Comprehensive analysis of two hotspot codons in the TUBB4B gene and associated phenotypes.

Our purpose was to elucidate the genotype and ophthalmological and audiological phenotype in TUBB4B-associated inherited retinal dystrophy (IRD) and sensorineural hearing loss (SNHL), and to model the effects of all possible amino acid substitutions at the hotspot codons Arg390 and Arg391. Six patients from five families with heterozygous missense variants in TUBB4B were included in this observational study. Ophthalmological testing included best-corrected visual acuity, fundus examination, optical coherence tomography, fundus autofluorescence imaging, and full-field electroretinography (ERG). Audiological examination included pure-tone and speech audiometry in adult patients and auditory brainstem response testing in a child. Genetic testing was performed by disease gene panel analysis based on genome sequencing. The molecular consequences of the substitutions of residues 390 and 391 on TUBB4B and its interaction with α-tubulin were predicted in silico on its three-dimensional structure obtained by homology modelling. Two independent patients had amino acid exchanges at position 391 (p.(Arg391His) or p.(Arg391Cys)) of the TUBB4B protein. Both had a distinct IRD phenotype with peripheral round yellowish lesions with pigmented spots and mild or moderate SNHL, respectively. Yet the phenotype was milder with a sectorial pattern of bone spicules in one patient, likely due to a genetically confirmed mosaicism for p.(Arg391His). Three patients were heterozygous for an amino acid exchange at position 390 (p.(Arg390Gln) or p.(Arg390Trp)) and presented with another distinct retinal phenotype with well demarcated pericentral retinitis pigmentosa. All showed SNHL ranging from mild to severe. One additional patient showed a variant distinct from codon 390 or 391 (p.(Tyr310His)), and presented with congenital profound hearing loss and reduced responses in ERG. Variants at codon positions 390 and 391 were predicted to decrease the structural stability of TUBB4B and its complex with α-tubulin, as well as the complex affinity. In conclusion, the twofold larger reduction in heterodimer affinity exhibited by Arg391 substitutions suggested an association with the more severe retinal phenotype, compared to the substitution at Arg390.

Variability in Cochlear Implantation Outcomes in a Large German Cohort With a Genetic Etiology of Hearing Loss.

OBJECTIVES: The variability in outcomes of cochlear implantation is largely unexplained, and clinical factors are not sufficient for predicting performance. Genetic factors have been suggested to impact outcomes, but the clinical and genetic heterogeneity of hereditary hearing loss makes it difficult to determine and interpret postoperative performance. It is hypothesized that genetic mutations that affect the neuronal components of the cochlea and auditory pathway, targeted by the cochlear implant (CI), may lead to poor performance. A large cohort of CI recipients was studied to verify this hypothesis. DESIGN: This study included a large German cohort of CI recipients (n = 123 implanted ears; n = 76 probands) with a definitive genetic etiology of hearing loss according to the American College of Medical Genetics (ACMG)/Association for Molecular Pathology (AMP) guidelines and documented postoperative audiological outcomes. All patients underwent preoperative clinical and audiological examinations. Postoperative CI outcome measures were based on at least 1 year of postoperative audiological follow-up for patients with postlingual hearing loss onset (>6 years) and 5 years for children with congenital or pre/perilingual hearing loss onset (≤6 years). Genetic analysis was performed based on three different methods that included single-gene screening, custom-designed hearing loss gene panel sequencing, targeting known syndromic and nonsyndromic hearing loss genes, and whole-genome sequencing. RESULTS: The genetic diagnosis of the 76 probands in the genetic cohort involved 35 genes and 61 different clinically relevant (pathogenic, likely pathogenic) variants. With regard to implanted ears (n = 123), the six most frequently affected genes affecting nearly one-half of implanted ears were GJB2 (21%; n = 26), TMPRSS3 (7%; n = 9), MYO15A (7%; n = 8), SLC26A4 (5%; n = 6), and LOXHD1 and USH2A (each 4%; n = 5). CI recipients with pathogenic variants that influence the sensory nonneural structures performed at or above the median level of speech performance of all ears at 70% [monosyllable word recognition score in quiet at 65 decibels sound pressure level (SPL)]. When gene expression categories were compared to demographic and clinical categories (total number of compared categories: n = 30), mutations in genes expressed in the spiral ganglion emerged as a significant factor more negatively affecting cochlear implantation outcomes than all clinical parameters. An ANOVA of a reduced set of genetic and clinical categories (n = 10) identified five detrimental factors leading to poorer performance with highly significant effects ( p < 0.001), accounting for a total of 11.8% of the observed variance. The single strongest category was neural gene expression accounting for 3.1% of the variance. CONCLUSIONS: The analysis of the relationship between the molecular genetic diagnoses of a hereditary etiology of hearing loss and cochlear implantation outcomes in a large German cohort of CI recipients revealed significant variabilities. Poor performance was observed with genetic mutations that affected the neural components of the cochlea, supporting the "spiral ganglion hypothesis."

