Qatar Foundation Annual Research Forum Volume 2013 Issue 1

Obesity has increased at an alarming rate over the past three decades. It is likely caused by increased caloric intake combined with genetic predisposing factors and is a major risk factor for type 2 diabetes (T2D). Obesity is linked to chronic inflammation, which was proposed as a cause for insulin resistance and T2D. The obese state creates a microenvironment within the adipose tissue that is susceptible to accumulation of reactive oxygen species (ROS). Accumulated ROS leads to DNA damage and activation of DNA damage response. When DNA is severely damaged and can't be repaired, the cell undergoes senescence, an irreversible cell cycle arrest. Senescence has been linked to aging illnesses and even to obesity with accumulation of senescent pre-adipocytes. A major player in detecting and defending against oxidative stress is PARP-1. PARP-1 activation has been shown to be associated to melanoma senescence, inflammation, obesity and diabetes. The role of PARP-1 in ROS-induced senescence and inflammation of pre-adipocytes has not yet been investigated. Therefore, to study PARP-1 function in pre-adipocytes senescence, we generated and characterized an in vitro experimental model for cellular senescence in primary human and mice pre-adipocytes using hydrogen peroxide (H2O2) as a source of ROS. Our preliminary data shows PARP-1 induction in ROS-treated pre-adipocytes. We are currently using this senescence model to characterize the function of PARP-1 by using gene-silencing approaches.

Obesity is an established risk factor for hypertension. About 1 billion adults are overweight globally and numbers appear to be increasing. Stimulating endogenous activation of brown adipose tissue (BAT) mass that has unprecedented metabolic capacity can combat obesity, reverse insulin resistance and reduce comorbidities. Renalase is a recently discovered flavin adenine dinucleotide (FAD)-dependent oxidase, predominantly secreted into the circulation from the kidney and regulates catecholamine degradation and metabolism. Renalase gene is also present in heart muscle, skeletal muscle and liver cells in humans, and in mouse testicles. Four isoforms of renalase gene has been identified in humans (hRenalase1 to hRenalase4), however only hRenalase1 is detected in human blood suggesting that hRenalase2 to 4 may have alternative function. Unlike the classical amine oxidases which are expressed intracellularly, renalase is present intracellularly and is also secreted into the circulation. Circulating renalase appears to mirror sympathetic tone, a brief increase in catecholamines results in significant up-regulation of renalase synthesis, secretion and activity. Catecholamines are principle activators of BAT thermogenesis and angiogenesis both in rodents and humans. Characterization studies in renalase‐knockout mice shows that these mice have about 25% reduced body weight compared to control, increased circulating catecholamines, are hypertensive, and have cardiovascular defects. Renalase‐knockout mice have activated sympathetic system and possibly have increased BAT activity as a result of elevated catecholamine's in the circulation. Our findings in adipose tissue demonstrate that the renalase gene and protein is expressed in both white and brown adipose tissue depots. Expression of renalase increases in BAT of mice during non-shivering thermogenesis and in diet-induced obese mice. The expression of renalase gene, protein and secretion are significantly higher in differentiated mature brown and white adipocytes compared to preadipocytes. Stimulation of mature brown adipocytes with norepinephrine, the main catecholamine released during cold induced non-shivering thermogenesis in vivo, results in significant increase in renalase expression suggesting the importance of renalase in non-shivering thermogenesis. In white adipocytes, renalase expression is up-regulated in response to treatment with obesity linked adipokines, specifically, leptin and insulin. We report renalase as a novel adipokine expressed and secreted from both BAT and WAT. From our preliminary findings and observations in renalase knockout mice having increased sympathetic activity and circulating catecholamines, we hypothesise "renalase regulates BAT development, thermogenesis and metabolism". Therefore further studies are needed in renalase knockout mice to understand the role of renalase in adipose tissue metabolism which could provide us clues on its role in obesity and insulin resistance. Understanding the mechanisms of renalase action may provide translational data that underpins future treatment in obesity associated cardio-metabolic complications.

Calcium is a ubiquitous signaling molecule involved in various cellular processes, including fertilization, muscle contraction or synaptic transmission. There are two major sources for Ca2+: the extracellular media and intracellular Ca2+ stores, particularly the endoplasmic reticulum (ER). When intracellular stores are depleted, a signal is transmitted from a Ca2+ sensor protein that localizes to the ER membrane (STIM) to the plasma membrane to trigger the opening of the Ca2+ channel Orai. This mechanism, known as store-operated calcium entry (SOCE) activates multiple physiological processes and provides Ca2+ to the SERCA pump to refill the ER stores. To avoid unspecific Ca2+ diffusion in the cytosol, SOCE is a highly localized signal, spatially restricted to dense domains (clusters) created by protein-protein interactions between STIM and Orai. Ca2+-sensitive effectors that respond rapidly to Ca2+ influx through SOCE are therefore in the immediate vicinity of the cluster. We here describe a novel mechanism that expands this Ca2+ signaling microdomain through functional coupling of SOCE, SERCA and the IP3 receptor, to allow efficient activation of Ca2+-activated Chloride channels (CACC) localized away from SOCE clusters. When intracellular Ca2+ stores were emptied using ionomycin, a small CACC activation by SOCE was observed. Conversely, when the stores were depleted following injection of IP3 there was a significantly larger CACC activation (2.5 ± 0.5 nA, n=14 vs 0.08 ± 0.02 nA, n=20). Surprisingly the size of the SOCE current was similar in both conditions, indicating that similar levels of Ca2+ influx lead to different CACC activation. The same mechanism could also be induced when IP3 production was stimulated by lysophosphatidic acid (LPA) and we did show that the cell membrane depolarization induced by LPA required SOCE activation, indicating a physiological function of the process in regulating membrane potential. Ca2+ injection experiments ruled out any increase in the CACC sensitivity to Ca2+, while imaging intracellular Ca2+ levels reflected the amplitude of the Cl- currents Analysis of the localization of the Xenopus CACC (TMEM16a) and of the ER calcium sensor STIM1 indicated that they did not co-localize but rather have a tendency to exclude each other following store depletion. Simultaneous expression of STIM1, Orai1 and SERCA2b tagged with fluorescent markers indicated that the three proteins co-localized in clusters at the plasma membrane following store depletion, creating a very restricted cytoplasmic volume where Ca2+ is increased prior to its pumping into the ER lumen. Finally, GFP-tagged IP3 receptors were not found to be enriched in the clusters. Our results show functional coupling between SOCE, SERCA and IP3 receptors to effectively activate CACCs in response to agonist induced store depletion. Here, Ca2+ entering the cell through SOCE is rapidly taken up into the ER by SERCAs and released through open IP3 receptors close to its target, the CACC. This mechanism extends the function of SOCE to the activation of channels that or not located in the immediate vicinity of the extracellular Ca2+ source without requiring large intracellular calcium events to target distant Ca2+ sensitive elements.

