Increased risk of hearing loss associated with MT-RNR1 gene mutations: a real-world investigation among Han Taiwanese Population.

BACKGROUND: Previous studies have implicated inherited mutations in mitochondrial DNA (mtDNA) in sensorineural hearing loss (SNHL). However, the definitive association between mitochondrial 12S rRNA (MT-RNR1) variants and hearing loss in the population has not been well established, particularly in Asia. The objective of this retrospective cohort study was to assess the association between MT-RNR1 variants and the risk of SNHL in patients in Taiwan. METHODS: The cohort included 306,068 participants from Taiwan between January 2003 and December 2020. Participants were classified based on genetic variants, particularly mitochondrial mutations (rs267606618, rs267606619, rs267606617). MT-RNR1 variant cases were matched 1:10 with non-mutant patients by age, gender, and visit year, excluding those with pre-existing hearing loss. The primary endpoint was SNHL, identified using specific ICD-TM codes with a 90% positive predictive value. Medication exposure history was determined via self-report or electronic medical records in the hospital. Cox proportional hazard regression models were used to assess the association between MT-RNR1 variants and hearing loss, adjusting for various covariates. Kaplan-Meier survival curves and log-rank tests compared hearing loss incidence between groups. RESULTS: The mean age of the mtDNA variants group is 32.4 years, with a standard deviation of 19.2 years. The incidence density of hearing loss for the mutation group was 36.42 per 10,000 person-years (95% Confidence Interval [CI], 27.21-47.73), which was higher than the 23.77per 10,000 person-years (95% CI, 21.32-26.42) in the wild-type group (p = 0.0036). Additionally, diabetes mellitus was associated with an increased risk of developing SNHL in individuals with MT-RNR1 variants (adjusted hazard ratio = 1.76 [95% CI, 1.00-3.09], p < 0.05). CONCLUSION: This study highlights the increased risk of hearing loss in patients carrying MT-RNR1 variants, particularly those with diabetes mellitus. Future research that integrates genetic and clinical data is crucial for developing more precise interventions to monitor and treat hearing loss in this vulnerable population.

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

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

Cochlear Implantation in Patients With Osteolytic Labyrinthitis: A Case Series.

OBJECTIVE: To describe the rare process of osteolytic labyrinthitis, previously referred to as labyrinthine sequestrum, which involves progressive obliteration of the bony and membranous labyrinth with eventual supplantation with soft tissue and, in some cases, bony sequestrum. PATIENTS: Three patients with diverse presentations of osteolytic labyrinthitis from two tertiary care academic medical centers. INTERVENTIONS: Case series report analyzing the relevant clinical, radiologic, pathologic, and surgical data on our patients with osteolytic labyrinthitis and comparing these index cases to the existing literature. MAIN OUTCOME MEASURES: We describe the varying image findings seen in osteolytic labyrinthitis on computed tomography and magnetic resonance imaging. Also, we report successful surgical intervention and hearing rehabilitation with cochlear implantation in patients with osteolytic labyrinthitis. RESULTS: Our three patients presented with profound sudden sensorineural hearing loss and vertigo consistent with labyrinthitis. None of the three patients had a history of chronic otitis media. Imaging workup revealed varying degrees of erosion to the otic capsule bone demonstrating the spectrum of disease seen in osteolytic labyrinthitis. Although two cases showed osteolytic changes to the semicircular canals and vestibule, the first case revealed frank bony sequestrum within the obliterated labyrinth. The three cases were taken for surgical debridement and cochlear implantation. CONCLUSIONS: We propose the new term, osteolytic labyrinthitis-previously referred to as labyrinthine sequestrum-to describe the rare spectrum of disease characterized by destruction of the osseous and membranous labyrinth and potential supplantation with bony sequestrum. Cochlear implantation is a viable option in selected patients with osteolytic labyrinthitis.

Assessing risk of stroke after idiopathic sudden sensorineural hearing loss using data from general practice.

