Reconstruction of the mouse otocyst and early neuroblast lineage at single-cell resolution.

The otocyst harbors progenitors for most cell types of the mature inner ear. Developmental lineage analyses and gene expression studies suggest that distinct progenitor populations are compartmentalized to discrete axial domains in the early otocyst. Here, we conducted highly parallel quantitative RT-PCR measurements on 382 individual cells from the developing otocyst and neuroblast lineages to assay 96 genes representing established otic markers, signaling-pathway-associated transcripts, and novel otic-specific genes. By applying multivariate cluster, principal component, and network analyses to the data matrix, we were able to readily distinguish the delaminating neuroblasts and to describe progressive states of gene expression in this population at single-cell resolution. It further established a three-dimensional model of the otocyst in which each individual cell can be precisely mapped into spatial expression domains. Our bioinformatic modeling revealed spatial dynamics of different signaling pathways active during early neuroblast development and prosensory domain specification.

Early Timing of Thyroidectomy for Hyperthyroidism in Graves' Disease Improves Biochemical Recovery.

BACKGROUND: The role of thyroidectomy as an early treatment for hyperthyroidism has been poorly investigated. Our aim was to examine its success rates, particularly focusing on thyroidectomy as an early treatment. METHODS: Patients with thyroidectomy for hyperthyroidism between February 2008 and October 2014 were included. They were divided into two groups (early and delayed thyroidectomy), and patient characteristics, treatment indications, complications and time to biochemical recovery were analyzed. RESULTS: Ninety-nine patients met the inclusion criteria, of whom 65 (66%) suffered from Graves' disease, 25 (25%) from toxic goiters and 9 (9%) from amiodarone-induced hyperthyroidism. Structural abnormalities of the thyroid (39 patients, 39%) represented the most frequent indications for thyroidectomy. Forty-six patients (46%) underwent an early and 53 (54%) a delayed surgical approach. Patients with Graves' disease undergoing early thyroidectomy did not suffer more often from complications but had a significantly faster biochemical recovery after surgery than those with a delayed thyroidectomy, as judged by a shorter time to reach TSH (121 ± 24 vs. 240 ± 31 days, p = 0.007) and fT4 (91 ± 29 vs. 183 ± 31 days p = 0.015) levels in the normal range. As expected, there were no recurrences of hyperthyroidism. CONCLUSIONS: Early thyroidectomy was neither associated with permanent complications nor thyroid storm, but with a significantly improved biochemical recovery and therefore has to be recommended early in patients with Graves' disease.

Delayed diagnosis of sinonasal lymphoma due to bilateral manifestation.

The objective of this study is to analyze the presenting symptoms, the time to correct diagnosis and outcome of a European patient cohort with sinonasal lymphoma focusing on unilateral vs. bilateral sinonasal involvement. In a retrospective setting in a European tertiary referral center, eleven patients (9 males, 2 females) with sinonasal lymphoma diagnosed between 2002 and 2015 were identified and divided into a unilateral and bilateral group according to their CT finding. Clinical findings on first presentation, the presence of B symptoms, the radiologic findings, overall survival and disease-specific survival were assessed. 55 % of the patients suffered from bilateral manifestation, which was associated with a delayed diagnosis (10 vs. 1.5 months, p < 0.05). B symptoms (67 vs. 0 %) and death of disease (50 vs. 0 %) were observed only in the bilateral group. Nasal NK/T-cell lymphoma was the most frequent diagnosis, followed by diffuse large B-cell lymphoma. Bilateral mucosal manifestation with B symptoms was shown to be common within the rare entity of sinonasal lymphomas and patients with bilateral sinonasal manifestation are at risk for a delayed diagnosis with worse outcome.

Sound localization measured by eye-tracking.

OBJECTIVE: To introduce a new method of measuring sound localization ability based on eye-tracking and to test this method by analysing the influence of mild induced conductive hearing loss on sound localization. DESIGN: Sound signals were presented from different angles, and the participant's responses were measured using an eye-tracking device. For validation, a comparison of responses to visual stimuli was performed. To test the clinical application of this method, a mild conductive hearing loss was simulated, and the impact of this change on sound localization was measured. STUDY SAMPLE: Fifteen participants. RESULTS: The system provided repeatable measurements, and there was a good correlation of sound and visual signals. A large number of trials could be completed fairly rapidly. Following the induced conductive hearing loss, a decline of 5.5° in the accuracy of sound localization in the horizontal plane was found towards the side of the non-impaired ear for frontal presentations. CONCLUSIONS: Quantifying sound localization by eye-tracking was found to be feasible, fast and accurate. A mild conductive hearing loss caused a slight degradation of sound localization accuracy within the 30° frontal sector, which is in good agreement with results found using methods requiring more extensive instrumentation.