Title: Preliminary Results and Clinical Relevance of Next Generation Sequencing in Hypertrophic Cardiomyopathy Patients in Qatar. Kholoud Al-Shafai 1, Despina Sanoudou 1,2, Paul Barton 3 , Lama Shuayb 1 , Emmeleia Nana 2 , Pothitos Pitychoutis 2 , Rachel Buchan 3 , Roddy Walsh 3 , Stuart Cook 3, Magdi Yacoub 1,3, Mohammed Alhashemi 4 1 Qatar Cardiovascular Research Center (QCRC), Qatar Foundation, Doha, Qatar, 2 Department of Pharmacology, Medical School, University of Athens ,Greece, 3National Heart & Lung Institute, Imperial College London, London, UK. 4Cardiac OPD and Rehabilitation, Heart Hospital, Doha, Qatar. Hypertrophic cardiomyopathy (HCM) is the most common inherited heart muscle disease with a prevalence of 1 in 500 in the general population. HCM exhibits a remarkable clinical and genetic heterogeneity, with over 30 genes being implicated so far. However, the full spectrum of genes and mutations leading to HCM remains to be discovered to help the understanding of genotype-phenotype relationship and its clinical implications. Next generation sequencing (NGS) technologies are powerful tools to study these issues. Here, we utilized NGS technologies to sequence the exomes of over 170 genes including all known HCM genes. Preliminary results of seventeen HCM patients recruited at the Heart Hospital-Qatar is presented, with particular reference to the clinical implications of NGS in early disease detection, diagnosis and disease management. Different previously known HCM disease-causing genetic variants were detected, within sarcomeric genes including TNNI3, MYBPC3, MYL3 and MYH7. Patients carrying those variants were offered genetic counseling and advised for clinical and genetic screening of relatives, leading to the early detection of HCM in a 13 years old boy, coupled with efforts to detect genotype-positive phenotype-negative relatives. Of particular interest are genetic variants found within PRKAG2, NEXN that have not been previously described in HCM and need to be further assessed and screened in relatives. In addition, two genetic variants were detected in SOS1 and RAF1 that were previously related to Noonan Syndrome leading to the diagnosis of Noonan syndrome variants in these patients with cardiac hypertrophy associated phenotype. This is an ongoing program which is expected to yield further valuable information which could influence the management in these patients.

The interest in smart body‐centric wireless networks (BCWNs) for healthcare applications is increasing as clinical acceptance of wireless technology is growing; they potentially combine ease of use with greater independence to the patient. BCWNs are emerging for in‐patient and out‐patient monitoring of ECGs, pulse oximeter, blood pressure, insulin pumps and blood glucose. Coupled with the use of location‐based systems, BCWNs can be applied to ensure the well‐being and safety of aged people in different scenarios with continuous monitoring and tracking. Particularly, Wearable electrocardiogram (W-ECG) recorders are increasingly in use for long-term care for patients with chronic disease, assistive technology for the elderly, risk management for people in rehabilitation, lifestyle monitoring, pre-and post-chirurgical monitoring, and heart anomalies early detection [1]. Devices currently available in the market can typically provide an activity-aware, 2 channels, 3-channels ECG or a 5-channels ECG [2]. However, the systems mentioned are limited in the quality of ECG singles received due to the restrictions on the number of electrodes used. A 12-channels ECG would give a more detailed look at the heart's three areas (anterior, lateral, inferior), and changes in certain segments of the ECG in the related leads for each area suggest the area of concern. Thus, this work addresses the demand of a wireless activity-aware 12-channels ECG to replace inconvenient wires. Available off-the-shelf programmable sensors is initially applied to test the functionality of the algorithms and also to identify the required components aiding in reducing size and cost. A key point of the successful deployment is a long-term test trial performed within a partnered cardiologist institution, to verify ECGs data against obtained with data from standardized devices. Eliminating wires attached to the patient that usually strap the patient and limit his/her movement and activities would make a patient more comfortable while wearing the ECG system and therefore allow continuous monitoring over a longer period of time. Moreover, the compensation of ECG noise due to the body movement enables the patient to wear the W-ECG while during normal life activities. In this way, a long-term evaluation monitoring the heart activities after a surgery, enabling an early detection of several heart-related diseases or predict heart activity failures can be performed without the patient repeatedly having to visit the doctor or being in bed, with a dramatic improvement of quality of life. Fig. 1 shows measured average power consumption against margins for multi-hop (MH) and single-hop (SH) networks in W-ECG monitoring applications tested on real subject. References: [1] J. Sriram, M. Shin, T. Choudhury, D. Kotz, "Activity-aware ECG-based patient authentication for remote health monitoring", ICMI-MLMI '09 Proceedings of the 2009 international conference on Multimodal interfaces, Pages 297-304. [2] Shuo Xiao; Dhamdhere, A.; Sivaraman, V.; Burdett, A.; , "Transmission Power Control in Body Area Sensor Networks for Healthcare Monitoring," Selected Areas in Communications, IEEE Journal on , vol.27, no.1, pp.37-48, January 2009

Background: Developing effective public health policies and strategies for interventions necessitate an assessment of the structure, dynamics, disease rates and causes of death in a population. Lately, Qatar has undertaken development resurgence in health and economy that resulted in improving the standard of health services leading to enhanced life expectancy as was evident in the entire Qatari population (i.e., Qatari nationals and non-Qatari residents). No study has attempted to examine the influence of improving the health services on the homogenous, stable population of Qatari nationals. Objective: The present study examines the population structure and dynamics and the related changes in the cause-specific mortality rates and disease prevalence in the Qatari nationals. Methods: This is a retrospective, analytic descriptive analysis covering a period of 5 years (2007-2011) and utilizes a range of data sources from the State of Qatar including the population structure, disease-related mortality rates, and the prevalence of a range of chronic and infectious diseases. Factors reflecting population dynamics such as crude death (CDR), crude birth (CBR), total fertility (TFR) and infant mortality (IMR) rates were also calculated. Results: The Qatari nationals is an expansive population with an annual growth rate of ~4% and a stable M:F ratio. The CDR declined by 15% within the study period whereas the CBR was almost stable. The total disease-specific death rate, however, was decreased in the Qatari nationals by 23% due to the decline in mortality rates attributed to diseases of the blood and immune system (43%), nervous system (44%) and cardiovascular system (41%). There was a high prevalence of a range of chronic diseases whereas very low frequencies of the infectious diseases within the study population. Conclusion: Public health strategies, approaches and programs, developed to reduce diseases burden and the related death, should be tailored to target the population of Qatari nationals since this population exhibits characteristics that vary from the entire Qatari population.

