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The in situ measurement technique for a metal/metal-oxide mixture at extra-high temperature above 2000 K has been desired in the field of nuclear safety engineering. In the present study, we succeeded in simultaneous XAFS–XRD measurements of the Zr oxidation [Zr + O → Zr(O) + ZrO2] up to 1952 K and ZrO2–Y2O3 reaction from 1952 to 2519 K. The chemical shift during Zr oxidation was observed in the absorption spectra around the Zr K-edge, and the interatomic cation–cation and cation–oxygen distances obtained by the fitting analysis of EXAFS during the Y2O3–ZrO2 reaction are explained. Also, the temperature dependency of the anharmonic effect was investigated by comparing the fitted second- and third-order cumulants with the theoretical ones in which the Morse potential was applied as an interatomic potential, giving a good explanation about the local structure dynamics. Finally, the applicability of the developed system to investigation of nuclear fuel materials, such as UO2–Zr, is discussed.

BackgroundThe rate of recurrent spontaneous preterm delivery (sPTD) ranges between 27% and 34% and is 22.3% in Japan. Although it currently remains unclear whether probiotics prevent sPTD, retrospective studies recently reported a reduction in the rate of recurrent sPTD with the administration of probiotics including Clostridium spp., which induce regulatory T cells that play an important role in maintaining pregnancy. ObjectiveThe objective of this trial is to evaluate the preventative effects of available oral probiotics, including Clostridium butyricum, on recurrent sPTD. MethodsThis is a prospective, single-arm, nonblinded, multicenter trial in Japan. The sample size required for this trial is 345 pregnant women with a history of sPTD, considering a clinically significant reduction in the relative risk of 30% (risk ratio=0.7). The primary endpoint is the rate of recurrent sPTD at

Gonadal soma-derived factor (Gsdf) is a member of the transforming growth factor beta (TGF-β) superfamily and a teleost-specific gene. Early studies suggested that Gsdf promotes spermatogonial proliferation; however recent reports have shed light on its role in sex differentiation based on expression profiles and gain- and loss-of-function studies. This paper discusses the involvement of Gsdf in gonadal sex differentiation and sex changes in teleosts.

The relationship between participation in extracurricular school club activities in adolescence and subsequent depressive state experiences in adulthood, after joining the workforce, is unclear. The present study aimed to explore this relationship in new recruits of the Japan Ground Self-Defense Force (JGSDF). In April 2013, 925 recruits of the JGSDF, all of whom were male and aged 18–27 years, were enrolled. Club activity status during high school was categorized as follows: participated in sports club, participated in nonsport club, or no club participation. Depressive symptoms were assessed with the 20-item version of the Center for Epidemiologic Studies Depression Scale (CES-D), at the baseline survey and a second survey conducted 2 months later, in June 2013. Analysis of covariance was used for association between club activity status and changes in CES-D scores. After a 2-month period, results showed a significantly higher average of CES-D score changes for participants in nonsport club activities (β = 3.90, 95% confidence interval = 2.22–6.71) or those with no club activities (β = 2.24, 95% confidence interval = 0.20–2.94), compared to those who participated in a sports club. These findings were adjusted for age, baseline CES-D score, regular exercise, smoking status, alcohol consumption, sleep duration, and breakfast habits. Recruits without a history of sports club participation may be at higher risk of developing depressive symptoms than those who participated in a sports club. Our results may be useful for the early detection of people who are susceptible to depression engaged in occupations such as the JDSF.

