Faculty Bibliography

INTRODUCTION AND PROBLEM STATEMENT/UNASSIGNED:As the role of teleneurology expands, it is important to prepare trainees to perform virtual encounters proficiently. OBJECTIVES/UNASSIGNED:We created a comprehensive multimodality teleneurology curriculum for residents to teach key aspects of telehealth encounters including the virtual examination and skill development across several environments. METHODS AND CURRICULUM DESCRIPTION/UNASSIGNED:We developed and implemented a teleneurology curriculum focused on teaching the virtual neurologic examination, measuring teleneurology competency, and providing opportunities for trainees to perform telehealth encounters in multiple settings. Residents (N = 22) were first surveyed on what methods would be most helpful to learn teleneurology. Trainees observed a faculty member conducting a teleneurology visit with another faculty member playing a patient. Residents then practiced a teleneurology encounter during a 10-minute objective structured clinical examination (OSCE) at a simulation center. After positive feedback from the fall of 2020, we adapted the OSCE to be completely remote in the spring of 2021 for senior residents. Trainees then performed teleneurology visits during their continuity clinics and subspecialty clinic rotations. RESULTS AND ASSESSMENT DATA/UNASSIGNED:< 0.05) and requested more access to simulations during training. Sensorimotor assessment and adequate visualization of the affected limb were identified as areas for improvement. DISCUSSION AND LESSONS LEARNED/UNASSIGNED:Our multimodal 3-year teleneurology curriculum provides opportunities for residents to learn and apply teleneurology. Survey tools helped strengthen the curriculum to optimize educational potential. We implemented a teleneurology simulation with and without the use of a simulation center. We plan to expand our teleneurology clinical and simulation experiences to trainees based on our data and further developments in teleneurology and to track the progress of teleneurology skills as residents advance through training.

Mitigating the substantial public health impact of concussion is a particularly difficult challenge. This is partly because concussion is a highly prevalent condition, and diagnosis is predominantly symptom-based. Much of contemporary concussion management relies on symptom interpretation and accurate reporting by patients. These types of reports may be influenced by a variety of factors for each individual, such as preexisting mental health conditions, headache disorders, and sleep conditions, among other factors. This can all be contributory to non-specific and potentially misleading clinical manifestations in the aftermath of a concussion. This review aimed to conduct an examination of the existing literature on emerging approaches for objectively evaluating potential concussion, as well as to highlight current gaps in understanding where further research is necessary. Objective assessments of visual and ocular motor concussion symptoms, specialized imaging techniques, and tissue-based concentrations of specific biomarkers have all shown promise for specifically characterizing diffuse brain injuries, and will be important to the future of concussion diagnosis and management. The consolidation of these approaches into a comprehensive examination progression will be the next horizon for increased precision in concussion diagnosis and treatment.

PURPOSE/OBJECTIVE:Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive soft-tissue sarcomas that lack effective treatments, underscoring the urgent need to uncover novel mediators of MPNST pathogenesis that may serve as potential therapeutic targets. Tumor angiogenesis is considered a critical event in MPNST transformation and progression. Here, we have investigated whether endoglin (ENG), a TGF-β coreceptor with a crucial role in angiogenesis, could be a novel therapeutic target in MPNSTs. EXPERIMENTAL DESIGN/METHODS:ENG expression was evaluated in human peripheral nerve sheath tumor tissues and plasma samples. Effects of tumor cell-specific ENG expression on gene expression, signaling pathway activation and in vivo MPNST growth and metastasis were investigated. The efficacy of ENG targeting in monotherapy or in combination with MEK inhibition was analyzed in xenograft models. RESULTS:ENG expression was found to be upregulated in both human MPNST tumor tissues and plasma circulating small extracellular vesicles. We demonstrated that ENG modulates Smad1/5 and MAPK/ERK pathway activation and pro-angiogenic and pro-metastatic gene expression in MPNST cells and plays an active role in tumor growth and metastasis in vivo. Targeting with ENG-neutralizing antibodies (TRC105/M1043) decreased MPNST growth and metastasis in xenograft models by reducing tumor cell proliferation and angiogenesis. Moreover, combination of anti-ENG therapy with MEK inhibition effectively reduced tumor cell growth and angiogenesis. CONCLUSIONS:Our data unveil a tumor-promoting function of ENG in MPNSTs and support the use of this protein as a novel biomarker and a promising therapeutic target for this disease.