Background: The incidence of Colorectal Cancer (CRC) peaks in the sixth and seventh decade of life and its precursor lesions a decade earlier in average risk population. American College of physicians (ACP) recent guidelines suggests CRC screening at 50 years of age and older in average risk persons to detect and treat colorectal cancer precursor lesions and early cancers. Objective: To delineate the incidence of Colorectal Cancer (CRC) and Cancer Precursor Lesions (CPL) in the 30 - 49 years age group in symptomatic and asymptomatic average risk population of Doha, Qatar. Method: Lower gastrointestinal endoscopies are routinely done in Qatar for diagnosis and treatment for patients presenting with lower abdominal pain, bleeding or worsening constipation. A retrospective collection of data was done to know the incidence of CRC and CPL among all the patients reporting to our hospital with above mentioned symptoms. Based on the results of this data, a cut off age was calculated with highest sensitivity and specificity for detection of CPL. A CRC screening program was then initiated among asymptomatic subjects with positive immunological fecal occult blood (iFOBT) and age > 40 years were invited for screening colonoscopy. Incidence of CPL (colorectal adenomas) and CRC was calculated prospectively in the average risk asymptomatic population among various age groups. Data regarding the incidence of CRC and CPL among symptomatic and asymptomatic (screened) population was compared. Results: A total of 1489 lower gastrointestinal endoscopies were done in symptomatic patients over a one year period. The mean age was 47.5 years, 935 were males with 71.3 % being expatriates. Overall, among the symptomatic people, CPL were detected in 14.5 % (n= 216) and CRC in 5.6 % (n= 84).Of these, CPL and CRC was detected in 22.6 % (n= 49) and 34 % (n=29) respectively in the age group of 30-49 years. Among the asymptomatic 1242 people who participated in the CRC screening keeping a cut-off age of > 40 years, 57 people (4.6%) were found to be positive for occult blood in stool. Of them, seven and five patients were detected to have CPL and CRC respectively between the age group of 40-74 years. In the 30-49 years age group, CPL was detected in 14.3 % (n=1) but without any CRC. Table 1. Conclusion: One-third of cancers (34%) and one-fifth of cancer precursor lesions (22 %) are detected in the 30-49 years age group in symptomatic patients in Qatar. Among the young (fourth decade of life) asymptomatic subjects, the incidence of cancer precursor lesion remains similar to symptomatic patients but without any obvious cancer. Hence, it is recommended that young symptomatic patients should undergo lower endoscopy early to detect cancer and cancer precursors. Larger studies are required in the asymptomatic subjects of 40-49 years age group to estimate the incidence of pre-cancerous lesions that might benefit from CRC screening.

In recent years a specialist interest has developed worldwide in Advanced Wound Management for difficult to heal chronic wounds. This is timely given the increasing number of elderly in the population and the growing burden of diabetes, obesity and cardiovascular disease that all contribute to an increase in hard to heal wounds. Further progress in Advanced Wound Management will require an improvement in personalised medicine for the patient and in particular an improvement in the availability of diagnostic tests and parameters that fulfil clinical need in wound management decisions. At the current time in wound care there is little available in near patient testing for clinical diagnostics. This research project focuses on a number of metrics for wound condition and wound healing: wound moisture, wound fluid pH, and wound matrix metalloproteinases (MMP) enzyme activity. To observe these important markers a state of the art sensor for wound moisture monitor is being deployed in clinical studies and new sensors are currently in development for both pH and MMP-9 enzyme level. Moisture levels in wounds can determine how well a wound heals and in addition it is possible to make decisions on the need for dressing changes based upon moisture readings taken from inside the dressing. The pH of a wound can affect many different phases of the healing process such as oxygen levels, cell proliferation, protease enzyme activity and bacterial growth. If the pH level of a wound can be effectively monitored then it can act as a biological marker to aid in diagnostics and in establishing the optimum conditions for healing. The pH electrode has not been successfully adapted into smaller and alternate packaging because the membrane that forms the selective part of the electrode, being made of silicon glass, is fragile, thus limiting manufacture, sterilisation and practical application. A disposable sensor has been produced through a screen printing method with an ion-selective membrane. The sensor is able to detect the pH in an operational range in the pH 3.5-10 with as little 10µL of fluid. MMPs are involved in every phase of wound healing. If the balance of the MMPs is upset within a wound it can upset the cellular processes preventing healing and eventually causing further damage to the wound. In chronic wounds the amount of MMP-9 activity has been found to be 30 times more than in acute wounds. By measuring the MMP-9 level of a wound the clinician will be able to choose treatment appropriately to return the MMP level to optimum healing conditions. The project has developed an assay for measuring MMP-9 at physiologically relevant levels between 0.01-100ng/ml. These sensors will enable the wound healing markers of moisture, pH and MMP enzyme activity to be studied and profiled in Hamad Medical Corporation which will further the understanding of these markers and their relationship in the complex healing process involved in chronic wound healing.

Background and Objectives-Salmonella enterica is one of the most commonly reported causes of bacterial foodborne illness around the world. Many factors, including food of animal sources, play a role in the predominance of certain serovars. The occurrence of S. enterica serovars varies between different geographical regions and data on their occurrence in Qatar is lacking. Knowledge on the occurrence of zoonotic serovars and associated factors will help to design cost-effective risk mitigation strategies. This risk of salmonellosis has been exacerbated by the ease of travel around the world, increase in world trade of food and animal items, and continued migration of people. Qatar is one of the countries where the factors that exacerbate the risk of foodborne diseases intersect. We carried out a combination of epidemiologic and molecular studies to investigate the distribution of S. enterica serovars in this highly diverse population, and to identify the factors that play a role in the predominance of a particular serovar. Methods-We carried out a repeat cross-sectional study in which human and non-human samples were collected and Salmonella spp. were detected using a combination of bacterial enrichment and real-time PCR. Salmonella isolates were analysed using the Multi-locus sequence typing (MLST) scheme and assigned accordingly by their eBURST groups (eBGs). We used the minimal spanning tree (MST) analysis to investigate the relationship among the isolates from different sources. Data on putative risk factors were collected and analysed for significance of association with particular serovars. Results-We identified 27 different sequence types (STs) and the most common were ST11 (29.5%) and ST19 (11.5%). Among the 27 STs, seven were novel (ST1695, ST1696, ST1697, ST1698, ST1699, ST1702, and ST1703). The STs related to serovar Enteritidis were ST-11, ST1695, and ST-1702; to Typhimurium were ST-15, ST-19, and ST-568; and to Newport were ST-31, ST-808, and ST-1698. Three of them were revealed to be common serovars in this study. In the MST analysis, three major clusters were presented in the overall population: Enteritidis, Newport and Typhimurium. Furthermore, it also revealed the possibility of transmission of strains between human and animal sources according to the lineages of STs. It was more likely to detect serovar Enteritidis in Qataris and serovar Typhimurium in non-Qataris in this study population. Conclusions—A diverse set of serovars were identified among the samples which could be due to the large scale of emigration and importation of animal feed and products in Qatar. Overall, our data also reveals the possibility of transmission of Salmonella isolates between human and animals; however, a detailed analysis of larger sample over a longer period of time using whole genome sequencing (WGS) could help to shed more light on the dynamics of transmission between these populations.

