In vivo biodistribution and ototoxicity assessment of cationic liposomal-ceftriaxone via noninvasive trans-tympanic delivery in chinchilla models: Implications for otitis media therapy.

OBJECTIVES: We report the in vivo biodistribution and ototoxicity of cationic liposomal-ceftriaxone (CFX) delivered via ear drop formulation in adult chinchilla. METHODS: CFX was encapsulated in liposomes with size of ∼100 nm and surface charge of +20 mV. 100 µl liposomes or free drug was applied twice daily in both external ear canals of adult chinchillas for either 3 or 10 days. Study groups included free ceftriaxone (CFX, Day 3: n = 4, Day 10: n = 8), liposomal ceftriaxone (CFX-Lipo, Day 3: n = 4, Day 10: n = 8), and a systemic control group (Day 3: n = 4, Day 10: n = 4). Ceftriaxone delivery to the middle ear and systemic circulation was quantified by HPLC assays. Liposome transport was visualized via confocal microscopy. Auditory brainstem response (ABR) tests and cochlear histology were used to assess ototoxicity. RESULTS: Liposomal ceftriaxone (CFX-Lipo) displayed a ∼658-fold increase in drug delivery efficiency in the middle ear relative to the free CFX (8.548 ± 0.4638% vs. 0.013 ± 0.0009%, %Injected dose, Mean ± SEM). CFX measured in blood serum (48.2 ± 7.78 ng/ml) following CFX-Lipo treatment in ear was 41-fold lower compared to systemic free-CFX treatment (1990.7 ± 617.34 ng/ml). ABR tests and histological analysis indicated no ototoxicity due to the treatment. CONCLUSION: Cationic liposomal encapsulation results in potent drug delivery across the tympanic membrane to the middle ear with minimal systemic exposure and no ototoxicity.

Chronic tympanic membrane perforation repair with a collagen-based scaffold: An in vivo model.

OBJECTIVE: The aim of this study was to assess the in vivo efficacy of a novel regenerative collagen-based scaffold developed by the Royal College of Surgeons in Ireland in a chronic tympanic membrane perforation (TMP) using a chinchilla model. METHODS: Bilateral TMPs were induced in 17 mixed gender chinchillas using tympanic membrane resection followed by a mixture of topical Mitomycin C and dexamethasone for 3 days. These were monitored with weekly otoscopy for 8 weeks. Animals were excluded if signs of infection developed in the follow up period (n = 8). At 8 weeks, intervention began and 18 TMPs were assigned to either treatment with the collagen-based scaffold (treated group) or spontaneous healing (control group). Animals were euthanized 6 weeks post-intervention. Otoscopic imaging and auditory brain response (ABR) were conducted at baseline, 8 weeks post-TMP induction and 6 weeks post-intervention. All TMPs were then evaluated at 6 weeks post-intervention and bullae underwent histologic evaluation. RESULTS: At 6 weeks post-intervention, otoscopic imaging demonstrated various degrees of healing in the treated ears. The treated group was noted to have an increased rate of healing when compared to the control group. Histologic evaluation demonstrated a variation in the degree of perforation healing within groups, with some animals in the treated group showing high levels of perforation healing. At 8 weeks after the TMP procedure, most of the animals had worsened hearing response. At 6-week post the collagen-based scaffold treatment, about 50 % (4/8) of the treated ears had improved in hearing response as compared to those of non-treated ears. CONCLUSION: Given the initial histologic evidence of partial healing in scaffold-treated ears, the post-intervention period should be extended to monitor the potential for complete healing. Given the overall positive findings related to healing with the scaffold-treated ears, this material warrants further investigation.

Cochlear Implant Performance in Candidates With Moderate Hearing Loss Qualifying in Noise.