This study investigated the individual and combined utility of 10 embedded validity indicators (EVIs) within executive functioning, attention/working memory, and processing speed measures in 585 adults referred for an attention-deficit/hyperactivity disorder (ADHD) evaluation. Participants were categorized into invalid and valid performance groups as determined by scores from empirical performance validity indicators. Analyses revealed that all of the EVIs could meaningfully discriminate invalid from valid performers (AUCs = .69-.78), with high specificity (≥90%) but low sensitivity (19%-51%). However, none of them explained more than 20% of the variance in validity status. Combining any of these 10 EVIs into a multivariate model significantly improved classification accuracy, explaining up to 36% of the variance in validity status. Integrating six EVIs from the Stroop Color and Word Test, Trail Making Test, Verbal Fluency Test, and Wechsler Adult Intelligence Scale-Fourth Edition was as efficacious (AUC = .86) as using all 10 EVIs together. Failing any two of these six EVIs or any three of the 10 EVIs yielded clinically acceptable specificity (≥90%) with moderate sensitivity (60%). Findings support the use of multivariate models to improve the identification of performance invalidity in ADHD evaluations, but chaining multiple EVIs may only be helpful to an extent.

CSF1R-related leukoencephalopathy is an autosomal dominant neurological disorder causing microglial dysfunction with a wide range of neurologic complications, including motor dysfunction, dementia and seizures. This case report highlights an unusual presentation of CSF1R-related leukoencephalopathy with radiographic spinal cord involvement initially diagnosed as multiple sclerosis. The case highlights the importance of considering adult-onset neurogenetic disorders in the setting of white matter disease. Genetic testing provides a confirmatory diagnosis for an expanding number of adult-onset leukoencephalopathies and informs therapeutic decision-making.

STUDY OBJECTIVES/OBJECTIVE:Obstructive sleep apnea (OSA) has been associated with more severe acute coronavirus disease-2019 (COVID-19) outcomes. We assessed OSA as a potential risk factor for Post-Acute Sequelae of SARS-CoV-2 (PASC). METHODS:We assessed the impact of preexisting OSA on the risk for probable PASC in adults and children using electronic health record data from multiple research networks. Three research networks within the REsearching COVID to Enhance Recovery initiative (PCORnet Adult, PCORnet Pediatric, and the National COVID Cohort Collaborative [N3C]) employed a harmonized analytic approach to examine the risk of probable PASC in COVID-19-positive patients with and without a diagnosis of OSA prior to pandemic onset. Unadjusted odds ratios (ORs) were calculated as well as ORs adjusted for age group, sex, race/ethnicity, hospitalization status, obesity, and preexisting comorbidities. RESULTS:Across networks, the unadjusted OR for probable PASC associated with a preexisting OSA diagnosis in adults and children ranged from 1.41 to 3.93. Adjusted analyses found an attenuated association that remained significant among adults only. Multiple sensitivity analyses with expanded inclusion criteria and covariates yielded results consistent with the primary analysis. CONCLUSIONS:Adults with preexisting OSA were found to have significantly elevated odds of probable PASC. This finding was consistent across data sources, approaches for identifying COVID-19-positive patients, and definitions of PASC. Patients with OSA may be at elevated risk for PASC after SARS-CoV-2 infection and should be monitored for post-acute sequelae.

A workshop titled "Beyond the Symptom: The Biology of Fatigue" was held virtually September 27-28, 2021. It was jointly organized by the Sleep Research Society and the Neurobiology of Fatigue Working Group of the NIH Blueprint Neuroscience Research Program. For access to the presentations and video recordings, see: https : //neuroscienceblueprint.nih.gov/about/event/beyond-symptom-biology-fatigue. The goals of this workshop were to bring together clinicians and scientists who use a variety of research approaches to understand fatigue in multiple conditions and to identify key gaps in our understanding of the biology of fatigue. This workshop summary distills key issues discussed in this workshop and provides a list of promising directions for future research on this topic. We do not attempt to provide a comprehensive review of the state of our understanding of fatigue, nor to provide a comprehensive reprise of the many excellent presentations. Rather, our goal is to highlight key advances and to focus on questions and future approaches to answering them.