Background and objectives-Foodborne illness has been determined to be one of the major limitations to the advancement of world health and with the ease of travel around the world and the increase in trade of food and animal products, the risk has been exacerbated in recent years. It has been proclaimed as one of the high priority issues in the Qatar National Food Security Master Plan. Different estimates of burden of disease consistently indicate a high cost per episode, irrespective of the country where the study is conducted. The mechanism by which foodborne pathogens cause disease is complex and the cytolethal distending toxin (CDT) has been identified as one of the virulence factors that contributes to gastroenteritis. The CDT is a trimeric subunit toxin produced by gram-negative bacteria that causes cell-cycle arrest and causes affected cells to die by apoptosis. In an effort to understand the mechanisms by which foodborne pathogens put humans at risk of chronic gastroenteritis sequelae, this study investigated the occurrence of the CDT among Salmonella spp., Escherichia coli serogroups and Campylobacter spp. isolates recovered from animals and humans in Qatar. Methods—Samples collected from animals and humans were screened for the presence of these three foodborne pathogens using a combination of bacterial enrichment and molecular detection. Positive samples were further examined for the presence of the CDT gene and its three subunits (cdtA, cdtB, cdtC) using a polymerase chain reaction (PCR) approach. Results—To date the cdtB gene was detected in C. jejuni and C. coli isolates from animals at a rate of 70 and 89%, respectively. The cdtC gene was detected in 72% of the C. jejuni animal samples examined to date. Only cdtB was detected in Salmonella spp. and E. coli spp. isolates from animals and at a much lower rate. Both cdtB and cdtC were detected at a higher rate among C. jejuni and C. coli recovered from human cases enrolled in this study (Figure 1). Conclusions—The high prevalence of the CDT genes among Campylobacter isolates in both animal samples and human clinical cases suggests a possible critical role for the toxin in the pathogenesis of the diseases caused by these pathogens. By virtue of its toxicity, CDT has been incriminated in the risk of chronic gastroenteritis sequelae, including Inflammatory Bowel Disease and is likely to play role in the risk of this disease among human population in Qatar.

There are obvious and well known links between air quality and acute respiratory illnesses that are common in Qatar and other Middle Eastern countries. For example, recent studies have documented a number of respiratory problems associated with inhalation of dust during dry, windy periods. In Qatar, exposure to dust and sand are anecdotally associated with a variety of respiratory issues including asthma and chronic obstructive pulmonary disease (COPD). These illnesses may be brought about by physical damage caused by the particles themselves, or by microorganisms that can be associated with these particles. In this study we will examine the relationship between different climatic variables, daily airborne particulate matter, and hospital admissions for respiratory problems over an eight month period to establish possible relationships. The results of the study will shed light on the importance of weather phenomena, particularly windy conditions, in impacting respiratory health in Qatar. These data are particularly important as respiratory problems are expected to increase as climate change results in hotter, drier conditions over the next few decades.

Abstract (342 words) Background: The scale and nature of hepatitis C virus (HCV) disease burden in Qatar is poorly known. In addition to establishing the level of infection among the Qatari population, characterizing HCV disease burden is of particular relevance as Qatar has a large expatriate population some of whom are from countries with substantial HCV prevalence. Objective: To investigate the epidemiology of HCV in Qatar among Qataris and expatriate resident populations. Methods: We conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Sources of data included PubMed and Embase databases. Our analysis included all primary studies reporting HCV prevalence or incidence measures in Qatar. Extracted measures were then classified and analyzed on the basis of the study population's risk of acquiring HCV. Meta-analyses were conducted incorporating inverse variance weighting and using a random-effects model to pool summary estimates of HCV prevalence, among general population groups, for Qataris and the population as a whole. Results: We identified seven studies providing a total of 23 measures on HCV prevalence and none on incidence in Qatar. HCV prevalence in the general population was 0.51% (95% confidence interval (CI): 0.43-0.59) among Qataris, and 1.01% (95% CI: 0.43-1.82) overall. Among blood donors the prevalence ranged from 0.3-11.2% depending on country of origin. The highest prevalence was reported among Egyptian migrants followed, though by a large margin, by Pakistani migrants. Among high risk populations, HCV prevalence was as high as 44.6% in hemodialysis patients, 25.8% among cirrhosis patients, and 9.0% among lichen planus patients. Conclusions: National-level HCV prevalence in Qatar is comparable to that in developed countries, but higher prevalence is found in specific expatriate populations reflecting the higher prevalence in the countries of origin. The high prevalence found among high risk groups possibly dates back to exposures that occurred prior to the enforcement of stringent infection control and blood screening protocols, implemented in the 1990s after the virus discovery. Since HCV prevalence is rather low, HCV prevention policy in Qatar should focus mainly on prevention and infection control in clinical settings.

Dilated Cardiomyopathy (DCM) is a leading cause for heart failure characterized by an enlarged ventricular cavity causing systolic dysfunction. Although a multifactorial disease, DCM has been attributed to gene mutations in approximately 30-50% of cases. However, the full spectrum of the genetic basis of DCM remains elusive. QCRC-IGC is a Doha-centered intercontinental consortium comprising teams from Egypt, Greece, UK, Italy and the USA. It aims at discovering novel gene variants implicated in DCM pathogenesis and/or progression, through the establishment of a multinational DCM patient cohort and the genetic investigation of over 170 genes (including all DCM genes) using the cutting-edge technology of Next Generation Sequencing (NGS). Herein we present the genetic screening of sixteen DCM patients (5 sporadic and 11 familial), as confirmed by echocardiography and/or MRI, who did not have a history of alcoholism or coronary angiography findings. Over 1,600 variants were detected in each patient, the vast majority of which represent well documented benign polymorphisms. Forty variants had never been reported before, involving the genes: TTN, SYNE1, MYH6, ALMS1, SDHA, MYPN, LAMA2, TPM1, PLEC, FOXD4, ILK, SGCB and DSP. TTN mutations are being detected in 27% of DCM cases. Of particular interest is the polymorphism observed in the gene DSP, as it was detected in two affected sisters of the same family, it represents the only common potentially pathogenic variant shared between them, and it is bioinformatically predicted to lead to a dysfunctional protein product. Importantly, other mutations in DSP have been previously associated with DCM as well as ARVC. Significant findings of immediate research and ultimately diagnostic/prognostic value are beginning to emerge. Additionally, the discovery of novel pathogenic mutations would unveil promising new therapeutic targets. QCRC is currently intensifying the patient recruitment process at the clinical level, while focusing on the molecular characterization of the emerging novel variants using in silico modeling, induced pluripotent stem cells, and systems biology approaches.

