Study Profile of the Tsuruoka Metabolomics Cohort Study (TMCS).

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 used 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, 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.

A population-based urinary and plasma metabolomics study of environmental exposure to cadmium.

BACKGROUND: The application of metabolomics-based profiles in environmental epidemiological studies is a promising approach to refine the process of health risk assessment. We aimed to identify potential metabolomics-based profiles in urine and plasma for the detection of relatively low-level cadmium (Cd) exposure in large population-based studies. METHOD: We analyzed 123 urinary metabolites and 94 plasma metabolites detected in fasting urine and plasma samples collected from 1,412 men and 2,022 women involved in the Tsuruoka Metabolomics Cohort Study. Regression analysis was performed for urinary N-acetyl-beta-D-glucosaminidase (NAG), plasma, and urinary metabolites as dependent variables, and urinary Cd (U-Cd, quartile) as an independent variable. The multivariable regression model included age, gender, systolic blood pressure, smoking, rice intake, BMI, glycated hemoglobin, low-density lipoprotein cholesterol, alcohol consumption, physical activity, educational history, dietary energy intake, urinary Na/K ratio, and uric acid. Pathway-network analysis was carried out to visualize the metabolite networks linked to Cd exposure. RESULT: Urinary NAG was positively associated with U-Cd, but not at lower concentrations (Q2). Among urinary metabolites in the total population, 45 metabolites showed associations with U-Cd in the unadjusted and adjusted models after adjusting for the multiplicity of comparison with FDR. There were 12 urinary metabolites which showed consistent associations between Cd exposure from Q2 to Q4. Among plasma metabolites, six cations and one anion were positively associated with U-Cd, whereas alanine, creatinine, and isoleucine were negatively associated with U-Cd. Our results were robust by statistical adjustment of various confounders. Pathway-network analysis revealed metabolites and upstream regulator changes associated with mitochondria (ACACB, UCP2, and metabolites related to the TCA cycle). CONCLUSION: These results suggested that U-Cd was associated with metabolites related to upstream mitochondrial dysfunction in a dose-dependent manner. Our data will help develop environmental Cd exposure profiles for human populations.

Changes in Smoking Habits and Behaviors Following the Introduction and Spread of Heated Tobacco Products in Japan and Its Effect on FEV1 Decline: A Longitudinal Cohort Study.

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 (FEV1) decline. METHODS: Participants consisted of a resident population (n = 2,612; mean age, 67.7 years) with FEV1 measurement in 2012-2014 and 2018-2019, and a worksite population (n = 722; mean age 49.3 years) without FEV1 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 FEV1 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 FEV1 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 FEV1 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 FEV1 decline. Tobacco policy should consider dual use as high-risk.

Psychotropics use and occurrence of falls in hospitalized patients: A matched case-control study.

AIM: Several studies have suggested the use of psychotropics as a possible risk factor for falling. However, there were several limitations to these previous studies, such as the use of data obtained from administrative databases and the lack of information about the time interval between psychotropics use and falling. Therefore, in this study, we aimed to assess the association between psychotropics use and falling in hospitalized patients, using reliable data collected from medical records. METHODS: A matched (age, sex, and inpatient department) case-control study of patients hospitalized at Tokyo Medical University Hospital was performed using the new-user design, based on data extracted from medical records. The outcome was the occurrence of falls. The use of four classes of psychotropics (antipsychotics, antidepressants, anxiolytics, and hypnotics) was compared between 254 cases (patients who experienced falls) and 254 controls (patients without falls). Multivariable logistic regression analysis was performed to clarify the associations between falling and the use of these psychotropics. RESULTS: Univariable analyses demonstrated that the use of every class of psychotropic was statistically significantly associated with falling. Moreover, the association of the use of hypnotics with falls remained significant in the multivariable logistic regression model built including potential confounding factors, such as age, sex, inpatient department, body mass index, fall risk score measured by a fall risk assessment sheet completed on hospital admission, and the use of other classes of psychotropics. CONCLUSIONS: Our findings suggest that the use of hypnotics may be a risk factor for falling in hospitalized patients.

