Ion Selectivity, Current, and Water Flow Regulation in Ti3C2 MXene Nanopores.

Recent years have seen a growing interest in zero-dimensional (0D) transport phenomena occurring across two-dimensional (2D) materials for their potential applications to nanopore technology such as ion separation and molecular sensing. Herein, we investigate ion transport through 1 nm-wide nanopores in Ti3C2 MXene using molecular dynamics simulations. The high polarity and fish-bone arrangement of the Ti3C2 MXene offer a built-in potential and an atomic-scale distortion to the nanopore, causing an adsorption preference for cations. Our observation of variable cation-specific ion selectivity and Coulomb blockade highlights the complex interplay between adsorption affinity and cation size. The cation-specific ion selectivity can induce both the ion current and electro-osmotic water transmission, which can be regulated by tailoring the ions' preferential pathways through electric field tilting. Our finding underscores the pivotal role of the atomic arrangement of MXenes in 0D ion transport and provides fundamental insight into the application of 2D material in nanopores-based technologies.

Large-scale prediction of adverse drug reactions-related proteins with network embedding.

MOTIVATION: Adverse drug reactions (ADRs) are a major issue in drug development and clinical pharmacology. As most ADRs are caused by unintended activity at off-targets of drugs, the identification of drug targets responsible for ADRs becomes a key process for resolving ADRs. Recently, with the increase in the number of ADR-related data sources, several computational methodologies have been proposed to analyze ADR-protein relations. However, the identification of ADR-related proteins on a large scale with high reliability remains an important challenge. RESULTS: In this article, we suggest a computational approach, Large-scale ADR-related Proteins Identification with Network Embedding (LAPINE). LAPINE combines a novel concept called single-target compound with a network embedding technique to enable large-scale prediction of ADR-related proteins for any proteins in the protein-protein interaction network. Analysis of benchmark datasets confirms the need to expand the scope of potential ADR-related proteins to be analyzed, as well as LAPINE's capability for high recovery of known ADR-related proteins. Moreover, LAPINE provides more reliable predictions for ADR-related proteins (Value-added positive predictive value = 0.12), compared to a previously proposed method (P < 0.001). Furthermore, two case studies show that most predictive proteins related to ADRs in LAPINE are supported by literature evidence. Overall, LAPINE can provide reliable insights into the relationship between ADRs and proteomes to understand the mechanism of ADRs leading to their prevention. AVAILABILITY AND IMPLEMENTATION: The source code is available at GitHub (https://github.com/rupinas/LAPINE) and Figshare (https://figshare.com/articles/software/LAPINE/21750245) to facilitate its use. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

A nonsense TMEM43 variant leads to disruption of connexin-linked function and autosomal dominant auditory neuropathy spectrum disorder.

Genes that are primarily expressed in cochlear glia-like supporting cells (GLSs) have not been clearly associated with progressive deafness. Herein, we present a deafness locus mapped to chromosome 3p25.1 and an auditory neuropathy spectrum disorder (ANSD) gene, TMEM43, mainly expressed in GLSs. We identify p.(Arg372Ter) of TMEM43 by linkage analysis and exome sequencing in two large Asian families segregating ANSD, which is characterized by inability to discriminate speech despite preserved sensitivity to sound. The knock-in mouse with the p.(Arg372Ter) variant recapitulates a progressive hearing loss with histological abnormalities in GLSs. Mechanistically, TMEM43 interacts with the Connexin26 and Connexin30 gap junction channels, disrupting the passive conductance current in GLSs in a dominant-negative fashion when the p.(Arg372Ter) variant is introduced. Based on these mechanistic insights, cochlear implant was performed on three subjects, and speech discrimination was successfully restored. Our study highlights a pathological role of cochlear GLSs by identifying a deafness gene and its causal relationship with ANSD.

Genomic Landscape of Branchio-Oto-Renal Syndrome through Whole-Genome Sequencing: A Single Rare Disease Center Experience in South Korea.