Objective assessment of stapedotomy surgery from round window motion measurement.

OBJECTIVES: As prostheses and techniques related to stapes surgery develop and improve, there is a need to assess the functional outcomes of the surgery objectively. This study provides a bench test method to assess the functional results of stapes surgery by measuring volume displacement at the round window (RW), which is closely related to pressure propagation of the travelling wave inside the cochlea and thus to hearing. DESIGN: Motion of the RW membrane in fresh temporal bones was measured using a scanning laser Doppler interferometry system for normal and reconstructed conditions, and the performance of the reconstruction with stapes surgery was quantitatively assessed by comparison of the volume displacements at the RW between the two conditions. To obtain optimal measurements, reflectivity of the laser beam of the scanning laser Doppler interferometry system was improved by retroreflective beads coated onto the surface of the RW, and orientation of the RW membrane relative to the laser beam was obtained using micro-computed tomography imaging. RESULTS: From measurements in 12 temporal bones, difference in the RW volume displacement between normal ears and ears reconstructed with stapes surgery was approximately 15 dB below 2 kHz and approximately 10 dB above 4 kHz, which was comparable with air-bone gaps in patients after stapes surgery. Two different sizes of the stapes prostheses were also tested (n = 3), and a tendency toward a better outcome with a larger diameter was found. CONCLUSION: The method developed in this study can be used to assess various prostheses and surgical conditions objectively in controlled laboratory environments. It may also have potential for providing ways to assess other middle- and inner-ear surgeries, and to study other aspects of hearing science.

Cost-Effectiveness of Septorhinoplasty.

Importance: Septorhinoplasties are performed for functional, aesthetic, or a combination of these indications. As a nonvital intervention, cost-effectiveness may be questioned. Objective: To determine the cost-effectiveness of septorhinoplasty. Design and Setting: The literature was reviewed for revision rates (RRs) and health utility values (HUVs) for both septorhinoplasty and revision septorhinoplasty. Age-specific mortality rates and life expectancies were used. Costs were gathered from international settings and analyzed in an adapted Markov model. Intervention: Septorhinoplasty versus no intervention. Main Outcomes and Measures: Cost-efficiency was calculated for different willingness-to-pay thresholds in a probabilistic sensitivity analysis. The effect of different parameters (costs, RRs, HUVs, age, gender) were reviewed and addressed in a sensitivity analysis for an incremental cost-effectiveness ratio (ICER) willingness-to-pay threshold of $50,000/quality-adjusted life year (QALY). Results: The ICER for septorhinoplasty for a 40-year-old woman ranges from $1216 to $3509/QALY (depending on the country) in comparison with no intervention. Septorhinoplasty is cost-effective in 98.8% (for a $50,000/QALY threshold). The sensitivity analysis showed high robustness of the cost-effectiveness for various scenarios. Conclusions and Relevance: Septorhinoplasty is a highly cost-effective treatment.

Cost Effectiveness of Cochlear Implantation in Single-Sided Deafness.

OBJECTIVE: To analyze the cost effectiveness of cochlear implantation (CI) for the treatment of single-sided deafness (SSD). STUDY DESIGN: Cost-utility analysis in an adapted Markov model. SETTING: Adults with single-sided deafness in a high-income country. INTERVENTION: Unilateral CI was compared with no intervention. MAIN OUTCOME MEASURE: Incremental cost-effectiveness ratios were compared with different cost-effectiveness thresholds ($10,000 to $150,000) for different age, sex, and cost combinations. The calculations were based on the quality-adjusted life year (QALY), national life expectancy tables, and different cost settings. The health utility values for the QALY were either directly collected from published data, or, derived from published data using a regression model of multiple utility indices (regression estimate). RESULTS: The regression estimate showed an increase of the health utility value from 0.62 to 0.74 for SSD patients who underwent CI. CI for SSD was cost effective for women up to 64 years ($50,000 per-QALY threshold), 80 years ($100,000 per-QALY threshold), and 86 years ($150,000 per-QALY threshold). For men, these values were 58, 77, and 84, respectively. Changing the discount rate by up to 5% further increased the cutoff ages up to 5 years. A detailed cost and age sensitivity analysis is presented and allows testing for cost effectiveness in local settings worldwide. CONCLUSIONS: CI is a cost-effective option to treat patients with SSD.

