PROJECT SUMMARY/ABSTRACT Tibial shaft fractures are the most common major fracture of the lower leg and are frequently associated with a break in the skin known as an open fracture. Because the bone is exposed by the open wound, open tibial fractures are often complicated by infection and failure of bone healing, which can lead to long-lasting disability and in some cases amputation. Intravenous antibiotics administered early after injury are a well-established measure to prevent fracture-related infection (FRI), but their effectiveness is limited by poor blood flow at the fracture site and inability to achieve high local concentrations with systemic administration. Gentamicin applied locally within the open fracture wound is a promising adjunctive measure to reduce the risk of FRI after these injuries, but there are no high-quality clinical trials evaluating its use. The candidate proposes to gain skills in randomized controlled trials, observational research design, and cost- effectiveness analysis. The primary study is a pilot trial to assess the feasibility of a masked, randomized trial to compare the effectiveness of locally applied gentamicin to saline placebo to prevent FRI after open tibia fractures (aim 1). The study will be conducted at the Muhimbili Orthopaedic Institute, a tertiary referral hospital in Tanzania with a higher rate of open fractures and infection than trauma centers in North America. A secondary analysis of pooled observational data from the pilot trial and prior studies evaluating open tibial fractures will be used to assess the impact of FRI on quality-of-life and fracture healing (aim 2). The cost-effectiveness of local gentamicin will be estimated by gathering cost data alongside the clinical outcomes in the primary study. These data will be projected beyond the trial endpoint using modelling techniques (aim 3). This will be the first randomized trial evaluating locally administered gentamicin to reduce infection in a fracture population. If efficacious, local gentamicin is likely to be a highly cost-effective preventive strategy for FRI and may ultimately be cost saving. Although these findings will originate from a low-income country, results may be generalizable to populations in both high and low-income countries and could therefore significantly reduce the global burden of open fractures. Through the conduct of the proposed studies, the principal investigator will gain skills in clinical trial design, observational data analysis, and economic analysis from a multidisciplinary team of experts in these domains. In addition, the candidate will gain the clinical research experience necessary and generate preliminary data to successfully compete for an R01 award studying interventions that aim to improve outcomes for orthopedic trauma victims.