Race-Neutral Equations and Pulmonary Function Test Interpretation in Two Pediatric Cohorts.

OBJECTIVE: To investigate the changes in predicted lung function measurements when using race-neutral equations in children, based upon the new Global Lung Initiative (GLI) reference equations, utilizing a race-neutral approach in interpreting spirometry results compared with the 2012 race-specific GLI equations. STUDY DESIGN: We analyzed data from 2 multicenter prospective cohorts comprised of healthy children and children with history of severe (requiring hospitalization) bronchiolitis. Spirometry testing was done at the 6-year physical exam, and 677 tests were analyzed using new GLI Global and 2012 GLI equations. We used multivariable logistic regression, adjusted for age, height, and sex, to examine the association of race with the development of new impairment or increased severity (forced expiratory volume in the first second (FEV1) z-score ≤ -1.645) as per 2022 American Thoracic Society (ATS) guidelines. RESULTS: Compared with the race-specific GLI, the race-neutral equation yielded increases in the median forced expiratory volume in the first second and forced vital capacity (FVC) percent predicted in White children but decreases in these two measures in Black children. The prevalence of obstruction increased in White children by 21%, and the prevalence of possible restriction increased in Black children by 222%. Compared with White race, Black race was associated with increased prevalence of new impairments (aOR 7.59; 95%CI, 3.00-19.67; P < .001) and increased severity (aOR 35.40; 95%CI, 4.70-266.40; P = .001). Results were similar across both cohorts. CONCLUSIONS: As there are no biological justifications for the inclusion of race in spirometry interpretation, use of race-neutral spirometry reference equations led to an increase in both the prevalence and severity of respiratory impairments among Black children.

Infant Bronchiolitis Endotypes and the Risk of Developing Childhood Asthma: Lessons From Cohort Studies.

Severe bronchiolitis (i.e., bronchiolitis requiring hospitalization) during infancy is a heterogeneous condition associated with a high risk of developing childhood asthma. Yet, the exact mechanisms underlying the bronchiolitis-asthma link remain uncertain. Birth cohort studies have reported this association at the population level, including only small groups of patients with a history of bronchiolitis, and have attempted to identify the underlying biological mechanisms. Although this evidence has provided valuable insights, there are still unanswered questions regarding severe bronchiolitis-asthma pathogenesis. Recently, a few bronchiolitis cohort studies have attempted to answer these questions by applying unbiased analytical approaches to biological data. These cohort studies have identified novel bronchiolitis subtypes (i.e., endotypes) at high risk for asthma development, representing essential and enlightening evidence. For example, one distinct severe respiratory syncytial virus (RSV) bronchiolitis endotype is characterized by the presence of Moraxella catarrhalis and Streptococcus pneumoniae, higher levels of type I/II IFN expression, and changes in carbohydrate metabolism in nasal airway samples, and is associated with a high risk for childhood asthma development. Although these findings hold significance for the design of future studies that focus on childhood asthma prevention, they require validation. However, this scoping review puts the above findings into clinical context and emphasizes the significance of future research in this area aiming to offer new bronchiolitis treatments and contribute to asthma prevention.

Mortality After Alcohol Septal Ablation vs. Septal Myectomy in Patients With Obstructive Hypertrophic Cardiomyopathy.

Background: Alcohol septal ablation (ASA) and septal myectomy (SM) are 2 options for septal reduction therapy (SRT) to treat medication-resistant symptomatic obstructive hypertrophic cardiomyopathy (HCM). Because differences in mortality rates after these different SRT methods have not been extensively investigated in real-world settings, in this study compared the 1-year mortality rates after ASA and SM using population-based database. Methods and Results: Utilizing New York Statewide Planning and Research Cooperative System (SPARCS) data from 2005 to 2016, we performed a comparative effectiveness study of ASA vs. SM in patients with HCM. The outcome was all-cause death up to 360 days after SRT. We constructed a multivariable logistic regression model and performed sensitivity analysis with propensity score (PS)-matching and inverse probability of treatment weighting (IPTW) methods. We identified 755 patients with HCM who underwent SRT: 348 with ASA and 407 with SM. The multivariable analysis showed that all-cause deaths were significantly fewer in the ASA group at 360 days after SRT (adjusted odds ratio=0.34; 95% confidence interval [CI] 0.13-0.84; P=0.02). The PS-matching and IPTW methods also supported a lower mortality rate in the ASA group at 360 days post-SRT. Conclusions: In this population-based study of patients with HCM who underwent SRT in a real-world setting, the 1-year all-cause mortality rate was significantly lower in patients who underwent ASA compared with SM.

