Ozanimod-mediated remission in experimental autoimmune encephalomyelitis is associated with enhanced activity of CNS CD27low/- NK cell subset.

Background: Ozanimod (RPC1063) is an immunomodulator that has been recently approved by the FDA (2020) for the treatment of relapsing-remitting multiple sclerosis (RRMS). It is a selective agonist of the sphingosine-1-phophate receptors 1 and 5, expressed on naïve and central memory T and B cells, as well as natural killer (NK) cells, and is involved in lymphocyte trafficking. Oral administration of ozanimod was reported to result in rapid and reversible reduction in circulating lymphocytes in multiple sclerosis (MS) patients, however, only minimal effect on NK cells was observed. In this study, we sought to investigate the effect of ozanimod on NK cells and assess whether they play any role in ozanimod-induced remission in experimental autoimmune encephalomyelitis (EAE), the animal model of MS. Methods: Active EAE induction was done in C57BL/6 female mice, followed by daily oral treatment with ozanimod (0.6mg/kg) starting at disease onset (score 1). Flow cytometry of blood and CNS was performed 24 hours after the last oral dose of ozanimod treatment in diseased mice. Histological analysis of lumbar spinal cord was performed for evaluating the level of inflammation and demyelination. Depletion of peripheral NK cells was done using anti-NK1.1 mouse antibody (mAb) at day 5 post-EAE induction. Results: Ozanimod was effective in reducing the clinical severity of EAE and reducing the percentage of autoreactive CD4+ and CD8+ T cells along with significant inhibition of lymphocyte infiltration into the spinal cord, accompanied by reversed demyelination. Furthermore, ozanimod treatment resulted in a significant increase in the frequency of total NK cells in the blood and CNS along with upregulation of the activating receptor NKG2D on CD27low/- NK cell subset in the CNS. The effectiveness of ozanimod treatment in inhibiting the progression of the disease was reduced when NK cells were depleted using anti-NK1.1 mAb. Conclusion: The current study demonstrated that ozanimod treatment significantly improved clinical symptoms in EAE mice. Ozanimod and anti-NK1.1 mAb appear to function in opposition to one another. Collectively, our data suggest that ozanimod-mediated remission is associated with an increased percentage of total NK cells and CD27low/- NK cells expressing the activating receptor, NKG2D in the CNS.

Effect of Sirolimus/Metformin Co-Treatment on Hyperglycemia and Cellular Respiration in BALB/c Mice.

Sirolimus (SRL) is widely used as an immunosuppressant to prevent graft rejection, despite the risk of impairing glucose metabolism. Metformin (MET) can reduce the detrimental effects of SRL in many patients, including diabetes and renal transplant recipients. Limited in vivo studies have reported on SRL and MET therapy, particularly in relation to cellular bioenergetics, glucose metabolism, and insulin resistance. Herein, we investigated the efficacy of SRL and MET co-treatment in BALB/c mice over 4 weeks. Balb/c mice (4-6 weeks old) were divided into four groups and injected intraperitoneally (i.p.) with water (control, CTRL), MET (200 µg/g), SRL (5 µg/g), or MET (200 µg/g) +SRL (5 µg/g) over a period of one month. We evaluated the body weight, food consumption rate, random blood glucose (BG), insulin levels, serum biochemistry parameters (ALT, Albumin, BUN, Creatinine), and histomorphology in all groups using standardized techniques and assays. All drug-treated groups showed a statistically significant decrease in weight gain compared to the CTRL group, despite normal food intake. Treatment with SRL caused elevated BG and insulin levels, which were restored with SRL + MET combination. Serum biochemical parameters were within the normal range in all the studied groups. SRL+ MET co-treatment decreased liver cellular respiration and increased cellular ATP levels in the liver. In the pancreas, co-treatment resulted in increased cellular respiration and decreased cellular ATP levels. Liver and pancreatic histology were unchanged in all groups. This study showed that co-treatment of SRL with MET alleviates hyperglycemia induced by SRL without any deleterious effects. These results provide initial insights into the potential use of SRL + MET therapy in various settings.

Sirolimus treatment induces dose-dependent involution of the thymus with elevated cellular respiration in BALB/c mice.

