Integrated-omics analysis with explainable deep networks on pathobiology of infant bronchiolitis.

Bronchiolitis is the leading cause of infant hospitalization. However, the molecular networks driving bronchiolitis pathobiology remain unknown. Integrative molecular networks, including the transcriptome and metabolome, can identify functional and regulatory pathways contributing to disease severity. Here, we integrated nasopharyngeal transcriptome and metabolome data of 397 infants hospitalized with bronchiolitis in a 17-center prospective cohort study. Using an explainable deep network model, we identified an omics-cluster comprising 401 transcripts and 38 metabolites that distinguishes bronchiolitis severity (test-set AUC, 0.828). This omics-cluster derived a molecular network, where innate immunity-related metabolites (e.g., ceramides) centralized and were characterized by toll-like receptor (TLR) and NF-κB signaling pathways (both FDR < 0.001). The network analyses identified eight modules and 50 existing drug candidates for repurposing, including prostaglandin I2 analogs (e.g., iloprost), which promote anti-inflammatory effects through TLR signaling. Our approach facilitates not only the identification of molecular networks underlying infant bronchiolitis but the development of pioneering treatment strategies.

Nasal microRNA signatures for disease severity in infants with respiratory syncytial virus bronchiolitis: a multicentre prospective study.

BACKGROUND: Respiratory syncytial virus (RSV) bronchiolitis contributes to a large morbidity and mortality burden globally. While emerging evidence suggests that airway microRNA (miRNA) is involved in the pathobiology of RSV infection, its role in the disease severity remains unclear. METHODS: In this multicentre prospective study of infants (aged<1 year) hospitalised for RSV bronchiolitis, we sequenced the upper airway miRNA and messenger RNA (mRNA) at hospitalisation. First, we identified differentially expressed miRNAs (DEmiRNAs) associated with higher bronchiolitis severity-defined by respiratory support (eg, positive pressure ventilation, high-flow oxygen therapy) use. We also examined the biological significance of miRNAs through pathway analysis. Second, we identified differentially expressed mRNAs (DEmRNAs) associated with bronchiolitis severity. Last, we constructed miRNA-mRNA coexpression networks and determined hub mRNAs by weighted gene coexpression network analysis (WGCNA). RESULTS: In 493 infants hospitalised with RSV bronchiolitis, 19 DEmiRNAs were associated with bronchiolitis severity (eg, miR-27a-3p, miR-26b-5p; false discovery rate<0.10). The pathway analysis using miRNA data identified 1291 bronchiolitis severity-related pathways-for example, regulation of cell adhesion mediated by integrin. Second, 1298 DEmRNAs were associated with bronchiolitis severity. Last, of these, 190 DEmRNAs were identified as targets of DEmiRNAs and negatively correlated with DEmiRNAs. By applying WGCNA to DEmRNAs, four disease modules were significantly associated with bronchiolitis severity-for example, microtubule anchoring, cell-substrate junction. The hub genes for each of these modules were also identified-for example, PCM1 for the microtubule anchoring module, LIMS1 for the cell-substrate junction module. CONCLUSIONS: In infants hospitalised for RSV bronchiolitis, airway miRNA-mRNA coexpression network contributes to the pathobiology of bronchiolitis severity.

Maternal excessive weight gain as a potential risk factor for prolonged labor in Japanese pregnant women: The Japan Environment and Children's Study.

