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Abstract 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.

Background: A key measure of the effectiveness of end-of-life care is the place of death. The coronavirus disease 2019 (COVID-19) pandemic affected end-of-life care and the circumstances of patients with dementia. Methods: This observational, retrospective cohort study used Japanese national data to examine the numbers and locations of reported deaths among patients with dementia older than 65 years during the COVID-19 pandemic. Locations were grouped as medical institutions, nursing facilities, homes, or all settings. The quasi-Poisson regression model known as the Farrington algorithm was employed. Results: Between December 30, 2019, and January 29, 2023, 279,703 patients who died of causes related to dementia were reported in Japan. A decline was seen in early 2020, followed by increased numbers of deaths in homes, medical facilities, and nursing homes beginning in October 2020, December 2020, and March 2021, respectively. In 2021, the percentage of excess deaths at home peaked at 35.2%, while in 2022, those in medical facilities and nursing homes peaked at 18.8% and 16.6%, respectively. In 2022, the percentage of excess deaths in nursing homes exceeded that of other locations. Conclusion: The results suggest a change in the preferred place of death, along with pandemic-related visitation restrictions among healthcare facilities. Excess deaths also suggest strained medical resources and limited access to care. Methodological limitations include data from a limited period (2017 onwards) and post-2020 data used to estimate data after 2021, albeit with weighting. Considering these findings, physicians should reconfirm preferred places of death among older patients with dementia.

Background: The novel coronavirus disease 2019 (COVID-19) pandemic has significantly impacted end-of-life decisions for cancer patients in Japan, with disparities existing between preferred and actual care settings. Our study investigates the potential shifts in cancer death locations during the pandemic and if there were excess cancer deaths. Methods: Utilizing national mortality data from the Ministry of Health, Labour and Welfare from January 2012 to February 2023, we identified cancer deaths using International Classification of Disease, 10th revision codes. We assessed death locations, including medical institutions, nursing facilities, and homes. The Farrington algorithm was employed to estimate expected death counts, and the differences between observed and expected counts were denoted as excess deaths. Results: From January 2018 to February 2023, there was consistently increase in the weekly observed cancer deaths. The presence of a definitive excess during the pandemic period remains uncertain. The percentage of deaths in medical institutions declined from 83.3% to 70.1%, while home deaths increased from 12.1% to 22.9%. Between April 2020 and February 2023, deaths in medical institutions frequently fell below the 95% prediction lower limit. Home deaths consistently exceeded the 95% prediction upper limit, with significant excess deaths reported annually. Conclusion: Our study found a shift in cancer death locations from medical institutions to homes in Japan during the COVID-19 pandemic. Our study did not confirm an overall increase in cancer deaths during this period. As with global trends, the profound shift from hospitals to homes in Japan calls for a comprehensive exploration to grasp the pandemic’s multifaceted impact on end-of-life cancer care decisions.

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.

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.

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.

Depression frequently occurs in patients with liver cirrhosis, yet the reasons for this correlation are not fully understood. Dysbiosis of gut microbiota has been implicated in depression through the gut–brain axis via the vagus nerve. This study explored the potential role of the gut–liver–brain axis via the vagus nerve in depression-like phenotypes in mice with liver cirrhosis. These mice underwent common bile duct ligation (CBDL), a method used to stimulate liver cirrhosis. To assess depression-like behaviors, behavioral tests were conducted 10 days following either sham or CBDL surgeries. The mice with CBDL displayed symptoms such as splenomegaly, elevated plasma levels of interleukin-6 and tumor necrosis factor-α, depression-like behaviors, decreased levels of synaptic proteins in the prefrontal cortex (PFC), disrupted gut microbiota balance, and changes in blood metabolites (or lipids). Additionally, there were positive or negative correlations between the relative abundance of microbiome and behavioral data or blood metabolites (or lipids). Significantly, these changes were reversed in CBDL mice by performing a subdiaphragmatic vagotomy. Intriguingly, depression-like phenotypes in mice with CBDL were improved after a single injection of arketamine, a new antidepressant. These results suggest that CBDL-induced depression-like phenotypes in mice are mediated through the gut–liver–brain axis via the subdiaphragmatic vagus nerve, and that arketamine might offer a new treatment approach for depression in liver cirrhosis patients.

Abstract 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.

