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The aging of concrete structures has become a serious problem in Japan, and periodic maintenance is essential for preventing accidents caused by structural aging. In this study, a method for estimating defects in concrete using data from hammering tests on a concrete plate using machine learning was developed. A neural network based on self-attention (SAN) to estimate the three-dimensional position and size of the defects was constructed. Moreover, a dataset was created from the topology of the internal defects and the acceleration response waveform when a concrete plate was struck. The entire plate was represented as a non-dimensional density matrix. The SAN used scalograms of the acceleration responses as the input. Furthermore, two types of data augmentation ('Flip' and 'Rotate') were proposed. The use of both data augmentation techniques achieved the highest accuracy. By setting an appropriate number of rotations, the model was able to estimate all defects in the dataset. [ABSTRACT FROM AUTHOR]

To determine whether maximum bite force ( MBF), an objective measure of oral function, is associated with development of frailty in community-dwelling older adults. This prospective cohort study included community-dwelling Japanese adults aged 75 years at baseline (n = 322). Baseline MBF was measured using an electronic recording device (Occlusal Force-Meter GM10). Follow-up examinations, including physical fitness and anthropometric evaluation and structured questionnaires, were administered annually over a 5-year period to determine the incidence of frailty, which was defined by the presence of 3 or more of the following 5 components derived from the Cardiovascular Health Study: low level of mobility, low physical activity level, weakness, shrinking and poor endurance and energy. Adjusted hazard ratios ( HRs) of incidence of frailty according to sex-stratified tertiles of baseline MBF were calculated using Cox proportional hazards regression models. During the follow-up, 49 participants (15.2%) developed frailty. Participants in the lower tertile of MBF exhibited a significantly greater risk of frailty than those in the upper tertile. After adjustment for sex, depression, diabetes and Eichner index, the adjusted HRs for frailty in the upper through lower tertiles of MBF were 1.00 (reference), 1.27 (95% confidence interval [ CI]: 0.50-3.20) and 2.78 (95% CI: 1.15-6.72), respectively ( P for trend = .01). Poor oral function, as indicated by low MBF, increases the risk of development of frailty among elderly men and women. [ABSTRACT FROM AUTHOR]

Japan Atomic Energy Agency (JAEA) started sub- and full-scale trials to qualify and optimize manufacturing procedure of ITER TF coil from March 2009 under the contract with Toshiba. As major outcome of these trials, feasibility of high accuracy of winding, prediction of the conductor elongation due to heat treatment and radial plate manufacture is confirmed. Therefore, JAEA can mostly establish manufacturing plan for the TF coil and then, start the first TF coil procurement from 2013, following to full demonstration through manufacturing a dummy double-pancake in 2012. [ABSTRACT FROM PUBLISHER]

Background: Hepatectomy with extensive lymph node dissection is the standard operation for intrahepatic cholangiocarcinoma (IHCC). However, lymph node dissection may not always be effective at reducing tumour recurrence. Methods: Forty-nine patients with IHCC who underwent hepatectomy were investigated to determine patterns of tumour recurrence and to estimate the value of lymph node dissection during resection. Results: At hepatectomy most metastatic lymph nodes were identified at least to the level of group 2 lymph nodes. Among 23 patients who developed recurrence, 17 had liver metastases and the other six had recurrence at other sites, mainly in the peritoneum. Poorly differentiated histology was related to the development of liver metastases. No patient with the intraductal growth type of IHCC had tumour recurrence. Lymph node dissection did not appear to improve patient survival. Histological findings of lymph node metastases and intrahepatic metastases were independent indicators of poor prognosis. Conclusion: Lymph node metastases were seldom limited to the regional lymph nodes; most tumour recurrence occurred in the liver. Lymph node dissection did not appear to improve patient survival. Lymph node dissection alone is not likely to improve the prognosis without further control of liver metastases. [ABSTRACT FROM AUTHOR]

Summary 1. Time-series data from a twice-replicated population experiment (consisting of a seed beetle (host), Callosobruchus chinensis, and two parasitoids, Anisopteromalus calandrae and Heterospilus prosopidis) were studied in order to identify and to estimate the density-dependent structure. 2. A non-parametric host–parasitoid model based on the Nicholson–Bailey model, was studied through non-parametric autoregressive modelling. An additive non-linear structure was found in the population growth/parasitism rates for all three species. 3. The analysis suggests that the abundance of A. calandrae only weakly affects its own parasitism rate as well as H. prosopidis parasitism rate. 4. The analysis also suggests that the net population growth rate of C. chinensis is highly non-linear, which may be due to disproportionately higher egg mortality at high adult densities. 5. Non-linearity was also demonstrated in the parasitism rate of H. prosopidis, which is consistent with assuming that the density-dependent mutual interference becomes disproportionately higher at high H. prosopidis adult densities. [ABSTRACT FROM AUTHOR]

The Global Rain Forest Mapping (GRFM) project is an international endeavour led by the National Space Development Agency of Japan (NASDA), with the aim of producing spatially and temporally contiguous Synthetic Aperture Radar (SAR) data sets over the tropical belt on the Earth by use of the JERS-1 L-band SAR, through the generation of semi-continental, 100 m resolution, image mosaics. The GRFM project relies on extensive collaboration with the National Aeronautics and Space Administration (NASA), the Joint Research Centre of the European Commission (JRC) and the Japanese Ministry of International Trade and Industry (MITI) for data acquisition, processing, validation and product generation. A science programme is underway in parallel with product generation. This involves the agencies mentioned above, as well as a large number of international organizations, universities and individuals to perform field activities and data analysis at different levels. The GRFM project was initiated in 1995 and, through a dedicated data acquisition policy by NASDA, data acquisitions could be completed within a 1.5-year period, resulting in a spatially and temporally homogeneous coverage to encompass the entire Amazon Basin from the Atlantic to the Pacific; Central America up to the Yucatan Peninsular in Mexico; equatorial Africa from Madagascar and Kenya in the east to Sierra Leone in the west; and south-east Asia, including Papua New Guinea and northern Australia. Over the Amazon and Congo river basins, the project aimed to provide complete cover at two different seasons, featuring the basins at high and low water. In total, the GRFM acquisitions comprise some 13000 SAR scenes, which are currently in the course of being processed and compiled into image mosaics. In March 1999, SAR mosaics over the Amazon Basin (one out of two seasonal coverages) and equatorial Africa (both seasonal coverages) were completed; the data are available on CD-ROM and, at a coarser resolution, via the Internet. Coverage of the second-season Amazon and Central America will be completed during 1999, with the south-east Asian data sets following thereafter. All data are being provided free of charge to the international science community for research and educational purposes. [ABSTRACT FROM AUTHOR]

