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Abstract Natural killer group 2 member D ligands (NKG2DLs) are expressed as stress response proteins in cancer cells. NKG2DLs induce immune cell activation or tumor escape responses, depending on their expression. Human pancreatic cancer cells, PANC-1, express membrane MHC class I polypeptide-related sequence A/B (mMICA/B), whereas soluble MICB (sMICB) is detected in the culture supernatant. We hypothesized that sMICB saturates NKG2D in NKG2DLow T cells and inhibits the activation signal from mMICB to NKG2D. Knockdown of MICB by siRNA reduced sMICB level, downregulated mMICB expression, maintained NKG2DLow T cell activation, and inhibited NKG2DHigh T cell activation. To maintain mMICB expression and downregulate sMICB expression, we inhibited a disintegrin and metalloproteinase (ADAM), a metalloproteinase that sheds MICB. Subsequently, the shedding of MICB was prevented using ADAM17 inhibitors, and the activation of NKG2DLow T cells was maintained. In vivo xenograft model revealed that NKG2DHigh T cells have superior anti-tumor activity. These results elucidate the mechanism of immune escape via sMICB and show potential for the activation of NKG2DLow T cells within the tumor microenvironment.

Abstract To examine whether patterns, such as the timings of onset or recovery from sleep disturbance, are associated with later developmental problems, including autism spectrum disorder (ASD). Mothers participating in the Japan Environment and Children’s Study with a child aged 3 years were included in the analyses. Children were assessed for short sleep and frequent awakenings at 1 month, 6 months, and 1 year of age. Developmental problems were evaluated at 3 years of age based on ASD diagnosis and developmental delay, using the Japanese translation of the Ages and Stages Questionnaire (ASQ) 3rd edition. Sleep disturbance patterns were classified by onset age, and developmental problem risks were examined based on onset/recovery ages. Among 63,418 mother-infant dyads, 0.4% of infants were later diagnosed with ASD, and 14.4% had abnormal scores on any ASQ domains. The later the onset of short sleep, the lower the risk of abnormal ASQ scores (RR of short sleep onset at 1 year: 1.41; 6 months: 1.52; 1 month: 1.57). The earlier the infants recovered from short sleep persistence, the lower the risk of developmental delay (RR of remittance of sleep problems identified at 1 month by 6 months: 1.07; 1 year: 1.31; not before 1 year: 1.57). Although not all patterns were significant, later short sleep onset and earlier recovery were associated with lower ASD risk. These findings may have significant implications for future interventions in infant development.

Abstract The low response rate of immune checkpoint inhibitors (ICIs) is a challenge. The efficacy of ICIs is influenced by the tumour microenvironment, which is controlled by the gut microbiota. In particular, intestinal bacteria and their metabolites, such as short chain fatty acids (SCFAs), are important regulators of cancer immunity; however, our knowledge on the effects of individual SCFAs remains limited. Here, we show that isobutyric acid has the strongest effect among SCFAs on both immune activity and tumour growth. In vitro, cancer cell numbers were suppressed by approximately 75% in humans and mice compared with those in controls. Oral administration of isobutyric acid to carcinoma-bearing mice enhanced the effect of anti-PD-1 immunotherapy, reducing tumour volume by approximately 80% and 60% compared with those in the control group and anti-PD-1 antibody alone group, respectively. Taken together, these findings may support the development of novel cancer therapies that can improve the response rate to ICIs.

Abstract Coronary heart disease (CHD) risk is influenced by socioeconomic status-related parameters, particularly occupation. We investigated occupational gaps in CHD risk and how the introduction of remote work moderated the observed occupational differences in CHD risk during the coronavirus disease 2019 pandemic in Japan. Data from a web-based, nationwide cohort study, comprising 17,640 workers (aged 20–65 years) with baseline data from December 2020, were analyzed. Participants were grouped by occupation as upper-level nonmanual workers (managers/professionals) and others (reference group). The primary outcome was CHD (angina pectoris/myocardial infarction) onset retrospectively confirmed at the 1-year follow-up survey. Upper-level nonmanual workers exhibited a higher CHD incidence than others (2.3% vs. 1.7%). This association was pronounced in the younger (20–49 years) population, with a significant CHD risk (adjusted risk ratio = 1.88). Upper-level nonmanual workers exhibited nearly 15% higher remote work prevalence, with a significant remote work-related CHD risk (adjusted risk ratio = 1.92). The mediating effects of remote work explained an overall disparity of 32% among the younger population. Occupational gaps in CHD incidence in Japan differ from those in Western countries, where upper-level nonmanual workers have lower cardiovascular risk. In Japan, remote work can mediate CHD risk in the younger population of upper-level nonmanual workers.

Background: Lifelong health is dependent on prenatal growth and development, influenced by the placental intrauterine environment. Charged with dual functions––exchange of oxygen and nutrients as well as a barrier against toxins––the placenta itself is susceptible to environmental exposure to heavy metals. Objective: To examine the use of placenta weight as a biomarker for heavy metal exposure using a large Japanese cohort of pregnant women. Methods: The placenta weight, as a biomarker of exposure to heavy metals (cadmium, lead, and mercury), was investigated using data from the Japan Environment and Children’s Study (2011–2014). Selenium and manganese were included as factors directly affecting fetal growth or heavy metal toxicity. Maternal blood samples collected in the second or third trimester were used to measure heavy metal concentrations. The association between maternal blood metal concentrations and placenta weight was explored by applying Z scores and multivariable logistic regression analysis and classifying participants into quartiles (Q1, Q2, Q3, and Q4) according to metal concentrations. Results: This study included a total of 73,005 singleton pregnant women who delivered via live births and met the inclusion criteria. The median heavy metal concentrations in the maternal whole blood were 0.662 ng/g cadmium, 5.85 ng/g lead, 3.61 ng/g mercury, 168 ng/g selenium, and 15.3 ng/g manganese. Regression analysis revealed a significant correlation between placenta weight Z scores and maternal blood metal concentrations: cadmium, 0.0660 (standard error = 0.0074, p

Abstract Background Bisphenol A diglycidyl ether (BADGE) and Bisphenol F diglycidyl ether (BFDGE) are used in medical devices, such as intravenous sets, syringes, and catheters. Several studies have reported that these compounds are endocrine disruptors, cytotoxic, and genotoxic, raising concerns about their adverse effects on infants, in a stage of remarkable growth and development. The present study aimed to measure the serum concentrations of BADGE, derivatives of BADGE, and BFDGE in infants and examine the factors that influence them. Methods Ten infants admitted to the neonatal intensive care unit (NICU) were enrolled in the present study. Blood samples from each infant and questionnaires from their mothers were collected twice, at 1–2 months and 7 months of age. BADGE, BADGE·H2O, BADGE·2H2O, and BFDGE were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results Serum BADGE·2H2O was identified in all infants, at both 1–2 months (2.30–157.58 ng/ml) and 7 months of age (0.86–122.85 ng/ml). One of the two infants who received invasive ventilation showed a substantially increased BADGE·2H2O concentration. There was no significant difference in BADGE·2H2O concentrations at 7 months of age between the group that ate commercial baby food at least ≥ 1 time per week and the group that did not. Conclusions BADGE·2H2O was detected in the serum of all infants with a history of NICU hospitalization. Future studies are needed to determine the source of BADGE exposure and investigate its effects on infant development.

