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Objective: To evaluate the long-term hearing outcome after translabyrinthine resection of tumors within the internal auditory canal (IAC) with simultaneous cochlear implantation (CI)., Study Design: Prospective study., Setting: Tertiary referral center., Patients: Thirty-seven patients with tumors of the IAC undergoing translabyrinthine tumor surgery as a first-line therapy., Interventions: Intraoperatively, electrically evoked auditory brainstem response audiometry (eABR) was performed in all patients to assess cochlear nerve (CN) integrity. In case of preserved CN function after tumor removal, CI was subsequently performed. Postoperatively, patients were regularly followed up to evaluate pure-tone hearing as well as speech recognition with a monosyllabic word comprehension test., Main Outcome Measures: Postoperative hearing thresholds and word recognition scores., Results: Of 37 included patients, 22 (59.46%) had positive eABR responses after tumor removal. Twenty-one of these underwent simultaneous CI directly after tumor surgery and were followed-up for 24.24 ± 19.83 months after surgery. Hearing of these patients significantly improved from 73.87 ± 21.40 dB preoperatively to a mean pure-tone average of 41.56 ± 18.87 dB 1 year (p = 0.0008) and 34.58 ± 2.92 dB 3 years after surgery (p = 0.0157). Speech recognition significantly recovered from 13.33 ± 25.41% to 58.93 ± 27.61% 1 year (p = 0.0012) and 51.67 ± 28.58% 3 years postoperatively (p = 0.0164)., Conclusions: Regardless of tumor histopathology, CI is an effective option to restore patients' hearing after translabyrinthine tumor surgery. After CI, patients hearing can be restored over a long-term period of a minimum of 3 years post-surgery. Furthermore, eABR proves to be a practical tool to evaluate CN function and screen for patients eligible for CI., Competing Interests: Sources of support and disclosure of funding: C.A. received a research grant by MED-EL. All other authors report no conflict of interest. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors., (Copyright © 2024, Otology & Neurotology, Inc.)

Sensorineural hearing loss (SNHL) is the most common sensory deficit worldwide. Due to the heterogeneity of causes for SNHL, effective treatment options remain scarce, creating an unmet need for novel drugs in the field of otology. Cochlear implantation (CI) currently is the only established method to restore hearing function in profound SNHL and deaf patients. The cochlear implant bypasses the non-functioning sensory hair cells (HCs) and electrically stimulates the neurons of the cochlear nerve. CI also benefits patients with residual hearing by combined electrical and auditory stimulation. However, the insertion of an electrode array into the cochlea induces an inflammatory response, characterized by the expression of pro-inflammatory cytokines, upregulation of reactive oxygen species, and apoptosis and necrosis of HCs, putting residual hearing at risk. Here, we characterize the small molecule AC102, a pyridoindole, for its protective effects on residual hearing in CI. In a gerbil animal model of CI, AC102 significantly improves the recovery of hearing thresholds across multiple frequencies and confines the cochlear trauma to the directly mechanically injured area. In addition, AC102 significantly preserves auditory nerve fibers and inner HC synapses throughout the whole cochlea. In vitro experiments in an ethanol challenged HT22 cell-line revealed significant and dose-responsive anti-apoptotic effects following the treatment of with AC102. Further, AC102 treatment resulted in significant downregulation of the expression of pro-inflammatory cytokines in an organotypic ex vivo model of electrode insertion trauma (EIT). These results suggest that AC102's effects are likely elicited during the inflammatory phase of EIT and mediated by anti-apoptotic and anti-inflammatory properties, highlighting AC102 as a promising compound for hearing preservation during CI. Moreover, since the inflammatory response in CI shares similarities to that in other etiologies of SNHL, AC102 may be inferred as a potential general treatment option for various inner ear conditions., (© 2024. The Author(s).)

