Ultra-Rapid and Specific Gelation of Collagen Molecules for Transparent and Tough Gels by Transition Metal Complexation.

Collagen is the most abundant protein in the human body and one of the main components of stromal tissues in tumors which have a high elastic modulus of over 50 kPa. Although collagen has been widely used as a cell culture scaffold for cancer cells, there have been limitations when attempting to fabricate a tough collagen gel with cells like a cancer stroma. Here, rapid gelation of a collagen solution within a few minutes by transition metal complexation is demonstrated. Type I collagen solution at neutral pH shows rapid gelation with a transparency of 81% and a high modulus of 1,781 kPa by mixing with K2 PtCl4 solution within 3 min. Other transition metal ions also show the same rapid gelation, but not basic metal ions. Interestingly, although type I to IV collagen molecules show rapid gelation, other extracellular matrices  do not exhibit this phenomenon. Live imaging of colon cancer organoids in 3D culture indicates a collective migration property with modulating high elastic modulus, suggesting activation for metastasis progress. This technology will be useful as a new class of 3D culture for cells and organoids due to its facility for deep-live observation and mechanical stiffness adjustment.

Cigarette smoke extract impairs gingival epithelial barrier function.

We previously showed that junctional adhesion molecule 1 (JAM1) and coxsackievirus and adenovirus receptor (CXADR), tight junction-associated proteins, have important roles to maintain epithelial barrier function in gingival tissues. Smoking is considered to be a significant risk factor for periodontal disease. The present study was conducted to examine the effects of cigarette smoke extract (CSE) on JAM1 and CXADR in human gingival epithelial cells. CSE was found to cause translocation of JAM1 from the cellular surface to EGFR-positive endosomes, whereas CXADR did not. Using a three-dimensional multilayered gingival epithelial tissue model, CSE administration was found to increase permeability to lipopolysaccharide and peptidoglycan, whereas overexpression of JAM1 in the tissue model prevented penetration by those substrates. Furthermore, vitamin C increased JAM1 expression, and inhibited penetration of LPS and PGN induced by CSE. These findings strongly suggest that CSE disrupts gingival barrier function via dislocation of JAM1, thus allowing bacterial virulence factors to penetrate into subepithelial tissues. Furthermore, they indicate that vitamin C increases JAM1 expression and prevents disruption of gingival barrier function by CSE.

Metabolic Syndrome and the Increased Risk of Medically Certified Long-term Sickness Absence: A Prospective Analysis Among Japanese Workers.

BACKGROUND: Metabolic syndrome (MetS) has been associated with various chronic diseases that may lead to long-term sickness absence (LTSA), but there is lacking information on the direct association between MetS and LTSA. The present study aimed to investigate the all-cause and cause-specific associations between MetS and the risk of medically certified LTSA among Japanese workers. METHODS: We recruited 67,403 workers (57,276 men and 10,127 women), aged 20-59 years from 13 companies in Japan during their health check-ups in 2011 (11 companies) and 2014 (2 companies), and we followed them for LTSA events (≥30 consecutive days) until March 31, 2020. MetS was defined according to the Joint Interim Statement. A Cox proportional hazards regression model was used to estimate hazard ratios (HRs) and its 95% confidence intervals (CIs) for LTSA associated with MetS and its components. RESULTS: During 408,324 person-years of follow-up, 2,915 workers experienced LTSA. The adjusted HR for all-cause LTSA was 1.54 (95% CI, 1.41-1.68) among those with MetS compared to those without MetS. In cause-specific analysis, HRs associated with MetS significantly increased for LTSA due to overall physical disorders (1.76); cardiovascular diseases (3.16); diseases of the musculoskeletal system and connective tissue (2.01); cancers (1.24); obesity-related cancers (1.35); mental, behavioral, and neurodevelopmental disorders (1.28); reaction to severe stress and adjustment disorders (1.46); and external causes (1.46). The number of MetS components were also significantly associated with increased LTSA risk. CONCLUSION: MetS was associated with an increase in the risk of LTSA due to various diseases among Japanese workers.

Surface pre-reacted glass-ionomer eluate protects gingival epithelium from penetration by lipopolysaccharides and peptidoglycans via transcription factor EB pathway.

