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Hearing loss (HL) is a heterogeneous condition that causes partial or complete hearing impairment. Hundreds of variants in60 genes have been reported to be associated with Hereditary HL (HHL), variants of the GJB2 gene are the most common cause of congenital SNHL, with100 variants reported. The HHL prevalence is thought to be high in the Arab population; however, the genetic epidemiology of HHL among Emirati populations is understudied.To shed light on the mutational spectrum of NSHL in Emirati patients seen in the genetic clinic over 10 years and to capture founder mutation(s) if any were identified.Retrospective chart review of all Emirati patients assessed by clinical geneticists due to NSHL during the period between January 2010 to December 2020. Genetic tests were done based on clinical phenotypes of the patient and family history including targeted mutation testing, next-generation sequencing, or whole-exome sequencing (solo or trio). The authors did literature reviews using PubMed for all previously reported articles related to NSHL genes from UAE.A total of 162 patients with HL, were evaluated during the period between January 2010 to December 2020. There were 82 patients with NSHL, and only 72 patients who completed the genetic evaluations were included in this retrospective study. Among the studied group, 42 (51.2%) were males and 40 (48.78%) were females. The youngest patient was 2 years old and the oldest patient was 50 years old. Consanguinity was documented in 76 patients (92.68%). A total of 14 mutations reported here are novel (23/72 i.e., 31.9%). Twelve missense mutations, 6 nonsense mutations, 6 frameshift mutations, 2 in-frame deletion mutations, and 1 splice site mutation was found. Variants in the GJB2 gene are the most commonly identified cause of NSHL, with c.35delG being the most followed by c.506G A. The second commonly found variant is c.934C G (p.Arg312Gly) in the CDC14A gene, found in 9 patients. This was followed by variants in OTOF and SLC26A4 genes, found in 8 patients, respectively. Chromosomal microdeletions encompassing genes causing NSHL were found in 3 patients. No mitochondrial mutations were found in this study group. A total of 11 previous reports about Emirati patients with NSHL were reviewed, with a total of 35 patients.Emirati patients with NSHL have several mutations, most notably missense mutations. Novel mutations are worth further testing and represent the area for future researches.

Clinical and molecular characterization of neuro-genetic disorders among UAE national patients seen in the Genetic Clinic at Tawam hospital over a period of 3 years. A retrospective chart review of all Emirati patients assessed by clinical geneticists due to neuro-genetic disorders including global developmental delay, ASD, ID, ADHD, and epilepsy in combination with abnormalities of other organ systems. Each patient had proper assessment including detailed history, three-generation family history, developmental history and detailed physical examination looking for other system involvement. Hearing test and ophthalmological examination were performed when needed. Magnetic Resonance Imaging (MRI) of the brain, echocardiogram, and renal ultrasound were pursued as indicated. Detailed psychological evaluation and psychometric assessment were done when indicated. The review was done for a period between January 2018 and December 2020. Genetic investigations included chromosome karyotype, FISH study, metabolic/biochemical tests, chromosome microarray, gene sequencing, targeted mutation testing, trio whole exome and trio genome sequencing. A Total of 644 patients with developmental delay, ID, learning difficulty, ASD, ADHD, or NNDs, were seen in genetic clinic from January 2018 to December 2020. A total of 506 patients were included in this review, all completed the genetic evaluations during the study period. There were 398 (61.8%) males and 246 (38.2%) females, with a ratio of 1.6:1. Positive family history of NDD was documented in 132 families, while 115 families had negative history and family history was unknown/unclear in the remaining. Fifty seven (11.26% [57/506]) patients had positive microarray results. Hundred ninety seven (38.9% [197/506]) patients had positive molecular testing. Genetic disorders were found in 133 (67.5% [133/197]) and inborn errors of metabolism were found in 42 (21.3% [42/197]). Consanguinity was documented in 139 patients with positive molecular diagnoses (139/197, 70.5%). Sixty nine (35% [69/197]) patients had autosomal dominant disorders, majority were de novo (84%). Ninety-five (48% [95/197]) patients had autosomal recessive diseases, 40 mutations involved inborn errors of metabolism and 50 mutations involved genetic disorders. Pathogenic variants causing both autosomal dominant and recessive disorders were found in 98 patients (49.7% [98/197]), likely pathogenic variants causing both autosomal dominant and recessive disorders were found in 66 patients (33.5% [66/197]). X-linked related disorders were found in 10 patients (5% [10/197]). Mitochondrial mutation was found in 1 patient. Novel mutations were found in 76 patients (76/197 i.e. 38.56%). Twenty two (22) patients had variants of unknown significant. The remaining 252 studied patients (252/506, i.e. 49.8%), remained undiagnosed. This study shows that neuro-genetic disorders in the UAE are very heterogeneous at clinical and molecular levels. Using microarray, WES and WGS a diagnosis was reached in 50% of the patients while no diagnosis was reached in other half of the studied patients. It is possible that some mutations were missed by WGS and WES. However, it is also possible that many of disorders in UAE population are novel and the causative mutation is not yet discovered. More researches need to be done in this population to uncover the molecular basis of these disorders.

Aim This study is a longitudinal multicenter study which aims to find the prevalence, the demographic data, survival and mortality rates of patients with systemic lupus erythematosus (SLE) in Oman. Method All Omani patients, pediatrics and adults diagnosed with SLE, who fulfill either the 1997 American College of Rheumatology or Systemic Lupus International Collaborating Clinics classifications criteria for SLE were included from January 2006 till February 2020. Results In total 1160 patients were included in this cohort. Data analysis showed that patient's ages ranged from 2-82 years with female predominance and female-to-male ratio of 7:1 (87.7% female,12.3% male). The mean prevalence of SLE among different age groups was 38.8 (range 5-63 per 100 000 inhabitants). The mortality rate was found to be 5%. Male patients had significantly higher mortality rate than females (7.6% vs 5.4%, P value = .04). Sepsis was the commonest cause of mortality (34%). The coexistence of systemic sclerosis correlates significantly with death (P = .002). Survival analysis in our data showed 5, 10, 20, 40-year survival rates of 100%, 100%, 99% and 90% respectively for antinuclear antibody (ANA) positive patients and lower survival rate for ANA negative patients with 5,10, 20, 40-year survival rates of 100, 99%, 99% and 75%, respectively. Conclusion This study showed that the mean prevalence of SLE in Oman to be 38.8 (range 5-63) per 100 000 inhabitants. The 40-year survival rate among patients with positive ANA was found to be 90%, while patients with negative ANA had worse survival outcomes.

Objectives To our knowledge, this study is the first in the United Arab Emirates (UAE) to investigate the prevalence of child maltreatment in relation to depressive symptoms and self-esteem. Study design Exposure to physical maltreatment, emotional abuse and neglect was evaluated in 518 adolescents (86% response rate) randomly selected from schools in Al Ain in the Emirate of Abu Dhabi. The Rosenberg self-esteem scale and the Beck Depression Inventory were used to measure self-esteem and depressive symptoms by using multivariate logistic regression analyses. Results The mean age of study participants was 14.3 years. Emotional abuse was the most frequent form of maltreatment (33.9%), physical abuse (12.6%) and neglect (12.1%) followed. Male sex was a positive predictor of physical abuse (OR = 2.12; 95% CI 1.18-3.77), whilst higher maternal level of education was protective (OR = 0.40; 95% CI 0.19-0.86). Daily screen time (OR = 2.77; 95% CI 1.17-6.56) and tobacco smoking (OR = 1.86; 95% CI 1.09-3.18) positively predicted emotional abuse. Emotionally maltreated and neglected participants were less likely to report high level of self-esteem and more likely to report symptoms of depression. Conclusions Child maltreatment in the UAE is of a similar magnitude to what reported in other countries around the world and significantly associated with low self-esteem and depressive symptoms.

