Faculty Bibliography

OBJECTIVES/UNASSIGNED:Removal of a cochlear implant and its intracochlear electrode array is sometimes necessary, potentially causing cochlear explant trauma. Explantation typically occurs years post-implantation by which time reactive tissue has formed around the electrode. We aimed to create an in-vitro electrode explant model to examine explant forces and intracochlear trauma across multiple electrode types and insertion depths. STUDY DESIGN/UNASSIGNED:An in-vitro model using gel to represent tissue surrounding the electrode was developed. Pre-curved electrodes and straight electrodes at different insertion depths (20mm, 25mm, 28mm) were explanted from the model. During explantation, explant force was measured, and high-definition videos were recorded to capture electrode exit path and gel disruption. RESULTS/UNASSIGNED:Explant force patterns varied based on electrode position in the scala tympani. Explant forces did not correlate with gel disruption, which represented explant trauma. The least gel disruption occurred with pre-curved electrodes and the under-inserted straight electrode. The greatest disruption occurred with the overly inserted straight electrode. CONCLUSION/UNASSIGNED:An in-vitro model using gel to mimic tissue surrounding the electrode may provide insights into potential electrode explant trauma. Explant force did not correlate with explant trauma in our model. Pre-curved electrodes and shallower insertion depth of a straight electrode resulted in the least amount of explant trauma.

OBJECTIVES/OBJECTIVE:Age of cochlear implantation (CI) is an important predictor of language development in those with congenital sensorineural hearing loss. Despite universal newborn hearing screening initiatives and the known benefits of early CI, a subset of congenitally deaf children continue to be evaluated for cochlear implants later in childhood. This study aims to identify the barriers to early cochlear implantation in these children. METHODS:A retrospective review was conducted for all pediatric cochlear implants aged 3 years or older performed at a single academic institution between 2013 and 2017. Children implanted before the age three, those with a prior unilateral cochlear implant, and those with progressive or sudden hearing loss were excluded. Variables included newborn hearing screen results, age at hearing loss diagnosis, time of initiation and documented benefit of hearing aids, age of implantation, pre/post-implantation evaluation scores, and reason for delayed referral for cochlear implantation. RESULTS:Thirty-one patients were identified meeting these inclusion criteria. Twenty-one children were subject to UNBS in the U.S. Fourteen of those children failed their newborn hearing screening. Average age at implantation was 6.2 years. Four reasons were identified for increased age at cochlear implantation. Two categories represent delays related to (1) Amplification continually prescribed even though the range of hearing loss and speech development assessment suggests CI may have been more appropriate well before referral (N = 13) (2) Patients were not subject to newborn hearing screening and/or timely diagnosis of their hearing loss (N = 8). In other cases, patients were appropriately fit with hearing aids until evidence that they derived limited benefit and then referred for CI (N = 8). Lastly, in a few cases, records were indeterminate with regards to the timing and appropriate diagnosis of their hearing loss (N = 2). CONCLUSION/CONCLUSIONS:Understanding the reasons for delayed cochlear implantation in congenitally deaf children might allow the development of targeted interventions to improve outcomes. Specifically, those children who were not referred before age 3 despite use of amplification with limited benefit offer one potential target population for earlier CI.

This article summarizes the available evidence on pediatric cochlear implantation to provide current guidelines for clinical protocols and candidacy recommendations in the United States. Candidacy determination involves specification of audiologic and medical criteria per guidelines of the Food and Drug Administration. However, recommendations for a cochlear implant evaluation also should maintain flexibility and consider a child's skill progression (i.e., month-for-month progress in speech, language, and auditory development) and quality of life with appropriately fit hearing aids. Moreover, evidence supports medical and clinical decisions based on other factors, including (a) ear-specific performance, which affords inclusion of children with asymmetric hearing loss and single-sided deafness as implant candidates; (b) ear-specific residual hearing, which influences surgical technique and device selection to optimize hearing; and (c) early intervention to minimize negative long-term effects on communication and quality of life related to delayed identification of implant candidacy, later age at implantation, and/or limited commitment to an audiologic rehabilitation program. These evidence-based guidelines for current clinical protocols in determining pediatric cochlear implant candidacy encourage a team-based approach focused on the whole child and the family system.

OBJECTIVES/HYPOTHESIS/OBJECTIVE:To create a model of the anatomic distribution, recurrence, and growth patterns of recurrent respiratory papillomatosis (RRP). STUDY DESIGN/METHODS:Prospective, multi-institutional cohort study. METHODS:Adult patients with a diagnosis of RRP evaluated between August 1, 2018 and February 1, 2021 at six participating centers were invited to enroll. At each office or operating room encounter, laryngologists recorded the location and size of RRP lesions using a 22-region schematic. A generalized linear mixed effects model was used to compare region variations in lesion prevalence and recurrence. RESULTS:The cohort comprised 121 patients: 74% were male, 81% had been diagnosed with adult-onset RRP, and a plurality (34%) had undergone 0 to 3 RRP interventions prior to enrollment. Across the study period, the odds of a lesion occurring in the glottis was significantly higher (odds ratio [OR]: 26.51; 95% confidence interval [CI]: 11.76-59.75, P < .001) compared with all other areas of the larynx and trachea. Within the true vocal folds, the membranous vocal folds had significantly higher odds (OR: 6.16; 95% CI: 2.66-14.30, P < .001) of lesion occurrence compared to the cartilaginous vocal folds. Despite these strong trends in lesion distribution, there were no differences in the odds of lesion recurrence, growth, or in the time to recurrence, between anatomic subsites. CONCLUSIONS:RRP lesions are most likely to occur in the glottis, particularly the membranous vocal folds, compared with other regions of the larynx or trachea. However, all lesions demonstrate similar behavior with respect to recurrence, growth, and time to recurrence regardless of anatomic location. LEVEL OF EVIDENCE/METHODS:3 Laryngoscope, 2022.

