Molecular Dynamic Simulation To Reveal the Mechanism Underlying MGL-3196 Resistance to Thyroxine Receptor Beta.

Thyroxine receptor beta (TRß) is a ligand-dependent nuclear receptor that participates in regulating multiple biological processes, particularly playing an important role in lipid metabolism regulation. TRß is currently a popular therapeutic target for nonalcoholic steatohepatitis (NASH), while no drugs have been approved to treat this disease. MGL-3196 (Resmetirom) is the first TRß agonist that has succeeded in phase III clinical trials for the treatment of NASH; therefore, studying its molecular mechanism of action is of great significance. In this study, we employed molecular dynamic simulation to investigate the interaction mode between MGL-3196 and TRß at the all-atom level. More importantly, by comparing the binding patterns of MGL-3196 in several prevalent TRß mutants, it was identified that the mutations R243Q and H435R located, respectively, around and within the ligand-binding pocket of TRß cause TRß to be insensitive to MGL-3196. This indicates that patients with NASH carrying these two mutations may exhibit resistance to the medication of MGL-3196, thereby highlighting the potential impact of TRß mutations on TRß-targeted treatment of NASH and beyond.

Functional characterization of two novel NKX2-1 frameshift variants that cause pulmonary surfactant dysfunction.

BACKGROUND: We aim to report two unrelated patients with pulmonary surfactant dysfunction (PSD) that carried two novel NKX2-1 frameshift variants, and evaluated the impact of these variants in vitro. METHODS: We enrolled children with PSD and NKX2-1 variants, and collected their clinical information and follow-up data. We constructed wild-type (WT) and variant NKX2-1 plasmids and transfected them into A549 and HEK293T cells. The functional characterization of variants was then evaluated by qRT-PCR, western blot, immunofluorescence, electrophoretic mobility shift assay, and dual-luciferase reporter assay. RESULTS: Two novel heterozygous frameshift variants of NKX2-1, i.e., c.705delC (Gly236Alafs*29) and c.313_316 dup (Asn106Lysfs*304), were identified in children from two unrelated families. We discerned attenuated mRNA and protein expression in the Asn106Lysfs*304 variant, and reduced DNA -binding as well as transcriptional activation capabilities in both variants. While the Asn106Lysfs*304 variant lost its synergistic interactions with PAX8 and TAZ, the Gly236Alafs*29 variant partially retained its residual transcriptional activation capabilities and synergistic interactions with PAX8 and TAZ. CONCLUSIONS: We reported on two children with two novel NKX2-1 frameshift variants. In vitro experiments revealed that the two frameshift variants have common and different mechanisms based on the loss or conservation of domains, which partially explained the phenotypical heterogeneity. IMPACT: Pulmonary surfactant dysfunction is a rare heterogeneous disease that exhibits a great burden on children's quality of life. We reported two novel NKX2-1 frameshift variants carried by two children with different clinical phenotypes, thus broadening our knowledge base of gene variations and phenotypes in NKX2-1. We performed an in vitro study and uncovered different pathogenic mechanisms underlying the actions of two novel variants, and thereby partially explained the mechanisms of phenotypical heterogeneity caused by NKX2-1 variants.

RNA m6A methylation modulates airway inflammation in allergic asthma via PTX3-dependent macrophage homeostasis.

N6-methyladenosine (m6A), the most prevalent mRNA modification, has an important function in diverse biological processes. However, the involvement of m6A in allergic asthma and macrophage homeostasis remains largely unknown. Here we show that m6A methyltransferases METTL3 is expressed at a low level in monocyte-derived macrophages from childhood allergic asthma patients. Conditional knockout of Mettl3 in myeloid cells enhances Th2 cell response and aggravates allergic airway inflammation by facilitating M2 macrophage activation. Loss and gain functional studies confirm that METTL3 suppresses M2 macrophage activation partly through PI3K/AKT and JAK/STAT6 signaling. Mechanistically, m6A-sequencing shows that loss of METTL3 impairs the m6A-YTHDF3-dependent degradation of PTX3 mRNA, while higher PTX3 expression positively correlates with asthma severity through promoting M2 macrophage activation. Furthermore, the METTL3/YTHDF3-m6A/PTX3 interactions contribute to autophagy maturation in macrophages by modulating STX17 expression. Collectively, this study highlights the function of m6A in regulating macrophage homeostasis and identifies potential targets in controlling allergic asthma.

