Faculty Bibliography

OBJECTIVES/OBJECTIVE:Vocal fold scar remains a therapeutic challenge. Vocal fold fibroblasts (VFFs) secrete extracellular matrix (ECM), and transforming growth factor-beta 1 (TGF-β1)-mediated fibroblast to myofibroblast differentiation is central to the development of fibrosis. The transient receptor potential (TRP) channel superfamily is a group of nonselective cation channels, and activation of TRP ankyrin 1 (TRPA1) channel has been shown to have antifibrotic effects through TGF-β1/Smad signaling in various organs. This study aimed to elucidate expression of TRPA1 and the impact of TRPA1 activation on TGF-β1/Smad signaling in VFFs. METHODS: M) for 4 or 24 h. Trpa1, Smad3, Smad7, Col1a1, Acta2, and Has1 mRNA expression were quantified via qPCR. RESULTS:TRPA1 was expressed in cultured VFFs and the lamina propria. TGF-β1 administration significantly increased Trpa1 compared to control. AITC alone did not alter Smad3, Smad7, Acta2, or ECM related genes. However, the combination of AITC and TGF-β1 significantly increased Smad3 and decreased Smad7 and Acta2 compared to TGF-β1 alone; A-967079 significantly reduced this response. CONCLUSIONS:VFFs expressed TRPA1, and the activation of TRPA1 regulated TGF-β1/Smad signaling in VFFs. These findings provide preliminary insights into potential anti-fibrotic mechanisms of TRPA1 activation through TGF-β1/Smad signaling in VFFs. LEVEL OF EVIDENCE/METHODS:NA Laryngoscope, 2024.

Perception can be refined by experience, up to certain limits. It is unclear whether perceptual limits are absolute or could be partially overcome via enhanced neuromodulation and/or plasticity. Recent studies suggest that peripheral nerve stimulation, specifically vagus nerve stimulation (VNS), can alter neural activity and augment experience-dependent plasticity, although little is known about central mechanisms recruited by VNS. Here we developed an auditory discrimination task for mice implanted with a VNS electrode. VNS applied during behavior gradually improved discrimination abilities beyond the level achieved by training alone. Two-photon imaging revealed VNS induced changes to auditory cortical responses and activated cortically projecting cholinergic axons. Anatomical and optogenetic experiments indicated that VNS can enhance task performance through activation of the central cholinergic system. These results highlight the importance of cholinergic modulation for the efficacy of VNS and may contribute to further refinement of VNS methodology for clinical conditions.

BACKGROUND:Preoperative review of computed tomography (CT) imaging assists with endoscopic sinus surgery (ESS) planning, where trainees may benefit from a systematic approach. We have previously developed an optimized preoperative checklist for sinus CT imaging using an iterative modified Delphi method. OBJECTIVE:In this study, we assess the utility of an optimized preoperative checklist for residents performing ESS. METHODS:Resident sinus CT scan education consisted of a preintervention questionnaire, an 18-min video outlining the optimized preoperative checklist, and a delayed postintervention questionnaire; these were distributed via Qualtrics to otolaryngology residents across 5 training programs in the NY metro area. The preintervention questionnaire contained 25 survey questions and a 225-point quiz on sinus CT anatomy; the delayed postintervention questionnaire contained the same 25 survey questions and a second, distinct 225-point quiz. RESULTS: < .001). Resident habitual utilization of a systematic preoperative CT imaging checklist increased significantly from 21.6% to 72.9% as a result of the curriculum intervention. CONCLUSION/CONCLUSIONS:We find that an educational program centered on an iteratively optimized preoperative checklist for ESS improves the ability of trainees to identify critical sinus CT structures. Further integration of checklists and educational curricula may enhance rhinology education efforts and improve surgical anatomy competency.

Humans can remember specific events without acting on them and can influence which memories are retrieved based on internal goals. However, current animal models of memory typically present sensory cues to trigger retrieval and assess retrieval based on action ^1-5 . As a result, it is difficult to determine whether measured patterns of neural activity relate to the cue(s), the retrieved memory, or the behavior. We therefore asked whether we could develop a paradigm to isolate retrieval-related neural activity in animals without retrieval cues or the requirement of a behavioral report. To do this, we focused on hippocampal "place cells." These cells primarily emit spiking patterns that represent the animal's current location (local representations), but they can also generate representations of previously visited locations distant from the animal's current location (remote representations) ^6-13 . It is not known whether animals can deliberately engage specific remote representations, and if so, whether this engagement would occur during specific brain states. So, we used a closed-loop neurofeedback system to reward expression of remote representations that corresponded to uncued, experimenter-selected locations, and found that rats could increase the prevalence of these specific remote representations over time; thus, demonstrating memory retrieval modulated by internal goals in an animal model. These representations occurred predominately during periods of immobility but outside of hippocampal sharp-wave ripple (SWR) ^13-15 events. This paradigm enables future direct studies of memory retrieval mechanisms in the healthy brain and in models of neurological disorders.

