'Personalized medicine': phenotyping pediatric obstructive sleep apnea.

PURPOSE OF REVIEW: Obstructive sleep apnea (OSA) is common in children. Phenotyping pediatric OSA has a crucial role in personalized diagnosis and treatment to improve outcomes for this population. This review sets forth a clinical approach that allows for phenotyping pediatric OSA. RECENT FINDINGS: The emerging concept of phenotyping pediatric OSA is based on identifying a primary cause, which leads to a more precise understanding of the pathogenesis in any individual patient. Phenotyping enables treatment focusing on the primary cause, but does not exclude the need for supplemental management strategies based on other recognizable traits. The identification of pediatric OSA phenotypes (POP) relies on observable characteristics with significant prevalence. This review will concentrate on the most important phenotypes seen in clinical practice: pediatric OSA with craniofacial abnormalities (POPCA); OSA with upper airway disease (POPUAD); OSA with obesity (POPO), and OSA associated with neuromuscular disease (POPNED). SUMMARY: Phenotyping pediatric OSA is a form of personalized medicine. By identifying clinical subtypes, individualized treatment plans can be devised in order to choose therapies that are associated with predictable responses. Moreover, it is rare that a therapeutic modality is devoid of possible complications; knowledge of the phenotype being treated can enable early intervention should those occur. Finally, all of the aforementioned phenotypes require personalized support incorporating individualized care plans so as to optimize the quality of life and overall sleep health of children with OSA.

Host and gut microbial tryptophan metabolism and type 2 diabetes: an integrative analysis of host genetics, diet, gut microbiome and circulating metabolites in cohort studies.

OBJECTIVE: Tryptophan can be catabolised to various metabolites through host kynurenine and microbial indole pathways. We aimed to examine relationships of host and microbial tryptophan metabolites with incident type 2 diabetes (T2D), host genetics, diet and gut microbiota. METHOD: We analysed associations between circulating levels of 11 tryptophan metabolites and incident T2D in 9180 participants of diverse racial/ethnic backgrounds from five cohorts. We examined host genome-wide variants, dietary intake and gut microbiome associated with these metabolites. RESULTS: Tryptophan, four kynurenine-pathway metabolites (kynurenine, kynurenate, xanthurenate and quinolinate) and indolelactate were positively associated with T2D risk, while indolepropionate was inversely associated with T2D risk. We identified multiple host genetic variants, dietary factors, gut bacteria and their potential interplay associated with these T2D-relaetd metabolites. Intakes of fibre-rich foods, but not protein/tryptophan-rich foods, were the dietary factors most strongly associated with tryptophan metabolites. The fibre-indolepropionate association was partially explained by indolepropionate-associated gut bacteria, mostly fibre-using Firmicutes. We identified a novel association between a host functional LCT variant (determining lactase persistence) and serum indolepropionate, which might be related to a host gene-diet interaction on gut Bifidobacterium, a probiotic bacterium significantly associated with indolepropionate independent of other fibre-related bacteria. Higher milk intake was associated with higher levels of gut Bifidobacterium and serum indolepropionate only among genetically lactase non-persistent individuals. CONCLUSION: Higher milk intake among lactase non-persistent individuals, and higher fibre intake were associated with a favourable profile of circulating tryptophan metabolites for T2D, potentially through the host-microbial cross-talk shifting tryptophan metabolism toward gut microbial indolepropionate production.

Lung-protective mechanical ventilation for patients undergoing abdominal laparoscopic surgeries: a randomized controlled trial.