Prediction of cardiac death in patients with hypertrophic cardiomyopathy using plasma adipokine levels.

BACKGROUNDS AND AIMS: Hypertrophic cardiomyopathy (HCM) causes cardiac death through both sudden cardiac death (SCD) and death due to heart failure (HF). Although adipokines lead to adverse cardiac remodeling in HCM, the prognostic value of plasma adipokines in HCM remains unknown. We aimed to predict cardiac death in patients with HCM using plasma adipokines. METHODS AND RESULTS: We performed a multicenter prospective cohort study of patients with HCM. The outcome was cardiac death including heart transplant, death due to HF, and SCD. With data from 1 institution (training set), a prediction model was developed using random forest classification algorithm based on 10 plasma adipokines. The performance of the prediction model adjusted for 8 clinical parameters was examined in samples from another institution (test set). Time-to-event analysis was performed in the test set to compare the rate of outcome events between the low-risk and high-risk groups determined by the prediction model. In total, 389 (267 in the training set; 122 in the test set) patients with HCM were included. During the median follow-up of 2.7 years, 21 patients experienced the outcome event. The area under the covariates-adjusted receiver-operating characteristics curve was 0.89 (95 % confidence interval [CI] 0.71-0.99) in the test set. revealed the high-risk group had a significantly higher risk of cardiac death (hazard ratio 17.8, 95 % CI 2.1-148.3, P = 0.008). CONCLUSION: The present multicenter prospective study demonstrated that a panel of plasma adipokines predicts cardiac death in patients with HCM.

Hypertensive disorders of pregnancy increase the incidence of febrile seizures in offspring.

BACKGROUND: Intrauterine exposure to hypertensive disorders of pregnancy (HDP) may increase the risk of neuropsychiatric disorders. This investigation examined for associations between maternal HDP and febrile seizures (FS) in offspring by the age of three years. METHODS: The present cohort study analyzed data from the Japan Environment and Children's Study, a large national birth cohort. We included mother-child pairs recruited between January 2011 and March 2014. Information regarding maternal HDP, the presence of FS in offspring up to 3 years of age, and potential confounding factors were assessed using written questionnaires administered to mothers. RESULTS: A total of 77,699 mother-child dyads were analyzed. The prevalence of FS was 8.4% in children without HDP exposure, 10.6% in those exposed to mild HDP, and 10.4% in those with severe HDP exposure. Among children with full-term birth, logistic regression analysis indicated that exposure to mild or severe HDP was significantly associated with a higher incidence of FS (adjusted odds ratio [95% confidence interval]: 1.27 [1.05-1.53] and 1.27 [0.90-1.78], respectively, P for trend = 0.008), compared with children without HDP exposure. CONCLUSION: In children with full-term birth, intrauterine exposure to HDP was significantly associated with FS by the age of three years. IMPACT: This study revealed a significant association between intrauterine exposure to hypertensive disorders of pregnancy (HDP) and the subsequent development of febrile seizures (FS) in offspring by three years. This increased incidence of FS by HDP was independent of preterm birth status. This is the first large nationwide birth cohort study showing the impact of intrauterine exposure to HDP on FS in early childhood.

Bacterial small RNAs may mediate immune response differences seen in respiratory syncytial virus versus rhinovirus bronchiolitis.