Age Dependent Cost-Effectiveness of Cochlear Implantation in Adults. Is There an Age Related Cut-off?

OBJECTIVE: To analyze the impact of age at implantation on the cost-effectiveness of cochlear implantation (CI). STUDY DESIGN: Cost-utility analysis in an adapted Markov model. SETTING: Adults with profound postlingual hearing loss in a "high income" country. INTERVENTION: Unilateral and sequential CI were compared with hearing aids (HA). MAIN OUTCOME MEASURE: Incremental cost-effectiveness ratio (ICER), calculated as costs per quality adjusted life year (QALY) gained (in CHF/QALY), for individual age and sex combinations in relation to two different willingness to pay thresholds. 1 CHF (Swiss franc) is equivalent to 1.01 USD. RESULTS: When a threshold of 50,000 CHF per QALY is applied, unilateral CI in comparison to HA is cost-effective up to an age of 91 for women and 89 for men. Sequential CI in comparison to HA is cost-effective up to an age of 87 for women and 85 for men. If a more contemporary threshold of 100,000 CHF per QALY is applied, sequential CI in comparison to unilateral CI is cost-effective up to an age of 80 for women and 78 for men. CONCLUSIONS: Performing both sequential and unilateral CI is cost-effective up to very advanced ages when compared with hearing aids.

The Role of Non-Echoplanar Diffusion-Weighted Magnetic Resonance Imaging in Diagnosis of Primary Cholesteatoma and Cholesteatoma Recidivism as an Adjunct to Clinical Evaluation.

INTRODUCTION:: The aim of this study was to analyze the sensitivity and specificity of non-echoplanar (non-EPI) diffusion-weighted (DW) magnetic resonance imaging (MRI) for the detection of cholesteatoma, with a focus on its value as an adjunct to clinical examination. METHODS:: In a prospective cohort study, 92 cases were divided into 2 groups: "clinically cholesteatoma" ( n = 79) and "clinically no cholesteatoma" ( n = 13). Non-EPI DW MRI was performed preoperatively in all cases. The presence of a cholesteatoma was assessed by clinicians otoscopically, by neuroradiologists on non-EPI DW MRI, by the surgeon intraoperatively, and finally by the pathologist postoperatively. Data analysis was performed for specificity, sensitivity, positive predictive value, negative predictive value, and interrater variability. RESULTS:: The sensitivity and specificity were 89.3% and 75%, respectively, in the "clinically cholesteatoma" group and 0% and 100% in the "clinically no cholesteatoma" group. Non-EPI DW MRI had a positive predictive value of 98.5% when cholesteatoma was suspected clinically and a negative predictive value of 84.6% when cholesteatoma was not suspected clinically. CONCLUSION:: If cholesteatoma is suspected clinically, non-EPI DW MRI is not necessary. If there is no clinical suspicion of cholesteatoma in second-look situations, sensitivity is low and serial follow-up MRI with long intervals is advised.

Perineural Invasion in Squamous Cell Carcinoma of the Oral Cavity: Histology, Tumor Stage, and Outcome.