[Hereditary hearing loss]. / Hereditäre Schwerhörigkeit.

Understanding the genetic basis of hearing loss is becoming increasingly relevant, as 50-70% of congenital hearing loss is hereditary and postlingual hearing loss is also often of hereditary origin. To date, more than 220 genes for hearing loss have been identified and more than 600 syndromes with hearing loss described. This review article explains the classification of genetic hearing loss into syndromic versus non-syndromic forms and the modes of inheritance involved. Some of the most common syndromes (Usher, Pendred, Jervell-Lange-Nielsen, Waardenburg, branchiootorenal, and Alport syndrome) are introductorily described. New sequencing technologies have significantly expanded the diagnostic options for genetic hearing loss and made them more accessible. This text aims to encourage initiation of genetic diagnosis in hearing-impaired patients with suspected hereditary genesis in order to provide the best possible counseling for affected individuals and their families.

Accessing the stapedius muscle via novel surgical retrofacial approach during cochlear implantation surgery: Intraoperative results on feasibility and safety.

Human stapedius muscle (SM) can be directly and safely accessed via retrofacial approach, opening new approaches to directly measure the electrically evoked stapedius reflex threshold (eSRT). The measurement of the SM activity via direct surgical access represents a potential tool for objective eSRT fitting of cochlear implants (CI), increasing the benefit experienced by the CI users and leading to new perspectives in the development of smart implantable neurostimulators. 3D middle-ear reconstructions created after manual segmentation and related SM accessibility metrics were evaluated before the CI surgery for 16 candidates with assessed stapedius reflex. Retrofacial approach to access the SM was performed after facial recess exposure. In cases of poor exposition of SM, the access was performed anteriorly to the FN via drilling of the pyramidal eminence (PE). The total access rate of the SM via both the retrofacial and anterior approach of the FN was 100%. In 81.2% of cases (13/16), the retrofacial approach allowed to access the SM on previously categorized well exposed (8/8), partially exposed (4/5), and wholly concealed (1/3) SM with respect to FN. Following intraoperative evaluation in the remaining 18.8% (3/16), the SM was accessed anteriorly via drilling of the PE. Exposure of SM with respect to the FN and the sigmoid sinus's prominence was a predictor for the suitable surgical approach. The retrofacial approach offers feasible and reproducible access to the SM belly, opening direct access to electromyographic sensing of the eSRT. Surgical planner tools can quantitatively assist pre-surgical assessment.

Diagnostic Yield of Targeted Hearing Loss Gene Panel Sequencing in a Large German Cohort With a Balanced Age Distribution from a Single Diagnostic Center: An Eight-year Study.

