KLF15-activated MARCH2 boosts cell proliferation and epithelial-mesenchymal transition and presents diagnostic significance for hepatocellular carcinoma.

PURPOSE: Membrane associated ubiquitin ligase MARCH2 majorly involves in inflammation response and protein trafficking. However, its comprehensive role in hepatocellular carcinoma (HCC) is largely unknown. METHODS: Firstly, multiple bioinformatic analyses were applied to determine MARCH2 mRNA level, its expression comparison in diverse molecular and immune subtypes, and diagnostic value in HCC. Subsequently, RNA-seq, real-time quantitative PCR, immunohistochemistry and cell proliferation assay are used to explore the epithelial-mesenchymal transition (EMT) and proliferation by gene-silencing or overexpressing in cultured HCC cells or in vivo xenograft. Moreover, dual luciferase reporter assay and immunoblotting are delved into verify the transcription factor that activating MARCH2 promoter. RESULTS: Multiple bioinformatic analyses demonstrate that MARCH2 is upregulated in multiple cancer types and exhibits startling diagnostic value as well as distinct molecular and immune subtypes in HCC. RNA-seq analysis reveals MARCH2 may promote EMT, cell proliferation and migration in HepG2 cells. Furthermore, overexpression of MARCH2 triggers EMT and significantly enhances HCC cell migration, proliferation and colony formation in a ligase activity-dependent manner. Additionally, above observations are validated in the HepG2 mice xenografts. For up-stream mechanism, transcription factor KLF15 is highly expressed in HCC and activates MARCH2 expression. CONCLUSION: KLF15 activated MARCH2 triggers EMT and serves as a fascinating biomarker for precise diagnosis of HCC. Consequently, MARCH2 emerges as a promising candidate for target therapy in cancer management.

Rotavirus hospitalization in early childhood: fine motor skills and cognition at six years old-Population-based cohort study.

Rotavirus is linked to severe childhood gastroenteritis and neurological complications, but its impact on neurodevelopment remains uncertain. We examined data from 1,420,941 Korean children born between 2009 and 2011, using the Korean National Health Insurance System. At age 6, we assessed neurodevelopmental outcomes using the validated Korean Developmental Test, covering six major domains. Utilizing propensity score-based Inverse Probability Weighting to ensure covariates including considering covariates including sex, birth weight, changes in body weight from birth to 4-6 months of age, head circumference at 4-6 months of age, residence at birth, economic status, infant feeding types, and birth year. The main analysis that encompassed 5,451 children with rotavirus hospitalization and 310,874 unexposed individuals reveled heightened odds of suspected delays in fine motor skills and cognition among exposed children. Our results suggest an association between rotavirus-related hospitalization in infancy and suspected delays in fine motor function and cognition in 6-year-olds.

Cascade of atopic dermatitis comorbidities in children after birth for 15 years.

BACKGROUND: Individuals with atopic dermatitis often develop other conditions. OBJECTIVE: This study aimed to determine how atopic dermatitis comorbidities develop in children over time. METHODS: This population-based administrative cohort study used national health insurance data. We traced individuals born in Korea between 2002 and 2003 to 2018. The date of initial atopic dermatitis diagnosis was set as the index date. Fifty-three childhood comorbidities of atopic dermatitis were identified as outcomes of interest by performing a comprehensive literature search and comparing the prevalence of diagnostic codes in children with and without atopic dermatitis. Four control children per individual in the atopic dermatitis group were randomly matched based on sex and index date. The association between atopic dermatitis and the development of each specified disease was assessed using proportional hazard assumption, followed by mapping of the temporal sequences of interconnected comorbidities. RESULTS: The atopic dermatitis and control groups contained 67,632 and 270,528 individuals, respectively. The median age at the index date was 10 months, whereas the median follow-up period was 15 years. Twenty diseases that were associated with a higher risk of atopic dermatitis were identified and a chain of interconnected conditions created. The progression began in childhood with febrile seizures, constipation, and asthma, and was later associated with the emergence of food allergy, allergic rhinitis, psychiatric disorders, and autoimmune diseases. CONCLUSION: Our study highlights the temporal nature of atopic dermatitis comorbidities in children, and indicates that an understanding of the comorbidities may inform its clinical management and treatment.

Neurodevelopment in Term Infants with Normal Birthweight following Postnatal Systemic Steroid Exposure.