Airway microbiota correlated with pulmonary exacerbation in primary ciliary dyskinesia patients.

IMPORTANCE: PCD is a rare disease characterized by productive cough, rhinitis, and recurrent infections of the upper and lower airways. Because the diagnosis of PCD is often delayed, patients receive more antibiotics, experience a heavier financial burden, and have a worse prognosis; thus, it is very important to identify the pathogeny and use the correct antibiotic. In this large single-center study of PCD microbiota, we identified an outline of the bacterial microbes from the respiratory tract; furthermore, we found that the microbiota diversity in pediatric sputum was richer than that in pediatric BALF through sequencing, indicating a heterogeneous community structure. The microbiota diversity and richness were lower during pulmonary exacerbation than during pulmonary stabilization. A significantly higher abundance of Pseudomonas had a moderate distinguishing effect for lung exacerbation, which attracted more attention for the study of Pseudomonas therapy in pediatric patients with PCD.

[Congenital pulmonary alveolar proteinosis in a neonate]. / æ–°ç”Ÿå„¿å ˆå¤©æ€§è‚ºæ³¡è›‹ç™½æ²‰ç§¯ç—‡1例.

The male patient was referred to the hospital at 44 days old due to dyspnea after birth and inability to wean off oxygen. His brother died three days after birth due to respiratory failure. The main symptoms observed were respiratory failure, dyspnea, and hypoxemia. A chest CT scan revealed characteristic reduced opacity in both lungs with a "crazy-paving" appearance. The bronchoalveolar lavage fluid (BALF) showed periodic acid-Schiff positive proteinaceous deposits. Genetic testing indicated a compound heterozygous mutation in the ABCA3 gene. The diagnosis for the infant was congenital pulmonary alveolar proteinosis (PAP). Congenital PAP is a significant cause of challenging-to-treat respiratory failure in full-term infants. Therefore, congenital PAP should be considered in infants experiencing persistently difficult-to-treat dyspnea shortly after birth. Early utilization of chest CT scans, BALF pathological examination, and genetic testing may aid in early diagnosis.

Clinical features and outcomes of children's interstitial lung disease accompanied with connective tissue disease: A prospective cohort study.

BACKGROUND: Medical complexity of childhood interstitial lung disease (chILD) with connective tissue disease (CTD) poses a considerable challenge to pediatricians. METHODS: Clinical characteristics, laboratory findings, pulmonary function tests (PFTs), treatments and outcomes obtained for patients with CTD-chILD were analyzed in a prospective study. RESULTS: Patients' median age at diagnosis was 7 years old. About 29.4% (15/51) suffered rapidly progressive childhood ILD (RP-chILD) with a high mortality rate (33.3%, 5/15), and the incidence of RP-chILD in juvenile idiopathic inflammatory myopathies was as high as 41.6% and the mortality rate was 30% (3/10). More than 70% patients had decreased diffusion capacity. The mean interval from symptoms-onset to diagnosis was 11.3 months. Compared to chILD with known CTD, the chILD proceeded CTD had a longer diagnosis interval, higher mortality, hospital stays and costs (P < 0.05). Lung imaging (33.3%) and lung function (72.7%) were partially reversible. The average survival time was 68.6 months. Cox univariate analysis showed that HRCT score ≥3, experiencing RP-chILD, cyanosis, acute respiratory distress syndrome (ARDS) and CD4 T cell <200 were significant predictors of death for chILD, whereas Cox multivariate analysis showed that ARDS was significant predictor of death for CTD-chILD, while IVIG support combined with corticosteroids and immunosuppressants was a protective factor. CONCLUSIONS: Care providers should conduct an assessment for CTD in chILD as a longer interval between the diagnosis of chILD and the CTD is associated with increased mortality. Complications as ARDS predict poor outcome in CTD-chILD, while IVIG support combined with corticosteroids and immunosuppressants is a protective factor.

Etiology and clinical features of children with bronchiectasis in China: A 10-year multicenter retrospective study.