The cause of sudden sensorineural hearing loss (SSNHL) remains unknown in a significant number of cases, but vascular involvement in its pathophysiology has been proposed. Our study aimed to assess the incidence of stroke following idiopathic SSNHL (iSSNHL) and to evaluate associated cardiovascular risk factors and comorbidities. We extracted electronic medical record data from iSSNHL patients aged ≥ 50 years retrospectively from 84 general practices. Patients were matched for age, sex and general practice in a 1:4 ratio to controls. Primary outcome was the 5-years stroke risk following iSSNHL diagnosis. 480 iSSNHL cases could be matched to 1911 controls. The hazard ratio for iSSNHL compared with controls was 1.25 (95%CI 0.50-3.27; P = 0.646) for CVA (cerebrovascular accident) alone and 0.92 (95% CI 0.50-1.71; P = 0.804) for CVA and TIA (transient ischemic attack) combined. The hazard ratio for the interaction term between iSSNHL and age ≥ 60 years was 4.84 (95% CI 1.02-23.05; P = 0.048) for CVA and TIA combined. Patients with iSSNHL used antihypertensives and beta-blocking agents more frequently than controls (P = 0.006 and P = 0.022, respectively). In conclusion, no overall significant difference in the risk of stroke was observed, but the hazard ratio for stroke increased in iSSNHL patients aged 60 and older, suggesting potential vascular involvement in older subjects presenting with sudden sensorineural hearing loss.

Coexisting presentation of two rare genetic variants of autosomal dominant polycystic kidney disease and Alport syndrome.

Alport syndrome and autosomal dominant polycystic kidney disease are monogenic causes of chronic kidney disease and end-stage kidney failure. We present a case of a man in his 60s with progressive chronic kidney disease, bilateral sensorineural hearing loss and multiple renal cysts. Genetic analysis revealed a heterozygous variant in COL4A3 (linked to Alport syndrome) and in the GANAB gene (associated with a milder form of autosomal dominant polycystic kidney disease). Although each variant confers a mild risk of developing end-stage kidney disease, the patient presented a pronounced and accelerated progression of chronic kidney disease, which goes beyond what would be predicted by adding up their individual effects. This suggests a potential synergic effect of both variants, which warrants further investigation.

DDX58 variant triggers IFN-ß-induced autophagy in trabecular meshwork and influences intraocular pressure.

Singleton-Merten syndrome (SMS) is a rare immunogenetic disorder affecting multiple systems, characterized by dental dysplasia, aortic calcification, glaucoma, skeletal abnormalities, and psoriasis. Glaucoma, a key feature of both classical and atypical SMS, remains poorly understood in terms of its molecular mechanism caused by DDX58 mutation. This study presented a novel DDX58 variant (c.1649A>C [p.Asp550Ala]) in a family with childhood glaucoma. Functional analysis showed that DDX58 variant caused an increase in IFN-stimulated gene expression and high IFN-ß-based type-I IFN. As the trabecular meshwork (TM) is responsible for controlling intraocular pressure (IOP), we examine the effect of IFN-ß on TM cells. Our study is the first to demonstrate that IFN-ß significantly reduced TM cell viability and function by activating autophagy. In addition, anterior chamber injection of IFN-ß remarkably increased IOP level in mice, which can be attenuated by treatments with autophagy inhibitor chloroquine. To uncover the specific mechanism underlying IFN-ß-induced autophagy in TM cells, we performed microarray analysis in IFN-ß-treated and DDX58 p.Asp550Ala TM cells. It showed that RSAD2 is necessary for IFN-ß-induced autophagy. Knockdown of RSAD2 by siRNA significantly decreased autophagy flux induced by IFN-ß. Our findings suggest that DDX58 mutation leads to the overproduction of IFN-ß, which elevates IOP by modulating autophagy through RSAD2 in TM cells.

Unusual phenotype in 35delG mutation: a case report.