Branchio-oto-renal (BOR) and branchio-otic (BO) syndromes are characterized by anomalies affecting the ears, often accompanied by hearing loss, as well as abnormalities in the branchial arches and renal system. These syndromes exhibit a broad spectrum of phenotypes and a complex genomic landscape, with significant contributions from the EYA1 gene and the SIX gene family, including SIX1 and SIX5. Due to their diverse phenotypic presentations, which can overlap with other genetic syndromes, molecular genetic confirmation is essential. As sequencing technologies advance, whole-genome sequencing (WGS) is increasingly used in rare disease diagnostics. We explored the genomic landscape of 23 unrelated Korean families with typical or atypical BOR/BO syndrome using a stepwise approach: targeted panel sequencing and exome sequencing (Step 1), multiplex ligation-dependent probe amplification (MLPA) with copy number variation screening (Step 2), and WGS (Step 3). Integrating WGS into our diagnostic pipeline detected structure variations, including cryptic inversion and complex genomic rearrangement, eventually enhancing the diagnostic yield to 91%. Our findings expand the genomic architecture of BOR/BO syndrome and highlight the need for WGS to address the genetic diagnosis of clinically heterogeneous rare diseases.

Expanding Genotype-Phenotype Correlation of CLCNKA and CLCNKB Variants Linked to Hearing Loss.

The ClC-K channels CLCNKA and CLCNKB are crucial for the transepithelial transport processes required for sufficient urinary concentrations and sensory mechanoelectrical transduction in the cochlea. Loss-of-function alleles in these channels are associated with various clinical phenotypes, ranging from hypokalemic alkalosis to sensorineural hearing loss (SNHL) accompanied by severe renal conditions, i.e., Bartter's syndrome. Using a stepwise genetic approach encompassing whole-genome sequencing (WGS), we identified one family with compound heterozygous variants in the ClC-K channels, specifically a truncating variant in CLCNKA in trans with a contiguous deletion of CLCNKA and CLCNKB. Breakpoint PCR and Sanger sequencing elucidated the breakpoint junctions derived from WGS, and allele-specific droplet digital PCR confirmed one copy loss of the CLCNKA_CLCNKB contiguous deletion. The proband that harbors the CLCNKA_CLCNKB variants is characterized by SNHL without hypokalemic alkalosis and renal anomalies, suggesting a distinct phenotype in the ClC-K channels in whom SNHL predominantly occurs. These results expanded genotypes and phenotypes associated with ClC-K channels, including the disease entities associated with non-syndromic hearing loss. Repeated identification of deletions across various extents of CLCNKA_CLCNKB suggests a mutational hotspot allele, highlighting the need for an in-depth analysis of the CLCNKA_CLCNKB intergenic region, especially in undiagnosed SNHL patients with a single hit in CLCNKA.

Update on CD164 and LMX1A genes to strengthen their causative role in autosomal dominant hearing loss.

Novel hearing loss (HL) genes are constantly being discovered, and evidence from independent studies is essential to strengthen their position as causes of hereditary HL. To address this issue, we searched our genetic data of families with autosomal dominant HL (ADHL) who had been tested with high-throughput DNA sequencing methods. For CD164, only one pathogenic variant in one family has so far been reported. For LMX1A, just two previous studies have revealed its involvement in ADHL. In this study we found two families with the same pathogenic variant in CD164 and one family with a novel variant in LMX1A (c.686C>A; p.(Ala229Asp)) that impairs its transcriptional activity. Our data show recurrence of the same CD164 variant in two HL families of different geographic origin, which strongly suggests it is a mutational hotspot. We also provide further evidence for haploinsufficiency as the pathogenic mechanism underlying LMX1A-related ADHL.

Novel Molecular Genetic Etiology of Asymmetric Hearing Loss: Autosomal-Dominant LMX1A Variants.

