The leptin-melanocortin pathway is pivotal in appetite and energy homeostasis. Pathogenic variants in genes involved in this pathway lead to severe early-onset monogenic obesity (MO). The MC4R gene plays a central role in leptin-melanocortin signaling, and variants predominantly heterozygous in this gene are the most common cause of MO. We identified two novel heterozygous variants c,253A>G p.Ser85Gly and c.802T>C p.Tyr268His in the MC4R gene in two unrelated patients with morbid obesity and evaluated the functional impact of these variants. A targeted gene panel consisting of 52 obesity-related genes was undertaken. Variants were analyzed and filtered to identify potential disease-causing and validated using Sanger sequencing. The impact of the variants on the MC4R gene using in silico prediction tools and molecular dynamics simulation was assessed. To further study the pathogenicity of the identified variants, GT1-7 cells were transfected with plasmid DNA encoding either wild-type or mutant MC4R variants. The effects of allelic variations in MC4R gene on cAMP synthesis, MC4R protein level, and activation of ERB and CREB signaling pathways in both stimulated and unstimulated ɑ-MSH paradigms were determined for their functional implications. In-silico analysis suggested that the variants destabilized the MC4R structure and affect the overall dynamics of the MC4R protein, possibly leading to intracellular receptor retention. In-vitro analysis of the functional impact of these variants showed a significant reduction in cell surface receptor expression and impaired extracellular ligand binding activity, leading to reduced cAMP production. In-vitro analysis assays and in silico analysis revealed the pathogenicity of the two novel MC4R variants identified. Our analysis shows that the variants do not affect total protein expression; however, they are predicted to affect the post-translational localization of MC4R protein to the cell surface and impair downstream signaling cascades. This finding might help our patients to benefit from the novel therapeutic advances for monogenic forms of obesity.

Background: We aimed to describe the patterns, management, and outcome of traumatic femoral shaft fractures. Methods: An observational descriptive retrospective study was conducted for all trauma patients admitted with femoral shaft fractures between January 2012 and December 2015 at the only level 1 trauma center and tertiary hospital in the country. Data were analyzed and compared according to the time to intramedullary nailing, mechanisms of injury and age groups. Main outcomes included in-hospital complications and mortality Results: A total of 605 cases were analyzed, with mean age of 30.7±16.2 years. The majority of fractures were unilateral (96.7%) and 91% were closed fractures. Three-fourth of fractures were treated by reamed intramedullary nailing (rIMN); antegrade in 80%. The pyriform fossa nails were used in 71.6% while trochanteric entry nails were used in 28.4%. Forty-five (8.9%) of fractures were treated with external fixator, 37 (6.1%) had conservative management. Traffic-related injuries occurred more in patients aged 14-30 years whereas; injuries related to fall were significantly higher in patients aged 31-59 years. Thirty-one patients (7.8%) had rIMN < 6 h post-injury, 106 (25.5%) had rIMN < 6-12 h and 267 (66.8%) had rIMN > 12 h. The implant type, duration of surgery, DVT prophylaxis, in-hospital complications and mortality were comparable among the three treatment groups. Conclusion: In our center, the frequency of femoral fracture is 11% which mainly affects severely injured young males due to traffic-related collisions or falls. Further multicenter studies are needed to reach a consensus for the appropriate management based on the location and timing of injury

This case study is the first to be developed in the Middle East region to describe the timeline of the Middle East Respiratory Syndrome (MERS) epidemic events in Qatar along with the features of the implemented Emergency Risk Communication (ERC) activities. It sought to describe how the performed ERC strategy particularly during the first days (then over the course of the following phases) of the outbreak might have contributed to the authorities’ credibility, public trust, and outbreak control measures despite the overwhelming uncertainty. All of the relevant news stories during the period 24 Sep 2012 to 17 Mar 2014 were retrieved from a local daily, then were analyzed and interpreted before they were compiled and matched with the issued press releases, records of response activities and the public reactions along the course of the epidemic timeline. Despite the prevailing uncertainty, the health authorities’ early preparedness to the epidemic and its commitment to a proactive and open ERC strategy since the first days of the outbreak favored the authorities’ credibility and allowed for the quick initiation of the national response efforts during the course of the outbreak. However, there was some pitfalls as the print media reported some conflicting messages and paternalist approach during the early phases of the epidemic. Reliance solely on the print media is an acknowledged limitation to this study. Yet, it might be useful for emergency planners regarding what communication challenges to expect during the first days of a novel virus or similar threats.