Sustained corneal nerve loss predicts the development of diabetic neuropathy in type 2 diabetes.

Introduction: This study was undertaken to investigate whether sustained rather than a single measure of corneal nerve loss was associated with the onset of diabetic peripheral neuropathy (DPN) and the progression of neuropathic symptoms and deficits in individuals with type 2 diabetes (T2D). Methods: Participants underwent clinical, metabolic testing and assessment of neuropathic symptoms, vibration perception threshold (VPT), sudomotor function, and corneal confocal microscopy (CCM) at baseline, 1, 2, and 4-7 years. Sustained corneal nerve loss was defined as abnormal corneal nerve fiber density (CNFD, <24 fibers/mm2), corneal nerve branch density (CNBD, <21 branches/mm2), and corneal nerve fiber length (CNFL, <16 mm/mm2) persisting for ≥50% of the study duration. Results: A total of 107 participants with a mean duration of T2D of 13.3 ± 7.3 years, aged 54.8 ± 8.5 years, underwent baseline and follow-up assessments over a median duration of 4 years, ranging from 1 to 7 years. The DPN prevalence at baseline was 18/107 (16.8%), and of the 89 participants without DPN at baseline, 13 (14.6%) developed DPN during follow-up. Approximately half of the cohort had sustained corneal nerve damage, and corneal nerve measures were significantly lower in this group than those without sustained damage (p < 0.0001). Sustained corneal nerve damage was associated with the development of DPN (p < 0.0001), a progressive loss of vibration perception (p ≤ 0.05), an increased incidence of burning pain, numbness, or a combination of both (p = 0.01-0.001), and a borderline association with progressive sudomotor dysfunction (p = 0.07). Sustained abnormal CNFL effectively distinguished between participants who developed DPN and those who did not (AUC: 76.3, 95% CI: 65.9-86.8%, p < 0.0001), while baseline and other sustained measures did not predict DPN onset. Conclusion: Sustained abnormal CCM is associated with more severe corneal nerve damage, DPN development, and the progression of neuropathic symptoms and deficits. Regular CCM monitoring may enable the identification of those at greater risk of developing and worsening DPN who may benefit from more aggressive risk factor reduction.

Prevalence, Severity, and Treatment of Obstructive Sleep Apnea in Children with Down Syndrome in Qatar.

INTRODUCTION: Patients with Down syndrome (DS) are at risk for sleep disorder breathing (SDB) due to their abnormal craniofacial anatomy, hypotonia, and propensity for obesity. The prevalence and severity of SDB in this population vary between different cohorts due to the multifactorial nature of these patients and the different diagnostic criteria used. We aim to report the prevalence and severity of SDB in the DS population in Qatar. METHODS: This study is a retrospective review of all patients with genetically confirmed DS who completed a diagnostic polysomnography (PSG) study at Sidra Medicine in Doha, Qatar, which is the only pediatric sleep center in the country, between September 2019 and July 2022. Clinical and PSG data were collected from the patients' electronic medical records. Central and obstructive events were scored according to the American Academy of Sleep Medicine (AASM) criteria. Obstructive sleep apnea (OSA) diagnosis was made based on apnea-hypopnea index (AHI) and defined as AHI >1.5 events/hour. OSA was considered mild if AHI was ≥ 1.5 but < 5, moderate if AHI was ≥ 5 but < 10, and severe if AHI was ≥ 10 events/hour. Diagnosis with central apnea was considered if the central apnea index was > 5 events/hour. Hypoventilation was considered present if end-tidal/transcutaneous carbon dioxide gas was more than 50 mmHg for more than 25% of total sleep time. Multiple regression analysis was performed to evaluate predictors of high AHI and rapid eye movement (REM)-AHI. RESULTS: A total of 80 patients (49 males and 31 females) were included. Median (range) age was 7.3 years (0.9, 21). The mean (range) BMI z-score was 1.7 (-1.3, 4.3). Sixty-five patients were diagnosed with OSA, with a prevalence rate of 81%. OSA was mild in 25 (38.5%) patients, moderate in 15 (23.1%) patients, and severe in 25 (38.5%) patients. Only one patient was diagnosed with central apnea and five patients (6.9%) with alveolar hypoventilation. Multiple regression analysis showed BMI (P = 0.007) and snoring/apnea symptoms (P=0.023) to be predictive of high AHI. No correlation was found between the same variables and REM-AHI. Treatments used for OSA included anti-inflammatory medications in 37 (46%) patients, tonsillectomy/adenoidectomy in 13 (16.5%) patients, and positive airway pressure support in 10 (15%) patients. CONCLUSION: Our patient population with DS had a high prevalence of OSA comparable to other reported cohorts. High BMI and symptoms of snoring are predictive of OSA.