INTRODUCTION: Sensorineural hearing loss is the most common sensory disorder in humans. Genetic analyses have greatly increased our understanding of the pathogenic mechanisms in play. Thus, characterization of audiologic phenotypes by the genetic etiology may aid elucidation of the etiologies of certain types of inherited hearing loss. Further, delineation of specific audiologic phenotypes based on the genetic etiology aids our understanding of some types of inherited hearing loss in terms of the prediction of clinical course, revelation of genotype-phenotype correlations, and application of appropriate audiologic rehabilitation. Here, we describe the interesting audiologic characteristics of LMX1A -associated deafness, which revealed significant asymmetry between two ears. METHODS: Among 728 probands of which genomic DNA went through exome sequencing regardless of any specific audiologic phenotypes, probands for which exome sequencing was performed and a causative LMX1A variant was found were all included. Five LMX1A -associated DFNA7 families (approximately 0.7%), the pedigrees of whom indicated autosomal-dominant hearing loss, were identified, and segregation was studied using Sanger sequencing. The affected individuals underwent comprehensive evaluations, including medical history reviews, physical examinations, imaging, and auditory phenotyping. We functionally characterized the novel LMX1A variants via computational structural modeling and luciferase reporter assays. RESULTS: Among 728 probands of which genomic DNA went through exome sequencing, we identified four novel LMX1A heterozygous variants related to DFNA7 (c.622C>T:p.Arg208*, c.719A>G:p.Gln240Arg, c.721G>A:p.Val241Met, and c.887dup:p.Gln297Thrfs*41) and one harboring a de novo heterozygous missense LMX1A variant (c.595A>G;p.Arg199Gly) previously reported. It is important to note that asymmetric hearing loss was identified in all probands and most affected individuals, although the extent of asymmetry varied. Structural modeling revealed that the two missense variants, p.Gln240Arg and p.Val241Met, affected conserved residues of the homeodomain, thus attenuating LMX1A-DNA interaction. In addition, Arg208*-induced premature termination of translation destroyed the structure of the LMX1A protein, including the DNA-binding homeodomain, and p.Gln297Thrfs*41 led to the loss of the C-terminal helix involved in LIM2 domain interaction. Compared with the wild-type protein, all mutant LMX1A proteins had significantly reduced transactivation efficiency, indicating that the ability to elicit transcription of the downstream target genes of LMX1A was severely compromised. Thus, in line with the American College of Medical Genetics and Genomics guideline specified to genetic hearing loss, the four novel LMX1A variants were identified as "pathogenic" (p.Arg208* and p.Gln297Thrfs*41), "likely pathogenic" (p.Val241Met), and as a "variant of uncertain significance'' (p.Gln240Arg). CONCLUSION: For the first time, we suggest that LMX1A is one of the candidate genes which, if altered, could be associated with dominantly inherited asymmetric hearing loss. We also expand the genotypic spectrum of disease-causing variants of LMX1A causing DFNA7 by doubling the number of LMX1A variants reported thus far in the literature.

Natural course of residual hearing preservation with a slim, modiolar cochlear implant electrode array.

PURPOSE: Understanding residual hearing preservation and its natural course following cochlear implantation is important for developing rehabilitation strategies for hearing loss. However, non-uniform evaluation criteria and varying surgical skills pose challenges in fair comparison of the effect of different electrodes on residual hearing preservation. We compared the effect of a slim modiolar electrode (SME) and a slim straight electrode (SSE), implanted by a single surgeon, on progression of residual hearing using different parameters, based on cross-sectional and longitudinal audiological analyses. METHODS: Patients with preoperative low-frequency pure-tone average (LFPTA) ≤85 dB at 250 and 500 Hz and who underwent minimally traumatic surgical techniques were included. The progression of residual hearing using threshold shifts, hearing preservation rate according to the HEARRING classification, and maintenance of functional low-frequency hearing potentially qualifying for a hybrid stimulation was analyzed up to five time points throughout the 1-year follow-up period. RESULTS: Threshold shifts and hearing preservation rates according to the HEARRING classification of the electrodes were comparable from 3 months through 12 months postoperatively. Maintenance of functional low-frequency hearing, required for the usage of a hybrid stimulation, was similar for both electrodes. A substantial proportion of implantees with SME use a hybrid stimulation, resulting in long-term use. However, a difference in the pattern of postoperative residual hearing preservation between the two electrodes is possible, probably due to differences in their physical characteristics and location. Specifically, correlation analysis exhibited that significantly less tight modiolar proximity negatively affect the residual hearing preservation, albeit only at 3 months postoperatively, among patients with the SME. CONCLUSION: Collectively, both SME and SSE implantation showed favorable residual hearing preservation. Our findings further refine the recently proposed hearing preservation with the SME and suggest that the physical characteristics and location of electrodes, in terms of electrode-to-modiolus distance, could affect loss of acoustic hearing in various ways.