Background: The impact of COVID-19 infection on workers' work function persists even after the acute phase of the infection. We studied this phenomenon in Japanese workers. Methods: We conducted a one-year prospective cohort study online, starting with a baseline survey in December 2020. We tracked workers without baseline work functioning impairment and incorporated data from 14,421 eligible individuals into the analysis. We estimated the incidence rate ratio for new onset of work functioning impairment due to COVID-19 infection during follow-up, using mixed-effects Poisson regression analysis with robust variance. Results: Participants reporting infection between January and December 2021 showed a significantly higher incidence of new work functioning impairment (adjusted incidence rate ratio: 2.18, 95% confidence interval: 1.75–2.71, p

Abstract α-Synuclein (αS), the causative protein of Parkinson’s disease and other α-synucleinopathies, aggregates from a low molecular weight form (LMW-αS) to a high molecular weight αS oligomer (HMW-αSo). Aggregated αS accumulates intracellularly, induces intrinsic apoptosis, is released extracellularly, and appears to propagate disease through prion-like spreading. Whether extracellular αS aggregates are cytotoxic, damage cell wall, or induce cell death is unclear. We investigated cytotoxicity and cell death caused by HMW-αSo or LMW-αS. Extracellular HMW-αSo was more cytotoxic than LMW-αS and was a crucial factor for inducing plasma membrane damage and cell death. HMW-αSo induced reactive oxygen species production and phospholipid peroxidation in the membrane, thereby impairing calcium homeostasis and disrupting plasma membrane integrity. HMW-αSo also induced extrinsic apoptosis and cell death by activating acidic sphingomyelinase. Thus, as extracellular HMW-αSo causes neuronal injury and death via cellular transmission and direct plasma membrane damage, we propose an additional disease progression pathway for α-synucleinopathies.

Abstract Background Sleep problems and irritable temperaments are common among infants with autism spectrum disorder (ASD). The prospective association between such sleep problems and irritable temperaments and ASDs needs to be determined for elucidating the mechanism and exploring the future intervention study. Thus, in this study, we investigated whether sleep quality and temperament in 1-month-old infants are associated with the onset of ASD in 3-year-old children. We also assessed its sex-stratified associations. Methods We conducted a longitudinal study using data from 69,751 mothers and infants from a large-cohort study, the Japan Environment and Children’s Study. We examined the prospective association between infant sleep quality and temperament at 1 month of age and ASD diagnosis by 3 years of age. Results Here we show infants with longer daytime sleep have a higher risk of later ASD than those with shorter daytime sleep (risk ratio [RR]: 1.33, 95% confidence interval [CI]: 1.01–1.75). Infants who experienced intense crying have a higher risk of ASD than those who did not (RR: 1.31, 95% CI: 1.00–1.72). There is a difference in sex in the association between a bad mood and later ASD. In particular, female infants experiencing bad moods have a higher risk of ASD than others (RR: 3.59, 95% CI: 1.91–6.75). Conclusions The study findings provide important information for future intervention to reduce the risk of future ASD.

ABSTRACTObjectives The work style reforms and the coronavirus disease pandemic in Japan have prompted efforts toward teleworking, mainly work from home (WFH). This study aimed to prospectively evaluate the impact of WFH on job stress among Japanese workers.Methods This online survey-based prospective cohort study was conducted from December 2020 (baseline) to December 2021 (1-year follow-up) using self-administered questionnaires. At baseline, 27,036 participants completed the questionnaires, whereas 18,560 (68.7%) participated in the 1-year follow-up. After excluding the 11,604 participants who left or changed workplaces within 1 year or who were physical laborers and hospitality workers, data from 6,956 participants were analyzed. We asked participants about WFH frequency at baseline and conducted a follow-up using the Brief Job Stress Questionnaire (BJSQ). Participants were divided into four groups according to WFH frequency. The odds ratios of poor states of the association of the four subscales (job demand, job control, supervisor support, and coworker support) determined by the BJSQ with WFH frequency were estimated using a multilevel logistic model.Results In both the gender–age adjusted and multivariate models, compared to the non-WFH group, the medium and low WFH groups were less likely to have poor job control, whereas the high WFH group were likely to have similar levels as the non-WFH group. In both models, compared to non-WFH participants, the high WFH group were more likely to have poor supervisor and coworker support.Conclusions High-frequency WFH requires further attention, because it may increase job stress by exacerbating deficits of social support in the workplace. Medium- and low-frequency WFH workers were more likely to have satisfactory job control; therefore, limiting WFH to three or fewer days per week may lead to better job stress management.

Background: Tracking gestational weight gain (GWG) during pregnancy makes it possible to optimize pregnancy outcomes, and GWG growth curves are well suitable for this purpose. The GWG guidelines for Japanese were revised in 2021. However, currently, there are no GWG growth curves to guide women on how to gain weight to meet these guidelines. Methods: Using data on 96,631 live births from the Japan Environment and Children’s Study (JECS), we created descriptive GWG percentile curves estimating the trajectory of GWG required to meet the GWG guidelines stratified by pre-pregnancy body mass index (BMI). For both analyses, Bayesian mixed models with restricted cubic splines adjusted for maternal characteristics were used. Results: GWG curves substantially differed by pre-pregnancy BMI and were higher among multiparas and those with lower maternal age and with no previous disease. We estimated that underweight, normal weight, overweight, and obese women who gain 8.4 to 11.1 kg, 6.4 to 9.1 kg, 3.8 to 6.5 kg, and

Abstract Background Restricting the movement of the public to gathering places and limiting close physical contact are effective measures against COVID-19 infection. In Japan, states of emergency have been declared in specific prefectures to reduce public movement and control COVID-19 transmission. We investigated how COVID-19 infection related experiences including people with a history of infection, people with a history of close contact, and people whose acquaintances have been infected, affected self-restraint from social behaviors during the second state of emergency in Japan. Methods A prospective cohort study was conducted among workers aged 20–65 years using data from an internet survey. The baseline survey was conducted on December 22–25, 2020, and a follow-up survey was on February 18–19, 2021. There were 19,051 participants who completed both surveys and were included in the final analysis. We identified eight social behaviors: (1) eating out (4 people or fewer); (2) eating out (5 people or more); (3) gathering with friends and colleagues; (4) day trip; (5) overnight trip (excluding visiting home); (6) visiting home; (7) shopping for daily necessities; and (8) shopping for other than daily necessities. We set self-restraint regarding each social behavior after the second state of emergency was declared in January 2021 as the dependent variable, and COVID-19 infection related experiences as independent variables. Odds ratios were estimated using multilevel logistic regression analyses nested in the prefecture of residence. Results Significant differences by COVID-19 infection related experiences were identified: compared to people without COVID-19 related experiences, people with a history of COVID-19 were less likely self-restraint from most social behaviors. People whose acquaintance had been diagnosed with COVID-19 were significantly more likely to refrain from most social behaviors. There was no significant difference in any social behaviors for people with a history of close contact only. Conclusion To maximize the effect of a state of emergency, health authorities should disseminate information for each person in the target population, taking into account potential differences related to the infection related experiences.

Although pregnant women’s fish consumption is beneficial for the brain development of the fetus due to the DHA in fish, seafood also contains methylmercury (MeHg), which adversely affects fetal brain development. Epidemiological studies suggest that high DHA levels in pregnant women’s sera may protect the fetal brain from MeHg-induced neurotoxicity, but the underlying mechanism is unknown. Our earlier study revealed that DHA and its metabolite 19,20-dihydroxydocosapentaenoic acid (19,20-DHDP) produced by cytochrome P450s (P450s) and soluble epoxide hydrolase (sEH) can suppress MeHg-induced cytotoxicity in mouse primary neuronal cells. In the present study, DHA supplementation to pregnant mice suppressed MeHg-induced impairments of pups’ body weight, grip strength, motor function, and short-term memory. DHA supplementation also suppressed MeHg-induced oxidative stress and the decrease in the number of subplate neurons in the cerebral cortex of the pups. DHA supplementation to dams significantly increased the DHA metabolites 19,20-epoxydocosapentaenoic acid (19,20-EDP) and 19,20-DHDP as well as DHA itself in the fetal and infant brains, although the expression levels of P450s and sEH were low in the fetal brain and liver. DHA metabolites were detected in the mouse breast milk and in human umbilical cord blood, indicating the active transfer of DHA metabolites from dams to pups. These results demonstrate that DHA supplementation increased DHA and its metabolites in the mouse pup brain and alleviated the effects of MeHg on fetal brain development. Pregnant women’s intake of fish containing high levels of DHA (or DHA supplementation) may help prevent MeHg-induced neurotoxicity in the fetus.

