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Background: Associations of major risk factors for stroke with total and each type of stroke, as well as subtypes of ischemic stroke, and their population attributable fractions had not been examined comprehensively.Methods: Participants of the Japan Public Health Center-based prospective (JPHC) Study Cohort II without histories of cardiovascular disease and cancer (n = 14,797) were followed from 1993 through 2012. Associations of current smoking, hypertension, diabetes, overweight (body mass index ≥25 kg/m2), non-high-density lipoprotein cholesterol (non-HDLC) categories, low HDLC (<40 mg/dL), urine protein, and history of arrhythmia were examined in a mutually-adjusted Cox regression model that included age and sex. Population attributable fractions (PAFs) were estimated using the hazard ratios and the prevalence of risk factors among cases.Results: Subjects with hypertension were 1.63 to 1.84 times more likely to develop any type of stroke. Diabetes, low HDLC, current smoking, overweight, urine protein, and arrhythmia were associated with risk of overall and ischemic stroke. Hypertension and urine protein were associated with risk of intracerebral hemorrhage, while current smoking, hypertension, and low non-HDLC were associated with subarachnoid hemorrhage. Hypertension alone accounted for more than a quarter of stroke incidence, followed by current smoking and diabetes. High non-HDLC, current smoking, low HDLC, and overweight contributed mostly to large-artery occlusive stroke. Arrhythmia explained 13.2% of embolic stroke. Combined PAFs of all the modifiable risk factors for total, ischemic, and large-artery occlusive strokes were 36.7%, 44.5%, and 61.5%, respectively.Conclusion: Although there are differences according to subtypes, hypertension could be regarded as the most crucial target for preventing strokes in Japan.

Background: The term “nonrestorative sleep (NRS)” refers to an unrefreshed feeling at wake-up and is a domain of poor sleep quality. Previous research has demonstrated that NRS is linked to a number of diseases and adverse health outcomes, but less is known regarding the link between NRS and diabetes, particularly in Japanese.Methods: We studied 3,665 middle-aged male participants of the Aichi Workers’ Cohort Study who were followed-up from 2002 through 2019. Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) of incident type 2 diabetes mellitus (T2DM) in relation to NRS adjusted for potential confounding variables.Results: During a median follow-up of 14.6 years, 421 type 2 diabetes cases were identified. Participants with NRS had a higher crude incidence rate of T2DM (11.2/1,000 person-years), compared to participants without NRS (9.3/1,000 person-years). In the fully adjusted model, individuals who reported having NRS had a significantly higher risk of developing T2DM (HR1.36; 95% CI, 1.10–1.67). The association was observed only in participants under 50 years old (HR 1.82; 95% CI, 1.36–2.43), not in the older (50 years or older) participants (P for interaction = 0.025). In contrast, stratified analyses by the presence of shift work, obesity, or sleep duration showed similar associations in all the strata.Conclusion: NRS was associated with higher risk of T2DM in middle-aged Japanese male workers independent of a variety of lifestyle factors and other sleep problems.

Background: The association of body mass index (BMI) with risks of ischemic stroke subtypes have not been established. Methods: Cumulative average BMI was calculated using self-reported body weight and height obtained from baseline (Cohort I in 1990, and Cohort II from 1993–1994) and 5- and 10-year questionnaire surveys of Japan Public Health Center-based prospective (JPHC) study. A total of 42,343 men and 46,413 women aged 40–69 years were followed-up for the incidence of lacunar, large-artery occlusive, and cardioembolic strokes. A sub-distribution hazard model was used to estimate sub-distribution hazard ratios (SHRs) and the 95% confidence intervals (CIs). Results: During a median of 20.0 years of follow-up, we documented 809 and 481 lacunar, 395 and 218 large-artery occlusive, and 568 and 298 cardioembolic strokes in men and women, respectively. After adjustment for baseline age, updated smoking, alcohol consumption, leisure-time physical activity, and histories of hypertension, dyslipidemia, and diabetes mellitus, cumulative average BMI was positively linearly associated with lacunar (trend P = 0.007), large-artery occlusive (trend P = 0.002), and cardioembolic (trend P < 0.001) strokes in men, and with lacunar (trend P < 0.001) and large-artery occlusive (trend P = 0.003) strokes in women. There were approximately two-fold excess risk of cardioembolic stroke in both sexes and of lacunar and large-artery occlusive strokes in women for cumulative average BMI ≥30 kg/m2 compared to BMI 23–<25 kg/m2. Conclusion: Cumulative average BMI showed a positive linear effect on sub-distribution hazards of lacunar, large-artery occlusive, and cardioembolic strokes in both sexes, except for cardioembolic stroke in women.

