Metabolomic profiling revealed altered lipid metabolite levels in childhood food allergy.

BACKGROUND: The pathophysiology of childhood food allergy (FA) and its natural history are poorly understood. Clarification of the underlying mechanism may help identify novel biomarkers and strategies for clinical intervention in children with FA. OBJECTIVE: This study aimed to identify metabolites associated with the development and resolution of FA. METHODS: The metabolomic profiles of 20 children with FA and 20 healthy controls were assessed by liquid chromatography-tandem mass spectrometry. Comparative analysis was performed to identify metabolites associated with FA and FA resolution. For subjects with FA, serum samples were collected at the time of diagnosis and after resolution to identify the changes in metabolite levels. The selected metabolites were then quantified in a quantification cohort to validate the results. Finally, genome-wide association analysis of the metabolite levels was performed. RESULTS: The study demonstrated a significantly higher level of sphingolipid metabolites and a lower level of acylcarnitine metabolites in children with FA than those in healthy controls. At diagnosis, subjects with resolving FA had a significantly high level of omega-3 metabolites and a low level of platelet-activating factors compared to persistent FA. However, the level of omega-3 metabolites decreased in children with resolving FA but increased in children with persistent FA during the same time. The quantification data of omega-3-derived resolvins, platelet-activating factor, and platelet-activating factor acetylhydrolase activity further supported these results. CONCLUSION: The lipid metabolite profile is closely related to childhood FA and FA resolution. This study suggests potential predictive biomarkers and provides insight into the mechanisms underlying childhood FA.

Genome-wide association study identifies TNFSF15 associated with childhood asthma.

BACKGROUND: Genome-wide association studies (GWASs) of asthma have identified several risk alleles and loci, but most have been conducted in individuals with European-ancestry. Studies in Asians, especially children, are still lacking. We aimed to identify susceptibility loci by performing the first GWAS of asthma in Korean children with persistent asthma. METHODS: We used a discovery set of 741 children with persistent asthma as cases and 589 healthy children and 551 healthy adults as controls to perform a GWAS. We validated our GWAS findings using UK Biobank data. We then used the Genotype-Tissue Expression database to identify expression quantitative trait loci of candidate variants. Finally, we quantified proteins of genes associated with asthma. RESULTS: Variants at the 17q12-21 locus and SNPs in CYBRD1 and TNFSF15 genes were associated with persistent childhood asthma at genome-wide thresholds of significance. Four SNPs in the TNFSF15 gene were also associated with childhood-onset asthma in British white participants in the UK Biobank data. The asthma-associated rs7856856-C allele, the lead SNP, was associated with decreased TNFSF15 expression in whole blood and in arteries. Korean children with asthma had lower serum TNFSF15 levels than controls, and those with the asthma risk rs7856856-CC genotype exhibited the lowest serum TNFSF15 levels overall, especially asthmatic children. CONCLUSIONS: Our GWAS of persistent childhood asthma with allergic sensitization identified a new susceptibility gene, TNFSF15, and replicated associations at the 17q12-21 childhood-onset asthma locus. This novel association may be mediated by reduced expression of serum TNFSF15 and loss of suppression of angiogenesis.

Integrated genetic and epigenetic analyses uncover MSI2 association with allergic inflammation.

BACKGROUND: The relationship between allergic and eosinophilic inflammation, either systemic or local, in allergic diseases remains unclear. OBJECTIVE: We performed combined genome-wide association study (GWAS) and epigenome-wide (EWAS) for atopy and tissue eosinophilia to identify both genetic and epigenetic signatures between systemic and local allergic inflammation, and to capture global patterns of gene regulation. METHODS: We included 126 subjects for atopy analysis and 147 for tissue eosinophilia analysis, as well as 18 normal nasal tissue samples. We identified differentially methylated positions (DMPs) and genes associated with atopy and tissue eosinophilia. Furthermore, we performed mendelian randomization analysis and penalized regression along with replication in an independent cohort. RESULTS: EWAS identified genes, including Musashi RNA binding protein 2 (MSI2), associated with atopy, which contained enriched DMPs that genetically affect atopy. A direct association was observed between MSI2 single-nucleotide polymorphisms and atopy, as was a causal effect of changes in MSI2 expression and methylation on atopy, which was replicated in a Costa Rican population. Regarding tissue eosinophilia, EWAS identified genes with enriched DMPs directly contributing to tissue eosinophilia at the gene level, including CAMK1D. The gene ontology terms of the identified genes for both phenotypes encompassed immune-related terms. CONCLUSION: EWAS combined with GWAS identified novel candidate genes, especially the methylation of MSI2, contributing to systemic allergic inflammation. Certain genes displayed a greater association with either systemic or local allergic inflammation; however, it is expected that a harmonized effect of these genes influences immune responses.

