Background: Otolaryngologists are among the highest risk for COVID-19 exposure. Methods: This is a cross-sectional, survey-based, national study evaluating academic otolaryngologists. Burnout, anxiety, distress, and depression were assessed by the single-item Mini-Z Burnout Assessment, 7-item Generalized Anxiety Disorder Scale, 15-item Impact of Event Scale, and 2-item Patient Health Questionnaire, respectively. Results: A total of 349 physicians completed the survey. Of them, 165 (47.3%) were residents and 212 (60.7%) were males. Anxiety, distress, burnout, and depression were reported in 167 (47.9%), 210 (60.2%), 76 (21.8%), and 37 (10.6%) physicians, respectively. Attendings had decreased burnout relative

BackgroundIncreasing evidence supports a role for altered gene expression in mediating the lasting effects of cocaine on the brain, and recent work has demonstrated the involvement of chromatin modifications in these alterations. However, all such studies to date have been restricted by their reliance on microarray technologies that have intrinsic limitations.ResultsWe use next generation sequencing methods, RNA-seq and ChIP-seq for RNA polymerase II and several histone methylation marks, to obtain a more complete view of cocaine-induced changes in gene expression and associated adaptations in numerous modes of chromatin regulation in the mouse nucleus accumbens, a key brain reward region. We demonstrate an unexpectedly large number of pre-mRNA splicing alterations in response to repeated cocaine treatment. In addition, we identify combinations of chromatin changes, or signatures, that correlate with cocaine-dependent regulation of gene expression, including those involving pre-mRNA alternative splicing. Through bioinformatic prediction and biological validation, we identify one particular splicing factor, A2BP1(Rbfox1/Fox-1), which is enriched at genes that display certain chromatin signatures and contributes to drug-induced behavioral abnormalities. Together, this delineation of the cocaine-induced epigenome in the nucleus accumbens reveals several novel modes of regulation by which cocaine alters the brain.ConclusionsWe establish combinatorial chromatin and transcriptional profiles in mouse nucleus accumbens after repeated cocaine treatment. These results serve as an important resource for the field and provide a template for the analysis of other systems to reveal new transcriptional and epigenetic mechanisms of neuronal regulation.

TET enzymes mediate the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), which is enriched in brain, and its ultimate demethylation. However, the influence of TET and 5hmC on gene transcription in brain remains elusive. We demonstrate that TET1 is downregulated in nucleus accumbens (NAc), a key brain reward structure, by repeated cocaine administration, which enhances behavioral responses to cocaine. We then identify 5hmC induction in both putative enhancers and coding regions of genes that have pivotal roles in drug addiction. Such induction of 5hmC, which is induced similarly upon TET1 knockdown alone, correlates with increased expression of these genes as well as with their alternative splicing in response to cocaine administration. Additionally, 5hmC alterations at certain loci persist for at least one month after cocaine exposure. Together, these findings reveal a novel epigenetic mechanism of cocaine action, and provide new insight into how 5hmC regulates transcription in brain in vivo.

*These authors contributed equally to this work.In inflammatory central nervous system conditions such as multiple sclerosis, breakdown of the blood-brain barrier is a key event in lesion pathogenesis, predisposing to oedema, excitotoxicity, and ingress of plasma proteins and inflammatory cells. Recently, we showed that reactive astrocytes drive blood-brain barrier opening, via production of vascular endothelial growth factor A (VEGFA). Here, we now identify thymidine phosphorylase (TYMP; previously known as endothelial cell growth factor 1, ECGF1) as a second key astrocyte-derived permeability factor, which interacts with VEGFA to induce blood-brain barrier disruption. The two are co-induced NFB1-dependently in human astrocytes by the cytokine interleukin 1 beta (IL1B), and inactivation of Vegfa in vivo potentiates TYMP induction. In human central nervous system microvascular endothelial cells, VEGFA and the TYMP product 2-deoxy-D-ribose cooperatively repress tight junction proteins, driving permeability. Notably, this response represents part of a wider pattern of endothelial plasticity: 2-deoxy-D-ribose and VEGFA produce transcriptional programs encompassing angiogenic and permeability genes, and together regulate a third unique cohort. Functionally, each promotes proliferation and viability, and they cooperatively drive motility and angiogenesis. Importantly, introduction of either into mouse cortex promotes blood-brain barrier breakdown, and together they induce severe barrier disruption. In the multiple sclerosis model experimental autoimmune encephalitis, TYMP and VEGFA co-localize to reactive astrocytes, and correlate with blood-brain barrier permeability. Critically, blockade of either reduces neurologic deficit, blood-brain barrier disruption and pathology, and inhibiting both in combination enhances tissue preservation. Suggesting importance in human disease, TYMP and VEGFA both localize to reactive astrocytes in multiple sclerosis lesion samples. Collectively, these data identify TYMP as an astrocyte-derived permeability factor, and suggest TYMP and VEGFA together promote blood-brain barrier breakdown.