Abstract- Developing visual prosthesis in human cortex or on retina has gained some importance over years. However, visual prosthesis in thalamic region targeting lateral geniculate nucleus (LGN) has few advantages though. This paper proposes a simulation model for deep brain visual prosthesis that will harness the capacity of the residual central visual neurons. This prosthesis creates percepts, substituting an engineered prosthetic for the image capture and early visual processing properties of the LGN neurons that we plan to drive artificially. Introduction- Glaucoma is an incurable neurodegenerative disorder leading to permanent blindness. Glaucoma accounts for blindness in 4-5 million of the world's people and is unusually prevalent in Eastern Arabia. In Qatar, glaucoma is said to account for 40% of its cases of blindness and 16% of people above age 40 are affected by this disease. Restoration of visual function in glaucoma by stem cell therapy or genetic engineering could provide a quite good solution, but the likelihood of these approaches providing a cure for glaucoma in the near term is tenuous. A neuroprosthetic approach offers the most likely short-term treatment for glaucoma-induced blindness. This paper describes early progress made towards designing a visual prosthesis to treat blindness through glaucoma. In glaucoma, there is evidence that the LGN undergoes degenerative changes in human patients [1]. Obviously, LGN degeneration during glaucoma needs to be factored into the design of the electrode array. Design and Concept- The proposed design of the visual prosthetic requires many components (Fig 1). The electrodes are positioned in the dorsal layers of the LGN and all other components located outside the body. Images are captured and adjusted for position of gaze and processed by spatiotemporal filters to provide signals that can be used to drive LGN neurons similar to their natural drive. These signals drive the electrode array with a pattern of stimulation pulses. Electrical stimulation circuitry provides charge-balanced current pulses to the electrodes to activate LGN neurons. Results- An array of electrodes distributed across a semi-elliptical shaped flat surface that interfaces with the top three LGN layers (layers 6-4) is designed. The flat semi-elliptical shaped head, resembling the tip of a knife, facilitates easy penetration through the soft brain tissue. To match LGN dimensions, the head would be 2.5 mm wide, 2 mm deep and 50 µm thick. Fig 2 shows the proposed design with 184 hemispherical shape electrodes placed on either side of the lead with diameters of 50 µm and center to center spacing of 200 µm. The hemispherical shape of electrodes avoids concentration of current density at one place since it does not have any corners or edges. Thus these electrodes deliver uniform current density around the electrode minimizing the electrode and tissue damage. The electrodes are placed in a triangular array to maximize packing density and maintain equal distance between neighboring electrodes. Reference- [1] Gupta, N. et al., 2009. Atrophy of the lateral geniculate nucleus in human glaucoma detected by magnetic resonance imaging. The British journal of ophthalmology, 93(1), pp.56-60.

Design of a new Wavelet-based preprocessing stage for improved time-frequency detection of fetal movements Dr. Taoufik Ben Jabeur and Pr. Boualem Boashash Department of Electrical Engineering, Qatar University Background: Improving Newborn Health Outcomes can be achieved by monitoring Fetal Movement (FetMov) activity which relates directly to the fetus well-being. Several methods exist to record these Fetal movement (FetMov) signals including active (Ultrasounds) and passive ways (accelerometer). Ultrasound is an accurate measurement but expensive and intrusive; for these reasons, capturing FetMov through accelerometer sensors is a preferred option as it is low cost and nonintrusive. In this approach, different sensors are placed on the abdomen of the pregnant woman. Each sensor produces a FetMov signal. The recorded FetMov signals have been shown to be noisy and non-stationary signals containing several artifacts. Thus, a pre-processing stage is required to reduce the noise and eliminate the artifacts. Objectives: This work aims at designing a new pre-processing stage for improving FetMov detection by applying Wavelet de-noising algorithm followed by a threshold given by Kurtosis parameter. Methods: The new method is based on a Wavelet de-noising algorithm followed by a high pass filter to reduce some artifacts. A threshold given by Kurtosis parameter is used in the elimination of the artifacts. Results and conclusion: Simulation results show that the proposed pre-processing stage allows to reduce the noise and to eliminate more than 70% of the artifacts. Few artifacts are still present in the FetMov signals. As the FetMov signal is non-stationary, we use a Time Frequency Matched filter detector (TFMF) based on QTFDs to detect FetMov from these artifacts. The proposed preprocessing stage combined with TFMF detector improves significantly the performance of the detection of the FetMov signal leading to possible improvements in health outcomes for the fetus. Keywords: Fetal movement; Wavelet; Time frequency Matched Filter; Quadratic Time Frequency Distribution.

ABSTRACT Background and Objective HIV and herpes simplex virus type-2 (HSV-2) are sexually transmitted infections, with HSV-2 being nearly 10 times as infectious as HIV. HSV-2 prevalence has been established as an objective biomarker and a proxy measure of sexual risk behavior. HIV epidemics appear to be emerging in the Middle East and North Africa (MENA) region, but the time course and future size of these epidemics are still unknown. We assessed HIV epidemic potential across regions using the association between HSV-2 and HIV prevalence, and based on a global systematic review of HIV and HSV-2 prevalence and meta-analyses. Methods Sources of data were PubMed and Embase databases, and country-level reports. Data on the prevalence of HIV (PHIV) and of HSV-2 (PHSV2) in the same population were extracted from eligible studies. Our analysis included all population groups except adolescents and injecting drug users, where the dominant mode of HIV transmission was not sexual. Studies with sample sizes of less than 50 were excluded. Odds ratios were calculated as (PHSV2/ (1- PHSV2)) / (PHIV/ (1- PHIV)), and relative risks as (PHSV2/ PHIV). Meta-analyses were conducted incorporating the inverse variance method and using a random-effects model to pool summary estimates of odds ratios and relative risks in different geographical regions. Results The meta-analysis included 662 study measures with a total population of 590,220 individuals from 67 countries. The pooled odds ratio of HSV-2 prevalence relative to HIV prevalence was low in Sub-Saharan Africa, Asia, and North America/West Europe, 6.0 (95% CI 5.5-6.5), 10.4 (95% CI 9.2- 11.8), and 13.0 (95% CI 9.9- 17.8), respectively. We found high odds ratios in East Europe 73.6 (95% CI 32.8-165.5), MENA 38.0 (95% CI 15.2-95.0), and Latin America 30.4 (95% CI 22.4-41.4). The pooled estimates of relative risks followed the same pattern as the odds ratios across all regions. Discussion The small odds ratios in sub-Saharan Africa, Asia, and North America/West Europe suggest established HIV epidemics that have likely reached saturation. Meanwhile, the large odds ratios in MENA, East Europe, and Latin America, suggest emerging HIV epidemics that have not yet reached their epidemic potential. These results corroborate recent data about the trend of HIV epidemics in these regions. The findings are of concern for MENA as they suggest that the HIV epidemics are likely to grow within this decade and the next one. HIV response in MENA needs to be expanded through bio-behavioral surveillance, voluntary counseling, testing, and treatment services, and focus on HIV prevention.