BACKGROUND: Pneumoperitoneum and Trendelenburg position in laparoscopic surgeries could contribute to postoperative pulmonary dysfunction. In recent years, intraoperative lung-protective mechanical ventilation (LPV) has been reportedly able to attenuate ventilator-induced lung injuries (VILI). Our objectives were to test the hypothesis that LPV could improve intraoperative oxygenation function, pulmonary mechanics and early postoperative atelectasis in laparoscopic surgeries. METHODS: In this randomized controlled clinical trial, 62 patients indicated for elective abdominal laparoscopic surgeries with an expected duration of greater than 2 h were randomly assigned to receive either lung-protective ventilation (LPV) with a tidal volume (Vt) of 7 ml kg- 1 ideal body weight (IBW), 10 cmH2O positive end-expiratory pressure (PEEP) combined with regular recruitment maneuvers (RMs) or conventional ventilation (CV) with a Vt of 10 ml kg- 1 IBW, 0 cmH2O in PEEP and no RMs. The primary endpoints were the changes in the ratio of PaO2 to FiO2 (P/F). The secondary endpoints were the differences between the two groups in PaO2, alveolar-arterial oxygen gradient (A-aO2), intraoperative pulmonary mechanics and the incidence of atelectasis detected on chest x-ray on the first postoperative day. RESULTS: In comparison to CV group, the intraoperative P/F and PaO2 in LPV group were significantly higher while the intraoperative A-aO2 was clearly lower. Cdyn and Cstat at all the intraoperative time points in LPV group were significantly higher compared to CV group (p < 0.05). There were no differences in the incidence of atelectasis on day one after surgery between the two groups. CONCLUSIONS: Lung protective mechanical ventilation significantly improved intraoperative pulmonary oxygenation function and pulmonary compliance in patients experiencing various abdominal laparoscopic surgeries, but it could not ameliorate early postoperative atelectasis and oxygenation function on the first day after surgery. TRIAL REGISTRATION: https://www.clinicaltrials.gov/identifier: NCT04546932 (09/05/2020).

Ancestrally diverse genome-wide association analysis highlights ancestry-specific differences in genetic regulation of plasma protein levels.

Fully characterizing the genetic architecture of circulating proteins in multi-ancestry populations provides an unprecedented opportunity to gain insights into the etiology of complex diseases. We characterized and contrasted the genetic associations of plasma proteomes in 9,455 participants of European and African (19.8%) ancestry from the Atherosclerosis Risk in Communities Study. Of 4,651 proteins, 1,408 and 2,565 proteins had protein-quantitative trait loci (pQTLs) identified in African and European ancestry respectively, and twelve unreported potentially causal protein-disease relationships were identified. Shared pQTLs across the two ancestries were detected in 1,113 aptamer-region pairs pQTLs, where 53 of them were not previously reported (all trans pQTLs). Sixteen unique protein-cardiovascular trait pairs were colocalized in both European and African ancestry with the same candidate causal variants. Our systematic cross-ancestry comparison provided a reliable set of pQTLs, highlighted the shared and distinct genetic architecture of proteome in two ancestries, and demonstrated possible biological mechanisms underlying complex diseases.

Intercomparison of neutron personal dose equivalent measured by thermoluminescence dosimeters.

An intercomparison of neutron personal dose equivalent measured by the Harshaw thermoluminescence neutron dosimeters (TLDs) between the National Institute of Metrology of China (NIM) and the Institute for Nuclear Science and Technology of Vietnam (INST) was performed. Three sets of TLDs (each set consisting of five TLDs) were prepared for each laboratory. Each set was then irradiated to the corresponding same nominal standard value of neutron personal dose equivalent, Hp(10)n-stdi, of 1.0, 2.0, and 3.0 mSv, respectively at these two laboratories. The irradiated TLDs were then read-out at the INST using the Harshaw 4500-type TLD reader to obtain neutron personal dose equivalents at the NIM, Hp(10)n-NIMi and at the INST, Hp(10)n-INSTi, which are corresponding to different values of Hp(10)n-stdi. The TLDs' responses to different scattered components of neutrons in these two fields are also discussed. Comparisons between the corresponding pair values of Hp(10)n-NIMi and Hp(10)n-INSTi show good agreements within 10% with the standard uncertainty of 12.5% (k = 1). The measured values of Hp(10)n-NIMi and Hp(10)n-INSTi are satisfied the Trumpet curve criteria. This implies that the TLDs can be used for safety assessment of occupational neutron personal dose equivalents. This intercomparison result also confirms the capabilities of these two laboratories (i.e., NIM, INST) on deliveries of neutron personal dose equivalent standard values for calibrations.

Large scale plasma proteomics identifies novel proteins and protein networks associated with heart failure development.