Background: Plastic additives have adverse effects on human health. Children frequently use toys that contain various substances found in paints, plasticizers, and other materials, which heighten the risk of specific chemical exposure. Infants are particularly prone to chemical exposure through the “mouthing” behavior because of the possibility of placing toys in their mouths. Thus, this vulnerability should be considered during risk assessments of chemical exposure. Methods: This study performed a comprehensive analysis of the chemical components in various 84 plastic toys including “designated toys” (toys that may be harmful to infant health if in contact with their mouths: Article 78 of the Enforcement Regulations of the Food Sanitation Law by the Minister of Health, Labor and Welfare) such as dolls, balls, blocks, bathing toys, toy vehicles, pacifiers, and household items, purchased in the Japanese market by nontargeted and targeted analysis. Results: Plasticizers, flame retardants, and fragrances were the main compounds in almost all the toy products. The results showed that plastic products made in China tended to contain high levels of phthalate esters. In particular, hazardous plasticizers, such as diisodecyl, di-n-octyl, and diisononyl phthalates were detected above the regulatory limit (0.1%) in used products manufactured before regulations were passed in Japan. Furthermore, we detected alternative plasticizers, such as acetyl tributyl citrate (ATBC; 52%), diisononyl adipate (DINA; 50%), and di(2-ethylhexyl) terephthalate (DEHT; 40%). ATBC was detected at high concentrations in numerous toy products. Thus, infants with free access to indoor plastic toys might be exposed to these chemicals. Conclusions: This study observed that the chemical profiles of toy products were dependent on the year of manufacture. Furthermore, the detection of currently regulated plasticizers in secondhand products manufactured before regulations were enforced, along with the increasing trend of using alternative substances to regulated phthalate esters in products, suggests the potential exposure of infants to these plasticizers through the use of toys. Therefore, regular fact-finding surveys should continue to be conducted for the risk assessment and safety management of domestic toy products.

BackgroundGlobally, women experience healthcare inequalities, which may contribute to excessive mortality rates at various stages of their lives. Though Bangladesh has achieved excellent progress in providing healthcare, the country still has some critical challenges that need immediate attention. The objective of this study is to examine the association between social determinants and barriers to accessing healthcare among ever-married women aged 15-49 in Bangladesh.MethodsThe study was conducted among 20,127 women aged 15-49, using data from the 2017-2018 Bangladesh Demographic and Health Survey. Four barriers to healthcare were considered: whether women face problems with permission, obtaining money, distance, and companionship. The multivariable logistic regression analysis was used, with a broad array of independent variables (such as age, and educational level) to identify the determinants of barriers to healthcare access. The associations were expressed as adjusted odds ratios (AOR) with a 95% confidence interval (CI).ResultsMore than two-thirds (66.3%) of women reported having at least one perceived barrier to accessing healthcare. Women with a higher level of education (AOR = 0.49, 95% CI: 0.41-0.57), owning a mobile telephone (AOR = 0.78, 95% CI: 0.73-0.84), and those in the richest wealth quintile (AOR = 0.45, 95% CI: 0.38-0.52) had lower odds of having barriers to accessing healthcare. In addition, widowed (AOR = 1.53, 95% CI: 1.26-1.84), divorced (AOR = 1.91, 95% CI:1.47-2.48), or separated (AOR = 1.98, 95% CI: 1.46-2.69) women had higher odds of having a money barrier to accessing healthcare, than married women.ConclusionsThis study shows that individual-, household-, and community-level factors are associated with barriers to healthcare accessibility. To improve the state of women's health in Bangladesh, it is vital to consider these socio-economic factors and implement fundamental measures, such as supporting the national health policy, empowering women's socio-economic situation, and spreading the flexible way of healthcare access.

3,4-Methylenedioxymethamphetamine (MDMA) is the most widely used illicit substance worldwide. Nevertheless, recent observational studies demonstrated that lifetime MDMA use among U.S. adults was associated with a lower risk of depression and suicide thoughts. We recently reported that the gut–brain axis may contribute to MDMA-induced stress resilience in mice. To further explore this, we investigated the effects of subdiaphragmatic vagotomy (SDV) in modulating the stress resilience effects of MDMA in mice subjected to chronic restrain stress (CRS). Pretreatment with MDMA (10 mg/kg/day for 14 days) blocked anhedonia-like behavior and reduced expression of synaptic proteins and brain-derived neurotrophic factor in the prefrontal cortex (PFC) of CRS-exposed mice. Interestingly, SDV blocked the beneficial effects of MDMA on these alterations in CRS-exposed mice. Analysis of gut microbiome revealed alterations in four measures of α-diversity between the sham + MDMA + CRS group and the SDV + MDMA + CRS group. Moreover, specific microbes differed between the vehicle + CRS group and the MDMA + CRS group, and further differences in microbial composition were observed among all four groups. Untargeted metabolomics analysis showed that SDV prevented the increase in plasma levels of three compounds [lactic acid, 1-(2-hydroxyethyl)-2,2,6-tetramethyl-4-piperidinol, 8-acetyl-7-hydroxyvumaline] observed in the sham + MDMA + CRS group. Interestingly, positive correlations were found between the plasma levels of two of these compounds and the abundance of several microbes across all groups. In conclusion, our data suggest that the gut–brain axis via the subdiaphragmatic vagus nerve might contribute to the stress resilience of MDMA.

