Murine cochlear damage models in the context of hair cell regeneration research.

Understanding the complex pathologies associated with hearing loss is a significant motivation for conducting inner ear research. Lifelong exposure to loud noise, ototoxic drugs, genetic diversity, sex, and aging collectively contribute to human hearing loss. Replicating this pathology in research animals is challenging because hearing impairment has varied causes and different manifestations. A central aspect, however, is the loss of sensory hair cells and the inability of the mammalian cochlea to replace them. Researching therapeutic strategies to rekindle regenerative cochlear capacity, therefore, requires the generation of animal models in which cochlear hair cells are eliminated. This review discusses different approaches to ablate cochlear hair cells in adult mice. We inventoried the cochlear cyto- and histo-pathology caused by acoustic overstimulation, systemic and locally applied drugs, and various genetic tools. The focus is not to prescribe a perfect damage model but to highlight the limitations and advantages of existing approaches and identify areas for further refinement of damage models for use in regenerative studies.

Hyperosmotic Sisomicin Infusion: A Mouse Model for Hearing Loss.

Hearing impairment arises from the loss of either type of cochlear sensory hair cells. Inner hair cells act as primary sound transducers, while outer hair cells enhance sound-induced vibrations within the organ of Corti. Established models, such as systemic administration of ototoxic aminoglycosides, yield inconsistent and variable hair cell death in mice. Overcoming this limitation, we developed a method involving surgical delivery of a hyperosmotic sisomicin solution into the posterior semicircular canal of adult mice. This procedure induced rapid and synchronous apoptotic demise of outer hair cells within 14 hours, leading to irreversible hearing loss. The combination of sisomicin and hyperosmotic stress caused consistent and synergistic ototoxic damage. Inner hair cells remained intact until three days post-treatment, after which deterioration in structure and number was observed, culminating in cell loss by day seven. This robust animal model provides a valuable tool for otoregenerative research, facilitating single-cell and omics-based studies toward exploring preclinical therapeutic strategies.

Audiological Outcomes and Associated Factors after Pediatric Cochlear Reimplantation.

Cochlear implants are the most common and successful sensory neuroprosthetic devices. However, reimplantation can be required for medical reasons, device failure, or technological upgrading. Resolving the problem driving the intervention and offering stable or better audiological results are the main challenges. We aimed to analyze the success rate of this intervention and to identify factors influencing speech perception recovery after reimplantation in the pediatric population. We retrospectively collected the causes and the outcomes of 67 consecutive reimplantations in one cochlear implant center over 30 years. Reimplantation resolved the cause without recurrence for 94% of patients. The etiology of deafness, time since implantation, indication of reimplantation, sex, and age did not influence word discrimination test scores in silence, 3 years after surgery. However, adherence to a speech rehabilitation program was statistically associated with gain in perception scores: +8.9% [-2.2; +31.0%] versus -19.0% [-47.5; -7.6%] if no or suboptimal rehabilitation was followed (p = 0.0037). Cochlear reimplantation in children is efficient and is associated with predictable improvement in speech perception, 3 years after intervention. However, good adherence to speech rehabilitation program is necessary and should be discussed with the patient and parents, especially for the indication of reimplantation for technological upgrading.

A disease-associated mutation in thyroid hormone receptor α1 causes hearing loss and sensory hair cell patterning defects in mice.