Background Previous studies have developed risk stratification schemas to assess chemotherapy toxicity. However, the geriatric assessment variables that should be used to assess the individual risk of severe chemotherapy toxicity and clinical outcomes in elderly patients remain controversial. Methods Patients aged ≥70 years with advanced non-small cell lung cancer (NSCLC) who were treated at 24 National Hospital Organization institutions and completed a pre- first-line chemotherapy assessment were included in this study. The assessment included the following: patient characteristics, treatment variables (platinum doublet: PD, single agent: SA, tyrosine kinase inhibitor: TKI), laboratory test values, and geriatric assessment variables. We analyzed the correlations between each factor and clinical outcomes of chemotherapy and overall survival (OS). Results In total, 348 patients with advanced NSCLC, with a median age of 76 years (range, 70 to 95 years), joined this prospective study. In all patients, the best objective response rate and disease control rate were 35.6% and 81.0%, respectively. The median progression-free survival (PFS) and OS were 6.1 and 16.5 months, respectively. Performance status, treatment variables, and several laboratory test results (anemia, albumin, and C-reactive protein) affected the best response of chemotherapy (p = 0.0249, <0.001, <0.001, <0.001, and <0.001 respectively, between disease control and progressive disease cohorts). These factors also affected the PFS of first-line therapy (5.8 (PD) vs 3.5 (SA) vs 10.5 (TKI), and 2.9 vs 6.4, 2.9 vs 6.3, 3.0 vs 6.5, 3.0 vs 7.0 months respectively, between above or below each cutoff cohort) and OS (13.7 (PD) vs 10.4 (SA) vs 30.6 (TKI), and 7.0 vs 16.8, 6.3 vs 16.8, 6.6 vs 17.8, 6.2 vs 18.1 months, between above or below each cutoff cohort). Conclusions Performance status, treatment variables, and several laboratory test values independently predicted clinical outcomes of chemotherapy in elderly patients with advanced NSCLC. Clinical trial identification UMIN000010384. Legal entity responsible for the study National Hospital Organization. Funding National Hospital Organization. Disclosure All authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background Previous reports suggested that development of an immune-related adverse event (irAE), including thyroid disorder (TD), is associated with better outcomes of immune checkpoint inhibitor (ICI) therapy. Though TD has been reported most frequently as an irAE, it has not been well analyzed compared to life-threatening adverse events such as interstitial lung disease or colitis. Methods We conducted a chart-based retrospective analysis of patients (Pts) with advanced or recurrent non-small cell lung cancer (NSCLC), who are treated with monotherapy using nivolumab, pembrolizumab, or atezolizumab between January 2016 and June 2019 in two facilities in Japan. TD emerging after the first treatment with an ICI was considered as an irAE. Tumor response was evaluated with Response Evaluation Criteria in Solid Tumors version 1.1. Progression-free survival (PFS) and overall survival (OS) on ICIs were evaluated with Kaplan-Meier method. The correlations between time to onset of TD and PFS or OS were analyzed with Spearman's rank correlation coefficient. Results In total, 164 consecutive Pts were enrolled. The median age was 68 (range: 34-84) years, and 40 (24.4%) were women. TD of any grade occurred in 26 Pts (15.8%); 11/15/0/0/0 cases were classified as Grade 1/2/3/4/5, respectively, according to Common Terminology Criteria for Adverse Events version 5.0. Onset of TD ranged from 6 to 455 (median: 77.5) days after the first treatment with an ICI. Objective response rates in Pts with and without TD were 28.0% and 18.1%; disease control rates were 68.0% and 50.7%, respectively. Median PFS and OS were significantly longer in Pts with TD (PFS: 226 vs 100 days, p = 0.029; OS: not reached vs 434 days, p = 0.050, log-rank test). Among TD Pts, however, a positive correlation between time to onset of TD and PFS was identified (p = 0.0015). Significantly shorter PFS was observed in Pts with earlier TD onset, especially within 30 days, compared to Pts with later TD onset (median PFS: 72.5 vs 329 days, p = 0.00096, log-rank test). Conclusions Development of TD caused by ICIs was associated with longer PFS. Nevertheless, the prognosis of Pts with early onset of TD was poor. This study suggested that physicians should consider the onset of TD in Pts using ICIs. Legal entity responsible for the study Hiroyuki Yamaguchi. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background and Aims: Previous genome-wide association studies (GWAS) have indicated the involvement of shared (population-nonspecific) and nonshared (population-specific) susceptibility genes in the pathogenesis of primary biliary cholangitis (PBC) among European and East-Asian populations. Although a meta-analysis of these distinct populations has recently identified more than 20 novel PBC susceptibility loci, analyses of population-specific genetic architecture are still needed for a more comprehensive search for genetic factors in PBC., Approach and Results: Protein tyrosine phosphatase nonreceptor type 2 ( PTPN2) was identified as a novel PBC susceptibility gene locus through GWAS and subsequent genome-wide meta-analysis involving 2181 cases and 2699 controls from the Japanese population (GWAS-lead variant: rs8098858, p = 2.6 × 10 -8 ). In silico and in vitro functional analyses indicated that the risk allele of rs2292758, which is a primary functional variant, decreases PTPN2 expression by disrupting Sp1 binding to the PTPN2 promoter in T follicular helper cells and plasmacytoid dendritic cells. Infiltration of PTPN2-positive T-cells and plasmacytoid dendritic cells was confirmed in the portal area of the PBC liver by immunohistochemistry. Furthermore, transcriptomic analysis of PBC-liver samples indicated the presence of a compromised negative feedback loop in vivo between PTPN2 and IFNG in patients carrying the risk allele of rs2292758., Conclusions: PTPN2 , a novel susceptibility gene for PBC in the Japanese population, may be involved in the pathogenesis of PBC through an insufficient negative feedback loop caused by the risk allele of rs2292758 in IFN-γ signaling. This suggests that PTPN2 could be a potential molecular target for PBC treatment., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Previous studies have emphasized the necessity of surveillance and control measures for hepatitis E virus (HEV) infection in wild boars, an important reservoir of HEV. To assess the current situation of HEV infection in wild boars in Japan, this study investigated the prevalence and genetic diversity of HEV among wild boars captured in 16 prefectures of Japan during 2018-2023. Serum samples from 968 wild boars were examined for anti-HEV IgG antibodies and HEV RNA. The prevalence of anti-HEV IgG varied geographically from 0 % to 35.0 %. HEV RNA was detected in 3.6 % of boars, with prevalence varying by prefecture from 0 % to 22.2 %. Genotype 3 was the most prevalent genotype (91.9 %), followed by genotype 4 (5.4 %), with one strain closely related to genotype 6. The prevalence of HEV infection among wild boars decreased from 2018/2019 to 2022/2023 with significant declines in levels of anti-HEV IgG antibodies (14.5 % vs. 6.2 %, P < 0.0001) and HEV RNA (7.6 % vs. 1.5 %, P < 0.0001). Regional analysis showed varying trends, with no HEV RNA-positive boars found in several regions in recent years. A plausible factor contributing to the decline in HEV infection is the application of countermeasures, including installing fences to prevent intrusion into pig farms, implemented in response to the emergence of classical swine fever virus (CSFV) infection in wild boars and domestic pigs, with incidents reported annually since 2018. Further investigation is warranted to explore the association between countermeasures to CSFV infection and the decrease in HEV infection among wild boars., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: The association between pet exposure in infancy, early childhood eczema, and FLG mutations remains unclear., Methods: This was a birth cohort study performed in Tokyo, Japan. The primary outcome was current eczema based on questionnaire responses collected repeatedly from birth to 5 years of age. Generalized estimating equations and generalized linear modeling were used to evaluate the association., Results: Data from 1448 participants were used for analyses. Household dog ownership during gestation, early infancy, and 18 months of age significantly reduced the risk of current eczema. Household cat ownership also reduced the risk of current eczema, albeit without statistical significance. The combined evaluation of children from households with pets, be it cats, dogs or both, the risk of current eczema at 1-5 years of age was lower in those with household pet exposure ownership during gestation (RR = 0.59, 95 % CI 0.45-0.77) and at 6 months (RR = 0.49, 95 % CI 0.36-0.68). , Reduced risks of eczema were also observed at 2-5 (RR = 0.52, 95 % CI 0.37-0.73) and 3-5 years of age (RR = 0.50 95 % CI 0.35-0.74) when the respective household pet ownership were evaluated at 18 months and 3 years of age. These protective associations of reduced risk of eczema were only observed in children without FLG mutations., Conclusions: Household dog and pet (dog, cat, or both) ownership was protective against early childhood eczema in a birth cohort dataset. This protective association was observed only in children without FLG mutations, which should be confirmed in studies with larger cohorts., (Copyright © 2024 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Since 2022, fertility treatments have been partially covered by insurance in Japan. Women who wish to become pregnant may explore various means of conception as fertility treatments have shown low success rates. Therefore, we aimed to clarify the state of knowledge, behavior, and attitudes toward health foods among women who are actively trying to become pregnant., Methods: A web-based research company surveyed the eating attitudes and behaviors towards healthy foods of 900 women seeking to become pregnant. Regression analysis for the total amount spent on pregnancy was conducted, with "amount spent on actions undertaken to conceive" as the dependent variable. Multiple regression analysis on actions undertaken to conceive was performed using age, family income, body mass index, duration of hospital visits, duration of actions undertaken to conceive, cumulative amount incurred to conceive, awareness of dietary guidelines, adherence to dietary practices, number of types of health foods and supplements, whether participants considered consumption of nutritious foods and supplements to be important, and cumulative amount spent on healthy foods and supplements. The effect size for the Chi-square test was determined with Cramer's coefficient of association., Results: Increasing age was associated with a longer time to conceive, longer hospital visits, higher conception costs (including fertility treatment), and a higher intake of healthy food products. The number of healthy food types had the greatest impact on the cost incurred to conceive. Folic acid was the most commonly consumed healthy food, followed by iron and calcium., Conclusions: This study clarified the real-world situation regarding healthy foods for women seeking pregnancy in Japan. The information necessary for pregnant women to select safe healthy foods was clarified, which may lead to the establishment of risk-communication measures to ensure safety., Competing Interests: Declaration of competing interest Wada Y, Shimpo M, and Shimada M declare no conflicts of interest associated with this study. Kamioka H has supervised the systematic reviews of five corporations (FANCL CORPORATION; Morishita Jintan Co., Ltd.; KAGOME Co., Ltd.; MARUZEN PHARMACEUTICAL CO., LTD.; and SUNTORY WELLNESS LIMITED)., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Environmental phenols are widely distributed in the environment and human samples, suggesting potential exposure to these chemicals. We designed an intervention trial with 30 participants over 6 days to assess the urinary concentrations and half-lives of environmental phenols in Japanese young people. The target environmental phenols include three parabens (methyl paraben, ethyl paraben, and propyl paraben), two benzophenones (benzophenone 1 and 3), two bisphenols (bisphenol F and bisphenol S), and triclosan. Throughout the intervention, the participants consumed the same food and drinks and used personal care products provided by the project. The target phenols were measured in urine from the participants using a liquid chromatography-tandem mass spectrometer. We compared the measured concentrations between the study periods to better understand the exposure tendency. Some statistically significant differences were observed. All target analytes were detected in more than 50% of samples collected on Day 0 (the day before the intervention). Methyl paraben was the dominant phenol detected in urine (1640 μg/g-creatinine), followed by ethyl paraben (119 μg/g-creatinine). Downward trends in creatinine-corrected concentrations were observed for all target analytes in some instances. Non-compartment analysis was performed to estimate urinary excretion parameters. The estimated half-lives ranged from 7.69 to 20.3 h. Use of paraben-free products during the intervention period reduced the body burden., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Tomohiko Isobe reports financial support was provided by Environmental Restoration and Conservation Agency. Tomohiko Isobe reports financial support was provided by Japan Society for the Promotion of Science., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: The developing brains are sensitive to methylmercury (MeHg). However, the exposure to MeHg in baby foods and toddler meals remains unknown. This study aimed to determine MeHg intake from baby food or toddler meals, and to investigate the relationship with child hair total mercury (THg)., Methods: A total of 3 days of 24-hour dietary diet and hair samples were collected from 260 consenting children aged 0-5 years. We measured the concentrations of THg and MeHg in the diet and THg in the hair., Results: The results of measuring THg were below both the method detection and method quantification limits or either of both in powdered milk (93.8%), 5-6 months (53.3%), and 7-8 months (39.5%). The median daily THg intake was 20.3 (95% confidence interval 0.72-232.5) ng/kgbw. MeHg was not detected in 213 samples with dietary THg concentrations below 1 ng/g. The MeHg concentration with THg concentrations of 1 ng/g or higher was 1.70 (0.87-6.21) ng/g, and MeHg percentage in THg was 90.0%. To estimate MeHg intake, we multiplied the THg concentration by 90.0%, resulting in an estimated MeHg intake of 18.3 (0.65-209.2) ng/kgbw/day. The THg in children's hair was 1.05 (0.31-3.96) ppm, and a weak positive correlation was observed between hair THg and dietary MeHg (r = 0.170)., Conclusions: This study highlights the accurate estimation of MeHg intake in children using a duplicate method. Japanese children consume fish, the MeHg intakes exceeded the reference dose and/or provisional tolerable weekly intake in several children. Further discussion based on epidemiological data is required.