IntroductionProgrammed cell death ligand 1 (PD-L1) expression in tumor tissues is measured as a predictor of the therapeutic efficacy of immune checkpoint inhibitors (ICIs) in many cancer types. PD-L1 expression is evaluated by immunohistochemical staining using 3,3´-diaminobenzidine (DAB) chronogenesis (IHC-DAB); however, quantitative and reproducibility issues remain. We focused on a highly sensitive quantitative immunohistochemical method using phosphor-integrated dots (PIDs), which are fluorescent nanoparticles, and evaluated PD-L1 expression between the PID method and conventional DAB method.MethodsIn total, 155 patients with metastatic or recurrent cancer treated with ICIs were enrolled from four university hospitals. Tumor tissue specimens collected before treatment were subjected to immunohistochemical staining with both the PID and conventional DAB methods to evaluate PD-L1 protein expression.ResultsPD-L1 expression assessed using the PID and DAB methods was positively correlated. We quantified PD-L1 expression using the PID method and calculated PD-L1 PID scores. The PID score was significantly higher in the responder group than in the non-responder group. Survival analysis demonstrated that PD-L1 expression evaluated using the IHC-DAB method was not associated with progression-free survival (PFS) or overall survival (OS). Yet, PFS and OS were strikingly prolonged in the high PD-L1 PID score group.ConclusionQuantification of PD-L1 expression as a PID score was more effective in predicting the treatment efficacy and prognosis of patients with cancer treated with ICIs. The quantitative evaluation of PD-L1 expression using the PID method is a novel strategy for protein detection. It is highly significant that the PID method was able to identify a group of patients with a favorable prognosis who could not be identified by the conventional DAB method.

Amyloid β-peptide (Aβ) synthesis and deposition are the primary factors underlying the pathophysiology of Alzheimer’s disease (AD). Aβ oligomer (Aβo) exerts its neurotoxic effects by inducing oxidative stress and lesions by adhering to cellular membranes. Though several antidepressants have been investigated as neuroprotective agents in AD, a detailed comparison of their neuroprotection against Aβo-induced neurotoxicity is lacking. Here, we aimed to elucidate the neuroprotective effects of clinically prescribed selective serotonin reuptake inhibitors, serotonin–norepinephrine reuptake inhibitors, and noradrenergic and specific serotonergic antidepressants at the cellular level and establish the underlying mechanisms for their potential clinical applications. Therefore, we compared the neuroprotective effects of three antidepressants, fluoxetine (Flx), duloxetine (Dlx), and mirtazapine (Mir), by their ability to prevent oxidative stress-induced cell damage, using SH-SY5Y cells, by evaluating cell viability, generation of reactive oxygen species (ROS) and mitochondrial ROS, and peroxidation of cell membrane phospholipids. These antidepressants exhibited potent antioxidant activity (Dlx > Mir > Flx) and improved cell viability. Furthermore, pretreatment with a 5-hydroxytryptamine 1A (5-HT1A) antagonist suppressed their effects, suggesting that the 5-HT1A receptor is involved in the antioxidant mechanism of the antidepressants’ neuroprotection. These findings suggest the beneficial effects of antidepressant treatment in AD through the prevention of Aβ-induced oxidative stress.

Abstract Background Valproic acid (VPA) is a clinically used antiepileptic drug, but it is associated with a significant risk of a low verbal intelligence quotient (IQ) score, attention-deficit hyperactivity disorder and autism spectrum disorder in children when it is administered during pregnancy. Prenatal VPA exposure has been reported to affect neurogenesis and neuronal migration and differentiation. In addition, growing evidence has shown that microglia and brain immune cells are activated by VPA treatment. However, the role of VPA-activated microglia remains unclear. Methods Pregnant female mice received sodium valproate on E11.5. A microglial activation inhibitor, minocycline or a CCR5 antagonist, maraviroc was dissolved in drinking water and administered to dams from P1 to P21. Measurement of microglial activity, evaluation of neural circuit function and expression analysis were performed on P10. Behavioral tests were performed in the order of open field test, Y-maze test, social affiliation test and marble burying test from the age of 6 weeks. Results Prenatal exposure of mice to VPA induced microglial activation and neural circuit dysfunction in the CA1 region of the hippocampus during the early postnatal periods and post-developmental defects in working memory and social interaction and repetitive behaviors. Minocycline, a microglial activation inhibitor, clearly suppressed the above effects, suggesting that microglia elicit neural dysfunction and behavioral disorders. Next-generation sequencing analysis revealed that the expression of a chemokine, C–C motif chemokine ligand 3 (CCL3), was upregulated in the hippocampi of VPA-treated mice. CCL3 expression increased in microglia during the early postnatal periods via an epigenetic mechanism. The CCR5 antagonist maraviroc significantly suppressed neural circuit dysfunction and post-developmental behavioral disorders induced by prenatal VPA exposure. Conclusion These findings suggest that microglial CCL3 might act during development to contribute to VPA-induced post-developmental behavioral abnormalities. CCR5-targeting compounds such as maraviroc might alleviate behavioral disorders when administered early.

Nakahara, Michikawa et al determined the physical activity and sleep habits of women before and during pregnancy and compared these with diagnoses of autism spectrum disorder in their offspring. Abnormal sleep and reduced physical activity during pregnancy were associated with a diagnosis of autism spectrum disorder.

Abstract Background Women with nausea and vomiting of pregnancy (NVP) have higher birth weight infants, while those with hyperemesis gravidarum, a severe manifestation of NVP, have lower birth weight infants. We aimed to investigate the associations between maternal weight loss (a consequence of hyperemesis gravidarum), NVP, and infant birth weight. Methods This study was a secondary analysis of a nationwide birth cohort in Japan. Singleton pregnancies delivered at 28–41 weeks of gestation were included in the analysis. Women were categorized based on their weight change in the 1st trimester (as a proportion to their pre-pregnancy weight: > + 3%, > 0 to + 3%, > -3 to 0%, > -5 to -3%, ≤ -5%) and severity of NVP (no nausea, only nausea, vomiting but able to eat, vomiting and unable to eat). The effects of weight change and severity of NVP on infant birth weight and small for gestational age (SGA) were assessed using regression models. We further examined how these effects could be modified by maternal weight gain up to the 2nd trimester. Results Among 91,313 women, 5,196 (5.7%) lost ≥ 5% of their pre-pregnancy weight and 9,983 (10.9%) experienced vomiting and were unable to eat in the 1st trimester. Women with weight loss ≥ 5% in the 1st trimester had infants 66 (95% CI: 53, 78) g lighter and higher odds of SGA (aOR: 1.29; 95% CI: 1.14, 1.47) than women who gained > 3% during the same period. However, when adjusting for weight gain up to the 2nd trimester, women with weight loss ≥ 5% in the 1st trimester had infants 150 (95% CI: 135, 165) g heavier and lower odds of SGA (aOR: 0.39; 95% CI: 0.33, 0.46) than those who gained > 3% during the same period. In contrast, women with more severe NVP tended to have infants with larger birth weight and lower odds of SGA compared to women without NVP. These trends were strengthened when adjusting for weight gain up to the 2nd trimester. Conclusions Our study suggests the possibility that reduced fetal growth in pregnancies with hyperemesis gravidarum may be caused by the lack of catch-up in gestational weight gain up to the 2nd trimester.

