Defining the role of T lymphocytes in the immunopathogenesis of neuromyelitis optica spectrum disorder.

Auto-reactive T cells are fundamental to many autoimmune processes, including neuromyelitis optica spectrum disorder (NMOSD). Several lines of evidence indicate that an antibody against aquaporin-4 (AQP4) is present in NMOSD patients. Further, this AQP4 antibody is pathogenic and can cause profound neurological damage. T cells are fundamental to many autoimmune processes, including NMOSD. Here we review work from animal models to discuss mechanisms by which auto-reactive T cells modulate the process by which antibodies cross the blood-brain barrier and orchestrate the local inflammatory milieu underlying NMOSD pathophysiology. We also examine clinical studies that document the presence of AQP4-specific T cells and the unique cytokine profile of NMOSD patients. This work encourages a renewed and broadened attention to the fundamental role of T cells in neuroautoimmune conditions which will hopefully lead to new therapies and better patients' outcomes.

Cultivating Empathy Through Virtual Reality: Advancing Conversations About Racism, Inequity, and Climate in Medicine.

PROBLEM: Racism and bias are fundamental causes of health inequities, and they negatively affect the climate of academic medical institutions across the United States. APPROACH: In 2019, the Zucker School of Medicine and Northwell Health piloted a virtual reality (VR) racism experience as a component of professional development for medical school and health system leaders, faculty, and staff. Participants experienced a 60-minute, interactive, large-group session on microaggressions and, as individuals, a 20-minute VR module. These were followed by group reflection and debriefing. The sessions, developed in collaboration with a VR academic team, represented a response to institutional climate assessment surveys, which indicated the need for expanded professional training on cross-cultural communication and enhancing inclusion. OUTCOMES: In October 2019, 112 faculty and staff participated in the workshop. On a postworkshop survey, completed by 76 participants (67.9%), most respondents (90.8%) reported feeling engaged in the VR experience. Additionally, the majority agreed that VR was an effective tool for enhancing empathy (94.7%), that the session enhanced their own empathy for racial minorities (85.5%), and that their approach to communication would change (67.1%). In open-ended responses, participants frequently conveyed enthusiasm, powerful emotional and physiologic responses, and enhanced empathy. They also suggested more time for follow-up discussions. NEXT STEPS: Next steps include assessing the scalability of the VR module; determining effective complementary engagements; and measuring the module's longitudinal effects on racial empathy, discrimination, and institutional climate. As VR becomes more common in medical education, developing VR modules to address other forms of discrimination (e.g., sexism, homophobia) could also benefit the institutional climates of medical schools and health systems as academic medicine continues to build toward health equity.

How to Use Cognitively Diagnostic Assessments of Student Performance as a Method for Monitoring and Managing the Instructional Quality in Undergraduate Medical Education.

PURPOSE: Course evaluations by students are a standard tool that U.S. universities use to monitor the quality of their product. Here, the authors examine an alternative method of monitoring instructional quality that differs from traditional approaches in that it does not rely on students' ratings. The authors sought to glean relevant diagnostic information about course effectiveness from in-class exams used to assess students' learning progress (i.e., cognitively diagnostic assessments that explicitly target instructional content). METHOD: The authors used data from an end-of-course, cumulative exam given in 2015 and in 2016 to 200 first-year medical students. They mapped the exam questions to 4 attributes and analyzed the students' overall mastery of the content tested and the percentage of students mastering each attribute. RESULTS: Analyses of the cognitively diagnostic assessment data revealed the percentage of the cohort who achieved/failed to achieve mastery of each of the attributes, discreet mastery profiles that distinguish among students with similar scores, and the percentage of the cohort within each of the 16 attribute mastery profiles. Analysis allowed the authors to evaluate how well the course content was delivered. CONCLUSIONS: Cognitively diagnostic assessments enable in-class tests to appraise which skills specified in the curriculum have/have not been mastered by the students and how many students have mastered/failed to master which particular skills. Hence, if the learning goals have been well defined at the beginning of a course, then cognitively diagnostic assessments can show to what degree the instructional objectives have actually been accomplished.

Advancing drug delivery systems for the treatment of multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system. It is characterized by demyelination of neurons and loss of neuronal axons and oligodendrocytes. In MS, auto-reactive T cells and B cells cross the blood-brain barrier (BBB), causing perivenous demyelinating lesions that form multiple discrete inflammatory demyelinated plaques located primarily in the white matter. In chronic MS, cortical demyelination and progressive axonal transections develop. Treatment for MS can be stratified into disease-modifying therapies (DMTs) and symptomatic therapy. DMTs aim to decrease circulating immune cells or to prevent these cells from crossing the BBB and reduce the inflammatory response. There are currently 10 DMTs approved for the relapsing forms of MS; these vary with regard to their efficacy, route and frequency of administration, adverse effects, and toxicity profile. Better drug delivery systems are being developed in order to decrease adverse effects, increase drug efficacy, and increase patient compliance through the direct targeting of pathologic cells. Here, we address the uses and benefits of advanced drug delivery systems, including nanoparticles, microparticles, fusion antibodies, and liposomal formulations. By altering the properties of therapeutic particles and enhancing targeting, breakthrough drug delivery technologies potentially applicable to multiple disease treatments may rapidly emerge.

Molecular dissection of the eukaryotic initiation factor 4E (eIF4E) export-competent RNP.

The eukaryotic translation initiation factor 4E (eIF4E) controls gene expression through its effects on mRNA export and cap-dependent translation, both of which contribute to its oncogenic potential. In contrast to its translation function, the mRNA export function of eIF4E is poorly understood. Using an RNP isolation/mass spectrometry approach, we identified candidate cofactors of eIF4E mRNA export including LRPPRC. This protein associates with mRNAs containing the eIF4E-sensitivity element (4E-SE), and its overexpression alters the nuclear export of several eIF4E-sensitive mRNAs. LRPPRC-mediated alteration of eIF4E's mRNA export function requires the integrity of its eIF4E-binding site and it coincides with the subcellular re-distribution of eIF4E. The eIF4E export RNP is distinct in composition from the bulk mRNA export pathway, in that eIF4E- and eIF4E-sensitive mRNAs do not associate with general mRNA export factors such as TAP/NXF1 or REF/Aly. Our data indicate that mRNA export pathways have evolved for specific mRNAs enabling the differential regulation of biochemical pathways by modulating the expression of groups of genes at the level of their export.