This is a protocol for PPROM-AZM Study, phase II, nonblinded, randomized controlled trial. Bronchopulmonary dysplasia (BPD) at a postmenstrual age of 36 weeks (BPD36) is often observed in infants with preterm premature rupture of the membranes (pPROM). A regimen of ampicillin (ABPC) intravenous infusion for 2 days and subsequent amoxicillin (AMPC) oral administration for 5 days plus erythromycin (EM) intravenous infusion for 2 days followed by EM oral administration for 5 days is standard treatment for pPROM. However, the effect on the prevention of moderate/severe BPD36 using the standard treatment has not been confirmed. Recently, it is reported that ampicillin/sulbactam (ABPC/SBT) plus azithromycin (AZM) was effective for the prevention of moderate/severe BPD36 in pPROM patients with amniotic infection of Ureaplasma species. Therefore, our aim is to evaluate the occurrence rate of the composite outcome of "incidence rate of either moderate/severe BPD36 or intrauterine fetal death, and infantile death at or less than 36 weeks 0 days" comparing subjects to receive ABPC/SBT for 14 days plus AZM for 14 days (intervention group) and those to receive ABPC/SBT for 14 days plus EM for 14 days (control group), in a total of 100 subjects (women with pPROM occurring at 22-27 weeks of gestation) in Japan. The recruit of subjects was started on April 2022, and collection in on-going. We also investigate the association between the detection of Ureaplasma species and occurrence of BPD36. In addition, information on any adverse events for the mother and fetus and serious adverse events for infants are collected during the observation period. We allocate patients at a rate of 1:1 considering two stratification factors: onset of pPROM (22-23 or 24-27 weeks) and presence/absence of a hospital policy for early neonatal administration of caffeine. Trial registration: The trial number in the Japan Registry of Clinical Trials is jRCTs031210631.

Background Many prenatal factors are reported to be associated with congenital heart defects (CHD) in offspring. However, these associations have not been adequately examined using large‐scale birth cohorts. Methods and Results We evaluated a data set of the Japan Environmental and Children's Study. The primary outcome was a diagnosis of CHD by age 2 years. We defined the following variables as exposures: maternal baseline characteristics, fertilization treatment, maternal history of diseases, socioeconomic status, maternal alcohol intake, smoking, tea consumption, maternal dietary intake, and maternal medications and supplements up to 12 weeks of gestation. We used multivariable logistic regression analysis to assess the associations between various exposures and CHD in offspring. A total of 91 664 singletons were included, among which 1264 (1.38%) had CHD. In multivariable analysis, vitamin A supplements (adjusted odds ratio [aOR], 5.78 [95% CI, 2.30–14.51]), maternal use of valproic acid (aOR, 4.86 [95% CI, 1.51–15.64]), maternal use of antihypertensive agents (aOR, 3.80 [95% CI, 1.74–8.29]), maternal age ≥40 years (aOR, 1.59 [95% CI, 1.14–2.20]), and high maternal hemoglobin concentration in the second trimester (aOR, 1.10 per g/dL [95% CI, 1.03–1.17]) were associated with CHD in offspring. Conclusions Using a Japanese large‐scale birth cohort study, we found 6 maternal factors to be associated with CHD in offspring.

Background Coronary arterial aneurysms (CAAs) associated with Kawasaki disease (KD) significantly affect prognosis. However, the clinical course of CAAs and factors associated with CAA regression have not been well analyzed. Methods and Results The cohort of the Z‐Score 2nd Project Stage study, a multicenter, retrospective, cohort study involving 44 institutions in Japan including 1006 patients with KD, was examined. CAAs were classified by the z score of their internal diameter in the acute phase: small (z

Abstract Kawasaki disease (KD) is an acute systemic vasculitis that mainly affects infants and young children. The etiology of KD has been discussed for several decades; however, no reproducible risk factors have yet been proven. We used the Japan Environment and Children’s Study data to explore the association between the causal effects of exposure during the fetal and neonatal periods and KD onset. The Japan Environment and Children’s Study, a nationwide birth cohort study, has followed approximately 100,000 children since 2011. We obtained data on exposures and outcomes from the first trimester to 12 months after birth. Finally, we included 90,486 children who were followed for 12 months. Among them, 343 children developed KD. Multivariate logistic regression revealed that insufficient intake of folic acid during pregnancy (odds ratio [OR], 1.37; 95% CI 1.08–1.74), maternal thyroid disease during pregnancy (OR, 2.03; 95% CI 1.04–3.94), and presence of siblings (OR, 1.33; 95% CI 1.06–1.67) were associated with KD onset in infancy. In this study, we identified three exposures as risk factors for KD. Further well-designed studies are needed to confirm a causal relationship between these exposures and KD onset.