Surface pre-reacted glass-ionomer (S-PRG) filler, produced by PRG technology for use with various dental materials, is bioactive and known to release ions from a glass-ionomer phase. We previously reported that coxsackievirus and adenovirus receptor (CXADR), a tight junction associated protein, was located in the epithelial barrier of gingival epithelium. In the present study, the tissue protective effects of an S-PRG eluate prepared with S-PRG filler were investigated using a three-dimensional human gingival epithelial tissue model. The results showed that the S-PRG eluate specifically induced CXADR expression at the transcriptional level of messenger RNA as well as the protein level, and also nuclear translocation of transcription factor EB (TFEB) in gingival epithelial cells. Furthermore, shigyakusan, a TFEB inhibitor, canceled induction of the CXADR protein by the S-PRG eluate. Additionally, gingival epithelial permeation by 40-kDa dextran, lipopolysaccharide, and peptidoglycan in the 3D-tissue models was prevented by the eluate, with those effects abrogated by knockdown of CXADR. These findings suggest that S-PRG eluate increases CXADR expression via the TFEB pathway, thus inhibiting penetration of bacterial virulence factors into subepithelial tissues.

Non-High-Density Lipoprotein Cholesterol and Risk of Cardiovascular Disease: The Japan Epidemiology Collaboration on Occupational Health Study.

AIMS: We aimed to investigate the association between non-high-density lipoprotein cholesterol (non-HDL-C) levels and the risk of cardiovascular disease (CVD) and its subtypes. METHODS: In this contemporary cohort study, we analyzed the data of 63,814 Japanese employees aged ≥ 30 years, without known CVD in 2012 and who were followed up for up to 8 years. The non-HDL-C level was divided into 5 groups: ＜110, 110-129, 130-149, 150-169, and ≥ 170 mg/dL. The Cox proportional hazards model was used to calculate the hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) for CVD and its subtypes associated with each non-HDL-C group, considering 130-149 mg/dL as the reference group. RESULTS: During the study period, 271 participants developed CVD, including 78 myocardial infarctions and 193 strokes (102 ischemic strokes, 89 hemorrhagic strokes, and 2 unknowns). A U-shaped association between non-HDL-C and stroke was observed. In the analysis of stroke subtypes, the multivariable-adjusted HR (95% CI) for hemorrhagic stroke was 2.61 (1.19-5.72), 2.02 (0.95-4.29), 2.10 (1.01-4.36), and 1.98 (0.96-4.08), while that for ischemic stroke was 1.54 (0.77-3.07), 0.91 (0.46-1.80), 0.73 (0.38-1.41), and 1.50 (0.87-2.56) in the ＜110, 110-129, 150-169, and ≥ 170 mg/dL groups, respectively. Individuals with elevated non-HDL-C levels had a higher risk of myocardial infarction. CONCLUSIONS: High non-HDL-C levels were associated with an increased risk of myocardial infarction. Moreover, high and low non-HDL-C levels were associated with a high risk of stroke and its subtypes among Japanese workers.

Diagnosis-specific Cumulative Incidence of Return-to-work, Resignation, and Death Among Long-term Sick-listed Employees: Findings From the Japan Epidemiology Collaboration on Occupational Health Study.

BACKGROUND: While it is essential to understand how long is sufficient for return-to-work when designing paid sick-leave systems, little attempt has been done to collect cause-specific information on when and how many of sickness absentees returned to work, became unemployed, or passed away. METHODS: We studied the first sick-leave episode of ≥30 consecutive days in those ≤55 years of age during 2012-2013 among employees of 11 Japanese private companies (n = 1,209), which were followed until 2017. Overall and disease-specific cumulative incidences of return-to-work, resignations, and deaths were estimated using competing risk analysis. RESULTS: During the 3.5-year period (follow-up rate: 99.9%), 1,014 returned to work, 167 became unemployed, and 27 died. Overall, return-to-work occurred within 1 year in 74.9% of all absentees and in 89.3% of those who successfully returned to work. Resignation occurred within 1 year in 8.7% of all absentees and in 62.9% of all subjects who resigned. According to ICD-10 chapters, the cumulative incidence of return-to-work ranged from 82.1% for mental disorders (F00-F99) to 95.3% for circulatory diseases (I00-I99). The cumulative incidence of return-to-work due to mental disorders ranged from 66.7% in schizophrenia (F20) to 95.8% in bipolar affective disorders (F31). Death was rarely observed except for cases of neoplasms (C00-D48), of which the cumulative incidence of death reached 14.2% by 1.5 years. CONCLUSION: Return-to-work and resignations occurred commonly within 1 year of sick leave among long-term sickness absentees in the Japanese private companies. Our findings may assist occupational physicians and employers in developing effective social protection schemes.

