Pathophysiological Roles of the cGAS-STING Inflammatory Pathway.

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) inflammatory pathway is a component of the innate immune system that recognizes cytosolic nucleic acids. The pathway has been implicated in several processes including aging, autoinflammatory conditions, cancer, and metabolic diseases. The cGAS-STING pathway represents a promising therapeutic target in a variety of chronic inflammatory diseases.

Prevalence of perilymphatic fistula in patients with sudden-onset sensorineural hearing loss as diagnosed by Cochlin-tomoprotein (CTP) biomarker detection: its association with age, hearing severity, and treatment outcomes.

PURPOSE: To determine the prevalence of perilymphatic fistula (PLF) in sudden-onset sensorineural hearing loss (SSNHL) patients by employing the Cochlin-tomoprotein (CTP) detection test, a specific diagnostic marker for perilymph. We also analyzed the clinical characteristics associated with hearing outcomes in this cohort. METHODS: A total of 74 eligible patients were prospectively enrolled. Following myringotomy, middle ear lavage (MEL) samples underwent the CTP test to identify perilymph leakage. Intratympanic dexamethasone (IT-DEX) therapy was administered, and hearing outcomes were assessed. Control groups comprised patients with chronic otitis media (n = 40) and non-inflammatory middle ears (n = 51) with concurrent MEL sample collection. RESULTS: CTP was positive in 16 (22%) patients. No control samples showed positive results. Multiple regression analysis indicated that age and pre-treatment hearing levels significantly contributed to the CTP value. We found a positive correlation between CTP values, age, and pre-treatment pure-tone averages. Notably, CTP values in SSNHL cases aged 60 and above were significantly higher than in those below 60 years. Patients with positive CTP had significantly worse recovery rates after IT-DEX treatment. CONCLUSION: This study is the first prospective investigation demonstrating a positive relationship between CTP values, age, and hearing severity in SSNHL, indicating that PLF might be the essential cause of SSNHL, particularly in the elderly. Our findings suggest that IT-DEX may be less effective for PLF-associated SSNHL. Future research could reveal that PLF repair surgery is a viable treatment strategy for SSNHL. This study was registered under the UMIN Clinical Trials Registry (UMIN000010837) on 30/May/2013.

Functional Studies of Deafness-Associated Pendrin and Prestin Variants.

Pendrin and prestin are evolutionary-conserved membrane proteins that are essential for normal hearing. Dysfunction of these proteins results in hearing loss in humans, and numerous deafness-associated pendrin and prestin variants have been identified in patients. However, the pathogenic impacts of many of these variants are ambiguous. Here, we report results from our ongoing efforts to experimentally characterize pendrin and prestin variants using in vitro functional assays. With previously established fluorometric anion transport assays, we determined that many of the pendrin variants identified on transmembrane (TM) 10, which contains the essential anion binding site, and on the neighboring TM9 within the core domain resulted in impaired anion transport activity. We also determined the range of functional impairment in three deafness-associated prestin variants by measuring nonlinear capacitance (NLC), a proxy for motor function. Using the results from our functional analyses, we also evaluated the performance of AlphaMissense (AM), a computational tool for predicting the pathogenicity of missense variants. AM prediction scores correlated well with our experimental results; however, some variants were misclassified, underscoring the necessity of experimentally assessing the effects of variants. Together, our experimental efforts provide invaluable information regarding the pathogenicity of deafness-associated pendrin and prestin variants.

Novel approach of prophylactic radiation to reduce toxicities comparing 2-step40 with 56-Gy simultaneous integrated boost intensity-modulated radiation therapy for locally advanced squamous cell carcinoma of the head and neck, an intergroup phase III trial (JCOG1912, NEW BRIDGE).