Bronchiolitis, a viral lower respiratory infection, is the leading cause of infant hospitalization, which is associated with an increased risk for developing asthma later in life. Bronchiolitis can be caused by several respiratory viruses, such as respiratory syncytial virus (RSV), rhinovirus (RV), and others. It can also be caused by a solo infection (e.g., RSV- or RV-only bronchiolitis) or co-infection with two or more viruses. Studies have shown viral etiology-related differences between RSV- and RV-only bronchiolitis in the immune response, human microRNA (miRNA) profiles, and dominance of certain airway microbiome constituents. Here, we identified bacterial small RNAs (sRNAs), the prokaryotic equivalent to eukaryotic miRNAs, that differ between infants of the 35th Multicenter Airway Research Collaboration (MARC-35) cohort with RSV- versus RV-only bronchiolitis. We first derived reference sRNA datasets from cultures of four bacteria known to be associated with bronchiolitis (i.e., Haemophilus influenzae, Moraxella catarrhalis, Moraxella nonliquefaciens, and Streptococcus pneumoniae). Using these reference sRNA datasets, we found several sRNAs associated with RSV- and RV-only bronchiolitis in our human nasal RNA-Seq MARC-35 data. We also determined potential human transcript targets of the bacterial sRNAs and compared expression of the sRNAs between RSV- and RV-only cases. sRNAs are known to downregulate their mRNA target, we found that, compared to those associated with RV-only bronchiolitis, sRNAs associated with RSV-only bronchiolitis may relatively activate the IL-6 and IL-8 pathways and relatively inhibit the IL-17A pathway. These data support that bacteria may be contributing to inflammation differences seen in RSV- and RV-only bronchiolitis, and for the first time indicate that the potential mechanism in doing so may be through bacterial sRNAs.

A systematic review and meta-analysis on absolute eosinophil counts and the risk of asthma in preschool children with wheezing: An EAACI Task Force Report.

Preschool children with wheezing disorders pose diagnostic and therapeutic challenges and consume substantial healthcare resources. Peripheral eosinophil blood count (EBC) has been proposed as a potential indicator for future asthma development. This review by the European Academy of Allergy and Clinical Immunology (EAACI) Preschool Wheeze Task Force aimed to provide systematic evidence for the association between increased EBC and the risk of future asthma, as well as to identify potential cutoff values. In February 2023, a search of PubMed, EMBASE, and Cochrane Library databases was conducted to identify studies comparing EBCs in preschool children with wheezing who continued to wheeze later in life and those who did not. Included observational studies focused on children aged <6 years with a wheezing disorder, assessment of their EBCs, and subsequent asthma status. No language or publication date restrictions were applied. Among the initial 3394 studies screened, 10 were included in the final analysis, involving 1225 patients. The data from these studies demonstrated that high EBC in preschool children with wheezing is associated with future asthma development, with odds ratios of 1.90 (95% CI: 0.45-7.98, p = .38), 2.87 (95% CI: 1.38-5.95, p < .05), and 3.38 (95% CI: 1.72-6.64, p < .05) for cutoff values in the <300, 300-449, and ≥450 cells/µL ranges, respectively. Defining a specific cutoff point for an elevated EBC lacks consistency, but children with EBC >300 cells/µL are at increased risk of asthma. However, further research is needed due to the limitations of the included studies. Future investigations are necessary to fully elucidate the discussed association.

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.

Trends in emergency department visits for bronchiolitis, 1993-2019.

INTRODUCTION: Bronchiolitis is a leading indication for pediatric emergency department (ED) visits and hospitalizations. Our objective was to provide a comprehensive review of national trends and epidemiology of ED visits for bronchiolitis from 1993 to 2019 in the United States. METHODS: We retrospectively reviewed the National Hospital Ambulatory Medical Care Survey (NHAMCS) reporting of ED visits for bronchiolitis for children age <2 years from 1993 to 2019. Bronchiolitis cases were identified using billing codes assigned at discharge. The primary outcome was bronchiolitis ED visit rates, calculated using NHAMCS-assigned patient visit weights. We then evaluated for temporal variation in patient characteristics, facility location, and hospitalizations among the bronchiolitis ED visits. RESULTS: There were an estimated 8 million ED visits for bronchiolitis for children <2 years between 1993 and 2019. Bronchiolitis ED visits rates ranged from 28 to 36 per 1000 ED visits from 1993 to 2010 and increased significantly to 65 per 1000 ED visits in the 2017-2019 time period (p < 0.001). There was no significant change over time in patient age, sex, race and ethnicity, insurance status, hospital type, or triage level upon ED presentation. Approximately half of bronchiolitis ED visits occurred in the winter months throughout the study period. CONCLUSION: In this analysis of 27 years of national data, we identified a recent rise in ED visit rates for bronchiolitis, which have almost doubled from 2010 to 2019 following a period of relative stability between 1993 and 2010.

Analytical challenges in omics research on asthma and allergy: A National Institute of Allergy and Infectious Diseases workshop.