AIM: This study aimed to determine whether excessive maternal weight gain during pregnancy was associated with a higher risk of prolonged labor. METHODS: We analyzed the data regarding maternal weight gain during pregnancy for the participants of Japan Environment and Children's Study (JECS), which is an ongoing nationwide prospective birth cohort study in Japan. After excluding participants with multiple pregnancies, with deliveries before 37 or beyond 42 weeks of gestation, or who had undergone cesarean section, 71,154 (nulliparous, n = 28,442) Japanese women were included. Prolonged labor was defined by a cutoff ranking at the 95th percentile and consequently defined as labor duration exceeding 12.7 h in multiparous women and exceeding 23.2 h in nulliparous women. These classifications were made according to labor curves established by the Japanese Society of Obstetrics and Gynecology Perinatal Committee developed in June 2021. Considering that no studies have conducted an investigation based on this new guideline, we analyzed the association between excessive maternal weight gain during pregnancy and prolonged labor by parity. RESULTS: The overall incidence of prolonged labor was 10.2% (2,907/28,442) in nulliparous women and 6.1% (2,597/42,712) in multiparous women. Multivariable analysis indicated that excessive maternal weight gain was significantly associated with prolonged labor in nulliparous (adjusted odds ratio, 1.21; 95% confidence interval, 1.10-1.32) and multiparous women (adjusted odds ratio, 1.15; 95% confidence interval, 1.05-1.27). Kaplan-Meier survival analysis showed that as labor progressed, the percentage of women who had not yet delivered was higher among those with excessive maternal weight gain than among those with normal maternal weight gain in both the nulliparous (median labor duration 12.9 h vs 12.2 h, p<0.001) and multiparous (median labor duration 6.2 h vs 5.8 h, p<0.001) groups. CONCLUSION: Excessive maternal weight gain was significantly associated with prolonged labor in Japanese women.

Neonatal transfer and duration of hospitalization of newborns as potential risk factors for impaired mother-infant bonding: The Japan Environment and Children's Study.

BACKGROUND: Currently, there is no consensus regarding the relationship between neonatal transfer and duration of hospitalization in cases of impaired mother-infant bonding (MIB). This study aimed to determine whether neonatal transfer and duration of hospitalization of newborns increase the risk for impaired MIB. METHODS: The MIB Scale was used to assess impaired MIB 1 year after delivery, using data from the Japan Environment and Children's Study. A score ≥ 5 points indicated impaired MIB. Multiple logistic regression analyses were performed to estimate the association between neonatal transfer and duration of hospitalization of newborns with the risk of impaired MIB. RESULTS: A total of 66,402 pregnant women were included in the study. The overall incidence rate of impaired MIB was 11.2 %. The mean duration of hospitalization of newborns was 7.1 ± 6.4 days. After adjusting for potential confounders, neonatal transfer (adjusted odd ratio (OR): 1.13 [95 % confidence interval (CI)), 1.01-1.27]) and duration of hospitalization of newborns (adjusted OR 1.007; 95 % CI 1.003-1.010) were associated with impaired MIB. The area under the receiver operating characteristic curve for the duration of hospitalization of newborns for impaired MIB was 0.53. LIMITATIONS: Maternal childhood abuse and neglect history were not evaluated, and information regarding whether the infants were admitted to the neonatal intensive care unit was unavailable. CONCLUSIONS: Japanese women whose newborns underwent neonatal transfer should be followed up for at least 1 year after delivery, regardless of the duration of hospitalization of newborns.

Association of maternal leukocyte, monocyte, and neutrophil counts with hypertensive disorders of pregnancy: the Japan Environment and Children's Study (JECS).

Hypertensive disorders of pregnancy (HDP) increase the risk of preterm births and cesarean delivery. This study aimed to investigate whether maternal blood leukocyte, monocyte, or neutrophil counts in the first trimester are related to the development of HDP. Data were collected from the Japan Environment and Children's Study, a large birth cohort study (n = 38,194) that recruited pregnant women in 15 Regional Centers across Japan (from January 2011 to March 2014). The odds ratios (ORs) for mild/severe HDP according to the cut-off value of leukocyte/neutrophil/monocyte counts by the receiver operating characteristic curve showed high ORs. Furthermore, pregnant women with the highest quartiles of leukocyte and monocyte counts had higher adjusted ORs (aORs) for mild (leukocyte: aOR = 1.27, 95% confidence interval [CI]: 1.02-1.58; monocyte: aOR = 1.30, 95% CI 1.04-1.63) and severe HDP (leukocyte: aOR = 1.51, 95% CI 1.08-2.13; monocyte: aOR = 1.44, 95% CI 1.03-2.01) compared with those with the lowest quartiles of those counts. In addition, pregnant women with the highest neutrophil counts had higher aOR for mild HDP (aOR = 1.26, 95% CI 1.02-1.56) compared with those with the lowest count. In conclusion, high leukocyte and monocyte counts in the first trimester are associated with the development of HDP. Thus, they may be used to predict subsequent HDP.