Background: Acute myocardial infarction is a relatively rare phenomenon in the young population. The incidence has nevertheless increased from years past, likely due to the presence of multiple risk factors from an increasingly younger age. Regardless of whether they have atherosclerotic coronary artery disease or normal coronary angiogram, young patients with risk factors for coronary artery disease (CAD), chest pain, and positive troponin, are initially treated in a similar fashion. Our goal was to shed light on whether risk factors between these two groups differ to help guide physicians in clinically determining whether or not an atherosclerotic cardiovascular event has occurred, as well as to potentially identify young patients at risk of acute coronary syndrome (ACS) despite normal coronary arteries. Methods: A retrospective cross sectional study was undertaken over an 8 year period at Tawam Hospital. 576 patients aged 50 or under who underwent coronary angiography were selected for the study. Medical records were analyzed for the patient's demographics and CAD risk factor profile, including the following variables: family history of CAD, smoking status, Body Mass Index category, lipid profile, and diagnosis of hyperlipidemia, diabetes, or hypertension. Details of the coronary angiogram were also reviewed. Results: Statistically significant outcomes included a higher prevalence of diabetes, hyperlipidemia, and smoking history in patients with CAD compared to the patients with normal coronary angiogram. Diabetes was one of the strongest risk factors in CAD patients, with an odds ratio of 1.98 (p= 0.011), followed by hyperlipidemia at 1.85 (p= 0.021). Smoking history had an odds ratio of 2.93 (p

PURPOSE Cancer is a leading cause of increased morbidity and mortality worldwide. This work aims to study the Arab world males' cancers (AMCs) and the similarities and disparities with the world males' cancers (WMCs) from different burden points of view. MATERIALS AND METHODS A descriptive review of the 2020 Global Cancer Observatory revealed AMCs compared with the 2020 WMCs and the 2018 AMCs. Data on the top 27 AMCs were compared among the region's countries and the world groups. RESULTS In 2020, a total estimate of 217,203 new AMCs, 2.2% of WMCs, with an average age-standardized rate of 133.5/100,000 population, compared with 222/100,000 population of WMCs, was observed. Death estimates were 148,395, 2.7% of WMCs, with an average age-standardized rate of 95/100,000 population, compared with 120.8/100,000 population of WMCs. The five-year prevalence was observed in 442,014, 1.8% of WMCs. The average AMC mortality to incidence ratio (MIR) was 0.68, compared with 0.55 in WMCs and 0.54 in Arab females. Lung cancer was the top in incidence and mortality, whereas penile cancer was the lowest. The range of MIRs among the 27 cancer types was 0.19-0.96. CONCLUSION The descriptive review of the 2020 males' cancers in the Arab world revealed a relatively high MIR, compared with males' cancers worldwide and the females' cancers in the Arab world. This requires further evaluation to discern the underlying causes and address them systematically. More cancer control actions are warranted.

Background Grilling has become increasingly common in Germany. Although grilling is considered a non-negligible household burn hazard, few reports have assessed this type of injury. This study aimed to determine the patterns and characteristics of grill-related burn injuries and to compare these with other types of burn injuries. Methods This retrospective observational study included all grill-related burn injuries admitted to Cologne Merheim Burn Center during 1989–2017. The collected data were analyzed descriptively and compared statistically with other fire injuries. Results Of 1706 cases admitted with fire injuries during the study period, 160 (∼10%) involved grill-related injuries. Most cases (85%) involved men, with an average age of 34 years. Moreover, 48% and 38% of cases occurred in summer and spring, respectively. The most common mechanism of injury was ignition via fluid accelerant. The upper limb was the most commonly affected body part, followed by the head. Statistical analyses revealed that grill-related injuries were associated with a lower mean age and total body surface area, shorter in-hospital stay, and fewer complications than the other fire injury group. Conclusion Grill-related injuries are a relatively common cause of admission to the Cologne Burn Center. Although grill-related injuries underwent a less aggressive approach than the other investigated fire injuries, the former represent a public health concern because they mainly affect the upper body, with both psychologic and aesthetic consequences. We recommend a German nationwide multi-centric study of the patterns and characteristics of burn injury.

Glomerulonephritis (GN) is a rising paramount renal disease that varies in etiology from inherited or acquired factors. Its severity can range from asymptomatic depictions to end-stage renal disease. The aim of this study was to study the patterns of biopsy-proven GN based on the data from a multicenter in Abu Dhabi. Included kidney biopsies were from all patients above the age of 18 years, over a six-year period from 2010 to 2015, who had diagnosis of glomerular disease other than diabetes mellitus. The number of reviewed biopsies was 416. The most common type of GN among the study sample was IgA GN (22.8%) followed by focal segmental glomerulosclerosis (20.4%) and systemic lupus erythematosus (SLE) (19.7%). The least common types were pauciimmune (1.7%). There was female preponderance in lupus nephritis and pauciimmune GN. The nationality comparison did not reveal a predominate GN among Emirati nationals. The age relationship to GN types showed that majority (82.9%) of SLE patients, MCD (74.55%), and noncategorized (71.4%) patients are young aged between 18 and 39 years. On the other hand, 57.1%, 25%, and 16.7% of patients with pauciimmune, other GN types, and membranoproliferative GN, respectively, are 60 years and older. This study shows the histopathological variety of glomerular disease in Abu Dhabi. It could be a driving point to help understand GN better in the region.

Intellectual disability (ID) is one of the most common developmental disorders characterized by a congenital limitation in intellectual functioning and adaptive behavior. More than 800 genes have been implicated so far in the pathogenesis of syndromic and non-syndromic ID conditions with the actual number is expected to be over two thousand. The advent of next-generation sequencing resulted in the identification of many novel ID genes with new genes are being reported on weekly basis. The level of evidence on ID genes varies with some of them being preliminary. MAST1 have been hinted at as being causative of ID but the evidence has been very sketchy. Extensive search of the literature identified three heterozygous de novo missense variants in MAST1 as possible causes of syndromic ID in three individuals where intellectual disability has been a major feature. Using exome sequencing, we identified a novel missense variant c.3539T>G, p.(Leu1180Arg) in MAST1 in an Emirati patient with intellectual disability, microcephaly, and dysmorphic features. In silico pathogenicity prediction analyses predict that all the four missense variants reported in this study are likely to be damaging. Immunostaining of cells expressing human MAST1 showed that majority large proportion of the expressed protein is colocalized the microtubule filaments in the cytoplasm. However, the identified variant c.3539T>G, p.(Leu1180Arg) as well as the other three variants seem to localize in a similar pattern to wild-type indicating a disease mechanism not involving mis-targeting. We, therefore, suggest that mutations in MAST1 should be considered as strong candidates for intellectual disability in humans.

Objectives: This study aimed to determine the accuracy of renal point-of-care ultrasound (POCUS) performed by emergency physicians in detecting hydronephrosis in patients with renal colic. Methods: This prospective cross-sectional diagnostic study was conducted at the Emergency Department (ED) of Sultan Qaboos University Hospital from February 2017 to February 2018. All adult patients with suspected renal colic and who could give informed consent were included. The emergency physicians performed POCUS on both kidneys and graded hydronephrosis as none, mild, moderate or severe. The POCUS grade was compared to the non-contrast computed tomography (NCCT) grade. Results: A total of 303 participants were enrolled in the analysis. The majority of the study population comprised adult males (247 [81.5%]), and the mean age was 39 years. Among the samples, 71.3% of the patients exhibited a degree of hydronephrosis based on CT findings. Ultrasounds performed by emergency physicians had a sensitivity of 75.8% (95% CI: 69.5‒81.4), specificity of 55.2% (95% CI: 44.1‒65.8), a positive likelihood ratio of 1.69 (95% CI: 1.32‒2.16) and a negative likelihood ratio of 0.43 (95% CI: 0.32‒0.59) for hydronephrosis using CT as the criterion standard. Conclusion: When evaluating patients with suspected renal colic, a bedside renal POCUS performed by emergency physicians has a moderate sensitivity to detect hydronephrosis and grade its severity. Therefore, it should be utilised in the ED to screen patients for hydronephrosis; however, more training is required to improve the test’s accuracy. Keywords: Hematuria; Hydronephrosis; Nephrolithiasis; Point-of-Care Testing; Renal Colic; Ultrasonography; Oman.

Bilateral renal agenesis belongs to a group of perinatal lethal renal diseases. To date, pathogenic variants in three genes (ITGA8, GREB1L, and FGF20) have been shown to cause renal agenesis in humans. Recently GFRA1 has been linked to a phenotype consistent with a nonsyndromic form of bilateral renal agenesis. GFRA1 encodes a member of the glial cell line-derived neurotrophic factor receptor family of proteins. The receptor on the Wolffian duct regulates ureteric bud outgrowth in developing a functional renal system. We report on four additional affected neonates from a consanguineous family who presented with a similar lethal phenotype whereby whole exome sequencing identified a homozygous deleterious sequence variant in GFRA1 (NM_005264.8:c.628G > T:p.[Gly210Ter]). The current study represents a second confirmation report on the causal association of GFRA1 pathogenic variants with lethal nonsyndromic bilateral renal agenesis in humans.

