ABSTRACT We designed this proposal to address multiple CDC Epicenters' research priorities: preventing healthcare personnel (HCP) contamination, understanding and decreasing transmission of epidemiologically important pathogens including emerging respiratory viruses such as COVID-19, extending antimicrobial stewardship (AS), decreasing antimicrobial resistant infections, exploring sepsis epidemiology and prevention, quantifying and decreasing environmental contamination, implementing a decolonization program to obtain source control and decrease surgical site infections (SSI), applying innovative research methodology, and training the next generation of healthcare epidemiologists. Our proposed projects range from translational stage T0 to T2 and involve academic medical centers, a VA Medical Center, acute care hospitals, quick/urgent care centers (UCC), surgical patients, patients discharged from hospitals, and healthcare personnel (HCP) exposed to viral respiratory pathogens. Our long-term objectives are to: 1) improve the integration of infection prevention measures into HCP's patient care processes, 2) improve personal protective equipment (PPE) design and use to decrease HCP contamination and transmission, 3) improve surveillance for healthcare-associated infections (HAI), 4) identify practical ways to decrease spread of viral pathogens, 4) improve antibiotic use and decrease antimicrobial resistance, and 5) prevent hospital-onset sepsis (HOS) and HAI, including SSI. Core Project (CP) I uses methods from human factors engineering, ethnography, industrial hygiene, environmental microbiology, and computer visioning to improve PPE design, decrease HCP self-contamination, improve integration of PPE use and hand hygiene during patient care, and decrease bacterial and viral environmental contamination. CP II employs novel software via cellphones to expand surveillance for SSI and C. difficile infections after discharge and to monitor HCP exposed to respiratory viruses for signs or symptoms of infection. CP III and the Medium Optional Collaborative Project (OCP) address neglected opportunities for AS--UCC and patients at hospital discharge--by creating and testing novel AS metrics to decrease antibiotic prescriptions for acute respiratory tract infections in UCC (CP III) and by conducting a cluster-randomized trial of post-prescription audit-and-review to reduce unnecessary antibiotic use after discharge (Medium OCP). CP IV mines large administrative data sets and analyzes data from individual medical records to define the epidemiology of HOS, validate CDC's acute sepsis event algorithm for HOS, and identify remediable HOS risk factors that could be targets for preventive measures. The Large OCP will conduct a stepped wedge trial of a simple, inexpensive intervention—2 doses of intranasal povidone iodine—to prevent SSI in patients with high- energy lower extremity fractures, who are a high-risk population with few available preventive measures. The ...