A Simple Clinical Scoring System to Determine the Risk of Pancreatic Cancer in the General Population.

This study aimed to develop and validate a simple scoring system to determine the high-risk group for pancreatic cancer (PC) in the asymptomatic general population. The scoring system was developed using data from PC cases and randomly selected non-PC cases undergoing annual medical checkups between 2008 and 2013. The performance of this score was validated for participants with medical checkups between 2014 and 2016. In the development set, 45 PC cases were diagnosed and 450 non-PC cases were identified. Multivariate analysis showed three changes in clinical data from 1 year before diagnosis as independent risk factors: ΔHbA1c ≥ 0.3%, ΔBMI ≤ -0.5, and ΔLDL ≤ -20 mg/dL. A simple scoring system, incorporating variables and abdominal ultrasound findings, was developed. In the validation set, 36 PC cases were diagnosed over a 3-year period from 32,877 participants. The AUROC curve of the scoring system was 0.925 (95%CI 0.877-0.973). The positive score of early-stage PC cases, including Stage 0 and I cases, was significantly higher than that of non-PC cases (80% vs. 6%, p = 0.001). The simple scoring system effectively narrows down high-risk PC cases in the general population and provides a reasonable approach for early detection of PC.

Association between filaggrin gene mutations and the clinical features of molluscum contagiosum: The Yamanashi Adjunct Study of the Japan Environment and Children's Study.

Previous studies have reported swimming, atopic dermatitis, and filaggrin (FLG) gene mutations as risk factors for molluscum contagiosum (MC) infection. FLG gene mutations impair skin barrier function. The aim of this study was to determine the impact of FLG mutations on the incidence and clinical features of MC. We used data from 2036 children who participated in the Yamanashi Adjunct Study of the Japan Environment and Children's Study, a prospective, birth cohort study. A questionnaire for caregivers (when children were 4 and 8 years of age) asked about clinical features including previous MC incidence and treatment, number of MC lesions at first visit, and time to resolution. Participants underwent genotyping to detect six FLG mutations that are common in the Japanese population. A logistic regression model was used to analyze the association between MC incidence and FLG mutations, adjusted for potential confounders. The cumulative incidence of MC at age 8 years was 47.1%. Among participants with a history of MC, 67.6% had undergone curettage. FLG mutation was a significant risk factor for MC incidence (adjusted odds ratio [aOR] 1.69, 95% confidence interval [CI] 1.18-2.42). Swimming and atopic dermatitis were also significant risk factors for MC. There was no significant association between FLG mutation and the number of MC lesions at the first visit or the time to resolution of lesions. FLG mutation is a risk factor for MC incidence; however, FLG mutations do not affect the number of MC lesions at presentation or the time to resolution.

Nasopharyngeal airway long noncoding RNAs of infants with bronchiolitis and subsequent risk of developing childhood asthma.

BACKGROUND: Severe bronchiolitis (ie, bronchiolitis requiring hospitalization) during infancy is a major risk factor for developing childhood asthma. However, the biological mechanisms linking these 2 conditions remain unclear. OBJECTIVE: We sought to investigate the longitudinal relationship between nasopharyngeal airway long noncoding RNA (lncRNA) in infants with severe bronchiolitis and subsequent asthma development. METHODS: In this multicenter prospective cohort study of infants with severe bronchiolitis, we performed RNA sequencing of nasopharyngeal airway lncRNAs at index hospitalization. First, we identified differentially expressed lncRNAs (DE-lncRNAs) associated with asthma development by age 6 years. Second, we investigated the associations of DE-lncRNAs with asthma-related clinical characteristics. Third, to characterize the function of DE-lncRNAs, we performed pathway analysis for mRNA targeted by DE-lncRNAs. Finally, we examined the associations of DE-lncRNAs with nasal cytokines at index hospitalization. RESULTS: Among 343 infants with severe bronchiolitis (median age, 3 months), we identified 190 DE-lncRNAs (false-discovery rate [FDR] < 0.05) associated with asthma development (eg, LINC02145, RAMP2-AS1, and PVT1). These DE-lncRNAs were associated with asthma-related clinical characteristics (FDR < 0.05), for example, respiratory syncytial virus or rhinovirus infection, infant eczema, and IgE sensitization. Furthermore, DE-lncRNAs were characterized by asthma-related pathways, including mitogen-activated protein kinase, FcɛR, and phosphatidylinositol 3-kinase (PI3K)-protein kinase B signaling pathways (FDR < 0.05). These DE-lncRNAs were also associated with nasal cytokines (eg, IL-1ß, IL-4, and IL-13; FDR < 0.05). CONCLUSIONS: In a multicenter cohort study of infants with severe bronchiolitis, we identified nasopharyngeal airway lncRNAs associated with childhood asthma development, characterized by asthma-related clinical characteristics, asthma-related pathways, and nasal cytokines. Our approach identifies lncRNAs underlying the bronchiolitis-asthma link and facilitates the early identification of infants at high risk of subsequent asthma development.