OBJECTIVES: Hereditary hearing loss exhibits high degrees of genetic and clinical heterogeneity. To elucidate the population-specific and age-related genetic and clinical spectra of hereditary hearing loss, we investigated the sequencing data of causally associated hearing loss genes in a large cohort of hearing-impaired probands with a balanced age distribution from a single center in Southwest Germany. DESIGN: Genetic testing was applied to 305 hearing-impaired probands/families with a suspected genetic hearing loss etiology and a balanced age distribution over a period of 8 years (2011-2018). These individuals were representative of the regional population according to age and sex distributions. The genetic testing workflow consisted of single-gene screening (n = 21) and custom-designed hearing loss gene panel sequencing (n = 284) targeting known nonsyndromic and syndromic hearing loss genes in a diagnostic setup. Retrospective reanalysis of sequencing data was conducted by applying the current American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines. RESULTS: A genetic diagnosis was established for 75 (25%) of the probands that involved 75 causal variants in 35 genes, including 16 novel causal variants and 9 medically significant variant reclassifications. Nearly half of the solved cases (47%; n = 35) were related to variants in the five most frequently affected genes: GJB2 (25%), MYO15A, WFS1, SLC26A4, and COL11A1 (all 5%). Nearly one-quarter of the cases (23%; n = 17) were associated with variants in seven additional genes (TMPRSS3, COL4A3, LOXHD1, EDNRB, MYO6, TECTA, and USH2A). The remaining one-third of single cases (33%; n = 25) were linked to variants in 25 distinct genes. Diagnostic rates and gene distribution were highly dependent on phenotypic characteristics. A positive family history of autosomal-recessive inheritance in combination with early onset and higher grades of hearing loss significantly increased the solve rate up to 60%, while late onset and lower grades of hearing loss yielded significantly fewer diagnoses. Regarding genetic diagnoses, autosomal-dominant genes accounted for 37%, autosomal-recessive genes for 60%, and X-linked genes for 3% of the solved cases. Syndromic/nonsyndromic hearing loss mimic genes were affected in 27% of the genetic diagnoses. CONCLUSIONS: The genetic epidemiology of the largest German cohort subjected to comprehensive targeted sequencing for hereditary hearing loss to date revealed broad causal gene and variant spectra in this population. Targeted hearing loss gene panel analysis proved to be an effective tool for ensuring an appropriate diagnostic yield in a routine clinical setting including the identification of novel variants and medically significant reclassifications. Solve rates were highly sensitive to phenotypic characteristics. The unique population-adapted and balanced age distribution of the cohort favoring late hearing loss onset uncovered a markedly large contribution of autosomal-dominant genes to the diagnoses which may be a representative for other age balanced cohorts in other populations.

Activities of the Right Temporo-Parieto-Occipital Junction Reflect Spatial Hearing Ability in Cochlear Implant Users.

Spatial hearing is critical for us not only to orient ourselves in space, but also to follow a conversation with multiple speakers involved in a complex sound environment. The hearing ability of people who suffered from severe sensorineural hearing loss can be restored by cochlear implants (CIs), however, with a large outcome variability. Yet, the causes of the CI performance variability remain incompletely understood. Despite the CI-based restoration of the peripheral auditory input, central auditory processing might still not function fully. Here we developed a multi-modal repetition suppression (MMRS) paradigm that is capable of capturing stimulus property-specific processing, in order to identify the neural correlates of spatial hearing and potential central neural indexes useful for the rehabilitation of sound localization in CI users. To this end, 17 normal hearing and 13 CI participants underwent the MMRS task while their brain activity was recorded with a 256-channel electroencephalography (EEG). The participants were required to discriminate between the probe sound location coming from a horizontal array of loudspeakers. The EEG MMRS response following the probe sound was elicited at various brain regions and at different stages of processing. Interestingly, the more similar this differential MMRS response in the right temporo-parieto-occipital (TPO) junction in CI users was to the normal hearing group, the better was the spatial hearing performance in individual CI users. Based on this finding, we suggest that the differential MMRS response at the right TPO junction could serve as a central neural index for intact or impaired sound localization abilities.

Aberrant COL11A1 splicing causes prelingual autosomal dominant nonsyndromic hearing loss in the DFNA37 locus.

Alpha-chain collagen molecules encoded by genes that include COL11A1 are essential for skeletal, ocular, and auditory function. COL11A1 variants have been reported in syndromes involving these organ systems. However, a description of the complete clinical spectrum is lacking, as evidenced by a recent association of autosomal dominant nonsyndromic hearing loss due to a splice-altering variant in COL11A1, mapping the DFNA37 locus. Here, we describe two German families presenting prelingual autosomal dominant nonsyndromic hearing loss with novel COL11A1 heterozygous splice-altering variants (c.652-1G>C and c.4338+2T>C) that were molecularly characterized. Interestingly, the c.652-1G>C variant affects the same intron 4 canonical splice site originally reported in the DFNA37 family (c.652-2A>C) but elicits a different splicing outcome. Furthermore, the c.4338+2T>C variant originated de novo. We provide clinical and molecular genetic evidence to unambiguously confirm that COL11A1 splice-altering variants cause DFNA37 hearing loss and affirm that COL11A1 be included in the genetic testing of patients with nonsyndromic deafness.

Age-Dependency of Neurite Outgrowth in Postnatal Mouse Cochlear Spiral Ganglion Explants.