A deep learning model for real-time mortality prediction in critically ill children.

BACKGROUND: The rapid development in big data analytics and the data-rich environment of intensive care units together provide unprecedented opportunities for medical breakthroughs in the field of critical care. We developed and validated a machine learning-based model, the Pediatric Risk of Mortality Prediction Tool (PROMPT), for real-time prediction of all-cause mortality in pediatric intensive care units. METHODS: Utilizing two separate retrospective observational cohorts, we conducted model development and validation using a machine learning algorithm with a convolutional neural network. The development cohort comprised 1445 pediatric patients with 1977 medical encounters admitted to intensive care units from January 2011 to December 2017 at Severance Hospital (Seoul, Korea). The validation cohort included 278 patients with 364 medical encounters admitted to the pediatric intensive care unit from January 2016 to November 2017 at Samsung Medical Center. RESULTS: Using seven vital signs, along with patient age and body weight on intensive care unit admission, PROMPT achieved an area under the receiver operating characteristic curve in the range of 0.89-0.97 for mortality prediction 6 to 60 h prior to death. Our results demonstrated that PROMPT provided high sensitivity with specificity and outperformed the conventional severity scoring system, the Pediatric Index of Mortality, in predictive ability. Model performance was indistinguishable between the development and validation cohorts. CONCLUSIONS: PROMPT is a deep model-based, data-driven early warning score tool that can predict mortality in critically ill children and may be useful for the timely identification of deteriorating patients.

Pediatric Home Mechanical Ventilation in Korea: the Present Situation and Future Strategy.

BACKGROUND: The number of children using home mechanical ventilation (HMV) has increased markedly in Europe and North America, but little is known about the situation in Korea. We described the clinical characteristics of children using HMV and investigated the current situation of HMV utilization in children. METHODS: Data on HMV prescriptions in year 2016 for children under the age of 19 was retrieved from the National Health Insurance Service for nationwide information. For more detailed information, data from year 2016 to 2018 was also retrieved from a tertiary center, Severance Children's Hospital. RESULTS: Nationwide, 416 children were prescribed with HMV in 2016, with an estimated prevalence of 4.4 per 100,000 children, of which 64.2% were male and mean age was 6-year-old. The estimated number of patients using invasive ventilators via tracheostomy was 202 (49%). Neuromuscular diseases were the most frequent cause (217; 52%), followed by central nervous system diseases (142; 34%), and cardiopulmonary diseases (57; 14%). In the tertiary center, a total of 62 children were prescribed with HMV (19 [31%] with non-invasive ventilation; 43 [69%] with invasive ventilation]. The number of children with HMV increased from 11 in 2016 to 29 in 2018. The mean age for initiation of HMV was 3.1 years and male patients comprised 65%. The most frequent diagnostic reason for HMV was central nervous system diseases (68%), followed by cardiopulmonary diseases (19%) and neuromuscular diseases (13%). Five patients died during the study period and five patients weaned from HMV. CONCLUSION: This study provides insights on the present situation of HMV utilization in Korean children.

EMHP: an accurate automated hole masking algorithm for single-particle cryo-EM image processing.

SUMMARY: The Electron Microscopy Hole Punch (EMHP) is a streamlined suite of tools for quick assessment, sorting and hole masking of electron micrographs. With recent advances in single-particle electron cryo-microscopy (cryo-EM) data processing allowing for the rapid determination of protein structures using a smaller computational footprint, we saw the need for a fast and simple tool for data pre-processing that could run independent of existing high-performance computing (HPC) infrastructures. EMHP provides a data preprocessing platform in a small package that requires minimal python dependencies to function. AVAILABILITY AND IMPLEMENTATION: https://www.bitbucket.org/chazbot/emhp Apache 2.0 License. CONTACT: bowman@scripps.edu. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Oligohydramnios affects pulmonary functional/structural abnormalities in school-aged children with bronchopulmonary dysplasia.