Impact of COVID­19 pandemic restrictions and subsequent relaxation on the prevalence of respiratory virus hospitalizations in children.

BACKGROUND: The COVID-19 pandemic and the consequently adopted worldwide control measures have resulted in global changes in the epidemiology and severity of other respiratory viruses. We compared the number and severity of viral acute lower respiratory tract infection (ALRTI) hospitalizations and determined changes in causative respiratory pathogens before, during, and after the pandemic among young children in Qatar. METHODS: In this single-center retrospective study, we reviewed data of children ≤ 36 months old who were admitted to Sidra Medicine in Qatar with a viral ALRTI during winter seasons (September-April) between 2019 and 2023. The study period was divided into three distinct seasons based on the pandemic-imposed restrictions as follows: (1) the period between September 2019 and April 2020 was considered the pre-COVID-19 pandemic season; (2) the periods between September 2020 and April 2021, and the period between January and April 2022 were considered the COVID-19 pandemic seasons; and (3) the periods between September 2022 and April 2023 was considered the post-COVID-19 pandemic season. RESULTS: During the COVID-19 season, 77 patients were admitted, compared with 153 patients during the pre-COVID-19 season and 230 patients during the post-COVID-19 season. RSV was the dominant virus during the pre-COVID-19 season, with a detection rate of 50.9%. RSV infection rate dropped significantly during the COVID-19 season to 10.4% and then increased again during the post-COVID-19 season to 29.1% (P < 0.001). Rhinovirus was the dominant virus during the COVID-19 (39.1%) and post-COVID-19 seasons (61%) compared to the pre-COVID-19 season (31.4%) (P < 0.001). The average length of hospital stay was significantly longer in the post-COVID-19 season than in the pre-COVID-19 and COVID-19 seasons (P < 0.001). No significant differences in the pediatric intensive care unit (PICU) admission rate (P = 0.22), PICU length of stay (p = 0.479), or respiratory support requirements were detected between the three seasons. CONCLUSION: Our study showed reduced viral ALRTI hospitalizations in Qatar during the COVID-19 pandemic with reduced RSV detection. An increase in viral ALRTI hospitalizations accompanied by a resurgence of RSV circulation following the relaxation of COVID-19 restrictions was observed without changes in disease severity.

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.

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.

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.

Dietary long-chain omega 3 fatty acids modify sphingolipid metabolism to facilitate airway hyperreactivity.

Omega-3 polyunsaturated fatty acids (n-3 PUFAs) are essential nutrients that can affect inflammatory responses. While n-3 PUFAs are generally considered beneficial for cardiovascular disease and obesity, the effects on asthma, the most common inflammatory lung disease are unclear. While prenatal dietary n-3 PUFAs decrease the risk for childhood wheezing, postnatal dietary n-3 PUFAs can worsen allergic airway inflammation. Sphingolipid metabolism is also affected by dietary n-3 PUFAs. Decreased sphingolipid synthesis leads to airway hyperreactivity, besides inflammation, a cardinal feature of asthma, and common genetic asthma risk alleles lead to lower sphingolipid synthesis. We investigated the effect of dietary n-3 PUFAs on sphingolipid metabolism and airway reactivity. Comparing a fish-oil diet with a high n-3 PUFA content (FO) to an isocaloric coconut oil-enriched diet (CO), we found an n-3 PUFA-dependent effect on increased airway reactivity, that was not accompanied by inflammation. Lung and whole blood content of dihydroceramides, ceramides, sphingomyelins, and glucosylceramides were lower in mice fed the n-3 PUFA enriched diet consistent with lower sphingolipid synthesis. In contrast, phosphorylated long chain bases such as sphingosine 1-phosphate were increased. These findings suggest that dietary n-3 PUFAs affect pulmonary sphingolipid composition to favor innate airway hyperreactivity, independent of inflammation, and point to an important role of n-3 PUFAs in sphingolipid metabolism.

