PROJECT SUMMARY Overview of Project: Multisystem Inflammatory Syndrome in Children (MIS-C) is a serious condition affecting children after COVID-19 infection. MIS-C commonly results in severe critical illness and even death. We will provide an examination of MIS-C in 49 children’s hospitals throughout the United States. In this proposal, we will advance knowledge on MIS-C severity of illness as well as evaluate initial treatment regimens. We will describe differences in initial treatment decisions and their associated risk of treatment failure. The completion of this work will result in new knowledge regarding the most effective initial treatments for MIS-C. Environment: Cincinnati Children’s Hospital Medical Center (CCHMC) is the second largest pediatric recipient of funding from the NIH. Drs. Auger and Brady are members of the Division of Hospital Medicine at CCHMC. This division is among the most research-oriented pediatric hospital medicine divisions in the country with a focus on hospital quality and safety and with four faculty members currently on AHRQ grants. Both PIs receive extensive support including computers and software, biostatistical advisors, data management support, clinical research coordinators, grants management support, and discretionary funds. Drs. Auger and Brady are also a members of CCHMC’s James M. Anderson Center for Health Systems Excellence, a nationally renowned research division that focuses on assessing and improving pediatric health care delivery. This proposal additionally leverages the vast resources of the Children’s Hospital Association (CHA) and its experienced biostatistical and data analysis team. Dr. Matt Hall as the principal biostatistician at CHA has a decade-plus experience using the Pediatric Health Information System (PHIS) to ask and answer epidemiologic and comparative effectiveness research questions. He has an extensive record of collaboration with the entire research team, having coauthored over 100 publications with members of this team. Summary: This innovative proposal will generate new, significant knowledge on both the epidemiology and management of MIS-C. This critically important information is foundational for future randomized controlled trials for MIS-C treatment and for development of evidence-based treatment algorithms and pathways.