INTRODUCTION: Studies investigating the potential impact of systemic steroid exposure during early infancy on neurological development in full-term infants with normal birth weight are lacking. METHODS: This population-based administrative cohort study used data of national health insurance and a health-screening program for infants and children and included full-term infants who were born in Korea between 2008 and 2012 with normal birth weight and did not have any specific perinatal or neurodevelopmental diseases. The prescription of systemic steroids within the first 3 months of age was mainly considered. The neurological development of children was assessed using the Korean Development Screening Test (K-DST) at 6 years of age. To balance the baseline characteristics of the control and exposed groups, stabilized inverse probability of treatment weighting with trimming was performed in the main cohort. Ordinal logistic regression was used to assess the association between systemic steroid exposure and unfavorable results in the K-DST. RESULTS: The control and exposure groups had 246,168 and 5,083 children, respectively. The K-DST suggested unfavorable results in 8.1% and 8.6% children in the control and exposure groups, respectively (weighted odds ratio, 95% confidence interval, 1.03, 0.93-1.14). When each domain of the K-DST was considered separately, the risk of unfavorable results in the exposed group was not significantly different from that in the control group. CONCLUSIONS: No significant association was observed between exposure to systemic steroids during early infancy and neurodevelopmental impairment at 6 years of age.

Associations of personal urinary volatile organic compounds and lung function in children.

BACKGROUND: We investigated the correlation between urine VOC metabolites and airway function in children exposed to anthropogenic volatile organic compounds (VOCs), notable pollutants impacting respiratory health. METHODS: Out of 157 respondents, 141 completed skin prick tests, spirometry, IOS, and provided urine samples following the International Study of Asthma and Allergies in Childhood (ISAAC)-related questions. Allergic sensitization was assessed through skin prick tests, and airway functions were evaluated using spirometry and impulse oscillometry (IOS). Forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) was recorded and FEV1/FVC ratio was calculated. Airway mechanics parameters including respiratory resistance at 5 Hz (Rrs5) mean respiratory resistance between 5 Hz and 20 Hz (Rrs5-20), were also recorded. Urine concentrations of metabolites of benzene, ethylbenzene, toluene, xylene, styrene, formaldehyde, carbon-disulfide were analyzed by gas chromatography/tandem mass spectroscopy. RESULTS: The median age at study participation was 7.1 (SD 0.3) years. Muconic acid (benzene metabolites) and o-methyl-hippuric acid (xylene metabolites) above medians were associated with a significant increase in Rrs5 (muconic acid: aß = 0.150, p = .002; o-methyl-hippuric acid: aß = 0.143, p = .023) and a decrease in FEV1/FVC (o-methyl-hippuric acid: aß = 0.054, p = .028) compared to those below median. No associations were observed for Rrs5-20 and FEV1 between the groups categorized as above and below the median (all parameter p values > .05). CONCLUSIONS: Elevated levels of benzene and xylene metabolites were associated with a significant increase in Rrs5 and a decrease in FEV1/FVC, related to increased resistance and restrictive lung conditions compared to individuals with concentrations below the median.

The association between phthalate exposure and pubertal development.

Antiandrogenic effect of phthalates have been reported; however, results regarding the effect of phthalate exposure in pubertal children have been inconsistent. We aimed to investigate the relationship between phthalate exposure and pubertal development, especially whether high molecular weight phthalates (HMWP) and low molecular weight phthalates (LMWP) are differently associated in boys and girls. Urinary phthalate metabolites (4 HMWPs and 3 LMWPs) in Korean children (236 boys and 202 girls, aged 10 to 12 years) were measured. The association between phthalate levels and pubertal development (pubertal stages self-reported by parents and sex steroid levels) was analyzed by generalized linear regression after adjusting for age, body mass index z score, and premature birth and/or low birth weight. Both the highest quartile of HMWP (Q4 vs Q1, adjusted odds ratio [OR], 0.238; 95% confidence interval [CI], 0.090-0.627; p = 0.004) and LMWP (Q4 vs Q1, adjusted OR, 0.373; 95% CI, 0.151-0.918; p = 0.032) were inversely associated with pubertal stages in boys, whereas the highest quartile of LMWP (Q4 vs Q1, adjusted OR, 2.431; 95% CI, 1.024-5.768; p = 0.044) was significantly related to advanced pubertal stages in girls. Testosterone levels in boys were significantly lower at the highest quartile of HMWP (adjusted ß = - 0.251; 95% CI, - 0.476 to - 0.027; p = 0.028). However, in girls, we could not find any significant relationship between HMWP or LMWP and estradiol levels. CONCLUSIONS: Our results suggest that phthalate exposure, especially exposure to the HMWP, may have inverse association with male pubertal development. Further investigation is required to verify the relationship of phthalate exposure and pubertal development in girls. WHAT IS KNOWN: • Exposure to phthalates may have antiandrogenic effects. • Studies on the association between phthalates and pubertal development have yielded inconsistent results. WHAT IS NEW: • Phthalate levels were inversely associated with self-reported pubertal stages in boys. • Exposure to phthalates might have a negative influence on male pubertal development.

