Sphingolipids in Childhood Asthma and Obesity (SOAP Study): A Protocol of a Cross-Sectional Study.

Asthma and obesity are two of the most common chronic conditions in children and adolescents. There is increasing evidence that sphingolipid metabolism is altered in childhood asthma and is linked to airway hyperreactivity. Dysregulated sphingolipid metabolism is also reported in obesity. However, the functional link between sphingolipid metabolism, asthma, and obesity is not completely understood. This paper describes the protocol of an ongoing study on sphingolipids that aims to examine the pathophysiology of sphingolipids in childhood asthma and obesity. In addition, this study aims to explore the novel biomarkers through a comprehensive multi-omics approach including genomics, genome-wide DNA methylation, RNA-Seq, microRNA (miRNA) profiling, lipidomics, metabolomics, and cytokine profiling. This is a cross-sectional study aiming to recruit 440 children from different groups: children with asthma and normal weight (n = 100), asthma with overweight or obesity (n = 100), overweight or obesity (n = 100), normal weight (n = 70), and siblings of asthmatic children with normal weight, overweight, or obesity (n = 70). These participants will be recruited from the pediatric pulmonology, pediatric endocrinology, and general pediatric outpatient clinics at Sidra Medicine, Doha, Qatar. Information will be obtained from self-reported questionnaires on asthma, quality of life, food frequency (FFQ), and a 3-day food diary that are completed by the children and their parents. Clinical measurements will include anthropometry, blood pressure, biochemistry, bioelectrical impedance, and pulmonary function tests. Blood samples will be obtained for sphingolipid analysis, serine palmitoyltransferase (SPT) assay, whole-genome sequencing (WGS), genome-wide DNA methylation study, RNA-Seq, miRNA profiling, metabolomics, lipidomics, and cytokine analysis. Group comparisons of continuous outcome variables will be carried out by a one-way analysis of variance or the Kruskal-Wallis test using an appropriate pairwise multiple comparison test. The chi-squared test or a Fisher's exact test will be used to test the associations between categorical variables. Finally, multivariate analysis will be carried out to integrate the clinical data with multi-omics data. This study will help us to understand the role of dysregulated sphingolipid metabolism in obesity and asthma. In addition, the multi-omics data from the study will help to identify novel genetic and epigenetic signatures, inflammatory markers, and mechanistic pathways that link asthma and obesity in children. Furthermore, the integration of clinical and multi-omics data will help us to uncover the potential interactions between these diseases and to offer a new paradigm for the treatment of pediatric obesity-associated asthma.

Prevalence of Sleep-Disordered Breathing in Prader-Willi Syndrome.

Introduction: Sleep-disordered breathing (SDB) is common in patients with Prader-Willi Syndrome (PWS). However, the prevalence of SDB varies widely between studies. Early identification of SDB and factors contributing to its incidence is essential, particularly when considering growth hormone (GH) therapy. Objectives: The aims of the study were to describe the prevalence and phenotypes of sleep-disordered breathing (SDB) in patients with Prader-Willi syndrome (PWS) and to determine the effects of age, gender, symptoms, GH therapy and body mass index on SDB severity. Methods: This study was a retrospective chart review of all patients with genetically confirmed Prader-Willi syndrome who underwent diagnostic overnight polysomnography (PSG) in the sleep laboratory at Sidra Medicine. Clinical and PSG data of enrolled patients were collected. Results: We identified 20 patients (nine males, eleven females) with PWS who had overnight sleep polysomnography (PSG) at a median age (IQR) of 5.83 (2.7-12) years. The median apnea-hypopnea index (AHI) was 8.55 (IQR 5.8-16.9) events/hour. The median REM-AHI was 27.8 (IQR 15-50.6) events/hour. The median obstructive apnea-hypopnea index (OAHI) was 7.29 (IQR 1.8-13.5) events/hour. The median central apnea-hypopnea index (CAHI) was 1.77 (IQR 0.6-4.1) events/hour. Nineteen patients (95%) demonstrated SDB by polysomnography (PSG) based on AHI ≥1.5 events/hour. Nine patients (45%) were diagnosed with obstructive sleep apnea (OSA). Three patients (15%) were diagnosed with central sleep apnea (CSA). Seven patients (35%) were diagnosed with mixed sleep apnea. No correlations were observed between AHI and age, gender, BMI, symptoms, or GH therapy. However, REM-AHI was significantly correlated with BMI (P=0.031). Conclusion: This study shows a high prevalence of SDB among our patients with PWS. Obstructive sleep apnea was the predominant phenotype. BMI was the only predictor for high REM-AHI. Further studies of large cohorts are warranted to define SDB in PWS and design the appropriate treatment.