Maternal dietary zinc intake and childhood allergy have inconsistent relationships. Thus, this study aimed to evaluate the influence of low maternal dietary zinc intake during pregnancy on developing pediatric allergic diseases. This study was designed using the Japan Environment and Children's Study dataset. The model building used data from 74,948 mother-child pairs. Maternal dietary zinc intake was estimated based on the food frequency questionnaire, collecting the intake information of 171 food and beverage items. Fitted logistic regression models and generalized estimating equation models (GEEs) estimated the association between energy-adjusted zinc intake and childhood allergic conditions. The energy-adjusted zinc intake did not affect the risk of developing allergic disorders (wheeze, asthma, atopic dermatitis, rhinitis, and food allergy) in offspring. The GEE model revealed similar insignificant odds ratios. No significant association was found between zinc intake during pregnancy and allergic diseases in offspring in early childhood. Further study remains necessary to examine the association between zinc and allergy with reliable zinc status biomarkers in the body.

Prof. Setsuro Fujii achieved significant results in the field of drug discovery research in Japan. He developed nine well-known drugs: FT, UFT, S-1 and FTD/TPI are anticancer drugs, while cetraxate hydrochloride, camostat mesilate, nafamostat mesilate, gabexate mesilate and pravastatin sodium are therapeutic drugs for various other diseases. He delivered hope to patients with various diseases across the world to improve their condition. Even now, drug discovery research based on Dr. Fujii's ideas is continuing., (© 2023. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Background: The Foods with Function Claims (FFC) was introduced in Japan in April 2015 to make more products available that are labeled with health functions. The products' functionality of function claims must be explained by scientific evidence presented in systematic reviews (SRs), but the quality of recent SRs is unclear. This study assessed the quality of SRs in the FFC registered on the Consumer Affairs Agency (CAA) website in Japan., Methods: We searched the database from 1 April to 31 October 2022. Confidence in the methodological quality of each SR was evaluated by the AMSTAR 2 checklist., Results: Forty SRs were randomly extracted on the basis of the eligibility criteria and recruitment procedures. Overall confidence was rated as "high" ( N = 0, 0%), "moderate" ( N = 0, 0%), "low" ( N = 2, 5%), or "critically low" ( N = 38, 95%). The mean AMSTAR 2 score was 51.1% (SD 12.1%; range 19-73%). Among the 40 SRs, the number of critical domain deficiencies was 4 in 7.5% of SRs, 3 in 52.5% of SRs, 2 in 35% of SRs, and 1 in 5% of SRs. Registering the review's protocol and comprehensive search strategies were particularly common deficiencies. Additionally, the risk of bias (RoB) was insufficiently considered., Conclusion: Overall, the methodological quality of the SRs based on the FFC, introduced eight years earlier, was very poor. This was especially true in the interpretation and discussion of critical domains, which had many deficiencies in terms of protocol registration, a comprehensive literature search strategy, and accounting for the RoB.

Background: A paradigm shift has occurred in cancer chemotherapy from tumor-specific treatment with cytotoxic agents to personalized medicine with molecular-targeted drugs. Thus, it is essential to identify genomic alterations and molecular features to recommend effective targeted molecular medicines regardless of the tumor site. Nevertheless, it takes considerable expertise to identify treatment targets from primary-sequencing data in order to provide drug recommendations. The Molecular Tumor Board (MTB) denotes a platform that integrates clinical and molecular features for clinical decisions., Methods: This study retrospectively analyses all the cases of discussion and decision at the MTB in Tohoku University Hospital and summarizes genetic alterations and treatment recommendations., Results: The MTB discussed 1003 comprehensive genomic profiling (CGP) tests conducted in patients with solid cancer, and the resulting rate of assessing treatment recommendations was approximately 19%. Among hundreds of genes in the CGP test, only 30 genetic alterations or biomarkers were used to make treatment recommendations. The leading biomarkers that led to treatment recommendations were tumor mutational burden-high (TMB-H) (n = 32), ERBB2 amplification (n = 24), BRAF V600E (n = 16), and BRCA1/2 alterations (n = 32). Thyroid cancer accounted for most cancer cases for which treatment recommendation was provided (81.3%), followed by non-small cell lung cancer (42.4%) and urologic cancer (31.3%). The number of tests performed for gastrointestinal cancers was high (n = 359); however, the treatment recommendations for the same were below average (13%)., Conclusion: The results of this study may be used to simplify treatment recommendations from the CGP reports and help select patients for testing, thereby increasing the accuracy of personalized medicine., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: A research subgroup was established by the Japanese Society of Gastroenterological Surgery to improve the health care quality in the Chushikoku area of Western Japan., Methods: The records of four surgical procedures were extracted from the Japanese National Clinical Database and analyzed retrospectively to establish the association between hospital characteristics, defined using a combination of hospital case-volume and patients' hospital travel distance, and the incidences of perioperative complications of ≥ Grade 3 of the Clavien-Dindo classification after gastroenterological surgery., Results: This study analyzed 11,515 cases of distal gastrectomy for gastric cancer, 4,705 cases of total gastrectomy for gastric cancer, 4,996 cases of right hemicolectomy for colon cancer, and 5,243 cases of lower anterior resection for rectal cancer, with composite outcome incidences of 5.6%, 10.2%, 5.5%, and 10.7%, respectively. After adjusting for patient characteristics and surgical procedures, no association was identified between the hospital category and surgical outcomes., Conclusion: The findings of our study of the Chushikoku region did not provide positive support for the consolidation and centralization of hospitals, based solely on hospital case volume. Our grouping was unique in that we included patient travel distance in the analysis, but further investigations from other perspectives are needed., (© 2022. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Background: To our knowledge, the association of maternal exposure to metallic elements with weight trajectory pattern from the neonatal period has not been investigated., Objectives: The goals of this study were to identify infant growth trajectories in weight in the first 3 y of life and to determine the associations of maternal blood levels of lead, cadmium, mercury, selenium, and manganese with growth trajectory., Methods: This longitudinal study, part of the Japan Environment and Children Study, enrolled 103,099 pregnant women at 15 Regional Centres across Japan between 2011 and 2014. Lead, cadmium, mercury, selenium, and manganese levels were measured in blood samples collected in the second (14-27 wk gestational age) or third trimester ( ≥ 28 wk ). Growth trajectory of 99,014 children was followed until age 3 y. Raw weight values were transformed to age- and sex-specific weight standard deviation (SD) scores, and latent-class group-based trajectory models were estimated to determine weight trajectories. Associations between maternal metallic element levels and weight trajectory were examined using multinomial logistic regression models after confounder adjustment., Results: We identified 5 trajectory patterns based on weight SD score: 4.74% of infants were classified in Group I, very small to small; 31.26% in Group II, moderately small; 21.91% in Group III, moderately small to moderately large; 28.06% in Group IV, moderately large to normal; and 14.03% in Group V, moderately large to large. On multinomial logistic regression, higher maternal lead and selenium levels tended to be associated with increased odds ratios (ORs) of poor weight SD score trajectories (Groups I and II), in comparison with Group III. Higher levels of mercury were associated with decreased ORs, whereas higher levels of manganese were associated with increased ORs of "moderately large" trajectories (Groups IV and V)., Discussion: Maternal lead, mercury, selenium, and manganese blood levels affect infant growth trajectory pattern in the first 3 y of life. https://doi.org/10.1289/EHP10321.