OBJECTIVE: To determine postcochlear implantation performance for patients qualifying on preimplant testing in noise. STUDY DESIGN: Retrospective chart review of cochlear implant recipients. MAIN OUTCOME MEASURE: Performance on word and sentence testing in the implanted ear and bimodal condition were compared between pre- and postimplantation time points. RESULTS: At 2-years postimplantation, CNC testing in quiet in the implanted ear improved from an average percent correct score of 14.0 ±â€Š12.1% to 54.9 ±â€Š14.8% (n = 20, p < 0.0001, d = 3.0) for those qualifying at +8, and from 23.4 ±â€Š15.6% to 55.5 ±â€Š19.4% (n = 28, p < 0.0001, d = 1.8) for those qualifying at +5. Likewise, AzBio in quiet in the implanted ear improved from an average % correct score of 19.9 ±â€Š16.0% to 75.1 ±â€Š11.8% (n = 20, p < 0.0001, d = 4.0) for those qualifying at +8, and from 46.2 ±â€Š21.7% to 74.1 ±â€Š21.3% (n = 27, p < 0.0001, d = 1.4) for those qualifying at +5. CNC and AzBio performance in quiet in the bimodal condition also improved with those qualifying at +8 and +5 having similar average scores at 2-years post activation. For those qualifying at +8, performance improved on CNC and AzBio in the implanted ear in 95% of patients and in the bimodal condition in 89% of patients. The proportion of patients improving on both tests for those qualifying at +5 at 2 years was 85% in the implanted ear, and 72% in the bimodal condition. CONCLUSION: The majority of patients qualifying for cochlear implantation with the addition of noise showed improved speech perception in quiet. These data provide useful counseling tools for patients considering cochlear implantation who do not meet traditional eligibility requirements when tested in quiet.

A Longitudinal Comparison of Environmental Sound Recognition in Adults With Hearing Aids Before and After Cochlear Implantation.

Purpose The aims of this study were (a) to longitudinally assess environmental sound recognition (ESR) before and after cochlear implantation in a sample of postlingually deafened adults and (b) to assess the extent to which spectro-temporal processing abilities influence ESR with cochlear implants (CIs). Method In a longitudinal cohort study, 20 postlingually deafened adults were tested with hearing aids on the Familiar Environmental Sound Test-Identification and AzBio sentences in quiet pre-CI and 6 months post-CI. A subset of 11 participants were also tested 12 months post-CI. Pre-CI spectro-temporal processing was assessed using the Spectral-temporally Modulated Ripple Test. Results Average ESR accuracy pre-CI (M = 63.60%) was not significantly different from ESR accuracy at 6 months (M = 65.40%) or 12 months (M = 69.09%) post-CI. In 11 participants (55%), however, ESR improved following implantation by 10.91 percentage points, on average. Pre-CI ESR correlated moderately and significantly with pre-CI and 12-month post-CI AzBio scores, with a trend toward significance for AzBio performance at 6 months. Pre-CI spectro-temporal processing was moderately associated with ESR at 6 and 12 months post-CI but not with speech recognition post-CI. Conclusions The present findings failed to demonstrate an overall significant improvement in ESR following implantation. Nevertheless, more than half of our sample showed some degree of improvement in ESR. Several environmental sounds were poorly identified both before and after implantation. Spectro-temporal processing ability prior to implantation appears to predict postimplantation performance for ESR. These findings indicate the need for greater attention to ESR following cochlear implantation and for developing individualized targets for ESR rehabilitation. Supplemental Material https://doi.org/10.23641/asha.13876745.

Improved Speech Intelligibility in Subjects With Stable Sensorineural Hearing Loss Following Intratympanic Dosing of FX-322 in a Phase 1b Study.

OBJECTIVES: There are no approved pharmacologic therapies for chronic sensorineural hearing loss (SNHL). The combination of CHIR99021+valproic acid (CV, FX-322) has been shown to regenerate mammalian cochlear hair cells ex vivo. The objectives were to characterize the cochlear pharmacokinetic profile of CV in guinea pigs, then measure FX-322 in human perilymph samples, and finally assess safety and audiometric effects of FX-322 in humans with chronic SNHL. STUDY DESIGNS: Middle ear residence, cochlear distribution, and elimination profiles of FX-322 were assessed in guinea pigs. Human perilymph sampling following intratympanic FX-322 dosing was performed in an open-label study in cochlear implant subjects. Unilateral intratympanic FX-322 was assessed in a Phase 1b prospective, randomized, double-blinded, placebo-controlled clinical trial. SETTING: Three private otolaryngology practices in the US. PATIENTS: Individuals diagnosed with mild to moderately severe chronic SNHL (≤70 dB standard pure-tone average) in one or both ears that was stable for ≥6 months, medical histories consistent with noise-induced or idiopathic sudden SNHL, and no significant vestibular symptoms. INTERVENTIONS: Intratympanic FX-322. MAIN OUTCOME MEASURES: Pharmacokinetics of FX-322 in perilymph and safety and audiometric effects. RESULTS: After intratympanic delivery in guinea pigs and humans, FX-322 levels in the cochlear extended high-frequency region were observed and projected to be pharmacologically active in humans. A single dose of FX-322 in SNHL subjects was well tolerated with mild, transient treatment-related adverse events (n = 15 FX-322 vs 8 placebo). Of the six patients treated with FX-322 who had baseline word recognition in quiet scores below 90%, four showed clinically meaningful improvements (absolute word recognition improved 18-42%, exceeding the 95% confidence interval determined by previously published criteria). No significant changes in placebo-injected ears were observed. At the group level, FX-322 subjects outperformed placebo group in word recognition in quiet when averaged across all time points, with a mean improvement from baseline of 18.9% (p = 0.029). For words in noise, the treated group showed a mean 1.3 dB signal-to-noise ratio improvement (p = 0.012) relative to their baseline scores while placebo-treated subjects did not (-0.21 dB, p = 0.71). CONCLUSIONS: Delivery of FX-322 to the extended high-frequency region of the cochlea is well tolerated and enhances speech recognition performance in multiple subjects with stable chronic hearing loss.