BACKGROUND: The spatial gap between cochlear implants (CIs) and the auditory nerve limits frequency selectivity as large populations of spiral ganglion neurons (SGNs) are electrically stimulated synchronously. To improve CI performance, a possible strategy is to promote neurite outgrowth toward the CI, thereby allowing a discrete stimulation of small SGN subpopulations. Brain-derived neurotrophic factor (BDNF) is effective to stimulate neurite outgrowth from SGNs. METHOD: TrkB (tropomyosin receptor kinase B) agonists, BDNF, and five known small-molecule BDNF mimetics were tested for their efficacy in stimulating neurite outgrowth in postnatal SGN explants. To modulate Trk receptor-mediated effects, TrkB and TrkC ligands were scavenged by an excess of recombinant receptor proteins. The pan-Trk inhibitor K252a was used to block Trk receptor actions. RESULTS: THF (7,8,3'-trihydroxyflavone) partly reproduced the BDNF effect in postnatal day 7 (P7) mouse cochlear spiral ganglion explants (SGEs), but failed to show effectiveness in P4 SGEs. During the same postnatal period, spontaneous and BDNF-stimulated neurite outgrowth increased. The increased neurite outgrowth in P7 SGEs was not caused by the TrkB/TrkC ligands, BDNF and neurotrophin-3 (NT-3). CONCLUSIONS: The age-dependency of induction of neurite outgrowth in SGEs was very likely dependent on presently unidentified factors and/or molecular mechanisms which may also be decisive for the age-dependent efficacy of the small-molecule TrkB receptor agonist THF.

Poly (ADP-Ribose) Polymerase-1 (PARP1) Deficiency and Pharmacological Inhibition by Pirenzepine Protects From Cisplatin-Induced Ototoxicity Without Affecting Antitumor Efficacy.

Cisplatin remains an indispensable drug for the systemic treatment of many solid tumors. However, a major dose-limiting side-effect is ototoxicity. In some scenarios, such as treatment of germ cell tumors or adjuvant therapy of non-small cell lung cancer, cisplatin cannot be replaced without undue loss of efficacy. Inhibition of polyadenosine diphosphate-ribose polymerase-1 (PARP1), is presently being evaluated as a novel anti-neoplastic principle. Of note, cisplatin-induced PARP1 activation has been related to inner ear cell death. Thus, PARP1 inhibition may exert a protective effect on the inner ear without compromising the antitumor activity of cisplatin. Here, we evaluated PARP1 deficiency and PARP1 pharmacological inhibition as a means to protect the auditory hair cells from cisplatin-mediated ototoxicity. We demonstrate that cisplatin-induced loss of sensory hair cells in the organ of Corti is attenuated in PARP1-deficient cochleae. The PARP inhibitor pirenzepine and its metabolite LS-75 mimicked the protective effect observed in PARP1-deficient cochleae. Moreover, the cytotoxic potential of cisplatin was unchanged by PARP inhibition in two different cancer cell lines. Taken together, the results from our study suggest that the negative side-effects of cisplatin anti-cancer treatment could be alleviated by a PARP inhibition adjunctive therapy.

Triphasic Pulses in Cochlear Implant Patients With Facial Nerve Stimulation.

OBJECTIVE: Evaluation of triphasic pulse stimulation in comparison to the traditional biphasic pulse stimulation in cochlear implant (CI) patients with unintended facial nerve costimulation. STUDY DESIGN: Retrospective case review. SETTING: Cochlear Implant Center of a University Department of Otolaryngology, Head and Neck Surgery. PATIENTS: Fifteen CI patients (MED-EL, Innsbruck, Austria) received a triphasic fitting map instead of a biphasic fitting map due to a previous diagnosis of facial nerve stimulation or stimulus induced pain during the years 2014 to 2017. INTERVENTION(S): Application of a triphasic stimulation strategy. MAIN OUTCOME MEASURE(S): Reduction of facial nerve costimulation and speech understanding. Biphasic and triphasic fitting maps were compared to accurately assess the effects of the switch, and hearing tests (monosyllables and sentences in noise tests) were analyzed. RESULTS: Triphasic pulse stimulation showed a significant reduction of unintended side effects and resulted in an observed improved quality of life in most cases. Although there was no significant change in the understanding of speech with CI in all test situations, in many cases, improvement was observed. CONCLUSIONS: Triphasic pulse stimulation had a beneficial effect for CI patients with severe, unintended costimulation and should be considered a valuable tool during CI fitting.