Heart failure (HF) causes substantial morbidity and mortality but its pathobiology is incompletely understood. The proteome is a promising intermediate phenotype for discovery of novel mechanisms. We measured 4877 plasma proteins in 13,900 HF-free individuals across three analysis sets with diverse age, geography, and HF ascertainment to identify circulating proteins and protein networks associated with HF development. Parallel analyses in Atherosclerosis Risk in Communities study participants in mid-life and late-life and in Trøndelag Health Study participants identified 37 proteins consistently associated with incident HF independent of traditional risk factors. Mendelian randomization supported causal effects of 10 on HF, HF risk factors, or left ventricular size and function, including matricellular (e.g. SPON1, MFAP4), senescence-associated (FSTL3, IGFBP7), and inflammatory (SVEP1, CCL15, ITIH3) proteins. Protein co-regulation network analyses identified 5 modules associated with HF risk, two of which were influenced by genetic variants that implicated trans hotspots within the VTN and CFH genes.

Metabolomic Association and Risk Prediction With Heart Failure in Older Adults.

BACKGROUND: Older adults have markedly increased risks of heart failure (HF), specifically HF with preserved ejection fraction (HFpEF). Identifying novel biomarkers can help in understanding HF pathogenesis and improve at-risk population identification. This study aimed to identify metabolites associated with incident HF, HFpEF, and HF with reduced ejection fraction and examine risk prediction in older adults. METHODS: Untargeted metabolomic profiling was performed in Black and White adults from the ARIC study (Atherosclerosis Risk in Communities) visit 5 (n=3719; mean age, 75 years). We applied Cox regressions to identify metabolites associated with incident HF and its subtypes. The metabolite risk score (MRS) was constructed and examined for associations with HF, echocardiographic measures, and HF risk prediction. Independent samples from visit 3 (n=1929; mean age, 58 years) were used for replication. RESULTS: Sixty metabolites (hazard ratios range, 0.79-1.49; false discovery rate, <0.05) were associated with incident HF after adjusting for clinical risk factors, eGFR, and NT-proBNP (N-terminal pro-B-type natriuretic peptide). Mannonate, a hydroxy acid, was replicated (hazard ratio, 1.36 [95% CI, 1.19-1.56]) with full adjustments. MRS was associated with an 80% increased risk of HF per SD increment, and the highest MRS quartile had 8.7× the risk of developing HFpEF than the lowest quartile. High MRS was also associated with unfavorable values of cardiac structure and function. Adding MRS over clinical risk factors and NT-proBNP improved 5-year HF risk prediction C statistics from 0.817 to 0.850 (∆C, 0.033 [95% CI, 0.017-0.047]). The association between MRS and incident HF was replicated after accounting for clinical risk factors (P<0.05). CONCLUSIONS: Novel metabolites associated with HF risk were identified, elucidating disease pathways, specifically HFpEF. An MRS was associated with HF risk and improved 5-year risk prediction in older adults, which may assist at at-risk population identification.

Identification of allele-specific KIV-2 repeats and impact on Lp(a) measurements for cardiovascular disease risk.

The abundance of Lp(a) protein holds significant implications for the risk of cardiovascular disease (CVD), which is directly impacted by the copy number (CN) of KIV-2, a 5.5 kbp sub-region. KIV-2 is highly polymorphic in the population and accurate analysis is challenging. In this study, we present the DRAGEN KIV-2 CN caller, which utilizes short reads. Data across 166 WGS show that the caller has high accuracy, compared to optical mapping and can further phase approximately 50% of the samples. We compared KIV-2 CN numbers to 24 previously postulated KIV-2 relevant SNVs, revealing that many are ineffective predictors of KIV-2 copy number. Population studies, including USA-based cohorts, showed distinct KIV-2 CN, distributions for European-, African-, and Hispanic-American populations and further underscored the limitations of SNV predictors. We demonstrate that the CN estimates correlate significantly with the available Lp(a) protein levels and that phasing is highly important.

Epigenome-wide DNA Methylation Association Study of CHIP Provides Insight into Perturbed Gene Regulation.