Objective: Determining the concentration of prestin in human blood, cerebrospinal fluid (CSF), and perilymph (PL), and evaluating its suitability as a clinical biomarker for sensori-neural hearing loss (SNHL)., Study Design: Human blood, CSF, and PL samples were intraoperatively collected from 42 patients with tumors of the internal auditory canal or with intracochlear tumors undergoing translabyrinthine or middle fossa tumor removal. Prestin concentration was measured using enzyme-linked immunosorbent assay and linear regression analyses were performed to investigate its associations with audiological as well as vestibular test results., Setting: Tertiary referral center., Results: The median prestin concentration in blood samples of the 42 study participants (26 women, mean ± standard deviation age, 52.7 ± 12.5 years) was 1.32 (interquartile range, IQR, 0.71-1.99) ng/mL. CSF prestin levels were significantly higher with 4.73 (IQR, 2.45-14.03) ng/mL (P = .005). With 84.74 (IQR, 38.95-122.00) ng/mL, PL prestin concentration was significantly higher compared to blood (P = .01) and CSF (P = .03) levels. Linear regression analyses showed significant associations of CSF prestin concentration with preoperative hearing levels (pure-tone average and word recognition; P = .008, R 2  = 0.1894; P = .03, R 2  = 0.1857), but no correlations with blood or PL levels., Conclusion and Relevance: This study's findings highlight the volatile nature of prestin levels and provide the first insights into this potential biomarker's concentrations in body fluids apart from blood. Future investigations should comprehensively assess human prestin levels with different etiologies of SNHL, prestin's natural homeostasis and systemic circulation, and its temporal dynamics after cochlear trauma. Finally, clinically approved detection kits for prestin are urgently required prior to considering a potential translational implementation of this diagnostic technique., (© 2024 The Author(s). Otolaryngology–Head and Neck Surgery published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngology–Head and Neck Surgery Foundation.)

Introduction: Even with recent research advances, effective delivery of a compound to its target cells inside the inner ear remains a challenging endeavor due to anatomical and physiological barriers. Direct intracochlear drug administration with an inner ear catheter (IEC) aims to overcome this obstacle and strives to provide a safe and efficient way for inner ear pharmacotherapy. The goal of this study was to histologically and audiologically evaluate the traumatic properties of a novel IEC for intracochlear drug delivery in a large animal model., Methods: Seven inner ears of piglets that had undergone intracochlear fluorescein isothiocyanate dextran application via an IEC ( n  = 4) or round window membrane (RWM) puncture with a needle ( n  = 3) followed by sequential apical perilymph sampling were histologically analyzed. Additionally, obtained objective auditory compound action potential and cochlear microphonic measurements were compared. Cochlear cryosections were stained using hematoxylin and eosin, and preservation of inner ear structures was investigated. Moreover, one cochlea was methylmethacrylate-embedded and analyzed with the IEC in situ ., Results: Histological evaluation revealed an atraumatic insertion and subsequent compound application in a majority of IEC-inserted inner ears. Click cochlear compound action potential (CAP) shifts in the IEC groups reached a maximum of 5 dB (1.25 ± 2.5 dB) post administration and prior to perilymph sampling. In comparison, application by RWM puncture generated a maximum click CAP hearing threshold shift of 50 dB (23.3 ± 23.1 dB) coinciding with coagulated blood in the basal cochlear turn in one specimen of the latter group. Furthermore, in situ histology showed an atraumatic insertion of the IEC demonstrating preserved intracochlear structures., Conclusion: The IEC appears to be a promising and efficient way for inner ear drug delivery. The similarities between the porcine and human inner ear enhance the clinical translation of our findings and increase confidence regarding the safe applicability of the IEC in human subjects., Competing Interests: CA receives research funding from MED-EL. LL receives research funding from Decibel Therapeutics/Regeneron Pharmaceuticals and Amgen and has worked as an independent consultant for Gerson Lehrman Group and Conclave Capital. The funders were not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Gerlitz, Yildiz, Gadenstaetter, Niisuke, Kandathil, Nieratschker, Landegger, Honeder and Arnoldner.)

Vestibular schwannomas (VS) are often associated with debilitating hearing loss. Therefore, preservation and rehabilitation of hearing have become major therapeutic goals of VS management. Recently, cochlear implantation (CI) has been established as an effective treatment option for VS-associated hearing loss. Nevertheless, the integrity and proper function of the cochlear nerve must be evaluated before conducting CI to ensure optimal CI outcomes. Various methods to determine cochlear nerve integrity and functionality have emerged in the last few years. Of these, the use of electrically evoked auditory brainstem response audiometry (eABR) in particular has been proven to be a meaningful tool for monitoring cochlear nerve health during VS surgery. Here, the cochlear nerve can be electrically stimulated using an intracochlear test electrode before, during, and after tumor extirpation. Subsequently, the resulting brainstem responses can be measured and interpreted accordingly to obtain direct information on the cochlear nerve function. This allows for continuous monitoring of cochlear nerve function throughout the course of VS surgery and aids in the decision-making for CI candidacy. Finally, in the case of preserved brainstem responses, CI can be performed instantly after VS extirpation. This simultaneous approach offers several advantages over two-staged procedures and has been shown to be an efficient and safe procedure for restoring hearing after VS removal., (© 2024. The Author(s).)