INTRODUCTION: The current study aims to investigate the etiology spectrum and the clinical characteristics of bronchiectasis in Chinese children. METHODS: The study is designed as a multicenter retrospective study. 193 cases were enrolled in 13 centers in China between 2008 and 2017. The inclusive cases must meet the clinical as well as the HRCT criteria. Only if both two radiologists confirmed the diagnosis, the case could be enrolled. The cases that could not provide clinical and imageology data were excluded. The data were entered into the specialized system and then analyzed. RESULTS: One hundred sixty-nine cases (87%) were found to have the underlying etiology. Post-infective (46%), primary immunodeficiency (14%), and PCD (13%) were the common causes. All cases came from 28 provinces in Mainland China. The median age of symptom onset was 5.8 (2.0, 8.9) years. The median age of diagnosis was 8.4 (4.5, 11.6) years. The main symptoms were cough, sputum expectoration, and fever during the exacerbation. Nineteen percent of patients suffered from limited exercise tolerance. Clubbing was found in 17% of cases. Nearly 30% of patients presented growth limitations. On the HRCT findings, 126 cases had diffused bronchiectasis, and bilateral involvement was found in 94 cases. The lower lobes and right middle lobes were most commonly involved. Approximately 30% of cultures of sputum and bronchoalveolar lavage were positive. CONCLUSION: A majority of cases could be found the underlying etiology. Post-infective, primary immunodeficiency, and PCD were the most common causes. Some clinical figures might indicate a specific etiology.

Underlying causes and outcomes of recurrent pneumonia in hospitalized children.

OBJECTIVES: To describe the clinical characteristics and underlying causes of recurrent pneumonia (RP) among hospitalized children, and to identify risk factors associated with adverse outcomes. METHODS: We reviewed the medical records of hospitalized children diagnosed with RP at the Children's Hospital of Fudan University from January 2016 to January 2021 and then described clinical characteristics and underlying causes. The associations between factors and adverse outcomes were assessed using logistic regression. RESULTS: Of 551 children with RP, 483 (87.7%) manifested underlying causes, with recurrent aspiration (127, 23.0%), primary immunodeficiency (PID) (91, 16.5%), and congenital heart diseases (63, 11.4%) being the most common. Genetic defects were identified in about a quarter (158, 28.7%) of the patients. PID odds ratio (OR, 7.9; 95% confidence interval [CI], 2.8-22.8), primary ciliary dyskinesia (OR, 12.9; 95% CI, 3.0-54.8), bronchiolitis obliterans (OR, 7.0; 95% CI, 1.7-28.5), and a diagnosis of RP at an age of >3 years (OR, 3.4; 95% CI, 1.3-9.0) were risk factors for severe outcomes. Aspiration (OR, 2.9; 95% CI, 1.3-6.3) and an abnormal family history (OR, 3.3; 95% CI, 1.3-8.2) were risk factors for rehospitalization. CONCLUSIONS: The majority (87.7%) of hospitalized children with RP exhibited underlying causes, and genetic defects were common.

Pediatric bronchial Dieulafoy's disease with bronchial artery embolization: two case reports.

Background: Bronchial Dieulafoy's disease (BDD) is a vascular malformation characterized by the presence of a dysplastic artery in the bronchial submucosa. It is very rare in children but potentially fatal due to life-threatening hemoptysis. Case Description: An 8-year-old boy and a 6-year-old girl were referred to our hospital with recurrent moderate to massive hemoptysis. Intraluminal protrusions with a tendency to bleed were found by bronchoscopy in both patients. Computed tomography angiography (CTA) revealed an abnormal bronchial artery in one patient and a small intraluminal nodule with contrast enhancement in the other. An enlarged bronchial artery and bronchial-to-pulmonary fistulae corresponding to the lesion site were detected by bronchial arteriography in both patients. Based on the radiological findings, the diagnosis of BDD was established. Subsequent bronchial artery embolization (BAE) was successful, and no recurrence of hemoptysis was observed during the 15- to 18-month follow-up. Conclusions: Our cases highlighted the importance of considering BDD in the context of hemoptysis and endobronchial protrusion in children. Bronchial arteriography plays a critical role in diagnosis, especially in cases where CTA does not reveal vascular malformations. Early identification is essential as biopsy is contraindicated. BAE may be an appropriate treatment to improve the prognosis of children with BDD.

circS100A11 enhances M2a macrophage activation and lung inflammation in children with asthma.