This study explored the factors associated with healthcare avoidance behavior for menstrual disorders and menopausal symptoms among women in Japan. Using data from a nationally representative cross-sectional online survey conducted in September 2022, responses from 4,950 women aged 25–59 were analyzed. This study applied binomial logistic regression models specifically to participants who reported having ever felt the need to seek healthcare assistance due to health issues related to menstruation and menopause. We computed adjusted odds ratios for key sociodemographic traits, work environment factors, health literacy, menstrual and menopausal symptoms, and attitudes and understanding regarding women’s health, associated with healthcare avoidance behavior in the past 12 months. As a sensitivity analysis, a regression was performed limited to those who are working. The results showed that 50.6% of respondents recognized the need for healthcare support for menstrual or menopausal health issues, but 22.8% exhibited healthcare avoidance in the past year. Younger and high-income individuals showed higher avoidance rates. Those with diagnosed gynecological conditions and those perceiving menstrual pain as something to endure also displayed increased avoidance tendencies. Women experiencing significant health effects beyond work and those lacking understanding of the purpose of health check-ups were more prone to healthcare avoidance. Our results underscore the importance of implementing strategically tailored health education initiatives, and re-examining societal attitudes concerning women's health, in order to cultivate enhanced healthcare-seeking behaviors among women.

BackgroundSelf-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. ObjectiveOur 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. MethodsWe 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. ResultsData 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. ConclusionsThis 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.

Abstract Objective: Excessive salt intake raises blood pressure and increases the risk of non-communicable diseases (NCD), such as CVD, chronic kidney disease and stomach cancer. Reducing the Na content of food is an important public health measure to control the NCD. This study quantifies the amount of salt reduced by using umami substances, i.e. glutamate, inosinate and guanylate, for adults in the USA. 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-Na foods in the country. The salt reduction rates by using umami substances were estimated based on the previous study results. Setting: The USA Participants: 4139 individuals aged 20 years and older in the USA 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 and 7·18–13·53 % for men), which is equivalent to 0·61–1·13 g/d (0·54–0·98 g/d for women and 0·69–1·30 g/d for men) without compromising the taste. Approximately, 21·21–26·04 % of the US adults could keep their salt intake below 5 g/d, the WHO’s recommendation in the scenario where there is no low-Na 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: Increases in human mobility have been linked to rises in novel coronavirus disease 2019 (COVID-19) transmission. The pandemic era in Japan has been characterized by changes in inter-prefectural mobility across state of emergency (SOE) declarations and travel campaigns, but they have yet to be characterized. Methods: Using Yahoo Japan mobility data extracted from the smartphones of more than 10 million Japanese residents, we calculated the monthly number of inter-prefectural travel instances, stratified by residential prefecture and destination prefecture. We then used this adjacency matrix to calculate two network connectedness metrics, closeness centrality and effective distance, that reliably predict disease transmission. Results: Inter-prefectural mobility and network connectedness decreased most considerably during the first SOE, but this decrease dampened with each successive SOE. Mobility and network connectedness increased during the Go To Travel campaign. Travel volume between distant prefectures decreased more than travel between prefectures with geographic proximity. Closeness centrality was found to be negatively correlated with the rate of COVID-19 infection across prefectures, with the strength of this association increasing in tandem with the infection rate. Changes in effective distance were more visible among geographically isolated prefectures (Hokkaido and Okinawa) than among metropolitan, central prefectures (Tokyo, Aichi, Osaka, and Fukuoka). Conclusion: The magnitude of reductions in human mobility decreased with each subsequent state of emergency, consistent with pandemic fatigue. The association between network connectedness and rates of COVID-19 infection remained visible throughout the entirety of the pandemic period, suggesting that inter-prefectural mobility may have contributed to disease spread.

Per- and poly-fluoroalkyl substances (PFAS) exhibit high persistence in the environment and accumulate within the human body, warranting a thorough assessment of their toxicity. In this study, we exposed mice (male C57BL/6J mice aged 8 weeks) to a composite of nine PFAS, encompassing both long-chain PFAS (e.g., perfluorooctanoic acid and perfluorooctanesulfonic acid) and short-chain PFAS (e.g., perfluorobutanoic acid and perfluorobutanesulfonic acid). The exposure concentrations of PFAS were equivalent to the estimated daily human intake in the composition reported (1 µg/L (sum of the nine compounds), representing the maximum reported exposure concentration). Histological examination revealed hepatocyte vacuolization and irregular hepatocyte cord arrangement, indicating 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, with the annotation of substances such as glutathione and 5-aminovaleric acid. 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.

Abstract 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.