Several in vitro and in vivo studies have shown that the mammalian target of rapamycin (mTOR) inhibitor sirolimus (rapamycin) suppresses thymus cellular respiration. The objective of this study is to investigate the chronic dose-dependent effects of sirolimus in the thymus. This was monitored using body weight, histomorphology, caspase-3 expression, cytochrome C immunohistochemistry, and cellular bioenergetics as surrogate biomarkers. BALB/c mice received intraperitoneal injections of either sirolimus (2.5, 5, or 10 µg/g) or dimethyl sulfoxide (0.1 µL/g) as a control for 4 weeks. At the end of the treatment, fragments were collected from the thymus, small intestine, adrenal gland, and kidney. They were processed for assessing histologic changes, measuring cellular respiration and ATP levels. Immunohistochemical stain of caspase-3 and cytochrome C was performed on paraffin-embedded tissue. The treated animals exhibited a dose-dependent reduction in weight gain despite adequate food intake. Sirolimus produced significant thymic derangements, manifested by dose-dependent tissue involution, increased cortical apoptotic bodies, increased caspase-3-positive lymphocytes, and increased rate of cellular respiration without a concomitant increase in cellular ATP. There were no similar changes in cellular ATP in the other assessed organs. The effects on thymic cellular bioenergetics suggest mitochondrial derangements, uncoupling of oxidative phosphorylation, and induction of apoptosis.

Cellular Respiration in Thymic Fragments from Mice.

BACKGROUND: This report aims to detail the use of the phosphorescence oxygen analyzer for in vitro investigation of thymic responses to pharmaceutical agents, in particular immunosuppressants and immunomodulators. Sirolimus (a highly specific inhibitor of the 'molecular target of rapamycin', mTOR) and ozanimod (an agonist of the sphingosine 1-phosphate receptor, recently approved for treatment of multiple sclerosis and ulcerative colitis) are used for this purpose. METHODS: Thymic fragments from mice were placed in glass vials containing phosphate-buffered saline, bovine albumin, and Pd(II) meso-tetra (sulfophenyl) tetrabenzoporphyrin. The vials were sealed from air, and the cellular oxygen consumption was monitored as function of time. RESULTS: The decline of dissolved oxygen concentration with time (d[O2]/dt) was linear; thus, its rate (thymocyte respiration) was expressed as µM O2 min-1. Cyanide inhibited respiration, confirming the oxygen consumption was in cytochrome oxidase. In age-matched mice, the rate of thymocyte respiration (mean ± SD, in µM O2 min-1 mg-1) was 0.046 ± 0.011 (median = 0.043, range = 0.028 to 0.062, n = 10). In thymic fragments from littermates, this rate was inhibited in the presence of sirolimus (16% lower) or ozanimod (29% lower). CONCLUSIONS: Thymocyte respiration can serve as a surrogate biomarker for studying the mode-of-action and the cytotoxicity of immunotoxins and immunosuppressants.

Case Report: Reactive Lymphohistiocytic Proliferation in Infant With a Novel Nonsense Variant of IL2RG Who Received BCG Vaccine.

We present here a male young infant with X-linked severe combined immunodeficiency (MIM#300400) due to the novel nonsense variant of IL2RG (interleukin 2 receptor, gamma; MIM#308380), NM_000206.2(IL2RG):c.820_823dup p.Ser275Asnfs*29. He developed aggressive reactive lymphohistiocytic proliferation after receiving the live-attenuated Bacillus Calmette-Guérin (BCG) vaccine at birth. This report advocates for modifying the current practice of early use of BCG. The natural history of his disease also suggests considering IL2RG variants as a potential cause of "X-linked recessive Mendelian susceptibility to mycobacterial disease" (MSMD). His reactive lymphohistiocytic proliferation and massive hepatosplenomegaly simulated hemophagocytic lymphohistiocytosis (HLH, likely triggered by the BCG disease). This entity was masked by the absence of fever and markedly elevated inflammatory biomarkers. Thus, his findings stimulate discussion on the need to modify the diagnostic criteria of HLH, in order to accommodate conditions, such IL2RG variants that block systemic inflammation.

A Study on the Genetics of Primary Ciliary Dyskinesia.

