Project Summary Tuberculosis (TB) remains a global health emergency, responsible for 10 million new cases in 2021. Despite the global community's extensive effort to identify TB cases, 30% of the new cases were never diagnosed. Current efforts focus on active case finding of TB which is expensive and difficult to implement in practice. One approach that can address the challenges is self-testing. Self-testing for TB has not been widely implemented to date, due in part to a lack of appropriate testing modalities and studies evaluating this approach. However, recent advances in diagnostic tools make self-testing a realistic possibility, opening a new door for patient-centered TB care. I propose a type 3 hybrid implementation-effectiveness study to evaluate the feasibility of implementing self- testing for active TB. I will apply a currently available diagnostic tool – oral swab specimens for Xpert Ultra (which are easy to self-collect and highly sensitive but require shipping to a laboratory). I will first identify barriers to the implementation of TB self-testing and refine the implementation strategies to address these barriers by using qualitative interviews and quantitative surveys (Aim 1). I will then perform a prospective study in six high-risk occupational settings in South Africa, where working-age individuals are known to rarely seek care, placing oral swab kits in three interventional sites and maintaining the standard of care in three control sites (Aim 2). I will evaluate the implementation and effectiveness of each strategy guided by the Reach, Effectiveness, Adopt, Implementation, and Maintenance (RE-AIM) framework. My primary outcome will be an increase in the proportion of individuals receiving microbiological testing results, reflecting the acceptability and fidelity of TB self-testing. To achieve the aims, I will use a highly pragmatic study design in which the study team minimizes contact with the study sites. This will enable me to evaluate whether the implementation of TB self-testing is likely to impact case finding and improve working-aged individuals’ health outcomes in a “real world” setting. Completion of this study will generate pragmatic, preliminary data on the potential implementation and effectiveness of TB self-testing in high-burden settings, which if successful will justify a larger trial and if not will inform alternative approaches to overcoming barriers to seeking care for TB. In either case, these findings will motivate a larger R01 proposal at the end of the five-year grant period and advance the field of TB self-testing. While this proposal will evaluate self-testing using an available tool, a broader goal is to conceptualize the self- testing strategy in TB disease that will be applicable to future tools, thus representing a step toward improving patient-initiated or patient-centered TB care. The study will also serve as a vehicle for me to acquire skills in mixed methods study and implementation science, po...