Summary: Radium is refocused from the viewpoint of an environmental pollutant and cancer therapy using alpha particles, where it mainly exists as a hydrated ion. We investigated the radium hydration structure and the dynamics of water molecules by extended X-ray absorption fine structure (EXAFS) spectroscopy and ab initio molecular dynamics (AIMD) simulation. The EXAFS experiment showed that the coordination number and average distance between radium ion and the oxygen atoms in the first hydration shell are 9.2 ± 1.9 and 2.87 ± 0.06 Å, respectively. They are consistent with those obtained from the AIMD simulations, 8.4 and 2.88 Å. The AIMD simulations also revealed that the water molecules in the first hydration shell of radium are less structured and more mobile than those of barium, which is an analogous element of radium. Our results indicate that radium can be more labile than barium in terms of interactions with water.

Abstract Background Examining the predictors of summative assessment performance is important for improving educational programs and structuring appropriate learning environments for trainees. However, predictors of certification examination performance in pediatric postgraduate education have not been comprehensively investigated in Japan. Methods The Pediatric Board Examination database in Japan, which includes 1578 postgraduate trainees from 2015 to 2016, was analyzed. The examinations included multiple-choice questions (MCQs), case summary reports, and an interview, and the predictors for each of these components were investigated by multiple regression analysis. Results The number of examination attempts and the training duration were significant negative predictors of the scores for the MCQ, case summary, and interview. Employment at a community hospital or private university hospital were negative predictors of the MCQ and case summary score, respectively. Female sex and the number of academic presentations positively predicted the case summary and interview scores. The number of research publications was a positive predictor of the MCQ score, and employment at a community hospital was a positive predictor of the case summary score. Conclusion This study found that delayed and repeated examination taking were negative predictors, while the scholarly activity of trainees was a positive predictor, of pediatric board certification examination performance.

Background: Kawasaki disease (KD) is a systemic vasculitis complicated with coronary artery abnormalities (CAAs). Intravenous immunoglobulin reduces the occurrence of CAAs, but significant number of KD patients with CAAs still exists. Thus, new approaches to prevent and attenuate CAAs are warranted. Atorvastatin has been shown to promote endothelial cell homeostasis and suppress vascular inflammation and has received enthusiasm as a potentially new candidate treatment for KD. In the United States, a phase I/IIa dose-escalation study of atorvastatin in KD patients with CAAs demonstrated the safety and pharmacokinetic data of atorvastatin. However, due to the uncertainty in the application of these results to other populations, we aim to examine the tolerability and generate pharmacokinetics data in Japanese KD patients. Methods: This is a multicenter, single-arm, open-label, phase I/IIa study of atorvastatin in acute KD patients with CAAs in Japan. A minimum of 9 and a maximum of 18 KD patients (2 years–17 years old) will be recruited for a 3 + 3 dose-escalation study of a 6-week course of atorvastatin (0.125–0.5 mg/kg/day). The primary outcome will be safety of atorvastatin. The secondary outcomes will be pharmacokinetics of atorvastatin, activity of atorvastatin and echocardiographic assessment of CAAs. The activity of atorvastatin will include assessment of C-reactive protein or high sensitivity C-reactive protein and white blood cell levels. Discussion: This study will provide evidence of the safety, tolerability, and pharmacokinetics of atorvastatin in Japanese KD patients and may lead new standard therapy for acute-phase KD associated with CAA complications. Trial registration: Japan Registry of Clinical Trials (JRCTs031180057). Registered December 19, 2018, https://jrct.niph.go.jp/en-latest-detail/jRCTs031180057.

