PROJECT SUMMARY Syphilis rates in the United States (US) have reached their highest levels in decades, doubling in the past five years alone. In 2021, men who have sex with men (MSM) accounted for nearly half (46.5%) of all male primary and secondary (P&S) cases. The rate of congenital syphilis has increased by eight-fold since 2011 – reaching one in every 1,300 US births in 2021. The surge in syphilis cases is evident across the US, with highest concentration in urban areas. Amidst declining public health budgets, local policymakers face the challenge of identifying the most efficient and cost-effective ways to invest in these existing tools to alter the trajectory of the US syphilis epidemic. Innovations in syphilis prevention and diagnoses, such as doxycycline for post-exposure prophylaxis ("doxy-PEP") and new diagnostics like point-of-care (POC) or at-home testing, hold promise in reducing syphilis incidence. Efforts to curb new infections require multifactorial approaches addressing underlying transmission drivers and health disparities. To reverse syphilis trends, it is critical to identify the most efficient use of limited public health resources, recognizing that a one-size-fits-all solution may not be suitable for all US cities. Mathematical models of infectious disease dynamics serve as powerful tools for forecasting the impact of infection control strategies. Despite extensive applications in studying HIV and other sexually transmitted infections, there is a marked lack of modeling of US syphilis over the last decade. The absence of representative models for the US syphilis epidemic hinders the effective formulation of evidence-based policy to control further spread of infections. In this proposal, we plan to develop a novel suite of local-level syphilis epidemiologic and economic models (LSEEM) across 40 US cities with the highest syphilis diagnosis rates. The model will consider syphilis transmission, progression, HIV co-infection, STI care engagement dynamics, and demographic factors such as age, racial and ethnic disparities, risk profiles, and social determinants of health. In Aim 1, we will assess the potential impact of scaling up "existing" syphilis control interventions, focusing on increased testing, expanded partner tracing, and faster treatment initiation. Our objective is to provide achievable, cost-effective, and practical suggestions applicable to local jurisdictions. Aim 2 involves evaluating the scale-up of "emerging" diagnostics and biomedical interventions under various assumptions concerning population coverage and costs. Our goal is to determine the conditions under which these interventions would be cost-effective when entering the market. Finally, in Aim 3, we will develop a user- friendly online toolkit to enable decision-makers at local, state, and national levels to obtain customized projections of the impact from diagnostic or biomedical prevention interventions. This tool will aid in translating data into ev...