Obesity-Associated Non-T2 Mechanisms in Obese Asthmatic Individuals.

Obesity and asthma are two common health issues that have shown increased prevalence in recent years and have become a significant socioeconomic burden worldwide. Obesity increases asthma incidence and severity. Obese asthmatic individuals often experience increased exacerbation rates, enhanced airway remodeling, and reduced response to standard corticosteroid therapy. Recent studies indicate that obesity-associated non-T2 factors such as mechanical stress, hyperinsulinemia, systemic inflammation, adipose tissue mediators, metabolic dysregulation, microbiome dysbiosis, and high-fat-diet are responsible for increased asthma symptoms and reduced therapeutic response in obese asthmatic individuals. This manuscript reviews the recent findings highlighting the role of obesity-associated factors that contribute to airway hyper-reactivity, airway inflammation and remodeling, and immune cell dysfunction, consequently contributing to worsening asthma symptoms. Furthermore, the review also discusses the possible future therapies that might play a role in reducing asthma symptoms by diminishing the impact of obesity-associated non-T2 factors.

Advances in Cystic Fibrosis Research in Qatar: A Commentary.

Cystic fibrosis is a genetic disorder caused by a Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene defect. Many across the globe suffer the debilitating symptoms. The aim of this commentary is to briefly cover various aspects related to the disease in the Arab world and then in Qatar.

Health research-strengthening and capacity development: Research support system model in an academic healthcare system.

INTRODUCTION: Healthcare research contributes to the well-being of a population; hence, it is important to use the right system to ensure that junior researchers develop the required skills. Current research-strengthening and capacity development programs might lack a research process-based common framework or model leading to variable and suboptimal outcomes. This study aimed to describe the development and evaluation of a model for health research-capacity development at both individual and institutional levels in a Joint Commission International-accredited governmental healthcare organization in Qatar. METHODS: This retrospective observational study evaluated a research support system employed in Qatar for 1 year and constituted of16 stations, each covering a different topic and supported by an experienced faculty member. We recorded how many faculty members were involved and how many people accessed which stations. We developed an outcomes logistic model and obtained feedback about their experience of using the research support system through a short survey. RESULTS: Twenty-one faculty members supported a total of 77 participants, representing various professions and specialties. The majority of the participants received support on multiple stations, and the most solicited were study design and methodology (n = 45, 58.4%) and research idea (n = 29, 37.7%). The most common type of research that participants required support for was clinical research (n = 65, 84.4%). Moreover, 58.4% of the participants answered the survey, and their responses attested to their perceived benefit of making use of the research support system. CONCLUSION: The research support system presented was positively evaluated by participants and promoted networking. Such aspects are favorable to the development of a research culture within an organization and would be a good addition for implementation in universities running healthcare programs and hospitals with residency programs and a large and varied healthcare workforce. This would contribute to the development of health-related research capacity and quality of research outputs in these institutions.

Role of Obesity in Inflammation and Remodeling of Asthmatic Airway.

Obesity is considered as an important risk factor for the onset of asthma and plays a key role in enhancing the disease's severity. Obese asthmatic individuals represent a distinct phenotype of asthma that is associated with additional symptoms, more severe exacerbation, decreased response to standard medication, and poor quality of life. Obesity impairs the function of the lung airway in asthmatic individuals, leading to increased inflammation and severe remodeling of the bronchus; however, the molecular events that trigger such changes are not completely understood. In this manuscript, we review the current findings from studies that focused on understanding the role of obesity in modulating the functions of airway cells, including lung immune cells, epithelial cells, smooth muscle cells, and fibroblasts, leading to airway inflammation and remodeling. Finally, the review sheds light on the current knowledge of different therapeutic approaches for treating obese asthmatic individuals. Given the fact that the prevalence of asthma and obesity has been increasing rapidly in recent years, it is necessary to understand the molecular mechanisms that play a role in the disease pathophysiology of obese asthmatic individuals for developing novel therapies.

The prevalence of asthma, allergic rhinitis, and eczema among school-aged children in Qatar: A Global Asthma Network Study.

This cross-sectional study aims to utilize the Global Asthma Network (GAN) questionnaires to estimate the prevalence of asthma, allergic rhinitis, and eczema among children in Qatar. The study population was comprised of children ages 6-7 and 13-14 years, along with their parents or guardians. The English and Arabic versions of the GAN questionnaires were used to collect data for this study. A total of 2646 participants were recruited (1210 in the 6-7 years age group and 1436 in the 13-14 years age group), in addition to a total of 3831 parents or guardians. The overall prevalence of diagnosed asthma, lifetime allergic rhinitis, and diagnosed eczema in our study sample were as follows: 34.6%, 30.9%, and 37.4%, respectively. The current study showed an increased prevalence rate of asthma and eczema comparing to previous local estimates. These rates were higher in some cases or comparable in other cases to those found elsewhere. It is recommended that future research focus on studying the various factors contributing to the cases of asthma, allergic rhinitis, and eczema in Qatar. The reporting of this study conforms with the STROBE statement.

