Carcillo R01 Project Abstract Every year over 1 million American adults and children develop overwhelming infection leading to a rotting of their body we call ‘sepsis’, and death in up to 1 of 3 afflicted (www.nigms.nih.gov>NIGMS Home>Science Education). National efforts emphasizing early recognition, intravenous fluids to help organs, and antibiotics to kill infection, have reduced mortality so that now 1 of 4 die. We and others have asked the question “why do patients continue to die despite these national efforts?’ In the previous funding period we showed in 401 children with sepsis that those who developed organ shut down despite these efforts, did so because they were a) unable to fight germs causing unending infection, b) unable to stop clotting off their body causing kidney failure, and/or c) unable to kill viruses causing liver failure; all of which led to death from uncontrolled inflammation with clotting, bleeding and liver failure. Fortunately, each of these organ shutdown groups has hopeful treatments. With the new information we collected in the previous funding period we have already designed and started clinical trials testing these treatments including immune boosters for children unable to kill germs, plasma removal and replacement using plasma exchange for children unable to stop clotting, monoclonal antibodies to kill viruses and their homes to reverse liver failure in children unable to do so on their own, and anti-inflammatory proteins to reverse uncontrollable inflammation, in hopes of helping save many of the 1 of 4 children still dying from sepsis related organ shutdown. In this next funding period, we propose to use the clinical information and samples already obtained in our previous study to take advantage of the wonderful advances made this millenia in computer technology, big data, bioinformatics, and the study of human and virus genetics to perform Specific Aim 1) use a ‘Watson’ like approach to ask the computer to help us figure out if the children with sepsis have any other causes of organ shutdown that we can help, Specific Aim 2) use an ‘Ancestry.com’-like or ‘23 and me’-like approach to identify ‘precision medicine’ therapies for causes of organ shutdown that we can treat on a patient by patient basis, and Specific Aim 3) use a bedside molecular biology test approach to identify individualized therapies to kill DNA viruses and reduce cytokine inflammation. We think that DNA viruses are the unappreciated co-infection which causes uncontrolled cytokine inflammation and leads to organ shutdown. Our long term objective is to plan ‘precision’ medicine and ‘individualized’ medicine clinical trials testing therapies on an individual patient basis in order to further reduce death from sepsis organ shutdown in children.