Tight modiolar proximity and feasibility of slim modiolar cochlear implant electrode array insertion in diverse etiologies of hearing loss.

PURPOSE: To report on our experience with the slim modiolar electrode (SME) especially focusing on the wide range of etiologies including inner ear anomalies, tumors, ossifications, and even revision surgeries. METHODS: All the cochlear implantation cases performed from June 2018 to September 2019 by a single surgeon was prospectively recruited. The molecular/radiological etiology of hearing loss, intraoperative outcomes, and radiographic studies of cases where the SME was implanted was reviewed to evaluate compatibility of SME for the wide range of etiologies. For cases where SME replaced the other electrode as a revision, audiologic assessment was also made. RESULTS: Among the 99 ears implanted during the study period, the SME was successfully implanted in 86 ears. These SME cases comprised inner ear anomaly/cochear nerve deficiency (n = 21) including cochlear hypoplasia type IV with the modiolus, intracochlear schwannoma (n = 1), far advanced otosclerosis (n = 1) and 7 revision cases. The SME was successfully used in 7 revision surgeries to replace the existing electrode. Shorter spiral diameter and decreased intracochlear position index for SME was found compared with their previous electrodes. Four out of the 6 patients who received revision implantation showed better speech perception after their surgeries. CONCLUSION: The SME can be implanted in any cases unless the integrity of the modiolus is totally compromised. Due to its slim design and tight modiolar-hugging feature, good functional outcome can also be anticipated. Additionally, it is suitable for revision surgeries possibly allowing better hearing outcomes which may be attributed to its closer proximity to the modiolus.

Functional Outcomes of Cochlear Implantation in Children with Bilateral Cochlear Nerve Aplasia.

Background and Objectives: Many otologists face a dilemma in the decision-making process of surgical management of patients with cochlear nerve (CN) aplasia. The goal of this study is to provide fresh evidence on cochlear implantation (CI) results in patients with CN aplasia. Materials and Methods: We scrutinized functional outcomes in 37 ears of 21 children with bilateral CN aplasia who underwent unilateral or bilateral CI based on cross-sectional and longitudinal assessments. Results: The Categories of Auditory Performance (CAP) scores gradually improved throughout the 3-year follow-up; however, variable outcomes existed between individuals. Specifically, 90% of recipients with a 1-year postoperative CAP score ≤1 could not achieve a CAP score over 1 even at 3-year postoperative evaluation, while the recipients with a 1-year postoperative CAP score >1 had improved auditory performance, and 72.7% of them were able to achieve a CAP score of 4 or higher. Meanwhile, intraoperative electrically evoked compound action potential was not correlated with postoperative CAP score. Conclusions: Our results further refine previous studies on the clinical feasibility of CI as the first treatment modality to elicit favorable auditory performance in children with CN aplasia. However, special attention should be paid to pediatric patients with an early postoperative CAP score ≤1 for identification of unsuccessful cochlear implants and switching to auditory brainstem implants.

The balance between Bayesian inference and default mode determines the generation of tinnitus from decreased auditory input: A volume entropy-based study.