BackgroundAtopic dermatitis (AD) is a chronic and inflammatory skin disease that causes health-related burdens associated with pruritus and poor quality of life. Our previous study demonstrated that moisturizer (2e) application has a primary preventive effect on AD. However, this effect was not observed in recent randomized control trials. Thus, the ideal moisturizer type and application frequency for preventing AD development in infants remains unclear. We hypothesize that twice daily application of moisturizer is more effective than once daily application. We predict that applying sufficient amounts of high-quality moisturizer may be effective for preventing AD development in neonates and infants. Here, we describe a protocol for comparing the efficacy of twice daily and once daily application of Fam's Baby™ moisturizer and once daily application of 2e moisturizer for preventing AD in neonates.MethodsThis study is a single-center, three-parallel group, assessor-blind, superiority, individually randomized, controlled, phase II trial. Sixty newborns with at least one parent or sibling who has had AD is randomly assigned to application of Fam's Baby twice daily, Fam's Baby once daily, or 2e once daily in a 1:1:1 ratio until 32 weeks old. The primary outcome is the time to the first onset of AD during administration of the moisturizer.DiscussionThis is the first phase II randomized, controlled trial in Japan to estimate how effective the twice daily or once daily application of Fam's Baby moisturizer is in preventing AD compared to the once daily application of 2e moisturizer. In this study, we will use 2e once daily as a control to confirm the efficacy for primary prevention of AD as found in our previous trial. Based on the results of this study, we hope to conduct a phase III study to determine the optimal method for preventing AD via moisturizer application. Evaluation of application of moisturizers for preventing AD in this study is expected to contribute to a reduction in the prevalence of AD and a reduction in health care costs.Trial registrationJapan Registry of Clinical Trials (jRCT); ID: jRCTs031200070.

BackgroundThe role of antibiotics in the treatment of Shiga toxin-producing Escherichia coli (STEC) infection is controversial.ObjectivesTo evaluate the association between treatment (antibiotics, antidiarrheal agents, and probiotics) for STEC infection and hemolytic uremic syndrome (HUS) development.Patients and methodsWe performed a population-based matched case-control study using the data from the National Epidemiological Surveillance of Infectious Diseases (NESID) between January 1, 2017 and December 31, 2018. We identified all patients with STEC infection and HUS as cases and matched patients with STEC infection without HUS as controls, with a case-control a ratio of 1:5. Further medical information was obtained by a standardized questionnaire. Multivariable conditional logistic regression model was used.Results7760 patients with STEC infection were registered in the NESID. 182 patients with HUS and 910 matched controls without HUS were selected. 90 patients with HUS (68 children and 22 adults) and 371 patients without HUS (266 children and 105 adults) were included in the main analysis. The matched ORs of any antibiotics and fosfomycin for HUS in children were 0.56 (95% CI 0.32-0.98), 0.58 (0.34-1.01). The matched ORs for HUS were 2.07 (1.07-4.03), 0.86 (0.46-1.61) in all ages treated with antidiarrheal agent and probiotics.ConclusionsAntibiotics, especially fosfomycin, may prevent the development of HUS in children, while use of antidiarrheal agents should be avoided.

Objective: Previous studies showed the efficacy of glucocorticoids on prevention of coronary artery lesions (CAL) among Kawasaki disease (KD) patients, and clinical guideline for KD in Japan was changed regarding glucocorticoid use in 2012. However, little is known regarding how the guideline change had impacts on healthcare utilizations and clinical outcomes.Methods: We conducted a retrospective observational study using national inpatient database in Japan among KD patients aged under 18 years during 2010–2015. Recent trends in practice patterns were analyzed, and we divided the hospitals into four groups based on glucocorticoid use: (1) consistently using hospital, (2) started using hospital, (3) stopped using hospital, and (4) never using hospital. Then, we compared healthcare utilizations and risks of coronary artery lesions before and after the guideline change.Results: We identified 24,517 inpatients with KD. From 2010 to 2014, use of glucocorticoid increased from 8.9 to 17.4% of KD inpatients. All types of hospitals showed reduction in coronary artery lesions, but the reduction was the most prominent in hospitals that started using glucocorticoid therapy after clinical guideline change in 2012 (adjusted OR, 0.22; 95%CI, 0.07–0.68). Also, Glucocorticoid consistently using hospitals, started using hospitals, and never using hospitals showed reductions in hospitalization costs, whereas hospitals that stopped using glucocorticoids after clinical guideline change had elevated healthcare costs as opposed to natural trends observed in other groups. Guideline complying hospitals had the greatest reductions in healthcare costs.Conclusions: The early stage glucocorticoid use could be a cost-saving strategy for treatment for KD patients without increasing risks of CAL.