BACKGROUND: The relationship between early life factors and childhood pulmonary function and structure in preterm infants remains unclear. PURPOSE: This study investigated the impact of bronchopulmonary dysplasia (BPD) and perinatal factors on childhood pulmonary function and structure. METHODS: This longitudinal cohort study included preterm participants aged ≥5 years born between 2005 and 2015. The children were grouped by BPD severity according to National Institutes of Health criteria. Pulmonary function tests (PFTs) were performed using spirometry. Chest computed tomography (CT) scans were obtained and scored for hyperaeration or parenchymal lesions. PFT results and chest CT scores were analyzed with perinatal factors. RESULTS: A total 150 children (66 females) aged 7.7 years (6.4-9.9 years) were categorized into non/mild BPD (n=68), moderate BPD (n=39), and severe BPD (n=43) groups. The median z score for forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), FEV1/FVC ratio, and forced midexpiratory flow (FEF25%-75%) were significantly lower in the severe versus non/mild BPD group (-1.24 vs. -0.18, -0.22 vs. 0.41, -1.80 vs. -1.12, and -1.88 vs. -1.00, respectively; all P<0.05). The median z scores of FEV1, FEV1/ FVC, and FEF25%-75% among asymptomatic patients were also significantly lower in the severe versus non/mild BPD group (-0.82 vs. 0.09, -1.68 vs. -0.87, -1.59 vs. -0.61, respectively; all P<0.05). The severe BPD group had a higher median (range) CT score than the non/mild BPD group (6 [0-12] vs. 1 [0-10], P<0.001). Prenatal oligohydramnios was strongly associated with both low pulmonary function (FEV1/FVC

Association between bronchopulmonary dysplasia and early respiratory morbidity in children with respiratory distress syndrome: a case-control study using nationwide data.

Bronchopulmonary dysplasia (BPD) can cause respiratory morbidity beyond the neonatal period. We aimed to analyze the association of BPD on childhood lower respiratory illness (LRI) and asthma among patients diagnosed with respiratory distress syndrome (RDS). This case-control study analyzed data between 2002 and 2015 from a nationwide database. We included 55,066 children with RDS. Two-year LRI and asthma at ages 3 and 5 were assessed. Readmission for LRIs within 2 years of birth occurred in 53.9% and 37.9% of the BPD (n = 9470) and non-BPD (n = 45,596) cases, respectively. In the BPD group, the median number of hospitalizations, mechanical ventilation and oxygen use rates were significantly higher, while the hospitalization duration was significantly longer (P < 0.001 for all). The relative risk of BPD was 1.42 (1.39-1.45) on total readmission and 6.53 (5.96-7.15) on intensive care unit readmission. Asthma prevalence was significantly higher in BPD group (57.6% vs. 48.9% at age 3 and 44.3% vs. 38.2% at age 5, P < 0.001). In children with RDS, BPD could affect repetitive and worse LRI as an independent risk factor for respiratory morbidity during the first 2 years of life. BPD may also be a crucial risk factor for asthma in preschoolers.

Mortality and morbidity in children with asthma: A nationwide study in Korea.

OBJECTIVE: Childhood mortality due to asthma remains problematic; however, asthma-related mortality in Korean children has not been previously described. This study aimed to estimate asthma mortality and morbidity and determine to what extent asthma contributes to childhood mortality in Korea. METHODS: Data from 9 to 12 million children (aged < 18 years) per year recorded for each year between 2002 and 2015 were retrieved from the Korea National Health Insurance claims database. Patients with asthma during the year preceding death were investigated. Causes of death were analysed using data obtained from the Korean Statistical Information Service database. Cause-specific mortality was examined, and the mortality rate of children with asthma was compared to that of the general paediatric population with respect to the cause of death and age. Hospital use by patients with asthma, including intensive care unit admission and hospitalisation, was analysed. RESULTS: Asthma mortality decreased from 0.09 per 100,000 children in 2003 to 0.02 per 100,000 children in 2014, with an average mortality of 0.06 per 100,000 children. Mortality due to respiratory diseases was four times more common in patients with asthma than in the general population of children aged >5 years, despite decreases in asthma-related mortality. Asthma-related hospitalisations and intensive care interventions tended to decrease throughout the study period. CONCLUSIONS: Asthma mortality declined in children between 2003 and 2015 in Korea. Children with asthma are at a higher risk of death from respiratory diseases than the general population.

Predicting allergic diseases in children using genome-wide association study (GWAS) data and family history.

The recent rise in the prevalence of chronic allergic diseases among children has increased disease burden and reduced quality of life, especially for children with comorbid allergic diseases. Predicting the occurrence of allergic diseases can help prevent its onset for those in high risk groups. Herein, we aimed to construct prediction models for asthma, atopic dermatitis (AD), and asthma-AD comorbidity (also known as atopic march) using a genome-wide association study (GWAS) and family history data from patients of Korean heritage. Among 973 patients and 481 healthy controls, we evaluated single nucleotide polymorphism (SNP) heritability for each disease using genome-based restricted maximum likelihood (GREML) analysis. We then compared the performance of prediction models constructed using Least Absolute Shrinkage and Selection Operator (LASSO) and penalized ridge regression methods. Our results indicate that the addition of family history risk scores to the prediction model greatly increase the predictability of asthma and asthma-AD comorbidity. However, prediction of AD was mostly attributable to GWAS SNPs.