Phosphorus is one of the essential macronutrients required by plant growth and development, but phosphate resources are finite and diminishing rapidly because of the huge need in global agriculture. In this study, 11 genes were found in the Phosphate Transporter 1 ( PHT1 ) family of Medicago truncatula . Seven genes of the PHT1 family were available by qRT-PCR. Most of them were expressed in roots, and almost all genes were induced by low-phosphate stress in the nodule. The expression of MtPT6 was relatively high in nodules and induced by low-phosphate stress. The fusion expression of MtPT6 promoter- GUS gene in M. truncatula suggested that the expression of MtPT6 was induced in roots and nodules by phosphate starvation. In roots, MtPT6 was mainly expressed in vascular tissue and tips, and it was also expressed in cortex under low-phosphate stress; in nodules, it was mainly expressed in vascular bundles, cortical cells, and fixation zone cells. MtPT6 had a close relationship with other PHT1 family members according to amino acid alignment and phylogenetic analysis. Subcellular localization analysis in tobacco revealed that MtPT6 protein was localized to the plasma membrane. The heterologous expression of MtPT6 in Arabidopsis knockout mutants of pht1.1 and pht1.4 made seedlings more susceptible to arsenate treatment, and the phosphate concentrations in pht1.1 were higher in high phosphate condition by expressing MtPT6 . We conclude that MtPT6 is a typical phosphate transporter gene and can promote phosphate acquisition efficiency of plants.

Aim Care for people with schizophrenia is shifting the locus from long‐stay mental hospitals to nonspecialized community‐based settings. Knowledge on the care is not a sole property of psychiatric specialists. Community healthcare workers who do not specialize in psychiatry are recommended to learn more about schizophrenia. This review aimed to summarize recent findings on subjective well‐being and physical, psychiatric, and social comorbidities in individuals with schizophrenia. Methods A literature review was conducted. We retrieved findings from existing systematic reviews and meta‐analyses as our preferred method. When data were not available, we referred to other types of studies. Results As per our review, individuals with schizophrenia demonstrated poor subjective well‐being, happiness, and life satisfaction despite individual differences. Pharmacotherapy caused weight gain and constipation, whereas race and hospitalization might affect weight reduction. Individuals with schizophrenia demonstrated poor oral health, a high prevalence of noncommunicable diseases, and unique eating behaviors. Depression, sleep disorders, smoking, and alcohol and drug consumption were frequently found in the individuals. Research findings regarding problematic internet and smartphone use and stress perception were limited. Low health literacy and neglect of preventable behaviors were frequently seen in individuals with schizophrenia. They tended to be less educated, poor, unemployed, unmarried/unattached, and had poor social cognition, resulting in little social support and a small social network. Conclusion Retrieving recent data, we confirmed that individuals with schizophrenia had poor subjective well‐being and suffer from various physical, psychiatric, and social comorbidities.

Background: Relatively little evidence exists for type 2 diabetes mellitus (T2DM) prediction models from long-term follow-up studies in East Asians. This study aims to develop a point-based prediction model for 10-year risk of developing T2DM in middle-aged Japanese men. Methods: We followed 3,540 male participants of Aichi Workers’ Cohort Study, who were aged 35–64 years and were free of diabetes in 2002, until March 31, 2015. Baseline age, body mass index (BMI), smoking status, alcohol consumption, regular exercise, medication for dyslipidemia, diabetes family history, and blood levels of triglycerides (TG), high density lipoprotein cholesterol (HDLC) and fasting blood glucose (FBG) were examined using Cox proportional hazard model. Variables significantly associated with T2DM in univariable models were simultaneously entered in a multivariable model for determination of the final model using backward variable selection. Performance of an existing T2DM model when applied to the current dataset was compared to that obtained in the present study’s model. Results: During the median follow-up of 12.2 years, 342 incident T2DM cases were documented. The prediction system using points assigned to age, BMI, smoking status, diabetes family history, and TG and FBG showed reasonable discrimination (c-index: 0.77) and goodness-of-fit (Hosmer-Lemeshow test, P = 0.22). The present model outperformed the previous one in the present subjects. Conclusion: The point system, once validated in the other populations, could be applied to middle-aged Japanese male workers to identify those at high risk of developing T2DM. In addition, further investigation is also required to examine whether the use of this system will reduce incidence.

Studies have reported that short-term blood pressure (BP) variability (BPV) is associated with type 2 diabetes mellitus (T2DM) incidence, but the association with long-term BPV remains unclear. The present study investigated the associations of long-term BPV as well as the time trend of BP changes over time with the incidence of T2DM. This study followed a cohort of 3017 Japanese individuals (2446 male, 571 female) aged 36–65 years from 2007 through March 31, 2019. The root-mean-square error (RMSE) and the slope of systolic BP (SBP) change regressed on year were calculated individually using SBP values obtained from 2003 to baseline (2007). A multivariable Cox proportional hazard model was applied to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for tertiles of SBP RMSE and continuous SBP slopes adjusted for age, sex, smoking status, regular exercise, sodium intake, family history of diabetes, sleep disorder, body mass index (BMI), SBP, and fasting blood glucose (FBG) at baseline, and BMI slope from 2003 to 2007. The highest RMSE tertile compared to the lowest was associated with a significantly higher incidence of T2DM after adjusting for covariates (HR: 1.79, 95% CI: 1.15, 2.78). The slope was also significantly associated with T2DM incidence until baseline SBP and FBG were adjusted (HR: 1.03, 95% CI: 0.99, 1.07). In conclusion, long-term SBP variability was significantly associated with an increased incidence of T2DM independent of baseline age, sex, BMI, SBP, FBG, lifestyle factors and BMI slope from 2003 until baseline.Long-term variability of systolic blood pressure indicated by root mean square error is significantly associated with a higher risk of type 2 diabetes mellitus in middle-aged Japanese.