BACKGROUND: Dysregulation of circRNAs is associated with a variety of human diseases; however, its role in childhood asthma is undefined. METHODS: The differential expression profiles of circRNAs were analyzed by microarray. The effects and mechanisms by which circRNAs influence macrophage activation were detected by quantitative real-time PCR, RNA immunoprecipitation assay, and chromatin immunoprecipitation assay, among others. The roles of circRNA and its host gene in asthma were tested in a cockroach allergen extract (CRE)-induced murine asthma model. RESULTS: We identified 372 circRNAs that were differentially expressed in PBMCs of children with asthma as compared with healthy controls. A circRNA with unknown function, circS100A11, was dominantly expressed in monocytes and significantly upregulated in children with asthma. circS100A11 facilitated M2a macrophage activation by enhancing translation of its host gene, S100A11, and exacerbated lung inflammation in a CRE-induced murine asthma model with macrophage-specific overexpression of circS100A11. Mechanistically, circS100A11 promoted S100A11 translation by competitively binding to CAPRIN1 to decrease the suppression of CAPRIN1 upon S100A11 translation. Then, S100A11 liberated SP3 from nucleolin and promoted SP3 binding to the STAT6 promoter to enhance STAT6 expression and M2a macrophage activation. Macrophage-specific knockdown of S100A11 could alleviate lung inflammation in a CRE-induced murine asthma model in vivo. CONCLUSIONS: circS100A11 and S100A11 promote M2a macrophage activation and lung inflammation in asthma model and may serve as potential therapeutic and diagnostic targets in children with asthma.

Size-segregated particle number concentrations and outpatient-department visits for pediatric respiratory diseases in Shanghai, China.

BACKGROUND: Few studies have simultaneously explored which size of particles has the greatest impact on the risk for pediatric asthma, bronchitis and upper respiratory tract infections (URTIs). OBJECTIVES: To investigate the short-term association between size-segregated particle number concentrations (PNCs) and outpatient-department visits (ODVs) for major pediatric respiratory diseases. METHODS: Daily counts of pediatric ODVs for asthma, bronchitis and URTIs were obtained from 66 hospitals in Shanghai, China, from 2016 to 2018. Pollutant effects were estimated using Poisson generalized additive models combined with polynomial distributed lag models. We also fitted co-pollutant cumulative effects models included six criteria air pollutants and conducted stratifying analyses by gender, age, season and geographic distances. RESULTS: We identified a total of 430,103 patients with asthma, 1,547,013 patients with bronchitis, and 2,155,738 patients with URTIs from the hospitals. Effect estimates increased with decreasing particle size. Ultrafine particle (UFP) and PNCs of 0.10-0.40 µm particles (PNC0.10-0.40) were associated with increased ODVs for asthma, bronchitis and URTIs at cumulative lags up to 3d. Associations tended to appear stable after adjusting for criteria air pollutants. At the cumulative lag 0-2d, each interquartile range increase in UFP was associated with increased ODVs due to asthma (relative risk 1.21, 95% CI: 1.07, 1.38), bronchitis (1.20, 95% CI: 1.07, 1.34) and URTI (1.17, 95% CI: 1.06, 1.30), whereas the associations for PNC0.10-0.40 remained significant but attenuated in magnitude. CONCLUSIONS: UFP may be a leading contributor to the adverse respiratory effects of particulate air pollution and the effects increased with decreasing particle size.

Impact of maternal age on neonatal outcomes among very preterm infants admitted to Chinese neonatal intensive care units: a multi-center cohort study.

Background: The percentage of advanced maternal age (aged over 35 years) mothers has been rising across the world, the evidence of maternal age on neonatal outcomes from low- and middle-income countries is scarce. Our objective was to evaluate the effect of maternal age on mortality and major morbidity among very preterm infants admitted to Chinese neonatal intensive care units. Methods: Data from a retrospective multi-center cohort of all complete care very preterm infants admitted to 57 neonatal intensive care units that participated in the Chinese Neonatal Network from January 1st to December 31st, 2019 were analyzed. Neonatal outcomes including mortality or any major morbidity, defined as necrotizing enterocolitis stage 2 or 3, moderate & severe bronchopulmonary dysplasia, severe intraventricular hemorrhage, cystic periventricular leukomalacia, severe retinopathy of prematurity, or sepsis. A multiple logistic regression model was constructed to analyze the independent association between maternal age and neonatal outcome. Results: Among 7,698 eligible newborns, 80.5% of very preterm infants were born to mothers between the ages of 21 and 35 years, with 18.0% born to mothers >35 years and 1.5% born to mothers <21 years. Higher rates of maternal hypertension, maternal diabetes, cesarean deliveries, antenatal steroid usage were noted as maternal age increased. The proportion of prenatal care, cesarean section, antenatal steroid usage and inborn for very preterm infants born to mothers <21 years was lower than those of mothers of other ages. Compared to the ages of 21-35 years group, the odds of severe intraventricular hemorrhage (adjusted odd ratio: 2.00, 95% CI: 1.08-3.71) was significantly higher in the ages of 15-20 years group. Increasing maternal age was associated with higher rates of small for gestational age and lower birth weight of very preterm infants, but no correlation between advanced maternal age and very preterm infants mortality or major morbidity. Conclusions: Among very preterm infants, increasing maternal age was associated with higher rates of small for gestational age but not neonatal mortality or major morbidity. Young maternal age may increase the risk of severe intraventricular hemorrhage of very preterm infants.