Health-related quality of life (HRQoL) measures are important indicators of perceived physical and mental health and are affected by changes in health status, demographic characteristics, culture, and ethnicity. Although recent studies have reported on HRQoL in midlife women in the US, most notably the Study of Women's Health Across the Nation (SWAN), there has been little research conducted on quality of life issues experienced by midlife women in the Middle East. Qatar has a high prevalence of obesity, a known risk factor for many chronic diseases, including osteoarthritis (OA) and rheumatoid arthritis (RA), which adversely influences HRQoL. This study has the following goals: To compare HRQoL among midlife Arab women living in Qatar to that of women in the US, (2) to report the prevalence of osteoarthritis (OA), rheumatoid arthritis (RA), and symptoms of aches and stiffness in joints, (3) to examine the impact of OA and RA on HRQoL, and (4) to compare arthritis prevalence and HRQoL of Qatari women to that of non-Qatari Arab women living in Qatar. This is a cross-sectional study of 841 women aged 40-60 recruited from nine primary health centers. Height and weight were assessed by physical examination and body mass index (BMI) was calculated as weight (in kilograms) divided by the square of height (in meters). Face-to-face interviews included demographic questions as well as questions about whether women suffered from any of a list of medical conditions, including OA and RA. The SF-36 was used to assess HRQoL and eight subscales were computed. A higher score designates a more favorable health status. Overall, women in Qatar had significantly lower mean scores than women in the SWAN for bodily pain (53.0 vs 68.9, p=0.0001) and for vitality (49.6 vs. 54.8, p=0.0001). BMI = 35 was found in 41.4% of women. OA and RA were reported by 4.8% and 4.3% of women, respectively, yet 71.6% reported being bothered by aches or stiffness in joints within the past two weeks. Half of women reported that these symptoms were either quite bothersome or intense. Women who reported having OA or RA had significantly lower scores on physical function (p<0.0001 and p=0.0002, respectively). Those with RA also had significantly reduced functioning for role physical (p=0.001). There was a trend toward lower scores among women with RA on bodily pain, vitality, and social functioning and among women with OA on bodily pain compared to women not reporting arthritis. Qatari nationals had a significantly higher prevalence of OA compared to non-Qatari women (7.4% among Qatari nationals vs. 2.6% among non-Qatari women, p=0.001). Women of Qatari nationality reported lower mean scores on physical function than non-Qatari women (73.3 vs. 80.0, p<0.0001). Midlife women in Qatar reported more bodily pain and reduced vitality than women in the SWAN, which may be the result of joint pain. The high prevalence of obesity may be predisposing women in Qatar to arthritis, which appears to be underdiagnosed given the high prevalence and intensity of joint aches and stiffness. National surveillance of the population is warranted.

All muscles involve the interaction between two sets of filamentous proteins, actin and myosin, that leads to muscle contraction and force production mediated by the hydrolysis of ATP (Adenosine triphosphate). Actin filament structure is understood to high resolution, but myosin filament structure is much less well defined. The myosin filaments are formed from complicated arrangements of myosin molecules and accessory proteins. Myosin molecules are hexameric polypeptide chains, each consisting of two myosin heavy chains (MHC) and four myosin light chains (MLC). Accessory proteins are the myosin binding protein C (MyBP-C) and Titin. We have previously resolved the three-dimensional (3D) structure of myosin filaments in normal human heart muscles (AL-Khayat et al., Proc. Natl. Acad. Sci., USA, 110, 318-323). Mutations in cardiac muscle myosin (MHC or MLC) and its associated proteins (MyBP-C or Titin) are known to be associated with a number of myopathies (e.g. familial hypertrophic cardiomyopathy and dilated cardiomyopathy) which change the proteins involved in producing and regulating heart muscle contraction. In order to understand the effect of myosin-associated heart disease, it is important to understand the 3D structure of myosin filaments in both the normal as well as in the diseased human heart muscles. The aim of this project is to study and compare the arrangement of the myosin molecules and the accessory proteins in the human heart muscle myosin filaments and how these arrangements change in diseased human heart muscles, suffering from either hypertrophic or dilated cardiomyopathies. A laboratory method to isolate myosin filaments from normal undiseased human cardiac muscle that preserves the highly ordered pseudo-helical structure of the myosin filaments has already been developed. This led, for the first time, to the detailed analysis of the 3D structure of myosin filaments from normal human heart muscles by utilizing the experimental technique of transmission electron microscopy (EM) as well as the computational single particle image analysis, 3D reconstruction and structural interpretation. Knowledge of this 3D structure serves as the starting point from which myosin filaments isolated from human cardiomyopathic samples, with known mutations in either myosin or its associated proteins, will be studied later in detail. The 3D structure of mutated myosin filaments will be resolved by a state of the art Electron Microscopy Facility at QCRC which is now underway. This will have both the highest spatial and time resolution for collecting EM images. A laboratory method will also be developed to isolate myosin filaments from human cardiomyopathic samples, which will be examined by EM and single particle image analysis so that to determine the overall 3D structure of myosin filaments in diseased heart muscles. By direct comparison to the known 3D structure of myosin filaments from normal undiseased human cardiac muscle, this would eventually permit the structural effects of known myosin filaments-associated mutations to be investigated in detail as well as to relate structure-to-function-to the overall disease process. Detailed understanding of the disease process would then allow us to design possible.