Consumption of sugar-sweetened beverages before 2 years of age and attention-deficit/hyperactivity disorder.

INTRODUCTION: This study examined the association between sugar-sweetened beverage consumption before the first 24 months of life and attention-deficit/hyperactivity disorder (ADHD). METHODS: A population administrative cohort study was conducted in Korea (2008-2019) using linked national insurance data and a health screening survey. The cohort included 25,305 children in the exposed group with high sugar-sweetened beverage drinks (≥200 ml) and 339,931 in the reference groups (<200 ml) at 24 months of age. The primary outcome was the development of ADHD based on the International Classification of Disease (ICD) codes. Cox proportional model was used to identify the association between sugar-sweetened beverage consumption during early childhood and the later development of ADHD while controlling for multiple risk factors. RESULTS: Over a mean follow-up period of 9.2 years, the incidence rates of ADHD were 29.6 and 23.8 per 10,000 person-years (PY) in the exposed and reference groups, respectively. Compared with the reference group, children consuming high-sugar drinks were at an increased risk of ADHD (adjusted hazard ratio [aHR] 1.17, 95% confidence interval [CI] 1.08-1.27). These associations remained significant even after applying alternative ADHD definitions or adjusting for confounding variables. CONCLUSION: Children who consume sweetened beverages during early childhood are at increased risk of developing ADHD later in life.

Trends in Incidence and Drug Prescriptions for Croup in Children Under 5 Years of Age: A 2002-2019 Population-Based Study.

BACKGROUND: Tracking national croup trends can provide important insights for childhood health management. This study aimed to analyze the incidence and drug prescription trends in Korean children over a two-decade period. METHODS: This population-based study encompassed 479,783 children aged < 5 years from 2002-2019, utilizing the National Health Insurance Service-National Sample Cohort. We identified participants with a primary croup diagnosis who were admitted to or visited the emergency room. Age-specific and age-adjusted incidence rates/10,000 person-years were calculated. We assessed using orthogonal polynomial contrasts and stratified by various factors (sex, age, residential area, economic status, comorbidities, and healthcare facility types). We observed changes in the use of five medications: inhaled steroids, systemic steroids, inhaled epinephrine, antibiotics, and short-acting bronchodilators. Generalized binomial logistic regression was used to analyze factors influencing prescription strategies. RESULTS: In 2002, the croup-related visits were 16.1/10,000 person-years, increasing to 98.3 in 2019 (P for trend < 0.001). This trend persisted, regardless of age, sex, region, and economic status. Children with comorbid atopic dermatitis or asthma maintained consistent croup rates, while those without comorbidities increased. Treatment trends showed decreasing antibiotic (73-47%) and oxygen use (21.3-3.4%), with increasing nebulized epinephrine (9.3-41.5%) and multiple drug prescriptions (67.8-80.3%). Primary care centers exhibited a greater increase in prescription usage and hospitalization duration than did tertiary healthcare institutions. CONCLUSION: Over the past two decades, croup incidence has risen, accompanied by increased epinephrine use and decreased antibiotic prescriptions. Longer hospitalization and higher medication use were mainly observed in primary care facilities.

Unraveling the link between atopic dermatitis and autoimmune diseases in children: Insights from a large-scale cohort study with 15-year follow-up and shared gene ontology analysis.