Studies of asthma and allergy are generating increasing volumes of omics data for analysis and interpretation. The National Institute of Allergy and Infectious Diseases (NIAID) assembled a workshop comprising investigators studying asthma and allergic diseases using omics approaches, omics investigators from outside the field, and NIAID medical and scientific officers to discuss the following areas in asthma and allergy research: genomics, epigenomics, transcriptomics, microbiomics, metabolomics, proteomics, lipidomics, integrative omics, systems biology, and causal inference. Current states of the art, present challenges, novel and emerging strategies, and priorities for progress were presented and discussed for each area. This workshop report summarizes the major points and conclusions from this NIAID workshop. As a group, the investigators underscored the imperatives for rigorous analytic frameworks, integration of different omics data types, cross-disciplinary interaction, strategies for overcoming current limitations, and the overarching goal to improve scientific understanding and care of asthma and allergic diseases.

Signaling Pathways Associated With Prior Cardiovascular Events in Hypertrophic Cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiomyopathy. A subset of patients experience major adverse cardiovascular events (MACEs), including arrhythmias, strokes and heart failure. However, the molecular mechanisms underlying MACEs in HCM are still not well understood. Therefore, we conducted a multicenter case-control study of patients with HCM, comparing those with and without prior histories of MACEs to identify dysregulated signaling pathways through plasma proteomics profiling. METHODS: We performed plasma proteomics profiling of 4986 proteins. We developed a proteomics-based discrimination model in patients enrolled at 1 institution (training set) and externally validated the model in patients enrolled at another institution (test set). We performed pathway analysis of proteins dysregulated in patients with prior MACEs. RESULTS: A total of 402 patients were included, with 278 in the training set and 124 in the test set. In this cohort, 257 (64%) patients had prior MACEs (172 in the training set and 85 in the test set). Using the proteomics-based model from the training set, the area under the receiver operating characteristic curve was 0.82 (95% confidence interval, 0.75-0.90) in the test set. Patients with prior MACEs demonstrated dysregulation in pathways known to be associated with MACEs (eg, TGF-ß) and novel pathways (eg, Ras-MAPK and associated pathways). CONCLUSIONS: In this multicenter study of 402 patients with HCM, we identified both known and novel pathways dysregulated in a subset of patients with more advanced disease.

Association of respiratory virus types with clinical features in bronchiolitis: Implications for virus testing strategies. A systematic review and meta-analysis.

BACKGROUND: Bronchiolitis is a leading cause of infant hospitalization, linked to respiratory syncytial virus (RSV) and rhinovirus (RV). Guidelines lack specific viral testing for bronchiolitis management. To establish effective management strategies, it is crucial to assess whether specific respiratory virus types are correlated with distinct examination features. METHODS: Through a systematic search of three databases, 21 studies were qualitatively analyzed, with 18 used for meta-analysis. Various outcomes like wheezing on auscultation, fever, atopic traits, and infection severity were evaluated. RESULTS: RSV-positive bronchiolitis was associated with a higher need for oxygen supplementation (OR 1.78, 95% CI 1.04-3.02) in 5 studies, while RV-positive bronchiolitis was more frequently linked to personal history of eczema (OR 0.60, 95% CI 0.41-0.88) in 6 studies. No significant differences were observed in the other outcomes examined. CONCLUSIONS: Bronchiolitis caused by RSV or RV presents with similar clinical features. Despite the associations between RSV-positive bronchiolitis and need for oxygen supplementation, and RV-positive bronchiolitis and a history of eczema, our study shows that viral etiology of bronchiolitis cannot be determined solely based on clinical presentation. Tailored management strategies, informed by accurate viral testing, seem crucial in clinical practice for enhancing patient outcomes in severe bronchiolitis.

Impact of breastfeeding during infancy on functional constipation at 3 years of age: the Japan Environment and Children's Study.