Dynamic analysis of Porphyromonas gingivalis invasion into blood capillaries during the infection process in host tissues using a vascularized three-dimensional human gingival model.

Porphyromonas gingivalis, the pathogen of periodontal disease, is thought to be involved in various diseases throughout the body via gingival tissue blood capillaries. However, the dynamic analysis of the infection mechanism, particularly the deep invasion process of the gingival tissue, has not yet been elucidated because of the lack of both in vivo and in vitro models. In this study, we developed a vascularized three-dimensional (3D) gingival model with an epithelial barrier expressing cell-cell junctions using collagen microfibers (CMFs) to enable the dynamic analysis of the P. gingivalis invasion process. Lipid raft disruption experiments in the gingival epithelial cell layer demonstrated that P. gingivalis migrates into the deeper epithelium via the intercellular pathway rather than intracellular routes. P. gingivalis was shown to invade the 3D gingival model, being found inside blood capillaries during two days of culture. Notably, the number of bacteria had increased greatly at least two days later, whereas the mutant P. gingivalis lacking the cysteine proteases, gingipains, showed a significantly lower number of survivors. The secretion of interleukin-6 (IL-6) from the gingival tissue decreased during the two days of infection with the wild type P. gingivalis, but the opposite was found for the mutant suggesting that P. gingivalis infection disturbs IL-6 secretion at an early stage. By allowing the dynamic observation of the P. gingivalis invasion from the epithelial cell layer into the blood capillaries for the first time, this model will be a powerful tool for the development of novel therapeutics against periodontal infection related diseases.

Porphyromonas gingivalis induces penetration of lipopolysaccharide and peptidoglycan through the gingival epithelium via degradation of coxsackievirus and adenovirus receptor.

Porphyromonas gingivalis is a major pathogen of human periodontitis and dysregulates innate immunity at the gingival epithelial surface. We previously reported that the bacterium specifically degrades junctional adhesion molecule 1 (JAM1), causing gingival epithelial barrier breakdown. However, the functions of other JAM family protein(s) in epithelial barrier dysregulation caused by P. gingivalis are not fully understood. The present results show that gingipains, Arg-specific or Lys-specific cysteine proteases produced by P. gingivalis, specifically degrade coxsackievirus and adenovirus receptor (CXADR), a JAM family protein, at R145 and K235 in gingival epithelial cells. In contrast, a gingipain-deficient P. gingivalis strain was found to be impaired in regard to degradation of CXADR. Furthermore, knockdown of CXADR in artificial gingival epithelium increased permeability to dextran 40 kDa, lipopolysaccharide and peptidoglycan, whereas overexpression of CXADR in a gingival epithelial tissue model prevented penetration by those agents following P. gingivalis infection. Together, these results suggest that P. gingivalis gingipains breach the stratified squamous epithelium barrier by degrading CXADR as well as JAM1, which allows for efficient transfer of bacterial virulence factors into subepithelial tissues. TAKEAWAYS: P. gingivalis, a periodontal pathogen, degraded coxsackievirus and adenovirus receptor (CXADR), a JAM family protein, in gingival epithelial tissues. P. gingivalis gingipains, cysteine proteases, degraded CXADR at R145 and K235. CXADR degradation by P. gingivalis caused increased permeability to lipopolysaccharide and peptidoglycan through gingival epithelial tissues.

Visit-to-visit variability of blood pressure and cardiovascular events among the working-age population in Japan: findings from the Japan Epidemiology Collaboration on Occupational Health Study.