Along with phantom pain, tinnitus, a phantom auditory perception occurring in the absence of an external acoustic stimulus, is one of the most representative phantom perceptions that develops in subjects with decreased peripheral sensory input. Although tinnitus is closely associated with peripheral hearing loss (HL), it remains unclear why only some individuals with HL develop tinnitus. In this study, we investigated the differences between 65 HL with tinnitus (HL-T) and 104 HL with no tinnitus (HL-NT) using a resting-state electroencephalography data-based volume entropy model of the brain network, by comparing the afferent node capacities, that quantify the contribution of each node to the spread of information, of all Brodmann areas. While the HL-T group showed increased information flow in areas involved in Bayesian inference (the left orbitofrontal cortex, the left subgenual anterior cingulate cortex, and the left ventrolateral prefrontal cortex) and auditory memory storage (the right hippocampus/parahippocampus), the HL-NT group showed increased afferent node capacity in hub areas of the default mode network (DMN; the right posterior cingulate cortex and the right medial temporal gyrus). These results suggest that the balance of activity between the Bayesian inferential network (updating missing auditory information by retrieving auditory memories from the hippocampus/parahippocampus) and DMN (maintaining the "silent status quo") determines whether phantom auditory perception occurs in a brain with decreased peripheral auditory input.

Otological aspects of NLRP3-related autoinflammatory disorder focusing on the responsiveness to anakinra.

OBJECTIVES: Gradually progressive sensorineural hearing loss (SNHL) is a prevalent sensory defect. It is generally untreatable, making rehabilitation by hearing aid or cochlear implantation the only option. However, SNHL as one of the symptoms of the hereditary autoinflammatory systemic disease cryopyrin-associated periodic syndrome, or as the only symptom of the cochlea-specific form (DFNA34), was suggested to respond to IL-1 antagonist (anakinra) therapy, which ameliorates NLRP3 variants-induced over-secretion of IL-1ß. We analysed genotypic and phenotypic spectrum of cryopyrin-associated periodic syndrome or DFNA34, specifically focusing on the responsiveness of SNHL to anakinra. METHODS: Seventeen families diagnosed with either cryopyrin-associated periodic syndrome or DFNA34 were recruited. Genotyping and phenotyping including audiogram, MRI findings, and in vitro IL-1ß assay were performed. RESULTS: Our cohort had an etiologic homogeneity of 94.1% to NLRP3 variants and a high de novo occurrence (84.6%). We identified the second DNFA34 pedigree worldwide with a novel NLRP3 variant supported by in vitro analysis. Significant improvement of hearing status against the natural course, showing response to anakinra, was identified in three probands, one of whom used to have severe SNHL. Hearing threshold worse than 60 dB at the start of anakinra and cochlear enhancement on brain MRI seemed to be related with poor audiologic prognosis and responsiveness to anakinra therapy despite stabilized systemic symptoms and inflammatory markers. CONCLUSION: We propose a constellation of biomarkers comprising NLRP3 genotypes, hearing status at diagnosis, and cochlear radiological findings as prognostic factors of hearing status after anakinra treatment and possibly as sensitive parameters for treatment dosage adjustment.

Modiolar Proximity of Slim Modiolar Electrodes and Cochlear Duct Length: Correlation for Potential Basis of Customized Cochlear Implantation With Perimodiolar Electrodes.

OBJECTIVES: Recent studies have shown that cochlear duct length (CDL) varies among individuals and could significantly influence the final position of the electrode and its trajectory in the cochlea. Given this, we hypothesized that the degree of modiolar proximity of novel slim modiolar electrodes, such as CI532 and CI632, can also be affected by CDL. To test this hypothesis, we retrospectively evaluated individual CDL to determine if there is any significant correlation of CDL with degree of modiolar proximity. METHODS: Fifty-one ears from 38 subjects implanted with slim modiolar electrodes by a single surgeon through the round window approach using the pull-back technique were included. Our cohort was classified according to the deafness onset (congenital versus postlingual) and the degree of modiolar proximity (less versus tight) with reference to the spiral diameter made by the slim modiolar electrodes in situ on transorbital x ray. We then analyzed the CDL and its metrics using a readily available surgical preplanning tool (OTOPLAN) to obtain comparable data. RESULTS: Among 30 ears associated with congenital deafness, 9 ears (30%) showed less modiolar proximity, while none of the 21 ears from 19 subjects with postlingual deafness exhibited "less modiolar proximity" based on our criteria. In this study, CDL showed significant variation among subjects. Importantly, a significant inverse correlation between spiral diameter and CDL (ρ = -0.581, p < 0.001) was found, showing that shorter CDLs have longer spiral diameter and less modiolar proximity. Moreover, further pull-back technique characterized by pulling out the electrode a little bit more in cases with shorter CDL, if not always, exhibited tighter modiolar proximity. CONCLUSION: A preponderance of less modiolar proximity of the electrode was observed exclusively among congenital deafness cases, demonstrated by a less tight spiral configuration even under the pull-back technique. Our data suggest that shorter CDL is associated with a less tight spiral configuration of slim modiolar electrodes postoperatively. Depending on the insertion technique, the differential degree of modiolar proximity of slim modiolar electrodes can be alleviated in cases with short CDL, which justifies cochlear duct length-based customized insertion of slim modiolar electrodes.

