Faculty Bibliography

Recurrent episodes of neurological dysfunction and white matter lesions in a young adult raise suspicion for multiple sclerosis (MS). However, occlusive retinopathy, hearing loss and absence of CSF oligoclonal bands are atypical for MS and should make the clinician consider an alternative diagnosis. We describe a man with hearing loss, visual signs and symptoms, and an accumulating burden of brain lesions, who was treated for a clinical diagnosis of MS for nearly two decades. Genetic testing revealed a unifying diagnosis.

BACKGROUND:The COVID-19 pandemic led to profound changes in the organization of health care systems worldwide. AIMS/OBJECTIVE:We sought to measure the global impact of the COVID-19 pandemic on the volumes for mechanical thrombectomy (MT), stroke, and intracranial hemorrhage (ICH) hospitalizations over a 3-month period at the height of the pandemic (March 1 to May 31, 2020) compared with two control 3-month periods (immediately preceding and one year prior). METHODS:Retrospective, observational, international study, across 6 continents, 40 countries, and 187 comprehensive stroke centers. The diagnoses were identified by their ICD-10 codes and/or classifications in stroke databases at participating centers. RESULTS:The hospitalization volumes for any stroke, ICH, and MT were 26,699, 4,002, and 5,191 in the 3 months immediately before versus 21,576, 3,540, and 4,533 during the first 3 pandemic months, representing declines of 19.2% (95%CI,-19.7 to -18.7), 11.5% (95%CI,-12.6 to -10.6), and 12.7% (95%CI,-13.6 to -11.8), respectively. The decreases were noted across centers with high, mid, and low COVID-19 hospitalization burden, and also across high, mid, and low volume stroke/MT centers. High-volume COVID-19 centers (-20.5%) had greater declines in MT volumes than mid- (-10.1%) and low-volume (-8.7%) centers (p<0.0001). There was a 1.5% stroke rate across 54,366 COVID-19 hospitalizations. SARS-CoV-2 infection was noted in 3.9% (784/20,250) of all stroke admissions. CONCLUSION/CONCLUSIONS:The COVID-19 pandemic was associated with a global decline in the volume of overall stroke hospitalizations, MT procedures, and ICH admission volumes. Despite geographic variations, these volume reductions were observed regardless of COVID-19 hospitalization burden and pre-pandemic stroke/MT volumes.

The purpose of this investigation was to determine the effects of vocal training on neuromuscular junction (NMJ) morphology and muscle fiber size and composition in the thyroarytenoid muscle, the primary muscle in the vocal fold, in younger (9-month) and older (24-month) Fischer 344 × Brown Norway male rats. Over 4 or 8 weeks of vocal training, rats of both ages progressively increased their daily number of ultrasonic vocalizations (USVs) through operant conditioning and were then compared to an untrained control group. Neuromuscular junction morphology and myofiber size and composition were measured from the thyroarytenoid muscle. Acoustic analysis of USVs before and after training quantified the functional effect of training. Both 4- and 8-week training resulted in less NMJ motor endplate dispersion in the lateral portion of the thyroarytenoid muscle in rats of both ages. Vocal training and age had no significant effects on laryngeal myofiber size or type. Vocal training resulted in a greater number of USVs with longer duration and increased intensity. This study demonstrated that vocal training induces laryngeal NMJ morphology and acoustic changes. The lack of significant effects of vocal training on muscle fiber type and size suggests vocal training significantly improves neuromuscular efficiency but does not significantly influence muscle strength changes.