BACKGROUND: There is a lack of large, nationwide, birth cohort studies in Japan that examine the relationships of initial feeding habits and breastfeeding period duration with offspring functional constipation at 3 years of age. This study assessed the impact of breastfeeding during infancy on early childhood functional constipation. METHODS: The fixed data of 70,078 singleton births from the ongoing Japan Environment and Children's Study cohort study that commenced in 2011 were used to identify functional constipation as estimated by Rome III at 3 years of age. The exposure variables were breastfeeding period duration until 12 months of age (never, up to 6 months, or ≥ 7 months) as well as breastfeeding status at 1 month and 6 months of age (breastfeeding exclusively, partial breastfeeding, or infant formula feeding only). Multiple logistic regression analysis was employed to search for correlations for functional constipation development with breastfeeding period duration until 12 months of age and breastfeeding status during infancy. RESULTS: We identified 8,118 toddlers (11.6%) who met the Rome III criteria at 3 years of age. After controlling for potential covariates, a breastfeeding period duration of 7 months or more was inversely related to functional constipation development (≥ 7 months: adjusted odds ratio [OR] [95% confidence interval (CI)] 0.76 [0.65, 0.88] versus never breastfed, P for trend < 0.001). Other initial feeding methods were significantly related to an increased risk of functional constipation as compared with breastfeeding exclusively at 1 month of age (partial breastfeeding: adjusted OR [95% CI] 1.17 [1.11, 1.23], formula feeding only: 1.23 [1.07, 1.40]) and 6 months of age (partial breastfeeding: adjusted OR [95% CI] 1.18 [1.12, 1.24], formula feeding only: adjusted OR [95% CI] 1.42 [1.20, 1.68]). CONCLUSION: This large nationwide survey revealed a possible protective effect of a prolonged breastfeeding period duration and early exclusive breastfeeding in infancy on functional constipation at 3 years.

Corrigendum: Association of airway obstruction with first-pass success and intubation-related adverse events in the emergency department: multicenter prospective observational studies.

[This corrects the article DOI: 10.3389/fmed.2023.1199750.].

Association between the number of teeth and incident pre-diabetes among middle-aged adults with periodontal disease: a retrospective cohort analysis of Japanese claims data.

OBJECTIVES: To investigate the association between the number of teeth and the new onset of pre-diabetes. DESIGN: Retrospective cohort study. SETTING: The National Database of Health Insurance Claims and Specific Health Checkups of Japan, which holds information from both the yearly health check-up programme known as the 'Specific Health Checkup' and health insurance claims data. PARTICIPANTS: 1 098 371 normoglycaemic subjects who participated in the Specific Health Checkup programme every year from fiscal year (FY) 2015 to FY 2018 and had dental insurance claims data with a diagnosis of periodontal disease during FY 2016. OUTCOME MEASURES: Incidence of pre-diabetes or diabetes observed at the Specific Health Checkup during FY 2018. RESULTS: Among the participants, 1 77 908 subjects developed pre-diabetes, and 579 developed diabetes at the check-up during the subsequent follow-up year. Compared with the subjects with 26-28 teeth, those with 20-25, 15-19 or 1-14 teeth were associated with an increased likelihood of developing pre-diabetes or diabetes onset with adjusted ORs of 1.03 (95% CI: 1.02 to 1.05), 1.06 (1.03 to 1.09) and 1.07 (1.04 to 1.11), respectively. No clear modifications were observed for age, sex, body mass index or current smoking. CONCLUSIONS: Having fewer teeth was associated with a higher incidence of pre-diabetes. Due to the limitations of this study, however, causality remains undetermined.

Impact of dog and/or cat ownership on functional constipation at 3 years of age: the Japan Environment and Children's study.

PURPOSE: This investigation assessed the impact of dog and/or cat ownership during infancy on the presence of functional constipation (FC) at 3 years of age. METHODS: The fixed data of 73,936 singleton births from a large national birth cohort study commencing in 2011 were used to identify FC as estimated by Rome III at 3 years of age. Multiple logistic regression analysis was employed to search for correlations between FC development and dog and/or cat ownership in early childhood. RESULTS: A total of 8,459 toddlers (11.6%) met the Rome III criteria for FC at 3 years of age. Overall, 57,264 (77.5%) participants had never owned a dog or cat. We identified 7,715 (10.4%) infant-period owners, 1,295 (1.8%) current owners, and 7,762 (10.5%) long-term owners. Multivariate analysis showed that infant-period ownership remained significantly associated with the risk of developing FC at 3 years of age after adjusting for covariates (adjusted OR [95% CI] 1.09 [1.01-1.19] based on non-ownership). CONCLUSIONS: This Japanese large nationwide survey uncovered a possible adverse effect of infant-period dog and/or cat ownership prior to 6 months of age on FC status at 3 years of age.