Background Parkinson’s disease (PD), the second most common progressive neurodegenerative disorder, is characterized by the abnormal accumulation of intraneuronal inclusions enriched in aggregated α-synuclein (α-syn), known as Lewy bodies (LBs) and Lewy neurites (LNs), and significant loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) of the brain. Recent evidence suggests that the intrastriatal inoculation of α-syn preformed fibrils (PFF) in mice brain triggers endogenous α-syn in interconnected brain regions. 1-methyl, 4-phenyl, 1,2,3,6 tetrahydropyridine (MPTP), a mitochondrial neurotoxin, has been used previously to generate a PD mouse model. However, the common methods of MPTP exposure do not induce LB or α-syn aggregation in mice. In the present study, we evaluated the effect of different doses of MPTP (10 mg/kg.b.wt and/or 25 mg/kg.b.wt) on the spread, accumulation, and toxicity of endogenous α-syn in mice administered an intrastriatal injection of human α-syn PFF. Methods We inoculated human WT α-syn PFF in mouse striatum. At 6 weeks post PFF injection, we challenged the animal with two different doses of MPTP (10 mg/kg.b.wt and 25 mg/kg.b.wt) once daily for five consecutive days. At 2 weeks from the start of the MPTP regimen, we collected the mice brain and performed immunohistochemical analysis, and Rotarod test to assess motor coordination and muscle strength before and after MPTP injection. Results A single injection of human WT α-syn PFF in the mice striatum induced the propagation of α-syn, occurring as phosphorylated α-synuclein (pS129), towards the SNpc, within a very short time. Injection of a low dose of MPTP (10 mg/kg.b.wt) at 6 weeks post α-syn PFF inoculation further enhanced the spread, whereas a high dose of MPTP (25 mg/kg.b.wt.) reduced the spread. Majority of the accumulated α-syn were proteinase K resistant, as recognized using a conformation-specific α-syn antibody. Injection of α-syn PFF alone caused 12 % reduction in the number of tyrosine hydroxylase positive neurons while α-syn PFF + a low dose of MPTP caused 33 % reduction (loss), compared to the control mice injected with saline. This combination also reduced the motor coordination. Interestingly, a low dose of MPTP alone did not cause any significant reduction in the number of tyrosine hydroxylase positive neurons compared to saline treatment. Animals that received α-syn PFF and a high dose of MPTP showed massive activation of glial cells and decreased spread of α-syn, majority of which were detected in the nucleus. Conclusion Our results suggest that a combination of human WT α-syn PFF and a low dose of MPTP increases the pathological conversion and propagation of endogenous α-syn, and neurodegeneration, within a very short time. Our model can be used to study the mechanisms of α-syn propagation and screen for potential drugs against PD.

This cohort study examines the implementation of a microbiologic screening pilot program in Al Zahra Hospital in the United Arab Emirates for identifying presymptomatic COVID-19 in patients with cancer.

ObjectivesCardiovascular disease (CVD) risk prediction models are useful tools for identifying those at high risk of cardiovascular events in a population. No studies have evaluated the performance of such risk models in an Arab population. Therefore, in this study, the accuracy and clinical usefulness of two commonly used Framingham-based risk models and the 2013 Pooled Cohort Risk Equation (PCE) were assessed in a United Arab Emirates (UAE) national population.DesignA 10-year retrospective cohort study.SettingOutpatient clinics at a tertiary care hospital, Al-Ain, UAE.ParticipantsThe study cohort included 1041 UAE nationals aged 30–79 who had no history of CVD at baseline. Patients were followed until 31 December 2019. Eligible patients were grouped into the PCE and the Framingham validation cohorts.ExposureThe 10-year predicted risk for CVD for each patient was calculated using the 2008 Framingham risk model, the 2008 office-based Framingham risk model, and the 2013 PCE model.Primary outcome measureThe discrimination, calibration and clinical usefulness of the three models for predicting 10-year cardiovascular risk were assessed.ResultsIn women, the 2013 PCE model showed marginally better discrimination (C-statistic: 0.77) than the 2008 Framingham models (C-statistic: 0.74–0.75), whereas all three models showed moderate discrimination in men (C-statistic: 0.69‒0.70). All three models overestimated CVD risk in both men and women, with higher levels of predicted risk. The 2008 Framingham risk model (high-risk threshold of 20%) classified only 46% of women who subsequently developed incident CVD within 10 years as high risk. The 2013 PCE risk model (high-risk threshold of 7.5%) classified 74% of men who did not develop a cardiovascular event as high risk.ConclusionsNone of the three models is accurate for predicting cardiovascular risk in UAE nationals. The performance of the models could potentially be improved by recalibration.

Background Disorders of sex development (DSD) can result from congenital defect in sex determining pathway. Mitogen‐activated protein kinase kinase kinase 1 (MAP3K1) is one of the commonest genes that has been identified to cause 46, XY DSD. It can present as complete or partial gonadal dysgenesis even within the same kindred. Few mutations in this gene have previously been identified in a high proportion of individuals with 46, XY gonadal dysgenesis. Methods and Results We report three siblings with same novel variant in MAP3K1 gene presenting with variable degrees of partial gonadal dysgenesis. Clinical and genetic assessments were performed for the three siblings, while endocrine evaluation was done for two of them. The identified mutation (p.Thr657Arg) was previously classified as a pathogenic variant, although apparently there are no reported humans with this mutation. Conclusion This report adds to the genotype‐phenotype correlation, highlighting the clinical importance of considering MAP3K1 gene defects as part of the differential diagnosis for complete or partial gonadal dysgenesis especially with multiple affected family members., We describe in detail the clinical phenotypes of three affected siblings, with same novel variant in MAP3K1 gene presenting with variable degrees of partial gonadal dysgenesis. In this report, we declare the identification of a new disease causing missense variant in MAP3K1 gene which was not apparently described in humans before. Our report adds to the genotype‐phenotype correlation, highlighting the clinical importance of considering MAP3K1 gene defects as part of the differential diagnosis for complete or partial gonadal dysgenesis especially with multiple affected family members.

COVID-19 has become a serious hazard worldwide in a relatively short time. Scientific evidence supports that cancer patients infected with COVID-19 had a higher risk of developing severe complications. COVID-19 patients can be asymptomatic during part or all of their disease course, therefore it is a compelling need to develop universal pre-interventional COVID-19 screening guidelines. The aim of this study is to is review COVID-19 positive rate among asymptomatic cancer patients since the implementation of universal policy at our institution, and assess the impact of diagnosing COVID-19 on delay of oncologic interventions.The study population comprised of all cancer patients planned for high risk interventions between April 1, 2020 - May 14, 2020 at Cleveland Clinic Abu Dhabi [CCAD] after implementing universal COVID-19 screening policy.Nosocomial transmission of COVID-19 among cancer patients could result in poor outcomes. Universal screening for high-risk populations may facilitate earlier diagnosis of COVID-19 and implementation of control strategies. Our review demonstrated that [7.5%] of asymptomatic cancer patients tested positive for COVID-19 after implementation of universal prospective screening policy. The overall evidence supporting universal COVID-19 screening of cancer patients is limited, yet as tests become more widely available, it may be reasonable to screen all cancer patients for COVID-19 before anticancer therapies. While such policy may delay and affect the timing of anticancer therapy as shown in this report, it should improve the safety of care for oncology patients and help protect healthcare workers.COVID-19 infection rate is higher in cancer patients than general population and can present without symptoms. Universal COVID-19 screening of cancer patients before high risk interventions is supported by the present findings.

Background Primary prevention guidelines recommend the use of the Framingham risk score (FRS) to estimate the 10-year coronary heart disease (CHD) risk in patients without diabetes for statin eligibility. However, the FRS model has never been validated in an Arab population. Therefore, this study aimed to examine the clinical performance of the FRS model for predicting 10-year CHD risk in adult United Arab Emirates (UAE) nationals without diabetes. Methods This 10-year retrospective cohort study included patients from the primary care clinics and outpatient specialty departments of a large tertiary care hospital in Al-Ain, UAE. They were aged 30–79 without a baseline history of cardiovascular disease and diabetes. The FRS for each subject was calculated. Follow-up data on hard CHD (hCHD) events (myocardial infarction or coronary death) for each participant were collected from the baseline visit in 2008 until December 31, 2019. The area under the time-dependent receiver operating characteristic (ROC) curve (AUROC) was used to assess the FRS model discrimination. Calibration was measured by using the Hosmer-Lemeshow χ2 test and the calibration curve. The optimal cutoff-point for hCHD risk prediction was determined by ROC curve analysis. Results A total of 554 participants were included. The mean age was 48.0 ± 12.8 years and 45% were men. The mean predicted FRS of the study cohort was 5.2% and approximately 7% were classified as high-risk (≥ 20% threshold) by the FRS model. During a median follow-up of 10.2 years (interquartile range, 7.8–11.0 years), 26 hCHD events occurred. The FRS model displayed reasonably good discrimination (time-dependent AUROC value: 0.83) and calibration in predicting hCHD (Hosmer-Lemeshow χ2 statistic 11.2, P = 0.191). Applying the 20% high-risk threshold, the FRS model had a sensitivity of only 37% in identifying patients at high-risk for an hCHD event over 10 years. While a 7.5% optimal cutoff-point improved the sensitivity to 74%. Conclusions The FRS can be used in the prediction of coronary risk among UAE nationals without diabetes, however, the recommended hCHD risk threshold for statin eligibility may be too high. Lowering the cutoff-point to 7.5% could improve the identification of patients for preventive treatment.

