OBJECTIVES/SPECIFIC AIMS: 1.Identify barriers to pursuing research for physician trainees 2.Develop a sustainable pipeline of physician-scientists at Duke 3.Coordinate physician-scientist development programs across the School of Medicine under one central Office 4.Provide infrastructure and resources for all physician-scientists 5.Increase the number of MDs and MD/PhDs who pursue, succeed, and are retained in research METHODS/STUDY POPULATION: To establish a baseline understanding of the needs and concerns of physician-scientist trainees at Duke, we conducted focus groups using a standardized interview guide and thematic analysis. Findings from these focus groups were used to develop a framework for support, leading to the creation of the Office of Physician-Scientist Development (OPSD) housed centrally within the Duke School of Medicine. The OPSD integrates programs and resources for multiple populations including medical students, residents, fellows, junior faculty, and faculty mentors. Pipeline programs will also be developed to enhance research engagement in targeted student populations prior to medical school. RESULTS/ANTICIPATED RESULTS: A total of 45 students and faculty participated in the focus groups and structured interviews (1 st year medical student, n=11; 4 th year medical students, n=11; residents/fellows, n=13; junior faculty, n=11). While participants raised a number of specific issues, one key message emerged: non-PhD MDs in basic research felt they lacked opportunities for directed training. Moreover, they felt the need to teach themselves many critical skills through trial and error. This has led to perceptions that they cannot compete effectively with PhDs and MD-PhD scientists for research funding and positions. Consensus recommendations included: better guidance in choosing mentors, labs, and projects; central resource for information relevant to physician scientists; training specifically tailored to physician scientists conducting laboratory-based research; improved infrastructure and well-defined training pathways; and assistance with grant preparation. To-date, over 90 students, residents, and fellows have been identified who identify as laboratory-based physician scientists. Additional efforts are underway to identify and characterize the broader range of physician-scientist students and trainees at Duke. DISCUSSION/SIGNIFICANCE OF IMPACT: Our planning study revealed specific steps forward toward developing a robust community of physician-scientists at Duke. As a first step, the Dean of the School of Medicine has appointed an Associate Dean of Physician-Scientist Development to oversee a new Office of Physician-Scientist Development (OPSD) being launched in December of 2018. The OPSD will offer four primary programs. 1) A concierge mentoring program will assist new trainees in identifying research areas of interest and mentors. Trainees will receive periodic contact to provide additional support as needed and promote success. 2) A physician-scientist training program is being created to provide training specific to laboratory research skills as well as career and professional development training to complement existing clinical and translational research programs. 3) Integrated training pathways will provide additional mentored research training for those pursuing research careers. Pathways will capitalize on existing resources from R38 programs, while pursuing additional R38 and R25 support. 4) An MD-Scientist funding program has been developed to provide additional research funding and protected time for students pursuing a second research year. Through the support and programming offered by the OPSD, we anticipate decreased perceptions of barriers to pursuing a physician-scientist career and increased satisfaction with training opportunities. Over time, we expect such support to increase the number of MD students pursuing research as a career and the number of residents, fellows, and MD junior faculty remaining in research careers.
Heparin-induced thrombocytopenia (HIT) is an immune-mediated thrombocytopenic disorder associated with a severe prothrombotic state. We investigated whether neutrophils and neutrophil extracellular traps (NETs) contribute to the development of thrombosis in HIT. Using an endothelialized microfluidic system and a murine passive immunization model, we show that HIT induction leads to increased neutrophil adherence to venous endothelium. In HIT mice, endothelial adherence is enhanced immediately downstream of nascent venous thrombi, after which neutrophils undergo retrograde migration via a CXCR2-dependent mechanism to accumulate into the thrombi. Using a microfluidic system, we found that PF4 binds to NETs, leading them to become compact and DNase resistant. PF4-NET complexes selectively bind HIT antibodies, which further protect them from nuclease digestion. In HIT mice, inhibition of NET formation through Padi4 gene disruption or DNase treatment limited venous thrombus size. PAD4 inactivation did affect arterial thrombi or severity of thrombocytopenia in HIT. Thus, neutrophil activation contributes to the development of venous thrombosis in HIT by enhancing neutrophil-endothelial adhesion and neutrophil clot infiltration, where incorporated PF4-NET-HIT antibody complexes lead to thrombosis propagation. Inhibition of neutrophil endothelial adhesion, prevention of neutrophil chemokine-dependent recruitment of neutrophils to thrombi, or suppression of NET release should be explored as strategies to prevent venous thrombosis in HIT.
