the southeastern mainland (Tokai, Tonankai, and Nankai) was simulated and the repercussions on ventilator care in the prefectures adjacent to the damaged prefectures was estimated., Design, Setting, and Patients: Using the database of 2010 including 3,181,847 hospitalized patients among 952 hospitals, the maximum daily ventilator capacity in each hospital was calculated and the number of patients who were administered ventilation on October xx was counted., Interventions: Using GIS and patient zip code, the straight-line distances among the damaged hospitals, the hospitals in prefectures nearest to damaged prefectures, and ventilated patients' zip codes were measured. The authors simulated that ventilated patients were transferred to the closest hospitals outside damaged prefectures., Outcomes: The increase in the ventilator operating rates in three areas was aggregated., Results: One hundred twenty-four and 236 patients were administered ventilation in the damaged hospitals and in the closest hospitals outside the damaged prefectures of Tokai, 92 and 561 of Tonankai, and 35 and 85 of Nankai, respectively. The increases in the ventilator operating rates among prefectures ranged from 1.04 to 26.33-fold in Tokai; 1.03 to 1.74-fold in Tonankai, and 1.00 to 2.67-fold in Nankai., Conclusion: Administrative databases and GIS can contribute to evidenced-based disaster preparedness and the determination of appropriate receiving hospitals with available medical resources.

Objective: Because diabetes mellitus (DM) has been highlighted in several healthcare sectors, variations in the case mix of DM should be evaluated to promote effective disease management. Using a Japanese administrative database (2003), we investigated the impact of DM-related comorbidities and of their relevant care processes on healthcare costs incurred during hospitalization., Methods: Of 283,771 hospital admissions across 174 acute care hospitals, 27,853 patients with DM were analyzed. The following variables were analyzed according to age (<65 or ≥65 years), the presence of comorbidities, demographic characteristics, procedure-related complications, insulin use, surgical procedures (percutaneous minimally invasive intervention, hemodialysis, ventilation, and rehabilitation), length of stay (LOS), and total charge (TC; US$1=Y90). Multivariate analyses were applied to investigate the effects of DM-related complications and care processes associated with DM on TC., Results: The mortality and procedure-related complication rates were 2.1% and 2.7%, respectively. There were significant differences in the frequencies of comorbidities by age category. Among DM-related comorbidities, peripheral vascular disease had the greatest impact on increasing the LOS or TC. Minimally invasive procedures, hemodialysis, ventilation, and procedure-related complications were significant determinants of TC. Hemodialysis and invasive surgical procedures were independent predictors of procedure-related complications., Conclusions: DM-related comorbidities and care process representative of the DM case mix were responsible for variations in healthcare costs during hospitalization., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Little information is available on the analysis of medical costs of acute pancreatitis hospitalizations., Aim: This study aimed to determine the factors affecting medical costs of patients with acute pancreatitis during hospitalization using a Japanese administrative database., Methods: A total of 7193 patients with acute pancreatitis were referred to 776 hospitals. We defined "patients with high medical costs" as patients whose medical costs exceeded the 90th percentile in medical costs during hospitalization and identified the independent factors for patients with high medical costs with and without controlling for length of stay., Results: Multiple logistic regression analysis demonstrated that necrosectomy was the most significant factor for medical costs of acute pancreatitis during hospitalization. The odds ratio of necrosectomy was 33.64 (95% confidence interval, 14.14-80.03; p<0.001). Use of an intensive care unit was the most significant factor for medical costs after controlling for LOS. The OR of an ICU was 6.44 (95% CI, 4.72-8.81; p<0.001)., Conclusion: This study demonstrated that necrosectomy and use of an ICU significantly affected the medical costs of acute pancreatitis hospitalization. These results highlight the need for health care implementations to reduce medical costs whilst maintaining the quality of patient care, and targeting patients with severe acute pancreatitis., (Copyright © 2011 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Objective: This study aimed to investigate the relationship between hospital volume and clinical outcome in patients with acute pancreatitis, using a Japanese national administrative database., Methods: A total of 7007 patients with acute pancreatitis were referred to776 hospitals in Japan. Patient data were corrected according to the severity of acute pancreatitis to allow the comparison of risk-adjusted in-hospital mortality and length of stay in relation to hospital volume. Hospital volume was categorized based on the number of cases during the study period into low-volume (<10 cases), medium-volume (10-16 cases), and high-volume hospitals (HVHs, >16 cases)., Results: Increased hospital volume was significantly associated with decreased relative risk of in-hospital mortality in both patients with mild and those with severe acute pancreatitis. The odds ratios for HVHs were 0.424 (95% confidence interval [CI], 0.228-0.787; P = 0.007) and 0.338 (95% CI, 0.138-0.826; P = 0.017), respectively. Hospital volume was also significantly associated with shorter length of stay in patients with mild acute pancreatitis. The unstandardized coefficient for HVHs was -0.978 days (95% CI, -1.909 to -0.048; P = 0.039)., Conclusions: This study demonstrated that hospital volume influences the clinical outcome in both patients with mild and those with severe acute pancreatitis.