Primary ciliary dyskinesia (PCD) is a poorly understood disorder. It is primarily autosomal recessive and is prevalent in tribal communities of the United Arab Emirates due to consanguineous marriages. This retrospective study aimed to assess the pathogenicity of the genetic variants of PCD in indigenous patients with significant clinical respiratory problems. Pathogenicity scores of variants obtained from the chart review were consolidated using the Ensembl Variant Effect Predictor. The multidimensional dataset of scores was clustered into three groups based on their pathogenicity. Sequence alignment and the Jensen-Shannon Divergence (JSD) were generated to evaluate the amino acid conservation at the site of the variation. One-hundred and twelve variants of 28 genes linked to PCD were identified in 66 patients. Twenty-two variants were double heterozygous, two triple heterozygous, and seven homozygous. Of the thirteen novel variants, two, c.11839 + 1G > A in dynein, axonemal, heavy chain 11 (DNAH11) and p.Lys92Trpfs in dynein, axonemal, intermediate chain 1 (DNAI1) were associated with dextrocardia with situs inversus, and one, p.Gly21Val in coiled-coil domain-containing protein 40 (CCDC40), with absent inner dynein arms. Homozygous C1orf127:p.Arg113Ter (rs558323413) was also associated with laterality defects in two related patients. The majority of variants were missense involving conserved residues with a median JSD score of 0.747. Homology models of two deleterious variants in the stalk of DNAH11, p.Gly3102Asp and p.Leu3127Arg, revealed structural importance of the conserved glycine and leucine. These results define potentially damaging PCD variants in the region. Future studies, however, are needed to fully comprehend the genetic underpinnings of PCD.

Conserved spinal cord bioenergetics in experimental autoimmune encephalomyelitis in C57BL6 mice, measured using phosphorescence oxygen analyzer.

BACKGROUND: We have previously reported that spinal cord respiration (cellular mitochondrial oxygen consumption) and ATP content are conserved in the studied model of experimental autoimmune encephalomyelitis (EAE), foreseeing a recovery of the diseased rats. This exemplary lesion of multiple sclerosis is used here to measure spinal cord bioenergetics in C57BL6 mice. Our hypothesis is that, despite the well-known focal axonal mitochondrial pathology, bioenergetics of the CNS is reasonably preserved in this disease. METHODS: EAE was induced with an immunodominant myelin oligodendrocyte glycoprotein epitope in complete Freund's adjuvant, appended by injections of pertussis toxin. A low- and high-dose of the encephalitogen, administered into base of tail or hind-flank, were investigated. Control mice received only the incomplete adjuvant into tail. Oxygen measurements were based on quenching the phosphorescence of Pd(II) meso-tetra (sulfophenyl) tetrabenzoporphyrin by molecular oxygen. Cellular ATP was measured using the luciferin/luciferase system. RESULTS: The kinetics of spinal cord oxygen consumption was zero-order (linear with time) and inhibited by cyanide, confirming oxygen was reduced by cytochrome oxidase. The rate of respiration (in µM O2.min-1.mg-1; measured on Days 13-28) in control mice was (mean ± SD) 0.086 ± 0.024 (n = 8) and in immunized mice was 0.079 ± 0.020 (n = 15, P = 0.265, Mann-Whitney test). Consistently, cellular ATP (in µmol mg-1 dry pellet weight; measured on Days 13-28) in control mice was 0.068 ± 0.079 (n = 11) and in immunized mice was 0.063 ± 0.061 (n = 24, P = 0.887, Mann-Whitney U test). CONCLUSIONS: In vitro measurements of spinal cord bioenergetics show conservation of the mitochondrial function in mice with EAE. These results suggest the previously documented reduced mitochondrial electrochemical potential in this disease is alterable, and likely reflects the adverse events of neuroinflammation.

Case Report: A Case of Leukocyte Adhesion Deficiency, Type III Presenting With Impaired Platelet Function, Lymphocytosis and Granulocytosis.