BACKGROUND: Chemoradiotherapy (CRT) with concurrent cisplatin is the standard of care as a nonsurgical definitive treatment for patients with locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). However, CRT is associated with increased severe late adverse events, including swallowing dysfunction, xerostomia, ototoxicity, and hypothyroidism. Few strategies aimed at less invasive CRT without compromising treatment outcomes have been successful. The purpose of this study is to confirm the non-inferiority of reduced dose prophylactic radiation with 40 Gy compared to standard dose prophylactic radiation with 56 Gy in terms of the time to treatment failure (TTF) among patients with clinical stage III-IVB LA-SCCHN. METHODS: This study is a multicenter, two-arm, open-label, randomized phase III trial. Patients with LA-SCCHN excluding p16 positive oropharynx cancer are randomized to the standard arm or experimental arm. A total dose of 70 Gy for tumors with concurrent cisplatin at 100 mg/m2 are administered in both arms. For prophylactic field, patients in the standard arm receive a total dose of 56 Gy in 35 fractions for 7 weeks using simultaneous integrated boost (SIB56) and those in the experimental arm receive 40 Gy in 20 fractions using two-step methods for 4 weeks (2-step40). A total of 400 patients will be enrolled from 52 Japanese institutions within 5 years. The primary endpoint is TTF, and the secondary endpoints are overall survival, complete response rate, progression-free survival, locoregional relapse-free survival, acute and late adverse events, quality of life score, and swallowing function score. DISCUSSION: If the experimental arm is non-inferior to the standard arm in terms of TTF and superior on the safety endpoints, the 2-step40 procedure is the more useful treatment than SIB56 for definitive CRT. TRIAL REGISTRATION: This trial has been registered in the Japan Registry of Clinical Trials as jRCTs031210100 ( https://jrct.niph.go.jp/latest-detail/jRCTs031210100 ). Date of Registration: May 2021.

Variants encoding a restricted carboxy-terminal domain of SLC12A2 cause hereditary hearing loss in humans.

Hereditary hearing loss is challenging to diagnose because of the heterogeneity of the causative genes. Further, some genes involved in hereditary hearing loss have yet to be identified. Using whole-exome analysis of three families with congenital, severe-to-profound hearing loss, we identified a missense variant of SLC12A2 in five affected members of one family showing a dominant inheritance mode, along with de novo splice-site and missense variants of SLC12A2 in two sporadic cases, as promising candidates associated with hearing loss. Furthermore, we detected another de novo missense variant of SLC12A2 in a sporadic case. SLC12A2 encodes Na+, K+, 2Cl- cotransporter (NKCC) 1 and plays critical roles in the homeostasis of K+-enriched endolymph. Slc12a2-deficient mice have congenital, profound deafness; however, no human variant of SLC12A2 has been reported as associated with hearing loss. All identified SLC12A2 variants mapped to exon 21 or its 3'-splice site. In vitro analysis indicated that the splice-site variant generates an exon 21-skipped SLC12A2 mRNA transcript expressed at much lower levels than the exon 21-included transcript in the cochlea, suggesting a tissue-specific role for the exon 21-encoded region in the carboy-terminal domain. In vitro functional analysis demonstrated that Cl- influx was significantly decreased in all SLC12A2 variants studied. Immunohistochemistry revealed that SLC12A2 is located on the plasma membrane of several types of cells in the cochlea, including the strial marginal cells, which are critical for endolymph homeostasis. Overall, this study suggests that variants affecting exon 21 of the SLC12A2 transcript are responsible for hereditary hearing loss in humans.

Systematic quantification of the anion transport function of pendrin (SLC26A4) and its disease-associated variants.

Thanks to the advent of rapid DNA sequencing technology and its prevalence, many disease-associated genetic variants are rapidly identified in many genes from patient samples. However, the subsequent effort to experimentally validate and define their pathological roles is extremely slow. Consequently, the pathogenicity of most disease-associated genetic variants is solely speculated in silico, which is no longer deemed compelling. We developed an experimental approach to efficiently quantify the pathogenic effects of disease-associated genetic variants with a focus on SLC26A4, which is essential for normal inner ear function. Alterations of this gene are associated with both syndromic and nonsyndromic hereditary hearing loss with various degrees of severity. We established HEK293T-based stable cell lines that express pendrin missense variants in a doxycycline-dependent manner, and systematically determined their anion transport activities with high accuracy in a 96-well plate format using a high throughput plate reader. Our doxycycline dosage-dependent transport assay objectively distinguishes missense variants that indeed impair the function of pendrin from those that do not (functional variants). We also found that some of these putative missense variants disrupt normal messenger RNA splicing. Our comprehensive experimental approach helps determine the pathogenicity of each pendrin variant, which should guide future efforts to benefit patients.