Prognostic Significance of the Number and Extent of Metastatic Lymph Nodes in Patients with Esophageal Cancer: Comparison of the Union for International Cancer Control 8th Edition and Japan Esophageal Society Japanese Classification of Esophageal Cancer 11th Edition Classifications for Esophageal Cancer.

BACKGROUND: The tumor, node, metastasis staging system of the Union for International Cancer Control (UICC) has been used worldwide for esophageal cancer, and, in Japan, the Japan Esophageal Society Japanese Classification of Esophageal Cancer (JES) has also been used; however, there is a big difference between the two classifications with regard to node staging. We hypothesized that these two node staging systems may lead to different outcome predictions in terms of tumor location. METHODS: This study enrolled 409 patients who underwent esophagectomy at Keio University Hospital, Tokyo, Japan, between January 2005 and December 2017. We included those who underwent R0 or R1 resection or esophagectomy with additional organ excision, and excluded those who underwent salvage surgery. Thereafter, we investigated how the number or spread of metastatic lymph nodes affected the prognosis. RESULTS: For all 409 patients, the 5-year overall survival rate was 64.1% and the 5-year recurrence-free survival rate was 58.4%. The concordance indices were 0.756 for UICC 8th edition pathological node staging and 0.732 for JES 11th edition pathological node staging (p = 0.06). Based on tumor location, the difference in the concordance indices between these two classifications was greatest for lower thoracic esophageal tumors (p = 0.02). CONCLUSIONS: For all patients, the UICC 8th edition node staging system tended to reflect survival more precisely than that of the JES 11th edition. For lower thoracic esophageal tumors in particular, the former node staging system could be more useful.

Meta-Analysis of the Effect of Ventilation on Intellectual Productivity.

Indoor air quality (IAQ) influences the health and intellectual productivity of occupants. This paper summarizes studies investigating the relationship between intellectual productivity and IAQ with varying ventilation rates. We conducted a meta-analysis of five studies, with a total of 3679 participants, and performed subgroup analyses (arithmetic, verbal comprehension, and cognitive ability) based on the type of academic performance. The task performance speed and error rate were evaluated to measure intellectual productivity. The effect size of each study was evaluated using the standardized mean difference (SMD). In addition, we calculated a dose-response relationship between ventilation rate and intellectual productivity. The results show that the task performance speed improved, SMD: 0.18 (95% CI: 0.10-0.26), and the error rate decreased, SMD: -0.05 (95% CI: -0.11-0.00), with an increase in ventilation rate. Converting the intervention effect size on the SMD into the natural units of the outcome measure, our analyses show significant improvements in the task performance speed: 13.7% (95% CI: 6.2-20.5%) and 3.5% (95% CI: 0.9-6.1%) in terms of arithmetic tasks and cognitive ability, respectively. The error rate decreased by -16.1% (95% CI: -30.8-0%) in arithmetic tasks. These results suggest that adequate ventilation is necessary for good performance.

Identification of the simultaneous use of multiple hypnotics as a risk factor for falls in hospitalized patients by a matched case-control study.

AIM: The risk of falls owing to simultaneous use of multiple hypnotics has not been clarified. The aim of this study was to assess the association between the simultaneous use of 2 hypnotics and the occurrence of falls in hospitalized patients. METHODS: A matched case-control study was conducted at Tokyo Medical University Hospital in Tokyo, Japan, utilizing data from medical records. Cases were 434 hospitalized patients who experienced falls during their hospital stay between January 2016 and December 2016, and controls were 434 hospitalized patients without falls, individually matched by age, sex, and clinical department. The outcome was the occurrence of an in-hospital fall. The associations between the use of 1 hypnotic and falls, and between the use of 2 hypnotics and falls were assessed by conditional logistic regression analyses. The main multivariable conditional logistic regression model was adjusted for potential risk factors, including the use of other classes of psychotropics (antipsychotics, antidepressants, and anxiolytics), in addition to patient characteristics. RESULTS: The main multivariable conditional logistic regression analyses showed that the simultaneous use of 2 hypnotics (odds ratio [OR] = 2.986; 95% confidence interval [CI], 1.041-8.567), but not the use of a single hypnotic (OR = 1.252; 95% CI, 0.843-1.859), was significantly associated with an increased OR of falls. CONCLUSION: The simultaneous use of 2 hypnotics is a risk factor for falls among hospitalized patients, whereas the use of a single hypnotic may not.