With age, hematopoietic stem cells can acquire somatic mutations in leukemogenic genes that confer a proliferative advantage in a phenomenon termed "clonal hematopoiesis of indeterminate potential" (CHIP). How these mutations confer a proliferative advantage and result in increased risk for numerous age-related diseases remains poorly understood. We conducted a multiracial meta-analysis of epigenome-wide association studies (EWAS) of CHIP and its subtypes in four cohorts (N=8196) to elucidate the molecular mechanisms underlying CHIP and illuminate how these changes influence cardiovascular disease risk. The EWAS findings were functionally validated using human hematopoietic stem cell (HSC) models of CHIP. A total of 9615 CpGs were associated with any CHIP, 5990 with DNMT3A CHIP, 5633 with TET2 CHIP, and 6078 with ASXL1 CHIP (P <1×10-7). CpGs associated with CHIP subtypes overlapped moderately, and the genome-wide DNA methylation directions of effect were opposite for TET2 and DNMT3A CHIP, consistent with their opposing effects on global DNA methylation. There was high directional concordance between the CpGs shared from the meta-EWAS and human edited CHIP HSCs. Expression quantitative trait methylation analysis further identified transcriptomic changes associated with CHIP-associated CpGs. Causal inference analyses revealed 261 CHIP-associated CpGs associated with cardiovascular traits and all-cause mortality (FDR adjusted p-value <0.05). Taken together, our study sheds light on the epigenetic changes impacted by CHIP and their associations with age-related disease outcomes. The novel genes and pathways linked to the epigenetic features of CHIP may serve as therapeutic targets for preventing or treating CHIP-mediated diseases.

The role of nursing leadership in promoting evidence-based nursing practice.

Although the undermining of the nursing profession, time constraints, and the lack of inclusive teaching of evidence-based nursing (EBN) in the nursing school's curriculum have long been identified as being some of the main barriers to the adoption of evidence-based practice (EBP) by nurses, the specific role of nurse leaders in directly influencing and supporting evidence-based nursing is not well demonstrated. This opinion piece discusses potential factors that influence the implementation of EBP into clinical routine practice, as well as how nursing leadership styles can contribute to its promotion in contemporary healthcare settings.

Responsiveness of Inhaled Corticosteroid Treatment in Children with Asthma: The Role of rs242941 Polymorphism of CRHR1 Gene.

INTRODUCTION: Inhaled corticosteroid (ICS) is the most widely used and effective treatment of asthma. However, some patients do not respond to ICS, which might be due to various genetic factors. Hence, understanding the genetic factors involved in the ICS response could help physicians to individualize their treatment decision and action plans for given patients. This study aimed to analyze the characteristics of corticotropin-releasing hormone receptor 1 (CRHR1) genotypes in children with asthma and the correlation between rs242941 polymorphism of CRHR1 gene and ICS responsiveness. METHODS: This prospective study included children with uncontrolled asthma, assessing their eosinophil count, IgE concentration, lung function, and fractional concentration of nitric oxide in exhaled breath (FENO) and performing CRHR1 polymorphism sequencing. The level of asthma control was assessed by asthma control test (ACT); the responsiveness of asthma treatment with ICS was evaluated by measuring the change of ACT and forced expiratory volume in 1 s (FEV1) after treatment versus at inclusion. RESULTS: In total, 107 patients were analyzed for CRHR1 at rs242941. Among these, 86 (80.3%) had homozygous wild-type GG, 20 (18.7%) had heterozygous GT genotypes, and 1 (1.0%) had a homozygous variant for TT. Children with personal and family history of atopy were more likely to have GT and TT genotypes. The severity of asthma was similar between children with asthma in the three groups of GG, GT, and TT genotypes of CRHR1 at rs242941. FENO level, total IgE concentration, and eosinophilic count in children with asthma were not significantly different between GG and GT genotypes. The patient with a TT homozygous variant genotype had a higher level of FENO. There was no correlation between CRHR1 polymorphism at rs242941 and asthma control evaluated by asthma control test and lung function parameters. CONCLUSION: TT genotype of rs242941 in the CRHR1 gene is not frequent. Clinical and functional characteristics of children with asthma with rs242941 polymorphism of CRHR1 gene remain homogeneously similar. There is no correlation between rs242941 polymorphism and ACT or FEV1.

The first successful bone marrow transplantation in Vietnam for a young Vietnamese boy with chronic granulomatous disease: a case report.