ObjectivesA high body mass index (BMI) is associated with risk of type 2 diabetes mellitus (DM). The United Arab Emirates (UAE) is experiencing a marked increase in obesity. Nonetheless, no data are available regarding the incidence of type 2 DM in the high-risk adult UAE population. Therefore, this study aimed to evaluate the incidence rate and risk of developing type 2 DM among individuals with above-normal BMI in the UAE.DesignA retrospective cohort study.SettingOutpatient clinics at a tertiary care centre in Al Ain, UAE.ParticipantsThree hundred and sixty-two overweight or obese adult UAE nationals who visited outpatient clinics between April 2008 and December 2008.Primary outcome measurePatients with type 2 DM were identified based on diagnosis established by a physician or through glycated haemoglobin (HbA1c) levels ≥6.5% during the follow-up period (until April 2018).ResultsThe overall incidence rate of type 2 DM during the median follow-up time of 8.7 years was 16.3 (95% CI 12.1 to 21.4) cases per 1000 person-years. Incidence rates in men and women were 17.7 (95% CI 11.6 to 25.9) and 15.0 (95% CI 9.8 to 22.2) cases per 1000 person-years, respectively. Multivariable Cox proportional hazard analysis determined older age and obesity in women and pre-diabetes in men to be independent risk factors for developing type 2 DM.ConclusionsThe incidence rate of type 2 DM in overweight and obese UAE nationals is high. In addition to screening, current strategies should strongly emphasise lifestyle modifications to decrease HbA1c and BMI levels in this high-risk population.

Objectives Prediction models assist health-care providers in making patient care decisions. This study aimed to externally validate the REduction of Atherothrombosis for Continued Health (REACH) prediction model for recurrent cardiovascular disease (CVD) among the Emirati nationals. Results There are 204 patients with established CVD, attending Tawam Hospital from April 1, 2008. The data retrieved from electronic medical records for these patients were used to externally validate the REACH prediction model. Baseline results showed the following: 77.0% were men, 69.6% were diagnosed with coronary artery disease, and 87.3% have a single vascular bed involvement. The risk prediction model for cardiovascular mortality performed moderately well [C-statistic 0.74 (standard error 0.11)] in identifying those at high risk for cardiovascular death, whereas for recurrent CVD events, it performed poorly in predicting the next CVD event [C-statistic 0.63 (standard error 0.06)], over a 20-month follow-up. The calibration curve showed poor agreement indicating that the REACH model underestimated both recurrent CVD risk and cardiovascular death. With recalibration, the REACH cardiovascular death prediction model could potentially be used to identify patients who would benefit from aggressive risk reduction.

Background During the coronavirus disease (COVID-19) pandemic, patients with cancer in rural settings and distant geographical areas will be affected the most by curfews. Virtual management (telemedicine) has been shown to reduce health costs and improve access to care. Objective The aim of this survey is to understand oncologists’ awareness of and views on virtual management, challenges, and preferences, as well as their priorities regarding the prescribing of anticancer treatments during the COVID-19 pandemic. Methods We created a self-administrated electronic survey about the virtual management of patients with cancer during the COVID-19 pandemic. We evaluated its clinical sensibility and pilot tested the instrument. We surveyed practicing oncologists in Gulf and Arab countries using snowball sampling via emails and social media networks. Reminders were sent 1 and 2 weeks later using SurveyMonkey. Results We received 222 responses from validated oncologists from April 2-22, 2020. An awareness of virtual clinics, virtual multidisciplinary teams, and virtual prescriptions was reported by 182 (82%), 175 (79%), and 166 (75%) respondents, respectively. Reported challenges associated with virtual management were the lack of physical exam (n=134, 60%), patients’ awareness and access (n=131, 59%), the lack of physical attendance of patients (n=93, 42%), information technology (IT) support (n=82, 37%), and the safety of virtual management (n=78, 35%). Overall, 111 (50%) and 107 (48%) oncologists did not prefer the virtual prescription of chemotherapy and novel immunotherapy, respectively. However, 188 (85%), 165 (74%), and 127 (57%) oncologists preferred the virtual prescription of hormonal therapy, bone modifying agents, and targeted therapy, respectively. In total, 184 (83%), 183 (83%), and 176 (80%) oncologists preferred to continue neoadjuvant, adjuvant, and perioperative treatments, respectively. Overall, 118 (53%) respondents preferred to continue first-line palliative treatment, in contrast to 68 (30%) and 47 (21%) respondents indicating a preference to interrupt second- and third-line palliative treatment, respectively. For administration of virtual prescriptions, all respondents preferred the oral route and 118 (53%) preferred the subcutaneous route. In contrast, 193 (87%) did not prefer the intravenous route for virtual prescriptions. Overall, 102 (46%) oncologists responded that they would “definitely” prefer to manage patients with cancer virtually. Conclusions Oncologists have a high level of awareness of virtual management. Although their survey responses indicated that second- and third-line palliative treatments should be interrupted, they stated that neoadjuvant, adjuvant, perioperative, and first-line palliative treatments should continue. Our results confirm that oncologists’ views on the priority of anticancer treatments are consistent with the evolving literature during the COVID-19 pandemic. Challenges to virtual management should be addressed to improve the care of patients with cancer.

BackgroundPapillary thyroid carcinoma (PTC) is the most common malignant thyroid neoplasm comprising 80-90% of all thyroid malignancies. Molecular changes in thyroid follicular cells are likely associated with the development of PTC. Mutations in serine/threonine-protein kinase (BRAF) and Rat sarcoma viral oncogene homolog (RAS) are commonly seen in PTC.MethodsIn total, 90 cases of PTC are randomly selected from archive paraffin blocks and 10μm sections were cut and processed for DNA extraction. BRAF V600E mutation and 8 types of KRAS mutations were investigated using Real Time PCR.ResultsBRAF V600E mutation was identified in 46% of PTC while KRAS mutations were seen in 11% of PTC. There was significant correlation between BRAF V600E mutation and PTC larger than 5cm in diameter, positive surgical margin and lymph node metastasis. BRAF V600E mutation was significantly higher in patients with less than 55-year of age than those more than 55-year of age. BRAF V600E mutation was significantly higher in patients with family history of thyroid cancer than those without. There was no significant difference in BRAFV600E mutation between males and females, PTC classic and follicular variants, unifocal and multifocal PTC. There was a significant higher percentage of BRAF V600E mutation in classic PTC than papillary microcarcinoma variant. There was no significant age, gender, histologic type, tumor size, lymph node metastasis, tumor focality, and surgical margin status differences between KRAS mutated and non-mutated PTC.ConclusionBRAF V600E and KRAS mutation are seen in a significant number of PTC in the UAE. BRAF mutation is significantly correlated with large tumor size, positive surgical margins and lymph node metastasis suggesting an association between BRAF V600E mutation and tumor growth and spread.

Non-immune hydrops fetalis (NIHF) is the abnormal accumulation of serous fluid in more than two fetal or neonatal interstitial spaces due to nonimmune causes. It is a serious condition that requires extensive medical care as it indicates severe fetal compromise. We clinically evaluated four patients from two branches of a highly consanguineous family from the UAE with NIHF using whole exome sequencing and in silico analysis. Fetal onset pleural and peritoneal effusions were detected in all four patients and were born with moderate to severe hydrops fetalis that resolved with age. Follow up showed relatively normal growth and development apart from mild ascites and haemangiomas in all affected children, recurrent hydrocele in all affected males, intestinal malabsorption in two patients, dysmorphic features in two patients, and congenital cardiac defects in three out of four patients. Molecular testing identified a homozygous eight nucleotide deletion in THSD1 gene (NM_199263:c.1163_1170delGGCCAGCC, p.Arg388Glnfs*66) as the underlying cause of this phenotype in the affected children. The novel variant cosegregates with the described phenotype in an autosomal recessive mode of inheritance and is predicted to be pathogenic as it leads to a truncated protein that lost important structural and functional domains. Thrombospondin-1 domain containing protein 1 gene THSD1 has been recently associated with of NIHF and embryonic lethality. Here, we report the novel truncating THSD1 variant, and describe new clinical features that have not been reported previously thus expanding the phenotype associate with loss-of-function mutations in THSD1 causing NIHF.