Fermitin family homolog 3 (FERMT3), alternatively kindlin-3 (KIND3), is an integrin binding protein (of 667 residues) encoded by the FERMT3 gene. The molecule is essential for activating integrin αIIbß3 (the fibrinogen receptor) on platelets and for the integrin-mediated hematopoietic cell (including platelets, T lymphocytes, B lymphocytes, and granulocytes) adhesion. Its defects are associated with impaired primary hemostasis, described as "Glanzmann's thrombasthenia (MIM#273800)-like bleeding problem." The defects are also associated with infections, designated as "LAD1 (leukocyte adhesion deficiency, type I; MIM#116920)-like immune deficiency." The entity that joins the impaired primary hemostasis with the leukocyte malfunction has been termed "leukocyte adhesion deficiency, type III" (LAD3, autosomal recessive, MIM#612840), representing a defective activation of the integrins ß1, ß2, and ß3 on leukocytes and platelets. Here, we report a male toddler with novel compound heterozygous variants, NM_178443.2(FERMT3):c.1800G>A, p.Trp600* (a non-sense variant) and NM_178443.2(FERMT3):c.2001del p.*668Glufs*106 (a non-stop variant). His umbilical cord separated at about 3 weeks of age. A skin rash (mainly petechiae and purpura) and recurrent episodes of severe epistaxis required blood transfusions in early infancy. His hemostatic work-up was remarkable for a normal platelet count, but abnormal platelet function screen with markedly prolonged collagen-epinephrine and collagen-ADP closure times. The impaired platelet function was associated with reduced platelet aggregation with all agonists. The expression of platelet receptors was normal. Other remarkable findings were persistent lymphocytosis and granulocytosis, representing defects in diapedesis due to the integrin dysfunction. The natural history of his condition, structure and sequence analysis of the variations, and comparison with other LAD3 cases reported in the literature are presented.

A Single-Institution Experience in the Use of Chest Radiographs for Hospitalized Children Labeled as Asthma Exacerbation.

Background: Risks of diagnostic radiation have become more notable lately, particularly in young children with chronic medical conditions. This study reports on the cumulative radiation from chest radiographs in children with asthma. Its main purpose was to review our current practice and suggest minimizing the use of chest radiographs. Methods: The study was retrospective and conducted at a pediatric tertiary center. Eligibility criteria included children 2-15 y, admitted between January 2017 and December 2018 for asthma management. Results: Of the 643 children admitted as "asthma exacerbation," 243 [40% females; age (mean ± SD) 5.4±3.3 y] met the study criteria for inclusion. Ninety-two (38%) children had a temperature of 38.8±0.7°C on the day of admission. Antibiotics were prescribed for 148 (61%) children, mainly for presumed pneumonia. Chest radiographs were requested for 214 (88%) children, mainly on the day of admission. Only 38 (18%) chest radiographs showed focal/multifocal pneumonia justifying antibiotic use. Significant predictors for requesting chest radiographs were antibiotic use for presumed pneumonia, lower oxygen saturation at presentation, and a requested blood culture. The rate of chest radiographs per year was negatively related to the child's age; the younger the child the higher the rate (model coefficient -0.259, P < 0.001). For children < 5 y, the rate of chest radiographs was 1.39 ± 1.21/y and radiation dose 0.028 ± 0.025 mSv/y. The corresponding rates for children ≥5 y were 0.78 ± 0.72/y and 0.008 ± 0.007 mSv/y, respectively (P < 0.001). Conclusion: Chest radiographs were commonly requested for children with asthma, especially younger children. Prospective studies are necessary to measure the impact of this practice on the children's health.

Early (5-Day) Onset of Diabetes Mellitus Causes Degeneration of Photoreceptor Cells, Overexpression of Incretins, and Increased Cellular Bioenergetics in Rat Retina.

The effects of early (5-day) onset of diabetes mellitus (DM) on retina ultrastructure and cellular bioenergetics were examined. The retinas of streptozotocin-induced diabetic rats were compared to those of non-diabetic rats using light and transmission electron microscopy. Tissue localization of glucagon-like-peptide-1 (GLP-1), exendin-4 (EXE-4), and catalase (CAT) in non-diabetic and diabetic rat retinas was conducted using immunohistochemistry, while the retinal and plasma concentration of GLP-1, EXE-4, and CAT were measured with ELISA. Lipid profiles and kidney and liver function markers were measured from the blood of non-diabetic and diabetic rats with an automated biochemical analyzer. Oxygen consumption was monitored using a phosphorescence analyzer, and the adenosine triphosphate (ATP) level was determined using the Enliten ATP assay kit. Blood glucose and cholesterol levels were significantly higher in diabetic rats compared to control. The number of degenerated photoreceptor cells was significantly higher in the diabetic rat retina. Tissue levels of EXE-4, GLP-1 and CAT were significantly (p = 0.002) higher in diabetic rat retina compared to non-diabetic controls. Retinal cellular respiration was 50% higher (p = 0.004) in diabetic (0.53 ± 0.16 µM O2 min-1 mg-1, n = 10) than in non-diabetic rats (0.35 ± 0.07 µM O2 min-1 mg-1, n = 11). Retinal cellular ATP was 76% higher (p = 0.077) in diabetic (205 ± 113 pmol mg-1, n = 10) than in non-diabetic rats (116 ± 99 pmol mg-1, n = 12). Thus, acute (5-day) or early onslaught of diabetes-induced hyperglycemia increased incretins and antioxidant levels and oxidative phosphorylation. All of these events could transiently preserve retinal function during the early phase of the progression of diabetes.