Objective: Electrically evoked auditory brainstem response audiometry has emerged as a suitable option to intraoperatively assess cochlear nerve function during vestibular schwannoma resection. This study aimed to analyze the functional outcome and implant usage of patients with preserved auditory nerve responses after simultaneous translabyrinthine schwannoma resection and cochlear implantation., Study Design: Prospective study., Setting: Tertiary referral center., Methods: Patients with unilateral sporadic vestibular schwannoma underwent translabyrinthine tumor resection. Intraoperatively, electrically evoked auditory brainstem response audiometry was performed before and after tumor removal. Cochlear implantation was carried out if positive responses were detected after tumor removal indicating cochlear nerve function. Postoperatively, patients were biannually followed-up to assess aided sound field audiometry and word recognition as well as implant usage., Results: Overall, 26 patients with vestibular schwannoma underwent translabyrinthine schwannoma resection. Out of these patients, 15 had positive cochlear nerve responses after tumor removal and concurrently received a cochlear implant. In 13 patients with histologically confirmed vestibular schwannoma, hearing improved by 23.7 ± 33.2 decibels and word recognition by 25.0 ± 42.4% over a mean follow-up period of 18 months. Overall, 12 included patients were regular cochlear implant users., Conclusion: Patients with vestibular schwannoma can benefit substantially from cochlear implantation. Intraoperative assessment of cochlear nerve function using electrically evoked auditory brainstem response audiometry can help to better identify individuals eligible for simultaneous vestibular schwannoma resection and cochlear implantation., (© 2023 The Authors. Otolaryngology-Head and Neck Surgery published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngology-Head and Neck Surgery Foundation.)

Hearing impairment is the most common sensory disorder in humans, and yet hardly any medications are licensed for the treatment of inner ear pathologies. Intricate pharmacokinetic examinations to better understand drug distribution within this complex organ could facilitate the development of novel therapeutics. For such translational research projects, animal models are indispensable, but differences in inner ear dimensions and other anatomical features complicate the transfer of experimental results to the clinic. The gap between rodents and humans may be bridged using larger animal models such as non-human primates. However, their use is challenging and impeded by administrative, regulatory, and financial hurdles. Other large animal models with more human-like inner ear dimensions are scarce. In this study, we analyzed the inner ears of piglets as a potential representative model for the human inner ear and established a surgical approach for intracochlear drug application and subsequent apical sampling. Further, controlled intracochlear delivery of fluorescein isothiocyanate-dextran (FITC-d) was carried out after the insertion of a novel, clinically applicable CE-marked cochlear catheter through the round window membrane. Two, six, and 24 hours after a single injection with this device, the intracochlear FITC-d distribution was determined in sequential perilymph samples. The fluorometrically assessed concentrations two hours after injection were compared to the FITC-d content in control groups, which either had been injected with a simple needle puncture through the round window membrane or the cochlear catheter in combination with a stapes vent hole. Our findings demonstrate not only significantly increased apical FITC-d concentrations when using the cochlear catheter but also higher total concentrations in all perilymph samples. Additionally, the concentration decreased after six and 24 hours and showed a more homogenous distribution compared to shorter observation times., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Yildiz, Gadenstaetter, Gerlitz, Landegger, Liepins, Nieratschker, Glueckert, Staecker, Honeder and Arnoldner.)