BACKGROUND: Atopic dermatitis and autoimmune diseases are highly heritable conditions that may co-occur from an early age. METHODS: The primary study is a national administrative cohort study involving 499,428 children born in 2002, tracked until 2017. Atopic dermatitis was defined as five or more principal diagnoses of atopic dermatitis and two or more topical steroid prescriptions. We estimated the risks for the occurrence of 41 autoimmune diseases, controlling for risk factors. In addition, we sourced a gene library from the National Library of Medicine to conduct a comprehensive gene ontology. We used Gene Weaver to identify gene set similarity and clustering, and used GeneMania to generate a network for shared genes. RESULTS: Exposed and unexposed groups included 39,832 and 159,328 children, respectively. During a mean follow-up of 12 years, the exposed group had an increased risk of autoimmune disease (hazard ratio, 1.27 [95 % confidence interval, 1.23-1.32]) compared to the unexposed group. The hazard ratios of autoimmune illnesses consistently increased with two- and five years lag times and alternative atopic dermatitis definitions. Shared genes between atopic dermatitis and autoimmune diseases were associated with comorbidities such as asthma, bronchiolitis, and specific infections. Genetic interactions of these shared genes revealed clustering in Th1, Th2, Th17, and non-classifiable pathways. CONCLUSIONS: Atopic dermatitis was significantly associated with an increased risk of subsequent autoimmune disease. we identified the genetically associated disease in atopic dermatitis patients comorbid with autoimmune disease and demonstrated a genetic network between atopic dermatitis and autoimmune diseases.

Growth pattern during early infancy, body mass index during childhood and childhood asthma.

BACKGROUND: There is a lack of longitudinal studies of associations between growth from infancy to childhood and asthma development. OBJECTIVE: The objective of the study was to investigate the effects of weight change during infancy, body mass index (BMI) and the interaction of these factors on the risk of childhood asthma. METHODS: We enrolled children born in 2008 and 2009 at full-term and with normal birth weight. The weight change in infancy was grouped into slow, on-track and rapid. BMI status in childhood was stratified into low, normal and high groups and used as a time-varying variable. The outcome was asthma, defined as two or more diagnoses of asthma separated by at least 1 year after 2 years of age. The risk of asthma was assessed using Cox proportional hazard regression, with adjustment for sex, residence area at birth, economic status and feeding types in infancy. RESULTS: Of 917,707 children born in Korea in 2008 and 2009, 271,871 were eligible for analysis. The risk of asthma was greater in groups with low birth weight (aHR 1.06, 95% CI 1.04 to 1.08), rapid body weight change during early infancy (aHR 1.08, 95% CI 1.07 to 1.10) and high BMI during childhood (aHR 1.06, 95% CI 1.04-1.08). The interaction of weight change during early infancy with BMI during childhood was significant for asthma (p < .01). Rapid weight gain in infancy was associated with lower risk of asthma in those with low BMI during childhood; had no association with asthma in those with normal BMI during childhood; and was associated increased asthma risk in those with high BMI during childhood-aHR 1.26 (95% CI 1.19 to 1.33) and aHR 1.33 (95% CI 1.12 to 1.56) compared with on-track and slow infant weight gain, respectively. CONCLUSION: Low birth weight, high BMI during childhood and, in those with high childhood BMI, rapid weight gain during early infancy are associated with increased risk of childhood asthma.

Phosphoenolpyruvate induces endothelial dysfunction and cell senescence through stimulation of metabolic reprogramming.

Endothelial dysfunction is a key early link in the pathogenesis of atherosclerosis, and the accumulation of senescent vascular endothelial cells causes endothelial dysfunction. Phosphoenolpyruvate (PEP), which is a high-energy glycolytic intermediate, protects against ischemia-reperfusion injury in isolated rat lung, heart, and liver tissue by quickly providing ATP. However, it was reported that serum PEP concentrations are 13-fold higher in healthy elderly compare to the young. Unlike that of other cell types, the energy required for the physiological function of endothelial cells is mainly derived from glycolysis. Recently, it is unclear whether circulating accumulation of PEP affects endothelial cell function. In this study, we found for the first time that 50-250 µM of PEP significantly promoted THP-1 monocyte adhesion to human umbilical vein endothelial cells (HUVECs) through increased expression of vascular endothelial adhesion factor 1 (VCAM1) and intercellular adhesion factor 1 (ICAM1) in HUVECs. Meanwhile, 50-250 µM of PEP decreased the expression of endothelial nitric oxide synthase (eNOS) and cellular level of nitric oxide (NO) in HUVECs. Moreover, PEP increased levels of ROS, enhanced the numbers of SA-ß-Gal-positive cells and upregulated the expression of cell cycle inhibitors such as p21, p16 and the phosphorylation level of p53 on Ser15, and the expression of proinflammatory factors including TNF-α, IL-1ß, IL-6, IL-8, IL-18 and MCP-1 in HUVECs. Furthermore, PEP increased both oxygen consumption rate (OCR) and glycolysis rate, and was accompanied by reduced NAD+/NADH ratios and enhanced phosphorylation levels of AMPKα (Thr172), p38 MAPK (T180/Y182) and NF-κB p65 (Ser536) in HUVECs. Notably, PEP had no significant effect on hepG2 cells. In conclusion, these results demonstrated that PEP induced dysfunction and senescence in vascular endothelial cells through stimulation of metabolic reprogramming.

