江口 哲史

The increasing exposure to environmental chemicals calls for comprehensive non-targeted analysis to detect unrecognized substances in human samples. We examined human serum samples to classify compounds as endogenous or exogenous using public databases and to explore the relationships between exposure markers and metabolic patterns. Serum samples from 84 pregnant women at 32 weeks gestation were analyzed using LC-QToFMS. Using the PubChemLite for Exposomics database, we annotated and classified 106 compounds (51 endogenous, 55 exogenous). The compound patterns were analyzed using three dimensional reduction methods: Principal Component Analysis (PCA), regularized Generalized Canonical Correlation Analysis (rGCCA), and Uniform Manifold Approximation and Projection (UMAP). OPTICS clustering applied to these methods revealed two distinct clusters, with 89 % of significant compounds overlapping between clusters. The detected exogenous compounds included dietary substances, phthalates, nitrogenous compounds, and parabens. Pathway enrichment analysis showed that chemical exposure was linked to changes in amino acid metabolism, protein and mineral transport, and energy metabolism. While we found associations between exposure and metabolite changes, we could not establish causality. Our approach of analyzing both exogenous and endogenous chemicals from the same dataset using PubChemLite database presents a new method for exposome research, despite limitations in sample size and peak annotation accuracy. These findings contribute to understanding multiple chemical exposures and their metabolic effects in human biomonitoring.

The COVID-19 pandemic has highlighted the importance of understanding environmental factors in disease transmission. This study aims to explore the spatial association between nighttime light (NTL) from satellite imagery and COVID-19 mortality. It particularly examines how NTL serves as a pragmatic proxy to estimate human interaction in illuminated nocturnal area, thereby impacting viral transmission dynamics to neighboring areas, which is defined as spillover effect. Analyzing 43,199 COVID-19 deaths from national mortality data during January 2020 and October 2022, satellite-derived NTL data, and various environmental and socio-demographic covariates, we employed the Spatial Durbin Error Model to estimate the direct and indirect effect of NTL on COVID-19 mortality. Higher NTL was initially directly linked to increased COVID-19 mortality but this association diminished over time. The spillover effect also changed: during the early 3rd wave (December 2020 - February 2021), a unit (nanoWatts/sr/cm2) increase in NTL led to a 7.9% increase in neighboring area mortality (p = 0.013). In contrast, in the later 7th wave (July - September 2022), dominated by Omicron, a unit increase in NTL resulted in an 8.9% decrease in mortality in neighboring areas (p = 0.029). The shift from a positive to a negative spillover effect indicates a change in infection dynamics during the pandemic. The study provided a novel approach to assess nighttime human activity and its influence on disease transmission, offering insights for public health strategies utilizing satellite imagery, particularly when direct data collection is impractical while the collection from space is readily available.

OBJECTIVE: This paper provides an in-depth examination of public attitudes towards salt reduction across seven culturally diverse countries: the USA, the UK, France, Japan, Indonesia, Thailand, and Brazil. DESIGN: Cross-sectional regression analysis with questionnaire data. SETTING: An analysis of questionnaire study in seven countries. PARTICIPANTS: The study's questionnaire collected responses from 7090 participants across seven countries with the mean age of respondents being 46.06 years (SD 16.96). The gender distribution encompassed 3473 men (49.12%), 3582 women (50.66%), 24 non-binary individuals (0.34%) and 11 who identified as 'other' (0.16%). PRIMARY AND SECONDARY OUTCOME MEASURES: Attitudes toward sodium reduction were measured on a seven-point Likert scale. RESULTS: Regression analysis revealed significant associations between attitudes towards sodium reduction and various factors across countries. Gender was a significant factor in France, with women showing less awareness than men (coefficient -0.123, 95% CI -0.237 to -0.008). Age was a significant factor in Japan and Thailand, with older generations exhibiting stronger awareness. Occupation was a significant factor in France (grocery, 0.678, 0.229 to 1.127) and Japan (food service, 0.792, 0.300 to 1.283). In France (0.090, 0.033 to 0.146) and Brazil (0.092, 0.040 to 0.144), attitudes towards reducing sugar intake were positively associated with sodium reduction attitudes. Government interventions showed varying impacts, with positive associations in Thailand (0.004, 0.001 to 0.008) and negative associations in France (-0.003 -0.005 to -0.000). CONCLUSION: Our study reveals a complex array of factors shaping attitudes towards sodium reduction across seven countries. These findings support the need for nuanced, country-specific approaches in formulating sodium reduction strategies. Future research should validate these findings, explore further determinants and understand how attitudes translate into dietary behaviours.

Neonicotinoid (NN) pesticides have been linked to increased brain dysfunction in mammals, such as anxiety-like behavior; this is thought to involve monoamines (MA), neurotransmitters that control behavior, memory, and learning. However, the mechanism by which NNs affect the central nervous system is not fully understood. In this study, we aimed to investigate whether MAs affect NNs-induced anxiety-like behavior. Mice were orally administered acetamiprid (ACE), an NN, at the no observed adverse effect level (NOAEL) of mouse (20mg/kg body mass) set by the Food Safety Commission of Japan, and the elevated zero-maze (EZM) test was performed 30min after administration. After behavioral analysis, levels of four MA (dopamine, 3-MT, serotonin, and histamine) in selected brain regions were determined by liquid chromatography mass spectrometry (LC/MS/MS). In the exposed group, a trend toward increased anxiety-like behavior was observed, and at least one MA concentration was significantly increased in each region. Further, significant correlations were found between behavioral test results and hippocampal serotonin and striatal dopamine concentrations, as well as between dopamine and serotonin concentrations, in the exposed group. As anxiety can influence activity in the behavioral tests, the activity of neurons in the raphe nuclei (RN), a brain region greatly involved in anxiety via the serotonergic system, was examined by staining with anti-serotonin antibodies, and increased serotonergic activity was observed. Taken together, these results suggest that ACE regulates MA levels, notably serotonin levels in the hippocampus and that RN plays an important role in ACE-induced anxiety-like behavior.