Natural Course of Residual Hearing with Reference to GJB2 and SLC26A4 Genotypes: Clinical Implications for Hearing Rehabilitation.

BACKGROUND: Understanding the characteristics of residual hearing at low frequencies and its natural course in relation to molecular genetic etiology may be important in developing rehabilitation strategies. Thus, we aimed to explore the characteristics and natural course of residual hearing at low frequencies associated with the two most frequent deafness genes: GJB2 and SLC26A4. METHODS: Initially, 53 GJB2 and 65 SLC26A4 subjects were enrolled, respectively. Only those whose audiograms exhibited hearing thresholds ≤70 dB at 250 and 500 Hz, and who had at least 1-year follow-up period between the first and last audiograms, were included. Collectively, the clinical characteristics of 14 ears from eight subjects with GJB2 variants, and 31 ears from 22 subjects with SLC26A4 variants fulfilled the strict criteria. In this study, a dropout rate refers to an incidence of dropping out of the cohort by cochlear implant surgery due to severe hearing deterioration. RESULTS: Among the ears with complete serial audiogram data set, significant residual hearing at low frequencies at the time of inclusion was observed in 18.8% of those with GJB2 variants (15 out of 80 ears) and 42.6% of those with SLC26A4 variants (46 out of 108 ears), revealing a difference between two deafness genes. Subsequently, ears with SLC26A4 variants (11 of 46 ears, 23.9%) turned out to have a higher dropout rate for cochlear implantation due to hearing deterioration within the first year than those with GJB2 variants (1 of 15, 6.7%), albeit with no statistical significance. Throughout the follow-up period (mean: 37.2 ± 6.8, range: 12 to 80 months), deterioration of residual hearing at low frequencies at 250 Hz (dB HL/y) and 500 Hz (dB HL/y) of those with GJB2 variants exhibited 3.1 ± 1.3 (range: 0 to 15) and 5.2 ± 1.6 (range: 0 to 20), respectively, suggesting the deterioration of residual hearing in GJB2 variants was rather slow and gradual. Specifically, GJB2 p.Leu79Cysfs*3 show less remarkable residual hearing at low frequencies, but then a relatively stable nature. In contrast, SLC26A4 variants demonstrated a significantly higher dropout rate due to severe hearing deterioration requiring cochlear implantation compared with the GJB2 variants. This trend was observed not only in the first-year follow-up period but also in the follow-up periods thereafter. The p.His723Arg;c.919-2A>G genotype of SLC26A4, in particular, was associated with a high propensity for sudden hearing deterioration, as indicated by the dropout rate, which was as high as 46.2% for cochlear implantation due to hearing deterioration during the first year follow-up period. Furthermore, the dropout rate for cochlear implantation was observed in 7.1% of those with GJB2 variants (one out of 14 ears) and 30.3% of those with SLC26A4 variants (10 out of 33 ears) throughout the entire follow-up period. CONCLUSIONS: Our results suggest that there is a difference with respect to the progressive nature of residual hearing at low frequencies between the two most common genes responsible for hearing loss, which may provide clinical implications of having individualized rehabilitation and timely intervention.

Intratympanic steroid versus gentamicin for treatment of refractory Meniere's disease: A meta-analysis.