Infantile peanut introduction and peanut allergy in regions with a low prevalence of peanut allergy: the Japan Environment and Children's Study (JECS).

BACKGROUND: In regions with a high prevalence of peanut allergy (PA), there is a consensus that the introduction of peanuts in early infancy is preventive against the development of PA. However, few studies have investigated whether the introduction of peanuts to infants is associated with PA in regions with a low prevalence of PA, including Japan. METHODS: We used data from 74,240 mother-child pairs who participated in the Japan Environment and Children's Study, a prospective birth cohort recruited between January 2011 and March 2014. A logistic regression model was used to analyze the association between infantile peanut introduction and PA at the age of 4 years with non-infantile peanut introduction as the reference group, adjusted for potential confounders. RESULTS: The percentage of infantile peanut introduction was 4.9% (n=3294) and 286 (0.4%) participants had allergic symptoms to peanuts at 4 years of age. Of all participants, 129 (0.2%) had PA at 4 years of age, which was defined as allergic symptoms and sensitization to peanuts. Those with infantile peanut introduction had a lower prevalence of PA than those without infantile peanut introduction, although this did not reach statistical significance (adjusted odds ratio: 0.53, 95% confidence interval, 0.17-1.68). Sensitivity analysis using IgE-mediated symptoms caused by peanuts as the outcome showed a similar result in relation to infantile peanut introduction. CONCLUSIONS: In countries with a low prevalence of PA, the effect of infantile peanut introduction on PA prevention was unclear.

Antibiotic prescription for outpatients with influenza and subsequent hospitalisation: A cohort study using insurance data.

Background: Whether prophylactic administration of antibiotics to patients with influenza reduces the hospitalisation risk is unknown. We aimed to examine the association between antibiotic prescription in outpatients with influenza infection and subsequent hospitalisation. Methods: We conducted a cohort study using health insurance records of Japanese clinic and hospital visits between 2012 and 2016. Participants were outpatients (age, 0-74 years) with confirmed influenza infection who were prescribed anti-influenza medicine. The primary outcomes were the hospitalisation risk from all causes and pneumonia and the duration of hospitalisation due to pneumonia. Results: We analysed 903,104 outpatient records with 2469 hospitalisations. The risk of hospitalisation was greater in outpatients prescribed anti-influenza medicine plus antibiotics (0.31% for all causes and 0.18% for pneumonia) than in those prescribed anti-influenza medicine only (0.27% and 0.17%, respectively). However, the risk of hospitalisation was significantly lower in patients prescribed peramivir and antibiotics than in those prescribed peramivir only. Patients who received add-on antibiotics had a significantly longer hospital stay (4.12 days) than those who received anti-influenza medicine only (3.77 days). In all age groups, the hospitalisation risk from pneumonia tended to be greater in those who received antibiotics than in those prescribed anti-influenza medicine only. However, among older patients (65-74 years), those provided add-on antibiotics had an average 5.24-day shorter hospitalisation due to pneumonia than those provided anti-influenza medicine only (not significant). Conclusions: In outpatient cases of influenza, patients who are prescribed antibiotics added to antiviral medicines have a higher risk of hospitalisation and longer duration of hospitalisation due to pneumonia.

Refractive Error and Axial Length and Their Related Factors in 8-Year-Old Japanese Children: The Yamanashi Adjunct Study of the Japan Environment and Children's Study (JECS).