Background: EEG signal are widely used for detecting abnormalities such as seizures in newborn babies. EEG signals have non-stationary characteristic, therefore time frequency distributions (TFDs) are a preferred tool for their analysis. The classification performance of most time-frequency (t-f) methods is restricted by the resolution limitation of TFDs. Objective: The main objective of this research is to propose a new time-frequency pattern recognition technique that improves the performance of earlier methods by defining a new high resolution data adaptive time-frequency distribution. Methods: The key steps of the proposed t-f pattern recognition scheme are 1. Transformation of an EEG signal in the t-f domain by using a high resolution TFD. 2. Estimation of the instantaneous frequency (IF) and instantaneous amplitude (IA) of signal components. 3. Extraction of statistical features such as mean, variance, skewness and kurtosis from the estimated IF and IA. 4. Training of a support vector machines using extracted features. The accurate estimation of the IF and IA of signal components is a key step of the proposed t-f pattern recognition technique. Estimation of the IF and IA of signal components depends on the ability of a TFD to resolve closely spaced signal component. In order to overcome the resolution limitation of existing TFDs, we define a new high resolution data adaptive TFD that adapts the direction of its smoothing kernel at each point in the t-f plane based on the direction of energy concentration in the t-f plane. The proposed adaptive TFD out performs other standard methods of t-f analysis in terms of its resolution and instantaneous frequency estimation capabilities. Results: The proposed t-f pattern recognition methodology is applied to detect seizure activity in newborn EEG signals. The classification performance of widely used TFDs such as the extended modified B-distribution, compact support kernel, spectrogram, and proposed adaptive TFD is compared using the leave-one out cross-validation technique. The proposed TFD outperforms other TFDs as well as earlier methods of seizure detection by achieving the total accuracy of 97.5%. Conclusions: A new time-frequency pattern recognition technique for the classification of EEG signals is presented. Results indicate that the performance of the time frequency pattern recognition techniques is sensitive to the resolution performance of TFDs as high resolution TFDs have achieved better classification results.

Background. Ovarian cancer is the second leading cause of cancer-related death in women worldwide. Despite optimal cytoreduction and adequate adjuvant therapy, initial tumor response is often followed by relapse. Targeted therapies have been evaluated in ovarian cancer to overcome resistant disease. Among them anti-angiogenic therapies inhibit new blood vessel growth, induce endothelial cell apoptosis, and block the incorporation of haematopoietic and endothelial progenitor cells into new blood vessels. Despite in-vitro and in vivo successes anti-vascular therapy with bevacizumab targeting VEGF has limited efficacy in ovarian cancer. Anti-angiogenic treatment increases hypoxia, and might lead to tumor rebound and drug resistance. The precise molecular mechanisms underlying clinical resistance to anti-VEGF therapies are not well understood. But it became clear that the multiple changes in the stroma may determine the treatments outcome, Hypothesis. We hypothesized that abnormalities in the tumor endothelium may contribute to treatment resistance and produce and promote a residual microscopic disease and resistance to bevacizumab. Methods. We showed that Akt pathway is activated in vitro and in vivo in ovarian cancer endothelium. We used Akt-activated endothelial cells (E4+EC) that replicate tumor endothelium biology, and their control, HUVEC to investigate the anti-angiogenic activity of bevacizumab by angiogenesis and migration assays. We conducted XTT assay to examine the effect of bevacizumab on proliferation of VEGF producing human ovarian cancer cell lines. Expression of FGF-2, phospho-AKT was assessed by western blotting and flow cytometry. Finally, using a feeder-free matrigel and spheroid models of ovarian cancer we examined the effect of bevacizumab on residual disease. Results. Our study describes a comprehensive observational and functional investigation on the pivotal role played by the endothelium in the resistance to bevacizumab. We showed that the cross-talk between ovarian cancer cells and the endothelium activate PI3k/Akt. According to our findings, activated ECs expressing higher amount of VEGF-A tend to be less susceptible to the inhibitory effect of bevacizumab. Bevacizumab had no effect on the proliferation of Akt-activated EC, but significantly inhibited angiogenesis and delayed wound healing in HUVEC. We were able to show most primary ovarian cancer cells and ovarian cancer cells cultures secrete a large quantity of FGF-2 and showed that FGF-2 is able to revert the effect of bevacizumab on HUVEC. Our data suggest that an FGF-2/FGFR mediates a cross-talk between cancer and endothelium and is inviolved in an angicrine switch. We demonstrate the role of Akt-activated EC in supporting expansion and self-renewal of OCC in a residual disease context. Conclusion. We used the E4+ECs as a surrogate for tumor associated endothelium. We showed that an FGF-2/PI3K-AKT autocrine loop is required in ECs to perturb bevacizumab treatment. In summary, our study point out the role of an activated endothelium in the constitution of the residual disease and resistance to bevacizumab.

Both diabetes and cancer are prevalent diseases whose incidence is increasing worldwide and especially in countries that are undergoing rapid industrialization (i.e. Golf Countries). Lifestyle risk factors including diet, physical activity and obesity play a pivotal role in the etiology of both diseases. Epidemiological studies provide strong evidence that subjects with diabetes are at significantly higher risk of developing many forms of cancer and especially solid tumors. In addition to pancreatic and breast cancer, the incidence of colorectal cancer is increased in diabetes. A person with diabetes has a 38% higher risk of developing colon cancer compared to other people. Male diabetes patients were found to have a 20% higher risk of developing rectal cancer. While diabetes and especially type 2 diabetes and cancer share many risk factors, the biological links between the two diseases are poorly characterized. We have evidence that in human epithelial colorectal cancerous cells, either high glucose, insulin or their combination inactivates adenine monophosphate kinase (AMPK), induces the loss of function of the tumor suppressor gene, tuberous sclerosis complex 2, encoding tuberin, activates the mTOR/S6Kinase pathway and enhances the generation of mutagnic DNA, 8-oxodG. We also show that AMPK inactivation upregulates Nox1, which in turn inactivate tuberin and mTOR. These observations were associated with increased cellular proliferation, migration and fibronectin accumulation. Treatment of the cells with metformin, a potent AMPK activator or with rapamycin, an mTORC1 inhibitor, decreases the rate of cellular proliferation and migration and reverse the biochemical changes seen in cancerous cells treated with high glucose, insulin or their combination. In rodent models of diabetes, we find that loss of function of tuberin is associated with loss of function and mutations of OGG1 gene and accumulation of significant amounts of 8-oxodG and activation of the mTOR/S6Kinase pathway. These observations are paralleled by an increase in the levels of ROS production through an NADPH dependent mechanism. These observations indicate a critical role for AMPK, tuberin and mTOR in diabetes progression. These same observations were found in animal models that develop spontaneous colorectal cancer, APC mice. Activation of AMPK or blockage of mTORC1 pathways in the APC mice decreases ROS production, reverse OGG1 mutation and 8-oxo-dG accumulation in the colon and decrease tumor development. Our Findings may suggest that activation of AMPK, blockage of mTORC1 or inhibition of the NADPH oxidases pathways represent potential targets to reduce or to inhibit the onset and the progression of colorectal cancer in diabetes.

