PROJECT SUMMARY/ABSTRACT In many settings worldwide, harmful substance use coincides with other epidemics of communicable and non- communicable disease. Merrill Singer first theorized in 1996 the concept of a “syndemic”, which manifests when epidemics co-occur, are driven by harmful social conditions, and synergistically interact to amplify the burden of disease. The theory of syndemics has gained significant traction in the field, but existing empirical work has been criticized on both conceptual and empirical grounds. Until this gap in the literature is filled, efforts to develop clinical and structural interventions to reduce harmful substance use will remain limited. The objective of this K24 application is to characterize the syndemic of polysubstance use, HIV, and other communicable and non-communicable diseases among participants in the MACS/WIHS Combined Cohort Study, while enhancing the applicant's mentorship skills and expanding his capacity to provide mentorship to more Early-Stage Investigators seeking to conduct patient-oriented research on substance use-associated syndemics. The rationale for submitting this K24 application at this time is that the applicant's funding follows an academic physician-scientist “soft money” model, and new leadership roles have increased the number of prospective trainees seeking his research mentorship. Three specific aims will be achieved: Aim 1—Mentoring: The applicant will create a novel research mentoring program and expand his mentoring portfolio by providing mentorship in the conduct of patient-oriented research on substance use-associated syndemics to 3–5 additional Early-Stage Investigators, per year. Aim 2—Career Development: The applicant will undertake new training in the estimation of psychological symptom networks and simulation modeling, while building his skills as a mentor by completing courses informed by validated curricula in mentoring science. Aim 3—Research: Novel methods developed for the estimation of psychological symptom networks will be used to characterize the syndemic of polysubstance use, HIV, and other communicable and non-communicable diseases among participants in the MACS/WIHS Combined Cohort Study. Simulation modeling will be used to identify the most effective hypothetical clinical and structural intervention strategies for addressing the syndemic. The key significance and innovation of this proposal is its novel application of methods to characterize substance use- associated syndemics and to identify concrete strategies for intervention. If this K24 is awarded, the expected contribution is that the applicant will be able to fulfill a greater proportion of current requests for mentorship; make fundamental contributions to resolve longstanding challenges in understanding substance use- associated syndemics, leading to novel strategies for clinical and structural intervention; and use the K24- supported research studies as training vehicles for junior investigators inte...