Previous epidemiological studies have reported an increased risk of anemia in people with allergic disorders. However, previous studies have followed a cross-sectional design. The aim of this study was to investigate the association between the two conditions with a cohort dataset. We used data of 80,943 children in the Japan Environment and Children's Study, the largest birth cohort in Japan. The association between anemia and allergic disorders was evaluated with a logistic regression model and propensity score analysis. After adjusting for potential confounders, children with asthma (odds ratio [OR], 1.85; 95% confidence interval [CI], 1.32-2.60), atopic dermatitis (OR, 2.18; 95% CI, 1.66-2.85), allergic rhinitis (OR, 1.35; 95% CI, 1.05-1.74), allergic rhinoconjunctivitis (OR, 2.95; 95% CI, 1.91-4.54), and food allergies (OR, 1.92; 95% CI, 1.44-2.56) at 2 years of age predicted high odds of developing anemia in the next year. Any allergy at 2 years of age was associated with an increased risk of anemia at the age of 3 years (OR, 1.80; 95% CI, 1.41-2.29). The findings remained stable in the propensity score analysis. Results suggest that allergic diseases were related to caregiver-reported anemia in children.

Although geographical differences in the distribution of human papillomavirus genotypes have been observed worldwide, no studies have reported on national differences in the prevalence of human papillomavirus types in Japan. Here, we report a cross-sectional study to explore regional differences in the prevalence of human papillomavirus types among Japanese women with cervical intraepithelial neoplasia or invasive cervical cancer. Using human papillomavirus genotyping data from the nationwide prospective study on human papillomavirus vaccine effectiveness, we compared the frequency of detection of 15 high-risk and two low-risk human papillomavirus types in each disease category between the women who visited hospitals located in eastern Japan and those who visited hospitals located in western Japan. The risk of cervical intraepithelial neoplasia progression was assessed by calculating a prevalence ratio of each human papillomavirus type for cervical intraepithelial neoplasia grade 2/3 versus grade 1. Among the human papillomavirus types studied, human papillomavirus 52 was detected significantly more frequently in western hospitals than in eastern hospitals in cervical intraepithelial neoplasia grade 1 patients, but was less frequent in cervical intraepithelial neoplasia grade 2/3. The prevalence of particular human papillomavirus types was not significantly different between patients in hospitals in eastern Japan and those in hospitals in western Japan for invasive cervical cancer. In both eastern and western hospitals, a higher risk of cervical intraepithelial neoplasia progression was observed in patients infected with human papillomavirus 16, 31 or 58. In contrast, there was a significantly higher prevalence of human papillomavirus 52 infection in women with cervical intraepithelial neoplasia grade 2/3 than in those with cervical intraepithelial neoplasia grade 1 in eastern hospitals (prevalence ratio, 1.93; 95% confidence interval, 1.48-2.58), but not in western hospitals (prevalence ratio, 1.03; 95% confidence interval, 0.83-1.30). Regional differences of human papillomavirus 52 prevalence in cervical intraepithelial neoplasia lesions may exist and emphasize the importance of continuous monitoring of human papillomavirus type prevalence throughout the country in order to accurately assess the efficacy of human papillomavirus vaccines., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

In this study, we aimed to elucidate the bacterial biota of ayu-nazushi, which is a fermented salted fish dish made in Gifu City, Japan. In traditional Gifu ayu-nazushi, Lactobacillaceae (mainly Latilactobacillus sakei) was the most dominant family, followed by Enterobacteriaceae. Moreover, fermentation bacteria in ayu-nazushi came from the salted fish, and the bacterial biota in the ayu-nazushi transferred as the fermentation process progressed. In the early stage of fermentation, Leuconostoc mesenteroides was main species, and then in the late stage, L. sakei became predominant. We also observed that when non-salted fish was used for the manufacture of ayu-nazushi, Aeromonas veronii, which is a pathogen for humans, was observed in significant quantities. These results indicate that L. sakei and L. mesenteroides were influential lactic acid bacteria for the fermentation of Gifu ayu-narezushi, and that salting treatment of the fish is an indispensable step in the manufacturing process in order to suppress the growth of Aeromonas species., (Copyright © 2022 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.)

Background: Exposure to several metallic elements has been suggested as a risk factor for gestational diabetes mellitus (GDM), but inconsistent findings have been reported. This study aimed to examine the association between the maternal whole blood concentration of metallic elements (Hg, Pb, Cd, Mn, and Se) and GDM using the dataset of the Japan Environment and Children's Study (JECS), a nationwide birth cohort study, which was designed to examine the adverse effects of pre/post-natal exposure to hazardous environment., Methods: The data of 78,964 pregnant women who were participants of JECS were used. Blood samples were collected from the pregnant women at second/third trimester of gestation. We employed logistic regression analysis, quantile g-computation (QGC) and a distributed lag nonlinear model (DLNM) to examine the association between the blood concentration of metallic elements and the risk of GDM., Results: The prevalence of GDM was 2.1%. In the logistic regression analyses, maternal blood Hg was associated with an increased risk of GDM. In QGC analysis, although metallic elements mixtures were not related to an increased risk of GDM, Hg (52.6%) may be the main contributor. According to the results of DLNM, for maternal exposure to Hg, 4.99 ng/g was identified as its susceptible minimum window for elevated risk of GDM., Conclusions: Our findings highlighted an association between Hg exposure and an increased risk of GDM. Studies of the underlying mechanisms and potential contributing factors, including fish intake, of this association are warranted., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Adjuvant therapy is usually considered for surgically treated patients with uterine cervical cancer harboring intermediate risk (IR) factors such as large tumor diameter, stromal invasion to the outer half, and lymphovascular space invasion (LVSI). However, the indications and types of adjuvant therapy for the IR group remain controversial. This study aimed to analyze the differences in patient outcomes in the IR group to provide novel insights for tailoring adjuvant therapy., Methods: Data from 6192 patients with cervical cancer who underwent radical hysterectomy at 116 institutions belonging to the Japanese Gynecologic Oncology Group were reviewed., Results: In total, 1688 patients were classified into the IR group, of whom 37.3% did not receive adjuvant therapy. Conversely, approximately equal proportions of the remaining patients received adjuvant radiotherapy, concurrent chemoradiotherapy, and chemotherapy. Patients with all three risk factors showed worse overall survival than those with one or two risk factors. In addition to LVSI, non-squamous cell carcinoma histology, and vaginal invasion were identified as independent risk factors for both recurrence and mortality in multivariate analyses. Tumor diameter greater than 40 mm and surgical center volume were identified as independent risk factors for recurrence. Stromal invasion to the outer half and ovarian metastasis were identified as independent risk factors for mortality., Conclusions: This study revealed the significant differences in prognosis in the IR group. The indications for adjuvant therapy should be further studied, focusing on conventional risk factors and other pathological findings., (© 2022. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Excessive daytime sleepiness is characterized by a persistent feeling of having trouble staying awake, typically with inappropriate sleep episodes. Orexin (hypocretin) is a neuropeptide that regulates sleep-wake cycles and rapid eye movement sleep. Several large-scale genome-wide association studies (GWASs) in European populations have found genetic variants in orexin receptor-1 (OX1R) and -2 (OX2R) that are associated with sleep traits including daytime sleepiness. To identify genetic variants associated with daytime sleepiness, we performed an association study of genetic variants in prepro-orexin, OX1R, and OX2R in 14,329 Japanese individuals from the Tohoku Medical Megabank Project cohort. A genetic variant in OX2R was significantly associated with self-reported daytime sleepiness after Bonferroni correction (rs188018846: P = 8.4E-05). In addition, a missense variant in OX2R identified by the European GWASs showed a nominally significant association with daytime sleepiness in a Japanese population (p.Ile308Val, rs2653349: P = 0.044). Multiple genetic variants in OX2R can affect daytime sleepiness in general populations., (© 2022. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)