Background: Chronic granulomatous disease (CGD) is an inborn error of immunity (IEI) disorder that results from defects in the respiratory burst activity in phagocytes, leading to the inability to kill bacterial and fungal microorganisms. CGD patients usually have a high incidence of morbidity such as infections and autoinflammatory diseases and a high mortality rate. Allogeneic bone marrow transplantation (BMT) is the only definitive cure for patients who suffer from CGD. Case presentation: We report the first transplant case of chronic granulomatous disease in Vietnam. A 25-month-old boy with X-linked CGD underwent bone marrow transplantation from his 5-year-old, full-matched human leukocyte antigen (HLA)-carrier sibling after myeloablative conditioning regimen with busulfan 5.1 mg/kg/day for 4 days, fludarabine 30 mg/m2/day for 5 days, and rATG (Grafalon-Fresenius) 10 mg/kg/day for 4 days. Neutrophil was engrafted on day 13 posttransplant, donor chimerism was 100% on day 30 with the dihydrorhodamine-1,2,3 (DHR 123) flow cytometric assay test that reached 38% of the normal 45 days posttransplant. Five months after transplant, the patient was free of infection with stable DHR 123 assay at 37%, and donor chimerism remained 100%. No sign of a graft-versus-host disease had been observed posttransplant. Conclusion: We suggest that bone marrow transplantation is a safe and effectual cure for CGD patients, especially for patients with HLA-identical siblings.

Two novel CD40LG gene mutations causing X-linked hyper IgM syndrome in Vietnamese patients.

The X-linked hyper IgM syndrome is a primary immunodeficiency disorder (PID) due to mutations in the CD40LG gene. Hyper IgM syndrome is characterized by the absence or decreased levels of IgG and IgA and normal or elevated IgM levels in serum. Affected patients become susceptible to infections such as pneumonia, diarrhea, and skin ulcer types. Hematopoietic stem cell transplantation is the only treatment currently available and ideally performed before the age of 10 years. Early, accurate diagnosis will contribute to the effective treatment for patients with hyper IgM. The patients from different Vietnamese families who have been diagnosed with hyper IgM at The Allergy, Immunology and Rheumatology Department, Vietnam National Hospital Pediatrics, were performed a genetic analysis using whole exome sequencing. The mutations were confirmed by the Sanger sequencing method in patients and their families. The influence of the mutations was predicted with the in silico analysis tools: PROVEAN, SIFT, PolyPhen-2, and MutationTaster. In this study, two novel mutations (p.Thr254fs and p.Leu138Phe) in the CD40LG gene were found in Vietnamese patients with X-linked hyper IgM syndrome. Our results contribute to the general understanding of the etiology of the disease and can help diagnose the different forms of PID.

Transition practice for primary immunodeficiency diseases in Southeast Asia: a regional survey.

Introduction: With increased diagnostic capabilities and treatment modalities in the field of primary immunodeficiencies (PID), many pediatric patients survive beyond childhood and experience a change of care to the adult-oriented healthcare system. Unfortunately, the transition pathways for PID are less clearly defined, resulting in deterioration of quality of care in adulthood. Hence, this is the first regional study to address PID clinicians' opinions on practices and challenges of transition care in 7 Southeast Asia (SEA) countries. Methods: We adopted a cross-sectional study design through an online survey platform to enquire opinions of transition practices from expert representatives in 7 SEA countries. Results: Regionally, 3 out 7 countries reported having no practice of transition care. Among cited challenges were reluctant adaptation by patients and caregivers to unfamiliarized adult healthcare systems, inadequate ratio of adult immunologists to patients and lack of facilities for transfer. Discussion and conclusion: Our study provides evidence to advocate policy makers on the importance of standardized integration of transition practice towards betterment of transiting PID patients into adulthood.

Does COVID-19 pandemic cause natural resources commodity prices volatility? Empirical evidence from China.

COVID-19 pandemic caused havoc around the globe in both economic and non-economic sectors. This paper, unlike previous studies, evaluates the role of COVID-19 on the volatility in natural resources. The volatility of natural resources commodity prices has been the center of discussion, especially during the pandemic. Unlike previous studies, this study aims to evaluate the role of the pandemic, i.e., Covid-19 and its possible impact on volatility in natural resources commodity prices for China. China has been the center of this epidemic disease and is considered one of the major economies affected by the Covid-19; therefore, it is better to conduct this study for China. This study uses data from January 2020 till September 2021 to capture the peak time of Covid-19. Moreover, this study employs the novel wavelet power spectrum and wavelet coherence approach to better capture volatility within commodity prices volatility and Covid-19 and evaluate the association between both variables. The empirical results reveal that only natural resources commodity prices are volatile and only short. While Covid-19 positive cases and Covid-19 deaths are not vulnerable during the study period. Moreover, the wavelet coherence conforms that both Covid-19 positive cases and Covid-19 deaths significantly cause volatility in natural resources commodity prices. Although, volatility is found at different periods; still, volatility is observed only in the short-run. The study also provides relevant policy implications to ensure a relevant and timely solution for the existing issue. Moreover, future research guidelines and the study's limitations are also provided.