BACKGROUND: Mutations in the GJB2 gene, which encodes the protein connexin 26 and is involved in inner ear homeostasis, are identified in approximately 50% of patients with autosomal recessive nonsyndromic hearing loss, making it one of the primary causes of prelingual nonsyndromic hearing loss in various populations. The 35delG mutation, one of the most common mutations of the GJB2 gene, usually causes prelingual, bilateral mild to profound, nonprogressive sensorineural hearing loss. CASE PRESENTATION: We present an unusual case of an 18-year-old Turkish female with heterozygous 35delG mutation and postlingual, profound-sloping, progressive and fluctuating unilateral sensorineural hearing loss. The phenotype is different from the usual findings. CONCLUSIONS: The 35delG mutation causing hearing loss may not always be reflected in the phenotype as expected and therefore may have different audiologic manifestations.

A Novel COL2A1 Gene Pathogenic Variant in a Turkish Family With Ocular Stickler Syndrome.

A 6-month-old female infant with megalophthalmos was referred with the suspicion of congenital glaucoma. Refractive measurements obtained with handheld autorefractometry were -7.00 -2.00 × 90° in the right eye and -6.00 -2.00 × 100° in the left eye and ultrasonic axial lengths were 22.50 mm in both eyes. Intraocular pressures and vertical and horizontal corneal diameters of the proband were 11 mm Hg, 11 mm, and 11.50 mm in both eyes, respectively. She was diagnosed as having early-onset high myopia. Her father also had degenerative high myopia (-12.00 diopters) in the right eye, bilateral congenital lens opacities, and retinal detachment in the left eye. Her mother was emmetropic with normal eye examination results. Clinical exome sequencing analysis revealed a novel ENST00000380518.3 c.3528_3530 delins GACCATTAGCA (Chr12:48369813: GCA > TGCTAATGGTC) variant in the collagen type II alpha 1 chain (COL2A1) on chromosome 12q13 (OMIM 108300), consistent with the Stickler syndrome type 1. Subsequent segregation analysis revealed paternal inheritance. Although many pathogenic null variants have been described within the COL2A1 gene, there is currently no documented literature pertaining to this specific variant, making this the inaugural report of its manifestation in scientific discourse. [J Pediatr Ophthalmol Strabismus. 2024;61(3):e23-e27.].

[Bilateral vestibulopathy and sensorineural hearing loss in necrobiotic xanthogranuloma, multiple myeloma and amiloidosis]. / Dvustoronnyaya vestibulopatiya i sensonevral'naya tugoukhost' u patsienta s nekroticheskoi ksantogranulemoi, mnozhestvennoi mielomoi i amiloidozom.

This article describes a rare case of necrotic xanthogranuloma in a 46-year-old patient who presented with the development of periorbital xanthelasms, progressive bilateral sensorineural hearing loss and bilateral vestibulopathy, followed by multiple myeloma and amyloidosis. For several years, the patient underwent standard rehabilitation for chronic sensorineural hearing loss and was fitted with a hearing aid. During hospitalisation for exacerbation of chronic bronchitis, monoclonal gammopathy was identified, and later, after careful examination and repeated biopsies, necrotic xanthogranuloma, multiple myeloma and AL-amyloidosis were confirmed. Targeted immunochemotherapy resulted in improvement of hearing and significant recovery of the vestibuloocular reflex bilaterally.

Management of Idiopathic Sudden Sensorineural Hearing Loss (ISSNHL) Intratympanic Platelet-Rich Plasma (PRP) Versus Intratympanic Steroid Injections: A Cross-Sectional Study.