Increased visit-to-visit variability (VVV) of blood pressure, which is calculated based on several readings, has been suggested to be a significant predictor of cardiovascular events and mortality, independent of mean blood pressure. This study examined associations between the VVV of systolic blood pressure (SBP) measured annually and cardiovascular disease (CVD) events among 72,617 Japanese subjects. Data were obtained from the Japan Epidemiology Collaboration on Occupational Health Study, which is an ongoing epidemiological survey of workers in Japan. VVV was calculated as the coefficient of variation of SBP readings from 2008 to 2011; information on fatal and nonfatal CVD events was collected from registries of specific outcomes between April 2012 and March 2019. A Cox proportional hazards model was applied to investigate associations after adjusting for mean SBP between 2008 and 2011 and covariates. During the 7-year follow-up period, there were 63 CVD fatalities and 314 CVD events (combining fatal and nonfatal events). The results showed that a one-standard deviation increase in VVV was associated with a significant increase in the risk of CVD mortality (hazard ratio [HR] = 1.42; 95% confidence interval [CI] = 1.32-1.54); those in the highest tertile had a 3.20 times (95% CI = 1.26-8.17) higher risk of CVD mortality than those in the lowest tertile. We found less pronounced associations regarding CVD events (HR = 1.08, 95% CI = 1.02-1.15). In conclusion, VVV was significantly associated with CVD mortality in our Japanese working population.

Prediabetes, Diabetes, and the Risk of All-Cause and Cause-Specific Mortality in a Japanese Working Population: Japan Epidemiology Collaboration on Occupational Health Study.

OBJECTIVE: Prediabetes has been suggested to increase risk for death; however, the definitions of prediabetes that can predict death remain elusive. We prospectively investigated the association of multiple definitions of prediabetes with the risk of death from all causes, cardiovascular disease (CVD), and cancer in Japanese workers. RESEARCH DESIGN AND METHODS: The study included 62,785 workers who underwent a health checkup in 2010 or 2011 and were followed up for death from 2012 to March 2019. Prediabetes was defined according to fasting plasma glucose (FPG) or glycated hemoglobin (HbA1c) values or a combination of both using the American Diabetes Association (ADA) or World Health Organization (WHO)/International Expert Committee (IEC) criteria. The Cox proportional hazards regression model was used to investigate the associations. RESULTS: Over a 7-year follow-up, 229 deaths were documented. Compared with normoglycemia, prediabetes defined according to ADA criteria was associated with a higher risk of all-cause mortality (hazard ratio [HR] 1.53; 95% CI 1.12-2.09) and death due to cancer (HR 2.37; 95% CI 1.45-3.89) but not with death due to CVD. The results were materially unchanged when prediabetes was defined according to ADA FPG, ADA HbA1c, WHO FPG, or combined WHO/IEC criteria. Diabetes was associated with the risk of all-cause, CVD, and cancer deaths. CONCLUSIONS: In a cohort of Japanese workers, FPG- and HbA1c-defined prediabetes, according to ADA or WHO/IEC, were associated with a significantly increased risk of death from all causes and cancer but not CVD.

Smoking and Long-Term Sick Leave in a Japanese Working Population: Findings of the Japan Epidemiology Collaboration on Occupational Health Study.

BACKGROUND: Few studies have investigated the association between tobacco smoking and sick leave (SL) in Japan. METHODS: We followed 70 896 workers aged 20-59 years (60 133 males, 10 763 females) between April 2012 and March 2017. A Cox proportional hazards model was used to investigate the associations between smoking (smoking status and intensity) and long-term SL (ie, SL lasting ≥30 consecutive days). Cause-specific analyses were also conducted. RESULTS: A total of 1777 people took long-term SL during a follow-up of 307 749 person years. Compared with never-smokers, current smokers were at a higher risk of long-term SL (hazard ratio [HR] = 1.32; 95% confidence interval [CI] = 1.19 to 1.48). Cause-specific analyses revealed that current smoking was associated with a higher risk of SL due to all physical disorders (HR = 1.44, 95% CI = 1.22 to 1.69), cancer (HR = 1.49, 95% CI = 1.10 to 2.01), cardiovascular disease (CVD; HR = 2.16, 95% CI = 1.31 to 3.55), and injuries/external causes (HR = 1.83, 95% CI = 1.31 to 2.58). Former smokers were at a higher risk of SL due to cancer at a borderline significance level (HR = 1.38, 95% CI = 0.99 to 1.92). Low-intensity smoking (ie, 1-10 cigarettes smoked per day) was associated with all-cause SL, SL due to CVD, and SL due to injuries/external causes compared with never-smokers. CONCLUSION: In a large cohort of working-age Japanese, smoking was associated with a greater risk of long-term SL. Greater effort is needed to mitigate disease burden associated with smoking at workplace in Japan. IMPLICATIONS: Our study contributes to the literature on the association between smoking and SL in several ways. First, the study was conducted among a Japanese working population. While the association has been extensively studied in Western setting, few attempts have been made elsewhere. Second, cause-specific analyses were undertaken in our study. Third, we paid attention to the effect of low-intensity smoking on SL given that there is growing evidence of an elevated health risk associated with low-intensity smoking.