Clinical-functional characteristics of children with asthma and obstructive sleep apnea overlap associated with attention deficit hyperactivity disorder: A cross-sectional study.

Background: Asthma and obstructive sleep apnea (OSA) are common chronic respiratory disorders in children. The relationship between asthma and OSA is bidirectional; these conditions share multiple epidemiological risk factors. Untreated OSA may cause attention deficit hyperactivity disorder (ADHD) symptoms. This study aimed to assess the prevalence of ADHD in asthmatic children with OSA and the link between asthma control and lung function of children with asthma and OSA. Methods: A total of 96 children aged 6-15 years diagnosed with asthma, according to the Global Initiative for Asthma (GINA) 2020, were enrolled in this study. All demographic data, including age, gender, body mass index, asthma control status, therapy, the Vanderbilt ADHD Diagnostic Parent Rating Scale, lung function, and exhaled nitric oxide, were collected. In addition, home respiratory polygraphy was used to identify OSA in study subjects. Results: A total of 96 patients (8.4 ± 2.4 years) were included in the present study. OSA was identified in 60.4% of asthmatic children with a mean apnea-hypopnea index (AHI) of 3.5 ± 3.0 event/h. The inattentive ADHD subtype was significantly lower in the non-OSA asthmatic group than in the OSA asthmatic group (7.9 vs. 34.5%, p < 0.05). ADHD had a higher probability of presence (OR: 3.355; 95% CI: 1.271-8.859; p < 0.05) in the OSA group (AHI >1 event/h). Children with poorly controlled asthma had a significantly high risk of OSA (83.0 vs. 17.0%, p < 0.001) than children with well-controlled asthma. Allergic rhinitis increased the odds of having OSA in patients with asthma [OR: 8.217 (95% CI: 3.216-20.996); p < 0.05]. Conclusion: The prevalence of OSA is increased among poorly controlled asthma. ADHD may have a higher prevalence in children with OSA. Therefore, prompt diagnosis of OSA will lead to an accurate asthma control strategy in patients with asthma.

Successful Treatment of Carbamazepine-Induced Toxic Epidermal Necrolysis With Clinical Gastrointestinal Involvement: A Case Report.

Background: Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is a rare and life-threatening disease of the skin and mucosal surfaces. Although gastrointestinal manifestations in adults are potential prognostic factors for disease severity, there are limited data on such cases and their standard management in the pediatric population. Case Presentation: We herein report the case of an 8-year-old girl with a 1-year history of epilepsy, who presented with bilateral conjunctivitis and progressively widespread bullous, and pruritic eruption based on erythematous skin after administration of carbamazepine. A diagnosis of carbamazepine-induced TEN was made, and the drug was immediately discontinued. The result of genetic screening showed that the patient was positive for the HLA-B*15:02 allele. Then, her condition got worse by developing gastrointestinal involvement, including hematemesis and severe watery bloody diarrhea. A combination of the intravenous immunoglobulin and the appropriate dose of systemic steroids have contributed to a favorable outcome in this case. Multidisciplinary care of mucocutaneous involvement, supplemental nutrition, and fluid replacement was also critically warranted. This report aims to contribute to the current literature on TEN-related gastrointestinal manifestations in pediatrics and highlights the need for further investigations in determining the optimal treatment in such cases. Conclusion: In conclusion, we reported the successful treatment of TEN-related gastrointestinal manifestations in a pediatric patient, which should be critically considered in patients with SJS/TEN. Since it may significantly contribute to the poor prognosis of the illness, further investigations in determining standard management in such cases are necessary.

Clinical and functional characteristics of OSA in children with comorbid asthma treated by leukotriene receptor antagonist: A descriptive study.