Auditory brainstem responses in aging dark agouti rats.

The present study examined auditory function across age in the dark agouti (DA) rat strain. Auditory brainstem responses (ABRs) were measured for frequencies 8, 16, and 32 kHz in male and female DA rats from 3 to 18 months of age. Hearing thresholds and absolute and interpeak latencies (IPLs) were analyzed. Male hearing thresholds remained stable for the first year of life and then significantly increased at 18 months across all frequencies; female hearing remained stable at all tested ages out to 18 months. At 12 months, male DA rats showed significantly longer absolute latencies by age (i.e., compared with 3-month-old males) and sex (compared with 12-month-old females), with no differences in IPLs. At 18 months, female DA rats showed significantly longer absolute latencies with age (compared with 3-month-old females) and sex (compared with 18-month-old males), particularly for the later waves. Female IPLs were also significantly longer with age and by sex for the later waves. This report supports the feasibility of using male DA rats in studies to investigate age-related hearing loss (ARHL; presbycusis).

Development of in-house genetic screening for pediatric hearing loss.

OBJECTIVES: To evaluate the efficiency of in-house genetic testing for mutations causing the most common types of inherited, nonsyndromic, sensorineural hearing loss (SNHL). METHODS: Retrospective cohort study of 200 patients at a single, pediatric medical center with suspected or confirmed hearing loss who underwent either send out vs in-house genetic testing for mutations in GJB2/GJB6, SLC26A4, and MTRNR1. Primary outcome measure was the difference in mean turnaround time for send-out vs in-house genetic testing. Additional outcomes included associations between audiometric findings and genetic test results. RESULTS: One hundred four send-out tests were performed between October 2010 and June 2014, and 100 in-house tests were performed between November 2014 and November 2016. The mean turnaround time for send-out testing was 53.7 days. The mean turnaround time for in-house testing was 18.9 days. This difference was statistically significant (P < .001). The largest component of turnaround time was the amount of time elapsed between receipt of specimen in the lab and final test result. These intervals were 47.0 and 18.3 days for send-out and in-house tests, respectively. Notably, the longest turnaround time for in-house testing (43 days) was less than the average turnaround time for send-out testing. In addition, we identified two simple audiometric parameters (ie, bilateral newborn hearing screen referral and audiometry showing symmetric SNHL) that may increase diagnostic yield of genetic testing. CONCLUSIONS: The development of in-house genetic testing programs for inherited SNHL can significantly reduce testing turnaround times. Newborn hearing screening and audiometry results can help clinicians identify patients most likely to benefit from genetic testing. LEVEL OF EVIDENCE: IV.

TMTC2 variant associated with sensorineural hearing loss and auditory neuropathy spectrum disorder in a family dyad.

BACKGROUND: Sensorineural hearing loss (SNHL) is a common form of hearing loss that can be inherited or triggered by environmental insults; auditory neuropathy spectrum disorder (ANSD) is a SNHL subtype with unique diagnostic criteria. The genetic factors associated with these impairments are vast and diverse, but causal genetic factors are rarely characterized. METHODS: A family dyad, both cochlear implant recipients, presented with a hearing history of bilateral, progressive SNHL, and ANSD. Whole-exome sequencing was performed to identify coding sequence variants shared by both family members, and screened against genes relevant to hearing loss and variants known to be associated with SNHL and ANSD. RESULTS: Both family members are successful cochlear implant users, demonstrating effective auditory nerve stimulation with their devices. Genetic analyses revealed a mutation (rs35725509) in the TMTC2 gene, which has been reported previously as a likely genetic cause of SNHL in another family of Northern European descent. CONCLUSION: This study represents the first confirmation of the rs35725509 variant in an independent family as a likely cause for the complex hearing loss phenotype (SNHL and ANSD) observed in this family dyad.