Abstract Background Catch-up growth issues among children born small for gestational age (SGA) present a substantial public health challenge. Prenatal exposure to heavy metals can cause adverse effects on birth weight. However, comprehensive studies on the accurate assessment of individual blood concentrations of heavy metals and their effect on the failure to achieve catch-up growth remain unavailable. This study aimed to evaluate the effects of uterine exposure to toxic metals cadmium, lead, and mercury and essential trace metals manganese and selenium at low concentrations on the postnatal growth of children born SGA. Methods Data on newborn birth size and other factors were obtained from the medical record transcripts and self-administered questionnaires of participants in the Japan Environment and Children’s Study. The blood concentrations of lead, cadmium, mercury, selenium, and manganese in pregnant women in their second or third trimester were determined by inductively coupled plasma mass spectrometry. These heavy metal concentrations were also assessed in pregnant women’s cord blood. Furthermore, the relationship between each heavy metal and height measure/catch-up growth in SGA children aged 4 years was analyzed using linear and logistic regression methods. These models were adjusted for confounders. Results We studied 4683 mother–child pairings from 103,060 pregnancies included in the Japan Environment and Children’s Study. Of these, 278 pairs were also analyzed using cord blood. At 3 and 4 years old, 10.7% and 9.0% of children who were born below the 10th percentile of body weight had height standard deviation scores (SDSs) below 2, respectively. Cord blood cadmium concentrations were associated with the inability to catch up in growth by 3 or 4 years old and the height SDS at 3 years old. In maternal blood, only manganese was positively associated with the height SDS of SGA children aged 2 years; however, it was not significantly associated with catch-up growth in these children. Conclusion Cadmium exposure is associated with failed catch-up development in SGA children. These new findings could help identify children highly at risk of failing to catch up in growth, and could motivate the elimination of heavy metal (especially cadmium) pollution to improve SGA children’s growth.

Volatile organic compounds (VOCs) have been suspected to cause building-related symptoms (BRSs). Although some studies investigated the association between BRSs and VOCs in indoor air, those results were inconsistent. This study investigated the contamination status of VOCs in the indoor air of 154 houses in Japan. Additionally, these samples were grouped by hierarchical clustering analysis based on the VOC composition, and the relationship between a VOC cluster and the BRSs was investigated. The median concentration of the sum of VOCs (ΣVOCs) was 140 μg m-3 (range: 18-3500 μg m-3). The levels of acetaldehyde in four samples and p-dichlorobenzene in one sample exceeded the guideline value. As a result of the hierarchical clustering analysis, the samples in this study were divided into six characteristic clusters based on the VOC composition. The ΣVOCs in cluster 1 were significantly lower than those in other clusters. In cluster 2, acyclic and aromatic hydrocarbons were dominant. Cluster 3 had a relatively high proportion of limonene. In cluster 4, the concentrations and composition ratios of α-pinene were higher than those of other clusters. In cluster 5, p-dichlorobenzene accounted for 42 %-72 % of the total VOCs. Cluster 6 had a relatively high proportion of decamethyl cyclopentasiloxane. This clustering likely depended on the construction of houses and lifestyles. As a result of logistic regression analysis, cluster 5 was associated with the cough symptoms of the BRSs. The results of the present study suggest that investigating the association between VOCs and BRSs is necessary to consider not only total concentrations such as TVOC and ΣVOCs but also VOC composition.

Background Self-tracking smartphone apps have emerged as promising tools to encourage healthy behaviors. In this longitudinal study, we used gym use data from members of a major fitness club that operates gyms throughout Japan from January 2014 to December 2019. Objective Our objective was to assess the extent to which a health and fitness self-tracking mobile app introduced to gym members on January 1, 2018, contributed to their weight loss. The app allows users to input information regarding diet, sleep, weight, and gym exercise so that they can receive personalized feedback from an artificial intelligence chatbot to improve their health behaviors. Methods We used linear regression to quantify the association between app use and weight loss. The primary outcome of the study was the weight loss achieved by each gym user, which was calculated as the difference between their initial and final weights in kilograms, as recorded in the app. Individuals who did not attend the gym or failed to use the mobile app at least twice during the study period were excluded from the analysis. The model accounted for age, gender, distance between the gym and the member’s residence, average weekly number of times a member used the gym, user’s gym membership length in weeks, average weekly number of times a member input information into the app, and the number of weeks that the app was used at least once. Results Data from 26,589 participants were analyzed. Statistically significant associations were detected between weight loss and 2 metrics related to app use: the average weekly frequency of use and the total number of weeks in which the app was used at least once. One input per week was found to be associated with a loss of 62.1 (95% CI 53.8-70.5) g, and 1 week of app use was associated with 21.7 (95% CI 20.5-22.9) g of weight loss from the day of the first input to that of the final input to the app. Furthermore, the average number of times that a member used the gym weekly was also shown to be statistically significantly associated with weight loss: 1 use per week was associated with 255.5 (95% CI 228.5-282.6) g of weight loss. Conclusions This empirical study demonstrated a significant association between weight loss among gym members and not only the frequency of weekly gym use but also the use of a health and fitness self-tracking app. However, further work is needed to examine the mechanisms through which mobile apps affect health behaviors and to identify the specific app features that are most effective in promoting weight loss.