OBJECTIVES/HYPOTHESIS: To analyze the impact of different types of perineural invasion (PNI) in squamous cell carcinoma (SCC) of the oral cavity on overall survival and recurrence rate, with a special focus on histologic subtypes and tumor stage. STUDY DESIGN: Retrospective case-control study with clinicopathological analysis. METHODS: Seventeen patients who received primary surgical treatment for SCC of the oral cavity with PNI were matched to a control group. In a histologic review, PNI was classified into subtypes according to an adapted Liebig classification. The term type A was used to describe tumor invasion into the nerve, whereas type B was used to describe circumferential growth around the nerve. Clinical charts were reviewed, and a Kaplan-Meier survival analysis was performed. RESULTS: The recurrence-free survival rates were 47.1% versus 80.4% (PNI vs. matched control group, P < 0.05), 60.0% versus 94.1% (PNI in stage I and II disease vs. matched control group, P < 0.05) and 41.7% versus 73.5% (PNI in stage III and IV disease vs. matched control group, P < 0.05). In most cases (n = 9) of PNI, both histologic subtypes (type A and type B) were present. Five cases exclusively showed type A, and three cases exclusively showed type B. CONCLUSIONS: Perineural invasion in early disease oral carcinoma has a particularly high impact on survival. Both histologic subtypes showed a significantly worse recurrence-free survival rate when compared to the control group. LEVEL OF EVIDENCE: 3.

Detection of Helicobacter pylori in patients with head and neck cancer: Results from a prospective comparative study combining serology, polymerase chain reaction, and rapid urease test.

BACKGROUND: The purpose of this study was to evaluate prospectively the presence and impact of the gastric carcinogen Helicobacter pylori (H. pylori) in the upper aerodigestive tract. Previous studies suggested it could represent a risk factor for head and neck squamous cell carcinoma (HNSCC). METHODS: Serology, rapid urease test, and quantitative polymerase chain reaction (qPCR) for H. pylori were performed in patients with head and neck cancer (N = 56) and cancer-free controls (N = 90). Comparison between groups was done using logistic regression analysis. RESULTS: Rates of positive serology and rapid urease test did not differ between the 2 groups in logistic regression analysis (p = .677 and p = .633, respectively). Birth in a developing country and age above 50 years old were predictors of positive serology (p < .001 and p = .040, respectively). Using qPCR, no biopsy showed the presence of H. pylori. CONCLUSION: This study challenges the concept that H. pylori may be a risk factor for HNSCC.

Ballistic Reconstruction of a Migrating Bullet in the Parapharyngeal Space.

A 21-year-old male suffering from severe throat pain after being hit by a bullet in Syria claimed that he was shot through his eye and that the bullet subsequently descended behind his throat. Even though the first medical report stated that this course is implausible, meticulous workup provided evidence that the bullet might have entered the parapharyngeal space in a more cranial position than the one it was found eight months later. Our case highlights that bullets are able to move within the body, rendering ballistic reconstruction difficult. However, after removal of the bullet the patient's symptoms completely resolved.

Functional Results and Subjective Benefit of a Transcutaneous Bone Conduction Device in Patients With Single-Sided Deafness.

OBJECTIVE: To analyze speech discrimination scores and subjective benefit of a transcutaneous bone conduction device (tBCD) in adults with single-sided deafness (SSD). STUDY DESIGN: Prospective cohort study. SETTING: Tertiary referral center. PATIENTS: Nine adults with SSD for more than 1 year and normal hearing on the contralateral side (PTA <30 dB HL) were implanted with a tBCD. INTERVENTIONS: Transmastoidal implantation of a Bonebridge (BB, MED-EL) tBCD. MAIN OUTCOME MEASURES: Aided and unaided speech discrimination scores in three different spatial settings were measured using the Oldenburg sentence test (OLSA). Quality of life was assessed by two questionnaires, the Bern Benefit in Single Sided Deafness Questionnaire (BBSS) and the Speech, Spatial and Qualities of Hearing scale for benefit questionnaire (SSQ-B). RESULTS: Speech discrimination scores measured by OLSA showed a mean signal-to-noise ratio improvement of 1.7 dB SPL for the aided condition compared with the unaided condition in the setting where the sound signal is presented on the side of the implanted ear and the noise is coming from the front (p < 0.05). In the other two settings (signal and noise from front; signal from normal hearing ear and noise from front), the signal-to-noise ratio did not change significantly. This benefit became manifest after 6 months. Good satisfaction was indicated by positive results on the questionnaires. CONCLUSION: Speech discrimination in noise for patients implanted with the BB is comparable with patients with other bone conduction hearing aids. A learning curve is clearly detectable. The subjective benefit was rated positively by the patients. With the advantage of intact skin conditions after implantation, the BB is an adequate option for patients with SSD.

Identification and characterization of mouse otic sensory lineage genes.