Effects of acute high intraocular pressure on red-green and blue-yellow cortical color responses in non-human primates.

Glaucoma is a leading cause of irreversible blindness worldwide, and intraocular pressure (IOP) is an established and modifiable risk factor for both chronic and acute glaucoma. The relationship between color vision deficits and chronic glaucoma has been described previously. However, the effects of acute glaucoma or acute primary angle closure, which has high prevalence in China, on color vision remains unclear. To address the above question, red-green or blue-yellow color responses in V1, V2, and V4 of seven rhesus macaques were monitored using intrinsic-signal optical imaging while monocular anterior chamber perfusions were performed to reversibly elevate IOP acutely over a clinically observed range of 30 to 90 mmHg. We found that the cortical population responses to both red-green and blue-yellow grating stimuli, systematically decreased as IOP increased from 30 to 90 mmHg. Although a similar decrement in magnitude was noted in V1, V2, and V4, blue-yellow responses were consistently more impaired than red-green responses at all levels of acute IOP elevation and in all monitored visual areas. This physiological study in non-human primates demonstrates that acute IOP elevations substantially depress the ability of the visual cortex to register color information. This effect is more severe for blue-yellow responses than for red-green responses, suggesting selective impairment of the koniocellular pathways compared with the parvocellular pathways. Together, we infer that blue-yellow color vision might be the most vulnerable visual function in acute glaucoma patients.

Prevalence of monogenic disease in paediatric patients with a predominant respiratory phenotype.

OBJECTIVE: This study aimed to investigate the prevalence and clinical characteristics of monogenic disease in paediatric patients with a predominant respiratory phenotype. METHODS: Exome sequencing was performed in a cohort of 971 children with a predominant respiratory phenotype and suspected genetic aetiology. A total of 140 positive cases were divided into subgroups based on recruitment age and the primary biological system(s) involved. RESULTS: There were 140 (14.4%) patients with a positive molecular diagnosis, and their primary clinical manifestations were respiratory distress (12.9%, 18 of 140), respiratory failure (12.9%, 18 of 140) and recurrent/persistent lower respiratory infections (66.4%, 93 of 140). Primary immunodeficiency (49.3%), multisystem malformations/syndromes (17.9%), and genetic lung disease (16.4%) were the three most common genetic causes in the cohort, and they varied among the age subgroups. A total of 72 (51.4%) patients had changes in medical management strategies after genetic diagnosis, and the rate in those with genetic lung disease (82.6%, 19 of 23) was far higher than that in patients with genetic disease with lung involvement (45.3%, 53 of 117) (p=0.001). CONCLUSION: Our findings demonstrate that exome sequencing is a valuable diagnostic tool for monogenic diseases in children with a predominant respiratory phenotype, and the genetic spectrum varies with age. Taken together, genetic diagnoses provide invaluable clinical and prognostic information that may also facilitate the development of precision medicine for paediatric patients.

Cas9-Cleavage Sequences in Size-Reduced Plasmids Enhance Nonviral Genome Targeting of CARs in Primary Human T Cells.

T cell genome editing holds great promise to advance a range of immunotherapies but is encumbered by the dependence on difficult-to-produce and expensive viral vectors. Here, small double-stranded plasmid DNA modified to mediate high-efficiency homologous recombination is designed. The resulting chimeric antigen receptor (CAR)-T cells display a similar phenotype, transcriptional profile, and in vivo potency to CAR-T cells generated using adeno-associated viral vector. This method should simplify and accelerate the use of precision engineering to produce edited T cells for research and clinical purposes.

Respiratory symptoms as initial manifestations of interstitial lung disease in clinically amyopathic juvenile dermatomyositis: a case report with literature review.

