PROJECT SUMMARY This mentored patient-oriented research career development award will prepare the candidate, a pediatric nurse practitioner with doctoral training in tuberculosis (TB) research, to become an independent nurse-scientist with expertise in implementation science. The candidate's long-term goal is to lead interdisciplinary global health research to improve patient and population TB and TB/HIV health outcomes. TB is the leading cause of death in South Africa, where 63% of individuals with TB are co-infected with HIV. As in most high TB burden countries, South Africa has historically focused TB efforts on treating those already sick with TB, while the use of highly effective TB preventive therapy (TPT) has not been widely deployed. Zithulele District Hospital in the Eastern Cape Province is incorporating TPT into its practice through a household- delivered TPT program (King Sabata Dalindyebo district (KSD) Without TB, aka KWIT-TB). This study will provide evidence regarding household-delivered TPT in a rural setting with a high burden of TB. We will measure the reach, implementation, and effectiveness of nurses and community health workers providing screening in households, tests to rule out TB disease, and initiation and completion of TPT. Aim 1 will assess a cascade of care to understand risk factors for failing to screen for TB disease, initiate TPT, and complete TPT. Aim 1 will examine the reach of the KWIT-TB program through the multiple steps of the care cascade. This will provide evidence of what steps to target to optimize TPT programs in the future. Aim 2 will assess the effectiveness of this KWIT-TB program among individuals who complete the full TPT course (six months of daily isoniazid), and examine the role of HIV and anti-retroviral therapy as modifiers of effectiveness. Finally, aim 3 will qualitatively characterize perceptions of eligible TB household contacts on factors influencing initiation and completion of TPT. This aim will provide rich data regarding barriers and facilitators to consider when scaling up TPT efforts in similar settings. The candidate has carefully developed a career trajectory for patient-oriented implementation science, meeting NINR's programmatic priorities to promote health and prevent disease, and to advance nursing science to improve the health and well-being of the world's citizens. This career development plan integrates coursework with practical mentored research to achieve three training goals: (1) develop skills in implementation science, (2) develop expertise in the application of quantitative and qualitative methods in nursing and public health research, and (3) build nursing leadership and managerial skills to lead well- organized, scaled research and clinical trials.