A Big Data Perspective on the Genomics of Hearing Loss. / Big data in der Diagnostik genetischer Schwerhörigkeit.

The completion of the human genome, the most fundamental example of big data in science and medicine, is the remarkable product of multidisciplinary collaboration and is regarded as one of the largest and most successful undertakings in human history. Unravelling the human genome means not only identifying the sequence of its more than 3.2 billion nucleotide bases, but also understanding disease-associated variations and applying this knowledge to patient-tailored precision medicine approaches. Genomics has moved at a remarkable pace, with much of the propelling forces behind this credited to technological developments in sequencing, computing, and bioinformatics, that have given rise to the term "big genomics data." The analysis of genetics data in a disease context involves the use of several big data resources that take the form of clinical genetics data repositories, in silico prediction tools, and allele frequency databases. These exceptional developments have cultivated high-throughput sequencing technologies that are capable of producing affordable high-quality data ranging from targeted gene panels to exomes and genomes. These new advancements have revolutionized the diagnostic paradigm of hereditary diseases including genetic hearing loss.Dissecting hereditary hearing loss is exceptionally challenging due to extensive genetic and clinical heterogeneity. There are presently over 150 genes involved in non-syndromic and common syndromic forms of hearing loss. The mutational spectrum of a single hearing loss associated-gene can have several tens to hundreds of pathogenic variants. Moreover, variant interpretation of novel variants can pose a challenge when conflicting information is deposited in valuable databases. Harnessing the power that comes from detailed and structured phenotypic information has proven promising for some forms of hearing loss, but may not be possible for all genetic forms due to highly variable clinical presentations. New knowledge in both diagnostic and scientific realms continues to rapidly accumulate. This overwhelming amount of information represents an increasing challenge for medical specialists. As a result, specialist medical care may evolve to take on new tasks and facilitate the interface between the human genetic diagnostic laboratory and the patient. These tasks include genetic counselling and the inclusion of genetics results in patient care.This overview is intended to serve as a reference to otolaryngologists who wish to gain an introduction to the molecular genetics of hearing loss. Key concepts of molecular genetic diagnostics will be presented. The complex processes underlying the identification and interpretation of genetic variants in particular would be inconceivable without the enormous amount of data available. In this respect, "big data" is an indispensable prerequisite for filtering genetic data in specific individual cases and making it clear and useful, especially for clinicians in contact with patients.

Olfactory Dysfunction in Patients With CNGB1-Associated Retinitis Pigmentosa.

Importance: Co-occurrence of retinitis pigmentosa (RP) and olfactory dysfunction may have a common genetic cause. Objective: To report olfactory function and the retinal phenotype in patients with biallelic mutations in CNGB1, a gene coding for a signal transduction channel subunit expressed in rod photoreceptors and olfactory sensory neurons. Design, Setting, and Participants: This case series was conducted from August 2015 through July 2017. The setting was a multicenter study involving 4 tertiary referral centers for inherited retinal dystrophies. Participants were 9 patients with CNGB1-associated RP. Main Outcomes and Measures: Results of olfactory testing, ocular phenotyping, and molecular genetic testing using targeted next-generation sequencing. Results: Nine patients were included in the study, 3 of whom were female. Their ages ranged between 34 and 79 years. All patients had an early onset of night blindness but were usually not diagnosed as having RP before the fourth decade because of slow retinal degeneration. Retinal features were characteristic of a rod-cone dystrophy. Olfactory testing revealed reduced or absent olfactory function, with all except one patient scoring in the lowest quartile in relation to age-related norms. Brain magnetic resonance imaging and electroencephalography measurements in response to olfactory stimulation were available for 1 patient and revealed no visible olfactory bulbs and reduced responses to odor, respectively. Molecular genetic testing identified 5 novel (c.1312C>T, c.2210G>A, c.2492+1G>A, c.2763C>G, and c.3044_3050delGGAAATC) and 5 previously reported mutations in CNGB1. Conclusions and Relevance: Mutations in CNGB1 may cause an autosomal recessive RP-olfactory dysfunction syndrome characterized by a slow progression of retinal degeneration and variable anosmia or hyposmia.

Positioning a Novel Transcutaneous Bone Conduction Hearing Implant: a Systematic Anatomical and Radiological Study to Standardize the Retrosigmoid Approach, Correlating Navigation-guided, and Landmark-based Surgery.