Case Report: BCG-Triggered Hemophagocytic Lymphohistiocytosis in an Infant With X-Linked Recessive Mendelian Susceptibility to Mycobacterial Disease Due to a Variant of Chronic Granulomatous Disease.

In the United Arab Emirates, BCG (Bacillus Calmette-Guérin) is administered to all newborns. We present here a young infant with an inborn error of immunity (IEI) who developed fatal adverse events to this live-attenuated vaccine. This male infant received BCG (Serum Institute of India Pvt., Ltd., India) on Day 11 of life. On Day 25, he developed fever, followed by cervical lymphadenitis and bilateral otitis media with fluid drainage. On Day 118, he was admitted with severe hemophagocytic lymphohistiocytosis (HLH), and passed away on Day 145. The diagnostic exome sequencing test identified a hemizygous nonsense variant, NM_000397.3(CYBB):c.676C>T, p.Arg226* (rs137854592). Pathogenic variants of CYBB [cytochrome b(-245), beta subunit; Mendelian Inheritance in Man [MIM] accession code, 300481] are known to cause "immunodeficiency 34, mycobacteriosis, X-linked" (IMD34, MIM#300645) and "chronic granulomatous disease, X-linked" (CGDX, MIM#306400). The natural history of his illness is consistent with "X-linked recessive Mendelian susceptibility to mycobacterial disease (MSMD)." This entity is responsible for his BCG disease and is a likely trigger of his HLH. This disastrous event underlines the importance of developing worldwide policies that target BCG disease prevention, especially in communities with high prevalence of IEI. Moreover, screening for genetic causes of MSMD in the community could pave the way, at least partially, for scale-up of tuberculosis (TB) prevention.

The use of phosphorescence oxygen analyzer to measure the effects of rotenone and 1-methyl-4-phenylpyridinium on striatal cellular respiration in C57BL6 mice.

BACKGROUND: We have previously reported on the use of the phosphorescence oxygen analyzer for measuring spinal cord cellular respiration. This analytical tool is used here to investigate the effects of two inhibitors of NADH:ubiquinone oxidoreductase, rotenone and 1-methyl-4-phenylpyridinium, on cellular respiration in striatal tissue. Both neurotoxins can induce Parkinson's disease-like symptoms, and have been used to study this disease in animals. Our hypothesis is that striatal cellular respiration is a sensitive biomarker for the adverse effects of toxins, and the phosphorescence oxygen analyzer can be used as a screening tool for this purpose. METHODS: Striatal fragments were collected from C57BL6 mice and immersed in Pd phosphor solution [phosphate-buffered saline, 3.0 µM 'Pd(II)-meso-tetra (sulfophenyl) tetrabenzoporphyrin' and 0.5% fat-free albumin, with and without 5.0 mM glucose]. The sample was transferred to a glass vial containing 2-mL Pd phosphor solution. The vial was sealed from air and placed in the instrument that measures dissolved oxygen as function of time. Immunoblots of the studied tissue were positive for the dopamine neuronal cell biomarker tyrosine hydroxylase. RESULTS: Striatal oxygen consumption was linear with time, exhibiting zero-order kinetics of oxygen reduction by cytochrome oxidase. Cyanide sensitive respiration was ≥90%, confirming oxygen was reduced by cytochrome oxidase. The rate of respiration increased by ~2-fold in the presence of glucose. Striatal oxygen consumption in the presence of rotenone or 1-methyl-4-phenylpyridinium was exponential, demonstrating impaired respiration. CONCLUSION: Striatal cellular mitochondrial oxygen consumption was impaired by the studied inhibitors of complex I of the respiratory chain. This effect is expected to deplete NAD+ (oxidized nicotinamide adenine dinucleotide), a principle driver of glycolysis. In vivo studies are required to determine if these toxin-induced metabolic derangements contribute to the development of sporadic Parkinson's disease. This analytic tool can be used to screen environmental toxins for their in vitro effects on the striatum.