Abstract Background Atopic dermatitis is the first clinical manifestation of the atopic march, with the highest incidence in the first year of life. Those affected often go on to develop other allergic diseases including food allergy, asthma, and allergic rhinitis. Recent evidence suggests that sensitization to foods may occur through a defective skin barrier which is common in atopic dermatitis in early life. We hypothesize that therapeutic aggressive intervention to treat new onset atopic dermatitis may prevent the development of later allergen sensitization, and associated food allergy, asthma, and allergic rhinitis. Methods This study is a multi-center, pragmatic, two-parallel group, assessor-blind, superiority, individually randomized controlled trial. Atopic dermatitis infants (N = 650) 7–13 weeks old who develop an itchy rash within the previous 28 days are randomly assigned to the aggressive treatment or the conventional treatment in a 1:1 ratio. The primary outcome is oral food challenge-proven IgE-mediated hen’s egg allergy at the age of 28 weeks. Discussion This is a novel pragmatic RCT study to examine the efficacy of early aggressive treatment for atopic dermatitis to prevent later food allergy. If our hypothesis is correct, we hope that such a strategy might impact on disease prevention in countries where food allergy is common, and that our results might reduce the frequency and associated costs of all food allergies as well as hens egg food allergy. Long-term follow and other similar studies will help to determine whether such a strategy will reduce the burden of other allergic diseases such as asthma and allergic rhinitis. Trial registration UMIN-CTR: UMIN000028043

Background: Acute coronary syndrome (ACS), which is emerging in adults long after confirmed (followed-up or lost-to-follow), or missed Kawasaki disease (KD), is poorly characterized.Methods and Results: A Japanese retrospective nationwide hospital-based questionnaire survey of ACS during 2000–09 was conducted to characterize such patients. Among a total of 67 patients (median age 35, male 76%) recruited, low conventional coronary risks (≤1/6) was noted in 75%, a diagnosis of ST-elevation and myocardial infarction or cardiac arrest in 66%, medication before ACS in 22% (warfarin in 4%), and no prior history of acute myocardial infarction in 94%. One-month mortality was 19%. KD diagnosis was made in 32 during acute illness (Group A), in which 17 were lost to follow, and retrospectively in the other 35 from coronary imaging at ACS (Group B). Group A developed ACS at lower coronary risks (≤2/5 in 87 vs. 65% in group B, p = 0.043) at a younger age (26.5 vs. 40 yo, p < 0.001). In group A, followed-up patients developed ACS under medication before ACS (87 vs. 0% in lost-to-follow patients, p < 0.001) for giant aneurysm in culprit lesions (69 vs. 29%, p = 0.030). One-month mortality was comparable between groups A and B, and between patients followed-up and lost-to-follow in group A. The culprit lesion in group A was characterized by the association of an aneurysm ≥6 mm in acute KD (100%), lack of significant stenosis (61%) or giant aneurysm (50%) in the long-term (median interval 16 y), and the presence of intravascular ultrasound-derived calcification at ACS (86%).Conclusions: The present retrospective nationwide questionnaire survey demonstrated nationwide emergence of initial ACS in young adults at low coronary risks, who are followed-up or lost-to-follow after confirmed KD and initial coronary aneurysms ≥6 mm.

Background:: The forced oscillation technique (FOT) is useful for studying pulmonary function in children, as well as in school children with asthma. However, the standard values for respiratory resistance (Rrs) in Asian school children remain unknown. We evaluated the standard Rrs using a type of FOT, impulse oscillometry (IOS), in healthy Japanese children at elementary and junior high schools. Methods:: A total of 795 children (age range: 6-15 years; mean age ± SD: 11.1 ± 2.4 years; 404 boys, 391 girls) at elementary and junior high schools participated in the study. Of the 795 children, we evaluated the Rrs of 537 children aged 6-15 years (mean ± SD: 10.8 ± 2.4 years) using IOS. Results:: Regression analyses with three IOS parameters, Rrs at 5 Hz (R5), Rrs at 20 Hz (R20), and Rrs difference between 5 Hz and 20 Hz (R5-R20), for age, height, weight, and degree of obesity as independent variables demonstrated the strongest correlation between each parameter and children’s height. All parameters decreased with increasing height. Using the lambda-mu-sigma (LMS) method, we created standard curves for the Rrs values based on height. Conclusions:: Our standard curves could be useful for diagnosis and control evaluation of childhood asthma.

