West Virginia Rural Roots to Research - West Virginia (WV), the only state entirely within Appalachia, has the highest all-cause mortality rate in the nation (2022 data), the highest prevalence of diabetes, obesity, and (by far) the highest drug overdose mortality rate. Yet, WV is among the states with the fewest clinical trials and rural residents (constituting nearly half the population) are consistently underrepresented in clinical studies. We seek to change all of this through implementation of our network, West Virginia Rural Roots to Research (WVR3). The West Virginia Clinical and Translational Research Institute (WVCTSI), will serve as the WVR3 hub, leveraging past experience as a network hub for clinical trials and our long-standing partnership with the West Virginia Practice Based Research Network (WVPBRN). Five clinical trial sites located in rural areas with some of the highest mortality rates in the state have been selected. The overall goal of WVR3 is to expand impactful clinical trials - those that result in WV primary care practice modifications, changes in health behaviors, and ultimately improvement in health outcomes. We will accomplish this goal through the following specific aims. Specific Aim 1. Establish a comprehensive infrastructure that optimizes the efficiency, coordination, and quality of clinical studies. Using implementation science methodology, we will optimize clinical trial performance in WVR3 sites through defining clinic workflows, identifying efficiencies, and incorporating feedback to improve trial implementation processes. Strategies to ease burden on sites and study participants include centralized regulatory support, a mobile clinical trials unit, regionally based research coordinators ( Flex Coordinators), and use of electronic consent and telemedicine. A sitespecific performance dashboard will be established, and a Site Performance Committee will review site performance metrics monthly. Specific Aim 2. Effectively communicate with participating communities - before, during, and after trial implementation. Community forums will be conducted in all WVR3 communities, ensuring that community members have input as to the types of clinical trials that are selected. The community's perspective will guide community education and trial messaging. Specific Aim 3. Ensure trial results positively impact primary care practice. lmpactful clinical studies inform clinical practice when effective collaboration and trusted platforms exist that not only communicate relevant research results to healthcare providers but afford discussion of effective strategies for integrating research findings into medical practice. WVR3 will leverage the Community of Practice that already exists through WVCTSI Project ECHO, an effective platform where primary care providers discuss relevant resu Its, implications of those results, and share best practices for integrating new findings into their clinic, thereby resulting in a sustainable learning health system. Abstract