CFTR modulator therapy for cystic fibrosis caused by the rare c.3700A>G mutation.

BACKGROUND: The c.3700A>G mutation, a rare cystic fibrosis (CF)-causing CFTR mutation found mainly in the Middle East, produces full-length transcript encoding a missense mutation (I1234V-CFTR), and a cryptic splice site that deletes 6 amino acids in nucleotide binding domain 2 (I1234del-CFTR). METHODS: FRT cell models expressing I1234V-CFTR and I1234del-CFTR were generated. We also studied an I1234del-CFTR-expressing gene-edited human bronchial (16HBE14o-) cell model, and primary cultures of nasal epithelial cells from a c.3700A>G homozygous subject. To identify improved mutation-specific CFTR modulators, high-throughput screening was done using I1234del-CFTR-expressing FRT cells. Motivated by the in vitro findings, Trikafta was tested in two c.3700A>G homozygous CF subjects. RESULTS: FRT cells expressing full-length I1234V-CFTR had similar function to that of wildtype CFTR. I1234del-CFTR showed reduced activity, with modest activation seen with potentiators VX-770 and GLPG1837, correctors VX-809, VX-661 and VX-445, and low-temperature incubation. Screening identified novel arylsulfonyl-piperazine and spiropiperidine-quinazolinone correctors, which when used in combination with VX-445 increased current ~2-fold compared with the VX-661/VX-445 combination. The combination of VX-770 with arylsulfonamide-pyrrolopyridine, piperidine-pyridoindole or pyrazolo-quinoline potentiators gave 2-4-fold greater current than VX-770 alone. Combination potentiator (co-potentiator) efficacy was also seen in gene-edited I1234del-CFTR-expressing human bronchial epithelial cells. In two CF subjects homozygous for the c.3700A>G mutation, one subject had a 27 mmol/L decrease in sweat chloride and symptomatic improvement on Trikafta, and a second subject showed a small improvement in lung function. CONCLUSIONS: These results support the potential benefit of CFTR modulators, including co-potentiators, for CF caused by the c.3700A>G mutation.

TRPV2: A Cancer Biomarker and Potential Therapeutic Target.

The Transient Receptor Potential Vanilloid type-2 (TRPV2) channel exhibits oncogenicity in different types of cancers. TRPV2 is implicated in signaling pathways that mediate cell survival, proliferation, and metastasis. In leukemia and bladder cancer, the oncogenic activity of TRPV2 was linked to alteration of its expression profile. In multiple myeloma patients, TRPV2 overexpression correlated with bone tissue damage and poor prognosis. In prostate cancer, TRPV2 overexpression was associated with the castration-resistant phenotype and metastasis. Loss or inactivation of TRPV2 promoted glioblastoma cell proliferation and increased resistance to CD95-induced apoptotic cell death. TRPV2 overexpression was associated with high relapse-free survival in triple-negative breast cancer, whereas the opposite was found in patients with esophageal squamous cell carcinoma or gastric cancer. Another link was found between TRPV2 expression and either drug-induced cytotoxicity or stemness of liver cancer. Overall, these findings validate TRPV2 as a prime candidate for cancer biomarker and future therapeutic target.

A comparison between high-flow nasal cannula and noninvasive ventilation in the management of infants and young children with acute bronchiolitis in the PICU.