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.

Progressive loss of corneal nerve fibers is associated with physical inactivity and glucose lowering medication associated with weight gain in type 2 diabetes.

AIMS/INTRODUCTION: Limited studies have identified risk factors linked to the progression of diabetic peripheral neuropathy (DPN) in type 2 diabetes. This study examined the association of risk factors with change in neuropathy measures over 2 years. MATERIALS AND METHODS: Participants with type 2 diabetes (n = 78) and controls (n = 26) underwent assessment of clinical and metabolic parameters and neuropathy using corneal confocal microscopy (CCM), vibration perception threshold (VPT), and the DN4 questionnaire at baseline and 2 year follow-up. RESULTS: Participants with type 2 diabetes had a lower corneal nerve fiber density (CNFD), branch density (CNBD), and fiber length (CNFL) (P ≤ 0.0001) and a higher VPT (P ≤ 0.01) compared with controls. Over 2 years, despite a modest reduction in HbA1c (P ≤ 0.001), body weight (P ≤ 0.05), and LDL (P ≤ 0.05) the prevalence of DPN (P = 0.28) and painful DPN (P = 0.21) did not change, but there was a significant further reduction in CNBD (P ≤ 0.0001) and CNFL (P ≤ 0.05). CNFD, CNBD, and CNFL decreased significantly in physically inactive subjects (P < 0.05-0.0001), whilst there was no change in CNFD (P = 0.07) or CNFL (P = 0.85) in physically active subjects. Furthermore, there was no change in CNFD (P = 0.82), CNBD (P = 0.08), or CNFL (P = 0.66) in patients treated with glucose lowering medication associated with weight loss, whilst CNBD (P = 0.001) decreased in patients on glucose lowering medication associated with weight gain. CONCLUSIONS: In participants with type 2 diabetes, despite a modest improvement in HbA1c, body weight, and LDL there was a progressive loss of corneal nerve fibers; except in those who were physically active or on glucose lowering medication associated with weight loss.

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.

First report of the cystic fibrosis transmembrane conductance regulator mutation c.1521_1523delCTT (p. Phe508del) in two Qatari patients with cystic fibrosis.

We report two cases of Qatari children with cystic fibrosis (CF) from different families presenting the homozygous CFTR 1521_1523delCTT (p. Phe508del) mutation with classic CF phenotypes. This gene mutation is considered the second CF mutation identified in Qatar. Herein, we review the frequency and distribution of this mutation in Arab countries.

A Novel STK4 Mutation Impairs T Cell Immunity Through Dysregulation of Cytokine-Induced Adhesion and Chemotaxis Genes.

PURPOSE: Human serine/threonine kinase 4 (STK4) deficiency is a rare, autosomal recessive genetic disorder leading to combined immunodeficiency; however, the extent to which immune signaling and host defense are impaired is unclear. We assessed the functional consequences of a novel, homozygous nonsense STK4 mutation (NM_006282.2:c.871C > T, p.Arg291*) identified in a pediatric patient by comparing his innate and adaptive cell-mediated and humoral immune responses with those of three heterozygous relatives and unrelated controls. METHODS: The genetic etiology was verified by whole genome and Sanger sequencing. STK4 gene and protein expression was measured by quantitative RT-PCR and immunoblotting, respectively. Cellular abnormalities were assessed by high-throughput RT-RCR, RNA-Seq, ELISA, and flow cytometry. Antibody responses were assessed by ELISA and phage immunoprecipitation-sequencing. RESULTS: The patient exhibited partial loss of STK4 expression and complete loss of STK4 function combined with recurrent viral and bacterial infections, notably persistent Epstein-Barr virus viremia and pulmonary tuberculosis. Cellular and molecular analyses revealed abnormal fractions of T cell subsets, plasmacytoid dendritic cells, and NK cells. The transcriptional responses of the patient's whole blood and PBMC samples indicated dysregulated interferon signaling, impaired T cell immunity, and increased T cell apoptosis as well as impaired regulation of cytokine-induced adhesion and leukocyte chemotaxis genes. Nonetheless, the patient had detectable vaccine-specific antibodies and IgG responses to various pathogens, consistent with a normal CD19 + B cell fraction, albeit with a distinctive antibody repertoire, largely driven by herpes virus antigens. CONCLUSION: Patients with STK4 deficiency can exhibit broad impairment of immune function extending beyond lymphoid cells.