<b><br>Introduction:</b> Idiopathic sensorineural hearing loss of 30 decibels (dB) or more over at least three contiguous audiometric frequencies with an onset of less than 3 days is referred to as sudden sensorineural hearing loss (ISSNHL) and is known as an ENT (ear, nose, and throat) emergency. When a patient's hearing suddenly deteriorates, they become confused, anxious, and worried. One of the primary therapies for sudden sensorineural hearing loss is intratympanic steroids. Intratympanic injections of platelet-rich plasma (PRP) improve inner ear hair cells, which enhances hearing.</br> <b><br>Aim:</b> To show the safety and efficacy of intratympanic PRP injection in the management of ISSNHL in comparison with intratympanic steroid injection.</br> <b><br>Methods:</b> The study group was comprised of 100 patients who had experienced ISSNHL within 30 days with no retrocochlear pathology, as demonstrated by a negative MRI scan. 50 patients received 6 intratympanic steroid injections, while the remaining 50 patients received 2 intratympanic injections of PRP at a 1-week interval.</br> <b><br>Results:</b> A total of 39 patients with PRP injection noted an improvement in their hearing of 25 db after 2 weeks and of 30 db after 2 months, with improved speech discrimination of 26% after 2 weeks and of 28% after 2 months. 31 patients with intratympanic steroid injection noted an improvement in their hearing of 18 db after 2 weeks and of 22 db after 2 months, with improved speech discrimination of 21% after 2 weeks and of 24% after 2 months.</br> <b><br>Conclusions:</b> PRP appears safe and efficient for the treatment of ISSNHL, with a low cost and no systemic side effects, as with oral steroids. Therefore, such research should be continued.</br>.

[Evaluation of the outcomes of cochlear implant in children with auditory neuropathy].

Objective: To investigate the auditory and speech abilities of children with congenital auditory neuropathy (AN) after cochlear implant (CI), and to analyze the role of genetic testing in predicting the postoperative outcomes of CI in AN patients. Methods: Fourteen children diagnosed with AN by audiological battery test and underwent CI surgery in Xijing Hospital of the Air Force Medical University from 2002 to 2021 were included in this study (9 males and 5 females), with an implantation age of (3.1±1.7) years (mean±standard deviation, the same as follows). The preoperative audiological results and deafness gene results were analyzed. Another 52 children with ordinary sensorineural hearing loss (SNHL) were selected as the control group (30 males and 22 females), with an implantation age of (2.2±0.9) years. The demographic factors such as age and gender were matched with those of the AN group. The modified Category Auditory Performance (CAP-Ⅱ) and Speech Intelligence Rate (SIR) were used to evaluate the development of postoperative auditory and speech abilities in two groups. The Mandarin Speech Test System was used to test the speech recognition rate of monosyllabic and disyllabic words and sentences. Matlab 2022 software was used to analyze the data. Results: The results of gene in 14 children with AN showed that 6 cases had OTOF gene mutations, 2 cases (siblings) were confirmed to have TNN gene mutations through whole exome sequencing, and the remaining 6 cases were not find any clear pathogenic gene mutations. All subjects underwent CI surgery with electrodes implanted into the cochlea smoothly, and there were no postoperative complications. After surgery, all AN children had improved auditory and speech abilities, but only 64% (9/14) of AN children with CI had auditory ability scores comparable to the control group of SNHL children (including 2 children with TNN gene mutations), and 36% (5/14) of AN children had lower scores than the control group of SNHL children.The average speech recognition rate of two children with TNN gene mutations was 86.5%, and of two children with OTOF gene mutations was 83.2%. Conclusions: AN children achieved varying degrees of auditory and speech abilities after CI, but the postoperative effects varied greatly. Some children achieved similar results as ordinary SNHL children, but there were still some children whose effects were worse than those of ordinary SNHL children. The postoperative efficacy of CI in two children with AN caused by TNN pathogenic genes were comparable to that of ordinary SNHL in children. Genetic testing had certain reference value for predicting the postoperative effect of CI in AN children.

Comprehensive Genetic Evaluation in Patients with Special Reference to Late-Onset Sensorineural Hearing Loss.