Recently, prediction of gestational diabetes mellitus (GDM) using artificial intelligence (AI) from medical records has been reported. We aimed to evaluate GDM-predictive AI-based models using birth cohort data with a wide range of information and to explore factors contributing to GDM development. This investigation was conducted as a part of the Japan Environment and Children's Study. In total, 82,698 pregnant mothers who provided data on lifestyle, anthropometry, and socioeconomic status before pregnancy and the first trimester were included in the study. We employed machine learning methods as AI algorithms, such as random forest (RF), gradient boosting decision tree (GBDT), and support vector machine (SVM), along with logistic regression (LR) as a reference. GBDT displayed the highest accuracy, followed by LR, RF, and SVM. Exploratory analysis of the JECS data revealed that health-related quality of life in early pregnancy and maternal birthweight, which were rarely reported to be associated with GDM, were found along with variables that were reported to be associated with GDM. The results of decision tree-based algorithms, such as GBDT, have shown high accuracy, interpretability, and superiority for predicting GDM using birth cohort data.

Accurately estimating the timing of pathogen exposure plays a crucial role in outbreak control for emerging infectious diseases, including the source identification, contact tracing, and vaccine research and development. However, since surveillance activities often collect data retrospectively after symptoms have appeared, obtaining accurate data on the timing of disease onset is difficult in practice and can involve “coarse” observations, such as interval or censored data. To address this challenge, we propose a novel likelihood function, tailored to coarsely observed data in rapid outbreak surveillance, along with an optimization method based on an ‐accelerated EM algorithm for faster convergence to find maximum likelihood estimates (MLEs). The covariance matrix of MLEs is also discussed using a nonparametric bootstrap approach. In terms of bias and mean‐squared error, the performance of our proposed method is evaluated through extensive numerical experiments, as well as its application to a series of epidemiological surveillance focused on cases of mass food poisoning. The experiments show that our method exhibits less bias than conventional methods, providing greater efficiency across all scenarios.

Abstract Per- and poly-fluoroalkyl substances (PFAS) have been utilized extensively for various applications owing to their distinctive chemical properties. They exhibit high persistence in the environment and accumulate within the human body, necessitating toxicity assessments. However, the consequences of prolonged, low-level exposure to PFAS and concurrent exposure to multiple PFAS have not been explored. In this study, male C57BL/6J mice (aged 8 weeks) were exposed to a composite of nine PFAS, which include long-chain PFAS (e.g. perfluorooctanoic acid and perfluorooctanesulfonic acid) and short-chain PFAS (e.g. perfluorobutanoic acid and perfluorobutanesulfonic acid) at concentrations equivalent to the estimated daily human intake in the composition reported (1 µg/L [sum of the nine compounds], the maximum reported exposure concentration) via drinking water. Histological examination revealed vacuolization of hepatocytes and irregular arrangement of hepatocyte cords, suggesting that exposure to low levels of the PFAS mixture causes morphological changes in liver tissues. Transcriptome analysis revealed that PFAS exposure mainly altered a group of genes related to metabolism and chemical carcinogenesis. Machine learning analysis of the liver metabolome showed a typical concentration-independent alteration upon PFAS exposure, and in addition to known substances such as glutathione, a compound with unknown biological function; 2,5-dihydro-2,4-dimethyloxazole was found. This study demonstrates that daily exposure to PFAS leads to morphological changes in liver tissues and alters the expression of metabolism-and cancer-related genes as well as phospholipid metabolism. Future studies are required to evaluate the chronic toxicity of prolonged, low-level exposure to PFAS mixtures and to investigate the health effects of PFAS.

Semi-volatile organic compounds (SVOCs), such as phthalates and organophosphate flame retardants (OPFRs), are used in plastic products and electrical and electronic applications as plasticisers or flame retardants. There has been a growing concern that exposure to SVOCs can have an adverse impact on human health. Several large-scale epidemiological studies employ the sampling of house dust using household vacuum cleaners as the standard method. However, in this method, house dust samples might be contaminated by flame retardants and plasticisers because of the presence of these chemicals in the plastic materials of cleaners. Therefore, this study aimed to develop a low-cost, easy-to-distribute sampling method to collect house dust using a mop and analyse OPFRs, phthalate esters, and alternative plasticisers in house dust. Our findings show that the proposed mop sampling method can be easily distributable and lower contamination from a sampling tool. Moreover, the proposed house dust sampling method is extremely useful for a large-scale survey such as a cohort study.

The spleen is a key immune-related organ that plays a role in communication between the brain and the immune system through the brain-spleen axis and brain-gut-microbiota axis. However, how the gut microbiota affects spleen and brain function remains unclear. Here, we investigated whether microbiome depletion induced by administration of an antibiotic cocktail (ABX) affects spleen and brain function. Treatment with ABX for 14 days resulted in a significant decrease in spleen weight and significant alterations in splenic functions, including the percentage of neutrophils, NK cells, macrophages, and CD8+ T cells. Furthermore, ABX treatment resulted in the depletion of a large portion of the gut microbiota. Untargeted metabolomics analysis showed that ABX treatment caused alterations in the levels of certain compounds in the plasma, spleen, and brain. Moreover, ABX treatment decreased the expression of microglia marker Iba1 in the cerebral cortex. Interestingly, correlations were found between the abundance of different microbiome components and metabolites in various tissues, as well as splenic cell populations and spleen weight. These findings suggest that ABX-induced microbiome depletion and altered metabolite levels may affect spleen and brain function through the gut-microbiota-spleen-brain axis.