Objectives The work system reform and the COVID-19 pandemic in Japan have prompted efforts toward telecommuting in Japan. However, only a few studies have investigated the stress and health effects of telecommuting. Therefore, this study aimed to clarify the relationship between telecommuting and job stress among Japanese workers. Material and Methods This was a cross-sectional study. In December 2020, during the “third wave” of the COVID-19 pandemic, an Internet-based nationwide health survey of 33 087 Japanese workers (The Collaborative Online Research on Novel-coronavirus and Work, CORoNaWork study) was conducted. Data of 27 036 individuals were included after excluding 6051 invalid responses. The authors analyzed a sample of 13 468 office workers from this database. The participants were classified into 4 groups according to their telecommuting frequency, while comparing scores on the subscale of the Job Content Questionnaire (JCQ) and subjective job stress between the high-frequency, medium-frequency, low-frequency, and non-telecommuters groups. A linear mixed model and an ordinal logistic regression analysis were used. Results A significant difference in the job control scores of the JCQ among the 4 groups was found, after adjusting for multiple confounding factors. The high-frequency telecommuters group had the highest job control score. Further, after adjusting for multiple confounding factors, the subjective job stress scores of the high- and medium-frequency telecommuters groups were significantly lower than those of the non-telecommuters group. Conclusions This study revealed that high-frequency telecommuting was associated with high job control and low subjective job stress. The widespread adoption of telecommuting as a countermeasure to the public health challenges associated with the COVID-19 pandemic may also have a positive impact on job stress. Int J Occup Med Environ Health. 2022;35(3):339–51

IntroductionImmune checkpoint inhibitors have had a major impact on cancer treatment. Gut microbiota plays a major role in the cancer microenvironment, affecting treatment response. The gut microbiota is highly individual, and varies with factors, such as age and race. Gut microbiota composition in Japanese cancer patients and the efficacy of immunotherapy remain unknown. MethodsWe investigated the gut microbiota of 26 patients with solid tumors prior to immune checkpoint inhibitor monotherapy to identify bacteria involved in the efficacy of these drugs and immune-related adverse events (irAEs).ResultsThe genera Prevotella and Parabacteroides were relatively common in the group showing efficacy towards the anti-PD-1 antibody treatment (effective group). The proportions of Catenibacterium (P = 0.022) and Turicibacter (P = 0.049) were significantly higher in the effective group than in the ineffective group. In addition, the proportion of Desulfovibrion (P = 0.033) was significantly higher in the ineffective group. Next, they were divided into irAE and non-irAE groups. The proportions of Turicibacter (P = 0.001) and Acidaminococcus (P = 0.001) were significantly higher in the group with irAEs than in those without, while the proportions of Blautia (P = 0.013) and the unclassified Clostridiales (P = 0.027) were significantly higher in the group without irAEs than those with. Furthermore, within the Effective group, Acidaminococcus and Turicibacter (both P = 0.001) were more abundant in the subgroup with irAEs than in those without them. In contrast, Blautia (P = 0.021) and Bilophila (P= 0.033) were statistically significantly more common in those without irAEs.DiscussionOur Study suggests that the analysis of the gut microbiota may provide future predictive markers for the efficacy of cancer immunotherapy or the selection of candidates for fecal transplantation for cancer immunotherapy.

Background: Encouraging the implementation of infection prevention and control (IPC) measures has been necessary to prevent workplace infections caused by the coronavirus disease 2019 (COVID-19). However, the effectiveness of these measures in reducing infections has not been thoroughly evaluated. We evaluated employees’ COVID-19 infection rates in relation to the implementation of IPC measures at their workplaces to identify effective workplace measures. Methods: This prospective cohort study was conducted between December 2020 and December 2021 using Internet-based self-assessment questionnaires, with 11,982 participants included from the baseline. To estimate whether implementing workplace IPC measures was associated with COVID-19 incidence rates among participants, we estimated multivariate-adjusted relative risk (RR) using a log-binomial model. Results: After adjusting for sex, age, education, household members, occupation-related factors, and personal preventive behaviors, requesting ill employees to refrain from going to work showed significantly lower COVID-19 infection rates than not requesting it (RR: 0.56, 95% CI: 0.34–0.91, p = 0.019). Conclusions: Employees restricted from reporting to work when ill had significantly lower COVID-19 infection rates than those who did not follow this measure. The results indicated that not coming to work when ill was effective in reducing COVID-19 infections at the workplace. We suggest that companies proactively adopt this policy and encourage their employees to comply with it.

ObjectivesThe coronavirus disease 2019 (COVID-19) pandemic has significantly impacted working life quality. This study investigated whether changes in work/sleep patterns due to the pandemic are related to poor psychological status among Japanese workers during the third wave of the COVID-19 pandemic (December 2020). We hypothesized that workers who experienced drastic changes in working hours and sleep duration would be at an increased risk of psychological distress.MethodsA cross-sectional self-administered Internet survey was conducted that included questions regarding socio-demographics, lifestyle, health, and occupational background and conditions. Multivariable logistic regression models were utilized to examine the association between psychological distress and a combination of changes in working hours and sleep duration.ResultsAmong 25,762 workers, decreased work hours and decreased sleep duration presented 2.59 times higher odds of psychological distress (95% confidence interval [CI] = 2.05–3.28) compared to those who had no changes in work hours combined with unchanged sleep duration (reference group). Increased work hours and decreased sleep duration were associated with 1.98 times higher odds of psychological distress (95% CI = 1.64–2.39).ConclusionOur observations confirmed that decreased sleep duration could be a key factor for psychological distress, irrespective of working hours. Interestingly, workers with a combination of decreased work hours and sleep duration posed the highest risk of psychological distress. Decreased work hours accompanied by financial difficulties in the early stage of the pandemic may have caused decreased sleep duration, resulting in a high prevalence of psychological distress. Our study underlined the importance of sleep management in maintaining workers’ mental health, moreover, the need to consider situations and conditions of other daily tasks, such as work hours, for better sleep management.

Abstract Background To prevent the spread of coronavirus disease (COVID-19), it is important to avoid 3Cs (closed spaces, crowded places, and close-contact settings). However, the risk of contact with an unspecified number of people is inevitable while commuting to and from work. In this study, we investigated the relationship between commuting, and the risk of COVID-19 and COVID-19-induced anxiety. Methods An internet-based questionnaire survey was conducted to obtain a dataset from 27,036 respondents. One-way commuting time was evaluated using a five-case method. The commuting distance was estimated using zip codes of the home and workplace. Logistic regression analysis was performed with the following outcomes: COVID-19 risk, close contact, infection anxiety, and infection anxiety due to commuting. Commuting distance and commuting time were analyzed separately in the model. We excluded participants with incalculable commuting distance, commuting distance exceeding 300 km, commuting distance of 0 km, or who telecommuted at least once a week. Results The total number of participants included in the analysis was 14,038. The adjusted odds ratios (aORs) of using public transportation for severe acute respiratory syndrome coronavirus 2 infection were 4.17 (95% confidence interval [CI]: 2.51–6.93) (commuting time) and 5.18 (95% CI: 3.06–8.78) (commuting distance). The aOR of COVID-19 diagnosis decreased significantly with increasing commuting distance. The aORs of using public transportation to infection anxiety were 1.44 (95% CI: 1.31–1.59) (commuting time) and 1.45 (95% CI: 1.32–1.60) (commuting distance). The longer the commuting time, the more the aOR increased. Conclusions COVID-19 risk, close contact, and infection anxiety were all associated with the use of public transportation during commuting. Both commuting distance and time were associated with infection anxiety due to commuting, and the strength of the association increased with increase in commuting time distance. Since transportation by commuting is associated with COVID-19 risk and anxiety, we recommend the use of telecommuting and other means of work.

