H Syndrome: Three New Cases from Morocco.

A 19-year-old girl presented with symmetric and bilateral hyperpigmentation, an indurated lesion that initially appeared on the axillary fold at the age of 14, which then extended to the lower back, anterior aspect of both thighs, and popliteal fold. No hypertrichosis was observed (Figure 1).The patient was the youngest of the four children, born from the first-degree consanguineous marriage. She was born at full term and weighed 2,420 g at birth. No similar patient was present in the family. The patient experienced delayed motor acquisition and stature growth (3rd percentile) until the age of 4. Right hypoacusis was diagnosed at the age of 6. She developed hallux valgus, flexion contracture of the fin-gers and toes, barrel deformity of the anterior thorax, and recurrent fever. The laboratory tests, including fasting blood glucose, -triglycerides, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) were normal. Her abdominal, pelvic, and transthoracic ultrasound scans were normal, with no hepatosplenomegaly, lymphadenopathy, or cardiac abnormalities. Histologic analysis demonstrated patchy acanthosis of the epidermis, with orthokeratotic hyperkeratosis. Keratinocyte hyperpigmentation and spongiosis at certain areas were observed with moder-ate inflammation because of the infiltration of lymphocytes, histiocytes, and plasma cells. Immunohistochemical analysis showed macrosialin (CD68+) and common gamma chain (γc) CD132. Germline mutations in the SLC29A3 gene were not analyzed. The patient was prescribed dermocorticoids with depigmentation therapy, which demonstrated moderate clinical evolution.

Hearing instability and abnormal auditory pathways in infants with congenital cytomegalovirus infection: An audiological and radiological single-centre prospective cohort analysis.

INTRODUCTION: This prospective cohort study aims to investigate the hearing dynamics and the changes in the central auditory pathways in infants with congenital cytomegalovirus (cCMV) infection. MATERIALS AND METHODS: cCMV-infected neonates aged ≤3 weeks old were recruited and underwent clinical and laboratory tests to detect viremia and symptomatic infection, hearing examinations at three and six months of age, and radiological imaging of brain auditory pathways using diffusion tensor imaging. RESULTS: From 26 eligible infants (52 ears), we detected symptomatic infection in nine (34.6%), viremia in 14 (14/25; 56.0%) and sensorineural hearing loss (SNHL) in 14 infants (53.8%). We observed 40 ears (76.9%) with unstable hearing thresholds, 17 (42.5%) of which fluctuated. Hearing fluctuation and progressivity were more common in symptomatic infection (66.7% vs. 14.7%, p<0.001; and 38.9% vs. 2.9%, p=0.002; respectively). A substantial proportion of ears had reduced fractional anisotropy (FA) in the medial geniculate body (59.1%), superior olivary nucleus (45.5%), trapezoid body (40.9%), auditory radiation (36.4%) and inferior colliculus (31.8%). Symptomatic infection was associated with an increased FA in the medial geniculate body (mean difference, MD: 0.12; 95% Confidence Intervals, 95%CI: 0.03, 0.22) and viremia in the inferior colliculus (MD: 0.09; 95%CI: 0.02, 0.16). An FA in the inferior colliculus of ≥0.404 had a sensitivity and specificity of 68.8% and 83.3% in predicting viremia (area under the curve 0.823; 95%CI: 0.633, 1.000, p=0.022). CONCLUSION: SNHL along with its fluctuation and progression are common in cCMV-infected infants. cCMV infection may induce structural changes in the central auditory pathway.

Heterozygous variants in transmembrane channel-like 1 gene cause autosomal recessive nonsyndromic hearing loss.