Abstract Background Interrupted time series (ITS) analysis has become a popular design to evaluate the effects of health interventions. However, the most common formulation for ITS, the linear segmented regression, is not always adequate, especially when the timing of the intervention is unclear. In this study, we propose a new model to overcome this limitation. Methods We propose a new ITS model, ARIMAITS-DL, that combines (1) the Autoregressive Integrated Moving Average (ARIMA) model and (2) distributed lag functional terms. The ARIMA technique allows us to model autocorrelation, which is frequently observed in time series data, and the decaying cumulative effect of the intervention. By contrast, the distributed lag functional terms represent the idea that the intervention effect does not start at a fixed time point but is distributed over a certain interval (thus, the intervention timing seems unclear). We discuss how to select the distribution of the effect, the model construction process, diagnosing the model fitting, and interpreting the results. Further, our model is implemented as an example of a statement of emergency (SoE) during the coronavirus disease 2019 pandemic in Japan. Results We illustrate the ARIMAITS-DL model with some practical distributed lag terms to examine the effect of the SoE on human mobility in Japan. We confirm that the SoE was successful in reducing the movement of people (15.0–16.0% reduction in Tokyo), at least between February 20 and May 19, 2020. We also provide the R code for other researchers to easily replicate our method. Conclusions Our model, ARIMAITS-DL, is a useful tool as it can account for the unclear intervention timing and distributed lag effect with autocorrelation and allows for flexible modeling of different types of impacts such as uniformly or normally distributed impact over time.

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.

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.

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.

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.

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.

Understanding COVID-19 risk perception may help inform public health messaging aimed at encouraging preventive measures and improving countermeasures against the pandemic. We conducted an online survey of 29,708 Japanese adults in February 2021 and estimated the associations between COVID-19 risk perception and a broad array of individual factors. Two logistic regressions were constructed to estimate factors associated with the risk perception of COVID-19 (defined as responding that one might become infected within the next 6 months), and of severe illness among those who responded that they might become infected (defined as responding that one would become severely ill). After adjusting for covariates, those with a higher perceived risk of the COVID-19 vaccine had higher odds of risk perception for both infection and severe illness. Interestingly, those with higher odds of risk perception of being infected were more likely to report obtaining their information from healthcare workers whereas those with lower odds were more likely to report obtaining their information from the Internet or the government; those with lower odds of risk perception of being severely ill were more likely to report obtaining their information from the Internet. The higher the trust level in the government as a COVID-19 information source, the lower the odds of both risk perception of being infected and becoming severely ill. The higher the trust levels in social networking services as a COVID-19 information source, the higher the odds of risk perception of becoming severely ill. Public health messaging should address the factors identified in our study.

Immigrants in Japan face multiple health care challenges. There is limited research addressing how all-cause mortality differs between foreign residents and Japanese citizens, including the impact of the COVID-19 pandemic. We assessed whether all-cause mortality rates between Japanese citizens and foreign residents living in Japan differ, and whether these differentials changed after the start of the COVID-19 pandemic. We conducted a cross-sectional analysis using vital statistical data of all deaths among citizens and foreign residents that occurred within Japanese borders aggregated every 6 months between January 1, 2015 and June 30, 2021. Data were used to calculate sex-, region-, and 20-year age group-specific standardized mortality rates using the direct method based on the population distribution of Japanese citizens in 2021 by sex, region, and 20-year age groups. Chi-squared tests and linear regression were used to assess whether the pandemic was associated with changes in mortality rates among groups and changes in the mortality differentials between citizens and non-citizens, respectively. All-cause mortality increased monotonically with age for men and women. Men had higher mortality than women, regardless of age or nationality. All-cause mortality is lower among immigrants than Japanese citizens between the ages of 20–59, but higher under the age of 20 and over the age of 59. The pandemic was associated with significant changes in mortality in most groups, but no statistically significant changes in the mortality differentials between immigrants and Japanese citizens were detected. Young immigrants are generally healthier than their Japanese counterparts, in line with the healthy migrant hypothesis. Younger migrants are at higher risk of mortality, possibly due to increased vulnerability to psychologic stress. Older migrant mortality converged with citizen mortality, consistent with acculturation that occurs with longer duration of residence. The pandemic did not exacerbate health inequities for foreign residents with respect to mortality.

To provide insight into the mortality burden of coronavirus disease (COVID-19) in Japan, we estimated the excess all-cause deaths for each week during the pandemic, January–May 2020, by prefecture and age group. We applied quasi-Poisson regression models to vital statistics data. Excess deaths were expressed as the range of differences between the observed and expected number of all-cause deaths and the 95% upper bound of the 1-sided prediction interval. A total of 208–4,322 all-cause excess deaths at the national level indicated a 0.03%–0.72% excess in the observed number of deaths. Prefecture and age structure consistency between the reported COVID-19 deaths and our estimates was weak, suggesting the need to use cause-specific analyses to distinguish between direct and indirect consequences of COVID-19.