Purpose: The concept of 'diversity and inclusion' is being adopted worldwide, but it is not yet understood well in Japan. We conducted this study to evaluate the impact of a lecture aimed at increasing awareness of academic careers and the benefits of having diversity and inclusion., Methods: Two female surgeons delivered a 120-min lecture on "diversity and inclusion" to third-year medical students at Tokushima University. To assess the impact of the lecture, a questionnaire was distributed, for participants to complete anonymously before and after the lecture., Results: Eighty-two students participated in the study (39 men, 38 women, and 5 unknown). Based on the questionnaire responses, 57.1% of the students had already perceived inequality in conduct because of gender. A comparison of pre- and post-lecture responses revealed a significant increase in confidence to succeed in their medical career (56.5% vs. 77.5%, p < 0.01). Learners were more likely to believe that gender would not become a barrier to career development (42.4% vs. 66.7%, p < 0.01). Moreover, 90.4% of the students felt positively about a career in surgery following the lecture., Conclusion: The lecture promoted awareness about diversity, self-awareness, and career development and motivated students to consider specializing in surgery later in their career., (© 2021. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Background: The Japan Environment and Children's Study (JECS) is a nationwide birth cohort study investigating environmental effects on children's health and development. A Sub-Cohort Study has begun, conducting extended exposure and outcome measurements by targeting a subgroup randomly selected from the JECS Main Study. We report the Sub-Cohort Study methodology and participants' baseline profiles., Methods: Of 100,148 children in the JECS Main Study, children born after April 1, 2013 who met eligibility criteria ([1] all questionnaire and medical record data from children and their mothers collected from the first trimester to 6 months of age, [2] biospecimens [except umbilical cord blood] from children and their mothers collected at first to second/third trimester and delivery) were randomly selected for each Regional Centre at regular intervals. Face-to-face assessment of neuropsychiatric development, body measurement, paediatrician's examination, blood/urine collection for clinical testing and chemical analysis, and home visits (ambient and indoor air measurement and dust collection) are conducted. Participants are followed up at 1.5 and 3 years old for home visits, and 2, 4, 6, and 8 years old for developmental/medical examination. The details of protocols after age 10 are under discussion., Results: Of 10,302 selected children, 5,017 participated. The profiles of the participating mothers, fathers and children did not substantially differ between the Main Study and Sub-Cohort Study., Conclusion: The JECS Sub-Cohort Study offers a platform for investigating associations between environmental exposure and outcomes.

Objective: The mainstay of treatment for uterine endometrial cancer is surgery, and recurrent-risk cases require multidisciplinary treatment, including surgery, chemotherapy and radiation therapy., Methods: The standard surgery for uterine endometrial cancer is hysterectomy and bilateral salpingooophorectomy, with additional retroperitoneal lymph node dissection and omentectomy, depending on the case. The appropriate treatment is determined based on the risk classification, such as the depth of invasion into the myometrium, diagnosis of histological type and grade, and risk assessment of lymph node metastasis., Results: Recently, minimally invasive surgery has been widely used not only in low-risk patients but also in intermediate- and high-risk patients. In low-risk patients, the possibility of ovarian preservation is discussed from a healthcare perspective for young women. Determining the need for retroperitoneal lymph node dissection based on sentinel lymph node evaluation may contribute in minimizing the incidence of post-operative lymphedema while ensuring accurate diagnosis of lymph node metastasis. Recently, many studies using sentinel lymph nodes have been reported for patients with uterine endometrial cancer, and the feasibility of sentinel lymph node mapping surgery has been proven. Unfortunately, sentinel lymph node biopsy and sentinel lymph node mapping surgery have not been widely adopted in surgery for uterine cancer in Japan. In addition, the search for biomarkers, such as RNA sequencing using The Cancer Genome Atlas, metabolic profile and lipidomic profile for early detection and prognostic evaluation, has been actively pursued., Conclusions: Gynecologic oncologists expect to be able to provide uterine endometrial cancer patients with appropriate treatment that preserves their quality of life without compromising oncologic outcomes in the near future., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The Japan Environment and Children's Study (JECS) is a nationwide birth cohort study of environmental factors affecting children's health and development. We summarize the complete blood count and chemistry panel statistical data from pregnant women enrolled in JECS., Methods: Statistical data of up to 58,056 mother's sample in their first (gestational age ≤ 13 weeks) and second trimester (22-27 weeks) were calculated., Results: Mean (SD) values in the first trimester were: white blood cell count, 7866 (1906)/μL; red blood cell count, 417 (33) 10 4 /μL; hemoglobin, 12.4 (1.0) g/dL; hematocrit, 37.1 (2.6)%; mean corpuscular volume, 89.2 (4.7) fL; mean corpuscular hemoglobin, 29.8 (1.9) pg; mean corpuscular hemoglobin concentration, 33.3 (0.9)%; platelet count, 24.8 (5.2) 10 4 /μL; HbA1c, 5.26 (0.26)%; total cholesterol, 181 (28) mg/dL; low density lipoprotein cholesterol, 95 (23) mg/dL; high density lipoprotein cholesterol, 73 (13) mg/dL; free cholesterol, 41 (7) mg/dL; triglycerides, 109 (47) mg/dL; total protein, 6.9 (0.4) g/dL; and albumin, 4.1 (0.2) g/dL. Mean values (SD) in the second trimester were: total cholesterol, 246 (38) mg/dL; free cholesterol, 61 (9) mg/dL; triglycerides, 183 (70) mg/dL; total protein, 6.5 (0.4) g/dL; and albumin, 3.6 (0.2) g/dL., Conclusions: These data will be useful for future JECS studies.

Background: The Japan Pharmaceutical Association has conducted drug event monitoring to detect drug events related to pemafibrate. As there are a few studies on the safety of pemafibrate in clinical settings, a pilot study evaluating the association between drug use and detected events was performed in Japan., Aims: In this study, the association between detected events and the use of pemafibrate, utilizing pharmacy records maintained by community pharmacists, was investigated. We identified the newuser cohort using a test and active comparison drug and collected the baseline information. An active comparison group comprising new users was used to assess the events., Methods: A retrospective cohort study using questionnaires regarding baseline and event data was conducted by community pharmacists belonging to the Japan Pharmaceutical Association. The incidence of event and estimated hazard ratio were calculated using the Cox proportional hazards model that was adjusted for confounding factors, such as age and sex., Results: A total of 1294 patients using pemafibrate and 508 patients using fenofibrate were identified as new drug users. The most reported events involving suspected adverse reactions and add-on drugs were increased blood pressure and lipid-lowering effects with pemafibrate use, and nasopharyngitis, pruritus, dizziness, and lipid-lowering effects with fenofibrate use. No significant differences were found in commonly occurring events, except that an add-on anti-hypertensive drug has been used by pemafibrate users compared to fenofibrate users., Conclusion: This study conducted by pharmacists can facilitate the safety assessment of newly marketed drugs, as few drug use investigations with a comparator are carried out by the Japanese authority for pharmaceutical companies. However, further research is required., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: We aimed to discuss and compare reported adverse reactions and drug add-ons associated with elobixibat and lubiprostone use in chronic constipation treatment, as the safety of these drugs has not been well examined in post-marketing clinical settings., Research Design and Methods: In this retrospective cohort study, using records of community pharmacies in Japan, we identified new users of elobixibat and lubiprostone. The Japan Pharmaceutical Association sent questionnaires regarding baseline and event data to community pharmacists. The incidence of events and hazard ratio (HR) associated with the study drugs were evaluated., Results: New users of elobixibat (n = 979) and lubiprostone (n = 829) were identified (mean age: 74 and 77 years; females: 59% and 53%, respectively). Although the crude risk ratio of adverse events for elobixibat was 0.79 (95% confidence interval: 0.63-0.99), there was no significant difference in the HR for any of the common events, including drug add-ons (n ≥ 5), compared with those for lubiprostone., Conclusion: No new safety concerns have been raised in relation to elobixibat and lubiprostone use for treating chronic constipation, although the HR of different events varied. Further larger-scale study is needed as the estimates for events of small numbers were unstable.