Relationship Between Feeding to Sleep During Infancy and Subsequent Childhood Disease Burden.

OBJECTIVE: To investigate the association of feeding to sleep during infancy and subsequent childhood health burdens. STUDY DESIGN: Information was collected from the parents of children who participated in the national health screening survey when the child was 9-12 months old. The exposure group included participants who were fed to sleep. The primary outcome was all-cause hospital admission (inpatient care, intensive care unit [ICU] admission, or general anesthesia) after age 24 months. Secondary outcomes were subsequent childhood diseases (ie, adenoidectomy and/or tonsillectomy, nasal polyps, allergic rhinitis, acute otitis media, asthma, pneumonia, and aspiration pneumonia), and growth status, as measured by weight-to-age and height-to-age z-scores. RESULTS: The study cohort consisted of 224 075 children who participated in the health screening program, 29 392 of whom (13.1%; 51% males) were fed to sleep. Exposure was associated with an increased risk of all-cause hospitalization after age 24 months (hazard ratio [HR], 1.05; 95% CI, 1.03-1.07), but not with admission to an ICU or receipt of general anesthesia. This also was related to adenoidectomy and/or tonsillectomy (HR, 1.08; 95% CI, 1.01-1.15), dental caries (HR, 1.32; 95% CI, 1.23-1.40), asthma (HR, 1.14; 95% CI, 1.14-1.24), pneumonia (HR, 1.10; 95% CI, 1.07-1.13), overweight (HR, 1.06; 95% CI, 1.03-1.09), and obesity (HR, 1.11; 95% CI, 1.06-1.16). CONCLUSIONS: Several adverse health outcomes are related to feeding to sleep during early childhood.

Acquired susceptibility to autoimmune diseases in pediatric patients with Escherichia coli infection: A population-matched retrospective cohort study.

BACKGROUND: Escherichia coli (E.coli) infection has been proposed to play an important role as an initial trigger in the development of autoimmunity via molecular mimicry. However, there has been no preliminary cohort study to establish the association of E.coli infection with autoimmune diseases. Therefore, we conducted a large scale, population-matched cohort study to determine the risk of autoimmune disease among patients with exposure to E.coli. METHODS: Utilizing the National Health Insurance Service database, we retrospectively analyzed a total of 259,875 Korean children that consisted of 23,625 exposed and 236,250 unexposed persons from January 1, 2002 to December 31, 2017. The exposed cohort was defined as patients diagnosed with E.coli infection. Unexposed controls were matched by birth year and sex at a 1:10 ratio for each exposed patient, using incidence density sampling. The primary outcome was autoimmune disease development. We used the Cox model to estimate the risks of autoimmune diseases among patients diagnosed with E.coli infection. RESULTS: Over a mean follow-up of 10 years, there were 1455 autoimmune disease cases among exposed patients (incidence rate, 63.6 per 10,000 person-years) and 11,646 autoimmune disease cases among unexposed persons (incidence rate, 50.4 per 10,000 person-years), with an adjusted hazard ratio (HR) of 1.254 (95% CI 1.187-1.325). E.coli infection was associated with increased risks of autoimmune diseases; Reactive arthritis, HR 1.487, 95% CI 1.131-1.956; Henoch Schönlein purpura, HR 1.265, 95% CI 1.050-1.524; Systemic lupus erythematosus, HR 1.838, 95% CI 1.165-2.898; Sjögren's syndrome, HR 2.002, 95% CI 1.342-2.987; IgA nephropathy, HR 1.613, 95% CI 1.388-1.874. Kaplan-Meier cumulative incidence curves also showed a significant association between E.coli infection and incident autoimmune disease (p < 0.0001). This relationship was not only independent of demographic variables, but also remained consistent across various sensitivity analyses. On the other hand, patients with longer hospital stay for E.coli infection were at a higher risk of autoimmune disease (p = 0.0003), and the risk of autoimmune disease also tended to increase, as the frequency of E.coli infection was higher. Moreover, the relative risk of autoimmune disease seemed to be attenuated by use of antibiotics and a history of intestinal infectious disease, but elevated by coexistence of other autoimmune diseases. CONCLUSIONS: Our cohort study indicates that E.coli infection was significantly associated with increased susceptibility to autoimmune diseases, even after adjusting for different factors. Thus, among environmental factors, a previous history of E.coli infection could be a predisposing risk factor in the development of autoimmune diseases.