Resistance to thyroid hormone due to mutations in THRA, which encodes the thyroid hormone receptor α (TRα1), shows variable clinical presentation. Mutations affecting TRß1 and TRß2 cause deafness in mice and have been associated with deafness in humans. To test whether TRα1 also affects hearing function, we used mice heterozygous for a frameshift mutation in Thra that is similar to human THRA mutations (ThraS1/+ mice) and reduces tissue sensitivity to thyroid hormone. Compared to wild-type littermates, ThraS1/+ mice showed moderate high-frequency sensorineural hearing loss as juveniles and increased age-related hearing loss. Ultrastructural examination revealed aberrant orientation of ~20% of sensory outer hair cells (OHCs), as well as increased numbers of mitochondria with fragmented morphology and autophagic vacuoles in both OHCs and auditory nerve fibers. Molecular dissection of the OHC lateral wall components revealed that the potassium ion channel Kcnq4 was aberrantly targeted to the cytoplasm of mutant OHCs. In addition, mutant cochleae showed increased oxidative stress, autophagy, and mitophagy associated with greater age-related cochlear cell damage, demonstrating that TRα1 is required for proper development of OHCs and for maintenance of OHC function. These findings suggest that patients with THRA mutations may present underdiagnosed, mild hearing loss and may be more susceptible to age-related hearing loss.

Nasopharyngeal Tube and Functional Treatment in Pierre Robin Sequence: A Tertiary Clinical Experience From 150 Cases.

OBJECTIVES: To describe the initial care practices for children with Pierre Robin sequence (PRS) and analyze the factors predicting the severity of the obstruction breathing disorders. DESIGN: A retrospective single-center study of 150 children with PRS. SETTING: Single tertiary care center, Regional Competence Center for the diagnosis and treatment of PRS. PATIENTS: A total of 150 children with PRS consecutively followed between 1986 and 2017. Group 1 comprises children without specific respiratory management; group 2, children requiring prone positioning to alleviate their respiratory distress symptoms; and group 3, children requiring nasopharyngeal airway tube (NT) or nonconservative surgical treatment. MAIN OUTCOME MEASURES: Evolution and results of the initial treatment of PRS. RESULTS: Forty-two percent (n = 63) were attributed to group 1, 39% (n = 50) to group 2, and 19% (n = 29) to group 3. Preterm birth, birth weight, or associated congenital malformations were not significantly different between the groups. However, the age of exclusive oral feeding was significantly different: 1 day (quartiles: 0-3) for group 1; 11 days (quartiles: 1-28) for group 2; 39 days (quartiles: 19-111) for group 3 (P < .0001). Considering the NT, its use relieves the upper airway obstruction, assessed by a respiratory polygraphy, in 14 children. CONCLUSIONS: Nasopharyngeal airway tube has become our major first-line treatment, avoiding more complex procedures in most of the cases. The achievement of exclusive oral feeding seems to be a good predictor of the severity of respiratory symptoms in PRS.

Use of simulation-based training of surgical technical skills among ENTs: an international YO-IFOS survey.

PURPOSE: The aim of this study was to investigate and compare the use of simulation-based technical skills training (SBTST) in the otolaryngology curriculum in different countries, and to explore the needs and opinions about the use of simulation among young otolaryngologists. METHODS: An e-survey conducted among Young Otolaryngologists of the International Federation of Oto-rhino-laryngological Societies (Yo-IFOS) members. RESULTS: 139 Yo-IFOS members from 51 countries completed the survey. During residency training, 82.7% of respondents have used SBTST on cadavers, 51.8% on physical simulators, and 43.8% on virtual reality simulators. High costs (65.5%), lack of availability (49.2%) and lack of time (25.5%) were the main barriers limiting the practice of SBTST. These barriers also limited teaching using simulation. Sinonasal surgery (72.7%), temporal bone surgery (67.6%), and head/neck surgery (44.6%) were significantly more frequently taught using SBTST than suspension microlaryngoscopy (25.9%) and pediatric surgery (22.3%) (p < 0.001). The procedures rated as the most important to learn through SBTST were tracheotomy (50.4%), emergency cricothyroidotomy (48.9%), and rigid bronchoscopy (47.5%). On an analogic visual scale (0-100) for the question "how important will simulation be for future ENTs in surgical training?", the mean score was 79.5/100 (± 23.3), highlighting the positive attitude toward the use of SBTST in otorhinolaryngology training. CONCLUSION: SBTST is an attractive learning and teaching method in otorhinolaryngology, but associated costs, lack of access, and lack of time are the main barriers limiting its use. Emergency procedures are key technical skills to be learned using simulation but in some cases, lack relevant simulators for training.