Objective: The goal of this retrospective study was to clarify the clinical implications of immunohistochemically detected protein expression for genes that are frequently mutated in pancreatic neuroendocrine tumors (PNETs)., Background: The clinical management of PNETs is hindered by their heterogenous biological behavior. Whole-exome sequencing recently showed that 5 genes (DAXX/ATRX, MEN1, TSC2, and PTEN) are frequently mutated in PNETs. However, the clinical implications of the associated alterations in protein expression remain unclear., Methods: We collected Grade 1 and 2 (World Health Organization 2017 Classification) primary PNETs samples from 100 patients who underwent surgical resection. ATRX, DAXX, MEN1, TSC2, and PTEN expression were determined immunohistochemically to clarify their relationships with prognosis and clinicopathological findings., Results: Kaplan-Meier analysis indicated that loss of TSC2 (n = 58) or PTEN (n = 37) was associated with significantly shorter overall survival, and that loss of TSC2 or ATRX (n = 41) was associated with significantly shorter recurrence-free survival. Additionally, loss of ATRX or TSC2 was significantly associated with nodal metastasis. In a multivariate analysis, combined loss of TSC2 and ATRX (n = 31) was an independent prognostic factor for shorter recurrence-free survival (hazard ratio 10.1, 95% confidence interval 2.1-66.9, P = 0.003) in G2 PNETs., Conclusions: Loss of ATRX, TSC2, and PTEN expression might be useful as a method of clarifying the behavior and clinical outcomes of Grade 1 and 2 PNETs in routine clinical practice. Combined loss of TSC2 and ATRX had an especially strong, independent association with shorter recurrence-free survival in patients with G2 PNETs. Loss of pairs in ATRX, TSC2, or PTEN would be useful for selecting the candidate for postoperative adjuvant therapy., Competing Interests: The authors have no financial conflicts of interest related to this work. The authors report no conflicts of interest., (Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.)

The expression of programmed death 1 (PD-1) and programmed death-ligand 1 (PD-L1) indicate the efficacy of anti-PD-1/PD-L1 therapy in colorectal cancer (CRC), but are less useful for monitoring the efficacy of therapy of CRC liver metastasis (CRLM). This study investigated the effects of immune molecules on the prognosis of CRLM. We enrolled 71 patients with CRLM who underwent curative resection for CRC. We used immunohistochemistry to analyze the expression of PD-1, PD-L1, indoleamine-pyrrole 2,3-dioxygenase (IDO), and CD163 (a marker of tumor-associated macrophages [TAMs]) in metastatic tumors. The immune molecules PD-1, PD-L1, IDO, and TAMs were expressed in 32.3%, 47.8%, 45.0%, and 47.9% of metastatic CRC samples, respectively. The 5-year overall survival rates associated with immune molecule-positive groups were significantly better than in the negative groups (PD-1: 87.7% vs 53.2%, p = 0.023; PD-L1: 82.4% vs 42.3%, p = 0.007; IDO: 80.7% vs 43.5%, p = 0.007; TAMs: 82.6% vs 48.0%, p = 0.005). Multivariate analysis revealed PD-1 expression (p = 0.032, hazard ratio: 0.19), IDO expression (p = 0.049, hazard ratio: 0.37), and tumor differentiation (p<0.001, hazard ratio: 0.02) as independent prognostic indicators. PD-1 and TAMs in metastases were associated with less aggressive features such as smaller tumors. Furthermore, TAMs positively and significantly correlated with PD-1 expression (p = 0.011), PD-L1 expression (p = 0.024), and tended to correlate with IDO expression (p = 0.078). PD-1, PD-L1, IDO, and TAMs in CRLM were associated with less aggressive features and better prognosis of patients with CRC, indicating adaptive antitumor immunity vs immune tolerance. These molecules may therefore serve as prognostic markers for CRLM., Competing Interests: The authors have declared that no competing interests exist.

Background: Prenatal cadmium exposure has been associated with adverse neurodevelopmental outcomes. However, previous findings are contradictory, and little is known about the potential modifiers of the cadmium-related neurodevelopmental risk. We investigated the associations between prenatal cadmium exposure and neurodevelopment in 2-year-old children and examined the influence of mother/child characteristics., Methods: We recruited 3545 mother-child pairs from the Japan Environment and Children's Study. We collected maternal blood during mid/late pregnancy and cord blood at delivery, and measured cadmium concentrations using inductively coupled plasma mass spectrometry. Neurodevelopment was assessed using the Kyoto Scale of Psychological Development (KSPD), which includes cognitive-adaptive (C-A), language-social (L-S), postural-motor (P-M) and developmental quotient (DQ) domains. Associations between cadmium and KSPD scores were tested using multivariable models after controlling for confounders., Results: Median levels (interquartile ranges) of cadmium in maternal and cord blood were 0.70 (0.52-0.95) and 0.04 (0.03-0.06) μg/L, respectively. Maternal blood cadmium concentrations were inversely associated with P-M scores in boys (β = -1.4, 95% confidence interval (CI): -2.7, -0.038), DQ in children of mothers who smoked during pregnancy (β = -2.9, 95% CI: -5.7, -0.12), P-M (β = -5.4, 95% CI: -10, -0.67), C-A (β = -6.1, 95% CI: -11, -1.8), L-S (β = -9.0, 95% CI: -13, -4.8) and DQ scores (β = -6.4, 95% CI: -9.6, -3.1) in children born to mothers with gestational diabetes. Cord blood cadmium concentrations were negatively associated with L-S scores (β = -6.0., 95% CI: -11, -0.91) in children born to mothers with gestational diabetes., Conclusions: Prenatal cadmium exposure was negatively associated with neurodevelopment in boys, in children whose mothers smoked, and in children born to mothers with gestational diabetes. Further studies in other populations are needed to confirm our findings., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Intermediate-sized insertions are one of the structural variants contributing to genome diversity. However, due to technical difficulties in identifying them, their importance in disease pathogenicity and gene expression regulation remains unclear. We used whole-genome sequencing data of 174 Japanese samples to characterize intermediate-sized insertions using a highly-accurate insertion calling method (IMSindel software and joint-call recovery) and obtained a catalogue of 4254 insertions. We constructed an imputation panel comprising of insertions and SNVs from all samples, and conducted imputation of intermediate-sized insertions for 82 publicly-available Japanese samples. Positive Predictive Value of imputation, evaluated using Nanopore long-read sequencing data, was 97%. Subsequent eQTL analysis predicted 128 (~ 3.0%) insertions as causative for gene expression level changes. Enrichment analysis of causal insertions for genome regulatory elements showed significant associations with CTCF-binding sites, super-enhancers, and promoters. Among 17 causal insertions found in the same causal set with GWAS hits, there were insertions associated with changes in expression of cancer-related genes such as BRCA1, ZNF222, and ABCB10. Analysis of insertions sequences revealed that 461 insertions were short tandem duplications frequently found in early-replicating regions of genome. Furthermore, comparison of functional importance of intermediate-sized insertions with that of intermediate-sized deletions detected in the same sample set in our previous study showed that insertions were more frequent in genic regions, and proportion of functional candidates was smaller in insertions. Here, we characterize a high-confidence set of intermediate-sized insertions and indicate their importance in gene expression regulation. Our results emphasize the importance of considering intermediate-sized insertions in trait association studies.

Exposure to particulate matter (PM) is one of the important risk factors for morbidity and mortality. Although PM concentrations have been assessed using air quality monitoring stations or modelling, few studies have measured indoor PM in large-scale birth cohorts. The Japan Environment and Children's Study (JECS) measured indoor and outdoor air quality in approximately 5000 households when the participating children were aged 1.5 and 3 years. PM was collected using portable pumps for 7 days (total of 24 h), inside and outside each home. Prediction models for indoor PM concentrations were built using data collected at age 1.5 years and post-validated against data collected at age 3 years. Median indoor/outdoor PM 2.5 and PM 10-2.5 concentrations at age 1.5 years [3 years] were 12.9/12.7 [12.5/11.3] μg/m 3 and 5.0/6.3 [5.1/6.1] μg/m 3 , respectively. Random forest regression analysis found that the major predictors of indoor PM 2.5 were indoor PM 10-2.5 , outdoor PM 2.5 , indoor smoking, observable smoke and indoor/outdoor temperature. Indoor PM 2.5 , outdoor PM 10-2.5 , indoor humidity and opening room windows were important predictors of indoor PM 10-2.5 concentrations. Indoor benzene, acetaldehyde, ozone and nitrogen dioxide concentrations were also found to predict indoor PM 2.5 and PM 10-2.5 concentrations, possibly due to the formation of secondary organic aerosols. These findings demonstrate the importance of reducing outdoor PM concentrations, avoiding indoor smoking, using air cleaner in applicable and diminishing sources of VOCs that could form secondary organic aerosols, and the resulting models can be used to predict indoor PM concentrations for the rest of the JECS cohort., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Social determinants of health (SDHs) are social factors that affect human health; loneliness and social isolation are core SDH factors. There is a possibility that SDHs are related to passive decision-making. However, few studies have evaluated SDHs, especially social isolation and loneliness, among lung cancer patients. This study aims to investigate the effects of social isolation and loneliness on the diagnosis and treatment of Japanese lung cancer patients., Methods: This is a prospective cohort study that was conducted in a tertiary referral hospital in Japan (University Hospital Medical Information Network registration: UMIN000031810). The enrollment period was between April 2018 and March 2020. Patients with clinical and/or pathological diagnosis of lung cancer were enrolled in this study. Exposures were social isolation and loneliness, and main outcomes were diagnosis methods and whether the initial treatment involved active therapy or best supportive care (BSC). The confounding factors were defined as sex, age, smoking status, respiratory symptoms, weight loss, presentation with any symptoms, Eastern Cooperative Oncology Group (ECOG) performance status, tumor nodes metastasis (TNM) classification, driver gene mutations [i.e., epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK)], and programmed death-ligand 1 (PD-L1) tumor proportion score., Results: The study enrolled 264 patients who were divided into quartiles according to their loneliness scores and into two groups according to the social isolation level. Univariate analysis, complete case analysis, and multivariate analysis with multiple imputation failed to detect significant differences in diagnostic method or initial treatment strategy according to loneliness or social isolation level., Conclusions: Physicians may not need to consider a patient's loneliness and/or social isolation when diagnosing lung cancer and selecting treatment under universal health insurance coverage. Further studies are needed to understand the influences of loneliness and social isolation on the prognosis of lung cancer patients.