Association between atopic dermatitis and school readiness in preschool children.

BACKGROUND: Although atopic dermatitis (AD) in children affects diverse stages of life, no studies have reported on the association between school readiness and AD. METHODS: This study used Korean National Health Insurance data and the Health Screening Program for Infants and Children. Among all children born between 2008 and 2012 in Korea, those who were assessed for school readiness through questionnaires in a health screening program performed at 54 and 60 months old were enrolled. AD was defined based on the International Classification of Diseases codes, with two or more prescriptions of topical corticosteroids during the first 54-60 months of life. The primary outcome was the association between school readiness and AD. The questionnaire relating to school readiness comprised six items - cognitive skills, social development, activeness, concentration, emotional development, and language skills. Logistic regression analysis was used to identify the associations between school readiness and AD. RESULTS: This study included 239,673 children without AD and 38,229 children with AD. The average age at which school readiness was assessed was 4.8 years. AD was associated with vulnerability in activeness (adjusted odds ratio: 1.127; 95% confidence interval: 1.071-1.186) and concentrations (1.170; 1.093-1.254). The impact of AD on concentrations showed consistent results regardless of sex, exposure to systemic corticosteroids and antihistamines, and age at the diagnosis of AD. CONCLUSIONS: Children with AD have vulnerability in school readiness in the aspects of activeness and concentration.

Association between complementary food introduction before age 4 months and body mass index at age 5-7 years: A retrospective population-based longitudinal cohort study.

BACKGROUND: The optimal time of starting complementary foods (CFs) in infants remains a subject of debate. This population-based longitudinal cohort study evaluated the association between early CF introduction and body mass index (BMI) in children aged 5-7 years. METHODS: The present study included 917,707 children born in Korea during 2008-2009. Initial timing of CF introduction was obtained by questionnaires administered between 4 and 6 months and 9 and 12 months of age. The cohort consisted of 154,565 eligible individuals who properly completed the screening programme, including structured questionnaires, anthropometric measurements and physical examinations. To balance baseline characteristics, children were subjected to propensity score matching based on 95 covariates, including indicators of baseline health such as perinatal condition, birth weight, economic status, clinical disease and drug exposure. Exposure was defined as introduction to CF at age < 4 months, and outcomes were overweight (BMI z-score > 85th percentile) and obesity (BMI z-score > 95th percentile) at ages 5-7 years. RESULTS: Of the 154,565 eligible children in the observed cohort, 10,499 (6.8%) were introduced to CF at age < 4 months and 144,066 (93.2%) at age ≥ 4 months. Propensity score matching yielded 9680 children introduced to CF at age < 4 months and 35,396 at age ≥ 4 months. The risk for being overweight or obese at age 5-7 years was slightly higher among those who started CF at age < 4 months than at age ≥4 months (adjusted relative risk = 1.06; 95% confidence interval = 1.02-1.09). A similar but stronger association was observed for being obese at age 5-7 years (adjusted relative risk = 1.12; 95% confidence interval = 1.05-1.19). CONCLUSIONS: Early CF introduction before age 4 months was associated with increased BMI at age 5-7 years.

Associations Between Phthalate, Eosinophil, and Aeroallergen Sensitization in Schoolchildren.