Prostate cancer (PC) is the second leading cause of cancer related death in men in several countries and is the most common cancer in men in Qatar according to recent statistics of the years 2010 and 2011. Understanding the molecular mechanisms underlying the development of PC progression is critical for developing novel therapies. Neuroendocrine (NE) differentiation of PC cells is an oncogenic process that has been reported as a mechanism contributing to hormone refractory PC progression. NE cells are found in most prostate adenocarcinoma that are significantly enriched as disease progresses, and are extremely resistant to apoptosis caused by androgen ablation therapy, therapeutic drugs or radiation. However, the mechanism of resistance to apoptosis of these cells is not clearly understood resulting in major impediment in PC treatments. The current study aims to initially identify the optimal conditions to induce NE phenotype in PC cells in vitro and to identify the molecules or pathways responsible for resistance to apoptosis in NE cells of prostate adenocarcinoma. Since NE cells are also quiescent as cancer stem cells (CSC), we investigated the relation between NE cells and CSC. Using the expression of NE-specific markers such as Chromogranin A and Neuron specific Enolase (NSE) an optimal method for the differentiation of PC cells to NE cells was identified and used to generate a repertoire of NE-induced PC cells for genome-wide analysis. Our analysis identified differential regulation of pro-apoptotic and anti-apoptotic molecules in NE cells accounting for resistance to apoptosis. We also show that the NE repertoire is highly enriched in CSC as demonstrated by sphere formation method. The identification of key molecules involved in resistance to apoptosis is critical for the development of novel therapeutic drugs that can interfere with NE differentiation and thus PC progression.

Background: Egypt has by far the highest national-level hepatitis C virus (HCV) prevalence in the world, with more than 14% of the general population infected with the virus. The drivers of such epidemic are still not completely identified, with previous parenteral antischistosomal therapy (PAT) campaigns conducted throughout Egypt proposed as the major contributor of the high HCV prevalence. In an effort to clarify specific drivers of the HCV epidemic in Egypt, and to identify priority populations for HCV prevention interventions, we conducted a comprehensive statistical analysis and mapping of the spatial distribution of HCV infection across Egypt. Methods: We conducted statistical analysis of the world's largest cross-sectional study of HCV conducted by the Demographic and Health Survey in Egypt (EDHS) in 2008 including demographic, health, and HCV biomarker information for a sample of over 11,000 individuals aged 15-49 years. We also identified and compared spatial clusters with high numbers of HCV infections using Kulldorff spatial scan test. The test locates areas with higher numbers of HCV infections than expected under spatial randomness. For each identified cluster, a likelihood ratio test was computed. A P-value was determined through Monte Carlo simulations to evaluate the statistical significance of each cluster. Results: The analysis of the EDHS data indicated that only 9.1% of the population aged 15-59 was exposed to PAT; from this fraction, 28.6% are infected with HCV. These values suggest that PAT might be responsible for only about 8% of the total HCV infections in Egypt. Moreover, ever had a blood transfusion, ever had a dental treatment, and ever had a surgery significantly increased the odds of testing positive for HCV by 54%, 45%, and 28%, respectively. Our results also indicated substantial geographical clustering of HCV infections in Egypt. We identified settings with high HCV prevalence distributed in six geographical clusters located at the interface between the governorates of Beni Suef and Minya, Faiyum, Dakahlia, Kafr el-Sheikh, Monufia, and Minya. Conclusion: The small fraction of the population with previous exposure to PAT suggests that other modes of transmission fueled the HCV epidemic, and could be playing an essential role in the current spread of the HCV infection in Egypt. Our study provides direct evidence for strong geographic clustering of HCV infection in Egypt and locates priority geographic areas for spatially targeted interventions.

Abstract Objective: To compare the efficacy and safety of 5%, 3%, and 0.9% saline solution for treating acute bronchiolitis in the prehospital setting. Study design: This was a double-blind trial including consecutive infants aged <18 months treated in an urban urgent care setting. A total of 165 patients were randomized to receive nebulized 5%, 3%, or 0.9% (normal) saline with epinephrine every 4 hours. The primary efficacy outcome was bronchiolitis severity score improvement at 48 hours (c2 analysis). Scores and oxygen saturation immediately before and after each treatment were recorded to assess safety. Results: A total of 187 previously healthy infants (median age, 3.1 months) diagnosed with bronchiolitis were enrolled. Positivity for respiratory syncytial virus was similar in the 3 treatment groups (mean, 56%). At 48 hours, the mean severity score for the 5% saline group was 3.69 _ 1.09, and that for the 0.9% saline group was 4.12 _ 1.11 (P = .04; difference, 0.43, 95% confidence interval for the difference, 0.02-0.88). The mean severity score for the 3% saline group was intermediate at 4.00 _ 1.22. Revisit rates after discharge were similar in the 3 treatment groups. No adverse reactions or other safety concerns were identified. Conclusions: Nebulization with 5% hypertonic saline is safe, can be widely generalizable, and may be superior to current treatment for early outpatient treatment of bronchiolitis.

Introduction Colorectal cancer (CRC) is increasing in incidence in several Asian countries but screening programs are lacking. In Qatar, ,we embarked on a pilot study for Colo-Rectal Cancer (CRC) screening based at 3 primary health centers among subjects with average risk for colorectal cancer. Aim To devise a national screening program for the early detection of colonic cancer among persons at average risk for Colorectal cancer (CRC) ,based on the outcome of our pilot study Methods All subjects aged 40-74 years at average risk for CRC ie that is individuals without history of polyps or documented cancer or inflammatory bowel disease in the past and absent family history are included. They are subjected to screening by immunochemical fecal occult blood testing at the primary health centers. Subjects positive for stool occult blood undergo total colonoscopy at the tertiary care hospital. Cancers and polyps picked up are documented and subjected to appropriate investigations and therapy Results A total number of 1242 healthy subjects at average risk for CRC, between ages of 40-74 years underwent stool occult blood testing by immunochemical fecal occult test. 57 (4.5%)were found to be positive and referred for colonoscopy. Of the 57 eligible persons, invited for colonoscopy, 32(56.4%) underwent the procedure , of whom 7 had polyps and 5 patients had cancer or advanced adenoma. Conclusions Cancers and adenomatous polyps which are treatable and curable can be successfully picked up by primary care level screening programs. Relevance, feasibility and cost effectiveness of such screening programs in Middle East has to be confirmed by community based programmatic screening studies in our region