Background: Skipping breakfast has been suspected as a risk factor for type 2 diabetes (T2DM), but the associations are not entirely consistent across ethnicities or sexes, and the issue has not been adequately addressed in the Japanese population. Methods: We followed 4631 participants (3600 men and 1031 women) in a work-site cohort of participants aged 35-66 years in 2002 through 2011 for T2DM development. Frequency of eating breakfast was self-reported and was subsequently dichotomized to breakfast skippers, who eat breakfast 3-5 times/week or less, and to eaters. Cox proportional hazards models were used to adjust for potential confounding factors, including dietary factors, smoking and other lifestyles, body mass index (BMI), and fasting blood glucose (FBG) at baseline. Results: During 8.9 years of follow-up, 285 T2DM cases (231 men and 54 women) developed. Compared to participants who reported eating breakfast every day, maximally-adjusted hazard ratios and 95% confidence intervals (CI) of those with the frequency of almost every day and 3-5, 1-2, and 0 days/week were: 1.06 (95% CI, 0.73-1.53), 2.07 (95% CI, 1.20-3.56), 1.37 (95% CI, 0.82-2.29), and 2.12 (95% CI, 1.19-3.76), respectively. In a dichotomized analysis, breakfast skipping was positively associated with T2DM incidence (maximally-adjusted hazard ratio 1.73; 95% CI, 1.24-2.42). The positive associations were found in both men and women, current and non-current smokers, normal weight and overweight (BMI ≥25 kg/m2), and normal glycemic status and impaired fasting glycemic status (FBG 110 to <126 mg/dL) individuals at baseline (Ps for interaction all >0.05). Conclusions: The present study in middle-aged Japanese men and women suggests that skipping breakfast may increase the risk of T2DM independent of lifestyles and baseline levels of BMI and FBG.

Aims/Introduction To prospectively investigate whether simultaneous elevation of gamma‐glutamyl transferase (GGT) and alanine aminotransferase (ALT) is associated with the increase of type 2 diabetes mellitus incidence independent of alcohol drinking, body mass index and triglycerides. Methods A total of 2,775 Japanese male workers who had no history of type 2 diabetes mellitus were followed. High GGT and ALT were defined as the top tertiles (GGT cutpoint: 49 IU/L, ALT cutpoint: 28 IU/L). Three groups were created using these dichotomized GGT and ALT cutpoints: both low, either high or both high. Multivariable Cox proportional hazards models were carried out adjusted for potential confounding factors. Results A total of 276 type 2 diabetes mellitus cases were identified during 12 years (27,040 person‐years) of follow up. Participants with simultaneously elevated GGT and ALT had a significantly higher incidence of type 2 diabetes mellitus, even after adjustment for fasting insulin and fasting blood glucose compared with the group without GGT or ALT elevation. Similar associations were observed in non‐ or light‐to‐moderate alcohol drinkers, as well as in participants with normal weight. However, the association was weaker in participants with triglycerides <150 mg/dL. We then evaluated whether the addition of GGT and ALT would improve the prediction of type 2 diabetes mellitus incidence, and found that their inclusion significantly increased the C‐statistic, net reclassification improvement and integrated discrimination improvement. Conclusions Simultaneous elevation of GGT and ALT was significantly associated with type 2 diabetes mellitus incidence, independent of potential confounding factors, including alcohol drinking and obesity, although the association might require concomitant elevation of triglycerides. Inclusion of GGT and ALT improved type 2 diabetes mellitus risk prediction. Simultaneous elevation of GGT and ALT was significantly associated with type 2 diabetes mellitus incidence, independent of potential confounding factors, including alcohol drinking and obesity although the association might require concomitant elevation of triglycerides. Inclusion of GGT and ALT improved type 2 diabetes mellitus risk prediction model. We suggested from the present findings that elucidation of the molecular pathway leading from the concomitant elevation of triglycerides, ALT, and GGT to type 2 diabetes mellitus development might be important for planning type 2 diabetes mellitus prevention program.

Calcitriol is an active analog of vitamin D3 and has excellent physiological activities in regulating healthy immune function. To synthesize the calcitriol compound, the concept of total synthesis is often adopted, which typically involves multiple steps and results in an overall low yield. Herein, we envisioned an enzymatic approach for the synthesis of calcitriol. Peroxygenase from Agrocybe aegerita (AaeUPO) was used as a catalyst to hydroxylate the C-H bond at the C-25 position of alfacalcidol and yielded the calcitriol in a single step. The enzymatic reaction yielded 80.3% product formation in excellent selectivity, with a turnover number up to 4000. In a semi-preparative scale synthesis, 72% isolated yield was obtained. It was also found that AaeUPO is capable of hydroxylating the C-H bond at the C-1 position of vitamin D3, thereby enabling the calcitriol synthesis directly from vitamin D3.