HYPOTHESIS: Anatomical and radiological evaluation improves safety and accuracy of the retrosigmoid approach for positioning a transcutaneous bone conduction implant and provides anatomical reference data for standardized, landmark-based implantation at this alternative site. BACKGROUND: The primary implantation site for the floating mass transducer of a novel bone conduction hearing implant is the mastoid. However, anatomical limitations or previous mastoid surgery may prevent mastoid implantation. Therefore, the retrosigmoid approach has been introduced as an alternative. METHODS: Mastoid and retrosigmoid implantation sites were radiologically identified and evaluated in preoperative computed tomography scans of anatomical head specimens. Navigation-guided implantation was then performed in the retrosigmoid site (n = 20). The optimal retrosigmoid position was determined in relation to both the asterion and the mastoid notch as surgical landmarks in an anatomical coordinate system. RESULTS: Preoperative radiological analysis revealed spatial limitations in the mastoid in 45% of the specimens. Navigation-guided retrosigmoid implantation was possible without affecting the sigmoid sinus in all the specimens. The optimal implantation site was located 1.9 ±â€Š0.1 cm posterior/1.7 ±â€Š0.1 cm inferior to the asterion and 3.3 ±â€Š0.2 cm posterior/2.1 ±â€Š0.1 cm superior to the mastoid notch.Retrosigmoid skull thickness was 6.6 ±â€Š0.4 mm, measured anatomically, 7.0 ±â€Š0.4 mm, measured radiologically and 6.7 ±â€Š0.5 mm, measured with the navigation software. CONCLUSION: The navigation-guided retrosigmoid approach seemed to be a reliable procedure in all the specimens. Measurements of bone thickness revealed the need for spacers in 95% of the specimens. Reference coordinates of the optimal implantation site are provided and can confirm image-guided surgery or facilitate orientation if a navigation system is not available.

Long-Term Outcomes of Vibroplasty Coupler Implantations to Treat Mixed/Conductive Hearing Loss.

OBJECTIVE: To evaluate the long-term safety and performance of four different vibroplasty couplers (round window, oval window, CliP and Bell coupler) in combination with an active middle ear implant. METHODS: This was a multicentre, prospective, long-term study including 5 German hospitals. Thirty adult subjects suffering from conductive or mixed hearing loss were initially enrolled for the study, 24 of these were included in the final analysis with up to 36 months of postsurgical follow-up data. Bone conduction and air conduction were measured pre- and postoperatively to evalu ate safety. Postoperative aided sound field thresholds and Freiburger monosyllable word recognition scores were compared to unaided pre-implantation results to confirm performance. Additional speech tests compared postoperative unaided with aided results. To determine patient satisfaction, an established quality-of-life questionnaire developed for conventional hearing aid usage was administered to all subjects. RESULTS: Mean postoperative bone conduction thresholds remained stable throughout the whole study period. Mean functional gain for all couplers investigated was 38.5 ± 11.4 dB HL (12 months) and 38.8 ± 12.5 dB HL (36 months). Mean word recognition scores at 65 dB SPL increased from 2.9% in the unaided by 64.2% to 67.1% in the aided situation. The mean postoperative speech reception in quiet (or 50% understanding of words in sentences) shows a speech intelligibility improvement at 36 months of 17.8 ± 12.4 dB SPL over the unaided condition. The signal-to-noise ratio (SNR) improved by 5.9 ± 7.2 dB SNR over the unaided condition. High subjective device satisfaction was reflected by the International Inventory for Hearing Aids scored very positively. CONCLUSION: A significant improvement was seen with all couplers, and audiological performance did not significantly differ between 12 and 36 months after surgery.

Attitudes Toward e-Health: The Otolaryngologists' Point of View.