Abstract Background In Japan, the latest estimates of excess all-cause deaths through January to July 2020 showed that the overall (direct and indirect) mortality burden from the Coronavirus Disease 2019 (COVID-19) in Japan was relatively low compared to Europe and the United States. However, consistency between the reported number of COVID-19 deaths and excess all-cause deaths was limited across prefectures, suggesting the necessity of distinguishing the direct and indirect consequences of COVID-19 by cause-specific analysis. To examine whether deaths from road injuries decreased during the COVID-19 pandemic in Japan, consistent with a possible reduction of road transport activity connected to Japan’s state of emergency declaration, we estimated the exiguous deaths from road injuries in each week from January to September 2020 by 47 prefectures. Methods To estimate the expected weekly number of deaths from road injuries, a quasi-Poisson regression was applied to daily traffic fatalities data obtained from Traffic Accident Research and Data Analysis, Japan. We set two thresholds, point estimate and lower bound of the two-sided 95% prediction interval, for exiguous deaths, and report the range of differences between the observed number of deaths and each of these thresholds as exiguous deaths. Results Since January 2020, in a few weeks the observed deaths from road injuries fell below the 95% lower bound, such as April 6–12 (exiguous deaths 5–21, percent deficit 2.82–38.14), May 4–10 (8–23, 21.05–43.01), July 20–26 (12–29, 30.77–51.53), and August 3–9 (3–20, 7.32–34.41). However, those less than the 95% lower bound were also observed in weeks in the previous years. Conclusions The number of road traffic fatalities during the COVID-19 pandemic in Japan has decreased slightly, but not significantly, in several weeks compared with the average year. This suggests that the relatively small changes in excess all-cause mortality observed in Japan during the COVID-19 pandemic could not be explained simply by an offsetting reduction in traffic deaths. Considering a variety of other indirect effects, evaluating an independent, unbiased measure of COVID-19-related mortality burden could provide insight into the design of future broad-based infectious disease counter-measures and offer lessons to other countries.

Background: Manganese (Mn) is an essential trace metal and a neurotoxicant. Adverse effects of Mn exposure on the neurodevelopment of children have been reported. However, there is limited information on the effects of maternal exposure during pregnancy. Objectives: We aimed to investigate the association between maternal and cord blood Mn levels and neurodevelopment in children aged between 6 months and 3 years using data from a Japanese nationwide birth cohort study. Methods: We used the data of 63,767 mother–child pairs with maternal blood Mn measurements recorded during the second and third trimester and of 3,787 mother–child pairs with cord blood Mn measurements. Neurodevelopment was assessed using the Japanese version of the Ages and Stages Questionnaires, third edition (J-ASQ-3), which was completed by parents or guardians at 6 months, 1 year, 1.5 years, 2 years, 2.5 years, and 3 years of age. Results: The median maternal and cord blood Mn levels were 15.2 and 44.5 ng/g, respectively. After adjusting for covariates, both maternal and cord blood Mn levels were negatively associated with J-ASQ-3 scores. Maternal blood Mn levels were negatively associated with gross motor function scores at all ages except for that at 1.5 years (adjusted β: −0.55 to −1.23 for a two-fold increase in maternal Mn levels). The risk of developmental delay (score below the cut-off) in gross motor function increased at the same time points (adjusted odds ratio: 1.08 to 1.13). In the subgroup, cord blood Mn levels were negatively associated with gross motor function scores at 1, 2, and 2.5 years (adjusted β: −1.84 to −3.27). Discussion: Maternal blood Mn levels during pregnancy and cord blood Mn levels were negatively associated with neurodevelopment in children up to 3 years of age. Excessive maternal and fetal exposure to Mn may have adverse effects on neuromotor function in children.

Background: The World Health Organization declared the novel coronavirus outbreak (COVID-19) to be a pandemic on March 11, 2020. Large-scale monitoring for capturing the current epidemiological situation of COVID-19 in Japan would improve preparation for and prevention of a massive outbreak. Methods: A chatbot-based healthcare system named COOPERA (COvid-19: Operation for Personalized Empowerment to Render smart prevention And care seeking) was developed using the LINE app to evaluate the current Japanese epidemiological situation. LINE users could participate in the system either though a QR code page in the prefectures’ websites or a banner at the top of the LINE app screen. COOPERA asked participants questions regarding personal information, preventive actions, and non-specific symptoms related to COVID-19 and their duration. We calculated daily cross correlation functions between the reported number of infected cases confirmed using polymerase chain reaction and the symptom-positive group captured by COOPERA. Results: We analyzed 206,218 participants from three prefectures reported between March 5 and 30, 2020. The mean age of participants was 44.2 (standard deviation, 13.2) years. No symptoms were reported by 96.93% of participants, but there was a significantly positive correlation between the reported number of COVID-19 cases and self-reported fevers, suggesting that massive monitoring of fever might help to estimate the scale of the COVID-19 epidemic in real time. Conclusions: COOPERA is the first real-time system being used to monitor trends in COVID-19 in Japan and provides useful insights to assist political decisions to tackle the epidemic.

Abstract Aims/Introduction Gut microbiota have various effects on human health. Some previous reports have shown that gut microbiota change during pregnancy and affect metabolism, but others have shown that microbiota do not change. Here, we examined the gut microbiota and glycoalbumin levels of 45 healthy Japanese women during pregnancy. Materials and Methods We carried out 16S rRNA gene sequencing analyses of maternal stool samples and compared the gut microbiota composition of samples from women in early and late pregnancy. We also examined the association between gut microbiota and maternal characteristics, including glycoalbumin. Results Microbiota composition in early and late pregnancy did not differ, according to principal coordinate analysis of weighted and unweighted UniFrac distances. Shannon indices were not different between early and late pregnancy. The proportion of one phylum, TM7, significantly decreased in late pregnancy compared with early pregnancy, but the proportions of other major phyla did not change. The Shannon index of late pregnancy was negatively associated with pregestational body mass index and positively correlated with glycoalbumin level, with adjustment of covariates. Conclusions We concluded that Japanese women did not show obvious differences in gut microbiota during pregnancy, except for TM7, and that the diversity of gut microbiota might affect maternal metabolism. As this study had limited statistical power, further large‐scale studies are required.