The α7 subtype of the nicotinic acetylcholine receptor (α7 nAChR: coded by Chrna7) is known to regulate the cholinergic ascending anti-inflammatory pathway. We previously reported that Chrna7 knock-out (KO) mice show depression-like behaviors through abnormal composition of gut microbiota and systemic inflammation. Given the role of subdiaphragmatic vagus nerve in gut-microbiota-brain axis, we investigated whether subdiaphragmatic vagotomy (SDV) could affect depression-like behaviors, abnormal composition of gut microbiota, and microbes-derived metabolites in Chrna7 KO mice. SDV blocked depression-like behaviors and reduced expression of synaptic proteins in the medial prefrontal cortex (mPFC) of Chrna7 KO mice. LEfSe (linear discriminant analysis effect size) analysis revealed that the species Lactobacillus sp. BL302, the species Lactobacillus hominis, and the species Lactobacillus reuteri, were identified as potential microbial markers in the KO + SDV group. There were several genus and species altered among the three groups [wild-type (WT) + sham group, KO + sham group, KO + SDV group]. Furthermore, there were several plasma metabolites altered among the three groups. Moreover, there were correlations between relative abundance of several microbiome and behavioral data (or synaptic proteins). Network analysis showed correlations between relative abundance of several microbiome and plasma metabolites (or behavioral data). These data suggest that Chrna7 KO mice produce depression-like behaviors and reduced expression of synaptic proteins in the mPFC through gut-microbiota-brain axis via subdiaphragmatic vagus nerve.

Dichlorodiphenyltrichloroethane (DDT) is an organochlorine insecticide used worldwide. Several studies have reported the toxic effects of DDT and its metabolites on steroid hormone biosynthesis; however, its environmental effects are not well understood. This study examined wild rats collected in DDT-sprayed areas of South Africa and quantified plasma metabolites using liquid chromatography quadrupole time-of-flight mass spectrometry (LC-Q-TOF-MS). Fold change analysis of the metabolome revealed the effect of DDT on bile acid biosynthesis. Gene expression of the related enzyme in rat liver samples was also quantified. Significant association was found between DDT and gene expression levels related to constitutive androstane receptor mediated enzymes, such as Cyp2b1 in rat livers. However, our results could not fully demonstrate that enzymes related to bile acid biosynthesis were strongly affected by DDT. The correlation between DDT concentration and gene expression involved in steroid hormone synthesis in testis was also evaluated; however, no significant correlation was found. The disturbance of metabolic enzymes occurred in rat liver in the target area. Our results suggest that DDT exposure affects gene expression in wild rats living in DDT-sprayed areas. Therefore, there is a need for DDT toxicity evaluation in mammals living in DDT-sprayed areas. We could not find an effective biomarker that could reflect the mechanism of DDT exposure; however, this approach can provide new insights for future research to evaluate DDT effects in sprayed areas.

3,4-Methylenedioxymethamphetamine (MDMA), the most widely used illicit compound worldwide, is the most attractive therapeutic drug for post-traumatic stress disorder (PTSD). Recent observational studies of US adults demonstrated that lifetime MDMA use was associated with lower risk of depression. Here, we examined whether repeated administration of MDMA can affect resilience versus susceptibility in mice exposed to chronic social defeat stress (CSDS). CSDS produced splenomegaly, anhedonia-like phenotype, and higher plasma levels of interleukin-6 (IL-6) in the saline-treated mice. In contrast, CSDS did not cause these changes in the MDMA-treated mice. Analysis of gut microbiome found several microbes altered between saline + CSDS group and MDMA + CSDS group. Untargeted metabolomics analysis showed that plasma levels of N-epsilon-methyl-L-lysine in the saline + CSDS group were significantly higher than those in the control and MDMA + CSDS groups. Interestingly, there were positive correlations between plasma IL-6 levels and the abundance of several microbes (or plasma N-epsilon-methyl-L-lysine) in the three groups. Furthermore, there were also positive correlations between the abundance of several microbes and N-epsilon-methyl-L-lysine in the three groups. In conclusion, these data suggest that repeated administration of MDMA might contribute to stress resilience in mice subjected to CSDS through gut-microbiota-brain axis.

Multiple sclerosis (MS) is the most common demyelinating disease that attacks the central nervous system. Dietary intake of cuprizone (CPZ) produces demyelination resembling that of patients with MS. Given the role of the vagus nerve in gut-microbiota-brain axis in development of MS, we performed this study to investigate whether subdiaphragmatic vagotomy (SDV) affects demyelination in CPZ-treated mice. SDV significantly ameliorated demyelination and microglial activation in the brain compared with sham-operated CPZ-treated mice. Furthermore, 16S ribosomal RNA analysis revealed that SDV significantly improved the abnormal gut microbiota composition of CPZ-treated mice. An untargeted metabolomic analysis demonstrated that SDV significantly improved abnormal blood levels of metabolites in CPZ-treated mice compared with sham-operated CPZ-treated mice. Notably, there were correlations between demyelination or microglial activation in the brain and the relative abundance of several microbiome populations, suggesting a link between gut microbiota and the brain. There were also correlations between demyelination or microglial activation in the brain and blood levels of metabolites. Together, these data suggest that CPZ produces demyelination in the brain through the gut-microbiota-brain axis via the subdiaphragmatic vagus nerve.

OBJECTIVE: Excessive salt intake raises blood pressure and increases the risk of non-communicable diseases (NCDs), such as cardiovascular disease, chronic kidney disease, and stomach cancer. Reducing the sodium content of food is an important public health measure to control the NCDs. This study quantifies the amount of salt reduced by using umami substances, i.e., glutamate, inosinate, and guanylate, for adults in the United States (US). DESIGN: The secondary data analysis was performed using data of the US nationally representative cross-sectional dietary survey, the National Health and Nutrition Examination Survey (NHANES) 2017-2018. Per capita daily salt intake corresponding to the NHANES food groups was calculated in the four hypothetical scenarios of 0%, 30%, 60%, and 90% market share of low-sodium foods in the country. The salt reduction rates by using umami substances were estimated based on the previous study results. SETTING: The United States. PARTICIPANTS: 4,139 individuals aged 20 years and older in the US. RESULTS: Replacing salt with umami substances could help the US adults reduce salt intake by 7.31-13.53% (7.50-13.61% for women; 7.18-13.53% for men), which is equivalent to 0.61-1.13g/day (0.54-0.98g/day for women; 0.69-1.30g/day for men) without compromising the taste. Approximately, 21.21-26.04% of the US adults could keep their salt intake below 5 g/day, the World Health Organization's recommendation in the scenario where there is no low-sodium product on the market. CONCLUSIONS: This study provides essential information that the use of umami substances as a substitute for salt may help reduce the US adults' salt intake.