A Single Cisterna Magna Injection of AAV Leads to Binaural Transduction in Mice.

Viral-mediated gene augmentation, silencing, or editing offers tremendous promise for the treatment of inherited and acquired deafness. Inner-ear gene therapies often require a safe, clinically useable and effective route of administration to target both ears, while avoiding damage to the delicate structures of the inner ear. Here, we examined the possibility of using a cisterna magna injection as a new cochlear local route for initiating binaural transduction by different serotypes of the adeno-associated virus (AAV2/8, AAV2/9, AAV2/Anc80L65). The results were compared with those following canalostomy injection, one of the existing standard inner ear local delivery routes. Our results demonstrated that a single injection of AAVs enables high-efficiency binaural transduction of almost all inner hair cells with a basal-apical pattern and of large numbers of spiral ganglion neurons of the basal portion of the cochlea, without affecting auditory function and cochlear structures. Taken together, these results reveal the potential for using a cisterna magna injection as a local route for binaural gene therapy applications, but extensive testing will be required before translation beyond mouse models.

rAAV-Mediated Cochlear Gene Therapy: Prospects and Challenges for Clinical Application.

Over the last decade, pioneering molecular gene therapy for inner-ear disorders have achieved experimental hearing improvements after a single local or systemic injection of adeno-associated, virus-derived vectors (rAAV for recombinant AAV) encoding an extra copy of a normal gene, or ribozymes used to modify a genome. These results hold promise for treating congenital or later-onset hearing loss resulting from monogenic disorders with gene therapy approaches in patients. In this review, we summarize the current state of rAAV-mediated inner-ear gene therapies including the choice of vectors and delivery routes, and discuss the prospects and obstacles for the future development of efficient clinical rAAV-mediated cochlear gene medicine therapy.

Early needle aspiration of large infant cephalohematoma: a safe procedure to avoid esthetic complications.

Cephalohematoma is a common pathology in newborns. Observation is the primary treatment for most patients with small uncomplicated cephalohematoma. Conversely, a large cephalohematoma can lead to calcification with unesthetic local deformation or deformational plagiocephaly. The objective of the study was to evaluate the iatrogenic risk associated with early puncture under local anesthesia and oral sucrose. This is a retrospective study of 67 consecutive newborns followed at Montpellier University Hospital, France, between 2010 and 2017. Large cephalohematoma was defined on the basis of the bump projection. Due to the uncertainty of the spontaneous resorption and the risk of calcification after 4 weeks which render the needle aspiration ineffective, puncture was performed between 2 and 4 weeks of life after coagulation evaluation and ultrasound of the skull and scalp. Puncture was performed in 43 boys (64%) and 24 (36%) girls between day 15 and day 30 after birth. The cephalohematoma maximal projection measured by ultrasound ranged from 9 to 13 mm (Q1,Q4) with a median value of 12 mm. No puncture-related complication was recorded during the intervention and at the 1-month follow-up visit.Conclusion: In newborns with large and persistent unesthetic cephalohematoma, puncture under local anesthesia with oral sucrose can be safely proposed between day 15 and day 30 after birth.What is Known:• Infant cephalohematoma is a frequent pathology of newborns, consisting of a traumatic subperiosteal hematoma of the skull. Most cephalohematomas are small and require no treatment because they spontaneously disappear within the first month.• Large and non-resorptive cephalohematomas may have significant esthetic and functional consequences.What is New:• Early puncture under local anesthesia is a safe, effective, and rapid procedure, decreasing the risk of persistent skull deformities.• Puncture can be proposed for newborns with a large (high projection and/or high angle connection) persistent anesthetic cephalohematoma, between day 15 and day 30, before spontaneous calcification.