Remote Work Decreases Psychological and Physical Stress Responses, but Full-Remote Work Increases Presenteeism.

Introduction: Remote work was widely promoted in 2020, as a result of the COVID-19 pandemic. However, the effects of remote work on psychological and physical stress responses and presenteeism of workers remain unclear. This research aims to provide empirical evidence of the implications for people and organizations of this new scenario of working from home. Methods: A two-wave panel survey of before and after the pandemic was performed to investigate the effects of remote work on these aspects among office workers. A total of 3,123 office workers from 23 tertiary industries responded to a questionnaire. Participants were surveyed about their job stress conditions and sleep practices in both 2019 and 2020, who had not done remote work as of 2019 were included in the study. The effects of remote work on psychological and physical stress responses and presenteeism were analyzed by multivariate analysis, with the adjustment of age, gender, overtime, job stressors, social support, and sleep status. Results: The multivariate logistic regression analysis demonstrated that remote work was associated with the reduction of psychological and physical stress responses independently of changes of job stressors, social support, sleep disturbance, and total sleep time on workdays. On the other hand, remote work of 5 days a week (full-remote) was associated with the reduction of work productivity. Conclusion: Promoting remote work can reduce psychological and physical stress responses, however, full-remote work has the risk of worsening presenteeism. From the viewpoint of mental health, the review of working styles is expected to have positive effects, even after the end of the COVID-19 pandemic.

A Longitudinal Study of Subjective Daytime Sleepiness Changes in Elementary School Children Following a Temporary School Closure Due to COVID-19.

Excessive daytime sleepiness is increasingly being recognized as a major global health concern. However, there have been few studies related to sleepiness and its associated factors in elementary school children. In Japan, all schools were closed from February to May 2020 to prevent coronavirus disease 2019 (COVID-19) outbreaks. The aim of this study was to identify changes in the subjective sleepiness of pupils during the 1.5-year period and to elucidate factors associated with changes in sleepiness. Questionnaire surveys about pupils' sleep habits and the Japanese version of the Pediatric Daytime Sleepiness Scale (PDSS-J) were conducted longitudinally at one elementary school in June 2019, January 2020, and June 2020. The average ∆PDSS score was 0.94 ± 5.51 (mean ± standard deviation) from June 2019 to January 2020 and -1.65 ± 5.71 (t[498] = 6.13, p < 0.01) from January 2020 to June 2020. Univariate and multivariate logistic regression analyses revealed that decreasing social jetlag was associated with decreasing PDSS scores (OR = 0.77, 95% CI: 0.62-0.96, p = 0.02) during the school closure. A less restrictive school schedule secondary to a COVID-19-related school closure decreased sleepiness in children and was associated with decreasing social jetlag.

Association of drugs with special caution in the guidelines with falls: A case-control and case-crossover study in Japan.