BACKGROUND: Phthalates and bisphenol A (BPA) are endocrine-disrupting chemicals and may cause immunological disorders in children. Therefore, according to the region, we investigated urinary phthalates and BPA levels and the relationship between urinary phthalate, aeroallergen sensitization, and eosinophil count during the coronavirus disease 2019 pandemic. METHODS: In total, 203 schoolchildren (134 residential and 69 industrial) aged 7-10 years were enrolled between July 2021 and July 2022. The BPA, metabolites of four high-molecular-weight phthalates (Σ4HMWP) and three low-molecular-weight phthalates (Σ3LMWP), were measured in the urine samples. Total eosinophil count and transepidermal water loss (TEWL) were also measured along with the skin prick test. RESULTS: The two groups had no differences in terms of BPA. The industrial group had significantly more plastic container usage, and there was a difference in the Σ3LMWP (P < 0.001) between the two groups but no difference in the Σ4HMWP (P = 0.234). The quartiles of urinary Σ4HMWP and Σ3LMWP (P < were not associated with the total eosinophil count, vitamin D level, or TEWL. After adjusting for cofactors, the quartiles of urinary Σ4HMWP and Σ3LMWP were significantly associated with total eosinophil count (P < 0.001) but not with aeroallergen sensitization or vitamin D. CONCLUSION: Exposure to phthalates was significantly associated with eosinophil count but not with aeroallergen sensitization or vitamin D. Therefore, reducing the use of plastic containers may effectively prevent exposure to phthalates and reduce Th2 cell-mediated inflammation in children.

Association Between Receipt of General Anesthesia During Childhood and Attention Deficit Hyperactive Disorder and Neurodevelopment.

BACKGROUND: There are inconsistent reports regarding the association between general anesthesia and adverse neurodevelopmental and behavioral disorders in children. METHODS: This nationwide administrative cohort study included children born in Korea between 2008 and 2009, and followed until December 31, 2017. The cohort included 93,717 participants who received general anesthesia with endotracheal intubation (ETI) who were matched to unexposed subjects in a 1:1 ratio. General anesthesia was defined by National Health Insurance Service treatment codes with intratracheal anesthesia, and the index date was the first event of general anesthesia. The primary outcome was attention deficit hyperactive disorder (ADHD), which was defined as at least a principal diagnosis of 10th revision of the International Classification of Diseases code F90.X after the age of 72 months. Neurodevelopment, which was assessed using a developmental screening test (Korean-Ages and Stages Questionnaire [K-ASQ]), was a secondary outcome. The K-ASQ is performed annually from 1 to 6 years of age and consists of 5 domains. The association between general anesthesia and ADHD was estimated using a Cox hazard model, and its association with neurodevelopment was estimated using a generalized estimation equation, with control for multiple risk factors beyond 1 year after the index date. RESULTS: The median age at the index date was 3.8 (95% confidence interval [CI], 1.7-5.8) years, and there were 57,625 (61.5%) men. During a mean follow-up period of 5 years, the incidence rate of ADHD was 42.6 and 27.7 per 10,000 person-years (PY) in the exposed and unexposed groups, respectively (absolute rate difference 14.9 [95% CI, 12.5-17.3] per 10,000 PY). Compared to the unexposed group, the exposed group had an increased risk of ADHD (adjusted hazard ratio, 1.41 [95% CI, 1.30-1.52]). In addition, a longer duration of anesthesia with ETI and more general anesthesia procedures with ETI were associated with greater risk of ADHD. General anesthesia with ETI was also associated with poorer results in the K-ASQ. CONCLUSION: Administration of general anesthesia with ETI to children is associated with an increased risk of ADHD and poor results in a neurodevelopmental screening test.

Neurodevelopment at 6 years of age in children with atopic dermatitis.

BACKGROUND: Few studies have reported an association between atopic dermatitis and cognitive impairment in children. Therefore, we evaluated the association between atopic dermatitis (AD) and neurodevelopmental dysfunction in children. METHODS: We analyzed 2,395,966 children born between 2008 and 2012 in Korea. All data were acquired from the databases of the Korean National Health Insurance System. AD was defined as five or more diagnoses before age 24 months. The outcome was suspected neurodevelopmental dysfunction in the gross motor skill, fine motor skill, cognition, language, sociality, and self-care domains of the Korean Developmental Screening Test for Infants and Children at age 6 years. The positive control outcome was defined as attention deficit hyperactive disorder (ADHD). The associations were assessed using ordinal logistic regression, adjusting for asthma and allergic rhinitis. RESULTS: Among the eligible children, 89,452 and 30,557 were allocated to the control and AD groups, respectively. In the weighted data, the AD group showed a higher risk of suspected neurodevelopmental dysfunction in the total score (weighted adjusted odds ratio [95% CI] 1.10 [1.05-1.16]), gross motor skills (1.14 [1.04-1.25]), and fine motor skills (1.15 [1.06-1.25]) than the control group. The AD with steroids or hospitalization groups showed an increased risk of suspected neurodevelopmental dysfunction. In addition, the AD group showed a significant association with mental retardation, psychological development disorder, and behavioral and emotional disorders as well as ADHD. CONCLUSIONS: AD before age 2 years may be associated with an increased risk of neurodevelopmental dysfunction including gross and fine motor skills in the young childhood period.