Kawasaki disease (KD; MIM#61175) is a systemic vasculitis syndrome with unknown etiology which predominantly affects infants and children. Recent findings of susceptibility genes for KD suggest possible involvement of the Ca(2+)/NFAT pathway in the pathogenesis of KD. ORAI1 is a Ca(2+) release activated Ca(2+) (CRAC) channel mediating store-operated Ca(2+) entry (SOCE) on the plasma membrane. The gene for ORAI1 is located in chromosome 12q24 where a positive linkage signal was observed in our previous affected sib-pair study of KD. A common non-synonymous single nucleotide polymorphism located within exon 2 of ORAI1 (rs3741596) was significantly associated with KD (P = 0.028 in the discovery sample set (729 KD cases and 1,315 controls), P = 0.0056 in the replication sample set (1,813 KD cases vs. 1,097 controls) and P = 0.00041 in a meta-analysis by the Mantel-Haenszel method). Interestingly, frequency of the risk allele of rs3741596 is more than 20 times higher in Japanese compared to Europeans. We also found a rare 6 base-pair in-frame insertion variant associated with KD (rs141919534; 2,544 KD cases vs. 2,414 controls, P = 0.012). These data indicate that ORAI1 gene variations are associated with KD and may suggest the potential importance of the Ca(2+)/NFAT pathway in the pathogenesis of this disorder.

The refining of platinum group metals is based mainly on solvent extraction methods, whereas Ru is selectively recovered by distillation as RuO4. Replacement of distillation by extraction is expected to simplify the purification process. To develop an effective extraction system for Ru, we analyzed the Ru species in HCl with ultraviolet-visible (UV-Vis) and Ru K-edge extended X-ray absorption fine structure (EXAFS) spectroscopies, and we examined the properties of Ru extracted with N-2-ethylhexyl-bis(N-di-2-ethylhexyl-ethylamide) amine (EHBAA) and trioctylamine (TOA). EXAFS and UV-Vis spectra of Ru in HCl solutions revealed that the predominant Ru species in 0.5–10 M HCl solutions changed from [RuCl4(H2O)2]− to [RuCl6]3− with the HCl concentration. The extraction percentages (E%) of Ru in the EHBAA system increased with increasing HCl concentration, reached 80% at [HCl] = 5 M, and decreased at higher HCl concentrations; the corresponding E% for TOA were low. EXAFS analysis of the extracted complex indicated that the Ru3+ had 5 Cl− and 1 H2O in its inner coordination sphere. The similarity of the dependence on HCl concentrations of the E% in the EHBAA system and the distribution profile of [RuCl5(H2O)]2− on [RuCln(H2O)6−n]3−n suggested that the EHBAA extracted the pentachlorido species.

In fish, oocyte meiotic maturation is regulated by 17α, 20β-dihydroxy-progesterone through cAMP. To study the role of cAMP response element binding protein (CREB) in meiotic maturation, we cloned and characterized the expression pattern of CREBs from two fish models, the Nile tilapia and catfish. In the Nile tilapia three different CREBs were identified where in CREB1 was found in many tissues including gonads with abundant expression in testis. CREB2, few amino acids shorter than CREB1, was expressed in several tissues with abundant expression in ovary. In addition, a 3'UTR variant form, CREB3 was exclusively found in ovary. During natural 14-day ovarian cycle of the Nile tilapia, CREB1 expression was stable throughout vitellogenesis with a sharp decrease on the day of spawning. In contrast, CREB2 remain unchanged throughout the ovarian cycle, however elevated in 11-day full-grown immature ovarian follicle and after hCG-induction. Interestingly, CREB3 expression was induced three folds on the day of spawning as well as during hCG-induced oocyte maturation. Based on the synergistic expression pattern, CREB1 is likely to control oocyte growth, whereas CREB 2 and 3 contribute to oocyte maturation in tilapia and the latter seems to be critical. In catfish, a single form of CREB showed a maximum expression during spawning phase and hCG-induced maturation both in vivo and in vitro augmented CREB expression. These results suggest that spatial and temporal expression of CREBs seems to be important for final oocyte maturation and may also regulate oocyte growth in fish.