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.

Interpreting patient-Specific risk prediction using contextual decomposition of BiLSTMs: application to children with asthma.

BACKGROUND: Predictive modeling with longitudinal electronic health record (EHR) data offers great promise for accelerating personalized medicine and better informs clinical decision-making. Recently, deep learning models have achieved state-of-the-art performance for many healthcare prediction tasks. However, deep models lack interpretability, which is integral to successful decision-making and can lead to better patient care. In this paper, we build upon the contextual decomposition (CD) method, an algorithm for producing importance scores from long short-term memory networks (LSTMs). We extend the method to bidirectional LSTMs (BiLSTMs) and use it in the context of predicting future clinical outcomes using patients' EHR historical visits. METHODS: We use a real EHR dataset comprising 11071 patients, to evaluate and compare CD interpretations from LSTM and BiLSTM models. First, we train LSTM and BiLSTM models for the task of predicting which pre-school children with respiratory system-related complications will have asthma at school-age. After that, we conduct quantitative and qualitative analysis to evaluate the CD interpretations produced by the contextual decomposition of the trained models. In addition, we develop an interactive visualization to demonstrate the utility of CD scores in explaining predicted outcomes. RESULTS: Our experimental evaluation demonstrate that whenever a clear visit-level pattern exists, the models learn that pattern and the contextual decomposition can appropriately attribute the prediction to the correct pattern. In addition, the results confirm that the CD scores agree to a large extent with the importance scores generated using logistic regression coefficients. Our main insight was that rather than interpreting the attribution of individual visits to the predicted outcome, we could instead attribute a model's prediction to a group of visits. CONCLUSION: We presented a quantitative and qualitative evidence that CD interpretations can explain patient-specific predictions using CD attributions of individual visits or a group of visits.

Point of Care Exome Sequencing Reveals Allelic and Phenotypic Heterogeneity Underlying Mendelian disease in Qatar.

The effectiveness of next generation sequencing at solving genetic disease has motivated the rapid adoption of this technology into clinical practice around the world. In this study, we use whole exome sequencing (WES) to assess 48 patients with Mendelian disease from 30 serial families as part of the "Qatar Mendelian Disease pilot program" - a coordinated multi-center effort to build capacity and clinical expertise in genetic medicine in Qatar. By enrolling whole families (parents plus available siblings), we demonstrate significantly improved discriminatory power for candidate variant identification over trios for both de novo and recessive inheritance patterns. For the same index cases, we further demonstrate that even in the absence of families, variant prioritization is improved up to 8-fold when a modest set of population-matched controls is used vs large public databases, stressing the poor representation of Middle Eastern alleles in presently available databases. Our in-house pipeline identified candidate disease variants in 27 of 30 families (90%), 23 of which (85%) harbor novel pathogenic variants in known disease genes, pointing to significant allelic heterogeneity and founder mutations underlying Mendelian disease in the Middle East. For 6 of these families, the clinical presentation was only partially explained by the candidate gene, suggesting phenotypic expansion of known syndromes. Our pilot study demonstrates the utility of WES for Middle Eastern populations, the dramatic improvement in variant prioritization conferred by enrolling population-matched controls and/or enrolling additional unaffected siblings at the point-of-care, and 25 novel disease-causing alleles, relevant to newborn and premarital screening panels in regional populations.

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.