The aim of this multicenter retrospective study is to characterize the histopathologic features of initial/early biopsies of proliferative leukoplakia (PL; also known as proliferative verrucous leukoplakia), and to analyze the correlation between histopathologic features and malignant transformation (MT). Patients with a clinical diagnosis of PL who have at least one biopsy and one follow-up visit were included in this study. Initial/early biopsy specimens were reviewed. The biopsies were evaluated for the presence of squamous cell carcinoma (SCCa), oral epithelial dysplasia (OED), and atypical verrucous hyperplasia (AVH). Cases that lacked unequivocal features of dysplasia were termed "hyperkeratosis/parakeratosis not reactive (HkNR)". Pearson chi-square test and Wilcoxon test were used for statistical analysis. There were 86 early/initial biopsies from 59 patients; 74.6% were females. Most of the cases had a smooth/homogenous (34.8%) or fissured appearance (32.6%), and only 13.0% had a verrucous appearance. The most common biopsy site was the gingiva/alveolar mucosa (40.8%) and buccal mucosa (25.0%). The most common histologic diagnosis was OED (53.5%) followed by HkNR (31.4%). Of note, two-thirds of HkNR cases showed only hyperkeratosis and epithelial atrophy. A lymphocytic band was seen in 34.8% of OED cases and 29.6% of HkNR cases, mostly associated with epithelial atrophy. Twenty-eight patients (47.5%) developed carcinoma and 28.9% of early/initial biopsy sites underwent MT. The mortality rate was 11.9%. Our findings show that one-third of cases of PL do not show OED with most exhibiting hyperkeratosis and epithelial atrophy, but MT nevertheless occurred at such sites in 3.7% of cases.

Efficacy of monoclonal antibodies against calcitonin gene-related peptide (CGRP) or its receptor (calcitonin receptor-like receptor/receptor activity modifying protein-1, CLR/RAMP1) implicates peripherally-released CGRP in migraine pain. However, the site and mechanism of CGRP-evoked peripheral pain remain unclear. By cell-selective RAMP1 gene deletion, we reveal that CGRP released from mouse cutaneous trigeminal fibers targets CLR/RAMP1 on surrounding Schwann cells to evoke periorbital mechanical allodynia. CLR/RAMP1 activation in human and mouse Schwann cells generates long-lasting signals from endosomes that evoke cAMP-dependent formation of NO. NO, by gating Schwann cell transient receptor potential ankyrin 1 (TRPA1), releases ROS, which in a feed-forward manner sustain allodynia via nociceptor TRPA1. When encapsulated into nanoparticles that release cargo in acidified endosomes, a CLR/RAMP1 antagonist provides superior inhibition of CGRP signaling and allodynia in mice. Our data suggest that the CGRP-mediated neuronal/Schwann cell pathway mediates allodynia associated with neurogenic inflammation, contributing to the algesic action of CGRP in mice.

G protein-coupled receptors (GPCRs) regulate many pathophysiological processes and are major therapeutic targets. The impact of disease on the subcellular distribution and function of GPCRs is poorly understood. We investigated trafficking and signaling of protease-activated receptor 2 (PAR₂) in colitis. To localize PAR₂ and assess redistribution during disease, we generated knockin mice expressing PAR₂ fused to monomeric ultrastable green fluorescent protein (muGFP). PAR₂-muGFP signaled and trafficked normally. PAR₂ messenger RNA was detected at similar levels in Par₂-mugfp and wild-type mice. Immunostaining with a GFP antibody and RNAScope in situ hybridization using F2rl1 (PAR₂) and Gfp probes revealed that PAR₂-muGFP was expressed in epithelial cells of the small and large intestine and in subsets of enteric and dorsal root ganglia neurons. In healthy mice, PAR₂-muGFP was prominently localized to the basolateral membrane of colonocytes. In mice with colitis, PAR₂-muGFP was depleted from the plasma membrane of colonocytes and redistributed to early endosomes, consistent with generation of proinflammatory proteases that activate PAR₂ PAR₂ agonists stimulated endocytosis of PAR₂ and recruitment of Gα_q, Gα_i, and β-arrestin to early endosomes of T84 colon carcinoma cells. PAR₂ agonists increased paracellular permeability of colonic epithelial cells, induced colonic inflammation and hyperalgesia in mice, and stimulated proinflammatory cytokine release from segments of human colon. Knockdown of dynamin-2 (Dnm2), the major colonocyte isoform, and Dnm inhibition attenuated PAR₂ endocytosis, signaling complex assembly and colonic inflammation and hyperalgesia. Thus, PAR₂ endocytosis sustains protease-evoked inflammation and nociception and PAR₂ in endosomes is a potential therapeutic target for colitis.

Efference copies of movement-inducing neural signals have been proposed to serve a role in gaze stabilization. Prior work has demonstrated a spino-extraocular motor circuit in the tadpole that relays copies of spinal commands to extraocular motor neurons. A recent study demonstrates the presence of this circuitry in mice, suggesting a unique method of gaze stabilization in the locomoting mouse.