Loss of Working Life Years Due to Mortality, Sickness Absence, or Ill-health Retirement: A Comprehensive Approach to Estimating Disease Burden in the Workplace.

BACKGROUND: While much effort has focused on quantifying disease burden in occupational health, no study has simultaneously assessed disease burden in terms of mortality and morbidity. We aimed to propose a new comprehensive method of quantifying the disease burden in the workplace. METHODS: The data were obtained from the Japan Epidemiology Collaboration on Occupational Health (J-ECOH) Study, a large-scale prospective study of approximately 80,000 workers. We defined disease burden in the workplace as the number of working years lost among the working population during a 6-year period (April 2012 to March 2018). We calculated the disease burden according to consequences of health problems (ie, mortality, sickness absence [SA], and ill-health retirement) and disease category. We also calculated the age-group- (20-39 and 40-59 years old) and sex-specific disease burden. RESULTS: The largest contributors to disease burden in the workplace were mental and behavioural disorders (47.0 person-years lost per 10,000 person-years of working years; ie, per myriad [proportion]), followed by neoplasms (10.8 per myriad) and diseases of the circulatory system (7.1 per myriad). While mental and behavioural disorders made a greater contribution to SA and ill-health retirement compared to mortality, the latter two disorders were the largest contributors to the disease burden in the workplace due to mortality. The number of working years lost was greater among younger versus older female participants, whereas the opposite trend was observed in males. CONCLUSIONS: Our approach is in contrast to those in previous studies that focused exclusively on mortality or morbidity.

Reduced lifespan of erythrocytes in Dahl/Salt sensitive rats is the cause of the renal proximal tubule damage.

We studied the mechanisms of anemia and the influence of anemia on renal pathology in Dahl/Salt Sensitive (Dahl/SS) rat, a model of cardio-renal-anemia syndrome. Erythrocyte lifespan was shortened and associated with decreased hemoglobin level in the Dahl/SS rats given high-salt diet. Serum haptoglobin decreased, reticulocytes increased, and erythropoiesis in the bone marrow and extramedullary hematopoiesis in the spleen was markedly stimulated by increased serum erythropoietin in them. As a mechanism of hemolysis, we investigated the incidence of eryptosis, suicidal death of erythrocytes. Eryptosis was increased, and red blood cell-derived microparticles, small particle which are generated in hemolytic disease, were also increased in Dahl/SS rats fed with high-salt diet. Deposition of hemosiderin and mitochondrial morphologic abnormality, a sign of ferroptosis, in proximal renal tubules was associated with intravascular hemolysis. Treatment with deferasirox, an oral iron chelator, reduced the renal proximal tubular injury and the glomerular sclerosis in Dahl/SS rats fed with high-salt diet. In conclusion, reduced half-life of erythrocytes induced by hemolysis is the major cause of anemia in Dahl/SS rat. Iron accumulation induced by hemolysis causes renal proximal tubule injury and accelerates renal damage in this model.

Regulation of Chondrocyte Differentiation by Changing Intercellular Distances Using Type II Collagen Microfibers.