Improved Speech Perception in Cochlear Implant Users With Interleaved High-Rate Pulse Trains.

OBJECTIVE: Electrical stimulation with a cochlear implant (CI) elicits abnormally high neural synchrony, which poses significant challenges for speech perception. Previous investigations showed that constant-amplitude high-rate pulse trains (HRPs) desynchronize neural responses and improve stimulus encoding. The study objective was to investigate the effects of HRP on speech perception in adult CI users. STUDY DESIGN: Prospective, within-subject design. SETTING: Tertiary CI center. PATIENTS: Ten adult CI recipients. INTERVENTION: Sentence stimuli were created by modifying a basic continuous interleaved sampling (CIS) strategy (1,000 pulses per second; pps) with interleaved biphasic pulse trains (3,000 pps) on even electrodes. Institute of Electrical and Electronics Engineers sentences in quiet and in noise were tested without HRP, and with HRPs of various stimulation levels. MAIN OUTCOME MEASURE: Sentence perception in percent correct was calculated for all conditions. The highest speech perception score with HRP stimulation was defined as "max-HRP." RESULTS: Group analyses showed significantly improved sentence perception in background noise with HRPs (p < 0.001). There was no significant difference for sentence perception in quiet for the group. However, seven of 10 subjects experienced some benefit from HRP stimuli in quiet and the degree of HRP benefit showed significant relationships with baseline performance and age at implantation, indicating that HRP stimuli may be most beneficial for older patients or poorer performers. CONCLUSIONS: Significant improvement in speech perception in noise was observed with HRP stimuli. Some recipients may also benefit from HRP stimulation in quiet. Interleaved HRPs hold promise as a novel stimulation paradigm with clinical sound processing strategies to improve patient performance.

Tablet-based Screening for Hearing Loss: Feasibility of Testing in Nonspecialty Locations.

OBJECTIVE: To determine the feasibility of audiometric screening with tablet-based applications in typical clinic locations: examination room and clinic waiting area. STUDY DESIGN: A randomized prospective study. SETTING: Tertiary referral center. PATIENTS: Participants included 107 adult patients referred for audiometric testing to assess hearing loss. INTERVENTION: Each patient completed standard audiometry testing and one of three tablet-based audiometric applications that included pure-tone air conduction testing. The tablet-based audiometric testing was completed in a quiet examination room and a clinic waiting area using noise-cancellation headphones. A 5-question patient satisfaction survey was completed at the end of the testing. MAIN OUTCOME MEASURE: Thresholds at each frequency were compared with those obtained from tablet-based audiometric applications in a quiet examination room and clinic waiting area. Sensitivity and specificity of each tablet-based audiogram in detecting a hearing loss at each frequency was determined. RESULTS: All three tablet-based audiometric applications were user-friendly for hearing screening. However, one application was shown to be feasible and the most accurate of the three tested with 92% of thresholds within 10 dB of conventional audiometry across all test conditions. This application had a sensitivity of 96 to 100% and specificity of 72 to 85% for identifying a hearing loss in each frequency tested. Variability was noted among applications between testing in a quiet clinic room and testing in the clinic waiting area. Patients showed no preference for either conventional audiometry or the tablet-based device. CONCLUSION: Tablet-based audiometric applications can be used to screen for hearing loss in typical clinic locations. This tool does not replace standard audiometry testing but allows for screening for hearing disorders when appropriate and in settings without access to audiometric equipment.

Multicenter US Clinical Trial With an Electric-Acoustic Stimulation (EAS) System in Adults: Final Outcomes.

OBJECTIVE: To demonstrate the safety and effectiveness of the MED-EL Electric-Acoustic Stimulation (EAS) System, for adults with residual low-frequency hearing and severe-to-profound hearing loss in the mid to high frequencies. STUDY DESIGN: Prospective, repeated measures. SETTING: Multicenter, hospital. PATIENTS: Seventy-three subjects implanted with PULSAR or SONATA cochlear implants with FLEX electrode arrays. INTERVENTION: Subjects were fit postoperatively with an audio processor, combining electric stimulation and acoustic amplification. MAIN OUTCOME MEASURES: Unaided thresholds were measured preoperatively and at 3, 6, and 12 months postactivation. Speech perception was assessed at these intervals using City University of New York sentences in noise and consonant-nucleus-consonant words in quiet. Subjective benefit was assessed at these intervals via the Abbreviated Profile of Hearing Aid Benefit and Hearing Device Satisfaction Scale questionnaires. RESULTS: Sixty-seven of 73 subjects (92%) completed outcome measures for all study intervals. Of those 67 subjects, 79% experienced less than a 30 dB HL low-frequency pure-tone average (250-1000 Hz) shift, and 97% were able to use the acoustic unit at 12 months postactivation. In the EAS condition, 94% of subjects performed similarly to or better than their preoperative performance on City University of New York sentences in noise at 12 months postactivation, with 85% demonstrating improvement. Ninety-seven percent of subjects performed similarly or better on consonant-nucleus-consonant words in quiet, with 84% demonstrating improvement. CONCLUSION: The MED-EL EAS System is a safe and effective treatment option for adults with normal hearing to moderate sensorineural hearing loss in the low frequencies and severe-to-profound sensorineural hearing loss in the high frequencies who do not benefit from traditional amplification.

