Detailed Clinical Features of PTPRQ-Associated Hearing Loss Identified in a Large Japanese Hearing Loss Cohort.

The PTPRQ gene has been identified as one of the genes responsible for non-syndromic sensorineural hearing loss (SNHL), and assigned as DFNA73 and DFNB84. To date, about 30 causative PTPRQ variants have been reported to cause SNHL. However, the detailed clinical features of PTPRQ-associated hearing loss (HL) remain unclear. In this study, 15,684 patients with SNHL were enrolled and genetic analysis was performed using massively parallel DNA sequencing (MPS) for 63 target deafness genes. We identified 17 possibly disease-causing PTPRQ variants in 13 Japanese patients, with 15 of the 17 variants regarded as novel. The majority of variants identified in this study were loss of function. Patients with PTPRQ-associated HL mostly showed congenital or childhood onset. Their hearing levels at high frequency deteriorated earlier than that at low frequency. The severity of HL progressed from moderate to severe or profound HL. Five patients with profound or severe HL received cochlear implantation, and the postoperative sound field threshold levels and discrimination scores were favorable. These findings will contribute to a greater understanding of the clinical features of PTPRQ-associated HL and may be relevant in clinical practice.

Gene expression of cytokines and prostaglandin metabolism-related proteins in eosinophilic otitis media.

The objective of this study was to investigate the levels of gene expression in the middle ear mucosa of 2 patients diagnosed with eosinophilic otitis media. One patient with severe hearing loss showed high expression levels of genes encoding IL-5 and IL-33 receptors.

Otological Features of Patients with Musculocontractural Ehlers-Danlos Syndrome Caused by Pathogenic Variants in CHST14 (mcEDS-CHST14).

Musculocontractural Ehlers-Danlos syndrome (EDS) caused by pathogenic variants in CHST14 (mcEDS-CHST14) is a subtype of EDS characterized by multisystem malformations and progressive fragility-related manifestations. A recent international collaborative study showed that 55% of mcEDS-CHST14 patients had hearing loss (HL), more commonly of the high-frequency type. Here, we report the first systemic investigation of the otological features of patients with this disorder based on the world's largest cohort at Shinshu University Hospital. Nine patients [18 ears; four male and five female patients; mean age, 18 years old (range, 10-28)] underwent comprehensive otological evaluation: audiogram, distortion product otoacoustic emission (DPOAE) test, and tympanometry. The audiogram, available in all 18 ears, showed HL in eight patients (8/9, 89%) and in 14 ears (14/18, 78%): bilateral in six patients (6/9, 67%) and unilateral in two (2/9, 22%); mild in eight ears (8/18, 44%) and moderate in six (6/18, 33%); and high-frequency HL in five (5/18, 28%) and low-frequency HL in five (5/18, 28%). An air-bone gap was detected in one ear (1/18, 6%). DPOAE was available in 13 ears, with the presence of a response in five (5/13, 38%) and the absence in eight (8/13, 62%), including in three ears of normal hearing. Tympanometry results were available in 12 ears: Ad type in nine (9/12, 75%) and As type in one (1/12, 8.3%). Patients with mcEDS-CHST14 had a high prevalence of HL, typically sensorineural and bilateral, with mild to moderate severity, of high-frequency or low-frequency type, and sometimes with no DPOAE response. The pathophysiology underlying HL might be complex, presumably related to alterations of the tectorial membrane and/or the basilar membrane of Corti associated with disorganized collagen fibril networks. Regular and careful check-ups of hearing using multiple modalities are recommended for mcEDS-CHST14 patients.

Wearable device and smartphone data quantify ALS progression and may provide novel outcome measures.

Amyotrophic lateral sclerosis (ALS) therapeutic development has largely relied on staff-administered functional rating scales to determine treatment efficacy. We sought to determine if mobile applications (apps) and wearable devices can be used to quantify ALS disease progression through active (surveys) and passive (sensors) data collection. Forty ambulatory adults with ALS were followed for 6-months. The Beiwe app was used to administer the self-entry ALS functional rating scale-revised (ALSFRS-RSE) and the Rasch Overall ALS Disability Scale (ROADS) surveys every 2-4 weeks. Each participant used a wrist-worn activity monitor (ActiGraph Insight Watch) or an ankle-worn activity monitor (Modus StepWatch) continuously. Wearable device wear and app survey compliance were adequate. ALSFRS-R highly correlated with ALSFRS-RSE. Several wearable data daily physical activity measures demonstrated statistically significant change over time and associations with ALSFRS-RSE and ROADS. Active and passive digital data collection hold promise for novel ALS trial outcome measure development.