PURPOSE: To investigate the distribution of visual acuity, refractive error, and axial length in 8-year-old children who participated in an additional survey in Yamanashi Prefecture of the Japan Environmental Children's Study (hereafter referred to as JECS-Y) conducted from 2019 to 2021. PARTICIPANTS AND METHODS: Eight-year-old children who participated in the JECS-Y study were subjected to noncycloplegic measurements of refractive error and axial length. If the uncorrected visual acuity was less than 20/20, the best corrected visual acuity was evaluated in accordance with the autorefraction data. A questionnaire was administered regarding the parent's history of eyeglass wear or contact lens use. RESULTS: Among the 400 participating children, the rate of uncorrected visual acuity of 20/20 or better in both eyes was 70.4%. The mean equivalent spherical equivalent error for both eyes was -0.366 ± 1.016 D. The mean axial length was 23.08 ± 0.225 mm in all patients. The males showed significantly longer axial length than the females despite no differences in body height. There was a significant correlation between axial length, spherical refractive, and uncorrected visual acuity. The children of parents with a history of wearing eyeglasses or contact lenses showed a significantly more myopic equivalent refractive error than those without a history. CONCLUSIONS: This study clarified the current state of refractive error in 8-year-old children and the association of inheritance with refractive error. In addition, the axials were significantly longer in male patients.

Obesity as a potential risk factor for stillbirth: The Japan Environment and Children's Study.

The relationship between high body mass index (BMI) >25 kg/m2 and risk for stillbirth in the Japanese population remains unclear. This study aimed to estimate the impact of maternal obesity on the risk of stillbirth in a Japanese population. This prospective cohort study used data from the Japan Environment and Children's Study, which recruited pregnant individuals between 2011 and 2014. A total of 93,772 fetuses were considered eligible for inclusion in this study. Stillbirth (fetal death before or during labor at ≥22 completed weeks of gestation) rates were compared among four pre-pregnancy BMI groups: underweight (<18.5 kg/m2), reference (18.5 to <25.0 kg/m2), overweight (25.0 to <30.0 kg/m2), and obese (≥30.0 kg/m2). The association between pre-pregnancy BMI and the risk of stillbirth was estimated using multiple logistic regression analyses. The overall stillbirth incidence was 0.33% (305/93,722). Compared with the reference group, the risk of stillbirth was significantly higher in the overweight group (adjusted odds ratio [aOR]: 1.55; 95% confidence interval [CI]: 1.08-2.23) and the obese group (aOR: 2.60; 95% CI: 1.59-4.24). The overall incidence of early stillbirth (i.e., <28 weeks) was 0.17% (155/93,722). Similarly, after adjusting for potential confounding factors, the risk of early stillbirth was significantly higher in the obese group (aOR: 4.33; 95% CI: 2.44-7.70). Increased maternal BMI was associated with an increased risk of stillbirth in the Japanese population. Therefore, counselling women planning for pregnancy on the importance of an appropriate pre-pregnancy BMI to minimize the risk of stillbirth is important.

Nasopharyngeal fungal subtypes of infant bronchiolitis and disease severity risk.

BACKGROUND: Bronchiolitis is a leading cause of infant hospitalization. Recent research suggests the heterogeneity within bronchiolitis and the relationship of airway viruses and bacteria with bronchiolitis severity. However, little is known about the pathobiological role of fungi. We aimed to identify bronchiolitis mycotypes by integrating fungus and virus data, and determine their association with bronchiolitis severity and biological characteristics. METHODS: In a multicentre prospective cohort study of 398 infants (age <1 year, male 59%) hospitalized for bronchiolitis, we applied clustering approaches to identify mycotypes by integrating nasopharyngeal fungus (detected in RNA-sequencing data) and virus data (respiratory syncytial virus [RSV], rhinovirus [RV]) at hospitalization. We examined their association with bronchiolitis severity-defined by positive pressure ventilation (PPV) use and biological characteristics by nasopharyngeal metatranscriptome and transcriptome data. RESULTS: In infants hospitalized for bronchiolitis, we identified four mycotypes: A) fungiM.restrictavirusRSV/RV, B) fungiM.restrictavirusRSV, C) fungiM.globosavirusRSV/RV, D) funginot-detectedvirusRSV/RV mycotypes. Compared to mycotype A infants (the largest subtype, n = 211), mycotype C infants (n = 85) had a significantly lower risk of PPV use (7% vs. 1%, adjOR, 0.21; 95% CI, 0.02-0.90; p = 0.033), while the risk of PPV use was not significantly different in mycotype B or D. In the metatranscriptome and transcriptome data, mycotype C had similar bacterial composition and microbial functions yet dysregulated pathways (e.g., Fc γ receptor-mediated phagocytosis pathway and chemokine signaling pathway; FDR <0.05). INTERPRETATION: In this multicentre cohort, fungus-virus clustering identified distinct mycotypes of infant bronchiolitis with differential severity risks and unique biological characteristics. FUNDING: This study was supported by the National Institutes of Health.