BACKGROUND: individual preventive behaviors are one of the key measures needed to prevent the spread of COVID-19. This study sought to identify the factors associated with the adoption of COVID-19 preventive measures, focusing specifically on information sources. METHODS: we conducted a nationally representative cross-sectional survey of 30,053 Japanese adults in February 2021. The survey asked about socioeconomic, health-related, and psychological characteristics, attitudes toward immunization, and the use of information sources regarding COVID-19. We have constructed multivariable logistic regression to estimate the factors associated with the adoption of three preventive measures: 3Cs avoidance, hand hygiene and respiratory hygiene. RESULTS: socioeconomic variables, psychological variables, and the use of information sources are significantly associated with the adoption of preventive measures. The more information sources one uses, the more likely one is to adopt preventive measures. Trust in healthcare professionals is positively associated with adopting preventive measures. On the other hand, negative correlations between trust in social media and preventive behaviors were observed. CONCLUSIONS: encouraging access to multiple information sources, utilizing communication channels, and modifying messaging according to target groups are essential to promote COVID-19 preventive measures.

The aetiology of building-related symptoms (BRSs) is not well supported by sufficient scientific evidence, and it remains unclear whether BRSs are mediated by psychosocial and personal factors or a genuine physical susceptibility to low-dose chemical exposure. In April 2014, a 40-year-old man consulted the Environmental Medical Clinic at Chiba University complaining of recurring BRSs. Indoor air samples were collected from the patient's house at 11 time points and subjected to chemical analyses. The patient simultaneously completed a questionnaire about his symptoms at the time of the measurements. Statistical examination of the indoor environmental factors and patient survey revealed that the patient's symptoms were highly correlated with the indoor air quality. Additionally, ventilation may have mitigated his BRSs, whereas aerial odour did not trigger symptoms. These findings suggest that exposure to specific airborne chemicals in an indoor environment can cause BRSs, and ventilation may be one of the treatment options to mitigate symptoms. Additional investigations on the adverse impacts of airborne environmental chemicals on human health are necessary to develop effective treatments and establish preventive measures for BRSs, and further improvement of ventilation systems is required to ensure clean indoor air.

BACKGROUND: The association between maternal antibiotic exposure during pregnancy and childhood obesity is still unclear. OBJECTIVES: The study aimed to evaluate the association between prenatal exposure to antibiotics and obesity at age 3 years using data from a large Japanese birth cohort. METHODS: The Japan Environment and Children's Study is a nationwide birth cohort study. In this study, singleton vaginal full-term births were included. Obesity was defined as body mass index ≥95th percentile according to child growth standards. Prenatal antibiotic exposure was defined as antimicrobial agent use during pregnancy and was collected from maternal interviews and medical record transcripts. Logistic regression analysis was performed to evaluate the association of prenatal antibiotic exposure with child obesity at 3 years. RESULTS: In the crude and adjusted models with all children, maternal antibiotic exposure during pregnancy showed a marginal relationship with child obesity at 3 years. In the analyses according to exposure period and sex, exposure to antibiotics during the second/third trimester was significantly associated with obesity at the age of 3 years in female infants, but not in male infants, although the exposure during the first trimester was not in both sexes. CONCLUSION: Maternal antibiotic exposure during mid/late pregnancy may result in child obesity.

AIMS: Acute lung injury (ALI) is an acute inflammatory disorder. However, the precise mechanisms underlying the pathology of ALI remain elusive. An increasing evidence suggests the role of the gut-microbiota axis in the pathology of lung injury. This study aimed to investigate whether antibiotic-induced microbiome depletion could affect ALI in mice after lipopolysaccharide (LPS) administration. MAIN METHODS: The effects of antibiotic cocktail (ABX) on ALI in the mice after intratracheally administration of LPS (5 mg/kg) were examined. Furthermore, 16s rRNA analysis and measurement of short-chain fatty acids in feces samples and metabolomics analysis of blood samples were performed. KEY FINDINGS: LPS significantly increased the interleukin-6 (IL-6) levels in the bronchoalveolar lavage fluid (BALF) of water-treated mice. Interestingly, an ABX significantly attenuated the LPS-induced increase in IL-6 in BALF and lung injury scores. Furthermore, ABX and/or LPS treatment markedly altered the α- and β-diversity of the gut microbiota. There were significant differences in the α- and β-diversity of the water + LPS group and ABX + LPS group. LEfSe analysis identified Enterococusfaecalis, Clostriumtertium, and Bacteroidescaecimyris as potential microbial markers for ABX + LPS group. Untargeted metabolomics analysis identified several plasma metabolites responsible for discriminating water + LPS group from ABX + LPS group. There were correlations between the relative abundance of the microbiome and plasma metabolites. Integrative network analysis showed correlations between IL-6 levels in BALF and several gut microbes (or plasma metabolites). SIGNIFICANCE: These data suggest that ABX-induced microbiome depletion could protect against LPS-induced ALI via the gut-microbiota-lung axis.