Purpose: To examine the circumstances of medical treatment for acute pancreatitis before publication of the new Japanese (JPN) guidelines using the Japanese administrative database associated with the Diagnosis Procedure Combination system., Methods: We collected data from 7,193 patients with acute pancreatitis in 2008 and examined the recommended medical treatment in the new JPN guidelines [from recommendations B (considered to be recommended treatments) to D (considered to be unacceptable treatments)] according to severity of acute pancreatitis. Patients were divided into two groups: mild cases (n = 6,520) and severe cases (n = 673)., Results: Enteral nutrition for severe cases without ileus (recommendation B) was uncommon (13.5%). In contrast, prophylactic antibiotics were administered in a large number (80.4%) of mild cases without acute cholangitis (recommendation D). Furthermore, administration of H(2) receptor antagonists, except for cases of upper gastrointestinal bleeding (recommendation D), were performed in many patients with both mild and severe cases (66.8 vs. 78.6%)., Conclusions: This study demonstrated a discrepancy between actual medical treatment performed and the new JPN guidelines with regard to some of the medical treatments. Future studies are required after publication of the new JPN guidelines to determine how they affect medical treatments.

Case-mix classification has made it possible to analyze acute care delivery case volumes and resources. Data arising from observed differences have a role in planning health policy. Aggregated length of hospital stay (LOS) and total charges (TC) as measures of resource use were calculated from 34 case-mix groups at 469 hospitals (1,721,274 eligible patients). The difference between mean resource use of all hospitals and the mean resource use of each hospital was subdivided into three components: amount of variation attributable to hospital practice behavior (efficiency); amount attributable to hospital case-mix (complexity); and amount attributable to the interaction. Hospital characteristics were teaching status (academic or community), ownership, disease coverage, patients, and hospital volume. Multivariate analysis was employed to determine the impact of hospital characteristics on efficiency. Mean LOS and TC were greater for academic than community hospitals. Academic hospitals were least associated with LOS and TC efficiency. Low disease coverage was a predictor of TC efficiency while low patient volume was a predictor of unnecessarily long hospital stays. There was an inverse correlation between complexity and efficiency for both LOS and TC. Policy makers should acknowledge that differentiation of hospital function needs careful consideration when measuring efficiency., (Copyright © 2010 John Wiley & Sons, Ltd.)

Background: Little information is available on the relationship between hospital volume and compliance with clinical practice guidelines (CPGs)., Objectives: To investigate the relationship between hospital volume and compliance with CPGs using a Japanese administrative database., Design and Subjects: This was an observational study that included 60,842 patients with acute cholangitis from 829 hospitals in Japan., Measures: Hospital volume was categorized into the following 3 groups based on the number of cases of acute cholangitis during the study period: low-volume hospitals (LVHs; n = 20,869), medium-volume hospitals (MVHs; n = 18,387), and high-volume hospitals (HVHs; n = 21,586). We further collected patient data with regard to CPGs for acute cholangitis, and counted the number of recommendations that had been complied with for each patient. CPGs compliance score was defined as the rate of compliance with these recommendations for each patient (range, 0-10). Aggregated CPGs compliance score was measured according to hospital volume., Results: Mean CPGs compliance score in HVHs was significantly higher than that in MVHs and LVHs (6.8 ± 1.6 vs. 5.6 ± 1.5 vs. 3.9 ± 1.4, respectively; P < 0.001). Multiple linear regression analysis revealed that hospital volume was most significantly associated with CPGs compliance score. The standardized coefficient for CPGs compliance score in HVHs was 0.689, whereas that of MVHs was 0.366 (P < 0.001)., Conclusions: This study demonstrated that hospital volume was significantly associated with compliance with CPGs and that the Japanese administrative database was a viable tool for the monitoring of compliance with CPGs.