Clinical Outcomes of the Cochlear™ Nucleus(®) 5 Cochlear Implant System and SmartSound™ 2 Signal Processing.

BACKGROUND: While published data exist regarding cochlear implant (CI) outcomes from large academic programs, evidence of benefit based on national, multicenter clinical trials is needed for information regarding typical patient outcomes of devices implanted by U.S. centers representing larger academic to smaller hospital-based programs. PURPOSE: This nationwide trial evaluated outcomes in a group of newly implanted adult recipients of the Cochlear™ Nucleus(®) 5 CI system and SmartSound™ 2 signal processing. Unlike previous clinical trials, the AzBio sentence test was used and represents recent transition in our field to use of more challenging test materials. It was hypothesized that (1) speech perception scores in quiet with SmartSound™ 2 signal processing would not be statistically different from previous-generation devices; (2) speech perception scores in noise with SmartSound™ 2 signal processing would be better with enhanced microphone directionality; (3) speech perception scores in noise will be better with the preferred SmartSound™ 2 program for listening in noise; and (4) cochlear implantation would improve quality of life as assessed by the updated Health Utility Index Mark 3 (HUI3). A secondary purpose was to examine the relationships among the current and previously used speech perception tests of the Minimum Speech Test Battery (MSTB). It was hypothesized that speech perception scores within the same test interval would show predictive relationships. RESEARCH DESIGN: Prospective, single-arm, repeated-measures study across 13 CI centers in the United States between February 2010 and June 2012. The participating centers ranged from larger academic to smaller hospital-based programs to accurately represent the diversity of programs in the United States. STUDY SAMPLE: Participants were 38 postlingually deafened adult CI candidates. DATA COLLECTION AND ANALYSIS: Primary measures were Consonant-Nucleus-Consonant (CNC) words in quiet and the AzBio Sentence Test in Quiet (AzBioQ) and in Noise (AzBioN) tested at preoperative, and 3-, 6-, and 12-mo postactivation intervals. Quality of life was measured with the HUI3. For the secondary objective, statistical analyses were performed to investigate the predictive properties between current and previously used MSTB tests. RESULTS: Mean CNC scores were significantly higher compared to the Nucleus(®) 24 Contour™ at 3 mo (p < 0.05) postactivation and showed no difference compared to the Nucleus(®) Freedom™ at 6 mo postactivation. Both SmartSound™ 2 FOCUS and NOISE programs provided significant improvements in performance in noise over the EVERYDAY program (p < 0.001), and performance with the FOCUS program was significantly better compared to the NOISE program (p < 0.001). Speech perception in noise was not related to patients' subjective program preferences. Quality-of-life outcomes showed significant improvements from the preoperative to 6-mo postactivation interval (p < 0.05-0.001). Strong and significant correlations were found between preoperative CNC and AzBioQ and preoperative Hearing-in-Noise Test sentences in Quiet (HINTQ) and AzBioQ. At 12-mo postactivation, there were strong and highly significant correlations between CNC and AzBioQ, HINTQ and AzBioQ, and Hearing-in-Noise Test sentences in Noise and AzBioN (all p < 0.001). CONCLUSIONS: Results of this national clinical trial showed significant improvements in speech perception and quality of life following cochlear implantation. SmartSound™ 2 signal processing features showed a significant benefit of FOCUS when listening in noise, although preference of signal processing feature did not correlate with performance. Significant correlations were observed between speech perception tests. The findings of this study can be applied in clinical assessment, programming, and follow-up for CI candidates and recipients.

Association of TMTC2 With Human Nonsyndromic Sensorineural Hearing Loss.