IntroductionThe Go To Travel campaign in Japan was launched to subsidize travel and accommodation costs for tourists through vouchers that could be used at domestic destinations. Infection prevention behavior can lead to refraining from travel owing to infection concerns; conversely, taking preventive action can promote travel. There is a lack of information about the association between infection prevention behaviors and desire to travel. During a pandemic of infection, there is the difficult challenge of balancing the promotion of infection prevention behavior with economic revitalization. Thus, we examined the relationship between personal infection prevention behaviors and using Go To Travel.MethodsWe conducted a cross-sectional study of 26,637 workers who responded to a large-scale questionnaire survey about COVID-19 in Japan. We built multilevel logistic regression models adjusted for confounders to assess the association between each personal infection prevention behavior and using Go To Travel. We analyzed the seven infection prevention behavior individually: wearing a mask when among other people; disinfecting hands with alcohol before going indoors; washing hands after using the toilet; gargling upon returning home; opening a window to ventilate a room; carrying an alcohol sanitizer; and disinfecting hands after touching objects outside.ResultsAmong the 26,637 participants, 7,959 (30%) used Go To Travel. For “wearing a mask in the presence of others” and “washing hands after using the toilet,” the majority of respondents answered “almost always: 86.5 and 85.6% respectively. Action “carrying alcohol disinfectant” was the least implemented, with 36.9% of respondents saying “almost never.” Two of the seven preventive behaviors (“disinfecting hands with alcohol before going indoors” and “carrying alcohol disinfectant”) were positively related to using Go To Travel, that is, the more of these actions they took, the more they used Go To Travel (p for trend

ObjectiveDue to the COVID-19 pandemic, non-married people are at high risk of loneliness. With social interactions restricted, it is important for non-married people to acquire a new romantic partner for their mental health and quality of life. We hypothesized that infection control efforts in the workplace influence people's social interactions, including romantic activities.MethodsWe conducted an internet-based prospective cohort study from December 2020 (baseline) to December 2021, using self-administered questionnaires. Briefly, 27,036 workers completed the questionnaires at baseline, and when followed up after 1 year, 18,560 (68.7%) participated. A total of 6,486 non-married individuals with no romantic relationship at baseline were included in the analysis. At baseline they were asked about the implementation of infection control measures in the workplace, and at follow-up they were asked about activities they performed with a view to romantic relationships during the period from baseline to follow-up.ResultsCompared to workers in workplaces with no infection control measures, the odds ratio (OR) associated with romance-related activities for those in workplaces with seven or more infection control measures was 1.90 (95% CI: 1.45–2.48, p < 0.001), and the OR associated with having a new romantic partner was 1.79 (95% CI: 1.20–2.66, p = 0.004).DiscussionUnder the COVID-19 pandemic, the implementation of infection control measures in the workplace and the expressed satisfaction with those measures promoted romantic relationships among non-married, single individuals.

Globally, residents of long-term care facilities (LTCFs) often experience adverse events (AEs) and corresponding lawsuits that result in suffering among the residents, their families, and the facilities. Hence, we conducted a study to clarify the factors related to the facilities' liabilities for damages for the AEs that occur at LTCFs in Japan. We analyzed 1,495 AE reports from LTCFs in one Japanese city. A binomial logistic regression analysis was conducted to identify factors associated with liability for damages. The independent variables were classified as: residents, organizations, and social factors. In total, 14% of AEs resulted in the facility being liable for damages. The predictors of liability for damages were as follows: for the resident factors, the increased need for care had an adjusted odds ratio (AOR) of 2.00 and care levels of 2-3; and AOR of 2.48 and care levels of 4-5. The types of injuries, such as bruises, wounds, and fractures, had AORs of 3.16, 2.62, and 2.50, respectively. Regarding the organization factors, the AE time, such as noon or evening, had an AOR of 1.85. If the AE occurred indoors, the AOR was 2.78, and if it occurred during staff care, the AOR was 2.11. For any follow-ups requiring consultation with a doctor, the AOR was 4.70, and for hospitalization, the AOR was 1.76. Regarding the type of LTCF providing medical care in addition to residential care, the AOR was 4.39. Regarding the social factors, the reports filed before 2017 had an AOR of 0.58. The results of the organization factors suggest that liability tends to arise in situations where the residents and their family expect high quality care. Therefore, it is imperative to strengthen organizational factors in such situations to avoid AEs and the resulting liability for damages.

Background: There are increasing concerns that prevention measures against coronavirus disease 2019 (COVID-19) such as social distancing and telework are leading to loneliness and poor lifestyle habits like increased alcohol consumption. The purpose of this study was to assess whether loneliness reported among workers during the COVID-19 pandemic is associated with changes in alcohol consumption. Methods: The study comprised a cross-sectional, online survey of 27,036 workers between December 22 and 26, 2020. A questionnaire was used to assess loneliness, usual alcohol consumption and whether that consumption had changed. Odds ratios (ORs) were estimated by logistic regression analysis. Results: A total of 2831 (10.5%) workers indicated they had increased alcohol consumption during the pandemic. Increased alcohol consumption was significantly associated with loneliness (OR = 1.94, 95%CI 1.70–2.21). This association held true for those who indicated they drank two or more days per week (OR = 1.98 95%CI 1.71–2.30) and those who drank less than one day per week (OR = 1.51 95%CI 0.71–3.25). In contrast, there was no association between increased alcohol consumption and loneliness among those who indicated they hardly ever drank (OR = 1.22 95%CI 0.55–2.72). Conclusions: Among those drinking more than once a week, increased alcohol consumption is associated with loneliness.

Many factors are related to vaccination intentions. However, gender differences in the determinants of intention to get the coronavirus disease 2019 (COVID-19) vaccine have not been fully investigated. This study examined gender differences in the determinants of willingness to get the COVID-19 vaccine among the working-age population in Japan. We conducted a cross-sectional study of Japanese citizens aged 20–65 years using an online self-administered questionnaire in December 2020. Logistic regression analysis was performed. Among 27,036 participants (13,814 men and 13,222 women), the percentage who were willing to get the COVID-19 vaccine was lower among women than among men (33.0% vs. 41.8%). Age and education level showed a gender gap regarding the association with willingness to get the COVID-19 vaccine: men who were older or had a higher level of education were more willing to get the vaccine, whereas women aged 30–49 years and those with a higher level of education showed a relatively low willingness to get the vaccine. For both men and women, marriage, higher annual household income, underlying disease, current smoking, vaccination for influenza during the current season, and fear of COVID-19 transmission were linked to a higher likelihood of being willing to get the COVID-19 vaccine. These findings give important insight into identifying target groups in need of intervention regarding COVID-19 vaccination, especially among women. Providing education about COVID-19 and influenza vaccination in the workplace may be an effective strategy to increase COVID-19 vaccine uptake.

BackgroundThe COVID-19 pandemic has dramatically transformed the work environment and practices worldwide. Long-term infection control practices may increase the psychological distress of workers, and, conversely, inadequate infection control practices in the working place may increase the fear of infection. This study aimed to determine the relationship between infection control practices in the working place and employee mental state during the COVID-19 pandemic in Japan.MethodsThis study was conducted in December 2020 and February 2021. The participants had undergone a preliminary survey, which revealed that they were in a good mental state. Their psychological distress was investigated via a second survey, and the factors associated with distress were studied using a logistic model.ResultsThe results of the second survey indicated that 15.3% of participants demonstrated psychological distress. This was associated with leave-of-absence instructions, instructions for shortening business hours, and requests to avoid the working place in case of any symptoms.ConclusionThe study found that while some infection control practices reduce workers' distress, others worsen it. Employers need to consider infection control practices as well as the worsening mental state of employees following a decrease in income caused by such measures. Follow-up studies may be necessary to clarify the long-term effects on workers' mental states.