Speech Perception in Noise and Sound Localization for Cochlear Implant With Single-Sided Deafness Compared With Contralateral Routing of Signal Hearing Aids.

OBJECTIVE: Cochlear implantation (CI) for the treatment of single-sided deafness (SSD) is a relatively new treatment modality. Although comparing the effectiveness of CI and contralateral routing of signal (CROS) hearing aids (HAs) is important, very few reports on this topic exist. In this study, objective assessments and subjective assessments were conducted to determine which SSD individuals would prefer CI or CROS HAs. MATERIALS AND METHODS: Objective assessments (speech perception and sound localization) and subjective assessments (Hearing Handicap Inventory for Adults (HHIA), Abbreviated Profile of Hearing Aid Benefit (APHAB), MOS Short-Form 36-Item Health Survey version 2 (SF-36v2)) were performed on 87 SSD patients. Of the 87 SSD patients, 33 patients hoped for CROS HAs, and 17 patients hoped for CI. The CI group underwent subjective and objective assessments at 6 and 12 months postoperatively. The CROS HAs group underwent objective assessments at 1 month after wearing CROS HAs. RESULTS: After the intervention, the localization ability was significantly improved in the CI group (p < 0.05) with no significant improvement in that of the CROS HAs group (p = 0.48). No significant improvement in speech perception in noise was observed in the CROS (Signal-to-Noise ratio + 10, p = 0.08; SN + 0, p = 0.17); however, a significant improvement in the CI group was observed at 12 months postoperatively. The APHAB subscale "background noise" and SF-36v2 health concepts of role-physical, general health, vitality, role-emotional, and mental health were significantly higher in the CI group. CONCLUSION: CI was superior to CROS HAs in speech perception in terms of noise and sound localization. Patients with postlingual acute-onset hearing loss and more handicaps and a more positive view of their hearing loss possibly tend to choose CI.

Efficacy and safety of 1.5% levofloxacin otic solution for the treatment of otitis media in a multicenter, randomized, double-blind, parallel-group, placebo-controlled, phase III study.

OBJECTIVE: The present study aimed to evaluate the efficacy and safety of 1.5% levofloxacin (LVFX) otic solution for the treatment of patients with otitis media. METHODS: This multicenter, randomized, double-blind, parallel-group, placebo-controlled phase 3 trial was conducted at 34 institutions in Japan. A total of 202 patients with chronic suppurative otitis media (CSOM) or acute otitis media (AOM) were randomized into either the LVFX group or placebo group. A total of 6-10 drops of 1.5% otic solution of LVFX or its matching placebo were administered in the diseased ear twice daily, in the morning and evening for up to 10 days. Images corresponding to three clinical findings-purulent otorrhea, hyperemia (redness), and granulation tissue formation in the middle ear and tympanic membrane-for each diseased ear were evaluated using digital endoscopy by a blinded central independent review committee (BICRC) at each visit after treatment administration. RESULTS: In total, the data of 201 participants (LVFX group, 99; placebo group, 102) were analyzed. The proportion of patients with disappearance (improvement rate) of all three clinical findings at the end of treatment or discontinuation by the BICRC was 46.5% (46/99) in the LVFX group and 23.5% (24/102) in the placebo group, and the difference (95% confidence interval) between the groups was 22.0% (8.7, 34.2), with a significantly higher improvement rate in the LVFX group than in the placebo group (p = 0.001; Cochran-Mantel-Haenszel test), demonstrating the efficacy of LVFX. The bacterial eradication rates were 93.9% (77/82) and 12.5% (11/88) in the LVFX and placebo groups, respectively, and the rate was significantly higher in the LVFX group than in the placebo group (p < 0.001). Treatment-related adverse events (AEs) occurred in 5.1% (5/99) and 7.8% (8/102) of the patients in the LVFX and placebo groups, respectively, and no significant difference was noted in incidence rate between the groups. CONCLUSION: The clinical efficacy of 1.5% LVFX otic solution for CSOM and AOM was demonstrated by the resolution of inflammation in the middle ear and tympanic membrane as well as through the high bacterial eradication rate observed. No deaths or serious treatment-related AEs were observed. The study provided confirmation that 1.5% LVFX otic solution is a safe, well-tolerated, and effective treatment for CSOM and AOM.

Analysis of outcomes for communication mode in cochlear implant in prelingually deafened adults.