INTRODUCTION: Online communication and the number of e-health applications have noticeably increased. However, little is known about the otolaryngologists' use behavior and their attitudes toward the potential of e-health. The aims of the study were to evaluate the documentation, information, and communication technologies used by otolaryngologists and to get a better understanding of their attitudes toward the potential of e-health for cross-sectoral patient care. METHODS: A survey was developed and tested by otolaryngologists, healthcare-information technology experts, and health services researchers. A total of 334 otolaryngologists in private practice were asked to participate in this cross-sectional study. In total, 234 of them took part in the study, and 157 returned completed questionnaires. Statistical analysis was performed by using crosstabs, including chi-square tests, and multivariate logistic regressions. Results and Materials: Digital technologies are widely used by otolaryngologists (e.g., 89.6% use an electronic health record). However, the majority of intersectoral communication is still based on analogue techniques (e.g., fax use in 63.7%). From the otolaryngologists' perspectives, the potential of e-health for intersectoral care is mostly in appointment scheduling, further referrals to hospitals, and automated appointment reminders. The physicians' attitudes toward e-health are associated with their Internet use behavior in daily life (odds ratio = 4.30, confidence interval 1.11-16.64, p = 0.035) but not with their demographics. DISCUSSION: The otolaryngologists are well prepared and have an overall positive attitude toward e-health for deeper use in cross-sectoral care. Therefore, e-health in otolaryngology needs more attention and resources for further studies, especially with a focus on quality and safety of care.

Myelin-induced inhibition in a spiral ganglion organ culture - Approaching a natural environment in vitro.

The performance of a cochlear implant depends on the defined interaction between afferent neurons of the spiral ganglion and the inserted electrode. Neurite outgrowth can be induced by neurotrophins such as brain-derived neurotrophic factor (BDNF) via tropomyosin kinase receptor B (TrkB). However, neurotrophin signaling through the p75 neurotrophin receptor (p75) inhibits neurite outgrowth in the presence of myelin. Organotypic cultures derived from postnatal (P3-5) mice were used to study myelin-induced inhibition in the cochlear spiral ganglion. Neurite outgrowth was analyzed and quantified utilizing an adapted Sholl analysis. Stimulation of neurite outgrowth was quantified after application of BDNF, the selective TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) and a selective inhibitor of the Rho-associated kinase (Y27632), which inhibits the p75 pathway. Myelin-induced inhibition was assessed by application of myelin-associated glycoprotein (MAG-Fc) to stimulate the inhibitory p75 pathway. Inhibition of neurite outgrowth was achieved by the selective TrkB inhibitor K252a. Stimulation of neurite outgrowth was observed after treatment with BDNF, 7,8 DHF and a combination of BDNF and Y27632. The 7,8-DHF-induced growth effects could be inhibited by K252a. Furthermore, inhibition of neurite outgrowth was observed after supplementation with MAG-Fc. Myelin-induced inhibition could be overcome by 7,8-DHF and the combination of BDNF and Y27632. In this study, myelin-induced inhibition of neurite outgrowth was established in a spiral ganglion model. We reveal that 7,8-DHF is a viable novel compound for the stimulation of neurite outgrowth in a myelin-induced inhibitory environment. The combination of TrkB stimulation and ROCK inhibition can be used to overcome myelin inhibition.

Biofunctionalized peptide-based hydrogels provide permissive scaffolds to attract neurite outgrowth from spiral ganglion neurons.

Cochlear implants (CI) allow for hearing rehabilitation in patients with sensorineural hearing loss or deafness. Restricted CI performance results from the spatial gap between spiral ganglion neurons and the CI, causing current spread that limits spatially restricted stimulation and impairs frequency resolution. This may be substantially improved by guiding peripheral processes of spiral ganglion neurons towards and onto the CI electrode contacts. An injectable, peptide-based hydrogel was developed which may provide a permissive scaffold to facilitate neurite growth towards the CI. To test hydrogel capacity to attract spiral ganglion neurites, neurite outgrowth was quantified in an in vitro model using a custom-designed hydrogel scaffold and PuraMatrix®. Neurite attachment to native hydrogels is poor, but significantly improved by incorporation of brain-derived neurotrophic factor (BDNF), covalent coupling of the bioactive laminin epitope IKVAV and the incorporation a full length laminin to hydrogel scaffolds. Incorporation of full length laminin protein into a novel custom-designed biofunctionalized hydrogel (IKVAV-GGG-SIINFEKL) allows for neurite outgrowth into the hydrogel scaffold. The study demonstrates that peptide-based hydrogels can be specifically biofunctionalized to provide a permissive scaffold to attract neurite outgrowth from spiral ganglion neurons. Such biomaterials appear suitable to bridge the spatial gap between neurons and the CI.

Multicenter Clinical Trial of Vibroplasty Couplers to Treat Mixed/Conductive Hearing Loss: First Results.