Vertebrate embryogenesis gives rise to all cell types of an organism through the development of many unique lineages derived from the three primordial germ layers. The otic sensory lineage arises from the otic vesicle, a structure formed through invagination of placodal non-neural ectoderm. This developmental lineage possesses unique differentiation potential, giving rise to otic sensory cell populations including hair cells, supporting cells, and ganglion neurons of the auditory and vestibular organs. Here we present a systematic approach to identify transcriptional features that distinguish the otic sensory lineage (from early otic progenitors to otic sensory populations) from other major lineages of vertebrate development. We used a microarray approach to analyze otic sensory lineage populations including microdissected otic vesicles (embryonic day 10.5) as well as isolated neonatal cochlear hair cells and supporting cells at postnatal day 3. Non-otic tissue samples including periotic tissues and whole embryos with otic regions removed were used as reference populations to evaluate otic specificity. Otic populations shared transcriptome-wide correlations in expression profiles that distinguish members of this lineage from non-otic populations. We further analyzed the microarray data using comparative and dimension reduction methods to identify individual genes that are specifically expressed in the otic sensory lineage. This analysis identified and ranked top otic sensory lineage-specific transcripts including Fbxo2, Col9a2, and Oc90, and additional novel otic lineage markers. To validate these results we performed expression analysis on select genes using immunohistochemistry and in situ hybridization. Fbxo2 showed the most striking pattern of specificity to the otic sensory lineage, including robust expression in the early otic vesicle and sustained expression in prosensory progenitors and auditory and vestibular hair cells and supporting cells.

Serial analysis of gene expression in the chicken otocyst.

The inner ear arises from multipotent placodal precursors that are gradually committed to the otic fate and further differentiate into all inner ear cell types, with the exception of a few immigrating neural crest-derived cells. The otocyst plays a pivotal role during inner ear development: otic progenitor cells sub-compartmentalize into non-sensory and prosensory domains, giving rise to individual vestibular and auditory organs and their associated ganglia. The genes and pathways underlying this progressive subdivision and differentiation process are not entirely known. The goal of this study was to identify a comprehensive set of genes expressed in the chicken otocyst using the serial analysis of gene expression (SAGE) method. Our analysis revealed several hundred transcriptional regulators, potential signaling proteins, and receptors. We identified a substantial collection of genes that were previously known in the context of inner ear development, but we also found many new candidate genes, such as SOX4, SOX5, SOX7, SOX8, SOX11, and SOX18, which previously were not known to be expressed in the developing inner ear. Despite its limitation of not being all-inclusive, the generated otocyst SAGE library is a practical bioinformatics tool to study otocyst gene expression and to identify candidate genes for developmental studies.

The influence of prosthesis diameter in stapes surgery: a meta-analysis and systematic review of the literature.

OBJECTIVE: To analyze the influence of stapes prosthesis diameter on postoperative hearing results after stapedotomy without interposition in otosclerotic patients. DATA SOURCES: PubMed search from 1970 to 2009 using the key words stapedotomy or stapedectomy or otosclerosis or stapesplasty. STUDY SELECTION: Inclusion criteria to select articles and patient groups for meta-analysis and statistical analyses were as follows: otosclerosis as diagnosis, clear description of technique and prosthesis size, calibrated stapedotomy, and complete report of functional results. DATA EXTRACTION: Five controlled studies were found analyzing the influence of prosthesis diameter and reporting the results in a comparable way for meta-analysis (n = 590). Sixty-two studies not analyzing the influence of prosthesis diameter contained comparable subgroups with a total of 9,536 cases. These cases were pooled according to their diameter (0.3, 0.4, 0.5, 0.6,and 0.8 mm). The results of air conduction, bone conduction, air-bone gap (ABG), and success rate (closure of the ABG within 10 dB as percentage of the total cases) for all groups and frequency-specific ABG results were gathered. Furthermore, 12 clinical and experimental studies were reviewed that did not contribute to the statistical analysis. DATA SYNTHESIS: A meta-analysis performed for success rate of the 5 controlled studies showed favorable results for 0.6-mm over 0.4-mm prostheses (success rate, 67% versus 58%, p = 0.05). In the statistical analysis of the pooled data, the 0.6-mm prosthesis showed better results compared with 0.4 mm (p < 0.001) in the postoperative air conduction threshold (29 dB versus 35 dB), postoperative ABG (7 dB versus 11 dB), ABG improvement (25 dB versus 21 dB), and success rate (81.1% versus 75.1%). The frequency-specific analysis of the postoperative ABG showed no advantage for the small prosthesis in the high frequencies. There was no difference in postoperative change of bone conduction in the 0.6- and 0.4-mm groups. Statistically significant results could not be assessed for other prosthesis diameters because of the small number of cases reported. CONCLUSION: A 0.6-mm diameter piston prosthesis is associated with significantly better results than a 0.4-mm prosthesis and should be used if the surgical conditions allow it.