BACKGROUND: Clinically amyopathic juvenile dermatomyositis (CAJDM) is a clinical subgroup of juvenile dermatomyositis (JDM), characterized by JDM rashes with little or no clinically evident muscle weakness. Interstitial lung disease (ILD) is an uncommon but potentially fatal complication of juvenile dermatomyositis (JDM). While adults with dermatomyositis-associated ILD usually present respiratory symptoms before or at the same time as skin muscle manifestations, only a few studies have covered the onset of respiratory symptoms of ILD in JDM patients, especially CAJDM. There is currently no clear effective treatment regime or any prognostic factors for CAJDM-associated ILD. CASE PRESENTATION: Here, we report the first case of a CAJDM patient who presented with respiratory symptoms as the initial manifestation. A 10-year-old male patient presented to the hospital with a complaint of progressive cough and chest pain. Violaceous macule and papules appeared a few days later and he was positive for anti-Ro-52 antibodies. Imaging showed diffuse interstitial infiltration in both lungs and lung function tests showed restrictive and obstructive ventilatory dysfunction. Muscular abnormalities were excluded by thigh magnetic resonance imaging (MRI) and electromyography. Skin biopsy showed pathognomonic findings consistent with DM. Lung biopsy indicated chronic inflammation of the mucosa. This patient was finally diagnosed with CAJDM complicated by ILD and prescribed methylprednisolone, immunoglobulin, prednisolone and mycophenolate mofetil (MMF) for treatment. The patient's cutaneous and respiratory manifestations were largely improved. We retrospectively reviewed this and another six cases with CAJDM-associated ILD reported previously to better understand its clinical characteristics and effective management. CONCLUSIONS: Initial respiratory symptoms with rapid progression in patients presenting Gottron papules should be considered manifestations of CAJDM-associated ILD. We also found a combination of corticosteroids, IVIG and MMF to be an effective method of arresting the progress of CAJDM-associated ILD and improving the prognosis of the patients.

Monolithic integration of nanorod arrays on microfluidic chips for fast and sensitive one-step immunoassays.

Here, we present integrated nanorod arrays on microfluidic chips for fast and sensitive flow-through immunoassays of physiologically relevant macromolecules. Dense arrays of Au nanorods are easily fabricated through one-step oblique angle deposition, which eliminates the requirement of advanced lithography methods. We report the utility of this plasmonic structure to improve the detection limit of the cardiac troponin I (cTnI) assay by over 6 × 105-fold, reaching down to 33.9 fg mL-1 (~1.4 fM), compared with an identical assay on glass substrates. Through monolithic integration with microfluidic elements, the device enables a flow-through assay for quantitative detection of cTnI in the serum with a detection sensitivity of 6.9 pg mL-1 (~0.3 pM) in <6 min, which was 4000 times lower than conventional glass devices. This ultrasensitive detection arises from the large surface area for antibody conjugation and metal-enhanced fluorescent signals through plasmonic nanostructures. Moreover, due to the parallel arrangement of flow paths, simultaneous detection of multiple cancer biomarkers, including prostate-specific antigen and carcinoembryonic antigen, has been fulfilled with increased signal-to-background ratios. Given the high performance of this assay, together with its simple fabrication process that is compatible with standard mass manufacturing techniques, we expect that the prepared integrated nanorod device can bring on-site point-of-care diagnosis closer to reality.

Characteristics of childhood allergic diseases in outpatient and emergency departments in Shanghai, China, 2016-2018: a multicenter, retrospective study.

BACKGROUND: The prevalence of allergic diseases (ADs), such as asthma and allergic rhinitis (AR), is increasing worldwide in both adults and children. Although ADs are common and frequently coexist in outpatient care, city-level data regarding the characteristics of childhood AD remain limited in China. This study aimed to assess the profile and characteristics of ADs in the city of Shanghai. METHODS: A multicenter retrospective study was designed to collect routine administrative data from outpatient and emergency departments from 66 hospitals in Shanghai, China, from 2016 to 2018. Children with asthma, AR, allergic conjunctivitis (AC), and allergic skin diseases were investigated. Demographic characteristics, patients visit pattern, spectrum of diagnosis, and comorbidities were analyzed. RESULTS: A total of 2,376,150 outpatient and emergency visits for ADs were included in the period from 2016 to 2018. Allergic skin diseases accounted for 38.9%, followed by asthma (34.8%), AR (22.9%), and AC (3.3%), with a male predominance in all four diseases. Asthma and allergic skin diseases were most frequent in the 1 to < 4 years of age group, while AR and AC were more common in the 4 to < 7 years of age group. Asthma accounted for the greatest number of annual and emergency visits. The most frequent comorbidity of asthma was lower respiratory tract infection (LRTI) (49.3%), followed by AR (20.5%) and upper respiratory tract infection (14.1%). The most common comorbidities of AR were otitis media (23.4%), adenoid hypertrophy/obstructive sleep apnea (22.1%), followed by LRTI (12.1%), asthma (9.4%) and chronic pharyngitis (8.9%). CONCLUSIONS: Asthma and allergic skin diseases were the most common ADs in outpatient and emergency departments in the study period. Respiratory tract infection was the most common comorbidity of asthma in children. More attention should be devoted to the treatment of comorbidities to improve childhood AD outcomes with a better understanding of the characteristics of ADs in outpatient care.