The extracellular loop of pendrin and prestin modulates their voltage-sensing property.

Pendrin and prestin belong to the solute carrier 26 (SLC26) family of anion transporters. Prestin is unique among the SLC26 family members in that it displays voltage-driven motor activity (electromotility) and concurrent gating currents that manifest as nonlinear cell membrane electrical capacitance (nonlinear capacitance (NLC)). Although the anion transport mechanism of the SLC26 proteins has begun to be elucidated, the molecular mechanism of electromotility, which is thought to have evolved from an ancestral ion transport mechanism, still remains largely elusive. Here, we demonstrate that pendrin also exhibits large NLC and that charged residues present in one of the extracellular loops of pendrin and prestin play significant roles in setting the voltage-operating points of NLC. Our results suggest that the molecular mechanism responsible for sensing voltage is not unique to prestin among the members of the SLC26 family and that this voltage-sensing mechanism works independently of the anion transport mechanism.

Late onset and high-frequency dominant hearing loss in a family with MYH9 disorder.

MYH9 disorder is a rare autosomal-dominant disorder. We previously reported that it is caused by mutations in the gene for nonmuscle myosin heavy chain IIA (NMMHC-IIA). MYH9 disorder causes congenital macrothrombocytopenia accompanied by progressive sensorineural hearing loss, nephropathy, and cataract. However, there are few reports that describe the audiological features of MYH9 disorder. The objective of this study was to characterize auditory and other phenotypes of patients with MYH9 disorder. We examined nine subjects from one Japanese family. Audiological, ophthalmological, hematological, and imaging examinations were used to assess clinical features. We carried out genetic analysis of the causative gene, MYH9. Five subjects exhibited macrothrombocytopenia and neutrophil cytoplasmic inclusion bodies. Immunofluorescence analysis of neutrophil NMMHC-IIA revealed abnormal type II localization. Two subjects had high-frequency dominant hearing loss, which was adult onset and progressive. Only one subject had cataract. MYH9 sequencing analysis of all thrombocytopenic subjects revealed a heterozygous c.4270G>A mutation in exon 30 (p.D1424N). We identified five patients with MYH9 disorder from the family. The hearing impairment associated with MYH9 disorder in this family was characterized as adult onset, progressive, and high-frequency dominant. Hematological manifestations of MYH9 disorder show complete penetrance, whereas extra-hematological manifestations show incomplete penetrance and variable expressivity in this family.

A novel frameshift mutation in KCNQ4 in a family with autosomal recessive non-syndromic hearing loss.

Mutation of KCNQ4 has been reported to cause autosomal dominant non-syndromic hearing loss (DFNA2A) that usually presents as progressive hearing loss starting from mild to moderate hearing loss during childhood. Here, we identified a novel KCNQ4 mutation, c.1044_1051del8, in a family with autosomal recessive non-syndromic hearing loss. The proband was homozygous for the mutation and was born to consanguineous parents; she showed severe hearing loss that was either congenital or of early childhood onset. The proband had a sister who was heterozygous for the mutation but showed normal hearing. The mutation caused a frameshift that eliminated most of the cytoplasmic C-terminus, including the A-domain, which has an important role for protein tetramerization, and the B-segment, which is a binding site for calmodulin (CaM) that regulates channel function via Ca ions. The fact that the heterozygote had normal hearing indicates that sufficient tetramerization and CaM binding sites were present to preserve a normal phenotype even when only half the proteins contained an A-domain and B-segment. On the other hand, the severe hearing loss in the homozygote suggests that complete loss of the A-domain and B-segment in the protein caused loss of function due to the failure of tetramer formation and CaM binding. This family suggests that some KCNQ4 mutations can cause autosomal recessive hearing loss with more severe phenotype in addition to autosomal dominant hearing loss with milder phenotype. This genotype-phenotype correlation is analogous to that in KCNQ1 which causes autosomal dominant hereditary long QT syndrome 1 with milder phenotype and the autosomal recessive Jervell and Lange-Nielsen syndrome 1 with more severe phenotype due to deletion of the cytoplasmic C-terminus of the potassium channel.