Objectives: Various animal models have been established and applied in hearing research. In the exploration of novel cochlear implant developments, mainly rodents have been used. Despite their important contribution to the understanding of auditory function, translation of experimental observations from rodents to humans is limited due to the size differences and genetic variability. Large animal models with better representation of the human cochlea are sparse. For this reason, we evaluated domestic piglets and Aachen minipigs for the suitability as a cochlear implantation animal model with commercially available cochlear implants., Methods: Four domestic piglets (two male and two female) and six Aachen minipigs were implanted with either MED-EL Flex24 or Flex20 cochlear implants respectively, after a step-by-step surgical approach was trained with pig cadavers. Electrophysiological measurements were performed before, during and after implantation for as long as 56 days after surgery. Auditory brainstem responses, electrocochleography as well as electrically and acoustically evoked compound action potentials were recorded. Selected cochleae were further analyzed histologically or with micro-CT imaging., Results: A surgical approach was established using a retroauricular single incision. Baseline auditory thresholds were 27 ± 3 dB sound pressure level (SPL; auditory brainstem click responses, mean ± standard error of the mean) and ranged between 30 and 80 dB SPL in frequency-specific responses (0.5 - 32 kHz). Follow-up measurements revealed deafness within the first two weeks after surgery, but some animals partially recovered to a hearing threshold of 80 dB SPL in certain frequencies as well as in click responses. Electrically evoked compound action potential thresholds increased within the first week after surgery, which led to lower stimulation responses or increase of necessary charge input. Immune reactions and consecutive scalar fibrosis following implantation were confirmed with histological analysis of implanted cochleae and may result in increased impedances. A three-dimensional minipig micro-CT segmentation revealed cochlear volumetric data similar to human inner ear dimensions., Conclusions: This study underlines the feasibility of cochlear implantation with clinically used cochlear implants in a large animal model with representative inner ear dimensions comparable to humans. To bridge the gap between small animal models and humans in translational research and to account for the structural and size differences, we recommend the minipig as a valuable animal model for hearing research. First insights into the induced trauma in minipigs after cochlear implant surgery and a partial hearing recovery present important data of the cochlear health changes in large animal cochleae., Competing Interests: Declaration of Competing Interest The other authors declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Adeno-associated viruses (AAVs) represent some of the most commonly employed vectors for targeted gene delivery and their extensive study has resulted in the approval of multiple gene therapies to treat human diseases. The intranasal route of vector application in gene therapy offers several advantages over traditional ways of administration. In addition to targeting local tissue like the olfactory epithelium, it provides minimally invasive access to various organ systems, including the central nervous system and the respiratory tract. Through a systematic literature review, a total of 53 articles that investigated the intranasal application of AAVs were identified, included, and summarized in this manuscript. Within these studies, AAV-based gene therapy was mainly investigated for its application in various infectious, pulmonary, or neurologic and/or psychiatric diseases. This review gives a comprehensive overview of the current technological state of the art regarding the intranasal application of AAVs for gene transfer and discusses remaining hurdles, which still have to be resolved before this approach can effectively be implemented in the routine clinical setting., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Nasopharyngeal swabbing (NPS) coupled with RT-PCR is the current gold standard for detecting SARS-CoV-2 infections. However, numerous studies have recently demonstrated the advantages of alternative nasal specimen collection approaches over NPS specifically for COVID-19 diagnosis. The present review was conducted according to PRISMA guidelines and summarises the current literature to give a clear overview of nasal specimen collection methods for SARS-CoV-2 detection. Publications investigating NPS and at least one other form of nasal specimen collection in combination with RT-PCR for viral detection in the context of COVID-19 were assessed. We identified 425 articles and ultimately included 18 studies in this systematic review. The suitable publications evaluated different forms of nasal specimen collection, with anterior nasal swabbing (ANS) and midturbinate swabbing (MTS) being the most frequently examined techniques. The analysed studies report sensitivity and specificity results (67.5-96.2% and 97.9-100.0%, respectively) similar to those achieved via NPS, especially in the early stages of disease or when paired with an oropharyngeal swab. Results from these studies suggest that ANS and MTS are suitable alternatives to NPS for COVID-19 testing. Due to their ease of collection, ANS and MTS collection techniques may facilitate broader testing strategies and allow for economization of medical staff.

Objective: To assess whether web-based public inquiries into pharyngitis-related search terms follow annual incidence peaks of acute pharyngitis in various countries from both hemispheres., Methods: Google Trends (GT) was utilized for systematic acquisition of pharyngitis-related search terms (sore throat, cough, fever, cold). Six countries from both hemispheres including four English (United Kingdom, United States, Canada, and Australia) and two non-English speaking countries (Austria and Germany) were selected for further analysis. Time series data on relative search interest for pharyngitis-related search terms, covering a timeframe between 2004 and 2019 were extracted. Following reliability analysis using the intra-class correlation coefficient, the cosinor time series analysis was utilized to determine annual peaks in public-inquiries., Results: The extracted datasets of GT proved to be highly reliable with correlation coefficients ranging from 0.83 to 1.0. Graphical visualization showed annual seasonal peaks for pharyngitis-related search terms in all included countries. The cosinor time series analysis revealed these peaks to be statistically significant during winter months (all p < 0.001)., Conclusion: Our study revealed seasonal variations for pharyngitis-related terms which corresponded to winter incidence peaks of acute pharyngitis. These results highlight the need for easily accessible information on diagnosis, therapy, and red-flag symptoms for this common disease. Accurately informed patients might contribute to a reduction of unnecessary clinic visits and potentially cutback the futile antibiotic overuse.