Oral squamous cell carcinoma (OSCC) is one of the most painful cancers, which interferes with orofacial function including talking and eating. We report that legumain (Lgmn) cleaves protease-activated receptor-2 (PAR₂) in the acidic OSCC microenvironment to cause pain. Lgmn is a cysteine protease of late endosomes and lysosomes that can be secreted; it exhibits maximal activity in acidic environments. The role of Lgmn in PAR₂-dependent cancer pain is unknown. We studied Lgmn activation in human oral cancers and oral cancer mouse models. Lgmn was activated in OSCC patient tumors, compared to matched normal oral tissue. After intraplantar, facial or lingual injection, Lgmn evoked nociception in wild-type (WT) female mice but not in female mice lacking PAR₂ in Na_V1.8-positive neurons (Par₂Na_v1.8), nor in female mice treated with a Lgmn inhibitor, LI-1. Inoculation of an OSCC cell line caused mechanical and thermal hyperalgesia that was reversed by LI-1. Par₂Na_v1.8 and Lgmn deletion attenuated mechanical allodynia in female mice with carcinogen-induced OSCC. Lgmn caused PAR₂-dependent hyperexcitability of trigeminal neurons from WT female mice. Par₂ deletion, LI-1 and inhibitors of adenylyl cyclase or protein kinase A prevented the effects of Lgmn. Under acidified conditions, Lgmn cleaved within the extracellular N-terminus of PAR₂ at Asn³⁰↓Arg³¹, proximal to the canonical trypsin activation site. Lgmn activated PAR₂ by biased mechanisms in HEK293 cells to induce Ca²⁺ mobilization, cAMP formation and protein kinase A/D activation, but not β-arrestin recruitment or PAR₂ endocytosis. Thus, in the acidified OSCC microenvironment Lgmn activates PAR₂ by biased mechanisms that evoke cancer pain.SIGNIFICANCE STATEMENTOral squamous cell carcinoma (OSCC) is one of the most painful cancers. We report that legumain (Lgmn), which exhibits maximal activity in acidic environments, cleaves protease-activated receptor-2 (PAR₂) on neurons to produce OSCC pain. Active Lgmn was elevated in OSCC patient tumors, compared to matched normal oral tissue. Lgmn evokes pain-like behavior through PAR₂ Exposure of pain-sensing neurons to Lgmn decreased the current required to generate an action potential through PAR₂ Inhibitors of adenylyl cyclase and protein kinase A prevented the effects of Lgmn. Lgmn activated PAR₂ to induce calcium mobilization, cAMP formation and activation of protein kinase D and A, but not β-arrestin recruitment or PAR₂ endocytosis. Thus, Lgmn is a biased agonist of PAR₂ that evokes cancer pain.

OBJECTIVE:To develop an expert consensus statement on pediatric drug-induced sleep endoscopy (DISE) that clarifies controversies and offers opportunities for quality improvement. Pediatric DISE was defined as flexible endoscopy to examine the upper airway of a child with obstructive sleep apnea who is sedated and asleep. METHODS:Development group members with expertise in pediatric DISE followed established guidelines for developing consensus statements. A search strategist systematically reviewed the literature, and the best available evidence was used to compose consensus statements regarding DISE in children 0 to 18 years old. Topics with significant practice variation and those that would improve the quality of patient care were prioritized. RESULTS:The development group identified 59 candidate consensus statements, based on 50 initial proposed topics, that focused on addressing the following high-yield topics: (1) indications and utility, (2) protocol, (3) optimal sedation, (4) grading and interpretation, (5) complications and safety, and (6) outcomes for DISE-directed surgery. After 2 iterations of the Delphi survey and removal of duplicative statements, 26 statements met the criteria for consensus; 11 statements were designated as no consensus. Several areas, such as the role of DISE at the time of adenotonsillectomy, were identified as needing further research. CONCLUSION/CONCLUSIONS:Expert consensus was achieved for 26 statements pertaining to indications, protocol, and outcomes for pediatric DISE. Clinicians can use these statements to improve quality of care, inform policy and protocols, and identify areas of uncertainty. Future research, ideally randomized controlled trials, is warranted to address additional controversies related to pediatric DISE.

OBJECTIVES/OBJECTIVE:To describe patterns of primary surgical treatments in patients with T4b oral cavity squamous cell carcinoma (OCSCC). STUDY DESIGN/METHODS:Historical cohort study. SETTING/METHODS:National Cancer Database. METHODS:Review of the National Cancer Database between 2004 and 2017 for all T4b OCSCCs. Only patients with curative treatment methods were included in the survival analysis. Surgical and nonsurgical outcomes were compared by multivariable and propensity score matching analysis. RESULTS:= .20). CONCLUSIONS:A minority of patients with T4b OCSCC undergo treatments with curative intent. A subset of patients underwent primary surgical treatment, which was associated with longer survival. The T4b classification might entail a heterogenous group, and further studies in revision of this classification might be justified.

PIM1 is a serine/threonine kinase that promotes and maintains prostate tumorigenesis. While PIM1 protein levels are elevated in prostate cancer relative to local disease, the mechanisms by which PIM1 contributes to oncogenesis have not been fully elucidated. Here, we performed a direct, unbiased chemical genetic screen to identify PIM1 substrates in prostate cancer cells. The PIM1 substrates we identified were involved in a variety of oncogenic processes, and included N-Myc Downstream-Regulated Gene 1 (NDRG1), which has reported roles in suppressing cancer cell invasion and metastasis. NDRG1 is phosphorylated by PIM1 at serine 330 (pS330), and the level of NDRG1 pS330 is associated higher grade prostate tumors. We have shown that PIM1 phosphorylation of NDRG1 at S330 reduced its stability, nuclear localization, and interaction with AR, resulting in enhanced cell migration and invasion.