Abstract Purpose This study aimed to investigate neurodevelopment in children conceived via in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) with several types of embryo transfers. Methods We analyzed data for 77 928 children and their mothers included in a Japanese birth cohort study. Among the included children, 4071 were conceived via IVF, while 1542 were conceived via ICSI. Neurodevelopmental delay at the age of 3 years was assessed using the Japanese version of the Ages and Stages Questionnaires, 3rd edition. Results In the crude model, the odds ratios for developmental delay in 1–4 domains were higher among children conceived via IVF, ICSI, and non‐ART (ovulatory induction or intrauterine insemination) than in spontaneously conceived children. After adjusting for parental background factors and the child's sex, there were no differences in the risk of developmental delay when comparing singletons conceived by IVF, ICSI, or non‐ART and those conceived spontaneously. Higher odds ratios for developmental delay in one domain were observed in singleton girls conceived via IVF when compared with those who were spontaneously conceived. Conclusion Most cases of developmental delay may be associated with multiple pregnancies and factors related to infertility, such as parental age, irrespective of the use of ART.

Summary: Background: Optimizing media campaigns for those who were unsure or unwilling to take coronavirus disease (COVID-19) vaccines is required urgently to effectively present public health messages aimed at increasing vaccination coverage. We propose a novel framework for selecting tailor-made media channels and their combinations for this task. Methods: An online survey was conducted in Japan during February to March, 2021, with 30,053 participants. In addition to their sociodemographic characteristics, it asked the attitude toward vaccination and information sources (i.e., media channels) for COVID-19 issues. Multinomial logic regression was fitted to estimate the combinations of the media channels and their odds ratio (OR) associated with vaccination attitudes. Findings: The proportion of respondents who were unsure or unwilling to take the vaccination was skewed toward younger generation: 58.1% were aged under 35, while 28.1% were 65 years or older. Media channels such as “Non-medical and Non-TV” and “Non-medical and Non-government” were associated with the unsure group: OR (95% Confidence intervals, (CI)) = 1.75 (1.62, 1.89) and 1.53 (1.44, 1.62), respectively. In addition, media channels such as “Newspapers or the Novel Coronavirus Expert Meeting”, “Medical or Local government”, and “Non-TV” were associated with the unwilling group: OR (95% CI) were 2.00 (1.47, 2.75), 3.13 (2.58, 3.81), and 2.25 (1.84, 2.77), respectively. Interpretation: To effectively approach COVID-19 vaccine unsure and unwilling groups, generation-specific online and offline media campaigns should be optimized to the type of vaccine attitude. Funding: Funded by the Ministry of Health, Labour and Welfare of Japan (H29-Gantaisaku-ippan-009) and the Japan Agency for Medical Research and Development (AMED) (JP20fk0108535).

Summary: Background: Identifying and understanding reasons for being unsure or unwilling regarding intention to be vaccinated against coronavirus disease (COVID-19) may help to inform future public health messages aimed at increasing vaccination coverage. We analyzed a broad array of individual's psychological dispositions with regard to decision-making about COVID-19 vaccination in Japan. Methods: A nationally representative cross-sectional web survey was conducted with 30053 Japanese adults aged 20 years or older at the end of February 2021. In addition to the question on the individual's intention to be vaccinated against COVID-19, respondents were asked about their sociodemographic, health-related, and psychological characteristics as well as information sources about COVID-19 and their levels of trust. Also, those who responded ‘not sure’ or ‘no’ regarding intention to take COVID-19 vaccine were asked why. Multinomial logistic regression with sparse group Lasso (Least Absolute Shrinkage and Selection Operator) penalty was used to compute adjusted odds ratios for factors associated with the intention (not sure/no versus yes). Findings: The percentages of respondents who answered ‘not sure’ or ‘no’ regarding intention to be vaccinated against COVID-19 vaccine were 32.9% and 11.0%, respectively. After adjusting for covariates, the perceived risks of COVID-19, perceived risk of a COVID-19 vaccine, perceived benefits of a COVID-19 vaccine, trust in scientists and public authorities, and the belief that healthcare workers should be vaccinated were significantly associated with vaccination intention. Several sources of information about COVID-19 were also significantly associated with vaccination intention, including physicians, nurses, and television, medical information sites with lower odds of being unsure or unwilling, and internet news sites, YouTube, family members, and scientists and researchers with higher odds. The higher the level of trust in television as a source of COVID-19 information, the higher the odds of responding ‘not sure’ (odds ratio 1.11, 95% confidence interval 1.01–1.21). We also demonstrated that many respondents presented concerns about the side effects and safety of a COVID-19 vaccine as a major reason for being unsure or unwilling. To decide whether or not to get the vaccine, many respondents requested more information about the compatibilities between the vaccine and their personal health conditions, whether other people had been vaccinated, the effectiveness of vaccines against variants, and doctors’ recommendations. Interpretation: Our findings suggest that public health messaging based on the sociodemographic and psychological characteristics of those who are unsure or unwilling regarding intention to be vaccinated against COVID-19 vaccine may help to increase vaccine uptake amongst this population. Funding: The present work was supported in part by a grant from the Ministry of Health, Labour and Welfare of Japan (H29-Gantaisaku-ippan-009).