PURPOSE: Intratympanic steroid injections (ITSI) have become a promising treatment for refractory Meniere's disease due to less cochleovestibular damage. However, whether ITSI would be a good alternative to intratympanic gentamicin injections (ITGI) for refractory Meniere's disease still remains controversial. Here we intended to compare the therapeutic effect of ITSI and ITGI in patients with Meniere's disease refractory to conservative treatments, in terms of vertigo control and hearing outcomes, via a meta-analysis. METHODS: Using MEDLINE, PubMed, and EMBASE databases, we calculated pooled odds ratio (OR) estimates of vertigo control rate (i.e., class A according to AAO-HNS guideline) and standardized mean differences (SMD) of spell count, pure tone audiometry (PTA) threshold and speech discrimination score (SDS) with a 95% confidence interval (CI). The trim-and-fill method and sensitivity analysis were used as post-hoc analyses to verify the integrity of the quantitative analysis results. Furthermore, subgroup analyses were performed according to steroid type (methylprednisolone versus dexamethasone) and follow-up period (>1-year versus <1-year). RESULTS: Five studies involving 332 patients with refractory unilateral Meniere's disease were included. In the pooled analysis, those treated with ITGI showed higher ORs than those treated with ITSI in terms of vertigo control rate (OR: 2.39, 95% CI: 0.84-6.79, P = 0.102) and spell counts (SMD: 0.24, 95% CI: -0.12-0.59, P = 0.195), but it did not reach statistical significance. However, a substantial amount of heterogeneity (I2 = 71.0%, Q = 13.79, P = 0.008) and publication bias was found, suggesting a significant small-study effect. Additionally, ITSI elicited better hearing outcomes of the mean PTA threshold (SMD: 3.08, 95% CI: -1.18-7.35) and mean SDS (SMD: 11.15, 95% CI: -23.21-0.90) compared with ITGI, although no statistical significance. In subgroup analysis, the difference in vertigo control rate between ITGI and ITSI was not significant, regardless of the follow-up period and steroid type. Further, methylprednisolone appeared to be superior to dexamethasone for vertigo control. No significant complications from either treatment were reported in the literature. CONCLUSION: The results of this study further refine the recently proposed efficacy of ITSI for the treatment of refractory Meniere's disease, demonstrating the comparable value of ITGI on vertigo control as well as better hearing preservation. Collectively, ITSI could be a safe and the effective treatment for refractory Meniere's disease. However, the current evidence on efficacy of ITSI for refractory Meniere's disease needs to be further clarified, given the substantial heterogeneity and potential biases.

Novel genotype-phenotype correlation of functionally characterized LMX1A variants linked to sensorineural hearing loss.

LMX1A, encoding the LIM homeobox transcription factor, is essential for inner ear development. Despite previous reports of three human LMX1A variants with nonsyndromic hearing loss (NSHL) in the literature, functional characterization of these variants has never been performed. Encouraged by identification of a de novo, heterozygous, missense variant (c.595A > G; p.Arg199Gly) located in the homeodomain of LMX1A in a subject with congenital severe-to-profound deafness through Exome sequencing, we performed luciferase assay to evaluate transcriptional activity of all LMX1A variants reported in the literature including p.Arg199Gly. Resultantly, p.Arg199Gly manifesting the most severe NSHL showed the biggest reduction of transcriptional activity in contrast with moderately reduced activity of p.Cys97Ser and p.Val241Leu associated with less severe progressive NSHL, proposing a genotype-phenotype correlation. Further, our dominant LMX1A variant exerted pathogenic effects via haploinsufficiency rather than dominant-negative effect. Collectively, we provide a potential genotype-phenotype correlation of LMX1A variants as well as the pathogenic mechanism of LMX1A-related NSHL.

Significant Mendelian genetic contribution to pediatric mild-to-moderate hearing loss and its comprehensive diagnostic approach.