The United States Medical Licensing Examination Step 1 was implemented in the 1990s as the most recent version of the National Board of Medical Examiners’ preclinical licensing examination originally created in the late 1960s. For the purposes of state licensure, the exam is pass/fail, but the Step 1 numeric score has in recent years become central to the residency application and selection process. Consequently, a medical student’s Step 1 score is increasingly viewed as a key outcome of preclinical medical education. In this Invited Commentary, students from various institutions across the country draw on their shared experiences to argue that the emphasis on Step 1 for residency selection has fundamentally altered the preclinical learning environment, creating a “Step 1 climate.” The authors aim to increase awareness of the harms and unintended consequences of this phenomenon in medical education. They outline how the Step 1 climate negatively impacts education, diversity, and student well-being, and they urge a national conversation on the elimination of reporting Step 1 numeric scores.

Objective: We describe our experience using the extracorporeal video microscope, the “exoscope” for various applications within the field of lateral skull base surgery. Study Design: A retrospective case series was performed investigating patient demographics, indications for surgery, procedure type, operative time, approach to the skull base, complications, adequacy of visualization, and surgeon comfortability. Patients: Six cases were performed with a three dimensional surgical exoscope, obviating the use of a traditional binocular microscope. Setting: Academic, tertiary referral center. Main Outcome Measures: Type of surgical approach, operative time, patient demographics, surgical complications, and surgeon comfortability. Results: The following procedures were performed; four vestibular schwannoma resections via suboccipital craniotomy and two combined transmastoid and transtemporal approaches for temporal lobe encephalocele repairs. The average operative time was 227 and 577 minutes for temporal lobe encephalocele repairs and vestibular schwannoma cases, respectively. No intraoperative complications were encountered during these cases. None of the procedures required abandonment of the exoscope in favor of the microscope during the procedure. Advantages include high-resolution three-dimensional visualization, increased degrees of freedom for exoscope adjustment, and reduced surgeon fatigue in a fixed, unnatural posture. Limitations include decreased depth perception and increased operative time. Conclusion: The exoscope system is a safe and effective alternative or adjunct to the existing binocular operating microscope for lateral skull based procedures. The exoscope provides the surgeon with a comfortable, high-resolution visualization without compromising surgical exposure and patient safety. Level of evidence: 4

Objective Nonphysician health care workers are involved in high-risk patient care during the COVID-19 pandemic, placing them at high risk of mental health burden. The mental health impact of COVID-19 in this crucial population has not been studied thus far. Thus, the objective of this study is to assess the psychosocial well-being of these providers. Study Design National cross-sectional online survey (no control group). Setting Academic otolaryngology programs in the United States. Subjects and Methods We distributed a survey to nonphysician health care workers in otolaryngology departments across the United States. The survey incorporated a variety of validated mental health assessment tools to measure participant burnout (Mini-Z assessment), anxiety (Generalized Anxiety Disorder–7), distress (Impact of Event Scale), and depression (Patient Health Questionnaire–2). Multivariable logistic regression analysis was performed to determine predictive factors associated with these mental health outcomes. Results We received 347 survey responses: 248 (71.5%) nurses, 63 (18.2%) administrative staff, and 36 (10.4%) advanced practice providers. A total of 104 (30.0%) respondents reported symptoms of burnout; 241 (69.5%), symptoms of anxiety; 292 (84.1%), symptoms of at least mild distress; and 79 (22.8%), symptoms of depression. Upon further analysis, development of these symptoms was associated with factors such as occupation, practice setting, and case load. Conclusion Frontline otolaryngology health care providers exhibit high rates of mental health complications, particularly anxiety and distress, in the wake of COVID-19. Adequate support systems must be put into place to address these issues.

Growth factors of the gp130 family promote oligodendrocyte differentiation, and viability, and myelination, but their mechanisms of action are incompletely understood. Here, we show that these effects are coordinated, in part, by the transcriptional activator Krüppel-like factor-6 (Klf6). Klf6 is rapidly induced in oligodendrocyte progenitors (OLP) by gp130 factors, and promotes differentiation. Conversely, in mice with lineage-selective Klf6 inactivation, OLP undergo maturation arrest followed by apoptosis, and CNS myelination fails. Overlapping transcriptional and chromatin occupancy analyses place Klf6 at the nexus of a novel gp130-Klf-importin axis, which promotes differentiation and viability in part via control of nuclear trafficking. Klf6 acts as a gp130-sensitive transactivator of the nuclear import factor importin-α5 (Impα5), and interfering with this mechanism interrupts step-wise differentiation. Underscoring the significance of this axis in vivo, mice with conditional inactivation of gp130 signaling display defective Klf6 and Impα5 expression, OLP maturation arrest and apoptosis, and failure of CNS myelination.