Abstract Aims/Introduction We aimed to explore novel predictive markers for gestational diabetes mellitus using metabolomic analysis in pregnant Japanese women. Materials and Methods We carried out a case–control study with a cohort of participants enrolled during the first or early second trimester in the Center of Chiba Unit of the Japan Environment and Children's Study. Participants were classified as either gestational diabetes mellitus cases or matched controls based on age, body mass index and parity. Metabolite levels of their serum and urine obtained randomly before the diagnosis of gestational diabetes mellitus were analyzed using hydrophilic interaction chromatography tandem mass spectrometry. Orthogonal projections to latent structures discriminant analysis was carried out to investigate metabolome profiles for the different groups. Metabolites with a variable importance in projection value of >1.5 were identified as potential markers. Results In total, 242 participants were enrolled in the study, of which 121 were cases. The R2X, R2Y and Q2 parameters for the discrimination ability of the resulting models were 0.388, 0.492 and 0.45 for serum, and 0.454, 0.674 and 0.483 for urine, respectively. We finally identified three metabolites in serum and 20 in urine as potential biomarkers. Glutamine in serum and ethanolamine and 1,3‐diphosphoglycerate in urine showed >0.8 area under the receiver operating characteristic curves. Conclusions The present study identified serum and urine metabolites that are possible predictive markers of subsequent gestational diabetes mellitus in Japanese women. Further studies are required to elucidate their efficacy.

Objective On 7 April 2020, the Japanese government declared a state of emergency in response to the novel coronavirus outbreak. To estimate the impact of the declaration on regional cities with low numbers of COVID-19 cases, large-scale surveillance to capture the current epidemiological situation of COVID-19 was urgently conducted in this study.Design Cohort study.Setting Social networking service (SNS)-based online survey conducted in five prefectures of Japan: Tottori, Kagawa, Shimane, Tokushima and Okayama.Participants 127 121 participants from the five prefectures surveyed between 24 March and 5 May 2020.Interventions An SNS-based healthcare system named COOPERA (COvid-19: Operation for Personalized Empowerment to Render smart prevention And care seeking) was launched. It asks questions regarding postcode, personal information, preventive actions, and current and past symptoms related to COVID-19.Primary and secondary outcome measures Empirical Bayes estimates of age-sex-standardised incidence rate (EBSIR) of symptoms and the spatial correlation between the number of those who reported having symptoms and the number of COVID-19 cases were examined to identify the geographical distribution of symptoms in the five prefectures.Results 97.8% of participants had no subjective symptoms. We identified several geographical clusters of fever with significant spatial correlation (r=0.67) with the number of confirmed COVID-19 cases, especially in the urban centres of prefectural capital cities.Conclusions Given that there are still several high-risk areas measured by EBSIR, careful discussion on which areas should be reopened at the end of the state of emergency is urgently required using real-time SNS system to monitor the nationwide epidemic.

Background: On April 7, 2020, the Japanese government declared a state of emergency regarding the novel coronavirus (COVID-19). Given the nation-wide spread of the coronavirus in major Japanese cities and the rapid increase in the number of cases with untraceable infection routes, large-scale monitoring for capturing the current epidemiological situation of COVID-19 in Japan is urgently required. Methods: A chatbot-based healthcare system named COOPERA (COvid-19: Operation for Personalized Empowerment to Render smart prevention And AN care seeking) was developed to surveil the Japanese epidemiological situation in real-time. COOPERA asked questions regarding personal information, location, preventive actions, COVID-19 related symptoms and their residence. Empirical Bayes estimates of the age-sex-standardized incidence rate and disease mapping approach using scan statistics were utilized to identify the geographical distribution of the symptoms in Tokyo and their spatial correlation r with the identified COVID-19 cases. Findings: We analyzed 353,010 participants from Tokyo recruited from 27th March to 6th April 2020. The mean (SD) age of participants was 42.7 (12.3), and 63.4%, 36.4% or 0.2% were female, male, or others, respectively. 95.6% of participants had no subjective symptoms. We identified several geographical clusters with high spatial correlation (r = 0.9), especially in downtown areas in central Tokyo such as Shibuya and Shinjuku. Interpretation: With the global spread of COVID-19, medical resources are being depleted. A new system to monitor the epidemiological situation, COOPERA, can provide insights to assist political decision to tackle the epidemic. In addition, given that Japan has not had a strong lockdown policy to weaken the spread of the infection, our result would be useful for preparing for the second wave in other countries during the next flu season without a strong lockdown. Funding: The present work was supported in part by a grant from the Ministry of Health, Labour and Welfare of Japan (H29-Gantaisaku-ippan-009).