IMPORTANCE: Sensorineural hearing loss (SNHL) is commonly caused by conditions that affect cochlear structures or the auditory nerve, and the genes identified as causing SNHL to date only explain a fraction of the overall genetic risk for this debilitating disorder. It is likely that other genes and mutations also cause SNHL. OBJECTIVE: To identify a candidate gene that causes bilateral, symmetric, progressive SNHL in a large multigeneration family of Northern European descent. DESIGN, SETTING, AND PARTICIPANTS: In this prospective genotype and phenotype study performed from January 1, 2006, through April 1, 2016, a 6-generation family of Northern European descent with 19 individuals having reported early-onset hearing loss suggestive of an autosomal dominant inheritance were studied at a tertiary academic medical center. In addition, 179 unrelated adult individuals with SNHL and 186 adult individuals reporting nondeafness were examined. MAIN OUTCOMES AND MEASURES: Sensorineural hearing loss. RESULTS: Nine family members (5 women [55.6%]) provided clinical audiometric and medical records that documented hearing loss. The hearing loss is characterized as bilateral, symmetric, progressive SNHL that reached severe to profound loss in childhood. Audiometric configurations demonstrated a characteristic dip at 1000 to 2000 Hz. All affected family members wear hearing aids or have undergone cochlear implantation. Exome sequencing and linkage and association analyses identified a fully penetrant sequence variant (rs35725509) on chromosome 12q21 (logarithm of odds, 3.3) in the TMTC2 gene region that segregates with SNHL in this family. This gene explains the SNHL occurrence in this family. The variant is also associated with SNHL in a cohort of 363 unrelated individuals (179 patients with confirmed SNHL and 184 controls, P = 7 × 10-4). CONCLUSIONS AND RELEVANCE: A previously uncharacterized gene, TMTC2, has been identified as a candidate for causing progressive SNHL in humans. This finding identifies a novel locus that causes autosomal dominant SNHL and therefore a more detailed understanding of the genetic basis of SNHL. Because TMTC2 has not been previously reported to regulate auditory function, the discovery reveals a potentially new, uncharacterized mechanism of hearing loss.

Temporal and spectral contributions to musical instrument identification and discrimination among cochlear implant users.

OBJECTIVE: To investigate the contributions of envelope and fine-structure to the perception of timbre by cochlear implant (CI) users as compared to normal hearing (NH) listeners. METHODS: This was a prospective cohort comparison study. Normal hearing and cochlear implant patients were tested. Three experiments were performed in sound field using musical notes altered to affect the characteristic pitch of an instrument and the acoustic envelope. Experiment 1 assessed the ability to identify the instrument playing each note, while experiments 2 and 3 assessed the ability to discriminate the different stimuli. RESULTS: Normal hearing subjects performed better than CI subjects in all instrument identification tasks, reaching statistical significance for 4 of 5 stimulus conditions. Within the CI population, acoustic envelope modifications did not significantly affect instrument identification or discrimination. With envelope and pitch cues removed, fine structure discrimination performance was similar between normal hearing and CI users for the majority of conditions, but some specific instrument comparisons were significantly more challenging for CI users. CONCLUSIONS: Cochlear implant users perform significantly worse than normal hearing listeners on tasks of instrument identification. However, cochlear implant listeners can discriminate differences in envelope and some fine structure components of musical instrument sounds as well as normal hearing listeners. The results indicated that certain fine structure cues are important for cochlear implant users to make discrimination judgments, and therefore may affect interpretation toward associating with a specific instrument for identification.

Differences in Perception of Musical Stimuli among Acoustic, Electric, and Combined Modality Listeners.