Abstract Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and lymphocyte-to-monocyte ratio (LMR), are three reportedly predictive biomarkers that reflect subclinical chronic inflammatory burden. However, how these biomarkers change during pregnancy and its clinical utility among pregnant women have been rarely studied. Among 76,853 singleton pregnancies delivered at 28–41 weeks of gestation that were enrolled in the Japan Environment and Children’s Study, we observed the distribution of maternal NLR, PLR, and LMR values from week 0 to week 36 using spline curves, as well as their predictive values for preterm delivery with and without hypertensive disorders in pregnancy, placental abruption and intrauterine growth restriction (collectively termed ischemic placental disease due to their shared pathological and pathophysiological features) for measurements at 8–11 weeks, 12–17 weeks, and 18–21 weeks. NLR and PLR increased, whereas LMR decreased, with increasing gestation. High LMR and low NLR observed at 18–21 weeks, but not at earlier gestations, were associated with higher risk of preterm delivery with IPD (odds ratio 1.80 [95% CI 1.02, 3.19] per log[LMR]; odds ratio 0.49 [95% CI 0.29, 0.82] per log[NLR]). All parameters were not predictive of preterm delivery without IPD. We provide a robust reference curve for maternal blood count parameters NLR, PLR, and LMR by gestational week.

Abstract This study investigated the association of maternal sleep before and during pregnancy with sleeping and developmental problems in 1-year-old infants. We used data from the Japan Environment and Children’s Study, which registered 103,062 pregnancies between 2011 and 2014. Participants were asked about their sleep habits prior to and during pregnancy. Follow-up assessments were conducted to evaluate the sleep habits and developmental progress of their children at the age of 1 year. Development during infancy was evaluated using the Ages and Stages Questionnaire (ASQ). Maternal short sleep and late bedtime before and during pregnancy increased occurrence of offspring’s sleeping disturbances. For example, infants whose mothers slept for less than 6 h prior to pregnancy tended to be awake for more than 1 h (risk ratio [RR] = 1.49, 95% confidence interval [CI] 1.34–1.66), sleep less than 8 h during the night (RR = 1.60, 95% CI 1.44–1.79), and fall asleep at 22:00 or later (RR = 1.33, 95% CI 1.26–1.40). Only subjective assessments of maternal sleep quality during pregnancy, such as very deep sleep and feeling very good when waking up, were inversely associated with abnormal ASQ scores in 1-year-old infants.

Background: Fish are a rich source of essential nutrients that protect against preterm birth. However, as fish can absorb environmental pollutants, their consumption can also increase the risk of preterm birth. This study aimed to assess whether maternal fish consumption during pregnancy is associated with preterm birth in a nationwide large Japanese cohort that consumed relatively high amounts and many types of fish. Methods: This study included 81,428 mother-child pairs enrolled in a nationwide prospective Japanese birth cohort study. Fish consumption was assessed using a validated food frequency questionnaire. Multivariate logistic regression was used to investigate the association of total consumption of fish, fatty fish and lean fish, fish paste, and seafood and clams with preterm birth, adjusted for potential confounders. Results: There was no association between overall fish consumption and preterm births. However, the highest quintile of fish paste consumption was significantly associated with an increased risk of preterm birth (odds ratio [OR]: 1.11; 95% confidence interval [CI: 1.04, 1.17]). The consumption of baked fish paste at least three times per week was significantly associated with preterm birth (OR: 1.20; 95% CI: 1.03, 1.40). Consumption of other types of fish, except fish paste, was not significantly associated with preterm birth risk. Conclusions: Fish paste consumption may increase the risk of preterm birth. Further studies are required to confirm this association.

Amyloid-β (Aβ) is one of the causes of Alzheimer’s disease (AD), damaging nerve membranes and inducing neurotoxicity. AD is more prevalent in female patients than in male patients, and women are more susceptible to developing AD due to the decline in estrogen levels around menopause. Raloxifene, a selective estrogen receptor modulator, exhibits protective effects by activating the transmembrane G-protein-coupled estrogen receptor (GPER). Additionally, raloxifene prevents mild cognitive impairment and restores cognition. However, the influence of raloxifene via GPER on highly toxic Aβ-oligomers (Aβo)-induced neurotoxicity remains uncertain. In this study, we investigated the GPER-mediated neuroprotective effects of raloxifene against the neurotoxicity caused by Aβo-induced cytotoxicity. The impact of raloxifene on Aβo-induced cell damage was evaluated using measures such as cell viability, production of reactive oxygen species (ROS) and mitochondrial ROS, peroxidation of cell-membrane phospholipids, and changes in intracellular calcium ion concentration ([Ca2+]i) levels. Raloxifene hindered Aβo-induced oxidative stress and reduced excessive [Ca2+]i, resulting in improved cell viability. Furthermore, these effects of raloxifene were inhibited with pretreatment with a GPER antagonist. Our findings suggest that raloxifene safeguards against Aβo-induced neurotoxicity by modifying oxidative parameters and maintaining [Ca2+]i homeostasis. Raloxifene may prove effective in preventing and inhibiting the progression of AD.

Abstract The aim of this study was to investigate the association between maternal physical activity (PA) before and during pregnancy and sleep and developmental problems in 1-year-old infants. We used data from a nationwide cohort study in Japan that registered 103,062 pregnancies between 2011 and 2014. Participants were asked about their PA before and during pregnancy, and the sleep and development of their children at the age of 1 year. Maternal PA was estimated using the International Physical Activity Questionnaire and was expressed in METs per week. We defined scores below the cut-off points of the Ages and Stages Questionnaire (ASQ) as abnormal for infant development. Based on the levels of PA before or during pregnancy, the participants were divided into five groups. In mothers with higher PA levels, the risk ratio for bedtime after 22:00 or abnormal ASQ scores in their 1-years-old infants were lower. These associations were observed for PA before and during pregnancy. Higher levels of maternal PA, both before and during pregnancy, may reduce sleep and developmental problems in infants.

The control of human flow has led to better control of COVID-19 infections. Japan’s state of emergency, unlike other countries, is not legally binding but is rather a request for individual self-restraint; thus, factors must be identified that do not respond to self-restraint, and countermeasures considered for those factors to enhance its efficacy. We examined the relationship between sociodemographic factors and self-restraint toward social behaviors during a pandemic in Japan. This cross-sectional study used data for February 18–19, 2021, obtained from an internet survey; 19,560 participants aged 20–65 were included in the analysis. We identified five relevant behaviors: (1) taking a day trip; (2) eating out with five people or more; (3) gathering with friends and colleagues; (4) shopping for other than daily necessities; (5) shopping for daily necessities. Multilevel logistic regression analyses were used to examine the relationship between sociodemographic factors and self-restraint for each of the behaviors. Results showed that for behaviors other than shopping for daily necessities, women, those aged 60–65, married people, highly educated people, high-income earners, desk workers and those who mainly work with interpersonal communication, and those with underlying disease reported more self-restraint. Older people had less self-restraint than younger people toward shopping for daily necessities; an underlying disease had no effect on the identified behavior. Specialized interventions for these groups that include recommendations for greater self-restraint may improve the efficacy of the implementing measures that request self-restraint.