Acoustic vocoders play a key role in simulating the speech information available to cochlear implant (CI) users. Traditionally, the intelligibility of vocoder CI simulations is assessed through speech recognition experiments with normally-hearing subjects, a process that can be time-consuming, costly, and subject to individual variability. As an alternative approach, we utilized an advanced deep learning speech recognition model to investigate the intelligibility of CI simulations. We evaluated model's performance on vocoder-processed words and sentences with varying vocoder parameters. The number of vocoder bands, frequency range, and envelope dynamic range were adjusted to simulate sound processing settings in CI devices. Additionally, we manipulated the low-cutoff frequency and intensity quantization of vocoder envelopes to simulate psychophysical temporal and intensity resolutions in CI patients. The results were evaluated within the context of the audio analysis performed in the model. Interestingly, the deep learning model, despite not being originally designed to mimic human speech processing, exhibited a human-like response to alterations in vocoder parameters, resembling existing human subject results. This approach offers significant time and cost savings compared to testing human subjects, and eliminates learning and fatigue effects during testing. Our findings demonstrate the potential of speech recognition models in facilitating auditory research.

Legumain is a cysteine protease broadly associated with inflammation. It has been reported to cleave and activate protease-activated receptor 2 to provoke pain associated with oral cancer. Outside of gastric and colon cancer, little has been reported on the roles of legumain within the gastrointestinal tract. Using a legumain-selective activity-based probe, LE28, we report that legumain is activated within colonocytes and macrophages of the murine colon, and that it is upregulated in models of acute experimental colitis. We demonstrated that loss of legumain activity in colonocytes, either through pharmacological inhibition or gene deletion, had no impact on epithelial permeability in vitro. Moreover, legumain inhibition or deletion had no obvious impacts on symptoms or histological features associated with dextran sulfate sodium-induced colitis, suggesting its proteolytic activity is dispensable for colitis initiation. To gain insight into potential functions of legumain within the colon, we performed field asymmetric waveform ion mobility spectrometry-facilitated quantitative proteomics and N-terminomics analyses on naïve and inflamed colon tissue from wild-type and legumain-deficient mice. We identified 16 altered cleavage sites with an asparaginyl endopeptidase signature that may be direct substrates of legumain and a further 16 cleavage sites that may be indirectly mediated by legumain. We also analyzed changes in protein abundance and proteolytic events broadly associated with colitis in the gut, which permitted comparison to recent analyses on mucosal biopsies from patients with inflammatory bowel disease. Collectively, these results shed light on potential functions of legumain and highlight its potential roles in the transition from inflammation to colorectal cancer.

PURPOSE/OBJECTIVE:A digital visual communication tool was recently developed by MyCareGorithm which incorporates explanations of treatments and procedures for cancer patients. This study will evaluate if this novel tool can enhance both patient and provider satisfaction. METHODS:In an IRB approved, prospective, pilot study, patients and caregivers at a single institution receiving head and neck cancer radiation underwent an initial consult using this digital tool and completed a survey of 6 questions to evaluate their understanding of their disease. Providers completed a 7-question survey to rate their satisfaction. Patients and caregivers with 4 or more "Yes" answers and providers with 5 or more "Yes" answers were defined as "Satisfied". In order to obtain 90% power to detect that the proportion of "Satisfied" patients (assumed 75%) is greater than 50% with a significance level 5% using a one-sided Z test, we planned to enroll 30 patients. RESULTS:Thirty patients enrolled and completed all surveys. Most patients were male (66%), white (60%) and spoke English as a primary language (93%). Patients most commonly had oropharyngeal cancer (23%). Overall, 27 out of 30 of patients (90%; one sided 95%CI: 76.1%) were satisfied (z = 4.38, p < 0.05), 16 of the 17 caregivers (94%; one sided 95% CI: 74.8%) were satisfied and 100% of providers were satisfied with the digital tool. Most patients (90%) and caregivers (94%) felt that the tool improved their understanding of the disease. One male answered "No" for all 6 questions commenting that it was only marginally helpful. One female also answered "No" for all questions commenting that she did not find it helpful on its own without the provider explanation. Out of the 30 patients, 26 (87%) stayed at our institution to receive treatment. CONCLUSIONS:These findings showed high rates of patient, caregiver and provider satisfaction with their initial consult when incorporating a digital visual tool. Its routine use in clinical practice should be strongly considered.