Osteoarthritis is a common degenerative disease that mainly occurs in older age groups, and the search for an effective cure remains a major global challenge. The technology of constructing 3D in vitro cartilage tissue with zonal differentiated structures for use as alternative implants for treating osteoarthritis has attracted researchers' attention. For this challenge, it is important for understanding the relationship between chondrocyte differentiation and the amount of extracellular matrix by modulating intercellular distance. This study investigates the interplay between chondrocyte differentiation and intercellular distance. Type II collagen microfibers (CMF II) were used as a distance regulator by varying their amounts. The results indicated that the secretion of cartilage-specific glycosaminoglycan after 2 weeks of differentiation from the chondrogenic cells, ATDC5, was decreased with an increased intercellular distance. Also, the shortest intercellular distance, being ATDC5 cells without CMF II, presented an upregulated gene expression profile of cartilage markers. The groups with CMF II-mediated intracellular distances, however, did not show the upregulation. The elastic modulus of the 3D samples increased depending on the amount of CMF II, relating to the differentiation preventing property of the CMF II. These findings suggest the promising potential of this approach for the modulation of chondrocyte differentiation.

Diabetes, prediabetes, and suicide deaths in a Japanese working population.

OBJECTIVE: To examine the association of diabetes and prediabetes with suicide deaths in a Japanese working population. METHODS: A nested case-control study was conducted using data from the Japan Epidemiology Collaboration on Occupational Health Study. During 8 years of follow-up, we identified 56 registered cases of suicide death that had information on fasting plasma glucose or glycated hemoglobin A1c at any health check-up during the past 3 years prior to suicide. For each case, we randomly selected five controls matched for age, sex, and worksite. We used the latest health check-up data for analysis. We defined diabetes status based on the American Diabetes Association criteria and used a conditional logistic regression model to investigate the association. RESULTS: Adjusted odds ratios and 95% confidence intervals for suicide death were 0.67 (0.32-1.41) and 3.53 (1.05-11.91) for prediabetes and diabetes, respectively, compared to normoglycemia. Similar results were obtained when diabetes status was exclusively defined by the fasting plasma glucose or glycated hemoglobin A1c level. CONCLUSION: Diabetes, but not prediabetes, was associated with a higher risk of suicide death, compared with normoglycemia, among a Japanese working population.

Fabrication of Artificial Nanobasement Membranes for Cell Compartmentalization in 3D Tissues.

In recent decades, tissue engineering techniques have attracted much attention in the construction of 3D tissues or organs. However, even though precise control of cell locations in 3D has been achieved, the organized cell locations are easily destroyed because of the cell migration during the cell culture period. In human body, basement membranes (BMs) maintain the precise cell locations in 3D (compartmentalization). Constructing artificial BMs that mimic the structure and biofunctions of natural BMs remains a major challenge. Here, a nanometer-sized artificial BM through layer-by-layer assembly of collagen type IV (Col-IV) and laminin (LM), chosen because they are the main components of natural BMs, is reported. This multilayered Col-IV/LM nanofilm imitates natural BM structure closely, showing controllable and similar components, thickness, and fibrous network. The Col-IV/LM nanofilms have high cell adhesion properties and maintain the spreading morphology effectively. Furthermore, the barrier effect of preventing cell migration but permitting effective cell-cell crosstalk between fibroblasts and endothelial cells demonstrates the ability of Col-IV/LM nanofilms for cell compartmentalization in 3D tissues, providing more reliable tissue models for evaluating drug efficacy, nanotoxicology, and implantation.

Neurological Prognostic Value of Adjusted Ca2+ Concentration in Adult Patients with Out-of-Hospital Cardiac Arrest.