Effects of Diabetes Prevention Education Program for Overweight and Obese Subjects with a Family History of Type 2 Diabetes Mellitus: A Pilot Study from the United Arab Emirates.

OBJECTIVES: The association of obesity and family history of type 2 diabetes mellitus (T2DM) provides an opportunity for risk stratification and prevention, as these two conditions are the most well-known risk factors for T2DM. We aimed to test the feasibility and effects of a diabetes mellitus prevention education program designed for overweight and obese Emirati people with at least one parent with T2DM. METHODS: We conducted a pilot study using a pre-post design without a control arm at the Diabetes Center at Tawam Hospital in Al Ain, UAE. Overweight and obese subjects with at least one parent with T2DM were invited to participate. Three study assessments were conducted at baseline, three months, and six months including a questionnaire, anthropometry, and laboratory assessments. Interventions included three individualized or family-engaged counseling sessions based on the DiAlert protocol. The study outcomes included awareness of risks and prevention opportunities to T2DM, behavior changes in nutrition and exercise, decreased waist-circumference, and clinical/metabolic/inflammatory markers. Pre-post changes were analyzed using repeated-measures analysis of variance. RESULTS: One hundred twenty-two overweight or obese individuals were approached. Forty-four individuals met the eligibility criteria, and 32 individuals (35.0±9.0 years; 75.0% female) completed the study. At six months, there were significant improvements in the glycated hemoglobin levels (p = 0.007), high-density lipoprotein (p < 0.049), serum creatinine (p < 0.025), estimated glomerular filtration rate (p = 0.009), and adiponectin levels (p < 0.024). Sixteen of 32 participants had ≥ 2 cm reduction in waist circumference. They demonstrated notable physical and laboratory improvements in moderate-vigorous activity, average activity counts per day, tumor necrosis factor-alpha, and interleukin-6 total cholesterol, triglyceride, and low-density lipoprotein. CONCLUSIONS: Offering family-oriented diabetes education to people at risk for T2DM is well received and has favorable effects on relevant risk factors. Better testing with large-scale randomized controlled studies is needed, and implementing similar educational programs for the Emirati population seems warranted.

Prevalence of thinness and its effect on height velocity in schoolchildren.

OBJECTIVE: In contrast to childhood obesity, studies involving thin children are much fewer, especially in developed countries. Furthermore, most reports do not address the impact of childhood thinness on height velocity. This study investigated the prevalence of thinness and its effect on height velocity in schoolchildren in the United Arab Emirates (UAE). Weight and height were measured in 29,410 schoolchildren (50.5% females), as part of the health assessment (academic year 2014-2015). The body mass index (BMI) was classified as normal, thinness, overweight, or obese using cutoffs established by the International Obesity Task Force (IOTF), World Health Organization, and Centers for Disease Control. RESULTS: The median age was 10.2 years (range, 3-19). Using the IOTF scale, one-quarter of the children aged 4-6 years and one-third of the children aged 7-9 years were thin (BMI ≤ 18.5 kg/m2). Thinness was less prevalent (8-10%) in adolescents. Group peak height velocity was delayed 1-3 years in thin children and was higher in children with excess body fat. In conclusion thinness was the highest (25-33%) in children aged 4-9 years of age and their peak height velocity was delayed 1-3 years when compared to the other children.

Genetic variants of small airways and interstitial pulmonary disease in children.