BACKGROUND: Different modalities of noninvasive respiratory support have been recommended for the management of acute bronchiolitis in the pediatric intensive care unit (PICU). High-flow nasal cannula (HFNC) is among the new modalities that have been widely used in the last decade. METHODS: This is a retrospective study involving infants and young children between the ages of 1 month and 2 years during the respiratory season of 2016-2017 (October-May). We compared the failure rate of HFNC with the failure rates of bi-level positive airway pressure (BiPAP) vs continuous positive airway pressure (CPAP) in the management of acute bronchiolitis in the PICU. Failure was defined as a change to another respiratory support modality or endotracheal intubation and mechanical ventilation. RESULTS: One hundred thirty-seven patients met the inclusion criteria, of which 77 patients needed HFNC, 10 needed CPAP, and 50 were on BiPAP. Among baseline characteristics, there were significant variations in age among the three groups. HFNC had a higher failure rate compared with the other two noninvasive ventilation modalities (50.6% for HFNC [n = 39 out of 77] vs 0% for CPAP [n = 0 out of 10] vs 8% for BiPAP [n = 4 out of 50], P < .01). Among the 39 patients who failed HFNC, 90% were successfully shifted to BiPAP and weaned off later, whereas the other 4 were intubated and required mechanical ventilation. However, all four patients who failed BiPAP were intubated and mechanically ventilated. No respiratory complications or mortalities were reported in the three groups. No differences were observed among the three groups in terms of the lengths of PICU or hospital stays. CONCLUSIONS: We observed a higher failure rate of HFNC compared with BiPAP or CPAP in the management of infants and children with acute bronchiolitis in the PICU. Further prospective randomized trials are recommended to confirm this finding.

Approaching two decades of cystic fibrosis research in Qatar: a historical perspective and future directions.

Cystic fibrosis (CF) is a genetic disease caused by a defect of CF transmembrane conductance regulator (CFTR) gene. CF affects multiple systems, predominantly with respiratory involvement. In Qatar, researchers have been exploring various aspects of the disease for almost 20 years. PubMed and Google Scholar were reviewed for articles related to CF in Qatar. The first publication appeared in the year 2000. Since then, several studies have been conducted on CF patients in Qatar considering a variety of topics. The presence of the CFTR I1234V mutation in a certain Arab tribe stands out as a distinguishing characteristic of CF patients in Qatar when compared to the larger Arab region or even worldwide. We aim here to summarize the existing CF research conducted in Qatar over the years as well as to introduce topics for future research.

Asthma and obesity in the Middle East region: An overview.

This paper aims to cover the current status of asthma and obesity in the Middle East, as well as to introduce the various studies tying the two diseases; further expanding on the proposed mechanisms. Finally, the paper covers recent literature related to sphingolipids and its role in asthma, followed by recommendations and future directions. In preparation of this paper, we searched PubMed and Google Scholar, with no restrictions, using the following terms; asthma, obesity, Middle East, sphingolipids. We also used the reference list of retrieved articles to further expand on the pool of articles that were used for this review.

Primary ciliary dyskinesia among Arabs: Where do we go from here?

Primary ciliary dyskinesia (PCD), also known as immotile-cilia syndrome, is a rare genetic disease that is inherited in an autosomal recessive manner. Several studies have explored certain aspects of PCD in the Arab world, yet much is still lacking in terms of identifying the different characteristics of this disease. In this paper, we aim to briefly cover those studies published about PCD in Arab countries, as well as to provide recommendations and guidelines for future studies.

Evaluation of cationic channel TRPV2 as a novel biomarker and therapeutic target in Leukemia-Implications concerning the resolution of pulmonary inflammation.

Patients treated during leukemia face the risk of complications including pulmonary dysfunction that may result from infiltration of leukemic blast cells (LBCs) into lung parenchyma and interstitium. In LBCs, we demonstrated that transient receptor potential vanilloid type 2 channel (TRPV2), reputed for its role in inflammatory processes, exhibited oncogenic activity associated with alteration of its molecular expression profile. TRPV2 was overexpressed in LBCs compared to normal human peripheral blood mononuclear cells (PBMCs). Additionally, functional full length isoform and nonfunctional short form pore-less variant of TRPV2 protein were up-regulated and down-regulated respectively in LBCs. However, the opposite was found in PBMCs. TRPV2 silencing or pharmacological targeting by Tranilast (TL) or SKF96365 (SKF) triggered caspace-mediated apoptosis and cell cycle arrest. TL and SKF inhibited chemotactic peptide fMLP-induced response linked to TRPV2 Ca2+ activity, and down-regulated expression of surface marker CD38 involved in leukemia and lung airway inflammation. Challenging lung airway epithelial cells (AECs) with LBCs decreased (by more than 50%) transepithelial resistance (TER) denoting barrier function alteration. Importantly, TL prevented such loss in TER. Therefore, TRPV2 merits further exploration as a pharmacodynamic biomarker for leukemia patients (with pulmonary inflammation) who might be suitable for a novel [adjuvant] therapeutic strategy based on TL.

Diagnosis of Primary Ciliary Dyskinesia. An Official American Thoracic Society Clinical Practice Guideline.