AIM: To determine the relationship between multiple medications and falls. METHODS: This case-control and case-crossover study was carried out at Kudanzaka Hospital in Chiyoda, Tokyo, Japan. A total of 325 patients who experienced their first falls when hospitalized between January 2016 and November 2018, and 1285 controls matched by sex, age and clinical departments were included in this study. Hospitalization duration and fall risk score were adjusted for in the analyses. RESULTS: In the case-control study, multivariable logistic regression showed that increasing the intake of oral medications was not significantly associated with the incidence of falls (odds ratio 1.02, 95% confidence interval 0.998-1.049). In contrast, drugs prescribed with special caution in accordance with the Elderly Oral Medication Guidelines were significantly associated with falls (odds ratio 1.17, 95% confidence interval 1.09-1.26). A similar pattern was observed in the case-crossover analysis. Among the drugs to be prescribed with special caution according to the guidelines, atypical antipsychotics, non-benzodiazepine hypnotics and magnesium oxide were significantly associated with the risk of falls. CONCLUSION: The drugs to be prescribed with special caution according to the guidelines were associated with an increased fall risk. The risk of falls in hospitalized older people due to multiple medications varies among medications. Geriatr Gerontol Int ••; ••: ••-•• Geriatr Gerontol Int 2021; ••: ••-••.

Correction: Non-GABA sleep medications, suvorexant as risk factors for falls: Case-control and case-crossover study.

[This corrects the article DOI: 10.1371/journal.pone.0238723.].

Reliability of urinary charged metabolite concentrations in a large-scale cohort study using capillary electrophoresis-mass spectrometry.

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.

Comprehensive and long-term surveys of COVID-19 sequelae in Japan, an ambidirectional multicentre cohort study: study protocol.

INTRODUCTION: The rapid spread of COVID-19 posed a global burden. Substantial number of people died of the disease in the acute phase of infection. In addition, a significant proportion of patients have been reported to suffer from post-acute phase symptoms, sequelae of COVID-19, which may negatively influence the quality of daily living and/or socioeconomic circumstances of the patients. However, no previous study has comprehensively and objectively assessed the quality of life of patients by using existing international scales. Further, evidence of socioeconomic consequences among patients with COVID-19 is scarce. To address the multidimensional issues from sequelae of COVID-19, evidence from comprehensive surveys beyond clinical perspectives is critical that investigates health, and social determinants of disease progression as well as socioeconomic consequences at a large scale. METHODS AND ANALYSIS: In this study, we plan to conduct a nationwide and comprehensive survey for the sequelae of COVID-19 in a total of 1000 patients diagnosed at 27 hospitals throughout Japan. This study will evaluate not only the health-related status of patients from clinical perspectives but also the Health-related Quality of Life (HRQoL) scores, socioeconomic status and consequences to discuss the sequelae of the disease and the related risk factors. The primary endpoint is the frequency of long-term complications of COVID-19 infection. The secondary endpoints are risk factors for progression to sequelae of COVID-19 infection. The study will provide robust and important evidence as a resource to tackle the issues from the sequelae of COVID-19 from the multi-dimensional perspectives. ETHICS AND DISSEMINATION: This trial was approved by the Keio University School of Medicine Ethics Committee (20200243, UMIN000042299). The results of this study will be reported at a society meeting or published in a peer-reviewed journal.

Association between work productivity and sleep health: A cross-sectional study in Japan.

OBJECTIVES: To examine the impact of sleep health on work in Japan and to investigate the relationship between presenteeism and sleep health. DESIGN: Cross sectional analysis of a questionnaire survey. SETTING: Seventeen offices in Tokyo, Japan. PARTICIPANTS: The study included 2897 participants, of which 1835 were men and 1062 women, aged between 18 and 76 years. MEASUREMENTS: Productivity loss was measured using the Short Form of the Work Limitations Questionnaire (WLQ-SF). RESULTS: The decline in productivity due to presenteeism of people with short sleep duration, between 5 and 6 h (ß = 0.068, p = 0.004) and less than 5 h (ß = 0.105, p < 0.001), was significantly greater compared with those with long sleep duration (7-8 h). Subjective sleep quality (ß = 0.124, p < 0.001), sleep latency (ß = 0.073, p < 0.001), sleep disturbance (ß = 0.123, p < 0.001), use of sleep medication (ß = 0.044, p = 0.007), and daytime dysfunction (ß = 0.359, p = 0.001) significantly affected presenteeism. When adjusting for confounding factors, sleep duration on workdays, sleep duration on free days, mid-sleep on free days corrected for sleep debt on workdays (MSFsc), and social jet lag were not associated with presenteeism in the multiple regression analysis. CONCLUSIONS: Sleep health is associated with presenteeism in Japan. Subjective sleep quality, daytime dysfunction, sleep disturbance, and use of sleep medicine are associated with presenteeism. Good sleep hygiene may be important for workers' productivity.