Maternal dietary fiber intake during pregnancy and child development: the Japan Environment and Children's Study.

Background: Animal studies have shown that maternal low-fiber diets during pregnancy may impair brain development and function in offspring, but this has not been validated by epidemiological studies. The aim of this study was to investigate the link between maternal dietary fiber intake during pregnancy and neurodevelopmental delay in offspring using a large birth cohort. Methods: A total of 76,207 mother-infant pairs were analyzed using data from the Japan Environment and Children's Study, a nationwide prospective cohort study. Maternal dietary fiber intake was estimated using the food frequency questionnaire in mid-pregnancy. Maternal dietary fiber intake was adjusted for energy and classified into quintiles. Developmental delay was assessed in five domains using the Japanese version of the Ages and Stages Questionnaire, Third Edition at the age of 3 years. The logistic regression analysis was performed to estimate the odds ratio (OR) and 95% confidence interval (CI) for the link between dietary fiber intake during pregnancy and developmental delay at the age of 3 years. Results: The lowest intake group of total dietary fiber had a higher risk of delayed communication [adjusted OR (aOR), 1.51; 95% CI, 1.32-1.74], fine motor (aOR, 1.45; 95% CI, 1.32-1.61), problem-solving (aOR, 1.46; 95% CI, 1.32-1.61), and personal-social skills (aOR, 1.30; 95% CI, 1.12-1.50) than did the highest intake group. An analysis that excluded the effects of insufficient folic acid intake during pregnancy also showed a similar trend. Conclusion: This study showed that maternal dietary fiber deficiency during pregnancy might influence an increased risk of neurodevelopmental delay in offspring.

A nationwide, prospective, cohort study on exogenous oxytocin and delays in early child development: the Japan environment and children's study.

Although it remains debatable, exogenous oxytocin, commonly used for labour induction and augmentation, reportedly increases risks of neurodevelopment delay, attention-deficit/hyperactivity disorder, and autism spectrum disorder among children prenatally exposed to exogenous oxytocin. However, only few studies have objectively examined exogenous oxytocin's impact on early childhood development through scoring evaluations. This study investigated the association between exogenous oxytocin exposure and neurodevelopment in 3-year-old children using the Ages and Stages Questionnaires, Third Edition. In this nationwide prospective cohort study, we extracted data from 104,062 foetal records regarding exogenous oxytocin use during labour from the Japan Environment and Children's Study. Participants completed questionnaires throughout the pregnancy and postpartum periods. Outcomes comprised the developmental status less than each cut-off value for the five domains of the Ages and Stages Questionnaire, Third Edition. We conducted multivariable logistic regression analyses on the data of 55,400 children after controlling for confounders. Among the 55,400 included women, 19.0% (n = 10,506) used exogenous oxytocin during labour and 81.0% (n = 44,894) did not. Children exposed to exogenous oxytocin showed no significantly increased risk of developmental delay in any domain (communication: odds ratio [OR] 1.04, 95% confidence interval [CI] 0.92-1.16; gross motor: OR 0.97, 95% CI 0.87-1.08; fine motor: OR 1.00, 95% CI 0.92-1.09; problem-solving: OR 1.02, 95% CI 0.94-1.11; personal-social: OR 0.91, 95% CI 0.80-1.03).   Conclusion: Exogenous oxytocin for labour induction did not adversely affect early childhood development. Further studies accounting for the degree of exogenous oxytocin exposure are required to confirm these results. What is Known: • In developed countries, labour is induced in 20-25% of all pregnancies, for which oxytocin is commonly used. • Studies have associated risks of neurodevelopment delay, attention-deficit/hyperactivity disorder, and autism spectrum disorder with exposure to exogenous oxytocin. What is New: • Evaluation with the Ages and Stages Questionnaire, Third Edition, revealed that exogenous oxytocin use did not adversely affect early childhood development. • This prospective study reinforced the lack of evidence of an association between exogenous oxytocin use and early childhood development after adjustment for confounding and rigorous bias elimination.

