Introduction:Translational Work Integrating Simulation and Systems Testing (TWISST) is a novel application of simulation that augments how we discover, understand, and mitigate errors in our system. TWISST is a diagnostic and interventional tool that couples Simulation-based Clinical Systems Testing with simulation-based training (SbT). TWISST tests environments and work systems to identify latent safety threats (LSTs) and process inefficiencies. In SbT, improvements made to the work system are embedded in hard wire system improvements, ensuring optimal integration into clinical workflow.Methods:Simulation-based Clinical Systems Testing approach includes simulated scenarios, Summarize, Anchor, Facilitate, Explore, Elicit debriefing, and Failure Mode and Effect Analysis. In iterative Plan-Simulate-Study-Act cycles, frontline teams explored work system inefficiencies, identified LSTs, and tested potential solutions. As a result, system improvements were hardwired through SbT. Finally, we present a case study example of the TWISST application in the Pediatric Emergency Department.Results:TWISST identified 41 latent conditions. LSTs were related to resource/equipment/supplies (n = 18, 44%), patient safety (n = 14, 34%), and policies/procedures (n = 9, 22%). Work system improvements addressed 27 latent conditions. System changes that eliminated waste or modified the environment to support best practices mitigated 16 latent conditions. System improvements that addressed 44% of LSTs cost the department $11,000 per trauma bay.Conclusions:TWISST is an innovative and novel strategy that effectively diagnoses and remediates LSTs in a working system. This approach couples highly reliable work system improvements and training into 1 framework.