PURPOSE: Timely diagnosis and identification of etiology of pediatric mild-to-moderate sensorineural hearing loss (SNHL) are both medically and socioeconomically important. However, the exact etiologic spectrum remains uncertain. We aimed to establish a genetic etiological spectrum, including copy-number variations (CNVs) and efficient genetic testing pipeline, of this defect. METHODS: A cohort of prospectively recruited pediatric patients with mild-to-moderate nonsyndromic SNHL from 2014 through 2018 (n = 110) was established. Exome sequencing, multiplex ligation-dependent probe amplification (MLPA), and nested customized polymerase chain reaction (PCR) for exclusion of a pseudogene, STRCP, from a subset (n = 83) of the cohort, were performed. Semen analysis was also performed to determine infertility (n = 2). RESULTS: Genetic etiology was confirmed in nearly two-thirds (52/83 = 62.7%) of subjects, with STRC-related deafness (n = 29, 34.9%) being the most prevalent, followed by MPZL2-related deafness (n = 9, 10.8%). This strikingly high proportion of Mendelian genetic contribution was due particularly to the frequent detection of CNVs involving STRC in one-third (27/83) of our subjects. We also questioned the association of homozygous continuous gene deletion of STRC and CATSPER2 with deafness-infertility syndrome (MIM61102). CONCLUSION: Approximately two-thirds of sporadic pediatric mild-to-moderate SNHL have a clear Mendelian genetic etiology, and one-third is associated with CNVs involving STRC. Based on this, we propose a new guideline for molecular diagnosis of these children.

Identification of a Potential Founder Effect of a Novel PDZD7 Variant Involved in Moderate-to-Severe Sensorineural Hearing Loss in Koreans.

PDZD7, a PDZ domain-containing scaffold protein, is critical for the organization of Usher syndrome type 2 (USH2) interactome. Recently, biallelic PDZD7 variants have been associated with autosomal-recessive, non-syndromic hearing loss (ARNSHL). Indeed, we identified novel, likely pathogenic PDZD7 variants based on the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines from Korean families manifesting putative moderate-to-severe prelingual ARNSHL; these were c.490C>T (p.Arg164Trp), c.1669delC (p.Arg557Glyfs*13), and c.1526G>A (p.Gly509Glu), with p.Arg164Trp being a predominantly recurring variant. Given the recurring missense variant (p.Arg164Trp) from our cohort, we compared the genotyping data using six short tandem-repeat (STR) markers within or flanking PDZD7 between four probands carrying p.Arg164Trp and 81 normal-hearing controls. We observed an identical haplotype across three out of six STR genotyping markers exclusively shared by two unrelated hearing impaired probands but not by any of the 81 normal-hearing controls, suggesting a potential founder effect. However, STR genotyping, based on six STR markers, revealed various p.Arg164Trp-linked haplotypes shared by all of the affected subjects. In conclusion, PDZD7 can be an important causative gene for moderate to severe ARNSHL in Koreans. Moreover, at least some, if not all, p.Arg164Trp alleles in Koreans could exert a potential founder effect and arise from diverse haplotypes as a mutational hot spot.

Coupling effects on turning points of infectious diseases epidemics in scale-free networks.

BACKGROUND: Pandemic is a typical spreading phenomenon that can be observed in the human society and is dependent on the structure of the social network. The Susceptible-Infective-Recovered (SIR) model describes spreading phenomena using two spreading factors; contagiousness (ß) and recovery rate (γ). Some network models are trying to reflect the social network, but the real structure is difficult to uncover. METHODS: We have developed a spreading phenomenon simulator that can input the epidemic parameters and network parameters and performed the experiment of disease propagation. The simulation result was analyzed to construct a new marker VRTP distribution. We also induced the VRTP formula for three of the network mathematical models. RESULTS: We suggest new marker VRTP (value of recovered on turning point) to describe the coupling between the SIR spreading and the Scale-free (SF) network and observe the aspects of the coupling effects with the various of spreading and network parameters. We also derive the analytic formulation of VRTP in the fully mixed model, the configuration model, and the degree-based model respectively in the mathematical function form for the insights on the relationship between experimental simulation and theoretical consideration. CONCLUSIONS: We discover the coupling effect between SIR spreading and SF network through devising novel marker VRTP which reflects the shifting effect and relates to entropy.