Prediction of postinfectious bronchiolitis obliterans prognosis in children.

INTRODUCTION: The prognosis of postinfectious bronchiolitis obliterans (PIBO) has many implications, ranging between reduced quality of life and life-threatening complications. We evaluated the prognostic factors for PIBO using the baseline clinical characteristics of patients and built a prediction model for determining the prognoses of PIBO patients using the identified parameters. METHODS: We included 47 PIBO patients who underwent spirometry and impulse oscillometry and followed them up for at least 1 year. A patient's prognosis was classified as poor if the patient experienced at least one of the following: persistent respiratory symptoms for more than 1 year, two or more instances of hospitalizations due to respiratory symptoms, or more than one intensive care unit admission. RESULTS: The prognoses of 32/47 (68.1%) patients was good, while that of 15/47 (31.9%) was poor. Spirometry results showed significantly lower forced vital capacity (FVC), forced expiratory volume in the first second (FEV1 ), forced expiratory flow at 25%-75% of FVC, and post-bronchodilator (BD) FEV1 values in the poor prognosis group; chest computed tomography (CT) demonstrated more inflammatory bronchiolitis findings. We created a nomogram for predicting prognoses using post-BD FEV1 and inflammatory bronchiolitis on chest CT. The area under the curve for the nomogram was 84.6% (95% confidence interval: 72.8%-96.4%). CONCLUSIONS: PIBO patients with lower pulmonary function values and more findings of inflammatory bronchiolitis on initial examination have poor prognoses. The nomogram for predicting PIBO prognosis is easy to use and can be applied at the time of diagnosis.

Gram-negative microbiota is related to acute exacerbation in children with asthma.

BACKGROUND: The upper-airway microbiota may be associated with the pathogenesis of asthma and useful for predicting acute exacerbation. However, the relationship between the lower-airway microbiota and acute exacerbation in children with asthma is not well understood. We evaluated the characteristics of the airway microbiome using induced sputum from children with asthma exacerbation and compared the microbiota-related differences of inflammatory cytokines with those in children with asthma. METHODS: We analysed the microbiome using induced sputum during acute exacerbation of asthma in children. We identified microbial candidates that were prominent in children with asthma exacerbation and compared them with those in children with stable asthma using various analytical methods. The microbial candidates were analysed to determine their association with inflammatory cytokines. We also developed a predictive functional profile using PICRUSt. RESULTS: A total of 95 children with allergic sensitisation including 22 with asthma exacerbation, 67 with stable asthma, and 6 controls were evaluated. We selected 26 microbial candidates whose abundances were significantly increased, decreased, or correlated during acute exacerbation in children with asthma. Among the microbial candidates, Campylobacter, Capnocytophaga, Haemophilus, and Porphyromonas were associated with inflammatory cytokines including macrophage inflammatory protein (MIP)-1ß, programmed death-ligand 1, and granzyme B. Both Campylobacter and MIP-1ß levels were correlated with sputum eosinophils. Increased lipopolysaccharide biosynthesis and decreased glycan degradation were observed in children with asthma exacerbation. CONCLUSION: Gram-negative microbes in the lower airway were related to acute exacerbation in children with asthma. These microbes and associated cytokines may play a role in exacerbating asthma in children.

Mitochondrial and Nuclear Mitochondrial Variants in Allergic Diseases.