Hearing loss (HL) is a common and multi-complex etiological deficit that can occur at any age and can be caused by genetic variants, aging, toxic drugs, noise, injury, viral infection, and other factors. Recently, a high incidence of genetic etiologies in congenital HL has been reported, and the usefulness of genetic testing has been widely accepted in congenital-onset or early-onset HL. In contrast, there have been few comprehensive reports on the relationship between late-onset HL and genetic causes. In this study, we performed next-generation sequencing analysis for 91 HL patients mainly consisting of late-onset HL patients. As a result, we identified 23 possibly disease-causing variants from 29 probands, affording a diagnostic rate for this study of 31.9%. The highest diagnostic rate was observed in the congenital/early-onset group (42.9%), followed by the juvenile/young adult-onset group (31.7%), and the middle-aged/aged-onset group (21.4%). The diagnostic ratio decreased with age; however, genetic etiologies were involved to a considerable degree even in late-onset HL. In particular, the responsible gene variants were found in 19 (55.9%) of 34 patients with a familial history and progressive HL. Therefore, this phenotype is considered to be a good candidate for genetic evaluation based on this diagnostic panel.

Predictors of cochlear implant outcomes in pediatric auditory neuropathy: A matched case-control study.

OBJECTIVES: Current evidence supports the benefits of cochlear implants (CIs) in children with hearing loss, including those with auditory neuropathy spectrum disorder (ANSD). However, there is limited evidence regarding factors that hold predictive value for intervention outcomes. DESIGN: This retrospective case-control study consisted of 66 children with CIs, including 22 with ANSD and 44 with sensorineural hearing loss (SNHL) matched on sex, age, age at CI activation, and the length of follow-up with CIs (1:2 ratio). The case and control groups were compared in the results of five open-set speech perception tests, and a Forward Linear Regression Model was used to identify factors that can predict the post-CI outcomes. RESULTS: There was no significant difference in average scores between the two groups across five outcome measures, ranging from 88.40% to 95.65%. The correlation matrix revealed that younger ages at hearing aid fitting and CI activation positively influenced improvements in speech perception test scores. Furthermore, among the variables incorporated in the regression model, the duration of follow-up with CIs, age at CI activation, and the utilization of two CIs demonstrated prognostic significance for improved post-CI speech perception outcomes. CONCLUSIONS: Children with ANSD can achieve similar open-set speech perception outcomes as children with SNHL. A longer CI follow-up, a lower age at CI activation, and the use of two CIs are predictive for optimal CI outcome.

Comparison of vestibular function in hereditary hearing loss patients with GJB2, CDH23, and SLC26A4 variants.

To investigate the association between hereditary hearing loss and vestibular function, we compared vestibular function and symptoms among patients with GJB2, SLC26A4, and CDH23 variants. Thirty-nine patients with sensory neural hearing loss (11 males and 28 females) with biallelic pathogenic variants in either GJB2, SLC26A4, or CDH23 were included in this study (13 GJB2, 15 SLC26A4, and 11 CDH23). The patients were examined using caloric testing and cervical and ocular vestibular-evoked myogenic potentials (cVEMP and oVEMP). We also compared vestibular function and symptoms between patients with these gene variants and 78 normal-hearing ears without vestibular symptoms as controls. The frequency of semicircular canal hypofunction in caloric testing was higher in patients with SLC26A4 variants (47%) than in those with GJB2 (0%) and CDH23 variants (27%). According to the cVEMP results, 69% of patients with GJB2 variants had saccular hypofunction, a significantly higher proportion than in those carrying other variants (SLC26A4, 20%; CDH23, 18%). In oVEMP, which reflects utricular function, no difference was observed in the frequency of hypofunction among the three genes (GJB2, 15%; SLC26A4, 40%; and CDH23, 36%). Hence, discernable trends indicate vestibular dysfunction associated with each gene.

Importance of small vessel disease as a possible cause of sudden sensorineural hearing loss.