RORα, the RAR-related orphan nuclear receptor alpha, is essential for cerebellar development. The spontaneous mutant mouse staggerer, with an ataxic gait caused by neurodegeneration of cerebellar Purkinje cells, was discovered two decades ago to result from homozygous intragenic Rora deletions. However, RORA mutations were hitherto undocumented in humans. Through a multi-centric collaboration, we identified three copy-number variant deletions (two de novo and one dominantly inherited in three generations), one de novo disrupting duplication, and nine de novo point mutations (three truncating, one canonical splice site, and five missense mutations) involving RORA in 16 individuals from 13 families with variable neurodevelopmental delay and intellectual disability (ID)-associated autistic features, cerebellar ataxia, and epilepsy. Consistent with the human and mouse data, disruption of the D. rerio ortholog, roraa, causes significant reduction in the size of the developing cerebellum. Systematic in vivo complementation studies showed that, whereas wild-type human RORA mRNA could complement the cerebellar pathology, missense variants had two distinct pathogenic mechanisms of either haploinsufficiency or a dominant toxic effect according to their localization in the ligand-binding or DNA-binding domains, respectively. This dichotomous direction of effect is likely relevant to the phenotype in humans: individuals with loss-of-function variants leading to haploinsufficiency show ID with autistic features, while individuals with de novo dominant toxic variants present with ID, ataxia, and cerebellar atrophy. Our combined genetic and functional data highlight the complex mutational landscape at the human RORA locus and suggest that dual mutational effects likely determine phenotypic outcome. ispartof: American Journal of Human Genetics vol:102 issue:5 pages:744-759 ispartof: location:United States status: published

Hypomyelinating leukodystrophies (HLDs) affect the white matter of the central nervous system and manifest as neurological disorders. They are genetically heterogeneous. Very recently, biallelic variants in NKX6-2 have been suggested to cause a novel form of autosomal recessive HLD. Using whole-exome or whole-genome sequencing, we identified the previously reported c.196delC and c.487C>G variants in NKX6-2 in 3 and 2 unrelated index cases, respectively; the novel c.608G>A variant was identified in a sixth patient. All variants were homozygous in affected family members only. Our patients share a primary diagnosis of psychomotor delay, and they show spastic quadriparesis, nystagmus and hypotonia. Seizures and dysmorphic features (observed in 2 families each) represent an addition to the phenotype, while developmental regression (observed in 3 families) appears to be a notable and previously underestimated clinical feature. Our findings extend the clinical and mutational spectra associated with this novel form of HLD. Comparative analysis of our 10 patients and the 15 reported previously did, however, not reveal clear evidence for a genotype-phenotype correlation.

Background Congenital hydrocephalus (CH) results from the accumulation of excessive amounts of cerebrospinal fluid (CSF) in the brain, often leading to severe neurological impairments. However, the adverse effects of CH can be reduced if the condition is detected and treated early. Earlier reports demonstrated that some CH cases are caused by mutations in L1CAM gene encoding the neural cell adhesion molecule L1. On the other hand, recent studies have implicated the multiple PDZ domain (MPDZ) gene in some severe forms of CH, inherited in an autosomal recessive pattern. Methods In this study, whole-exome and Sanger sequencing were performed on a 9 months old Emirati child clinically diagnosed by CH. In addition, in silico, cellular, and molecular assays have been conducted to confirm pathogenicity of the identified variants and to establish disease mechanism. Results Whole exome sequencing revealed two compound heterozygous novel variants (c.394G > A and c.1744C > G) in the affected child within the MPDZ gene. Segregation analysis revealed that each of the parents is heterozygous for one of the two variants and therefore passed that variant to their child. The outcome of the in silico and bioinformatics analyses came in line with the experimental data, suggesting that the two variants are most likely disease causing. Conclusions The compound heterozygous variants identified in this study are the most likely cause of CH in the affected child. The study further confirms MPDZ as a gene underlying some CH cases.

Glucose transport across the blood brain barrier and into neural cells is critical for normal cerebral physiologic function. Dysfunction of the cerebral glucose transporter GLUT1 (encoded by SLC2A1) is known to result in epilepsy, intellectual disability (ID), and movement disorder. Using whole-exome sequencing, we identified rare homozygous missense variants (c.526C>T [p.Arg176Trp] and c.629C>T [p.Ala210Val]) in SLC45A1, encoding another cerebral glucose transporter, in two consanguineous multiplex families with moderate to severe ID, epilepsy, and variable neuropsychiatric features. The variants segregate with the phenotype in these families, affect well-conserved amino acids, and are predicted to be damaging by in silico programs. Intracellular glucose transport activity of the p.Arg176Trp and p.Ala210Val SLC45A1 variants, measured in transfected COS-7 cells, was approximately 50% (p = 0.013) and 33% (p = 0.008) lower, respectively, than that of intact SLC45A1. These results indicate that residues at positions 176 and 210 are critical for the glucose transport activity of SLC45A1. All together, our data strongly suggest that recessive mutations in SLC45A1 cause ID and epilepsy. SLC45A1 thus represents the second cerebral glucose transporter, in addition to GLUT1, to be involved in neurodevelopmental disability. Identification of additional individuals with mutations in SLC45A1 will allow better definition of the associated phenotypic spectrum and the exploration of potential targeted treatment options.

Background Individuals with established cardiovascular disease (CVD) and risk factors such as age, smoking, hypertension, and diabetes mellitus are at an increased risk of recurrent cardiovascular events and death. The incidence rate of recurrent CVD events varies between countries and populations. The United Arab Emirates (UAE) has one of the highest age-standardized death rates for CVD worldwide. The aim of our study was to estimate the incidence rates and determine the predictors of recurrent CVD events among UAE nationals. Methods We investigated an outpatient-based cohort of patients with a history of CVD visiting Tawam Hospital between April 1, 2008 and December 31, 2008. They were followed-up until July 31, 2018. Univariable and multivariable Cox proportional hazards regression models were used to determine the association between major CVD risk factors and the risk of CVD recurrence. Results A total of 216 patients (167 males, 49 females) with a history of CVD were included. They were followed for a median (interquartile range) of 8.1 (5.5–9.3) years, with a total of 1184 patient-years of follow-up. The overall incidence rate of recurrent CVD events was 92.1 per 1000 patient-years. The 8-year cumulative incidence was 73.7%. Age, female sex, and diabetes mellitus were significant predictors of recurrent CVD events, where females had a 1.96 times higher risk of recurrent CVD events than males. Conclusion Significant predictors of recurrent CVD events are older age, female sex, and diabetes mellitus. The incidence rate of recurrent CVD events was 92.1 per 1000 patient-years. Preventive measures, based on international guidelines for CVD management, may improve CVD morbidity and mortality in the UAE population.

ObjectivesNumerous studies reported that achieving near-normal glycated haemoglobin (HbA1c) levels in patients with diabetes may delay or even prevent vascular complications. However, information regarding the impact of non-optimal HbA1c control on adverse health outcomes in an Arab population is unknown. The aim of this study was to estimate the fraction of deaths and potential years of life lost (PYLL) attributable to non-optimal HbA1c control among Emirati men and women with diabetes in the United Arab Emirates (UAE).DesignA retrospective cohort study.SettingThis study was conducted in outpatient clinics at a tertiary care centre in Al Ain, UAE, between April 2008 and September 2018.ParticipantsThe sample comprised of 583 adult UAE nationals, aged≥18 years, with diabetes. Overall, 57% (n=332) of the study participants were men and 43% (n=251) were women.ExposureNon-optimal HbA1c control, defined as HbA1c≥6.5%.Primary outcome measureAll-cause mortality, defined as death from any cause.ResultsAt the end of the 9-year follow-up period, 86 (14.8%) participants died. Overall, up to 33% (95% CI 2% to 63%) of deaths were attributable to non-optimal HbA1c control among patients with diabetes mellitus (DM). Stratified by sex, the adjusted fraction of avoidable mortality was 17% (95% CI −23% to 57%) for men and 50% (95% CI 3% to 98%) for women. Both deaths and PYLL attributable to non-optimal HbA1c control were higher in women compared with men.ConclusionsUp to one-third of all deaths in adult UAE nationals with DM could be attributed to non-optimal HbA1c control. Effective sex-specific interventions and healthcare quality‐improvement programmes should urgently be implemented.