Genetic variants of small airways and interstitial pulmonary disease have not been comprehensively studied. This cluster of respiratory disorders usually manifests from early infancy ('lung disease in utero'). In this study, 24 variants linked to these entities are described. The variants involved two genes associated with surfactant metabolism dysfunction (ABCA3 and CSF2RB), two with pulmonary fibrosis (MUC5B and SFTP), one with bronchiectasis (SCNN1B), and one with alpha-1-antitrypsin deficiency (SERPINA1). A nonsense variant, MUC5B:c.16861G > T, p.Glu5621*, was found in homozygous state in two siblings with severe respiratory disease from birth. One of the siblings also had heterozygous SFTPA1:c.675C > G, p.Asn225Lys, which resulted in a more severe respiratory disease. The sibling with only the homozygous MUC5B variant had lung biopsy, which showed alveolar simplification, interstitial fibrosis, intra-alveolar lipid-laden macrophages, and foci of foreign body giant cell reaction in distal airspaces. Two missense variants, MUC5B:c.14936 T > C, p.Ile4979Thr (rs201287218) and MUC5B:c.16738G > A, p.Gly5580Arg (rs776709402), were also found in compound heterozygous state in two siblings with severe respiratory disease from birth. Overall, the results emphasize the need for genetic studies for patients with complex respiratory problems. Identifying pathogenic variants, such as those presented here, assists in effective family counseling aimed at genetic prevention. In addition, results of genetic studies improve the clinical care and provide opportunities for participating in clinical trials, such as those involving molecularly-targeted therapies.

Novel genetic variants of inborn errors of immunity.

OBJECTIVES: Inborn errors of immunity (IEI) are prevalent in tribal cultures due to frequent consanguineous marriages. Many of these disorders are autosomal recessive, resulting from founder mutations; hence they are amenable to prevention. The primary objective of this study was to evaluate the pathogenicity of novel variants of IEI found among Emiratis. METHODS: This retrospective data collection study reports novel variants of IEI detected by diagnostic exome sequencing. Pathogenicity prediction was based on scoring tools, amino acid alignment, and Jensen-Shannon divergence values. RESULTS: Twenty-one novel variants were identified; nine were frameshift, three nonsense, four intronic (one pathogenic), and five missense (two pathogenic). Fifteen variants were likely pathogenic, of which 13 were autosomal recessive and two uncertain inheritance. Their clinical spectra included combined immunodeficiency, antibody deficiency, immune dysregulation, defects in intrinsic/innate immunity, and bone marrow failure. CONCLUSION: The described novel pathogenic variants are core to a planned national screening program that aims toward IEI prevention. Future studies, however, are needed to confirm their natural history in individual patients and estimate their prevalence in the community.

Perception of Cosmetic Procedures among Middle Eastern Youth.

BACKGROUND: In the past decade, there has been an increase in the number of cosmetic procedures performed globally. About one-third of individuals who undergo cosmetic procedures are under the age of 35. The United Arab Emirates (UAE) has become a regional hub for cosmetic procedures. This cross-sectional study examines the perception of cosmetic procedures among youth in the UAE. METHODS: A 63-question survey was electronically disseminated to university students to identify factors associated with the use of cosmetic procedures in this population. RESULTS: Ninety-one percent of the 178 participants were female, and 58 percent of them were aged 19 to 21. The majority of the participants felt cosmetic procedures are gaining acceptance in UAE society. Nearly 70 percent of participants felt that a legal and regulatory framework was important to determine the permissible age for undergoing cosmetic surgeries. LIMITATIONS: One limitation of the study lies in a modest response rate of 35.6 percent. There was a small number of male responders, and the assessment of differences between sex was not easy to conduct. CONCLUSION: Cosmetic procedures are increasingly being accepted among youth in the Middle East, with skin and nasal procedures being the most popular. The youth's concept of ideal body shape is in alignment with the Western ideas of beauty. Future research could characterize these perceptions in other cultures and explore differences in what is perceived to be beautiful in various parts of the world.

Adverse Events of the BCG (Bacillus Calmette-Guérin) and Rotavirus Vaccines in a Young Infant with Inborn Error of Immunity.

