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Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR), with approximately 90% of patients harboring at least one copy of the disease-associated variant F508del. We utilized a yeast phenomic system to identify genetic modifiers of F508del-CFTR biogenesis, from which ribosomal protein L12 (RPL12/uL11) emerged as a molecular target. In the present study, we investigated mechanism(s) by which suppression of RPL12 rescues F508del protein synthesis and activity. Using ribosome profiling, we found that rates of translation initiation and elongation were markedly slowed by RPL12 silencing. However, proteolytic stability and patch-clamp assays revealed RPL12 depletion significantly increased F508del-CFTR steady-state expression, interdomain assembly, and baseline open-channel probability. We next evaluated whether Rpl12-corrected F508del-CFTR could be further enhanced with concomitant pharmacologic repair (e.g., using clinically approved modulators lumacaftor and tezacaftor) and demonstrated additivity of these treatments. Rpl12 knockdown also partially restored maturation of specific CFTR variants in addition to F508del, and WT Cftr biogenesis was enhanced in the pancreas, colon, and ileum of Rpl12 haplosufficient mice. Modulation of ribosome velocity therefore represents a robust method for understanding both CF pathogenesis and therapeutic response.

Background: The prevalence of penetrating wartime trauma to the extremities has increased in recent military conflicts. Substantial controversy remains in the orthopaedic and prosthetic literature regarding which surgical technique should be performed to obtain the most functional transtibial amputation. We compared self-reported functional outcomes associated with two surgical techniques for transtibial amputation: bridge synostosis (modified Ertl) and non-bone-bridging (modified Burgess). Methods: A review of the prospective military amputee database was performed to identify patients who had undergone transtibial amputation between June 2003 and December 2010 at three military institutions receiving the majority of casualties from the most recent military conflicts; two of those institutions, Walter Reed Army Medical Center and National Naval Medical Center, have since been consolidated. Short Form-36, Prosthesis Evaluation Questionnaire, and functional data questions were completed by twenty-seven modified Ertl and thirty-eight modified Burgess isolated transtibial amputees. Results: The average duration of follow-up after amputation (and standard deviation) was 32 22.7 months, which was similar between groups. Residual limb length was significantly longer in the modified Ertl cohort by 2.5 cm (p 0.005), and significantly more modified Ertl patients had delayed amputations (p 0.005). There were no significant differences between groups with regard to any of the Short Form-36 domains or Prosthesis Evaluation Questionnaire subsections. Conclusions: The modified Ertl and Burgess techniques offer similar functional outcomes in the young, active-duty military population managed with transtibial amputation., Published in the Journal of Bone and Joint Surgery of America, v95A n10 p888-893, 15 May 2013. Sponsored in part by the Military Amputee Intramural Research Program (MAIRP) via the Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD.

While there are proponents of both bone=-bridging and non-bone bridging transtibial amputation techniques, there is a lack of evidence describing functional differences between these two techniques. The goal of the present investigation was to objectively compare the techniques of bone-bridging and non-bone-bridging with respect to limb socket displacement during physiologic loading., Published in The Journal of Bone and Joint Surgery p924-930, 2012.

Background: Many wounded warriors experienced high-energy lower-extremity trauma (HELET) that may be limb threatening. Volumetric muscle loss, post-traumatic osteoarthritis, nerve injuries, and pain may severely limit physical function. Several wounded warriors express a strong desire to return to their units and be deployed in their original military occupational specialty. We began the return-to-run (RTR) clinical pathway at our institution 2 years ago to facilitate high-performance goals such as these. It involves an energy storing ankle foot orthosis, the intrepid dynamic exoskeletal orthosis in combination with high-intensity, progression oriented rehabilitation. We sought to determine the rate of deployment or predeployment training after participation in this noninvasive intervention. METHODS: A retrospective analysis of the RTR databasewas performed to determine the rate of deployment or predeployment training among those servicemembers who began participation in the RTR between November of 2009 and March of 2011. Medical records were reviewed for demographics, injury, surgical data, and major complications. Requests for delayed amputation were recorded, and charts were reviewed to determine if patients eventually elected to proceed with amputation or if they chose to continue with limb salvage. RESULTS: Between November 2009 and March 2011, 87 service members completed the RTR. Of these, 17 (19.5%) have been deployed to combat or are in predeployment training. Sixteen serve in combat arms (nine Special Forces, four infantry/ranger, two combat engineers, and one gunner), and one is amember of the military intelligence community. Fifteen patients sustained their injuries as a result of HELET (four gunshot, five motor vehicle collisions, four explosions, one parachute injury, and one fall from height), one had idiopathic avascular necrosis of the talus, and one had an iatrogenic nerve injury after pelvic surgery., Published in the Journal of Trauma and Acute Care Surgery v73 n2 Supplement 1, pS112-S115, 2012. This study was presented at the Advanced Technology Applications for Combat Casualty Care Conference Held in Fort Lauderdale, Florida on August 15-18, 2011. This study was conducted under a protocol reviewed and approved by the US Army

The optimal surgical exposure to the posterior ankle for trauma and reconstruction is a source of debate. We hypothesized that the Achilles tendon-splitting approach would provide greater exposure to the posterior ankle than the posterolateral approach. Forty surgical approaches were performed from twenty fresh-frozen cadavers. Achilles tendon splitting and posterolateral approaches were performed using a randomized crossover design for surgical sequence. Six landmarks (medial malleolus, ankle joint, subtalar joint, incisura fibularis, lateral malleolus and medial gutter) were identified by direct visualization or palpation. A calibrated digital photograph was taken and Image J (http://rsb.info nih.gov/ij/) was used to calculate the surface area of the distal tibia and talus exposed in neutral and dorsiflexion. Results: Using a posterolateral approach, the average distal tibia exposed was 11.3cm2 in neutral and 10.2 cm2 in dorsiflexion. The average talus exposed was 2.0 cm2 in neutral and 2.4 cm2 in dorsiflexion. Using an Achilles tendon-splitting approach, the average exposed distal tibia was 33% more (15.0 cm2) in neutral and 43% more (14.6 cm2) in dorsiflexion. The average talus exposed was 47% more (3.0 cm2) in neutral and 76% more (4.2 cm2) in dorsiflexion. All increases in exposure were statistically significant., Published in Foot & Ankle International v33 n10 p900-904, Oct 2012.

Posttraumatic osteoarthritis affects approximately 5.6 million Americans annually. Those affected are typically younger and more active than persons with primary osteoarthritis. Arthrodesis is the typical management option for persons with end-stage ankle and subtalar posttraumatic arthritis. Arthroplasty is typically reserved for elderly persons. The functional limitations resulting from any of these strategies make treatment of this young population challenging. Combat wounds frequently lead to severe lower extremity injuries. We present a series of patients with severe posttraumatic osteoarthritis of the ankle and subtalar joint after combat trauma. They were treated at our institution with an integrated orthotic and rehabilitation initiative called the Return To Run clinical pathway. This clinical pathway may serve as an alternative or adjunct to arthrodesis and arthroplasty for young patients with severe posttraumatic osteoarthritis of the ankle and subtalar joint., Journal of the American Academy of Orthopaedic Surgeons, August 2012 vol. 20 no. suppl S48-S53. The original document contains color images.