Background: Despite the prevalence of laparoscopic surgery (LS), community-based appraisal of its benefit over open surgery (OS) has not been performed. This can be measured by increased total charge (TC) spent and decreased length of stay (LOS), which are indicative of greater resource use and opportunistic cost reduction. We prioritized the value of LS for eight abdominal procedures., Materials and Methods: We used a Japanese administrative database for the 6 mo leading up to December 2007. Study procedures were appendectomy, cholecystectomy, choledocholithotomy, herniorrhaphy, colectomy, partial or total gastrectomy, and small bowel resection (SBR) in adults. We analyzed patient demographics, mortality, comorbidity, complications, use of chemotherapy or postoperative pain control, hospital teaching status, postoperative LOS, and TCs. The impact of LS was determined using multivariate analysis on the propensity-score-matched cohorts of LS and OS., Results: Herniorrhaphy was most frequently performed (24,088 cases), whereas SBR was performed least (3404). LS was performed most often in cholecystectomy (81%) and least in herniorrhaphy (3.7%). LS did not increase complications in any procedure. Laparoscopic cholecystectomy and SBR were associated with shorter LOS and lower TC, whereas laparoscopic herniorrhaphy increased LOS and TC. Laparoscopic appendectomy and partial gastrectomy reduced LOS and increased TC., Conclusions: LS safety was confirmed. Laparoscopic cholecystectomy or SBR might have advantages, whereas laparoscopic was no better than open herniorrhaphy and might be decided by patient's preference. Considering the variation in the decremental opportunistic cost produced by incremental medical expenses observed among the procedures, policymakers should determine an appropriate reimbursement schedule., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Few reliable data are available on the incidence of snake bites in developing and developed nations. Insufficient epidemiologic data have hindered the recognition of snake bite as an important public health issue. We verified statistics of snake bites (mamushi and habu bites) in Japan by using a currently available, nationally representative, hospital-based database. We identified 1,670 inpatients with snake bites from 404 hospitals during July 1-December 31 in 2007 and 2008. More than 60% were males, the average age was 60.1 years, and the in-hospital mortality rate was 0.2%. The incidence of mamushi bite, distributed between latitudes 30°N and 46°N, was estimated to be 1.67 bites/100,000/6 months. It is important to continue collecting all available data to monitor the trends of this life-threatening disease.

Objective: Tsutsugamushi disease (scrub typhus) is caused by Orientia tsutsugamushi, and has been endemic in Asia and Western Pacific islands. Though sporadic case reports have described the clinical consequences of this vector-borne disease, data on the actual incidence of complications or mortality are scarce. It also remains unclear how a delay in effective treatments affects the occurrence of complications associated with this Rickettsial disease., Methods: Using the Japanese Diagnosis Procedure Combination inpatient database in Japan, we identified patients with Tsutsugamushi disease between July 1 and December 31 in 2007 and 2008. We examined location of hospitals, patient's age, sex, comorbidities, complications, inhospital deaths, date of admission, date of starting therapy with tetracyclines. A logistic regression was conducted to analyze the association between delay in effective treatments and the occurrence of complications., Results: A total of 210 cases were identified. Overall, 29 (13.8%) had at least one complication and two deaths were identified. Age was a significant risk factor for complications [odds ratio (OR), 1.48; 95% confidence interval (CI), 1.08-2.03; p=0.014, for a 10-year age increase]. Patients with ≥2 days delay in treatment with tetracyclines had a significantly higher risk of complications compared to those with no delay (OR, 2.71; 95% CI, 1.03-7.12; p=0.044)., Conclusion: Tsutsugamushi disease remains a threat to public health. Our study clearly indicates the importance of early diagnosis and immediate tetracycline treatment to prevent severe complications in Tsutsugamushi disease.