Increasing epidemiological evidence shows that the use of cannabis during adolescence could increase the risk for psychosis in adulthood. However, the precise mechanisms underlying long-lasting cannabis-induced risk for psychosis remain unclear. Accumulating evidence suggests the role of gut microbiota in the pathogenesis of psychiatric disorders. Here, we examined whether gut microbiota plays a role in the risk for psychosis of adult after exposure of cannabinoid (CB) receptor agonist WIN55,212-2 during adolescence. Repeated administration of WIN55,212-2 (2 mg/kg/day) during adolescence (P35-P45) significantly increased the expression of Iba1 (ionized calcium-binding adapter molecule 1) in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) of adult mice after administration of lipopolysaccharide (LPS: 0.5 mg/kg). In contrast, there were no changes in blood levels of pro-inflammatory cytokines between the two groups. Although alpha-diversity and beta-diversity of gut microbiota were no differences between the two groups, there were several microbes altered between the two groups. Interestingly, there were significant correlations between the relative abundance of microbiota and Iba1 expression in the mPFC and NAc. Furthermore, there were also significant correlations between the relative abundance of microbiota and several metabolites in the blood. These findings suggest that gut microbiota may play a role in the microglial activation in the mPFC and NAc of adult mice after repeated WIN55,212-2 exposure during adolescence. Therefore, it is likely that gut-microbiota-microglia crosstalk might play a role in increased risk for psychosis in adults with cannabis use during adolescence.

BACKGROUND: The Tokyo 2020 Summer Olympic Games (23 July-8 August 2021) were held in the middle of Japan's fifth wave of COVID-19, when the number of cases was on the rise, and coincided with the fourth state of emergency implemented by the host city, Tokyo. AIM: This study aimed to assess whether the hosting of the Games was associated with a change in the number of COVID-19 cases in Japan using a synthetic control method. METHODS: A weighted average of control countries with a variety of predictors was used to estimate the counterfactual trajectory of daily COVID-19 cases per 1 000 000 population in the absence of the Games in Japan. Outcome and predictor data were extracted using official and open sources spanning several countries. The predictors comprise the most recent country-level annual or daily data accessible during the Games, including the stringency of the government's COVID-19 response, testing capacity and vaccination capacity; human mobility index; electoral democracy index and demographic, socioeconomic, health and weather information. After excluding countries with missing data, 42 countries were ultimately used as control countries. RESULTS: The number of observed cases per 1 000 000 population on the last day of the Games was 109.2 (7-day average), which was 115.7% higher than the counterfactual trajectory comprising 51.0 confirmed cases per 1 000 000 population. During the Olympic period (since 23 July), the observed cumulative number of cases was 61.0% higher than the counterfactual trajectory, comprising 143 072 and 89 210 confirmed cases (p=0.023), respectively. The counterfactual trajectory lagged 10 days behind the observed trends. CONCLUSIONS: Given the increasing likelihood that new emerging infectious diseases will be reported in the future, we believe that the results of this study should serve as a sentinel warning for upcoming mega-events during COVID-19 and future pandemics.

INTRODUCTION: During the COVID-19 pandemic, the incidence of many droplet-transmitted infections decreased due to increased mask-wearing and social distancing. Contrastingly, there has been concern that COVID-19 countermeasures, such as lockdowns, may increase legionellosis incidence via water stagnation. During the pandemic in Japan, four state of emergency declarations were imposed between 2020-2021, which makes it particularly suitable to test this hypothesis. METHODS: We use country-level surveillance data from the National Institute of Infectious Diseases to track the relative incidence of legionellosis compared to invasive pneumococcal disease (IPD) during the COVID-19 pandemic in Japan, with a focus on the periods just after state of emergency declarations were lifted. RESULTS: The absolute number of legionellosis and IPD cases decreased in 2020 and 2021 compared to previous years. The average relative incidence of legionellosis as well as the variance of the relative incidence significantly increased during the pandemic compared to previous years. There were no increases in the relative incidence of legionellosis during the periods immediately following emergency declaration liftings, but the relative incidence did increase considerably during the first two states of emergency. CONCLUSIONS: COVID-19 countermeasures appear more effective at decreasing the incidence of human-to-human transmitted infections, such as IPD, compared to environmentally-transmitted infections, such as legionellosis. Though no evidence was found to suggest that legionellosis cases increased after state of emergency declarations, public health efforts should continue to emphasize the importance of routine sanitation and water system maintenance to prevent water stagnation and Legionellaspp. contamination.

Imiquimod (IMQ) is widely used as animal model of psoriasis, a chronic inflammatory skin disorder. Although topical application of IMQ to back skin causes splenomegaly in mice, how the spleen affects the psoriasis-like phenotype of IMQ-treated mice remains unclear. In this study, we analyzed the cellular composition of spleen and measured metabolites in blood of IMQ-treated mice. We also investigated whether splenectomy influences the degree of skin inflammation and pathology in IMQ-treated mice. Flow cytometry showed that the numbers of CD11b+Ly6c+ neutrophils, Ter119+ proerythroblasts, B220+ B cells, F4/80+ macrophages, and CD11c+ dendritic cells in the spleen were significantly higher in IMQ-treated mice compared to control mice. An untargeted metabolomics analysis of blood identified 14 metabolites, including taurine and 2,6-dihydroxybenzoic acid, whose levels distinguished the two groups. The composition of cells in the spleen and blood metabolites positively correlated with the weight of the spleen. However, splenectomy did not affect IMQ-induced psoriasis-like phenotypes compared with sham-operated mice, although splenectomy increased the expression of interleukin-17A mRNA in the skin of IMQ-treated mice. These data suggest that the spleen does not play a direct role in the development of psoriasis-like phenotype on skin of IMQ-treated mice, though IMQ causes splenomegaly.