Bronchopulmonary Dysplasia Predicted by Developing a Machine Learning Model of Genetic and Clinical Information.

BACKGROUND: An early and accurate evaluation of the risk of bronchopulmonary dysplasia (BPD) in premature infants is pivotal in implementing preventive strategies. The risk prediction models nowadays for BPD risk that included only clinical factors but without genetic factors are either too complex without practicability or provide poor-to-moderate discrimination. We aim to identify the role of genetic factors in BPD risk prediction early and accurately. METHODS: Exome sequencing was performed in a cohort of 245 premature infants (gestational age <32 weeks), with 131 BPD infants and 114 infants without BPD as controls. A gene burden test was performed to find risk genes with loss-of-function mutations or missense mutations over-represented in BPD and severe BPD (sBPD) patients, with risk gene sets (RGS) defined as BPD-RGS and sBPD-RGS, respectively. We then developed two predictive models for the risk of BPD and sBPD by integrating patient clinical and genetic features. The performance of the models was evaluated using the area under the receiver operating characteristic curve (AUROC). RESULTS: Thirty and 21 genes were included in BPD-RGS and sBPD-RGS, respectively. The predictive model for BPD, which combined the BPD-RGS and basic clinical risk factors, showed better discrimination than the model that was only based on basic clinical features (AUROC, 0.915 vs. AUROC, 0.814, P = 0.013, respectively) in the independent testing dataset. The same was observed in the predictive model for sBPD (AUROC, 0.907 vs. AUROC, 0.826; P = 0.016). CONCLUSION: This study suggests that genetic information contributes to susceptibility to BPD. The predictive model in this study, which combined BPD-RGS with basic clinical risk factors, can thus accurately stratify BPD risk in premature infants.

Associations of fine particulate matter and constituents with pediatric emergency room visits for respiratory diseases in Shanghai, China.

BACKGROUND: Although ambient fine particulate matter (PM2.5) has been associated with adverse respiratory outcomes in children, few studies have examined PM2.5 constituents with respiratory diseases in children in China. OBJECTIVES: To investigate the associations of short-term exposure to PM2.5 and its constituents with pediatric emergency room visits (ERVs) for respiratory diseases in Shanghai, China. METHODS: We collected daily concentrations of PM2.5 and its constituents in urban Shanghai from January 1, 2016, to December 31, 2018. Daily pediatric ERVs for four major respiratory diseases, including upper respiratory tract infection, bronchitis, pneumonia, and asthma, were obtained from 66 hospitals in Shanghai during the same period. Associations of exposure to daily PM2.5 and constituents with respiratory ERVs were estimated using the over-dispersed generalized additive models. RESULT: Short-term exposure to PM2.5 and its constituents were associated with increased pediatric ERVs for respiratory diseases. Specifically, an interquartile range increase in the 3-day average PM2.5 level (31 µg/m3) was associated with 1.86% (95%CI: 0.52, 3.22), 1.53% (95%CI: 0.01, 3.08), 1.90% (95%CI: 0.30, 3.52), and 2.67% (95%CI: 0.70, 4.68) increase of upper respiratory tract infection, bronchitis, pneumonia, and asthma ERVs, respectively. As for PM2.5 constituents, we found organic carbon, ammonium, nitrate, selenium, and zinc were associated with higher risk of respiratory ERVs in the single constituent and the constituent-PM2.5 models. CONCLUSION: Short-term exposure to PM2.5 was associated with increased pediatric ERVs for respiratory diseases. Constituents related to anthropogenic combustion and traffic might be the dominant contributors of the observed associations.