At present, there is a shortage of detailed data on head and neck cancer treatment in acute care hospitals in Japan. We conducted an analysis of the care process for laryngeal cancer inpatients in Japan using a national administrative database based on the case-mix system known as the Diagnosis Procedure Combination to evaluate the recent clinical situation of a relatively high incidence of head and neck cancers. We obtained discharge data relating to 2790 cases (one case = one hospitalization) involving 2319 laryngeal cancer patients from 346 acute care hospitals that participated in the Japanese national case-mix project between July and December of 2008. The details of their treatment procedures were analyzed according to the Japanese procedure codes managed by the Ministry of Health, Labour, and Welfare of Japan. There were 2156 male and 163 female patients. The median age was 69 years (range: 22-96 years). The most frequent surgical procedure was endoscopic resection which was performed for 781 cases. Chemotherapy was given in 31.6% of cases in the < 60 age group, 28.2% in the 60-79, and 14.1% in the ≥ 80. The most frequently used chemotherapy regimen was a single drug, S-1 (compound of tegafur, gimeracil and oteracil potassium), which was more frequently used in the ≥ 70 age group than in the younger age group. The Diagnosis Procedure Combination database, which collects a large volume of data from all over the country, is useful for analysis of the care process for head and neck cancers in Japan.

Background/purpose: We aimed to evaluate compliance with the clinical practice guidelines for acute cholangitis (Tokyo Guidelines) using the Japanese administrative database associated with the Diagnosis Procedure Combination (DPC) system., Methods: We collected database data from 60,842 acute cholangitis patients, examining 10 recommendations in the Tokyo Guidelines. We counted how many recommendations had been complied with for every patient. The patient compliance score was defined as the rate of compliance with these recommendations (score 0 = 0% to score 10 = 100%). An aggregated patient compliance score was measured according to the severity of acute cholangitis. Severity was categorized as grade I (mild cholangitis; n = 49,630), grade II (moderate cholangitis; n = 10,444), and grade III (severe cholangitis; n = 768)., Results: The mean patient compliance score was significantly higher for patients with grade III than for those with grades II and I (7.6 ± 2.1 vs. 6.5 ± 3.0 vs. 2.9 ± 0.9, p < 0.001, respectively). Multiple linear regression analysis revealed that the severity of acute cholangitis was the parameter most significantly associated with the patient compliance score. The standardized coefficient of grade III was higher than that of grade II (0.657 vs. 0.248, p < 0.001)., Conclusions: Compliance with the Tokyo Guidelines became higher in accordance with the severity of acute cholangitis.

Background: In 2008, the Japanese government implemented a program of health lifestyle interventions to reduce health care expenditure. This study evaluated whether these interventions decreased health care expenditures., Methods: The study enrolled 99 participants insured by Japanese National Health Insurance, who, in our previous study conducted in 2004, were allocated by random sampling into an intervention group (50 participants) and a control group (49 participants). In the intervention group, we used a health support method that facilitated the attainment of goals established by each participant. The control group received instruction in exercise, as well as health support using publically available media. Although 3 participants in the intervention group and 9 participants in the control group did not participate in a follow-up health examination 1 year after the intervention, the health care expenditures of all initial participants were assessed. Expenditures before and after the intervention were compared within and between groups. Data on health care expenditures were obtained from inpatient, outpatient, pharmacy, and dental health insurance claims., Results: After the intervention, the pharmacy and dental expenditures were significantly higher in the intervention group, while the pharmacy expenditure was significantly higher in the control group. However, there was no significant difference in any medical expenditure item between the intervention and control groups before or after the intervention., Conclusions: No significant differences were observed in short-term medical expenses for any medical expenditure item after a lifestyle intervention.