Excess deaths, including all-causes mortality, were confirmed for the first time in Japan in April 2021. However, little is known about the indirect effects of COVID-19 on the number of non-COVID-19-related deaths. We then estimated the excess deaths from non-COVID-19-related causes in Japan and its 47 prefectures from January 2020 through May 2021 by place of death. Vital statistical data on deaths were obtained from the Ministry of Health, Labour and Welfare. Using quasi-Poisson regression models, we estimated the expected weekly number of deaths due to all-causes excluding COVID-19 (non-COVID-19) and due to respiratory disease, circulatory disease, malignant neoplasms, and senility. Estimates were made separately for deaths in all locations, as well as for deaths in hospitals and clinics, in nursing homes and elderly care facilities, and at home. We defined a week with excess deaths as one in which the observed number of deaths exceeded the upper bound of the two-sided 95% prediction interval. Excess death was expressed as a range of differences between the observed and expected number of deaths and the 95% upper bound of the two-sided predictive interval. The excess percentage was calculated as the number of excess deaths divided by the expected number of deaths. At the national level, excess deaths from non-COVID-19-related all-causes were observed during April 19 to May 16, 2021. The largest excess percentage was 2.73-8.58% (excess deaths 689-2161) in the week of May 3-9. Similar trends were observed for all four cause categories. The cause-of-death categories which contributed to the excesses showed heterogeneity among prefectures. When stratified by place of death, excess mortality tended to be observed in nursing homes and elderly care facilities for all categories, in hospitals and clinics for circulatory disease, and at home for respiratory disease, malignant neoplasms, and senility. A caution is necessary that for the lastest three months (March-May 2021), adjusted data were used to account for possible reporting delays.

Environmental exposure to persistent organic pollutants during pregnancy has potential adverse health effects on the fetus. One of the environmental pollutants is polychlorinated biphenyl (PCB). Earlier, we reported the presence of PCBs in fetal tissues such as the umbilical cord. Telomere length (TL) is a biomarker of aging because it shortens with each cell division. According to the Developmental Origins of Health and Disease hypothesis, fetal exposure to environmental pollutants during pregnancy affects the occurrence of non-communicable diseases in later life. In the current study, we investigated the association between cord tissue TL and serum levels of PCBs. The subjects were 114 mother-child pairs participating in a birth cohort study, the Chiba Study of Mother and Child Health (C-MACH). Maternal serum was collected during pregnancy, and cord serum and tissue were obtained at birth. TL was assessed by qPCR using genomic DNA extracted from the cord tissue. Maternal and cord serum PCB congener levels were assessed using gas chromatography and negative ion chemical ionization qMS. In male fetuses, serum levels of PCB74 in the cord blood were significantly associated with TL following covariate adjustment, but no significant association was found in female fetuses. These data suggest that the TL of the umbilical cord is affected by fetal exposure to PCBs.

Depression is a high risk for osteoporosis, suggesting an association between depression and low bone mineral density (BMD). We reported that the novel antidepressant (R)-ketamine could ameliorate the reduced BMD in the ovariectomized (OVX) mice which is an animal model of postmenopausal osteoporosis. Given the role of gut microbiota in depression and bone homeostasis, we examined whether gut microbiota plays a role in the beneficial effects of (R)-ketamine in the reduced BMD of OVX mice. OVX or sham was operated for female mice. Subsequently, saline (10 ml/kg/day, twice weekly) or (R)-ketamine (10 mg/kg/day, twice weekly) was administered intraperitoneally into OVX or sham mice for the six weeks. The reduction of cortical BMD and total BMD in the OVX mice was significantly ameliorated after subsequent repeated intermittent administration of (R)-ketamine. Furthermore, there were significant changes in the α- and β-diversity between OVX + saline group and OVX + (R)-ketamine group. There were correlations between several OTUs and cortical (or total) BMD. There were also positive correlations between the genera Turicibacter and cortical (or total) BMD. Moreover, there were correlations between several metabolites in blood and cortical (or total) BMD. These data suggest that (R)-ketamine may ameliorate the reduced cortical BMD and total BMD in OVX mice through anti-inflammatory actions via gut microbiota. Therefore, it is likely that (R)-ketamine would be a therapeutic drug for depressed patients with low BMD or patients with osteoporosis.

The COVID-19 pandemic has disrupted health care access around the world, both for inpatients and outpatients. We applied a quasi-Poisson regression to national, monthly data on the number of outpatients, number of inpatients, length of average hospital stay, and the number of new hospitalizations from March 2015 to October 2021 to assess how these outcomes changed between June 2020 to October 2021. The number of outpatient visits were lower-than-predicted during the early phases of the pandemic but normalized by the fall of 2021. The number of inpatients and new hospitalizations were lower-than-predicted throughout the pandemic, and deficits in reporting continued to be observed in late 2021. The length of hospital stays was within the predicted range for all beds, but when stratified by bed type, was higher than predicted for psychiatric beds, lower-than-predicted for tuberculosis beds, and showed variable changes in long-term care insurance beds. Health care access in Japan was impacted by the COVID-19 pandemic.

