Moral Elevation, Physician Role Models, and Selected Markers of Professional Identity Formation and Well-Being: A Secondary Analysis from Two National Surveys.

OBJECTIVES: Moral elevation is the underlying emotion that arises when witnessing admirable acts, and it is theorized to be the psychological mechanism driving the impact that positive clinical role models have on medical students' professional identity formation (eg, growth in professional virtues, higher sense of meaning, and well-being). This proof-of-concept study explores the development of the Moral Elevation Scale in Medicine by testing the association of moral elevation with various markers of professional identity formation. METHODS: A secondary data analysis of two nationally representative samples of 960 medical students and 2000 physicians was performed. Respondents completed validated measures of moral elevation as well as markers of professional identity formation, including patient-centered virtues (empathic compassion, interpersonal generosity, mindfulness) and measures of well-being (life meaning, life satisfaction, spirituality, burnout). RESULTS: The study obtained adjusted response rates of 56.2% (1047/1863, physician survey) and 48.7% (448/919, student survey). The national estimates for mean moral elevation in medical students and physicians are 4.34/5.00 and 4.22/5.00, respectively. In medical students and physicians, high moral elevation was associated with higher empathic compassion (student odds ratio [OR] 1.30, 95% confidence interval [CI] 1.02-1.67; physician OR 1.22, 95% CI 1.23-1.65) and, similarly, generosity. In addition, higher moral elevation in the physician cohort was associated with greater life meaning (OR 2.03, 95% CI 1.25-3.32) and similarly spirituality. CONCLUSIONS: In medical students and practicing physicians, self-reported experiences of high moral elevation with physician role models were associated with higher self-reported measures of patient-centered virtues, spirituality, and life meaning. Our Moral Elevation Scale in Medicine demonstrates preliminary promise as a measure to assess environmental precursors needed for virtue development in professional identity formation, but further reliability and validity testing of this measure is needed.

Vincristine and bortezomib use distinct upstream mechanisms to activate a common SARM1-dependent axon degeneration program.

Chemotherapy-induced peripheral neuropathy is one of the most prevalent dose-limiting toxicities of anticancer therapy. Development of effective therapies to prevent chemotherapy-induced neuropathies could be enabled by a mechanistic understanding of axonal breakdown following exposure to neuropathy-causing agents. Here, we reveal the molecular mechanisms underlying axon degeneration induced by 2 widely used chemotherapeutic agents with distinct mechanisms of action: vincristine and bortezomib. We showed previously that genetic deletion of SARM1 blocks vincristine-induced neuropathy and demonstrate here that it also prevents axon destruction following administration of bortezomib in vitro and in vivo. Using cultured neurons, we found that vincristine and bortezomib converge on a core axon degeneration program consisting of nicotinamide mononucleotide NMNAT2, SARM1, and loss of NAD+ but engage different upstream mechanisms that closely resemble Wallerian degeneration after vincristine and apoptosis after bortezomib. We could inhibit the final common axon destruction pathway by preserving axonal NAD+ levels or expressing a candidate gene therapeutic that inhibits SARM1 in vitro. We suggest that these approaches may lead to therapies for vincristine- and bortezomib-induced neuropathies and possibly other forms of peripheral neuropathy.

Gene therapy targeting SARM1 blocks pathological axon degeneration in mice.

Axonal degeneration (AxD) following nerve injury, chemotherapy, and in several neurological disorders is an active process driven by SARM1, an injury-activated NADase. Axons of SARM1-null mice exhibit greatly delayed AxD after transection and in models of neurological disease, suggesting that inhibiting SARM1 is a promising strategy to reduce pathological AxD. Unfortunately, no drugs exist to target SARM1. We, therefore, developed SARM1 dominant-negatives that potently block AxD in cellular models of axotomy and neuropathy. To assess efficacy in vivo, we used adeno-associated virus-mediated expression of the most potent SARM1 dominant-negative and nerve transection as a model of severe AxD. While axons of vehicle-treated mice degenerate rapidly, axons of mice expressing SARM1 dominant-negative can remain intact for >10 d after transection, similar to the protection observed in SARM1-null mice. We thus developed a novel in vivo gene therapeutic to block pathological axon degeneration by inhibiting SARM1, an approach that may be applied clinically to treat manifold neurodegenerative diseases characterized by axon loss.