Background: Many studies have investigated the devastating health effects of heat waves, but less is known about health risks related to cold spells, despite evidence that extreme cold may contribute to a larger proportion of deaths., Objectives: We aimed to systematically investigate the association between cold spells and mortality in Japan., Methods: Daily data for weather conditions and 12 common causes of death during the 1972-2015 cold seasons (November-March) were obtained from 47 Japanese prefectures. Cold spells were defined as ≥ 2 consecutive days with daily mean temperatures ≤ 5 th percentile for the cold season in each prefecture. Quasi-Poisson regression was combined with a distributed lag model to estimate prefecture-specific associations, and pooled associations at the national level were obtained through random-effects meta-analysis. The potential influence of cold spell characteristics (intensity, duration, and timing in season) on associations between cold spells and mortality was examined using a similar two-stage approach. Temporal trends were investigated using a meta-regression model., Results: A total of 18,139,498 deaths were recorded during study period. Mortality was significantly higher during cold spell days vs. other days for all selected causes of death. Mortality due to age-related physical debilitation was more strongly associated with cold spells than with other causes of death. Associations between cold spells and mortality from all causes and several more specific outcomes were stronger for longer and more intense cold spells and for cold spells earlier in the cold season. However, although all outcomes were positively associated with cold spell duration, findings for cold spell intensity and seasonal timing were heterogeneous across the outcomes. Associations between cold spells and mortality due to cerebrovascular disease, cerebral infarction, and age-related physical debility decreased in magnitude over time, whereas temporal trends were relatively flat for all-cause mortality and other outcomes., Discussion: Our findings may have implications for establishing tailored public health strategies to prevent avoidable cold spell-related health consequences. https://doi.org/10.1289/EHP7109.

Purpose: To characterize the clinical features and outcome of patients treated at a specialized hospital for coronavirus disease 2019 (COVID-19)., Methods: We retrospectively reviewed the symptoms on admission, treatment, and outcome of a total of 300 patients with mild (peripheral oxygen saturation (SpO 2 ) ≥ 96%), moderate I (93% < SpO 2  < 96%), moderate II (SpO 2  ≤ 93%) and severe (requiring admission to the ICU or mechanical ventilation) COVID-19., Results: Median age was 53 (interquartile range [IQR] 33-72) years and 57% was male. The number of patients with mild, moderate I, II and severe condition was 85, 138, 61 and 16, respectively. Common presenting symptoms were cough (n = 71), loss of taste (42), loss of smell (39), fever ≥ 37.5 °C (36). Dyspnea was observed only 21 cases; 57 reported no symptoms on admission. Favipiravir, ciclesonide, dexamethasone, and heparin were administered in 106, 168, 65, and 38 patients, respectively, but not remdesivir. The median duration of hospitalization was 10 (7-15) days. All patients with mild and moderate I severity were discharged. Among the 77 patients classified as moderate II or severe, 3 were transferred to tertiary hospitals for further treatment on the day of admission. The respiratory condition worsened in 21 patients; 18 required transfer to tertiary hospitals 3 (median) days after admission and 3 died., Conclusion: Respiratory condition recovered in 92%; whereas it worsened in 7% and the mortality rate was 1%. The ratios of male patients, of patients with diabetes mellitus in those with the decreased respiratory condition, were significantly higher than recovered.

Volatile organic compounds (VOCs) are major indoor air pollutants. Quantification of indoor concentrations of VOCs and identification of factors associated with these concentrations can help manage indoor air quality. This study measured the concentrations of VOCs and inorganic gaseous pollutants in around 5000 households in Japan and utilised a random forest model to estimate these concentrations and identify important determinants. The homes of 5017 randomly selected participants in the Japan Environment and Children's Study (JECS) were visited twice, when the children were aged 1.5 and 3 years. Twelve VOCs and inorganic gaseous pollutants were measured during 7 days by passive samplers. Various factors in these households, including household appliances, building characteristics, cooking styles, use of consumer products, renovation, pets, personal behaviours and ventilation were recorded. A random forest model with recursive feature elimination was utilised to identify factors predictive of VOCs and inorganic gaseous pollutants. Toluene, formaldehyde and acetaldehyde were the dominant indoor VOCs. The 95th percentiles of indoor p-dichlorobenzene concentrations at 1.5 and 3 years were 67 μg/m 3 and 71 μg/m 3 , respectively. Random forest models with coefficients of determination ranging from 0.34 to 0.76 outperformed the traditional linear regression models. Factors associated with indoor VOC and inorganic gaseous pollutant concentrations included their outdoor concentrations, indoor and outdoor temperature and relative humidity, month of the year, hours windows were open, kerosene heater use and times of operation and building age. The results provided basic descriptions of indoor VOCs and inorganic gaseous pollutants in Japan and identified several determinants of these concentrations. These determinants should be considered to maintain indoor air quality. These results can be used in epidemiological assessments of the effects of VOCs and inorganic gaseous pollutants on health in children., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Organophosphate pesticides (OPPs) exhibit neurodevelopmental toxicity. To evaluate the effect of prenatal exposure to OPPs in the Japan Environment and Children's Study, a nationally representative birth cohort study, 4575 maternal urine samples were analysed for six OPP metabolites, i.e., dialkylphosphates (DAPs). This study aimed to investigate predictors of urinary DAPs using machine learning approaches and to assess the cumulative risk based on relative potency factors among Japanese pregnant women. The median creatinine-normalised urinary concentrations (interquartile ranges) of dimethylphosphate, dimethylthiophosphate and diethylphosphate, which had a detection rate of 50% or higher, were 3.53 (1.91-6.78), 4.09 (1.66-10.8) and 3.28 (1.88-5.98) µg/g-creatinine, respectively. Possible predictors of urinary DAP concentrations were the month of urine sampling, consumption of apple and maternal body mass index. When fenitrothion was used as an index chemical for cumulative risk assessment, 0.36% of participants exceeded the lower 95% confidence limit of the benchmark dose 10 ., Competing Interests: The authors declare no conflict of interest.