Association of influenza vaccination or influenza virus infection history with subsequent infection risk among children: The Japan Environment and Children's Study (JECS).

We measured the association between history of influenza vaccination by age 2 years and influenza virus (IFV) infection at ages 3 and 4 years by relative risk reduction. We also examined the association between history of IFV infection by age 2 years and recurrent IFV infection at age 3 years. This study included 73,666 children from a large Japanese birth cohort. Among children vaccinated never, once or twice when aged under 2 years, 16.0%, 10.8% and 11.3%, respectively, had been infected with IFV by age 3 years, and 19.2%, 14.5% and 16.0%, respectively, by age 4 years. Compared with no history of influenza vaccination, vaccination at ages 1 and/or 2 years reduced the risk of IFV infection at age 3 by 30%-32% and at age 4 by 17%-24%. The relative risk of recurrent IFV infection at ages 3 and 4 years increased in proportion to the number of prior infections by age 2. One-season-prior influenza vaccination history reduced the IFV infection risk at age 3 years by 25%-42%. Influenza vaccination most effectively protected children at age 3 who lacked older sibling(s) and did not attend nursery school. One-season-prior IFV infection increased the relative risk of recurrent infection at age 3 years (1.72-3.33). In conclusion, influenza vaccination-induced protection may partly extend to the next season. Owing to the relative risk reduction by influenza vaccination and the increased relative risk of IFV infection from prior-season infection, annual influenza vaccination is recommended.

Characteristic Gut Bacteria in High Barley Consuming Japanese Individuals without Hypertension.

BACKGROUND: Barley, a grain rich in soluble dietary fiber ß-glucan, is expected to lower blood pressure. Conversely, individual differences in its effects on the host might be an issue, and gut bacterial composition may be a determinant. METHODS: Using data from a cross-sectional study, we examined whether the gut bacterial composition could explain the classification of a population with hypertension risks despite their high barley consumption. Participants with high barley intake and no occurrence of hypertension were defined as "responders" (n = 26), whereas participants with high barley intake and hypertension risks were defined as "non-responders" (n = 39). RESULTS: 16S rRNA gene sequencing revealed that feces from the responders presented higher levels of Faecalibacterium, Ruminococcaceae UCG-013, Lachnospira, and Subdoligranulum and lower levels of Lachnoclostridium and Prevotella 9 than that from non-responders. We further created a machine-learning responder classification model using random forest based on gut bacteria with an area under the curve value of 0.75 for estimating the effect of barley on the development of hypertension. CONCLUSIONS: Our findings establish a link between the gut bacteria characteristics and the predicted control of blood pressure provided by barley intake, thereby providing a framework for the future development of personalized dietary strategies.

Immunoglobulin E-virus phenotypes of infant bronchiolitis and risk of childhood asthma.