Non-GABA sleep medications, suvorexant as risk factors for falls: Case-control and case-crossover study.

The aim of this study was to examine the risk of falls associated with the use of non-gamma amino butyric acid (GABA) sleep medications, suvorexant and ramelteon. This case-control and case-crossover study was performed at the Kudanzaka Hospital, Chiyoda Ward, Tokyo. A total of 325 patients who had falls and 1295 controls matched by sex and age were included. The inclusion criteria for the case group were hospitalized patients who had their first fall and that for the control were patients who were hospitalized and did not have a fall, between January 2016 and November 2018. The internal sleep medications administered were classified as suvorexant, ramelteon, non-benzodiazepines, benzodiazepines, or kampo. In the case-control study, age, sex, clinical department, the fall down risk score, and hospitalized duration were adjusted in the logistic regression model. In the case-control study, multivariable logistic regression showed that the use of suvorexant (odds ratio [OR]: 2.61, 95% confidence interval [CI]: 1.29-5.28), nonbenzodiazepines (OR: 2.49, 95% CI: 1.73-3.59), and benzodiazepines (OR: 1.65, 95% CI: 1.16-2.34) was significantly associated with an increased OR of falls. However, the use of ramelteon (OR: 1.40, 95% CI: 0.60-3.16) and kampo (OR: 1.55, 95% CI: 0.75-3.19) was not significantly associated with an increased OR of falls. In the case-crossover study, the use of suvorexant (OR: 1.78, 95% CI: 1.05-3.00) and nonbenzodiazepines (OR: 1.63, 95% CI: 1.17-2.27) was significantly associated with an increased OR of falls. Similar patterns were observed in several sensitivity analyses. It was suggested that suvorexant increases the OR of falls. This result is robust in various analyses. This study showed that the risk of falls also exists for non-GABA sleep medication, suvorexant, and thus it is necessary to carefully prescribe hypnotic drugs under appropriate assessment.

Control of a Nosocomial Outbreak of COVID-19 in a University Hospital.

BACKGROUND: Nosocomial spread of coronavirus disease 2019 (COVID-19) causes clusters of infection among high-risk individuals. Controlling this spread is critical to reducing COVID-19 morbidity and mortality. We describe an outbreak of COVID-19 in Keio University Hospital, Japan, and its control and propose effective control measures. METHODS: When an outbreak was suspected, immediate isolation and thorough polymerase chain reaction (PCR) testing of patients and health care workers (HCWs) using an in-house system, together with extensive contact tracing and social distancing measures, were conducted. Nosocomial infections (NIs) were defined as having an onset or positive test after the fifth day of admission for patients and having high-risk contacts in our hospital for HCWs. We performed descriptive analyses for this outbreak. RESULTS: Between March 24 and April 24, 2020, 27 of 562 tested patients were confirmed positive, of whom 5 (18.5%) were suspected as NIs. For HCWs, 52 of 697 tested positive, and 40 (76.9%) were considered NIs. Among transmissions, 95.5% were suspected of having occurred during the asymptomatic period. Large-scale isolation and testing at the first sign of outbreak terminated NIs. The number of secondary cases directly generated by a single primary case found before March 31 was 1.74, compared with 0 after April 1. Only 4 of 28 primary cases generated definite secondary infection; these were all asymptomatic. CONCLUSIONS: Viral shedding from asymptomatic cases played a major role in NIs. PCR screening of asymptomatic individuals helped clarify the pattern of spread. Immediate large-scale isolation, contact tracing, and social distancing measures were essential to containing outbreaks.