[Usefulness of Clinicobiological Data Obtained Prior to Cervical Lymph Node Biopsy].

INTRODUCTION: We commonly use data obtained prior to cervical lymph node biopsy for the diagnosis of malignant lymphoma. Based on such data, we can confirm whether a biopsy should be performed in some cases. Currently, the parameters used to indicate a presurgery examination prior to biopsy have been very few. So, we retrospectively analyzed cases of cervical lymph node biopsy. Moreover, we examined the usefulness of clinicobiological data obtained prior to cervical lymph node biopsy to evaluate various factors related to the diagnosis of malignant lymphoma. METHODS: This study included 77 patients for whom the initial diagnostic impression was malignant lymphoma before surgery. Of the 77 cases, 40 were diagnosed as having malignant lymphoma and 37 were diagnosed as having non-malignant lymphoma. We performed a case-controlled study to evaluate the differences in clinicobiological data between malignant and non-malignant lymphoma in terms of the following parameters: (1) age, (2) sex, (3) number of white blood cells, (4) white blood cell lymphocyte count, (5) percentage of white blood cell lymphocytes, (6) percentage of eosinophils (%), (7) percentage of monocytes (%), (8) atypical lymphocytes (%), (9) hemoglobin level, (10) lactate dehydrogenase level, (11) C-reactive protein level, (12) soluble interleukin-2 receptor (IL-2R) level, and (13) cytological findings. We used multivariate and univariate analyses to study the data statistically. RESULTS: The following 5 factors were found to be significant in a Wilcoxon t-test for malignant lymphoma: percentage of white blood cell lymphocytes, sIL-2R level, age, white blood cell lymphocyte count, and cytological findings; these factors were also significant when examined using a Pearson χ2 test. The other factors did not differ significantly between the malignant and non-malignant lymphomas. The percentage of white blood cell lymphocytes and the cytological findings were identified as significant independent factors for the diagnosis of malignant lymphoma in a multivariate analysis, whereas the other factors were not found to be significant. CONCLUSION: Based on the results of the univariate and multivariate analyses performed in the present study, the decline in the percentage of white blood cell lymphocytes and the cytological findings obtained prior to cervical lymph node biopsy are significant indicators of malignant lymphoma.

[Long-term effects of tinnitus retraining therapy involving monaural noise generators].

We have previously reported on the effects of tinnitus retraining therapy (TRT) involving monaural noise generators (NGs) up to 24 months after the start of treatment (Eur Arch Otorhinolaryngol. 2013 Feb; 270(2) : 443-8.) but very few reports exist about the long-term effects of TRT for periods of over 2 years. The aim of this study was to report the effects of TRT involving monaural NGs more than 24 months after the start of treatment. Thirty-three patients with chronic tinnitus were included in this study. All received directive counseling and monaural NGs without any other combination treatment. Effects were evaluated with the Tinnitus Handicap Inventory (THI) at their final visits to our clinic (average 31 months after the start of treatment). The average THI scores significantly improved from 55.3 +/- 19.7 at baseline to 33.5 +/- 23.3 at their final visits. Seventeen patients (52%) improved by more than 20 points from the baseline. Eleven patients who were treated with TRT for more than 3 years were individually observed in a detailed manner. Some of them experienced aggravation of their symptoms after 2 years' successful treatments. This study suggests that, although TRT seems effective more than 2 years after the start of treatment, the clinical course of each patient can vary and we need to follow them periodically depending on their situations and symptoms.

Idiopathic sudden sensorineural hearing loss: A review focused on the contribution of vascular pathologies.