BACKGROUND: Cochlear implants have shown vast improvements in speech understanding for those with severe to profound hearing loss; however, music perception remains a challenge for electric hearing. It is unclear whether the difficulties arise from limitations of sound processing, the nature of a damaged auditory system, or a combination of both. PURPOSE: To examine music perception performance with different acoustic and electric hearing configurations. RESEARCH DESIGN: Chord discrimination and timbre perception were tested in subjects representing four daily-use listening configurations: unilateral cochlear implant (CI), contralateral bimodal (CIHA), bilateral hearing aid (HAHA) and normal-hearing (NH) listeners. A same-different task was used for discrimination of two chords played on piano. Timbre perception was assessed using a 10-instrument forced-choice identification task. STUDY SAMPLE: Fourteen adults were included in each group, none of whom were professional musicians. DATA COLLECTION AND ANALYSIS: The number of correct responses was divided by the total number of presentations to calculate scores in percent correct. Data analyses were performed with Kruskal-Wallis one-way analysis of variance and linear regression. RESULTS: Chord discrimination showed a narrow range of performance across groups, with mean scores ranging between 72.5% (CI) and 88.9% (NH). Significant differences were seen between the NH and all hearing-impaired groups. Both the HAHA and CIHA groups performed significantly better than the CI groups, and no significant differences were observed between the HAHA and CIHA groups. Timbre perception was significantly poorer for the hearing-impaired groups (mean scores ranged from 50.3-73.9%) compared to NH (95.2%). Significantly better performance was observed in the HAHA group as compared to both groups with electric hearing (CI and CIHA). There was no significant difference in performance between the CIHA and CI groups. Timbre perception was a significantly more difficult task than chord discrimination for both the CI and CIHA groups, yet the easier task for the NH group. A significant difference between the two tasks was not seen in the HAHA group. CONCLUSIONS: Having impaired hearing decreases performance compared to NH across both chord discrimination and timbre perception tasks. For chord discrimination, having acoustic hearing improved performance compared to electric hearing only. Timbre perception distinguished those with acoustic hearing from those with electric hearing. Those with bilateral acoustic hearing, even if damaged, performed significantly better on this task than those requiring electrical stimulation, which may indicate that CI sound processing fails to capture and deliver the necessary acoustic cues for timbre perception. Further analysis of timbre characteristics in electric hearing may contribute to advancements in programming strategies to obtain optimal hearing outcomes.

Patient Outcomes in Magnet-Based Implantable Auditory Assist Devices.

IMPORTANCE: Magnet-based implantable auditory assist devices (MIAADs) are a recent development in bone-anchored hearing devices. This report increases the number of children studied with specific outcome criteria and provides detailed solutions to avoid device use difficulties in other centers considering this device. OBJECTIVE: To assess hearing thresholds, use rates, and complications in children implanted with a MIAAD for conductive hearing loss. DESIGN, SETTING, AND PARTICIPANTS: Retrospective analysis of children implanted with an MIAAD at an ambulatory care quaternary referral center since the Food and Drug Administration approved the Sophono device (Sophono Inc) for use in the United States (May 2011 through January 2013). Ten pediatric patients were implanted for conductive hearing loss (14 ears; mean age at implantation, 9 years [range, 3.8-17.2 years]). Diagnoses included aural atresia (n = 7) and chronic ear disease and cholesteatoma (n = 3). INTERVENTIONS: Implantation of MIAAD and management of skin complications. MAIN OUTCOMES AND MEASURES: Demographics, hearing thresholds, use rates, and complications were assessed. RESULTS: After fitting with the magnetic baseplate and sound processor, the mean (SD) aided pure-tone average was 20.2 (6.0) dB hearing level (HL), with a mean (SD) functional gain of 39.9 (12.4) dB HL. There were no surgical complications. Negative outcomes were assessed following fitting of the sound processor. The skin complication rate was 35.7%, including skin breakdown (n = 2) and pain and erythema (n = 5), which resulted in decreased use of the device for these patients. Intervention included decreasing the magnet strength, graduated wearing schedule, antibiotic ointment, barrier protection, and reoperation for well widening with Alloderm (LifeCell Corporation) placement. Patients without skin complications are consistent users of their device, with an average daily use of 8 to 10 hours. CONCLUSIONS AND RELEVANCE: The MIAAD device has equivalent levels of hearing restoration to other previously described methods of intervention for children with conductive hearing loss. This early report indicates high rates of skin difficulties and a need for improved methods of implantation, magnetic baseplate fitting, and device use. We suggest decreased magnet strength at the initial fitting, a graduated wearing schedule, caution with patients who have a history of skin issues from a bone-anchored hearing aid or multiple surgical procedures, and parent counseling regarding potential skin irritation.

A novel otoferlin splice-site mutation in siblings with auditory neuropathy spectrum disorder.

We characterize a novel otoferlin mutation discovered in a sibling pair diagnosed with auditory neuropathy spectrum disorder and investigate auditory nerve function through their cochlear implants. Genetic sequencing revealed a homozygous mutation at the otoferlin splice donor site of exon 28 (IVS28 + 1G>T) in both siblings. Functional investigation showed that the intronic sequence between exons 28 and 29 was retained in the mutated minigenes that were expressed in 293T cells. Auditory nerve compound action potential recovery functions in the siblings demonstrated different rates of neural recovery, with sibling AN1 showing rapid recovery (1.14 ms) and AN2 showing average recovery (0.78 ms) compared to subjects with sensorineural hearing loss (average: adults 0.71 ms, children 0.85 ms). Differences in neural recovery were consistent with speech perception differences between the siblings. Genotype information may indicate site of lesion in hearing loss; however, additional, as yet, unknown factors may impact clinical outcomes and must be considered.