OBJECTIVE: Recent studies have suggested that speech perception outcomes after cochlear implantation (CI) in prelingually deafened adults have improved with advances in CI technology and speech processing strategies. However, the outcomes vary from case to case. Communication mode has been reported in many studies as the factor that related to the post CI outcomes. This study aimed at investigating the post CI outcomes and the progress during 2 years for each communication mode. MATERIAL AND METHODS: The subjects were 17 prelingually deafened adults undergoing CI at our hospital between April 2013 and March 2019. We investigated preoperative factors affecting post CI outcomes. Also we analyzed post CI outcomes for each communication mode and compared preoperative factors for each communication mode. RESULTS: Communication mode and preoperative discrimination score were the factor affecting on postoperative discrimination score. The speech perception score after CI improved significantly in the oral and lip-reading group and total communication group. The speech perception scores in postlingually deafened adults improved significantly during the first six months and became to plateau after CI. On the other hand, the scores of prelingually deafened adults tended to improve gradually after six months postoperatively. Furthermore, the degree of improvement and progress differed by each communication mode. CONCLUSION: The communication mode is important factors in predicting outcomes in prelingually deafened adults after CI. Long-term auditory training is important for prelingually deafened adults who use visual information as their preoperative method of communication.

Advances in auditory implants.

Auditory implants are classified into bone conduction (BAHA and Bonebridge; BB) and active middle ear implants (Vibrant Soundbridge; VSB) that stimulate cochlear hair cells, and cochlear implants (CIs) that stimulate neural structures. CIs should be performed as early as possible, and bilateral CIs have become popular because sound localization and speech recognition can be improved. CI is also considered a desirable treatment option for patients with single-sided deafness. VSB provides a safe and effective option for patients with conductive or mixed hearing loss and moderate to severe sensorineural hearing loss (SNHL); however, it use in patients with conductive or mixed hearing loss have only been approved in Japan. BAHA and BB implants have been approved by national insurance in Japan as bone conduction implants for patients with conductive or mixed hearing loss. Two fully implantable devices (Cochlear Carina and Envoy Esteem) are provided for patients with SNHL.

Etiology of hearing loss affects auditory skill development and vocabulary development in pediatric cochlear implantation cases.

BACKGROUND: Cochlear implantation (CI) is an effective treatment for severe-to-profound hearing loss patients and is currently used as the standard therapeutic option worldwide. However, the outcomes of CI vary among patients. AIMS/OBJECTIVES: This study aimed to clarify the clinical features for each etiological group as well as the effects of etiology on CI outcomes. MATERIALS AND METHODS: We collected clinical information for 308 pediatric cochlear implant cases, including the etiology, hearing thresholds, age at CI, early auditory skill development, total development, monosyllable perception, speech intelligibility and vocabulary development in school age, and compared them for each etiology group. RESULTS: Among the 308 CI children registered for this survey, the most common etiology of hearing loss was genetic causes. The genetic etiology group showed the most favorable development after CI followed by the unknown etiology group, syndromic hearing loss group, congenital CMV infection group, inner ear malformation group, and cochlear nerve deficiency group. CONCLUSIONS AND SIGNIFICANCE: Our results clearly indicated that the etiology of HL affects not only early auditory skill development, but also vocabulary development in school age. The results of the present study will aid in more appropriate CI outcome assessment and in more appropriate intervention or habilitation programs.

Detailed clinical features and genotype-phenotype correlation in an OTOF-related hearing loss cohort in Japan.

Mutations in the OTOF gene are a common cause of hereditary hearing loss and the main cause of auditory neuropathy spectrum disorder (ANSD). Although it is reported that most of the patients with OTOF mutations have stable, congenital or prelingual onset severe-to-profound hearing loss, some patients show atypical clinical phenotypes, and the genotype-phenotype correlation in patients with OTOF mutations is not yet fully understood. In this study, we aimed to reveal detailed clinical characteristics of OTOF-related hearing loss patients and the genotype-phenotype correlation. Detailed clinical information was available for 64 patients in our database who were diagnosed with OTOF-related hearing loss. As reported previously, most of the patients (90.6%) showed a "typical" phenotype; prelingual and severe-to-profound hearing loss. Forty-seven patients (73.4%) underwent cochlear implantation surgery and showed successful outcomes; approximately 85-90% of the patients showed a hearing level of 20-39 dB with cochlear implant and a Categories of Auditory Performance (CAP) scale level 6 or better. Although truncating mutations and p.Arg1939Gln were clearly related to severe phenotype, almost half of the patients with one or more non-truncating mutations showed mild-to-moderate hearing loss. Notably, patients with p.His513Arg, p.Ile1573Thr and p.Glu1910Lys showed "true" auditory neuropathy-like clinical characteristics. In this study, we have clarified genotype-phenotype correlation and efficacy of cochlear implantation for OTOF-related hearing loss patients in the biggest cohort studied to date. We believe that the clinical characteristics and genotype-phenotype correlation found in this study will support preoperative counseling and appropriate intervention for OTOF-related hearing loss patients.