Background Patients with cardiovascular disease are at an increased risk of chronic kidney disease (CKD). However, data on incident CKD in patients with multiple vascular comorbidities are insufficient. In this study, we identified the predictors of CKD stages 3–5 in patients at risk of cardiovascular disease and used their estimated glomerular filtration rate (eGFR) to construct a nomogram to predict the 5-year risk of incident CKD. Methods Ambulatory data on 622 adults with preserved kidney function and one or more cardiovascular disease risk factors who attended outpatient clinics at a tertiary care hospital in Al-Ain, United Arab Emirates were obtained retrospectively. eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation and assessed every 3 months from baseline to December 12, 2017. Fine and Gray competing risk regression model was used to identify the independent variables and construct a nomogram to predict incident CKD at 5 years, which is defined as eGFR

Background Cardiovascular disease (CVD) is the leading cause of mortality worldwide; however, the epidemiology of CVD among nationals from the United Arab Emirates (UAE) remains unknown. This study aimed to estimate the 9-year incidence rate of CVD and determine the risk factors associated with CVD among UAE nationals at high cardiovascular risk. In addition, we investigated whether sex was an important modifier of the risk factors associated with incident CVD in this population. Methods A retrospective cohort study was conducted on 977 subjects, including 492 women, aged ≥18 years, who did not have histories of CVD, and who had ≥1 CVD risk factors. Multivariable Cox proportional hazards regression analyses stratified by sex were used to examine the predictors of major CVD events, namely, myocardial infarction (MI), stroke, and acute peripheral arterial occlusion. Results During a median follow-up period of 8.9 years, the incidence rate of major CVD was 12.7 per 1000 person-years (95% confidence interval [CI] 10.4–15.4), and among men and women were 16.8 (95% CI 12.9–21.4) and 9.0 (95% CI 6.4–12.4) per 1000 person-years, respectively. Major CVD and MI were significantly more frequent among men than women, and the stroke and acute peripheral arterial occlusion rates were similar for both sexes. Multivariable Cox analyses showed that the systolic blood pressure, estimated glomerular filtration rate, and serum glycosylated hemoglobin A1c level were strong predictors of major CVD in both sexes. Among women, the total cholesterol (TC)-to-high-density lipoprotein-cholesterol (HDL-C) ratio (hazard ratio [HR] 1.44, 95% CI 1.02–2.04) was an additional independent predictor of major CVD. Age (HR 1.50, 95% CI 1.19–1.89) and a history of smoking (HR 1.80, 95% CI 1.07–3.02) were significant risk factors associated with major CVD in men. Conclusions Among high-risk UAE nationals who did not have histories of CVD, the risk of major CVD was associated with high systolic blood pressure, a low estimated glomerular filtration rate, and poorly controlled diabetes. The high TC-to-HDL-C ratios, especially among women, and smoking among men, are modifiable risk factors that should be managed aggressively. Electronic supplementary material The online version of this article (10.1186/s12872-019-1131-2) contains supplementary material, which is available to authorized users.

Schindler disease is a rare autosomal recessive lysosomal storage disorder caused by a deficiency in alpha-N-acetylgalactosaminidase (α-NAGA) activity due to defects in the NAGA gene. Accumulation of the enzyme's substrates results in clinically heterogeneous symptoms ranging from asymptomatic individuals to individuals with severe neurological manifestations. Here, a 5-year-old Emirati male born to consanguineous parents presented with congenital microcephaly and severe neurological manifestations. Whole genome sequencing revealed a homozygous missense variant (c.838C>A; p.L280I) in the NAGA gene. The allele is a reported SNP in the ExAC database with a 0.0007497 allele frequency. The proband's asymptomatic sister and cousin carry the same genotype in a homozygous state as revealed from the family screening. Due to the extreme intrafamilial heterogeneity of the disease as seen in previously reported cases, we performed further analyses to establish the pathogenicity of this variant. Both the proband and his sister showed abnormal urine oligosaccharide patterns, which is consistent with the diagnosis of Schindler disease. The α-NAGA activity was significantly reduced in the proband and his sister with 5.9% and 12.1% of the mean normal activity, respectively. Despite the activity loss, p.L280I α-NAGA processing and trafficking were not affected. However, protein molecular dynamic simulation analysis revealed that this amino acid substitution is likely to affect the enzyme's natural dynamics and hinders its ability to bind to the active site. Functional analysis confirmed the pathogenicity of the identified missense variant and the diagnosis of Schindler disease. Extreme intrafamilial clinical heterogeneity of the disease necessitates further studies for proper genetic counseling and management.

Background: Liver reserve affects survival in hepatocellular carcinoma (HCC). Model for End-Stage Liver Disease (MELD) score is used to predict overall survival (OS) and to prioritize HCC patients on the transplantation waiting list, but more accurate models are needed. We hypothesized that integrating insulin-like growth factor 1 (IGF-1) levels into MELD score (MELD-IGF-1) improves OS prediction as compared to MELD. Methods: We measured plasma IGF-1 levels in training (n = 310) and validation (n = 155) HCC cohorts and created MELD-IGF-1 score. Cox models were used to determine the association of MELD and MELD-IGF-1 with OS. Harrell’s c-index was used to compare the predictive capacity. Results: IGF-1 was significantly associated with OS in both cohorts. Patients with an IGF-1 level of ≤26 ng/mL in the training cohort and in the validation cohorts had significantly higher hazard ratios than patients with the same MELD but IGF-1 >26 ng/mL. In both cohorts, MELD-IGF-1 scores had higher c-indices (0.60 and 0.66) than MELD scores (0.58 and 0.60) (p < 0.001 in both cohorts). Overall, 26% of training and 52.9% of validation cohort patients were reclassified into different risk groups by MELD-IGF-1 (p < 0.001). Conclusions: After independent validation, the MELD-IGF-1 could be used to risk-stratify patients in clinical trials and for priority assignment for patients on liver transplantation waiting list.

Background Neurodevelopmental disorders are genetically and phenotypically heterogeneous encompassing developmental delay (DD), intellectual disability (ID), autism spectrum disorders (ASDs), structural brain abnormalities, and neurological manifestations with variants in a large number of genes (hundreds) associated. To date, a few de novo mutations potentially disrupting TCF20 function in patients with ID, ASD, and hypotonia have been reported. TCF20 encodes a transcriptional co-regulator structurally related to RAI1, the dosage-sensitive gene responsible for Smith–Magenis syndrome (deletion/haploinsufficiency) and Potocki–Lupski syndrome (duplication/triplosensitivity). Methods Genome-wide analyses by exome sequencing (ES) and chromosomal microarray analysis (CMA) identified individuals with heterozygous, likely damaging, loss-of-function alleles in TCF20. We implemented further molecular and clinical analyses to determine the inheritance of the pathogenic variant alleles and studied the spectrum of phenotypes. Results We report 25 unique inactivating single nucleotide variants/indels (1 missense, 1 canonical splice-site variant, 18 frameshift, and 5 nonsense) and 4 deletions of TCF20. The pathogenic variants were detected in 32 patients and 4 affected parents from 31 unrelated families. Among cases with available parental samples, the variants were de novo in 20 instances and inherited from 4 symptomatic parents in 5, including in one set of monozygotic twins. Two pathogenic loss-of-function variants were recurrent in unrelated families. Patients presented with a phenotype characterized by developmental delay, intellectual disability, hypotonia, variable dysmorphic features, movement disorders, and sleep disturbances. Conclusions TCF20 pathogenic variants are associated with a novel syndrome manifesting clinical characteristics similar to those observed in Smith–Magenis syndrome. Together with previously described cases, the clinical entity of TCF20-associated neurodevelopmental disorders (TAND) emerges from a genotype-driven perspective. Electronic supplementary material The online version of this article (10.1186/s13073-019-0623-0) contains supplementary material, which is available to authorized users.

Purpose: Haploinsufficiency of DYRK1A causes a recognizable clinical syndrome. The goal of this paper is to investigate congenital anomalies of the kidney and urinary tract (CAKUT) and genital defects (GD) in patients with DYRK1A variants. Methods: A large database of clinical exome sequencing (ES) was queried for de novo DYRK1A variants and CAKUT/GD phenotypes were characterized. Xenopus laevis (frog) was chosen as a model organism to assess Dyrk1a’s role in renal development. Results: Phenotypic details and variants of 19 patients were compiled after an initial observation that one patient with a de novo pathogenic variant in DYRK1A had GD. CAKUT/GD data were available from 15 patients, 11 of whom present with CAKUT/GD. Studies in Xenopus embryos demonstrate that knockdown of Dyrk1a, which is expressed in forming nephrons, disrupts the development of segments of embryonic nephrons, which ultimately give rise to the entire genitourinary (GU) tract. These defects could be rescued by co-injecting wild-type human DYRK1A RNA, but not with DYRK1AR205* or DYRK1AL245R RNA. Conclusion: Evidence supports routine GU screening of all individuals with de novo DYRK1A pathogenic variants to ensure optimized clinical management. Collectively, the reported clinical data and loss of function studies in Xenopus substantiate a novel role for DYRK1A in GU development.