Background: Obstructive sleep apnea (OSA) is the most common form of respiratory disorders during sleep in children, especially those with severe asthma. However, optimal treatment of asthma might significantly improve OSA severity. Methods: It was a cohort study including children aged >5 years old and diagnosed with asthma according to GINA (Global Initiative for Asthma). The data related to age, gender, height, weight, body mass index (BMI), clinical symptoms and medical history of asthma, spirometry (FEV1: forced expiratory in 1 s), and exhaled nitric oxide (FENO) were recorded for analysis. Respiratory polygraphy (RPG) was done for each study subject to diagnose OSA and its severity. Results: Among 139 asthmatic children, 99 patients with OSA (71.2%) were included in the present study (9.3 ± 0.2 years): 58.6% with uncontrolled asthma and 32.3% with partial controlled asthma. The mean ACT (asthma control testing) score was 19.0 ± 3.4. The most frequent night-time symptoms were restless sleep (76.8%), snoring (61.6%), sweating (52.5%), and trouble breathing during sleep (48.5%). The common daytime symptoms were irritable status (46.5%) and abnormal behavior (30.3%). The mean AHI (apnea-hypopnea index) was 3.5 ± 4.0 events/h. There was a significant correlation between BMI and snoring index (R = 0.189 and P = 0.027), bronchial and nasal FENO with AHI (R = 0.046 and P < 0.001; R = 0.037 and P < 0.001; respectively). There was no significant correlation between asthma level, FEV1 and AHI. The severity of asthma and respiratory function were improved significantly after 3 months and 6 months of asthma treatment in combination with leukotriene receptor antagonist (LRA) treatment. The symptoms related to OSA were significantly improved after treatment with LRA. The severity of OSA was decreased significantly after 3 months and 6 months of treatment. Conclusion: The treatment of asthmatic children with comorbid OSA by LRA in combination with standard therapy for asthma could improve the control of asthma and the symptoms and severity of OSA.

Clonal hematopoiesis of indeterminate potential, DNA methylation, and risk for coronary artery disease.

Age-related changes to the genome-wide DNA methylation (DNAm) pattern observed in blood are well-documented. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by the age-related acquisition and expansion of leukemogenic mutations in hematopoietic stem cells (HSCs), is associated with blood cancer and coronary artery disease (CAD). Epigenetic regulators DNMT3A and TET2 are the two most frequently mutated CHIP genes. Here, we present results from an epigenome-wide association study for CHIP in 582 Cardiovascular Health Study (CHS) participants, with replication in 2655 Atherosclerosis Risk in Communities (ARIC) Study participants. We show that DNMT3A and TET2 CHIP have distinct and directionally opposing genome-wide DNAm association patterns consistent with their regulatory roles, albeit both promoting self-renewal of HSCs. Mendelian randomization analyses indicate that a subset of DNAm alterations associated with these two leading CHIP genes may promote the risk for CAD.

Genome-wide studies reveal factors associated with circulating uromodulin and its relationships to complex diseases.

Uromodulin (UMOD) is a major risk gene for monogenic and complex forms of kidney disease. The encoded kidney-specific protein uromodulin is highly abundant in urine and related to chronic kidney disease, hypertension, and pathogen defense. To gain insights into potential systemic roles, we performed genome-wide screens of circulating uromodulin using complementary antibody-based and aptamer-based assays. We detected 3 and 10 distinct significant loci, respectively. Integration of antibody-based results at the UMOD locus with functional genomics data (RNA-Seq, ATAC-Seq, Hi-C) of primary human kidney tissue highlighted an upstream variant with differential accessibility and transcription in uromodulin-synthesizing kidney cells as underlying the observed cis effect. Shared association patterns with complex traits, including chronic kidney disease and blood pressure, placed the PRKAG2 locus in the same pathway as UMOD. Experimental validation of the third antibody-based locus, B4GALNT2, showed that the p.Cys466Arg variant of the encoded N-acetylgalactosaminyltransferase had a loss-of-function effect leading to higher serum uromodulin levels. Aptamer-based results pointed to enzymes writing glycan marks present on uromodulin and to their receptors in the circulation, suggesting that this assay permits investigating uromodulin's complex glycosylation rather than its quantitative levels. Overall, our study provides insights into circulating uromodulin and its emerging functions.