BACKGROUND: This document presents the American Thoracic Society clinical practice guidelines for the diagnosis of primary ciliary dyskinesia (PCD). TARGET AUDIENCE: Clinicians investigating adult and pediatric patients for possible PCD. METHODS: Systematic reviews and, when appropriate, meta-analyses were conducted to summarize all available evidence pertinent to our clinical questions. Evidence was assessed using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach for diagnosis and discussed by a multidisciplinary panel with expertise in PCD. Predetermined conflict-of-interest management strategies were applied, and recommendations were formulated, written, and graded exclusively by the nonconflicted panelists. Three conflicted individuals were also prohibited from writing, editing, or providing feedback on the relevant sections of the manuscript. RESULTS: After considering diagnostic test accuracy, confidence in the estimates for each diagnostic test, relative importance of test results studied, desirable and undesirable direct consequences of each diagnostic test, downstream consequences of each diagnostic test result, patient values and preferences, costs, feasibility, acceptability, and implications for health equity, the panel made recommendations for or against the use of specific diagnostic tests as compared with using the current reference standard (transmission electron microscopy and/or genetic testing) for the diagnosis of PCD. CONCLUSIONS: The panel formulated and provided a rationale for the direction as well as for the strength of each recommendation to establish the diagnosis of PCD.

A new clinical algorithm scoring for management of suspected foreign body aspiration in children.

BACKGROUND: Foreign Body Aspiration (FBA) is a serious problem in children and delays in diagnosis and management can be devastating. The history is often vague, with subtle physical and chest radiograph abnormalities. This study aims to determine the indications for bronchoscopy in children with suspected FBA and evaluate the key clinical and statistically significant predictors of FBA, based on the patients' historical, physical and radiological findings at presentation. METHODS: This is a retrospective observational study, including patients who were admitted between January 2001 to January 2011 with suspected FBA. Their presenting history, physical exam, radiological and bronchoscopic findings were analyzed. RESULTS: Three hundred children with a mean age of 2.1 ± 1.7 years were included. In children with both abnormal physical and radiological findings, 47.2% had proven FBA. If either was abnormal, the likelihood reduced to 32-33.3%; if both were normal, only 7.4% had a FB. Witnessed choking (adjusted OR 2.1, 95% CI 1.03-4.3; P = 0.041), noisy breathing/stridor/dysphonia (adjusted OR 2.7, 95% CI 1.2-6.2; P = 0.015), new onset/recurrent /persistent wheeze (adjusted OR 4.6, 95% CI 1.8-11.8; P = 0.002), abnormal radiological findings (adjusted OR 4.0, 95% CI 1.9-8.5; P < 0.001), and unilateral reduced air entry (adjusted OR 2.9, 95% CI 1.5-5.5; P = 0.001) were significant predictors of FBA (P < 0.05). When three or more risk factors were present, the cumulative proportion of children with proven FBA increased significantly. The discriminative ability of the model was found to be good; the area under the ROC curve value was 0.76 (95% CI 0.70, 0.82). The predicted cutoff score derived using ROC analysis was found to co-relate well with known clinically significant predictors of FBA. This supports our algorithm and scoring system. CONCLUSIONS: A high index of suspicion is required in diagnosing airway FB. Our proposed clinical algorithm and scoring system hopes to empower physicians to accurately predict patients with a high likelihood of FBA.

Genetic, cell biological, and clinical interrogation of the CFTR mutation c.3700 A>G (p.Ile1234Val) informs strategies for future medical intervention.

PURPOSE: The purpose of this study was to determine the molecular consequences of the variant c.3700 A>G in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, a variant that has been predicted to cause a missense mutation in the CFTR protein (p.Ile1234Val). METHODS: Clinical assays of CFTR function were performed, and genomic DNA from patients homozygous for c.3700 A>G and their family members was sequenced. Total RNA was extracted from epithelial cells of the patients, transcribed into complementary DNA, and sequenced. CFTR complementary DNA clones containing the missense mutation p.Ile1234Val or a truncated exon 19 (p.Ile1234_Arg1239del) were constructed and heterologously expressed to test CFTR protein synthesis and processing. RESULTS: In vivo functional measurements revealed that the individuals homozygous for the variant c.3700 A>G exhibited defective CFTR function. We show that this mutation in exon 19 activates a cryptic donor splice site 18 bp upstream of the original donor splice site, resulting in deletion of six amino acids (r.3700_3717del; p.Ile1234_Arg1239del). This deletion, similar to p.Phe508del, causes a primary defect in folding and processing. Importantly, Lumacaftor (VX-809), currently in clinical trial for cystic fibrosis patients with the major cystic fibrosis-causing mutation, p.Phe508del, partially ameliorated the processing defect caused by p.Ile1234_Arg1239del. CONCLUSION: These studies highlight the need to verify molecular and clinical consequences of CFTR variants to define possible therapeutic strategies.