BACKGROUND: The Bacillus Calmette-Guérin (BCG) and rotavirus vaccines are live-attenuated preparations. In the United Arab Emirates, these products are universally administered to the young infants. This unguided practice does not account for the children with immunodeficiency, which frequently manifests after the administration of these vaccines. We present here a young infant with immunodeficiency that developed disseminated tuberculosis infection and severe diarrhea due to these improper immunizations. Case Presentation. This young infant was diagnosed at six months of age with "immunodeficiency type 19" (MIM#615617) due to homozygous nonsense variant, NM_000732.4 (CD3D):c.128G > A, p.Trp43∗ (variation ClinVar#VCV000643120.1; pathogenic). This variant creates premature stop-gain in CD3D (CD3 antigen, delta subunit, autosomal recessive; MIM#186790), resulting in loss-of-function. He also had "X-linked agammaglobulinemia" (MIM#300755) due to hemizygous missense variant, NM_001287344.1 (BTK):c.80G > A, p.Gly27Asp (novel). He had a sibling who passed away in infancy of unknown disease and family members with autoimmune disorders. Despite these clear clues, he was immunized with BCG at birth and rotavirus at 2 and 4 months. He was well in the first four months. He then developed high-fever, lymphadenopathy, and refractory diarrhea. Stool was positive for rotavirus, and lymph node biopsy showed acid-fast bacilli, consistent with tuberculosis lymphadenitis. These infections were serious and markedly complicated his clinical course, which included bone marrow transplantation from a matched sibling. CONCLUSIONS: These unfortunate events could have been avoided by compiling the available clinical information. This patient underscores the importance of implementing proper policies for BCG and rotavirus vaccinations. International registries of adverse events of universally administered vaccines are crucial.

Burden, associated risk factors and adverse outcomes of gestational diabetes mellitus in twin pregnancies in Al Ain, UAE.

BACKGROUND: Gestational diabetes mellitus (GDM) in singleton pregnancies represent a high-risk scenario. The incidence, associated factors and outcomes of GDM in twin pregnancies is not known in the UAE. METHODS: This was five years retrospective analysis of hospital records of twin pregnancies in the city of Al Ain, Abu Dhabi, UAE. Relevant data with regards to the pregnancy, maternal and birth outcomes and incidence of GDM was extracted from two major hospitals in the city. Regression models assessed the relationship between socio-demographic and pregnancy-related variables and GDM, and the associations between GDM and maternal and fetal outcomes at birth. RESULTS: A total of 404 women and their neonates were part of this study. The study population had a mean age of 30.1 (SD: 5.3), overweight or obese (66.5%) and were majority multiparous (66.6%). High incidence of GDM in twin pregnancies (27.0%). While there were no statistical differences in outcomes of the neonates, GDM mothers were older (OR: 1.09, 95% CI: 1.06-1.4) and heavier (aOR: 1.02, 95% CI: 1.00 -1.04). They were also likely to have had GDM in their previous pregnancies (aOR: 7.37, 95% CI: 2.76-19.73). The prognosis of mothers with twin pregnancies and GDM lead to an independent and increased odds of cesarean section (aOR: 2.34, 95% CI: 1.03-5.30) and hospitalization during pregnancy (aOR: 1.60, 95% CI: 1.16-2.20). CONCLUSION: More than a quarter of women with twin pregnancies were diagnosed with GDM. GDM was associated with some adverse pregnancy outcomes but not fetal outcomes in this population. More studies are needed to further investigate these associations and the management of GDM in twin pregnancies.

Nasopharyngeal Isolates from a Cohort of Medical Students with or without Pharyngitis.

OBJECTIVES: Few studies have investigated pharyngeal colonisation in the United Arab Emirates (UAE). This study aims to identify the pharyngeal organisms present in a cohort of medical students with and without symptomatic pharyngitis. METHODS: This study was conducted between September 2016 and June 2018 at the College of Medicine and Health Sciences, UAE University, Al-Ain. Nasopharyngeal swabs were collected from preclinical and clinical medical students attending the college during the study period. The specimens were tested for 16 viral and nine bacterial pathogens using a real-time polymerase chain reaction assay. RESULTS: A total of 352 nasopharyngeal swabs were collected from 287 students; of these, 22 (7.7%) had pharyngitis symptoms. Overall, the most common isolates were human rhinovirus, Streptococcus pneumoniae and Haemophilus influenzae, with no significant differences in terms of gender, year of study or stage of study. The prevalence of S. pyogenes in asymptomatic and symptomatic students was 1.1% and 0%, respectively. A Centor score of ≥2 was not associated with S. pyogenes-positive samples. Six pathogens were isolated from symptomatic students including H. influenzae. Fusobacterium necrophorum was not detected in any of the samples. CONCLUSION: The diagnosis and management of pharyngitis should be tailored to common pathogens in the region. This study found that S. pyogenes and F. necrophorum were not detected among students with symptoms of pharyngitis; moreover, Centor scores of ≥2 were not associated with the presence of S. pyogenes. This cut-off score therefore should not be employed as an empirical measure to initiate penicillin therapy in this population.