The COVID-19 pandemic is the largest viral pandemic of the 21st century. We aimed to study COVID-19 knowledge, attitudes, and practices (KAP) among medical and health sciences students in the United Arab Emirates (UAE). We performed a cross-sectional study between 2 June and 19 August 2020. The survey was distributed online using Survey Monkey. It was conducted in English and comprised two parts: socio-demographic characteristics, and KAP towards COVID-19. 712 responses to the questionnaire were collected. 90% of respondents (n = 695) were undergraduate students, while 10% (n = 81) were postgraduates. The majority (87%, n = 647) stated that they obtained COVID-19 information from multiple reliable sources. They were highly knowledgeable about the COVID-19 pandemic, but 76% (n = 539) did not recognize its routes of transmission. Medical students were significantly more knowledgeable compared with allied health students (P

Background Thyroid nodules are a common clinical finding and most are benign, however, 5–15% can be malignant. There is limited regional data describing the accuracy of ultrasound-guided fine needle aspiration (FNA) cytological examination compared to ultrasound examination of thyroid in patients who have undergone thyroid surgery. Methods A retrospective analysis of ultrasonographic (US) reports, FNA cytology reports and histopathology reports of 161 thyroid nodules presented at the endocrine center at Tawam hospital in Al Ain city, the United Arab Emirates during the period 2011–2019 was performed. US reports and images with FNA cytopathology reports and slides were reviewed by an independent radiologist and pathologist. Results In total, 40 nodules were reported as benign by US examination, while very low suspicious, low suspicious, intermediate suspicious and highly suspicious categories were reported in 21, 41, 14 and 45 nodules respectively. In addition, 68 nodules were reported as benign (Bethesda category II), while atypical follicular cells of unknown significance (Bethesda category III), follicular neoplasm (Bethesda category IV), suspicious for malignancy (Bethesda category V), and malignant (Bethesda category VI) categories were reported in 33, 9, 24 and 27 nodules respectively. The risk of malignancy for US benign nodules was 5%, while the risks of malignancy in very low suspicious, low suspicious, intermediate suspicious and highly suspicious nodules were 52%, 36%, 100% and 87%, respectively. The risk of malignancy for Bethesda category II was 3%, while the risks of malignancy in category III, IV, V and VI were 58%, 67%, 96% and 100%, respectively. Conclusion Thyroid FNA cytological examination and ultrasonography are key tools in predicting malignancy in thyroid nodules. Thyroid nodules with the diagnosis of Bethesda category III & IV run a high risk of malignancy thus more vigilance is required.

To present the pattern, causes and complications of uveitis in one of the tertiary eye centers in Saudi Arabia.In this retrospective study, clinical records of randomly selected cases of uveitis attending the King Khaled Eye Specialist Hospital, Saudi Arabia, from 2001 to 2010, were reviewed.Our series included 888 out of 1286 cases of uveitis. Among them, there were 390 men (43.9%) with a mean age of 39.6 ± 11 (range: 6-94 years). The prevalence of uveitis among all eye patients was 1.5% and the annual incidence was 129 cases. Uveitis was bilateral in 567 patients (63.8%), mainly anterior in 27.3%, intermediate in 12.7%, posterior in 7.1%, while 52.9% were panuveitis. Infective etiology was seen in 180 patients (20.3%), of which presumed tuberculous uveitis (PTU) was the commonest cause in 94 patients (52%), followed by herpetic in 46 (26%) and toxoplasmosis in 29 (16%). Vogt-Koyanagi-Harada (VKH) 22%, Behçet uveitis (BU) 14.6%, idiopathic anterior uveitis 12.5%, presumed tuberculous uveitis (PTU) 10.6%, and idiopathic intermediate uveitis (10.1%) accounted for the majority of cases, whereas other diagnostic entities accounted for 30%. The most common cause of anterior uveitis was idiopathic uveitis (101; 41.7%), followed by herpetic (46; 19%). Toxoplasmosis was the most frequent cause of posterior uveitis (29; 46.3%). Intermediate uveitis was most commonly idiopathic (86; 76.1%). VKH disease was the most common cause of panuveitis (195; 41.5%), followed by Behçet disease (118; 25.1%). The common complications of uveitis were glaucoma (34.1%), posterior synechiae (22.3%) and cataract (15.1%).The most common anatomic diagnosis was panuveitis. VKH disease and Behçet disease were the most frequent causes and glaucoma was the most common complication of uveitis.

Aim: We investigated the incidence of adverse drug reactions (ADRs) in patients treated with statins for cardiovascular (CV) risk among the United Arab Emirates (UAE) population. Methods: This is a retrospective cohort study conducted among statin users attending 2 tertiary care centres: Al Ain and Tawam hospitals in Al Ain city, UAE. We retrieved the clinical profile of all the patients taking statins from January 2011 to January 2015 using our electronic database (Cerner®). Results: Among 556 patients (418 men; 138 women) taking statins, 237 ADRs were reported (186 men; 51 women). The incidence of ADRs was 40.7%, and was more frequent among patients at “high CV disease (CVD) risk” and “moderate CVD risk” than other risk categories. High CVD risk (odds ratio, 1.67; 95% confidence interval [CI], 1.19-2.34), vitamin D deficiency 1.45 (95% CI, 0.89-2.38), type 2 diabetes 1.22 (95% CI, 0.84-1.77) and hypertension 1.13 (95% CI, 0.70-1.83) are some of the factors that were associated with statin ADRs. Conclusion: The incidence of ADRs among statin users was 42.6%, and frequent ADRs (49%) were noted in patients with high CVD risk. Early identification of these ADRs should improve patient adherence to life-saving statin treatment.

Purpose: To describe the clinical characteristics and surgical outcomes of panuveitis over a 10-year period.Methods: Data were collected on panuveitis etiology, treatment, surgery and change in vision.Results: Overall, 308 patients (594 eyes) were evaluated, 54.9% with non-granulomatous and 45.1% with granulomatous uveitis. Fifty-four patients had infectious and 254 had non-infectious uveitis. In infectious panuveitis, vision remained unchanged at last visit. The most frequent diagnosis was presumed intraocular tuberculosis (PIOTB) uveitis (48.1%). In the non-infectious subgroup vision increased significantly by 2 lines at last visit (p = 0.020). The most common diagnose was Vogt–Koyanagi–Harada (VKH) disease (38.6%). Initial therapy was oral prednisone in 86.6% with non-infectious etiology followed by immunosuppressive agents. Surgery secondary to complications (mainly cataracts) was performed in 46.7% patients.Conclusion: In Saudi Arabia, panuveitis was mainly due to VHK. PIOTB was the most comm...

Chronic kidney disease has become an increasingly significant clinical and public health issue, accounting for 1.1 million deaths worldwide. Information on the epidemiology of chronic kidney disease and associated risk factors is limited in the United Arab Emirates. Therefore, this study aimed to evaluate the incidence and causes of chronic kidney disease stages 3-5 in adult United Arab Emirates nationals with or at high risk of cardiovascular disease. This retrospective study included 491 adults with or at high risk of cardiovascular disease (diabetes mellitus or associated clinical disease) who attended outpatient clinics at a tertiary care hospital in Al-Ain, United Arab Emirates. Estimated glomerular filtration rate was assessed every 3 months from baseline to June 30, 2017. Chronic kidney disease stages 3-5 were defined as an estimated glomerular filtration rate < 60 mL/min/1.73 m2 for ≥ 3 months. Multivariable Cox's proportional hazards analysis was used to determine the independent risk factors associated with developing chronic kidney disease stages 3-5. The cumulative incidence of chronic kidney disease stages 3-5 over a 9-year period was 11.4% (95% confidence interval 8.6, 14.0). The incidence rate of these disease stages was 164.8 (95% confidence interval 121.6, 207.9) per 10,000 person-years. The independent risk factors for developing chronic kidney disease stages 3-5 were older age, history of coronary heart disease, history of diabetes mellitus, and history of smoking. These data may be useful to develop effective strategies to prevent chronic kidney disease development in high-risk United Arab Emirates nationals.

BACKGROUND: Bone dysplasias are a large group of disorders affecting the growth and structure of the skeletal system. METHODS: In the present study, we report the clinical and molecular delineation of a new form of syndromic autosomal recessive spondylometaphyseal dysplasia (SMD) in two Emirati first cousins. They displayed postnatal growth deficiency causing profound limb shortening with proximal and distal segments involvement, narrow chest, radiological abnormalities involving the spine, pelvis and metaphyses, corneal clouding and intellectual disability. Whole genome homozygosity mapping localised the genetic cause to 11q12.1–q13.1, a region spanning 19.32 Mb with ~490 genes. Using whole exome sequencing, we identified four novel homozygous variants within the shared block of homozygosity. Pathogenic variants in genes involved in phospholipid metabolism, such as PLCB4 and PCYT1A, are known to cause bone dysplasia with or without eye anomalies, which led us to select PLCB3 as a strong candidate. this gene encodes phospholipase c β 3, an enzyme that converts phosphatidylinositol 4,5 bisphosphate (PIP(2)) to inositol 1,4,5 triphosphate (IP(3)) and diacylglycerol. RESULTS: The identified variant (c.2632G>T) substitutes a serine for a highly conserved alanine within the Ha2’ element of the proximal C-terminal domain. This disrupts binding of the Ha2’ element to the catalytic core and destabilises PLCB3. Here we show that this hypomorphic variant leads to elevated levels of PIP(2) in patient fibroblasts, causing disorganisation of the F-actin cytoskeleton. CONCLUSIONS: Our results connect a homozygous loss of function variant in PLCB3 with a new SMD associated with corneal dystrophy and developmental delay (SMDCD).