BackgroundThe COVID-19 pandemic has resulted in treatment interruption for chronic diseases. The scale of COVID-19 in Japan has varied greatly in terms of the scale of infection and the speed of spread depending on the region. This study aimed to examine the relationship between local infection level and treatment interruption among Japanese workers.MethodsCross-sectional internet survey was conducted from December 22 to 26, 2020. Of 33,302 participants, 9,510 (5,392 males and 4,118 females) who responded that they required regular treatment were included in the analysis. The infection level in each participant's prefecture of residence was assessed based on the incidence rate (per 1,000 population) and the number of people infected. Age-sex and multivariate adjusted odds ratios (ORs) of regional infection levels associated with treatment interruption were estimated by multilevel logistic models, nested by prefecture of residence. The multivariate model was adjusted for sex, age, marital status, equivalent household income, educational level, occupation, self-rated health status and anxiety.ResultsThe ORs of treatment interruption for the lowest and highest levels of infection in the region were 1.32 [95 % confidence interval (CI) were 1.09–1.59] for the overall morbidity rate (per 1,000) and 1.34 (95 % CI 1.10–1.63) for the overall number of people infected. Higher local infection levels were linked to a greater number of workers experiencing treatment interruption.ConclusionsHigher local infection levels were linked to more workers experiencing treatment interruption. Our results suggest that apart from individual characteristics such as socioeconomic and health status, treatment interruption during the pandemic is also subject to contextual effects related to regional infection levels. Preventing community spread of COVID-19 may thus protect individuals from indirect effects of the pandemic, such as treatment interruption.

Abstract Abnormal autonomic function may cause false-positive non-reassuring foetal status (fpNRFS) and may also cause sleeping problems after birth. However, an association between fpNRFS and sleeping problems in infants has not been reported. We previously showed an association of NRFS with temperament, including bad mood and frequent crying for long durations in 1-month-old infants. In the present study, we aimed to assess this association in 1-year-old infants. A total of 62,612 single pregnant women were included in the analysis. fpNRFS was identified from medical records. Sleep problems, such as short sleep duration or crying at night, were investigated in 1-year-old infants using a questionnaire for mothers. We used a log-binominal regression model to explore the association of fpNRFS with each sleep problem and to estimate risk ratios (RRs). The number of fpNRFS cases was 2,071, with a frequency of 3.3%. We observed an association of fpNRFS with shorter sleep duration of less than 8 h a night (RR 1.30, 95% confidence intervals [CI] 1.10–1.54), crying at night (RR 1.19, 95% CI 1.03–1.39), and bedtime after 22:00 (RR 1.09, 95% CI 1.00–1.18). fpNRFS may be associated with sleep problems in 1-year-old infants.

Abstract This study aimed to investigate the association of maternal sleep before and during pregnancy with preterm birth, infant sleep and temperament at 1 month of age. We used the data of the Japan Environment and Children’s Study, a cohort study in Japan, which registered 103,099 pregnancies between 2011 and 2014. Participants were asked about their sleep before and during pregnancy, and the sleep and temperament of their newborns at 1 month of age. Preterm birth data were collected from medical records. Maternal sleep was not associated with preterm birth, but subjective sleep quality during pregnancy was associated with late preterm birth (birth at 34–36 weeks of gestation). For example, participants with extremely light subjective depth of sleep were more likely to experience preterm birth (RR = 1.19; 95% confidence interval [CI] = 1.04–1.35). Maternal sleep both before and during pregnancy seemed to be associated with infant sleep and temperament at 1 month of age. Infants, whose mothers slept for less than 6 hours before pregnancy, tended to cry intensely (RR = 1.15; 95% CI = 1.09–1.20). Maternal sleep problems before and during pregnancy were associated with preterm birth and child sleep problems and temperament.

BackgroundThe coronavirus disease 2019 (COVID-19) pandemic has been linked to a rise in loneliness. Loneliness is associated with sleep-related problems, which in turn can be a risk factor for various psychiatric disorders. However, it is unclear whether loneliness is linked to sleep-related problems during the pandemic. Here, we studied the association between loneliness and sleep-related problems during the COVID-19 pandemic in Japan.MethodsA total of 33,302 individuals who indicated they were employed were surveyed online. The survey responses of 27,036 participants were analyzed. Odds ratios (ORs) were estimated using univariate and multiple logistic regression analyses.ResultsOf those analyzed, 2,750 (10.2%) experienced feelings of loneliness. Further, sleep-related problems were significantly more common among those who felt lonely both in the short term (more than 3 days) and the long term (more than 3 months). The ORs were much weaker after adjusting for factors related to interpersonal connections, such as family and friendships, than after adjusting for factors related to socioeconomic status.ConclusionLoneliness may be a risk factor for sleep-related problems in the COVID-19 pandemic. Having connections with family and friends may have a moderating effect on the occurrence of sleep-related problems.

This study aimed to examine the relationship between telecommuting and the regional cumulative COVID-19 incidence. This was a cross-sectional study analyzing 13,468 office workers. The participant groups, according to the level of cumulative COVID-19 incidence by prefecture, were used as the predictor variable, and telecommuting frequency and preference were used as outcomes. We employed an ordinal logistic regression analysis. In regions with a high cumulative COVID-19 incidence, the proportion of participants who telecommuted more than 2 days per week was 34.7%, which was approximately 20% higher than in other regions. Telecommuting preference was stronger in areas with higher COVID-19 influence. However, in other regions, the proportion of participants who did not want to telecommute was higher than that of those who wanted to telecommute. We found that telecommuting frequency and preference were higher in regions with high cumulative COVID-19 incidence.

Abstract Background and Aims Maternal hemoglobin concentration during pregnancy is reported to be associated with various perinatal outcomes and may also be associated with infant development. This study aims to investigate the association between maternal hemoglobin levels during early or mid‐pregnancy and sleep and developmental problems in 1‐year‐old infants. Methods We used the data of 66,935 pregnant women who were participants of the Japan Environment and Children's Study, a nationwide cohort study in Japan, between 2011 and 2014. Maternal hemoglobin level was examined at recruitment (mean gestational age, 15.3 weeks; SD, 2.85 weeks; range, 6–22 weeks). Information on infant sleep and development at the age of 1 year was acquired using a questionnaire. Infant development was evaluated using the Ages and Stages Questionnaire (ASQ). Results The mean (SD) maternal hemoglobin level was 12.0 (1.0) g/dl. Maternal hemoglobin levels were not associated with the majority of infant sleep and developmental outcomes. In the group with maternal hemoglobin

BackgroundStudies have determined that exercise and physical activity positively affect physical and mental health, and that healthy workers contribute to increased work performance. The relationship between the time spent on exercise during leisure time and physical activity, including work, with health-related quality of life (HRQOL) in workers is unclear, with variations observed between occupational types. This cross-sectional study examined these associations among Japanese workers from various occupations during the COVID-19 pandemic.MethodsAn Internet-based national health survey—Collaborative Online Research on Novel-coronavirus and Work-study (CORoNaWork study)—was conducted among 33,087 Japanese workers in December 2020. After excluding invalid responses, 27,036 participants were categorized into four and five groups according to exercise and physical activity time, respectively. Each group's scores were compared on each of the four questions on the Japanese version of the Centers for Disease Control and Prevention Health-Related Quality of Life (CDC HRQOL-4) using generalized linear models. Age-sex adjusted and multivariate models were used to compare each index of the CDC HRQOL-4.ResultsCompared to the reference category (almost never), any level of exercise (ORs 0.56–0.77) and physical activity (ORs 0.93–0.88) were associated with better self-rated health in the multivariate model. Any exercise was also associated with significantly reduced odds for physically or mentally unhealthy days; however, high levels of physical activity (≥120 min/day) were associated with significantly increased odds for these outcomes (ORs = 1.11 and 1.16, respectively).ConclusionsThe results suggest that exercise habits are more critical to workers' HRQOL than physical activity. Interventions that encourage daily exercise even for a short time are likely to be associated with better workers' health and work performance.