Idiopathic sudden sensorineural hearing loss (ISSNHL) is characterized by abruptly appearing hearing loss, sometimes accompanied by vertigo. Vascular pathologies (e.g., cochlear ischemia, or cochlear infarction) are one of the most likely causes of ISSNHL. This review aims to present current understanding of inner ear anatomy, clinical features of ISSNHL, and its treatment strategies. The labyrinthine artery is the only end artery supplying blood to the inner ear, and it has three branches: the anterior vestibular artery, the main cochlear artery, and the vestibulo-cochlear artery (VCA). Occlusion of the VCA can be caused by a variety of factors. The VCA courses through a narrow bone canal. ISSNHL is usually diagnosed after excluding retrocochlear pathologies of sudden sensorineural hearing loss (SSNHL), such as vestibular schwannoma. Therefore, a head MRI or assessing auditory brainstem responses are recommended for patients with SSNHL. Severe SSNHL patients with high CHADS2 scores, an index of stroke risk, have a significantly lower rate of vestibular schwannoma than severe SSNHL patients with low CHADS2 scores, suggesting that severe ISSNHL in individuals at high risk of stroke is caused by vascular impairments. Intralabyrinthine hemorrhage causes SSNHL or vertigo, as in ISSNHL. The diagnosis of intralabyrinthine hemorrhage requires careful interpretation of MRI, and a small percentage of patients diagnosed with ISSNHL may in fact have intralabyrinthine hemorrhage. Many studies have reported an association between ISSNHL and atherosclerosis or cardiovascular risk factors (e.g., diabetes mellitus, hypertension, dyslipidemia and cardiovascular disease), and subsequent risk of stroke in patients with ISSNHL may be elevated compared to controls. Increased hearing level on the healthy ear side, high Framingham risk score, high neutrophil-to-lymphocyte ratio, high platelet-to-lymphocyte ratio, and severe white matter lesions may be poor prognostic factors for patients with ISSNHL. The association between thrombosis-related genes and susceptibility to ISSNHL has been reported in many studies (e.g., coagulation factor 2, coagulation factor 5, plasminogen activator inhibitor-1, platelet-associated genes, a homocysteine metabolism-related enzyme gene, endothelin-1, nitric oxide 3, phosphodiesterase 4D, complement factor H, and protein kinase C-eta). Treatment of ISSNHL with the aim of mitigating the vascular impairment in the inner ear includes systemically administered steroids, intratympanic steroid injections, hyperbaric oxygen therapy, prostaglandin E1, defibrinogenation therapy, and hydrogen inhalation therapy, but there is currently no evidence-based treatment for ISSNHL. Breakthroughs in the unequivocal diagnosis and treatment of ISSNHL due to vascular impairment are crucial to improve quality of life.

Prognostic significance vestibular examination results in patients with vestibular migraine.

Introduction: Vestibular migraine (VM) is a newly defined clinical condition. Several vestibular abnormalities have been reported in patients with VM. However, to date, no specific vestibular examinations are used to define VM. Therefore, the utility of vestibular examinations is limited. Currently, the role of vestibular examination has not been clearly defined. We speculated that the results of vestibular examinations could predict the prognosis of VM. We investigated the relationship between the vestibular examination results and clinical outcomes in patients with VM. Methods: This study included 25 patients with VM. Vestibular examinations, including the video head impulse test (V-HIT), cervical and ocular vestibular evoked myogenic potential (c-VEMP and o-VEMP), posturography, and several questionnaires, including the Dizziness Handicap Inventory (DHI), were conducted at the initial evaluation. Lifestyle modifications for VM and conventional pharmacological prophylactic treatments, including lomerizine, amitriptyline, and valproic acid, were performed. After 4 weeks of treatment, clinical improvements were evaluated using the Clinical Global Improvement Scale (CGI-s). The relationships among the CGI-S score, several clinical variables, and the results of several vestibular examinations were evaluated. Each patient was further classified into two subgroups according to treatment outcomes concerning vertigo and headache: CGI-S score from 0 to 2 (good response [GR]) and CGI-S score > 3 (poor response [PR]). Results: Overall, after treatment, most of the patients had improved dizziness and headache, and the CGI-s was 2.7 ± 1.3. There were 12 GRs, and 13 had PRs. Thus, neither V-HIT nor posturography predicted the prognosis. For c-VEMP, patients with GRs had significantly small AR concerning PR (19.2 ± 12.8 and 62.5 ± 42.5, respectively, [p < 0.01]). There were five normal, six unilateral, and 14 bilateral no response in 500hz o-VEMP. CGI-s of normal, unilateral, and bilateral no response was 1.4 ± 0.5, 2.8 ± 1.3, and 3.1 ± 1.2, respectively. There was a statistically significant difference between the normal and bilateral non-response o-VEMP groups (p < 0.05). Conclusion: Patients with VM had improvements in both headache and vertigo through a combination of lifestyle changes and prophylactic medications. Vestibular examinations, especially o- or c-VEMP, are beneficial for predicting the treatment outcomes of VM. The pathophysiology of VM is closely related to vestibular abnormalities, particularly the otolith-related pathways.