The reasons why clinical outcomes with auditory brainstem implants (ABIs) are generally poorer than with cochlear implants (CIs) are still somewhat elusive. Prior work has focused on differences in processing of spectral information due to possibly poorer tonotopic representation and higher channel interaction with ABIs than with CIs. In contrast, this study examines the hypothesis that a potential contributing reason for poor speech perception in ABI users may be the relative lack of temporal responsiveness of the primary neurons that are stimulated by the ABI. The cochlear nucleus, the site of ABI stimulation, consists of different neuron types, most of which have much more complex responses than the auditory nerve neurons stimulated by a CI. Temporal responsiveness of primary stimulated neurons was assessed in a group of ABI and CI users by measuring recovery of electrically evoked compound action potentials (ECAPs) from single-pulse forward masking. Slower ECAP recovery tended to be associated with poorer hearing outcomes in both groups. ABI subjects with the longest recovery time had no speech understanding or even no hearing sensation with their ABI device; speech perception for the one CI outlier with long ECAP recovery time was well below average. To the extent that ECAP recovery measures reveal temporal properties of the primary neurons that receive direct stimulation form neural prosthesis devices, they may provide a physiological underpinning for clinical outcomes of auditory implants. ECAP recovery measures may be used to determine which portions of the cochlear nucleus to stimulate, and possibly allow us to enhance the stimulation paradigms.

BACKGROUND:The misuse and abuse of opioids, including overprescription, has led to the current opioid epidemic and national crisis. There is a national effort to eliminate the unnecessary prescription of opioids for analgesia. METHODS:Seventy patients were randomized to receive postoperative analgesia with either 5 mg hydrocodone with 325 mg acetaminophen (opioid control group) or 400 mg of ibuprofen [nonsteroidal antiinflammatory drug (NSAID) experimental group]. Pain levels were assessed on postoperative days 1, 2, and 7. Outcome measures included numeric pain rating scores and assessments of frequency and amount of analgesic used. RESULTS:There was no significant difference in gender (p = 0.81) or age (p = 0.61) between groups. On postoperative day 0, the NSAID group (mean ± SD, 2.54 ± 1.57) was found to be noninferior to the opioid group (mean ± SD, 3.14 ± 1.75; p = 0.003). On postoperative day 1, the NSAID group showed a lower mean pain score (mean ± SD, 1.84 ± 1.29) than the opioid group (mean ± SD, 2.46 ± 1.90; p = 0.01). However, on postoperative day 7, the difference in pain scores between the NSAID (mean ± SD, 3.29 ± 2.14) and opioid (mean ± SD, 3.14 ± 2.12; p = 0.17) groups lost statistical significance. There was no significant difference in mean day of medication cessation between the NSAID (mean ± SD, 4.73 ± 1.57) and opioid (mean ± SD, 4.28 ± 2.23; p = 0.26) groups. Seventy-six percent of patients who were prescribed opioids took fewer than eight tablets. Five patients escalated from NSAIDs to opioids. There were no adverse effects related to NSAID use. CONCLUSIONS:NSAIDs are an acceptable and safe alternative to opioids for postoperative analgesia in rhinoplasty and potentially lead to better overall pain control in some patients. Significantly reducing or eliminating opioid prescriptions may be considered in light of the current opioid epidemic. CLINICAL QUESTION/LEVEL OF EVIDENCE/METHODS:Therapeutic, II.

Purpose of Review: Most thyroid nodules are benign and asymptomatic; however, some will ultimately cause compressive symptoms or develop autonomous function. Radiofrequency ablation (RFA) has emerged as a novel treatment option in lieu of other minimally invasive ablative techniques. This article discusses the role of RFA in the management of benign thyroid nodules and reviews recent literature comparing outcomes between RFA, surgery, and medical therapy. Recent Findings: Multiple studies have demonstrated the safety and efficacy of RFA in the treatment of autonomously functioning thyroid nodules (AFTN) and symptomatic, cold nodules (SCN). The "moving shot" technique has proven successful in normalizing thyroid function for ATFNs and decreasing cosmetic/symptomatic concerns for SCNs after a single treatment. Summary: Radiofrequency ablation is a viable treatment option for the treatment of AFTNs and SCNs in patients who refuse or are otherwise unable to tolerate surgery. Patient selection is critical and performance at high-volume centers is necessary for best outcomes.