CSF1R inhibition depletes brain macrophages and reduces brain virus burden in SIV-infected macaques.

Perivascular macrophages (PVMs) and, to a lesser degree, microglia are targets and reservoirs of HIV and simian immunodeficiency virus (SIV) in the brain. Previously, we demonstrated that colony-stimulating factor 1 receptor (CSF1R) in PVMs was upregulated and activated in chronically SIV-infected rhesus macaques with encephalitis, correlating with SIV infection of PVMs. Herein, we investigated the role of CSF1R in the brain during acute SIV infection using BLZ945, a brain-penetrant CSF1R kinase inhibitor. Apart from three uninfected historic controls, nine Indian rhesus macaques were infected acutely with SIVmac251 and divided into three groups (n = 3 each): an untreated control and two groups treated for 20-30 days with low- (10 mg/kg/day) or high- (30 mg/kg/day) dose BLZ945. With the high-dose BLZ945 treatment, there was a significant reduction in cells expressing CD163 and CD206 across all four brain areas examined, compared with the low-dose treatment and control groups. In 9 of 11 tested regions, tissue viral DNA (vDNA) loads were reduced by 95%-99% following at least one of the two doses, and even to undetectable levels in some instances. Decreased numbers of CD163+ and CD206+ cells correlated significantly with lower levels of vDNA in all four corresponding brain areas. In contrast, BLZ945 treatment did not significantly affect the number of microglia. Our results indicate that doses as low as 10 mg/kg/day of BLZ945 are sufficient to reduce the tissue vDNA loads in the brain with no apparent adverse effect. This study provides evidence that infected PVMs are highly sensitive to CSF1R inhibition, opening new possibilities to achieve viral clearance.

Exploring Impostor Phenomenon During Onboarding Into a Military Medical School.

INTRODUCTION: Impostor phenomenon (IP) is an experience where an individual believes that their success was because of chance or luck and was not associated with the mastery of skills. There is a gap in the literature in understanding what role, if any, onboarding (e.g., orientation weeks) into a military medical school plays into student experiences with IP. For many, onboarding serves as the first exposure to the climate, culture, and learning environment of both medical school and the military. Prevention, or early intervention, of IP may reduce potential effects on a medical trainee's confidence and competence in their profession, which may ultimately enhance health care team performance and impact patient outcomes. This study explores if and why military medical students experience IP during a 2-week-long orientation into a military medical school. MATERIALS AND METHODS: The study participants were medical students at a military medical school. Researchers conducted semi-structured interviews in August 2022 to explore if and why students experienced IP and deployed the Clance IP Scale as a measure with validity evidence for ascertaining the presence and magnitude of IP. Researchers calculated total scores from the Clance IP Scale and thematically analyzed interview transcripts. RESULTS: Researchers interviewed 29 matriculating military medical students. Twenty-one (75%) students reported frequent or intense IP experiences on the Clance IP Scale indicating that IP was present in our study sample. Thematic analysis identified six themes that drove one's experience with IP: reevaluation of merit, individualized diversity and inclusion experiences, administrative and financial support, preconceived expectations, building relationships, and new community roles. CONCLUSIONS: Our identified themes provide us with a better understanding of if and why military medical students experience IP during onboarding. Our findings are also consistent with the situated learning theory, which places emphasis on the sense of belonging and may provide a unique and insightful lens through which IP can be further explored and studied, particularly at a military medical school where various identities, dynamics, and aspirations can converge simultaneously. Additionally, our findings suggest that existing practices may benefit from a number of improvements including, but not limited to, tailoring onboarding activities to entail more reflective discussion using small groups, especially for topics related to diversity and inclusion, revisiting areas where students may feel inadequately prepared to transition and perform well in a medical school, reevaluating administrative and financial support that can be roadblocks to a student's transition into the new environment and removing these barriers, and ensuring cultural coherence (organizational alignment of vision and mission) among faculty, staff, and upperclassmen. Future research directions include better understanding how developing single or multiple, identities can impact a medical students' experience with IP during onboarding, pre-clerkship, clerkship, or post-clerkship period, if at all.