OBJECTIVE: Vascular disease like small-vessel disease (SVD) is the most likely cause among the potential causes of Sudden sensorineural hearing loss (SSNHL). Understanding the relationship between SVD and SSNHL is crucial for developing effective prevention and treatment strategies. To confirm the relationship between SVD and SSNHL, the effect of SVD is confirmed by focusing on the duration and recurrence of SSNHL. METHODS: This article reports a retrospective observational study that investigated the relationship between SVD and SSNHL using the South Korea Health Insurance Review and Assessment Service (HIRA) database from 2010 to 2020. This retrospective observational study included 319,569 SSNHL patients between 2010 and 2020. RESULTS: Participant demographics were controlled using Propensity Score Matching. The hazard ratios (HR) for the effect of SVD on the duration of SSNHL were 1.045 for the group with SVD before the onset of SSNHL and 1.234 for the group with SVD after the onset of SSNHL. SVD was statistically significant for the recurrence of SSNHL, with an odds ratio of 1.312 in the group with SVD compared to the group without SVD. The HR for the period until a recurrence in the group with SVD was 1.062. CONCLUSIONS: The study identified SVD as a possible cause of SSNHL and found that the duration of SSNHL increased only in the presence of SVD. SVD also affected the recurrence of SSNHL, with the recurrence rate being 1.312 times higher in the group with SVD.

Altered serum levels of neuronal proteins and antibodies to them in occupational diseases of the nervous system.

Aclinical and immunological examination of men with occupational pathology, including vibration disease (VD), occupational sensorineural hearing loss (SHL), and chronic mercury intoxication (CMI), was carried out. The comparison group consisted of men comparable in age and total work experience. Serum concentrations of neurotrophins (S100ß, MBP, BDNF) and antibodies (ABs) to S100ß and MBP proteins were determined by enzyme-linked immunosorbent assay. An increase in the level of the S100ß protein was shown in CMI, VD, and a tendency for its increase was found in SHL. In parallel, an increase in AB to the S100ß protein in VD and SHL and a decrease in AB in CMI were noted. A comparative assessment of MBP levels indicated a pronounced increase in its serum concentrations in patients with CMI and VD versus the comparison group. At the same time, an increase in the level of serum ABs to MBP in individuals with VD and SHL, and a decrease in patients with CMI were noted. In patients with CMI, a significant decrease in the BDNF concentration was found, while in SHL and VD, no statistically significant differences were found in comparison with the comparison group. The results obtained confirm importance of assessing serum concentrations of neurotrophic proteins and ABs to them in the case of occupational damage to the nervous system caused by exposure to physical and chemical factors.

Sensorineural hearing loss among type 2 diabetic patients and its association with peripheral neuropathy: a cross-sectional study from a lower middle-income country.

INTRODUCTION: Despite potential links between diabetes and sensorineural hearing loss (SNHL), routine hearing assessments for diabetic patients are not standard practice. Our study aimed to investigate the prevalence of SNHL and its association with diabetes-related factors among patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: This cross-sectional study was conducted at the Diabetes Clinic, Jinnah Postgraduate Medical Centre, Karachi, Pakistan, from May to September 2021. A total of 396 patients fulfilling the inclusion criteria participated after informed consent. Data collection involved a sociodemographic profile, Michigan Neuropathy Screening Instrument examination followed by pure-tone audiometry and laboratory tests including haemoglobin A1C (HbA1c). HL was defined using better ear four-frequency pure-tone average of ≥26 dB HL and graded as per WHO criteria. Statistical analyses were performed using SPSS. χ2, independent t-test and multinomial logistic regression analyses were applied. P<0.05 at 95% CI was considered significant. RESULTS: Our study revealed a high prevalence of SNHL among patients with T2DM. Mild HL was seen in 55.8%, while 18.7% suffered from moderate HL. Common audiological symptoms included difficulty understanding speech in noisy surroundings (44.2%), balance problems (42.9%), sentence repetition (35.9%), tinnitus (32.3%) and differentiating consonants (31.1%). Hearing impairment predominantly affected low (0.25-0.5 kHz) and high (4-8 kHz) frequencies with a significant difference at 4 kHz among both sexes (t (394)=2.8, p=0.004). Peripheral neuropathy was significantly associated with SNHL on multinomial logistic regression after adjusting with age, sex, body mass index and the presence of any comorbidities. Diabetes duration, HbA1c or family history of diabetes was found unrelated to SNHL severity. CONCLUSIONS: The study highlights the substantial prevalence of SNHL among patients with T2DM and emphasises the importance of targeted audiological care as part of a holistic approach to diabetes management. Addressing HL early may significantly improve communication and overall quality of life.