Oral cancer is notoriously painful. Activation of protease-activated receptor 2 (PAR₂, encoded by F2RL1) by proteases in the cancer microenvironment is implicated in oral cancer pain. PAR₂ is a G protein-coupled receptor (GPCR) expressed on neurons and cells in the cancer microenvironment. Sustained signaling of PAR₂ from endosomes of neurons mediates sensitization and nociception. We focused on the differential contribution of PAR₂ on oral cancer cells and neurons to oral cancer pain and whether encapsulation of a PAR₂ inhibitor, AZ3451 in nanoparticles (NP) more effectively reverses PAR₂ activation. We report that F2RL1 was overexpressed in human oral cancers and cancer cell lines. Deletion of F2RL1 on cancer cells reduced cancer-associated mechanical allodynia. A third-generation polyamidoamine dendrimer, functionalized with cholesterol was self-assembled into NPs encapsulating AZ3451. NP encapsulated AZ3451 (PAMAM-Chol-AZ NPs) more effectively reversed activation of PAR₂ at the plasma membrane and early endosomes than free drug. The PAMAM-Chol-AZ NPs showed greater efficacy in reversing nociception than free drug, with respect to both level and duration, in three preclinical mouse models of oral cancer pain. The antinociceptive efficacy was confirmed with an operant orofacial assay. Genetic deletion of F2RL1 on cancer cells or F2rl1 on neurons each partially reversed mechanical cancer allodynia. The remaining nociception could be effectively reversed by PAMAM-Chol-AZ NPs. These findings suggest that PAR₂ on oral cancer cells and neurons contribute to oral cancer nociception and NPs loaded with a PAR₂ antagonist provide increased antinociception and improved oral function compared to free drug.

OBJECTIVE:To better understand cochlear implant (CI) performance after reimplantation with a different device manufacturer. STUDY DESIGN/METHODS:Multisite retrospective review. SETTING/METHODS:Tertiary referral centers. PATIENTS/METHODS:Patients older than 4 years who received a CI and subsequently underwent CI reimplantation with a different manufacturer over a 20-year period. INTERVENTION/METHODS:Reimplantation. MAIN OUTCOME MEASURE/METHODS:The primary outcome was difference in the best CNC score obtained with the primary CI, compared with the most recent CNC score obtained after reimplantation. RESULTS:Twenty-nine patients met the criteria at three centers. The best average CNC score achieved by adult patients after primary cochlear implantation was 46.2% (n = 16), measured an average of 14 months (range: 3-36 mo) postoperatively. When looking at the most recent CNC score of adult patients before undergoing reimplantation, the average CNC score dropped to 19.2% (n = 17). After reimplantation, the average 3- to 6-month CNC score was 48.3% (n = 12), with most recent average CNC score being 44.4% (n = 17) measured an average of 19 months (range: 3-46 mo) postoperatively. There was no statistically significant difference (p = 0.321; t11 = 0.48) identified in performance between the best CNC score achieved by adult patients after primary cochlear implantation, and the most recent score achieved after reimplantation (n = 12). Analysis of prerevision and postrevision speech performance was not possible in pediatric patients (<18 yr old) because of differences in tests administered. CONCLUSION/CONCLUSIONS:Patients undergoing reimplantation with a different manufacturer achieved CNC score performance comparable to their best performance with their original device.

OBJECTIVE:To characterize transimpedance matrix (TIM) heatmap patterns in patients at risk of labyrinthine abnormality to better understand accuracy and possible TIM limitations. STUDY DESIGN/METHODS:Retrospective review of TIM patterns, preoperative, and postoperative imaging. SETTING/METHODS:Tertiary referral center. PATIENTS/METHODS:Patients undergoing cochlear implantation with risk of labyrinthine abnormality. INTERVENTION/METHODS:None. RESULTS:Seventy-seven patients were evaluated. Twenty-five percent (n = 19) of patients had a TIM pattern variant identified. These variants were separated into 10 novel categories. Overall, 9% (n = 6) of electrodes were malpositioned on intraoperative x-ray, of which 50% (n = 3) were underinserted, 17% (n = 1) were overinserted, 17% (n = 1) had a tip foldover, and 17% (n = 1) had a coiled electrode. The number of patients with a variant TIM pattern and normal x-ray was 18% (n = 14), and the number of patients with normal TIM pattern and malposition noted on x-ray was 3% (n = 2; both were electrode underinsertions that were recognized due to open circuits and surgical visualization).A newly defined skip heat pattern was identified in patients with IP2/Mondini malformation and interscalar septum width <0.5 mm at the cochlear pars ascendens of the basal turn. CONCLUSIONS:This study defines novel patterns for TIM heatmap characterization to facilitate collaborative and comparative research moving forward. In doing so, it highlights a new pattern termed skip heat, which corresponds with a deficient interscalar septum of the cochlea pars ascendens of the basal turn in patients with IP2 malformation. Overall, the data assist the surgeon in better understanding the implications and limitations of TIM patterns within groups of patients with risk of labyrinthine abnormalities.