Objective: The present study aimed to clarify the occurrence rate of lymphedema and prognosis in patients with endometrial cancer according to sentinel lymph node biopsy alone with intraoperative histopathological examination., Methods: The study included 45 consecutive patients with endometrial cancer treated at Tohoku University Hospital between October 2014 and August 2017. All patients had endometrial carcinoma with endometrioid histology Grade 1 or Grade 2 confirmed by biopsy and stage I on magnetic resonance imaging and/or computed tomography at their preoperative evaluation. Sentinel lymph node detection was performed by radioisotope and dye. Patients who were diagnosed intraoperatively as negative for sentinel lymph node metastasis did not undergo further systematic pelvic lymphadenectomy. The occurrence rate of lymphedema and prognosis was evaluated., Results: Bilateral sentinel lymph nodes were detected in 44 of 45 patients (97%). Forty-three patients underwent sentinel lymph node biopsy alone, and only two patients underwent systematic lymphadenectomy. Sentinel lymph node metastases were detected in one patient intraoperatively and two patients postoperatively as ITCs. No patients experienced recurrence. New symptomatic lower-extremity lymphedema was identified in one of 43 patients (2.3%) who underwent sentinel lymph node biopsy alone., Conclusion: Sentinel lymph node biopsy alone with intraoperative histopathological diagnosis appears to be a safe and effective strategy to detect lymph node metastasis and to reduce the number of patients with lower-extremity lymphedema among patients with endometrial cancer., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective　Obesity associated with an increased consumption of ultra-processed foods (UPF) has been reported by studies abroad using the NOVA food classification system, an international framework for classifying food according to the degree of processing. However, no such study has been conducted in Japan. In this study, we evaluated the association between UPF consumption, nutrient intake, and obesity using the NOVA system.Method　In September 2017, we conducted a survey using a questionnaire of patients who had attended routine health checkups in Manazuru Town, Kanagawa Prefecture and collected their three-day dietary records as well as medical examination results. The final analysis included 169 patients (66 men, 103 women). Food consumed by the respondents were classified into four groups of NOVA systems. The dietary share of UPF (UPF energy ratio) was compared to total energy intake (except alcoholic beverages and eating out). Nutrient intake and obesity risk were compared across the UPF energy ratio tertile (low, middle, and high intake). Covariance and logistic regression analysis were conducted and adjusted based on age, sex, household structure, education, income, and total energy intake (except energy-providing nutrients, macronutrients, and protein intake per body weight) to analyze the association between UPF consumption and nutrient intake. Finally, for obesity, we adjusted for physical activity and smoking status using a similar analysis of the relationship between UPF consumption and energy providing nutrients and macronutrients.Result　Approximately 75% of patients investigated were older than 65 years. The average (standard deviation) UPF energy ratio was 29.7% (15.0). There were no significant differences in socioeconomic status among groups according to the UPF energy ratio. The high-UPF group had a significantly greater total energy intake. However, the protein energy ratio, protein intake per body weight, dietary fiber, and vitamins A, E, K, B 1 , B 6 , C, niacin, folic acid, potassium, magnesium, and iron intake were significantly lower in the high-UPF group. Moreover, the high-UPF group had a significantly higher BMI. The odds ratio for obesity was higher (4.51[1.50-13.57]) in the high-UPF group than in the low-UPF group (1.00).Conclusion　Those who consumed more UPF had lower protein intake and suffered from multiple vitamin and mineral deficiencies. Furthermore, their energy intake was greater, and the odds ratio for obesity was significantly higher. It has been suggested that excessive UPF consumption warrants further attention.

Purpose: To identify the conflicts between a career as a surgeon and pregnancy and childbirth for women in Japan., Methods: The Japan Surgical Society conducted a nationwide survey on pregnancy and childbirth among its members who are women. The questionnaire included items regarding demography, working styles, and pregnancy and childbirth, including adverse events and harassment., Results: The response rate was 29.9% (1068 responses, median age, 37 years). Among the responders, 61% were married and 47% had children (average number of children, 1.7). Half of the respondents reported having experienced sexual harassment and 62% reported having received unwelcome comments about pregnancy. About 20% had undergone fertility treatment. In total, 51% had pregnancies, with miscarriages in 33% of these. The top answer for the best timing for pregnancy and childbirth was after becoming board-certified. Nearly one-third of first-time mothers experienced adverse events during pregnancy and delivery, and 28% quit or changed their job because of their pregnancy and the birth of their first child., Conclusions: Japanese women who choose a career as a surgeon face obstacles during pregnancy and childbirth. It is vital to share the findings of this study and understand the issues associated with pregnancy and childbirth regardless of gender. Interventions are essential to ensure that every pregnant surgeon has a safe working environment to allow unobstructed development of her career.

Identification of the population frequencies of definitely pathogenic germline variants in two major hereditary breast and ovarian cancer syndrome (HBOC) genes, BRCA1/2, is essential to estimate the number of HBOC patients. In addition, the identification of moderately penetrant HBOC gene variants that contribute to increasing the risk of breast and ovarian cancers in a population is critical to establish personalized health care. A prospective cohort subjected to genome analysis can provide both sets of information. Computational scoring and prospective cohort studies may help to identify such likely pathogenic variants in the general population. We annotated the variants in the BRCA1 and BRCA2 genes from a dataset of 3,552 whole-genome sequences obtained from members of a prospective cohorts with genome data in the Tohoku Medical Megabank Project (TMM) with InterVar software. Computational impact scores (CADD&#95;phred and Eigen&#95;raw) and minor allele frequencies (MAFs) of pathogenic (P) and likely pathogenic (LP) variants in ClinVar were used for filtration criteria. Familial predispositions to cancers among the 35,000 TMM genome cohort participants were analyzed to verify the identified pathogenicity. Seven potentially pathogenic variants were newly identified. The sisters of carriers of these moderately deleterious variants and definite P and LP variants among members of the TMM prospective cohort showed a statistically significant preponderance for cancer onset, from the self-reported cancer history. Filtering by computational scoring and MAF is useful to identify potentially pathogenic variants in BRCA genes in the Japanese population. These results should help to follow up the carriers of variants of uncertain significance in the HBOC genes in the longitudinal prospective cohort study., Competing Interests: The authors have declared that no competing interests exist.

Clinical guidelines including those set by the US Institute of Medicine, have based optimal gestational weight gain (GWG) on maternal pre-pregnancy body mass index (BMI), but have not considered the role of environmental toxicants such as heavy metals that can disrupt these processes. This study designed to determine optimal GWG ranges in women grouped according to BMI, and to assess whether blood concentrations of heavy metals alter the relationships between GWG and outcomes. A total of 103,060 participants in the Japan Environment and Children's Study recruited between 2011 and 2014 were followed until their children reached 3 years of age. Outcomes included 1 min Apgar score <7, caesarean delivery, childhood obesity, gestational diabetes, pregnancy-induced hypertension, low birth weight, large for gestational age, macrosomia, operative vaginal delivery, postpartum weight retention, preterm birth and small for gestational age. The optimal GWG ranges were determined using multivariate logistic regression models. Stratified analyses were performed to determine optimal GWG ranges according to quartiles of heavy metals. Optimal GWGs for underweight, normal weight and overweight women were found to be 10.0 to <14.0 kg, 6.0 to <12.0 kg and 4.0 to <8.0 kg, respectively. However, the benefits of optimal GWG were attenuated in women exposed to high concentrations of mercury (Hg), lead (Pb) and cadmium (Cd). Despite being within optimal GWG, underweight women with Hg > 5.21 ng/g and overweight women with Hg 3.67-5.21 ng/g, Pb > 7.31 ng/g and Cd > 0.66 ng/g had null effects. Heavy metals can modify the associations between GWG and outcomes, particularly for underweight and overweight women. Because of the complex interactions of environmental toxicants with pre-pregnancy BMI, GWG and adverse outcomes, GWG guidelines should be interpreted cautiously. Environmental toxicants may influence the determination of a clinical guideline., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The rate of exclusive breastfeeding at 3 months postpartum is only 50% in Japan. In order to increase this rate, we aimed to examine modifiable factors related to exclusive breastfeeding at 3 months postpartum by focusing on breastfeeding-related and psychosocial variables at 1 month postpartum., Methods: This prospective cohort study was conducted at a secondary medical care center in Osaka, Japan from February 2017 to October 2018. Demographic variables, infant feeding modality, breastfeeding-related variables, and psychosocial variables were obtained using questionnaires at 1 month postpartum. Daytime salivary cortisol levels before and after breastfeeding at 1 month postpartum were measured as a biological marker for stress responses associated with breastfeeding. Each infant's feeding modality was re-assessed at 3 months postpartum. Multiple logistic regression analyses were performed to examine factors affecting exclusive breastfeeding at 3 months postpartum., Results: Of the 104 participants, 61 reported exclusive breastfeeding at 3 months postpartum. The following factors were significantly associated with exclusive breastfeeding at 3 months postpartum: multiparity (adjusted odds ratio, 95% confidence interval: 11.13, 2.08-59.59), having a university degree (5.25, 1.04-26.53), no plan to return to work by 6 months postpartum (0.02, 0.00-0.46), and exclusive breastfeeding (42.84, 6.05-303.52), lower cortisol level after breastfeeding (0.00, 0.00-0.02), and higher breastfeeding self-efficacy scale score (1.07, 1.00-1.14) at 1 month postpartum. In parity-specific analyses, exclusive breastfeeding (25.33, 4.75-134.98) and lower cortisol level after breastfeeding (0.00, 0.00-0.21) at 1 month postpartum in primiparous women, and lower cortisol level after breastfeeding (0.00, 0.00-0.94), higher breastfeeding self-efficacy score (1.18, 1.05-1.32), and absence of breast complications (0.09, 0.01-0.82) at 1 month postpartum in multiparous women were associated with exclusive breastfeeding at 3 months postpartum., Conclusions: Stress levels after breastfeeding, breastfeeding self-efficacy, and the presence of breast complications could be modifiable factors associated with subsequent exclusive breastfeeding. Further research is needed to examine whether approaches to reducing breastfeeding-related stress, improving breastfeeding self-efficacy, and preventing breast complications during lactation are effective to increase exclusive breastfeeding practices.