DDX17 protects hepatocytes against oleic acid/palmitic acid-induced lipid accumulation.

Hepatic lipid accumulation is an initiation factor in fatty liver disease, and promoting a reduction in hepatic lipid accumulation is an important treatment strategy. DEAD box RNA helicase 17 (DDX17) is a member of the DEAD-box family and a molecular chaperone. Previous studies have demonstrated that DDX17 is a transcriptional coregulator of tumorigenesis, inflammation, and macrophage cholesterol efflux. The liver is the main site for lipid metabolism, and metabolic (dysfunction)-associated fatty liver disease (MAFLD) is one of the most common chronic liver diseases. However, the impact of DDX17 on hepatic lipid accumulation has not been verified. In this study, we found, for the first time, that oleic acid/palmitic acid (OA/PA)-induced lipid accumulation was largely abrogated by DDX17 overexpression in both HepG2 (a human hepatocellular carcinoma line) and Hep1-6 (a murine hepatocellular carcinoma line) cells, and this effect was due to a marked reduction in cellular triglyceride (TG) content. Moreover, the overexpression of DDX17 was accompanied by a significant decrease in the expression of genes involved in de novo fatty acid synthesis (FAS, ACC, and SCD-1) in both HepG2 and Hep1-6 cells. In conclusion, DDX17 protected against OA/PA-induced lipid accumulation in hepatocytes through de novo lipogenesis inhibition.

Association of clinical and social factors with risk of fracture in children with atopic dermatitis.

BACKGROUND: Children with atopic dermatitis (AD) have multiple risk factors for accidental fractures, injuries that can lead to significant morbidity and mortality. However, little is known about the factors that mediate the relationship between AD and fracture in children. OBJECTIVE: Our purpose was to examine the association of AD with fracture and to identify potential mediating factors. METHODS: This retrospective cohort study examined children with and without AD from a longitudinal matched cohort database of 353,040 children registered in the national health insurance service and participated in the national health-screening program of Korea. We defined AD using medical claims and medication prescription records. We investigated accidental fracture events between the index date and the end of follow-up in a propensity score-matched cohort. Pre-specified subgroup analyses considered fractures in four different regions of the body. The mediating effects of 10 possible clinical factors (including the use of antihistamines and systemic corticosteroids) and social factors (including nutritional status and parental safety awareness) were determined. RESULTS: There were 145,704 participating children, 20% with AD and 49% girls. Fractures occurred in 6,652 of the children with AD (23%, mean age: 64.6 ± 29.2 months) and in 24,698 of the control group (21%, mean age 65.0 ± 28.9 months). Children with AD had an 8% greater risk of fracture events overall (adjusted relative risk [aRR]: 1.08, 95% CI: 1.05-1.10). In subgroup analysis, AD was related to increased rates of skull and facial bone fracture (aRR: 1.09, 95% CI: 1.04-1.14), for trunk including vertebrae (aRR: 1.58, 95% CI: 1.22- 2.05), and for distal limbs (aRR: 1.11, 95% CI: 1.07-1.15). However, the relationship with proximal limb fracture was insignificant. Duration of systemic corticosteroid prescription was the largest mediating factor, followed by duration of antihistamine prescription, and infant feeding practices. In particular, the duration of systemic corticosteroid prescription was significantly associated with fracture events (incidence: 20.1% at the 25th percentile and 23.6% at the 75th percentile; difference: 3.4% [95% CI: 2.8-4.0%]). CONCLUSIONS: Children with AD were related to increased fracture events. The key factors with mediating effects were systemic use of corticosteroid and antihistamine. Infant feeding practices had weaker mediating effects.