Background: In the absence of widespread testing, symptomatic monitoring efforts may allow for understanding the epidemiological situation of the spread of coronavirus disease 2019 (COVID-19) in Japan. We obtained data from a social networking service (SNS) messaging application that monitors self-reported COVID-19 related symptoms in real time in Fukuoka Prefecture, Japan. We aimed at not only understanding the epidemiological situation of COVID-19 in the prefecture, but also highlighting the usefulness of symptomatic monitoring approaches that rely on self-reporting using SNS during a pandemic, and informing the assessment of Japan's emergency declaration over COVID-19. Methods: We analysed symptoms data (fever over 37.5° and a strong feeling of weariness or shortness of breath), reported voluntarily via SNS chatbot by 227,898 residents of Fukuoka Prefecture during March 27 to May 3, 2020, including April 7, when a state of emergency was declared. We estimated the spatial correlation coefficient between the number of the self-reported cases of COVID-19 related symptoms and the number of PCR confirmed COVID-19 cases in the period (obtained from the prefecture website); and estimated the empirical Bayes age- and sex-standardised incidence ratio (EBSIR) of the symptoms in the period, compared before and after the declaration. The number of symptom cases was weighted by age and sex to reflect the regional population distribution according to the 2015 national census. Findings: Of the participants, 3.47% reported symptoms. There was a strong spatial correlation of 0.847 (p

Polychlorinated biphenyls (PCBs) have been associated with adverse human reproductive and fetal developmental measures or outcomes because of their endocrine-disrupting effects; however, the biological mechanisms of adverse effects of PCB exposure in humans are not currently well established. In this study, we aimed to identify the biological pathways and potential biomarkers of PCB exposure in maternal and umbilical cord serum using a hydrophilic interaction chromatography-tandem mass spectrometry (HILIC-MS/MS) metabolomics platform. The median concentration of total PCBs in maternal (n = 93) and cord serum (n = 93) were 350 and 70 pg g−1 wet wt, respectively. PCB levels in maternal and fetal serum from the Chiba Study of Mother and Children's Health (C-MACH) cohort are comparable to those of earlier cohort studies conducted in Japan, the USA, and European countries.We used the random forest model with the metabolome profile to predict exposure levels of PCB (first quartile [Q1] and fourth quartile [Q4]) for pregnant women and fetuses. In the prediction model for classification of Q1 versus Q4 (area-under-curve [AUC]: pregnant women = 0.812 and fetuses = 0.919), citraconic acid level in maternal serum and ethanolamine, p-hydroxybenzoate, and purine levels in cord serum had >0.70 AUC values. These candidate biomarkers and metabolite included in composited models were related to glutathione and amino acid metabolism in maternal serum and the amino acid metabolism and ubiquinone and other terpenoid-quinone biosynthesis in cord serum (FDR

The DOHaD (developmental origins of health and disease) hypothesis claims that fetal malnutrition or exposure to environmental pollutants may affect their lifelong health. Epigenetic changes may play significant roles in DOHaD; however, access to human fetuses for research has ethical and technical hurdles. Umbilical cord blood (CB) has been commonly used as an epigenetic surrogate of fetuses, but it does not provide direct evidence of fetal exposure to pollutants. Here, we propose umbilical cord tissue (UC), which accumulates substances delivered to fetuses during gestation, as an alternative surrogate for epigenetic studies on fetuses. To explore the feasibility to examine UC epigenome by deep sequencing, we determined CpG methylation profiles of human postnatal UC by reduced representation bisulfite sequencing. Principal component analysis clearly separated the DNA methylomes of UC and CB pairs isolated from the same newborn (n = 10). Although all UC chromosomes were modestly hypomethylated compared to CB chromosomes, GO analysis revealed strong enrichment of differentially methylated regions (DMRs) at promoter-associated CpG islands in the HOX gene clusters and other genes encoding transcription factors involved in determination of the body pattern. DNA methylomes of UC autosomes were largely comparable between males and females. Deficiency of folate during pregnancy has been suggested to affect fetal DNA methylation to cause congenital anomalies. Whereas DNA methylome of UC was not significantly affected by early-gestational (12 weeks) low levels of maternal plasma folate (< 8 ng/ml, n = 10) compared to controls (>19 ng/mL, n = 10), two specific loci of LTR12C endogenous retroviruses in chromosome 12 were significantly hypermethylated in the low-folate group. Our study suggests that UC is useful as an alternative surrogate for studying environmental effects on DNA methylation in human fetuses, compensating CB by providing additional information about epigenetic regulation of genes involved in developmental body patterning and endogenous retroviruses.