Vibrant soundbridge implantation prior to auricular reconstruction with unilateral microtia-atresia.

We presented the first successful application of VSB implantation prior to auriculoplasty, which can provide hearing improvement in safe conditions and open new strategies for earlier hearing rehabilitation in unilateral microtia-atresia children.

IgG4 Expression in Patients with Eosinophilic Otitis Media.

OBJECTIVE: Eosinophilic otitis media (EOM) is an intractable middle ear disease recognized by an eosinophil enriched middle ear effusion and mucosa. Although precise pathogenesis of EOM remains unclear, it is characterized by type 2 inflammation. Since IgG4 is an IgG subclass induced by type 2 cytokines such as IL-4 and IL-13, we sought to characterize and compare local IgG4 expression in patients with and without EOM. METHODS: Twelve patients with bilateral profound hearing loss, 9 of which underwent a cochlear implant surgery, were enrolled in this study (6 with EOM and 6 without EOM). The surgical specimens were harvested during surgery and were subjected to IgG4 immunostaining. RESULT: The middle ear mucosa showed the presence of a large number of IgG4-positive cells in patients with EOM, which was significantly higher than that in patients without EOM. CONCLUSION: Local IgG4 expression was observed in patients with EOM in comparison to those without EOM, suggesting that IgG4 contributes to EOM pathogenesis.

Hippocampal beta oscillations predict mouse object-location associative memory performance.

Memorizing the locations of environmental cues is crucial for survival and depends on the hippocampus. We recorded local field potentials (LFPs) from the hippocampus of freely moving mice during an object location task. The power of beta-band (23-30 Hz) oscillations increased immediately before approaching objects in a memory-encoding phase. The exploration-induced beta oscillations gradually decreased during the memory-encoding session. Mice that exhibited stronger beta oscillation power exhibited better performance in the subsequent memory-retrieval test. These results suggest that beta oscillations in the hippocampal CA1 region are involved in the memory encoding of object-location associations.

Active middle ear implant (vibrant soundbridge) in children with unilateral congenital aural atresia.

BACKGROUND: Detailed studies have not been conducted on sound localization and speech perception in noise in patients with unilateral congenital aural atresia (UCAA). AIMS/OBJECTIVES: To evaluate the benefits of the use of the Vibrant Soundbridge (VSB) for UCAA by performing audiometric and sound localization tests. MATERIALS AND METHODS: Four children with UCAA underwent VSB (VORP 503) implantation from 2018 to 2019. Speech perception tests in noise were conducted using the Japanese monosyllable test. The spatial configuration for speech testing consisted of speech presented from the front and noise presented into the normal ear (S0N90). The sound localization test was conducted using nine loudspeakers equally distributed in a semicircle. RESULTS: The children's speech perception in noise 6 months after VSB activation was significantly better than before activation (p < .05). Additionally, the children's sound localization ability after VSB activation was significantly better than before VSB activation. CONCLUSION AND SIGNIFICANCE: The benefits of VSB use in children with UCAA were revealed using audiometric and sound localization tests.

Contextual Fear Memory Retrieval Is Vulnerable to Hippocampal Noise.

Memory retrieval depends on reactivation of memory engram cells. Inadvertent activation of these cells is expected to cause memory-retrieval failure, but little is known about how noisy activity of memory-irrelevant neurons impacts mnemonic processes. Here, we report that optogenetic nonselective activation of only tens of hippocampal CA1 cells (∼0.01% of the total cells in the CA1 pyramidal cell layer) impairs contextual fear memory recall. Memory recall failure was associated with altered neuronal reactivation in the basolateral amygdala. These results indicate that hippocampal memory retrieval requires strictly regulated activation of a specific neuron ensemble and is easily disrupted by the introduction of noisy CA1 activity, suggesting that reactivating memory engram cells as well as silencing memory-irrelevant neurons are both crucial for memory retrieval.

Novel ACTG1 mutations in patients identified by massively parallel DNA sequencing cause progressive hearing loss.