Intrinsic regenerative potential of murine cochlear supporting cells.

The lack of cochlear regenerative potential is the main cause for the permanence of hearing loss. Albeit quiescent in vivo, dissociated non-sensory cells from the neonatal cochlea proliferate and show ability to generate hair cell-like cells in vitro. Only a few non-sensory cell-derived colonies, however, give rise to hair cell-like cells, suggesting that sensory progenitor cells are a subpopulation of proliferating non-sensory cells. Here we purify from the neonatal mouse cochlea four different non-sensory cell populations by fluorescence-activated cell sorting (FACS). All four populations displayed proliferative potential, but only lesser epithelial ridge and supporting cells robustly gave rise to hair cell marker-positive cells. These results suggest that cochlear supporting cells and cells of the lesser epithelial ridge show robust potential to de-differentiate into prosensory cells that proliferate and undergo differentiation in similar fashion to native prosensory cells of the developing inner ear.

Subjective and objective results after bilateral cochlear implantation in adults.

OBJECTIVE: To assess and compare subjective and objective results after bilateral cochlear implantation with a special emphasis on time interval between the first and second implant. STUDY DESIGN: Clinical trial. SETTING: Tertiary referral center. PATIENTS: All consecutively bilaterally implanted adult patients who had used the second implant for more than 6 months were selected for the study. They had to have the mental capacity to answer questions regarding their hearing abilities and fill out a questionnaire (n = 34). Twenty-nine patients (85%) finally could be included in the study (age at first implantation, 31.0 +/- 16 yr [mean +/- standard deviation {SD}], time to second implantation, 5.6 +/- 5.7 yr [mean +/- SD]). In all patients, a full insertion (21 electrodes) of the implant was achieved. For the subjective part of the study, the patients were matched with unilaterally implanted subjects selected according to specified criteria. INTERVENTIONS: Sequential or simultaneous cochlear implantation with a Nucleus device. MAIN OUTCOME MEASURES: Speech comprehension measures were performed using the Oldenburger sentences in quiet and in noise with unilateral and bilateral implant use. Summation effect, head shadow effect, squelch effect, and interaural difference in quiet and noise were calculated. Advantage for binaural stimulation with respect to the unilateral condition was assessed for each individual. Additionally, a localization test was performed using 12 speakers arranged in a circle. Subjective benefit was assessed by a questionnaire (The Speech, Spatial and Qualities of Hearing Scale). Results were analyzed with special emphasis on effects of timing and intervals. RESULTS: There was a statistically significant advantage for the head shadow effect test (p < 0.05) when the sound source was located on the activated side. There was also a statistically significant correlation of the subjective and objective results and a strong correlation of the interaural difference of speech intelligibility in quiet and the time interval between the first and the second implant (p < 0.001; r = 55%). In the bi-implanted state, an interaural difference of 18 +/- 27% and 3 +/- 2.2 dB signal-to-noise ratio (mean +/- SD) was measured in quiet and noise, respectively. The mean results for the bilateral condition for the summation effect, the squelch effect, and speech discrimination in quiet were better than in the unilateral condition but were not statistically significant. The subjective results of the bilateral group were better in all categories than the results of the unilateral group but were just below statistical significance. CONCLUSION: Speech understanding in noise is improved with bilateral cochlear implantation with unambiguous evidence that the second implant expands the sound field for effective speech recognition. Communication in daily life is facilitated, as determined by the subjective Speech, Spatial and Qualities of Hearing Scale test. The correlation of the subjective and objective results confirms the practical benefits in daily activities. Although there was improvement with a second Cochlear implant even after a long implantation interval, short intervals lead to better results.