This study aimed to examine the association between infant sleep quality and temperament in one-month-old infants using a large cohort study data. We used data from the Japan Environment and Children's Study, a cohort study which follows around 100,000 women from pregnancy until their children's development. The mothers were asked about their infants' sleep and temperament using a structured questionnaire. Frequent crying (adjusted odds ratio [AOR]: 1.05, 95% confidence interval [CI]: 1.00-1.10) and intense crying (AOR: 1.19, 95% CI: 1.13-1.25) were positively associated with longer sleep periods during the day than at night. Female infants with longer daytime sleep periods than that at nighttime were more likely to cry frequently (AOR: 1.11, 95% CI: 1.04-1.20). Parous women with infants who had frequent night awakening believed their infants cried more intensely (AOR: 1.17, 95% CI: 1.03-1.31). The study demonstrated a specific association between sleep quality and temperament in one-month-old infants. Based on the results of this study, further sleep intervention studies are required to improve infant temperament.

One of the neuropathological hallmarks of Alzheimer's disease (AD)—causing neurodegeneration and consequent memory deterioration, and eventually, cognitive decline—is amyloid-β (Aβ) aggregation forming amyloid plaques. Our previous study showed the potential of a tocotrienol-rich fraction—a mixture of naturally occurring of vitamin E analogs—to inhibit Aβ aggregation and restore cognitive function in an AD mouse model. The current study examined the effect of three vitamin E analogs—α-tocopherol (α-TOC), α-tocotrienol (α-T3), and γ-tocotrienol (γ-T3)—on Aβ aggregation, disaggregation, and oligomerization in vitro. Thioflavin T (ThT) assay showed α-T3 reduced Aβ aggregation at 10 μM concentration. Furthermore, both α-T3 and γ-T3 demonstrated Aβ disaggregation, as shown by the reduction of ThT fluorescence. However, α-TOC showed no significant effect. We confirmed the results for ThT assays with scanning electron microscopy imaging. Further investigation in photo-induced cross-linking of unmodified protein assay indicated a reduction in Aβ oligomerization by γ-T3. The present study thus revealed the individual effect of each tocotrienol analog in reducing Aβ aggregation and oligomerization as well as disaggregating preformed fibrils.

Background: The current coronavirus (COVID-19) pandemic has had large impacts on society, including people practicing social distancing. This behavioral response has increased loneliness. Loneliness not only increases the risk of psychiatric disorders, but also affects occupational mental health. To avoid the negative effects of isolation, it is important to have social contact with other people, especially family members. Employment and economic instability caused by COVID-19 may have also affected family relationships. It is important to understand the association between family relationships and loneliness in workers under the pandemic.Methods: We collected usable data from 27,036 Japanese workers who completed an online survey during the COVID-19 pandemic. Participants were asked how long they spend with members of their family during mealtimes or at home, and if they experienced loneliness; the latter was assessed by a single question. Other questions included whether participants lived with their spouse, or with someone in need of care. To estimate the odds ratios (ORs) of time with family associated with loneliness we used a multilevel logistic model nested in the prefecture of residence, with adjustments for age, sex, marital status, presence of a cohabitant requiring care, equivalent income, educational level, number of employees in the workplace, frequency of remote work, availability of someone for casual chat, smoking, drinking, time for leisure interests, and cumulative rates of COVID-19 in the prefecture.Results: Ten percent (2,750) of the 27,036 participants reported loneliness. The survey showed a significant negative correlation between time spent with family and loneliness (p < ‘0.001): participants who spent more time with family were less likely to feel loneliness. In addition, not living with a spouse and living with someone in need of care were associated with loneliness (not living with a spouse: p < 0.001; living with someone in need of care: p < 0.001).Conclusion: Loneliness under COVID-19 pandemic conditions was negatively associated with time spent with family members, with the converse result found for participants cohabiting with someone in need of care. These associations suggest the potential value of changes to working practices and interventions to combat loneliness.

The purpose of this study was to examine the association between loneliness and psychological distress during the COVID-19 pandemic in Japan. We conducted a cross-sectional online study from 22 to 26 December 2020. A total of 27,036 participants, all employed at the time, were included in the analysis. Participants were asked if they felt loneliness in a single-item question. The Kessler 6 (K6) was used to assess psychological distress, defined as mild for K6 scores of 5 to 12 and severe for 13 or higher. The odds ratios (ORs) of psychological distress associated with loneliness were estimated using a multilevel logistic model nested in the prefecture of residence, with adjustment for age, sex, marital status, equivalent income, educational level, smoking, alcohol consumption, job type, number of workplace employees, and cumulative incidence rate of COVID-19 in the prefecture. Communication with friends, acquaintances, and family was strongly associated with psychological distress, so we adjusted for these factors and eating meals alone. Results showed a significant association between loneliness and psychological distress (OR = 36.62, 95% CI = 32.95–40.69). Lack of friends to talk to, lack of acquaintances to ask for help, and lack of people to communicate with through social networking sites were all strongly associated with psychological distress, as were family time and solitary eating. Even after adjusting for these factors, loneliness remained strongly associated with psychological distress (OR = 29.36, 95% CI = 26.44–32.98). The association between loneliness during the COVID-19 pandemic and psychological distress indicates the need for intervention.

Purpose: There is limited information about the association between workplace psychosocial factors and general worker mental health status during the COVID-19 pandemic. In the present study, we examined how anxiety about being infected by COVID-19 in the workplace affected the association between job demands and psychological distress (PD).Method: A cross-sectional online survey was conducted in December 2020. The final analyzed sample was 27,036. The dependent variable of PD was assessed using the Kessler Psychological Distress Scale (K6). Job demands were assessed using the Job Content Questionnaire. Feelings of anxiety were assessed by participants' responses to the following question: “Do you feel anxiety about being infected by COVID-19 in the workplace?” We used a two-level regression adjusting for prefectural level: each individual-level variable at level 1 was nested into each prefecture at level 2, stratified by presence of anxiety.Results: A total of 50.5% of participants felt anxious about being infected by COVID-19 in the workplace. The interaction between anxiety and job demands was significant. Job demands were positively associated with PD. In the stratified analysis, the associations were stronger among employees who experienced anxiety about COVID-19 infection in the workplace than among those who did not.Conclusion: The association between job demands and PD may be strengthened by anxiety about COVID-19 infection in the workplace.

Abstract Background Gestational diabetes mellitus (GDM) has serious effects on both mother and child. Like Type 2 Diabetes Mellitus, it is increasing in prevalence world-wide. In addition to obesity, sleep duration has been named an important risk factor. Using a large cohort study, including data from 48,787 participants of the Japan Environment and Children’s Study (JECS), we examined the association between sleep duration and both random blood glucose levels and GDM rates during pregnancy. Methods Random blood glucose levels were measured during pregnancy. GDM diagnosis was based on the results of 75 g oral glucose tolerance test. Additional anthropometric data was collected from questionnaires for statistical analysis. Results Compared to mothers averaging 7 to

Background: Metal exposures could possibly affect allergic responses in pregnant women, although no studies have yet shown a clear relationship between the two, and such exposures might also affect the development of allergic diseases in children. Methods: We investigated the relationship between metal concentrations in whole blood and immunoglobulin E (IgE; total and specific) in 14,408 pregnant women who participated in the Japan Environment and Children’s Study. The subjects submitted self-administered questionnaires, and blood samples were collected from them twice, specifically, during the first trimester and again during the second/third trimester. Concentrations of the metals Cd, Pb, Hg, Se, and Mn, as well as serum total and allergen-specific IgEs for egg white, house dust-mites (HDM), Japanese cedar pollen (JCP), animal dander, and moth, were measured. Allergen-specific IgE(s) were divided based on concentrations