Human ACTG1 mutations are associated with high-frequency hearing loss, and patients with mutations in this gene are good candidates for electric acoustic stimulation. To better understand the genetic etiology of hearing loss cases, massively parallel DNA sequencing was performed on 7,048 unrelated Japanese hearing loss probands. Among 1,336 autosomal dominant hearing loss patients, we identified 15 probands (1.1%) with 13 potentially pathogenic ACTG1 variants. Six variants were novel and seven were previously reported. We collected and analyzed the detailed clinical features of these patients. The average progression rate of hearing deterioration in pure-tone average for four frequencies was 1.7 dB/year from 0 to 50 years age, and all individuals over 60 years of age had severe hearing loss. To better understand the underlying disease-causing mechanism, intracellular localization of wild-type and mutant gamma-actins were examined using the NIH/3T3 fibroblast cell line. ACTG1 mutants p.I34M p.M82I, p.K118M and p.I165V formed small aggregates while p.R37H, p.G48R, p.E241K and p.H275Y mutant gamma-actins were distributed in a similar manner to the WT. From these results, we believe that some part of the pathogenesis of ACTG1 mutations may be driven by the inability of defective gamma-actin to be polymerized into F-actin.

Prevalence and clinical features of hearing loss caused by EYA4 variants.

Variants in the EYA4 gene are known to lead to autosomal dominant non-syndromic hereditary hearing loss, DFNA10. To date, 30 variants have been shown to be responsible for hearing loss in a diverse set of nationalities. To better understand the clinical characteristics and prevalence of DFNA10, we performed genetic screening for EYA4 mutations in a large cohort of Japanese hearing loss patients. We selected 1,336 autosomal dominant hearing loss patients among 7,408 unrelated Japanese hearing loss probands and performed targeted genome enrichment and massively parallel sequencing of 68 target genes for all patients. Clinical information of cases with mutations in EYA4 was gathered and analyzed from medical charts. Eleven novel EYA4 variants (three frameshift variants, three missense variants, two nonsense variants, one splicing variant, and two single-copy number losses) and two previously reported variants were found in 12 probands (0.90%) among the 1,336 autosomal dominant hearing loss families. The audiometric configuration of truncating variants tends to deteriorate for all frequencies, whereas that of non-truncating variants tends to show high-frequency hearing loss, suggesting a new correlation between genotype and phenotype in DFNA10. The rate of hearing loss progression caused by EYA4 variants was considered to be 0.63 dB/year, as found in this study and previous reports.

Mutational Spectrum and Clinical Features of Patients with LOXHD1 Variants Identified in an 8074 Hearing Loss Patient Cohort.

Variants of the LOXHD1 gene, which are expressed in hair cells of the cochlea and vestibule, have been reported to cause a progressive form of autosomal recessive non-syndromic hereditary hearing loss, DFNB77. In this study, genetic screening was conducted on 8074 Japanese hearing loss patients utilizing massively parallel DNA sequencing to identify individuals with LOXHD1 variants and to assess their phenotypes. A total of 28 affected individuals and 21 LOXHD1 variants were identified, among which 13 were novel variants. A recurrent variant c.4212 + 1G > A, only reported in Japanese patients, was detected in 18 individuals. Haplotype analysis implied that this variation occurred in a mutational hot spot, and that multiple ancestors of Japanese population had this variation. Patients with LOXHD1 variations mostly showed early onset hearing loss and presented different progression rates. We speculated that the varying severities and progression rates of hearing loss are the result of environmental and/or other genetic factors. No accompanying symptoms, including vestibular dysfunction, with hearing loss were detected in this study. Few studies have reported the clinical features of LOXHD1-gene associated hearing loss, and this study is by far the largest study focused on the evaluation of this gene.

Comprehensive analysis of syndromic hearing loss patients in Japan.

More than 400 syndromes associated with hearing loss and other symptoms have been described, corresponding to 30% of cases of hereditary hearing loss. In this study we aimed to clarify the mutation spectrum of syndromic hearing loss patients in Japan by using next-generation sequencing analysis with a multiple syndromic targeted resequencing panel (36 target genes). We analyzed single nucleotide variants, small insertions, deletions and copy number variations in the target genes. We enrolled 140 patients with any of 14 syndromes (BOR syndrome, Waardenburg syndrome, osteogenesis imperfecta, spondyloepiphyseal dysplasia congenita, Stickler syndrome, CHARGE syndrome, Jervell and Lange-Nielsen syndrome, Pendred syndrome, Klippel-Feil syndrome, Alport syndrome, Norrie disease, Treacher-Collins syndrome, Perrault syndrome and auditory neuropathy with optic atrophy) and identified the causative variants in 56% of the patients. This analysis could identify the causative variants in syndromic hearing loss patients in a short time with a high diagnostic rate. In addition, it was useful for the analysis of the cases who only partially fulfilled the diagnostic criteria.