Machine learning-based longitudinal prediction for GJB2-related sensorineural hearing loss.

BACKGROUND: Recessive GJB2 variants, the most common genetic cause of hearing loss, may contribute to progressive sensorineural hearing loss (SNHL). The aim of this study is to build a realistic predictive model for GJB2-related SNHL using machine learning to enable personalized medical planning for timely intervention. METHOD: Patients with SNHL with confirmed biallelic GJB2 variants in a nationwide cohort between 2005 and 2022 were included. Different data preprocessing protocols and computational algorithms were combined to construct a prediction model. We randomly divided the dataset into training, validation, and test sets at a ratio of 72:8:20, and repeated this process ten times to obtain an average result. The performance of the models was evaluated using the mean absolute error (MAE), which refers to the discrepancy between the predicted and actual hearing thresholds. RESULTS: We enrolled 449 patients with 2184 audiograms available for deep learning analysis. SNHL progression was identified in all models and was independent of age, sex, and genotype. The average hearing progression rate was 0.61 dB HL per year. The best MAE for linear regression, multilayer perceptron, long short-term memory, and attention model were 4.42, 4.38, 4.34, and 4.76 dB HL, respectively. The long short-term memory model performed best with an average MAE of 4.34 dB HL and acceptable accuracy for up to 4 years. CONCLUSIONS: We have developed a prognostic model that uses machine learning to approximate realistic hearing progression in GJB2-related SNHL, allowing for the design of individualized medical plans, such as recommending the optimal follow-up interval for this population.

Cryo-EM structures elucidate the multiligand receptor nature of megalin.

Megalin (low-density lipoprotein receptor-related protein 2) is a giant glycoprotein of about 600 kDa, mediating the endocytosis of more than 60 ligands, including those of proteins, peptides, and drug compounds [S. Goto, M. Hosojima, H. Kabasawa, A. Saito, Int. J. Biochem. Cell Biol. 157, 106393 (2023)]. It is expressed predominantly in renal proximal tubule epithelial cells, as well as in the brain, lungs, eyes, inner ear, thyroid gland, and placenta. Megalin is also known to mediate the endocytosis of toxic compounds, particularly those that cause renal and hearing disorders [Y. Hori et al., J. Am. Soc. Nephrol. 28, 1783-1791 (2017)]. Genetic megalin deficiency causes Donnai-Barrow syndrome/facio-oculo-acoustico-renal syndrome in humans. However, it is not known how megalin interacts with such a wide variety of ligands and plays pathological roles in various organs. In this study, we elucidated the dimeric architecture of megalin, purified from rat kidneys, using cryoelectron microscopy. The maps revealed the densities of endogenous ligands bound to various regions throughout the dimer, elucidating the multiligand receptor nature of megalin. We also determined the structure of megalin in complex with receptor-associated protein, a molecular chaperone for megalin. The results will facilitate further studies on the pathophysiology of megalin-dependent multiligand endocytic pathways in multiple organs and will also be useful for the development of megalin-targeted drugs for renal and hearing disorders, Alzheimer's disease [B. V. Zlokovic et al., Proc. Natl. Acad. Sci. U.S.A. 93, 4229-4234 (1996)], and other illnesses.