The mitochondrial genome encodes core catalytic peptides that affect major metabolic processes within a cell. Here, we investigated the association between mitochondrial DNA (mtDNA) variants and allergic diseases, including atopic dermatitis (AD) and asthma, alongside heteroplasmy within the mtDNA in subjects with allergic sensitization. We collected genotype data from 973 subjects with allergic sensitization, consisting of 632 children with AD, 498 children with asthma, and 481 healthy controls by extracting DNA from their blood samples. Fisher's exact test was used to investigate mtDNA and nuclear DNA variants related to mitochondrial function (MT-nDNA) to identify their association with allergic diseases. Among the 69 mtDNA variants, rs28357671 located on the MT-ND6 gene displayed statistically significant associations with allergic diseases (Bonferroni-corrected P < 7.25E-4), while 6, 4, and 2 genes were associated with allergic sensitization, AD, and asthma, respectively (P < 0.0002), including NLRX1, OCA2, and CHCHD3 among the MT-nDNA genes. Heteroplasmy of mitochondrial DNA associated with allergic sensitization was evaluated in a separate cohort of patients consisting of 59 subjects with allergic sensitization and 52 controls. Heteroplasmy was verified when a patient carried both alleles of a mitochondrial single-nucleotide polymorphism (SNP) when clustered. One of the 134 mitochondrial SNPs showed heteroplasmy at a level of 0.4313 when clustering was applied. The probe sequence located at mitochondrial position 16217 and within the D-loop, which acts as a major control site for mtDNA expression. This is the first study to evaluate the association between mitochondrial DNA variants and allergic diseases. A harmonized effect of genes related to mitochondrial function may contribute to the risk of allergic diseases.

Expression of glutamine metabolism-related proteins in Hürthle cell neoplasm of thyroid: Comparison with follicular neoplasm.

PURPOSE: We evaluated the expression of glutaminolysis-related proteins in Hurthle cell neoplasms (HCN) and follicular neoplasms (FN) of the thyroid, and investigated its clinical implication. METHODS: Tissue microarrays were constructed from 264 FNs (112 follicular carcinomas [FCs] and 152 follicular adenomas [FAs]) and 108 HCNs (27 Hurthle cell carcinomas [HCCs] and 81 Hurthle cell adenomas [HCAs]. The immunohistochemical staining result of 3 glutaminolysis-related proteins (Glutaminase 1 [GLS1], glutaminate dehydrogenase [GDH] and alanine- serine, cysteine-preferring transporter 2 [ASCT2]) was analyzed. RESULTS: GLS1 and GDH showed significantly higher expression rates in HCN compared to FN (P<0.001). More HCN cases showed co-positivity of multiple glutaminolysis-related proteins than those of FN cases (P<0.001). In silico analysis, both GLUD1 and GLUD2 showed higher expression rate in HCA compared to FA (P=0.027 and P=0.018, respectively). SLC1A5 expression was highest in HCA, followed by FC and FA (HCA vs FC, P=0.023; FC vs FA, P=0.002). CONCLUSION: FN and HCN exhibit a different expression pattern for glutaminolysis-related proteins, and GLS1 and GDH have higher expression rates in HCN and FN.

The role of tumor-associated macrophage in breast cancer biology.

Breast cancer is the most commonly diagnosed malignant tumor in women worldwide and contributes significantly as the primary cause of female cancer related mortality. Hence, research is focused on discovering new and effective treatment targets. The breast tumor microenvironment (TME) comprising of recruited host stromal cells and tumor cells, has recently emerged as an important player in tumor progression, with the potential for future treatment. The TME comprises immune system elements (such as macrophages and lymphocytes), cells composing blood vessel, fibroblast, myofibroblast, mesenchymal stem cells, adipocytes and extracellular matrix (ECM). Among these cells, tumor-associated macrophages (TAM) are the prominent components of TME in breast cancers. Macrophages exhibit a high plasticity in response to various external signals and participate in innate and adoptive immune responses to control numerous factors of TME. Depending on the microenvironmental signal present, macrophages are polarized into two distinct phenotypes, the classically activated (M1) or the alternative activated (M2) macrophages. Tumor-associated macrophages (TAMs) closely resemble the M2-polarized. Clinicopathological studies have suggested that TAM accumulation in tumors correlates with a poor clinical outcome. In human breast carcinomas, high TAM density correlates with poor prognosis. Over the years, studies into the role of TAMs in breast cancer progression have identified TAMs to be capable of inducing angiogenesis, remodelling the tumor extracellular matrix to aid invasion, modelling breast cancer cells to evade host immune system and recruiting immunosuppressive leukocytes to the tumor microenvironment. Along with these functions, the potential role for TAMs in activation of breast cancer stem cells (CSC) has also emerged. Thus, TAMs in breast cancer can enhance cancer cell invasion by degrading the ECM, stimulate tumor vascularization and angiogenesis and suppress the anti-tumor functions of cytotoxic T cells resulting in poor prognosis for patients. These observations make TAMs an attractive target for therapeutic intervention by targeting various aspects of their function. This review discusses the mechanisms responsible for TAM recruitment and highlights the roles of TAMs in regulating tumor angiogenesis, invasion, metastasis, immunosuppression, and chemotherapeutic resistance. Finally, the potential for TAM-targeted therapy as a promising novel strategy is also discussed.