Background: Bronchiolitis is the leading cause of infant hospitalization in U.S. and is associated with increased risk for childhood asthma. Immunoglobulin E (IgE) not only plays major roles in antiviral immune responses and atopic predisposition, but also offers a potential therapeutic target. Objective: We aimed to identify phenotypes of infant bronchiolitis by using total IgE (tIgE) and virus data, to determine their association with asthma development, and examine their biological characteristics. Methods: In a multicenter prospective cohort study of 1,016 infants (age <1 year) hospitalized for bronchiolitis, we applied clustering approaches to identify phenotypes by integrating tIgE and virus (respiratory syncytial virus [RSV], rhinovirus [RV]) data at hospitalization. We examined their longitudinal association with the risk of developing asthma by age 6 years and investigated their biological characteristics by integrating the upper airway mRNA and microRNA data in a subset (n=182). Results: In infants hospitalized for bronchiolitis, we identified 4 phenotypes: 1) tIgElowvirusRSV-high, 2) tIgElowvirusRSV-low/RV, 3) tIgEhighvirusRSV-high, and 4) tIgEhighvirusRSV-low/RV phenotypes. Compared to phenotype 1 infants (resembling "classic" bronchiolitis), phenotype 4 infants (tIgEhighvirusRSV-low/RV) had a significantly higher risk for developing asthma (19% vs. 43%; adjOR, 2.93; 95% CI, 1.02-8.43; P=.046). Phenotypes 3 and 4 (tIgEhigh) had depleted type I interferon and enriched antigen presentation pathways; phenotype 4 also had depleted airway epithelium structure pathways. Conclusions: In this multicenter cohort, tIgE-virus clustering identified distinct phenotypes of infant bronchiolitis with differential risks of asthma development and unique biological characteristics.

Interpregnancy weight change as a potential risk factor for large-for-gestational-age infants: the Japan Environment and Children's Study.

OBJECTIVE: This study aimed to estimate the impact of interpregnancy weight change from the first to the second pregnancy on the risk of infants being large for gestational age (LGA). METHODS: This nationwide prospective birth cohort analysis included 3245 women who delivered their first two live singletons between 2011 and 2014. Interpregnancy weight change was calculated as the difference between the prepregnancy body mass index (BMI) of the first and second pregnancies. LGA infants were compared among three interpregnancy weight change groups: weight loss (a BMI loss >1 unit), weight gain (a BMI gain >1 unit), and stable weight (BMI maintained within - 1 to <1 unit). Interpregnancy weight change was assessed in mothers with a BMI <25 and ≥25 kg/m2, and adjusted odds ratios (ORs) were calculated for LGA infants by multiple logistic regression. RESULTS: The incidence of LGA infants was 8.6% (279 out of 3245). Compared with the stable weight group, interpregnancy weight gain was associated with an increased risk of infants being LGA (adjusted OR: 1.69, 95% confidence interval: 1.21-2.36) in the normal BMI (<25 kg/m2) group. In contrast, in the overweight/obese BMI (≥25 kg/m2) group, interpregnancy BMI was not a significant risk factor for LGA infants. CONCLUSIONS: Accurate risk stratification using interpregnancy BMI could assist the clinical management of women with a normal BMI who are at risk of delivering LGA infants.

Effect of birth season on allergic rhinitis and cedar pollinosis considering allergen and vitamin D exposure: The Japan Environment and Children's study (JECS).

BACKGROUND: The relationship between the season of birth, allergen sensitization, and allergic rhinitis have been inconsistent, and there are no studies that simultaneously consider vitamin D and allergen exposure. This study aimed to determine the associations between the season of birth, house dust mite (HDM) and Japanese cedar pollen (JCP) sensitization, and allergic rhinitis and pollinosis, while taking vitamin D levels and allergen exposure into account. METHODS: This study included 4323 participants in the Sub-Cohort Study of the Japan Environment and Children's Study. A logistic regression model was used to analyze the association between the season of birth and sensitization to JCP or HDM (judged by specific immunoglobulin E) at age 2 and allergic rhinitis or pollinosis at age 3, adjusted for HDM or JCP exposure and vitamin D levels with potential confounders. RESULTS: Participants born in spring or summer were more likely to have pollinosis than were those born in winter (adjusted odds ratio [aOR]: 2.08, 95% confidence interval [CI]: 1.13-3.82 for spring; aOR: 1.89, 95% CI: 1.03-3.47 for summer). Participants born in summer were more likely to have HDM sensitization than were those born in winter (Der p 1, aOR: 1.53, 95% CI: 1.10-2.15; Der f 1, aOR: 1.44, 95% CI: 1.03-2.01). Exposure to JCP and HDM were associated with pollinosis and HDM sensitization, respectively. CONCLUSIONS: Spring and summer births were associated with the development of pollinosis, and summer birth was associated with HDM sensitization, even when vitamin D and allergen exposure were considered. Further studies on mechanisms other than vitamin D and allergen exposure are required.