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

Prediction and predictor elucidation of metabolic syndrome onset among young workers using machine learning techniques: A nationwide study in Japan

Objectives: Predictive models for the onset of metabolic syndrome (MS) for people in their 30s are scarce. This study aimed to construct a highly accurate model to predict MS onset by 40 years of age and to identify important predictors of MS onset using health checkup data of Japanese employees aged between 30 and 35 years. Methods: The study included 6,048 Japanese employees aged 40 years who underwent periodic health examinations over 10 years. We developed predictive models for MS onset using machine learning methods, including random forest and logistic regression models. The variable importance of each explanatory variable was calculated to identify important predictors of MS onset for the random forest models. Results: Of 2,998 participants, 164 participants aged 30 and 180 of 4,045 participants aged 35 years developed MS by age 40 years. The random forest models have the highest predictive power (e.g., AU-ROC 0.867 for males aged 30) compared to the logistic regression models. In these models, diastolic blood pressure was the most important predictor of MS onset for males, while body mass index was the most important predictor for females. Conclusions: We created machine learning models to predict MS onset at the age of 40 years with high accuracy from health examination data obtained at the age of 30 or 35 years. Sex differences in important predictors of MS onset were shown by the variable importance indices of the random forest. Applying our model in routine healthcare management could provide early health interventions to prevent MS onset

Individual and Regional Characteristics Associated with Maternal Smoking During Pregnancy in Japan: Healthy Parents and Children 21

Smoking during pregnancy causes various maternal and fetal health problems. Although there are considerable differences in maternal smoking proportions between localities, only a few studies have investigated the effects of regional characteristics on maternal smoking behavior. This study aimed to clarify the association between maternal smoking during pregnancy and individual and regional characteristics. We used data from a large nationwide birth cohort study in Japan that consisted of information on 20,267 women with children aged 3–4 months. The multilevel regression model was used to examine the association between smoking behavior during pregnancy and individual and regional characteristics. On multilevel analysis, late birth order, young age of the mother at birth, low birth weight, low economic status, husband’s smoking during pregnancy, maternal alcohol consumption during pregnancy, absence of a pregnancy counselor, and lack of participation in local events for childrearing were significantly associated with maternal smoking behavior during pregnancy at the individual level. Meanwhile, a high unemployment rate and a high number of nurseries were significantly associated with maternal smoking behavior during pregnancy at the regional level. In conclusion, we showed the relation between maternal smoking during pregnancy and the individual- and regional-level characteristics

Caregivers' mental distress and child health during the COVID-19 outbreak in Japan.

To clarify the physical and mental conditions of children during the coronavirus disease 2019 pandemic and consequent social distancing in relation to the mental condition of their caregivers. This internet-based nationwide cross-sectional study was conducted between April 30 and May 13, 2020. The participants were 1,200 caregivers of children aged 3-14 years. Child health issues were categorized into "at least one" or "none" according to caregivers' perception. Caregivers' mental status was assessed using the Japanese version of the Kessler Psychological Distress Scale-6. The association between caregivers' mental status and child health issues was analyzed using logistic regression models. Among the participants, 289 (24.1%) had moderate and 352 (29.3%) had severe mental distress and 69.8% of children in their care had health issues. The number of caregivers with mental distress was more than double that reported during the 2016 national survey. After adjusting for covariates, child health issues increased among caregivers with moderate mental distress (odds ratio 2.24, 95% confidence interval 1.59-3.16) and severe mental distress (odds ratio 3.05, 95% confidence interval 2.17-4.29) compared with caregivers with no mental distress. The results highlight parents' psychological stress during the pandemic, suggesting the need for adequate parenting support. However, our study did not consider risk factors of caregivers' mental distress such as socioeconomic background. There is an urgent need for further research to identify vulnerable populations and children's needs to develop sustainable social support programs for those affected by the outbreak

Nasopharyngeal lipidomic endotypes of infants with bronchiolitis and risk of childhood asthma: a multicentre prospective study

BACKGROUND: Bronchiolitis is the leading cause of hospitalisation of US infants and an important risk factor for childhood asthma. Recent evidence suggests that bronchiolitis is clinically heterogeneous. We sought to derive bronchiolitis endotypes by integrating clinical, virus and lipidomics data and to examine their relationship with subsequent asthma risk. METHODS: This is a multicentre prospective cohort study of infants (age \u3c12 months) hospitalised for bronchiolitis. We identified endotypes by applying clustering approaches to clinical, virus and nasopharyngeal airway lipidomic data measured at hospitalisation. We then determined their longitudinal association with the risk for developing asthma by age 6 years by fitting a mixed-effects logistic regression model. To account for multiple comparisons of the lipidomics data, we computed the false discovery rate (FDR). To understand the underlying biological mechanism of the endotypes, we also applied pathway analyses to the lipidomics data. RESULTS: Of 917 infants with bronchiolitis (median age, 3 months), we identified clinically and biologically meaningful lipidomic endotypes: (A) cinicallipid (n=263), (B) clinicallipid (n=281), (C) clinicallipid (n=212) and (D) clinicallipid (n=161). Endotype A infants were characterised by \u27classic\u27 clinical presentation of bronchiolitis. Profile D infants were characterised by a higher proportion of parental asthma, IgE sensitisation and rhinovirus infection and low sphingolipids (eg, sphingomyelins, ceramides). Compared with endotype A, profile D infants had a significantly higher risk of asthma (22% vs 50%; unadjusted OR, 3.60; 95% CI 2.31 to 5.62; p\u3c0.001). Additionally, endotype D had a significantly lower abundance of polyunsaturated fatty acids (eg, docosahexaenoic acid; FDR=0.01). The pathway analysis revealed that sphingolipid metabolism pathway was differentially expressed in endotype D (FDR=0.048). CONCLUSIONS: In this multicentre prospective cohort study of infants with bronchiolitis, integrated clustering of clinical, virus and lipidomic data identified clinically and biologically distinct endotypes that have a significantly differential risk for developing asthma.Delete