Variant discovery in targeted resequencing using whole genome amplified DNA.

BACKGROUND: Next generation sequencing and advances in genomic enrichment technologies have enabled the discovery of the full spectrum of variants from common to rare alleles in the human population. The application of such technologies can be limited by the amount of DNA available. Whole genome amplification (WGA) can overcome such limitations. Here we investigate applicability of using WGA by comparing SNP and INDEL variant calls from a single genomic/WGA sample pair from two capture separate experiments: a 50 Mbp whole exome capture and a custom capture array of 4 Mbp region on chr12. RESULTS: Our results comparing variant calls derived from genomic and WGA DNA show that the majority of variant SNP and INDEL calls are common to both callsets, both at the site and genotype level and suggest that allele bias plays a minimal role when using WGA DNA in re-sequencing studies. CONCLUSIONS: Although the results of this study are based on a limited sample size, they suggest that using WGA DNA allows the discovery of the vast majority of variants, and achieves high concordance metrics, when comparing to genomic DNA calls.

Statistical model for prediction of hearing loss in patients receiving cisplatin chemotherapy.

IMPORTANCE: This statistical model might be used to predict cisplatin-induced hearing loss, particularly in patients undergoing concomitant radiotherapy. OBJECTIVE: To create a statistical model based on pretreatment hearing thresholds to provide an individual probability for hearing loss from cisplatin therapy and, secondarily, to investigate the use of hearing classification schemes as predictive tools for hearing loss. DESIGN: Retrospective case-control study. SETTING: Tertiary care medical center. PARTICIPANTS: A total of 112 subjects receiving chemotherapy and audiometric evaluation were evaluated for the study. Of these subjects, 31 met inclusion criteria for analysis. MAIN OUTCOME MEASURES: The primary outcome measurement was a statistical model providing the probability of hearing loss following the use of cisplatin chemotherapy. RESULTS: Fifteen of the 31 subjects had significant hearing loss following cisplatin chemotherapy. American Academy of Otolaryngology-Head and Neck Society and Gardner-Robertson hearing classification schemes revealed little change in hearing grades between pretreatment and posttreatment evaluations for subjects with or without hearing loss. The Chang hearing classification scheme could effectively be used as a predictive tool in determining hearing loss with a sensitivity of 73.33%. Pretreatment hearing thresholds were used to generate a statistical model, based on quadratic approximation, to predict hearing loss (C statistic = 0.842, cross-validated = 0.835). The validity of the model improved when only subjects who received concurrent head and neck irradiation were included in the analysis (C statistic = 0.91). A calculated cutoff of 0.45 for predicted probability has a cross-validated sensitivity and specificity of 80%. CONCLUSIONS AND RELEVANCE: Pretreatment hearing thresholds can be used as a predictive tool for cisplatin-induced hearing loss, particularly with concomitant radiotherapy.

Recovery from forward masking in elderly cochlear implant users.

OBJECTIVE: To compare temporal aspects of peripheral neural responses and central auditory perception between groups of younger adult and elderly cochlear implant users. STUDY DESIGN: Cohort study. SETTING: Academic hospital and cochlear implant center. PATIENTS: Adult cochlear implant users aged 28 to 57 years in the younger group (n = 5) and 61 to 89 years (n = 9) in the elderly group. All subjects used Advanced Bionics devices. INTERVENTION: Diagnostic. MAIN OUTCOME MEASURES: Time constants of neural (i.e., electrically evoked compound action potentials [ECAPs]) and perceptual recovery from forward masking. Interstimulus intervals (ISIs) were varied in both experiments. RESULTS: ECAP recovery rates were equivalent between groups, and no correlation was found between ECAP recovery and age. No correlations were found between ECAP recovery and speech perception. Psychophysical recovery was significantly slower in the elderly compared with the younger subjects (p < 0.0005), with a significant effect of age (R2 = 0.70, p < 0.0005). At the longest ISI (240 ms), elderly subjects experienced a mean maximum threshold shift of 35.2% (relative to 1 ms ISI) versus 14.8% for younger subjects. There was a significant positive relationship between psychophysical recovery and consonant-nucleus-consonant word scores (R2 = 0.62, p < 0.001), although no relationship was found with Hearing in Noise Test sentences. CONCLUSION: These findings suggest that difficulties observed in speech perception by elderly CI users may be due to age-related changes in the central rather than peripheral auditory system. With further study, these results may provide information to allow clinicians to assess patients' temporal processing abilities and facilitate setting program parameters that will maximize their auditory perceptual experience with a cochlear implant.