Functional studies of deafness-associated pendrin and prestin variants.

Pendrin and prestin are evolutionary conserved membrane proteins that are essential for normal hearing. Pendrin is an anion transporter required for normal development and maintenance of ion homeostasis in the inner ear, while prestin is a voltage-dependent motor responsible for cochlear amplification essential for high sensitivity and frequency selectivity of mammalian hearing. Dysfunction of these proteins result in hearing loss in humans, and numerous deafness-associated pendrin and prestin variants have been identified in patients. However, the pathogenic impacts of many of these variants are ambiguous. Here we report results from our ongoing efforts in experimentally characterizing pendrin and prestin variants using in vitro functional assays, providing invaluable information regarding their pathogenicity.

Validity and utility of the Japanese version of the brief unhelpful thoughts and beliefs about stuttering scale: UTBAS-6-J.

Do adults who stutter have abnormally high social anxiety? Is it related to maladaptive cognition? As these are persistent, unresolved questions in stuttering research, it behooves clinicians to at least assess and attempt to identify social anxiety in patients who stutter and its basis before decisions are made about stuttering treatment. The Unhelpful Thoughts and Beliefs About Stuttering (UTBAS) scale is a self-administered questionnaire that measures the degree of non-adaptive cognition in people who stutter (PWS) due to social anxiety. The 66-item UTBAS is time-consuming to complete, prompting the development of a shorter 6-item version, the UTBAS-6, which is in English. Here, we aimed to assess some psychometric properties of the Japanese version of the UTBAS-6, the UTBAS-6-J, which has not been done to date. In 56 adult patients (mean 32.6 ± 11.1 years) who stutter, we quantified the reliability, the internal consistency, and the concurrent validity of the UTBAS-6-J. Along with the UTBAS-6-J, patients also were administered the Overall Assessment of the Speaker's Experience of Stuttering - Japanese version (OASES-A-J), the Modified Erickson Communication Attitude Scale - Japanese version (S-24-J), and the Liebowitz Social Anxiety Scale - Japanese version (LSAS-J). Cronbach's alpha for UTBAS-6-J total scores was 0.974, indicating excellent internal consistency. UTBAS-6-J scores were significantly correlated with scores on the OASES-A-J, the S-24-J, and the LSAS-J (all p < 0.005). Concurrent validity of the UTBAS-6-J with these three questionnaires was confirmed. The UTBAS-6-J has good internal consistency and concurrent validity, which will aid clinical decision-making about stuttering treatments.

Characteristics of pure tone audiogram in patients with untreated sporadic vestibular schwannoma: Analysis of audiometric shape and interaural differences stratified by age and mode of onset.

OBJECTIVE: Asymmetric sensorineural hearing loss (ASHL) is the most common symptom of sporadic vestibular schwannoma (VS). However, there is still no universally accepted MRI protocol for diagnosing VS. This study identified the characteristics of pure tone audiogram (PTA) in patients with VS. METHODS: We conducted a retrospective chart review of patients diagnosed with sporadic unilateral VS. In the analysis, we focused on the shape and interaural differences of PTA, stratified by the mode of onset and patient age. RESULTS: In total, 390 patients met the inclusion criteria. The U-shaped audiogram showed the highest proportion in patients with the onset of sudden sensorineural hearing loss (SSNHL). In patients with SSNHL, U-shaped audiograms were younger than other audiograms, and 86.7 % of patients under 40 had U-shaped audiograms. Patients with VS were more likely to have interaural differences at higher frequencies than at lower frequencies. Patients with SSNHL had a significantly higher percentage of interaural differences at 500-4000 Hz than those with onset other than SSNHL (non-SSNHL patients). In addition, non-SSNHL patients had a significant trend toward a higher percentage of interaural differences at all frequencies with increasing age. CONCLUSION: MRI screening can be considered in patients with SSNHL with U-shaped audiograms under 40 years of age. In ASHL, not SSNHL, MRI screening can be considered for older patients with interaural differences at wider continuous frequencies. Patients with interaural differences at high frequencies had a higher priority than those with interaural differences at low frequencies as indications for MRI screening for VS.