We tested the hypothesis that swim exercise can protect the articular cartilage from damages induced secondary to insulin-dependent diabetes mellitus in rats using the scanning electron microscopy and to monitor the blood levels of oxidative and antioxidative stress biomarkers that are known to be modulated in osteoarthritis (OA). A profound damage to the cartilage was observed in the diabetic rats. Our findings also show that swim exercise protects the knee joints from damage induced by diabetes as well as significantly inhibiting OA-induced upregulation of thiobarbituric acid reactive substances (TBARS) and tumor necrosis factor alpha (TNF-α) and augmented superoxide dismutase (SOD) inhibition by OA. Thus, we demonstrated an effective protection by swim exercise against diabetes-induced OA in a rat model of the disease.

Workforce planning is critical for being able to deliver appropriate health service and thus is relevant to medical education. It is, therefore, important to understand medical students' future specialty choices and the factors that influence them. This study was conducted to identify, explore, and analyze the factors influencing specialty preferences among medical students of the United Arab Emirates (UAE).A multiyear, multicenter survey of medical student career choice was conducted with all five UAE medical schools. The questionnaire consisted of five sections. Chi-squared tests, regression analysis, and stepwise logistic regression were performed.The overall response rate was 46% (956/2079). Factors that students reported to be extremely important when considering their future career preferences were intellectual satisfaction (87%), work-life balance (71%), having the required talent (70%), and having a stable and secure future (69%). The majority of students (60%) preferred internal medicine, surgery, emergency medicine, or family Medicine. The most common reason given for choosing a particular specialty was personal interest (21%), followed by flexibility of working hours (17%).The data show that a variety of factors inspires medical students in the UAE in their choice of a future medical specialty. These factors can be used by health policymakers, university mentors, and directors of residency training programs to motivate students to choose specialties that are scarce in the UAE and therefore better serve the health-care system and the national community.

Background: Hepatocellular carcinoma (HCC) prognosis depends on clinicopathological features in addition to the treatment provided. We aimed to assess the natural history of TNM stage I HCC tumors which received different treatment over a period of 20 years. Methods: Between 1992 and 2011, a total of 397 stage I HCC patients were included. Detailed information was retrieved from MD Anderson Cancer Center patients' medical records. The Kaplan-Meier method was used to calculate patients' overall survival (OS). Cox regression analysis was used to calculate the estimated hazard ratio and 95% confidence interval of different prognostic factors. Results: Out of 397 patients, 67.5% were males, 42.8% had hepatitis-related HCC, and 59.7% had underlying cirrhosis. After adjustment for confounding factors, we found that all therapeutic modalities were associated with a significant mortality rate reduction with an OS of 63, 42.03, 34.3, and 22.1 months among patients treated with surgery, ablation, local, and systemic therapy, respectively. A restricted analysis of cirrhotic and noncirrhotic patients showed that ablative and local therapy were significantly associated with a longer OS compared to systemic therapy. Conclusion: TNM stage I HCC patients have a favorable prognosis regardless of the type of treatment. Notably, ablative and local therapy significantly improved OS compared to systemic therapy.

Germline heterozygous mutations in the tumor suppresser NF1 gene cause a cancer predisposition syndrome known as neurofibromatosis type 1 (NF1). This disease is one of the most common multisystem disorders with an estimated incidence of 1 in 3,000 to 1 in 4,000 births. Clinically, NF1 patients are prone to develop “cafe au lait” spots, neurofibromas, Lisch nodules, freckling of the axillary, or inguinal region and optic nerve gliomas. In the present study, we report clinical and molecular findings of five unrelated patients and seven cases from four families with NF1 from UAE. To reveal the genetic defects underlying NF1 in our cohort of patients, we screened the whole coding and splice site regions of the NF1 gene. In addition, MLPA or CGH array has been used to screen for structural variations including deletions, indels, and complex rearrangements. This resulted in the identification of five distinct novel mutations and two previously reported ones. These variations included three missense and one nonsense mutations, one single base, one dinucleotide, and one large deletion. Four mutations were inherited, and the remaining were absent from both parents and therefore are “de novo” mutations. This analysis represents the spectrum of NF1 mutations in UAE and supports the premise of absence of hotspot mutations in the NF1 gene. Moreover, no obvious genotype-phenotype correlations were observed in our patients.

Toll like receptors are primary sensors of both innate and adaptive immune systems. They activate APCs and influence T-cell function in inflammatory autoimmune response. Studies have shown that TLR manipulation may lead to either tolerance or trigger autoimmunity. Using diabetogenic and subdiabetogenic multiple low doses of streptozotocin, we demonstrate here that Pam3 CYS-CK4 a TLR-2 agonist, enhances and promotes diabetes in C57BL/6 male mice following increased apoptosis of β islet cells. FACS analysis of isolated pancreatic lymph node cells revealed significant increased number of macrophages, dendritic cells, CD4(+) TNF-α(+), CD4(+) IFN-γ(+) and most significantly, CD4(+) IL-17(+) and reduced number of CD25(+)Fox p3(+) T cells after Pam3CSK4 treatment. Genetic deletion of IFN-γ prevents whereas deletion of IL-17 reduced severity of Pam3CSK4-induced enhancement of diabetes. TLR-2 agonist-enhanced diabetogenesis is also influenced by enhanced influx of antigen presenting cells and suppression of regulatory T cell activity.

Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) is an emerging pathogen in hospitalized patients worldwide. The present study was undertaken to identify CA-MRSA in hospitalized patients in a 350-bed tertiary care hospital in Sharjah, UAE over a 2-year period from January 2011 to December 2012. CA-MRSA was defined based on identification within first 48 h of admission in the hospital. Staphylococcal cassette chromosome (SCC) mec typing of the CA-MRSA isolates was carried out by multiplex polymerase chain reaction (PCR). Detection of PVL and mecA genes was done by PCR using the GenoType(®) MRSA test system (Hain Lifescience). Patient's clinical data and antimicrobial susceptibility pattern of the CA-MRSA isolates were also evaluated. Fifty seven of the 187 MRSA isolates were identified as CA-MRSA. All the CA-MRSA strains in our study belonged to SCCmecIV type and were positive for both PVL and mecA genes. The patients with CA-MRSA infections were young (median age, 32 years) and the majority of infections involved the skin and soft tissue (36%). Antimicrobial susceptibility pattern of the CA-MRSA isolates showed a better susceptibility profile to the non-beta-lactam antimicrobials with the exception of ciprofloxacin having 28% resistance. This study evidently strengthens the recent observation of an increase in CA-MRSA emergence among hospitalized patients in the UAE.

ABL1 is a proto-oncogene well known as part of the fusion gene BCR-ABL1 in the Philadelphia chromosome of leukemia cancer cells. Inherited germline ABL1 changes have not been associated with genetic disorders. Here we report ABL1 germline variants cosegregating with an autosomal dominant disorder characterized by congenital heart disease, skeletal abnormalities, and failure to thrive. The variant c.734A>G (p.Tyr245Cys) was found to occur de novo or cosegregate with disease in five individuals (families 1-3). Additionally, a de novo c.1066G>A (p.Ala356Thr) variant was identified in a sixth individual (family 4). We overexpressed the mutant constructs in HEK 293T cells and observed increased tyrosine phosphorylation, suggesting increased ABL1 kinase activities associated with both the p.Tyr245Cys and p.Ala356Thr substitutions. Our clinical and experimental findings, together with previously reported teratogenic effects of selective BCR-ABL inhibitors in humans and developmental defects in Abl1 knockout mice, suggest that ABL1 has an important role during organismal development.

Pyrroline-5-carboxylate reductase 2, encoded by PYCR2, is one of the three homologous enzymes that catalyze the last step of proline synthesis. Homozygous variants in PYCR2 have been reported in patients from multiple consanguineous families with hypomyelinating leukodystrophy 10 (HLD10) (MIM: 616420). Here, we report five additional patients from three families with homozygous nonsense or missense variants in PYCR2, identified through clinical exome sequencing. All patients presented with postnatally acquired microcephaly, moderate to profound global developmental delay, and failure to thrive. Brain MRI in these patients showed thin corpus callosum, delayed myelination, and generalized white-matter volume loss. Additional phenotypes that were less consistent among patients included seizures or seizure-like movements, spasticity and ataxic gait, recurrent vomiting, cortical blindness, dysmorphic features, joint contractures, and irritability. Exome sequencing identified homozygous variants in PYCR2 in the proband from each family: c.28C>T (p.(Glu10Ter)), c.796C>T (p.(Arg266Ter)), and c.577G>A (p.(Val193Met)). Subsequent targeted analyses demonstrated co-segregation of the disease with the variant in the family. Despite the metabolic role of PYCR2, routine serum metabolic test in these patients were normal. To further understand the disease etiology and functions of PYCR2, small molecule metabolomics profiling was performed in plasma from three severely affected patients. No significant changes were identified in proline biosynthesis pathway or related metabolites. Studying the clinical features and the metabolic profiles of the PYCR2-deficient patients provides a more comprehensive picture for this newly identified disorder and facilitates further research on the gene function and disease etiology. © 2016 Wiley Periodicals, Inc.