Many patients are transferred to hospital due to out-of-hospital cardiac arrest (OHCA), and, unfortunately, most suffer from cerebral damage. Currently, it is difficult to predict the recovery of neurological function after return of spontaneous circulation (ROSC) in the acute phase. Increased intracellular Ca2+ induces cell death in the acute phase. Accordingly, we predicted that serum adjusted Ca2+ will decrease following Ca2+ influx into cells. Consequently, serum adjusted Ca2+ in the acute phase may be able to predict recovery of neurological function in patients with ROSC from OHCA. This is a retrospective and observational study from 2 centers. A total of 190 consecutive patients with ROSC from OHCA were recruited, with 33 patients meeting the inclusion criteria. The relationship between serum adjusted Ca2+ within 48 hours after ROSC and neurological function at discharge (as evaluated by the Glasgow-Pittsburgh cerebral performance category) was examined. Serum adjusted Ca2+ was measured every 4 hours within a 48-hour period after ROSC. There were no significant differences in hemodynamical state and laboratory data between the 2 groups. However, lowest serum adjusted Ca2+ within 48 hours after ROSC was significantly lower in the poor neurological outcome group (0.96 ± 0.06 versus 1.02 ± 0.06 mmol/L, P = 0.011). Thus, lowest serum adjusted Ca2+ within 48 hours after ROSC may be a predictive factor for recovery of neurological function at discharge in patients with ROSC from OHCA.

BMI and Medically Certified Long-Term Sickness Absence Among Japanese Employees.

OBJECTIVE: In contrast to the association between excess weight and sickness absence (SA), the association in relation to underweight has been under-researched. This study aimed to examine the effects of BMI at both extremes of its distribution on SA. METHODS: Data came from the Japan Epidemiology Collaboration on Occupational Health study of 77,760 workers aged 20 to 59 years (66,166 males, 11,594 females). Information was collected on medically certified long-term SA (LTSA) (i.e., SA lasting ≥ 30 consecutive days) from April 2012 to March 2017. A sex-specific Cox proportional hazards model was used to investigate the associations. RESULTS: Among males, both obesity (hazard ratio [HR] = 1.81, 95% CI: 1.50-2.17) and underweight (HR = 1.56, 95% CI: 1.23-1.96) were significantly associated with LTSA compared with normal weight. This U-shaped association between BMI categories and LTSA was observed both for mental and physical disorders. Among females, an elevated risk was observed among those with overweight (HR = 1.54, 95% CI: 1.16-2.05). CONCLUSIONS: In a cohort of the Japanese working-age population, both obesity and underweight were associated with a greater risk of LTSA in males. Future research should not overlook the excess risk of LTSA associated with underweight.

Trajectories of body mass index and waist circumference before the onset of diabetes among people with prediabetes.

BACKGROUND & AIMS: To investigate trajectories of body mass index (BMI) and waist circumference (WC) among prediabetic people who progressed to diabetes, people who remained with prediabetes, and those who returned to normoglycemia. METHODS: We used data from 22,945 prediabetic people who received an annual health checkup for up to eight years. The development of diabetes was defined using the American Diabetes Association criteria. People who did not progress to diabetes during the observation period were classified as 'remained with prediabetes' or 'returned to normoglycemia', based on their last health checkup data. Trajectories of BMI and WC were evaluated using linear mixed models for repeated measures, with adjustment for a wide range of covariates. RESULTS: During the study period, 2972 people progressed to diabetes, 4706 returned to normoglycemia, and 15,267 remained with prediabetes. People who progressed to diabetes had a larger increase in mean BMI from 7 years to 1 year prior to diagnosis, which was about three times that of people who remained with prediabetes (annual change rate, 0.20 [95% confidence interval; 0.15 to 0.24] vs 0.06 [0.04 to 0.08] kg/m2 per year, P < 0.001), regardless of their BMI levels at the initial health checkup. Among people who returned to normoglycemia, mean BMI remained almost the same over time (-0.04 [-0.09 to 0.002] kg/m2 per year), except for those with obesity (-0.16 [-0.28 to -0.05] kg/m2 per year). As for WC, the annual change rate among people who developed diabetes was about 7 times that of people who remained with prediabetes (0.38 [0.32 to 0.45] vs 0.05 [0.03 to 0.08] cm per year, P < 0.001). We also observed a constant mean WC over time among people who had no central obesity and later returned to normoglycemia (-0.02 [-0.06 to 0.03] cm per year), and an annual decrease in mean WC among those who had central obesity and later returned to normoglycemia (-0.40 [-0.47 to -0.32] cm per year). CONCLUSIONS: Our study provides strong evidence that avoiding weight gain could help prediabetic people minimize the risk of developing diabetes, regardless of whether they are obese. Losing weight could help obese people restore normoglycemia from a prediabetic state, whereas maintaining current weight may help nonobese people return to normoglycemia.