Project Summary Tuberculosis (TB) is a leading cause of global morbidity and mortality; every year, nearly three million people develop TB disease but are never notified to public health authorities. Studies in Vietnam and Zimbabwe have shown that intensive efforts to find individuals with undiagnosed TB (“active case finding”, ACF) can greatly reduce TB burden. However, in high-burden countries, repeated population-level ACF is not a viable strategy. Therefore, it is critical to understand whether ACF can be implemented in a manner that is both economically/ logistically feasible and epidemiologically impactful. Additionally, as an estimated 23% of the world's population is infected with M. tuberculosis, it is increasingly clear that global targets to end TB cannot be achieved without scaling up TB preventive therapy (TPT). Since ruling out TB disease is essential before providing TPT, ACF offers a unique opportunity to expand TPT by screening a broader population for TB disease; however, most previous ACF campaigns in high-burden countries have not included linkage to TPT. Key recent technological innovations, including mobile chest X-ray devices, AI-based X-ray reading, and novel short-course TPT regimens, have made mass ACF with linkage to TPT feasible for the first time, with potential for transformative impact on TB burden. In our initial R01 study (STOMP-TB), we identified venue-based screening (VBS) as an efficient approach to ACF in an urban Ugandan community; nearly 3% of VBS attendees had undiagnosed TB disease. In this renewal project, we will rigorously evaluate the comparative effectiveness and implementation of two approaches to venue-based ACF with linkage to TPT, each building on specific findings from STOMP- TB. Specifically, we will conduct a multiple period, cluster randomized crossover trial (type 1 hybrid effectiveness-implementation design) comparing a health facility-based approach to ACF/TPT that incorporates existing infrastructure and patients' expressed preferences and a “hotspot”-based approach that brings testing directly to neighborhoods experiencing the highest burden of TB. In Aim 1, we will compare the effectiveness of hotspot-focused versus facility-based ACF/TPT in eight regions near Kampala, Uganda. Our primary outcome will be the number of individuals initiating treatment for confirmed pulmonary TB. Secondary analyses will include the number of people linked to TPT and notifications in the eight intervention regions compared to four control regions. In Aim 2, we will compare implementation (reach, implementation, and maintenance) and incremental cost-effectiveness of hotspot-focused versus facility-based ACF/TPT. In Aim 3, we will use modeling and simulation to estimate intervention effects on the proportion of cases diagnosed, time to TB diagnosis, and projected 10-year TB incidence and mortality. This study will provide randomized yet pragmatic evidence to support the implementation and effectiveness of fea...