PURPOSE/OBJECTIVE:To explore whether a machine-learning algorithm could accurately perform the initial screening of medical school applications. METHOD/METHODS:Using application data and faculty screening outcomes from the 2013 to 2017 application cycles (n = 14,555 applications), the authors created a virtual faculty screener algorithm. A retrospective validation using 2,910 applications from the 2013 to 2017 cycles and a prospective validation using 2,715 applications during the 2018 application cycle were performed. To test the validated algorithm, a randomized trial was performed in the 2019 cycle, with 1,827 eligible applications being reviewed by faculty and 1,873 by algorithm. RESULTS:The retrospective validation yielded area under the receiver operating characteristic (AUROC) values of 0.83, 0.64, and 0.83 and area under the precision-recall curve (AUPRC) values of 0.61, 0.54, and 0.65 for the invite for interview, hold for review, and reject groups, respectively. The prospective validation yielded AUROC values of 0.83, 0.62, and 0.82 and AUPRC values of 0.66, 0.47, and 0.65 for the invite for interview, hold for review, and reject groups, respectively. The randomized trial found no significant differences in overall interview recommendation rates according to faculty or algorithm and among female or underrepresented in medicine applicants. In underrepresented in medicine applicants, there were no significant differences in the rates at which the admissions committee offered an interview (70 of 71 in the faculty reviewer arm and 61 of 65 in the algorithm arm; P = .14). No difference in the rate of the committee agreeing with the recommended interview was found among female applicants (224 of 229 in the faculty reviewer arm and 220 of 227 in the algorithm arm; P = .55). CONCLUSIONS:The virtual faculty screener algorithm successfully replicated faculty screening of medical school applications and may aid in the consistent and reliable review of medical school applicants.

Mechanisms of resilience against tau pathology in individuals across the Alzheimer's disease spectrum are insufficiently understood. Longitudinal data are necessary to reveal which factors relate to preserved cognition (i.e. cognitive resilience) and brain structure (i.e. brain resilience) despite abundant tau pathology, and to clarify whether these associations are cross-sectional or longitudinal. We used a longitudinal study design to investigate the role of several demographic, biological and brain structural factors in yielding cognitive and brain resilience to tau pathology as measured with PET. In this multicentre study, we included 366 amyloid-β-positive individuals with mild cognitive impairment or Alzheimer's disease dementia with baseline 18F-flortaucipir-PET and longitudinal cognitive assessments. A subset (n = 200) additionally underwent longitudinal structural MRI. We used linear mixed-effects models with global cognition and cortical thickness as dependent variables to investigate determinants of cognitive resilience and brain resilience, respectively. Models assessed whether age, sex, years of education, APOE-ε4 status, intracranial volume (and cortical thickness for cognitive resilience models) modified the association of tau pathology with cognitive decline or cortical thinning. We found that the association between higher baseline tau-PET levels (quantified in a temporal meta-region of interest) and rate of cognitive decline (measured with repeated Mini-Mental State Examination) was adversely modified by older age (Stβinteraction = -0.062, P = 0.032), higher education level (Stβinteraction = -0.072, P = 0.011) and higher intracranial volume (Stβinteraction = -0.07, P = 0.016). Younger age, higher education and greater cortical thickness were associated with better cognitive performance at baseline. Greater cortical thickness was furthermore associated with slower cognitive decline independent of tau burden. Higher education also modified the negative impact of tau-PET on cortical thinning, while older age was associated with higher baseline cortical thickness and slower rate of cortical thinning independent of tau. Our analyses revealed no (cross-sectional or longitudinal) associations for sex and APOE-ε4 status on cognition and cortical thickness. In this longitudinal study of clinically impaired individuals with underlying Alzheimer's disease neuropathological changes, we identified education as the most robust determinant of both cognitive and brain resilience against tau pathology. The observed interaction with tau burden on cognitive decline suggests that education may be protective against cognitive decline and brain atrophy at lower levels of tau pathology, with a potential depletion of resilience resources with advancing pathology. Finally, we did not find major contributions of sex to brain nor cognitive resilience, suggesting that previous links between sex and resilience might be mainly driven by cross-sectional differences.