BACKGROUND: Growth restriction in the prenatal period is a significant public health concern. Metals can negatively affect birth size, and pregnant women may be exposed to metal mixtures. Comprehensive studies analyzing the effects of combined metal exposure with accurate individual blood metal concentrations are limited. The current study investigated the associations between maternal metal exposure and birth size in a large, nationwide Japanese cohort using individual and mixed model approaches. METHODS: Lead, cadmium, mercury, selenium, and manganese blood concentrations were measured in pregnant women in the Japan Environment and Children's Study (JECS). Measurements of infant birth size-including body weight, body length, and head and chest circumference-were collected. Linear and logistic regressions were used for birth size measurements and the odds of an infant being small in size for gestational age, respectively. Associations between combined metal mixtures and measurements at birth were evaluated using quantile g-computation and Bayesian kernel machine regression (BKMR). RESULTS: Of the 103,060 JECS pregnancies, 93,739 mother-infant pairs were analyzed. The linear regression models showed that lead, selenium, cadmium, and manganese-but not mercury-were associated with body weight. Cadmium was associated with length and chest circumference and mercury was associated with head circumference. Quantile g-computation revealed that manganese increased infant birth weight, length, head circumference, and chest circumference. Lead was the strongest negative factor for infant birth weight, length, head circumference, and chest circumference. The BKMR analysis revealed that the metals had an additive, rather than a synergistic effect. CONCLUSION: Metal exposure is associated with infant birth size, with lead and manganese playing a more significant role in Japan. The effects of prenatal combined metal exposure at low levels warrant public health attention.

Background: Research characterizing changes of heart with respect to vaccine intention is scarce, and very little research considers those who were initially vaccine willing but became hesitant. Here, we sought to assess the factors related to reversals of vaccine willingness. Methods: We conducted a longitudinal, national survey on vaccination intention among Japanese adults aged 20 years or older, with the first questionnaire performed in February-March 2021 (N = 30,053) and the follow-up in February 2022 (N = 19,195, response rate 63.9%). The study population comprised those who reported vaccine willingness in the first survey, with the outcome variable being development of vaccine hesitancy at follow-up. We performed a regression analysis of vaccination status using sociodemographic, health-related, psychologic/attitudinal, and information-related variables as predictors. We used the sparse group minimax concave penalty (MCP) to select the optimum group of covariates for the logistic regression. Findings: Of 11,118 (57.9%) respondents who previously expressed interest in vaccination, 10,684 (96.1%) and 434 (3.9%) were in the vaccine willing and hesitant groups, respectively. Several covariates were found to significantly predict vaccine hesitancy, including marital status, influenza vaccine history, COVID-19 infection/testing history, engagement in COVID-19 preventive measures, perceived risks/benefits of the COVID-19 vaccine, and attitudes regarding vaccination policies and norms. The use of certain information sources was also associated with vaccine hesitancy. Interpretation: Sociodemographic, health-related, psychologic/attitudinal, and information-related variables predicted the development of vaccine hesitancy among those with prior willingness. Most of these predictors were also associated with vaccination status. Funding: The present work was supported in part by a grant from the Kanagawa Prefectural Government of Japan and by AIST government subsidies.

Background: Vaccine hesitancy is a global public health threat. We present unique data that characterises those who experienced reversals of COVID-19 vaccination hesitancy in Japan. Methods: We administered a questionnaire on vaccination intention among 30053 Japanese adults aged 20 years or older before the COVID-19 vaccination was available to the general population (first survey) and conducted a follow-up survey on vaccination status one year later in February 2022 (second survey). Those who responded in the first survey that they did not intend to be vaccinated or were unsure and then responded in the second survey that they were vaccinated or intend to be vaccinated were asked about the reasons for their change of heart. Based on previous literature and expert opinion, 31 reasons for changing vaccination intention were compiled and respondents were asked to choose which among them applied to themselves, with multiple responses possible. Based on the results of those responses, each individual was then clustered using the Uniform Manifold Approximation and Projection (UMAP) dimensionality reduction technique and Ordering Points To Identify the Clustering Structure (OPTICS) algorithm. We then identified unique characteristics among each of the sub-populations (clusters). Findings: In the second survey we received 19195 responses (response rate 63.9%), of which 8077 responded 'no' or 'not sure' in the first survey regarding their intention to be vaccinated. Of these, 5861 responded having received or intending to receive the vaccine (72.6%). We detected six and five sub-populations (clusters) among the 'no' group and 'not sure' group, respectively. The clusters were characterized by perceived benefits of vaccination, including the COVID-19 vaccine, awareness of the COVID-19 vaccination status of those close to them, recognition of the social significance of COVID-19 vaccination for the spread of infection, and dispelled concerns about short-term adverse reactions and the safety of the COVID-19 vaccine. Work and personal relationship reasons were also found to be a unique overarching reason for vaccination changes of heart only among those who did not intend to vaccinate. Interpretation: Those who changed their intention to accept COVID-19 vaccination as well as their unique characteristics as detailed in this study will be important entry points when discussing how to promote vaccination to those who are hesitant to vaccinate in the future. Funding: The present work was supported in part by a grant from the Kanagawa Prefectural Government of Japan and by AIST government subsidies.

Companion animals are in close contact with the human surroundings, and there is growing concern about the effects of harmful substances on the health of pet cats. In this study, we investigated the potential health effects of organohalogen compounds (OHCs) on thyroid hormone (TH) homeostasis and metabolomics in Japanese pet cats. There was a significant negative correlation between concentrations of several contaminants, such as polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), hydroxylated PCBs (OH-PCBs), hydroxylated PBDEs (OH-PBDEs), and THs in cat serum samples. These results suggested that exposure to OHCs causes a decrease in serum TH levels in pet cats. In this metabolomics study, each exposure level of parent compounds (PCBs and PBDEs) and their hydroxylated compounds (OH-PCBs and OH-PBDEs) were associated with their own unique primary metabolic pathways, suggesting that parent and phenolic compounds exhibit different mechanisms of action and biological effects. PCBs were associated with many metabolic pathways, including glutathione and purine metabolism, and the effects were replicated in in-vivo cat PCB administration studies. These results demonstrated that OHC exposure causes chronic oxidative stress in pet cats. PBDEs were positively associated with alanine, aspartate, and glutamate metabolism. Due to the chronic exposure of cats to mixtures of these contaminants, the combination of their respective metabolic pathways may have a synergistic effect.