OBJECTIVE: To evaluate the safety and effectiveness of round window (RW), oval window (OW), CliP and Bell couplers for use with an active middle ear implant. METHODS: This is a multicenter, long-term, prospective trial with consecutive enrollment, involving 6 university hospitals in Germany. Bone conduction, air conduction, implant-aided warble-tone thresholds and Freiburger monosyllable word recognition scores were compared with unaided preimplantation results in 28 moderate-to-profound hearing-impaired patients after 12 months of follow-up. All patients had previously undergone failed reconstruction surgeries (up to 5 or more). In a subset of patients, additional speech tests at 12 months postoperatively were used to compare the aided with the unaided condition after implantation with the processor switched off. An established quality-of-life questionnaire for hearing aids was used to determine patient satisfaction. RESULTS: Postoperative bone conduction remained stable. Mean functional gain for all couplers was 37 dB HL (RW = 42 dB, OW = 35 dB, Bell = 38 dB, CliP = 27 dB). The mean postoperative Freiburger monosyllable score was 71% at 65 dB SPL. The postimplantation mean SRT50 (speech reception in quiet for 50% understanding of words in sentences) improved on average by 23 dB over unaided testing and signal-to-noise ratios also improved in all patients. The International Outcome Inventory for Hearing Aids (IOI-HA)quality-of-life questionnaire was scored very positively by all patients. CONCLUSION: A significant improvement was seen with all couplers, and patients were satisfied with the device at 12 months postoperatively. These results demonstrate that an active implant is an advantage in achieving good hearing benefit in patients with prior failed reconstruction surgery.

Assessing cisplatin-induced ototoxicity and otoprotection in whole organ culture of the mouse inner ear in simulated microgravity.

Cisplatin is a widely used anti-cancer drug. Ototoxicity is a major dose-limiting side-effect. A reproducible mammalian in-vitro model of cisplatin ototoxicity is required to screen and validate otoprotective drug candidates. We utilized a whole organ culture system of the postnatal mouse inner ear in a rotating wall vessel bioreactor under "simulated microgravity" culture conditions. As previously described this system allows whole organ culture of the inner ear and quantitative assessment of ototoxic effects of aminoglycoside induced hair cell loss. Here we demonstrate that this model is also applicable to the assessment of cisplatin induced ototoxicity. In this model cisplatin induced hair cell loss was dose and time dependent. Increasing exposure time of cisplatin led to decreasing EC50 concentrations. Outer hair cells were more susceptible than inner hair cells, and hair cells in the cochlear base were more susceptible than hair cells in the cochlear apex. Initial cisplatin dose determined the final extent of hair cell loss irrespective if the drug was withdrawn or continued. Dose dependant otoprotection was demonstrated by co-administration of the antioxidant agent N-acetyl l-cysteine. The results support the use of this inner ear organ culture system as an in vitro assay and validation platform for inner ear toxicology and the search for otoprotective compounds.

Temporal bone changes in patients with Goldenhar syndrome with special emphasis on inner ear abnormalities.

OBJECTIVE: Goldenhar syndrome is a developmental disorder presenting with orofacial and vertebral anomalies, which are also accompanied by abnormalities in other organs. We examined temporal bone changes with special emphasis on inner ear abnormalities in these patients. STUDY DESIGN: A retrospective review of 7 new cases in addition to a previously published series of 14 cases with clinically diagnosed Goldenhar syndrome was carried out to search for inner ear anomalies. In addition, temporal bone imaging studies from the literature were summarized and compared with our results. SETTING: Departments of Neuroradiology and Otorhinolaryngology at a university hospital. PATIENTS: In addition to the previous series of 14 patients, 7 new patients with Goldenhar syndrome were identified. INTERVENTIONS: Patients underwent otologic examination, audiometric studies, and high-resolution computed tomography (CT) or magnetic resonance imaging (MRI) of the temporal bone. MAIN OUTCOME MEASURE: Temporal bone changes and specifically inner ear malformations. RESULTS: Nineteen of 21 patients showed changes of the external and middle ear correlating with the literature. Seven of 21 patients showed inner ear abnormalities constituting one-third of all patients. These ranged from mild such as vestibular enlargement to severe defects such as cochlear hypoplasia and common cavity. CONCLUSION: Inner ear abnormalities were present in one-third of patients. Although in some cases, these might not be of clinical significance, some patients show severe defects of the inner ear requiring more complex hearing loss therapy. Therefore, imaging of the temporal bone structures is important in the care of these patients.