Swallowing Function and Quality of Life in Patients Treated With Transoral Videolaryngoscopic Surgery for Pharyngolaryngeal Cancer.

BACKGROUND: It is controversial whether transoral resection for early pharyngolaryngeal cancer preserves swallowing function and quality of life. We investigated swallowing function and quality of life before and after transoral videolaryngoscopic surgery (TOVS). METHODS: Seventy-three patients with pharyngolaryngeal cancer who underwent TOVS between July 2012 and July 2022 were enrolled in this prospective analysis. The Hyodo score and European Organization for Research and Treatment of Cancer Quality of Life Questionnaires were recorded preoperatively and at three, six, and 12 months postoperatively, in addition to the postoperative functional outcome swallowing scale (FOSS) at six months postoperatively. RESULTS: Although most patients could consume food orally without restrictions with a preferable FOSS score, 23 patients showed impaired Hyodo scores. Age ≥65 years significantly predicted impaired swallowing. Sub-scores of the impaired patient group showed worsening for the glottal closure reflex when the endoscope touched the epiglottis or arytenoid, as well as a reduction in the extent of pharyngeal clearance following the ingestion of blue-dyed water. CONCLUSION: After TOVS, swallowing function is generally well preserved. Elderly patients, especially those with laryngeal hypoesthesia and poor clearance, are at risk of swallowing dysfunction.

Correlation between genotype and phenotype with special attention to hearing in 14 Japanese cases of NF2-related schwannomatosis.

NF2-related schwannomatosis (NF2) is an autosomal dominant genetic disorder caused by variants in the NF2 gene. Approximately 50% of NF2 patients inherit pathogenic variants, and the remainder acquire de novo variants. NF2 is characterized by development of bilateral vestibular schwannomas. The genetic background of Japanese NF2 cases has not been fully investigated, and the present report performed a genetic analysis of 14 Japanese NF2 cases and examined genotype-phenotype correlations. DNA samples collected from peripheral blood were analyzed by next-generation sequencing, multiplex ligation-dependent probe amplification analysis, and in vitro electrophoresis. Ten cases had pathogenic or likely pathogenic variants in the NF2 gene, with seven truncating variants and three non-truncating variants. The age of onset in all seven cases with truncating variants was < 20 years. The age of onset significantly differed among cases with truncating NF2 variants, non-truncating NF2 variants, and no NF2 variants. However, the clinical course of tumor growth and hearing deterioration were not predicted only by germline pathogenic NF2 variants. The rate of truncating variants was higher in the present study than that of previous reports. Genotype-phenotype correlations in the age of onset were present in the analyzed Japanese NF2 cases.

Prevalence of Hearing Impairment by Age: 2nd to 10th Decades of Life.

Background: Accurate data on the prevalence of hearing impairment and severity across age and gender are paramount to formulate hearing health policies. Here, we sought to analyze audiometric data from a large group of age-diverse people in Japan, which has not been previously described in detail. Methods: We analyzed retrospective hearing threshold data of 23,860 participants (10−99 years; left-right hearing threshold difference <15 dB; air-bone gap ≤10 dB) at 500, 1000, 2000, and 4000 Hz, and then classified them for hearing impairment severity according to the WHO Classification. Findings: There was a significant gender difference in median hearing thresholds, starting in 20-year-olds up to early 80-year-olds. Twenty-five percent of men in their late 50s had some level of HI, ~50% in their late 60s, and ~75% in their late 70s. For women, 25% had some level of HI in their early 60s, ~50% in their early 70s, and ~75% in their late 70s. For participants in their early 80s, 50% of either gender had moderate or more severe HI. Interpretation: Our results, derived from a large number of participants, provide basic information about the prevalence of hearing loss by age decade. Since people can expect to live longer than those in previous generations, our detailed data can inform national social systems responsible for hearing screening in making decisions about hearing-aid qualification, which may reduce barriers to older people's independence, productivity, and quality of life.