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

Association of Nasopharyngeal and Serum Glutathione Metabolism with Bronchiolitis Severity and Asthma Risk: A Prospective Multicenter Cohort Study

Infants hospitalized for bronchiolitis are at high risk for asthma. Glutathione-related metabolites may antagonize oxidative stress, which induces airway injuries in respiratory infection and subsequent airway remodeling. However, little is known about the relationship of glutathione-related metabolites with bronchiolitis severity and the risk of asthma. In a multicenter prospective observational cohort study of infants hospitalized for bronchiolitis, we measured nasopharyngeal and serum glutathione-related metabolites by using liquid chromatography-tandem mass spectrometry. We then examined their association with bronchiolitis severity (defined by positive pressure ventilation (PPV) use). We also identified severity-related glutathione-related metabolite signatures and examined their association with asthma at age 6 years. In 1013 infants, we identified 12 nasopharyngeal and 10 serum glutathione-related metabolites. In the multivariable models, lower relative abundances of seven metabolites, e.g., substrates of glutathione, including cysteine (adjOR 0.21, 95%CI 0.06-0.76), glycine (adjOR 0.25, 95%CI 0.07-0.85), and glutamate (adjOR 0.25, 95%CI 0.07-0.88), were significantly associated with PPV use (all FDR \u3c 0.05). These associations were consistent with serum glutathione-related metabolites. The nasopharyngeal glutathione-related metabolite signature was also associated with a significantly higher risk of asthma (adjOR 0.90, 95%CI 0.82-0.99, = 0.04). In infants hospitalized for bronchiolitis, glutathione-related metabolites were associated with bronchiolitis severity and asthma risk

Proteomics endotyping of infants with severe bronchiolitis and risk of childhood asthma

BACKGROUND: Bronchiolitis is the leading cause of hospitalization in U.S. infants and a major risk factor for childhood asthma. Growing evidence supports clinical heterogeneity within bronchiolitis. We aimed to identify endotypes of infant bronchiolitis by integrating clinical, virus, and serum proteome data, and examine their relationships with asthma development. METHODS: This is a multicenter prospective cohort study of infants hospitalized for physician-diagnosis of bronchiolitis. We identified bronchiolitis endotypes by applying unsupervised machine learning (clustering) approaches to integrated clinical, virus (respiratory syncytial virus [RSV], rhinovirus [RV]), and serum proteome data measured at hospitalization. We then examined their longitudinal association with the risk for developing asthma by age 6 years. RESULTS: In 140 infants hospitalized with bronchiolitis, we identified three endotypes: (1) clinical virus proteome , (2) clinical virus proteome , and (3) clinical virus proteome endotypes. Endotype 1 infants were characterized by high proportion of IgE sensitization and RV infection. These endotype 1 infants also had dysregulated NFκB pathways (FDR \u3c 0.001) and significantly higher risks for developing asthma (53% vs. 22%; adjOR 4.04; 95% CI, 1.49-11.0; p = 0.006), compared with endotype 3 (clinically resembling classic bronchiolitis). Likewise, endotype 2 infants were characterized by low proportion of IgE sensitization and high proportion of RSV or RV infection. These endotype 2 infants had dysregulated tumor necrosis factor (TNF)-mediated signaling pathway (FDR \u3c0.001) and significantly higher risks for developing asthma (44% vs. 22%; adjOR 2.71; 95% CI, 1.03-7.11, p = 0.04). CONCLUSION: In this multicenter cohort, integrated clustering of clinical, virus, and proteome data identified biologically distinct endotypes of bronchiolitis that have differential risks of asthma development

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 \u3c1 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) fungivirus, B) fungivirus, C) fungivirus, D) fungivirus 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 \u3c0.05). 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

DNA methylation of GFI1 as a mediator of the association between prenatal smoking exposure and ADHD symptoms at 6 years: the Hokkaido Study on Environment and Children's Health

BackgroundPrenatal smoking exposure has been associated with childhood attention-deficit/hyperactivity disorder (ADHD). However, the mechanism underlying this relationship remains unclear. We assessed whether DNA methylation differences may mediate the association between prenatal smoking exposure and ADHD symptoms at the age of 6 years.ResultsWe selected 1150 mother-infant pairs from the Hokkaido Study on the Environment and Children's Health. Mothers were categorized into three groups according to plasma cotinine levels at the third trimester: non-smokers (= 11.49 ng/mL). The children's ADHD symptoms were determined by the ADHD-Rating Scale at the age of 6 years. Maternal active smoking during pregnancy was significantly associated with an increased risk of ADHD symptoms (odds ratio, 1.89; 95% confidence interval, 1.14-3.15) compared to non-smoking after adjusting for covariates. DNA methylation of the growth factor-independent 1 transcriptional repressor (GFI1) region, as determined by bisulfite next-generation sequencing of cord blood samples, mediated 48.4% of the total effect of the association between maternal active smoking during pregnancy and ADHD symptoms. DNA methylation patterns of other genes (aryl-hydrocarbon receptor repressor [AHRR], cytochrome P450 family 1 subfamily A member 1 [CYP1A1], estrogen receptor 1 [ESR1], and myosin IG [MYO1G]) regions did not exert a statistically significant mediation effect.ConclusionsOur findings demonstrated that DNA methylation of GFI1 mediated the association between maternal active smoking during pregnancy and ADHD symptoms at the age of 6 years