Autosomal recessive non-syndromic hearing loss (ARNSHL) can cause severe or very severe pre-speech hearing loss. Transmembrane channel-like 1 (TMC1) gene is the sixth deafness gene discovered, but the precise extent of its protein structure and function is unknown. First, history collection, audiology examination and imaging examination were performed on the proband and his family members. Peripheral blood of proband and family members was collected, genomic DNA was extracted, exon high-throughput sequencing technology was used to detect the deafness gene mutation of the proband, and Sanger sequencing was performed to verify the TMC1 gene of the proband's parents. The proband was born with hearing impairment, normal tympanic function, inability to induce acoustic reflex in both ears (acoustic reflex threshold is 100 dBHL), and severe sensorineural deafness. One of his sisters has severe sensorineural hearing loss, and neither his parents nor his other sister is hearing impaired. High-throughput sequencing of the proband identified mutations at c.741+3_741+6delAAGT (splicing) and c.884C>T (p.A295V) of the TMC1 gene, two of which were heterozygous mutations. Sanger sequencing confirmed that the c.884C > T mutation was inherited from the mother, while the c.741+3_741+6delAAGT mutation was derived from the father. Prediction of amino acid function suggested that both mutations were pathogenic mutations. In conclusion, we found a new pathogenic complex heterozygous mutation of the TMC1 gene, which enriched the mutation spectrum of the TMC1 gene and provided a basis for genetic counseling and prenatal diagnosis of ARNSHL.

Short- and long-term neurological outcomes of congenital cytomegalovirus infection.

Background/aim: Cytomegalovirus (CMV) is the most common congenital viral infection. Although most children with congenital CMV (approximately 85%-90%) are asymptomatic at birth, findings such as sensorineural hearing loss, microcephaly, and neurodevelopmental retardation can be observed during the follow-up. Among the brain magnetic resonance imaging (MRI) findings of CMV are white matter abnormalities, polymicrogyria, and periventricular calcification. Since a definitive diagnosis of congenital CMV cannot be made after the neonatal period, the identification of the associated phenotype is diagnostically important, but data are limited in patients who have been retrospectively diagnosed with congenital CMV infection. The aim of this study was to evaluate the short- and long-term neurological follow-up results of congenital CMV infections in a tertiary hospital. Materials and methods: The neurological results of fifteen patients under the age of 18 years, who had a definitive diagnosis of congenital CMV infection and were followed up in a tertiary care hospital between 2011 and 2020, were retrospectively evaluated. Results: Ten of the patients in our study group were male. The mean age at presentation for neurological evaluation was 2.02 ± 1.54 months, with a median follow-up time of 36.3 months (range: 9.3-129.4 months). Neurological disorders detected during the long-term follow-up included cerebral palsy (46.7%), cognitive impairment (46.7%), epilepsy (40%), and sensorineural hearing loss (26.7%). The most common abnormality observed on MRI scans was white matter involvement (53.3%). Conclusion: Early diagnosis and intervention are crucial in congenital CMV infection, as it commonly results in neurological involvement among the patients in our series. This preventable condition warrants further research regarding prenatal/neonatal screening.

Contemporary directions in the therapy of sensory hearing loss.

<b>Introduction:</b> More than 5% of the world's population experience hearing impairment. The most common form is presbycusis (age-related hearing loss; ARHL). It affects almost one in three people over the age of 65. The hair cells of the cochlea play an important role in the process of sound registration. Genetic mutations, aging and environmental factors can cause damage that contributes to the hearing loss.<b>Methods and results:</b> The currently explored research directions include drug treatments, gene therapies, and stem cell therapies. To date, no significant differences in the therapeutic effect depending on the route of corticosteroid administration have been demonstrated in patients with moderate to severe hearing loss. New dexamethasone-containing hydrogel formulations, as well as lipid formulations, thermosensitive polymers, and nanoparticles, have been developed to achieve high drug concentrations in the inner ear structures. Otoprotective effects of antioxidants or substances that modify the toxic effects of e.g. cisplatin, are also being studied. Attempts at auditory cells' regeneration seem promising in hearing loss research. Substances that regulate the central mechanisms of the Notch and Wnt pathways are being explored to this end. The genetic determinants of presbycusis suggest that interference at the level of specific genes may be a promising option for the treatment of this condition. With the CRISPR/Cas9 technology, the functions of inner ear genes can be effectively studied by disrupting normal gene alleles. The CRISPR/Cas9 complexes developed to target specific genes are delivered using cationic lipids, proteins, and viral vectors. They are then transported through the round window membrane by diffusion, without the need to surgically disrupt the inner ear. The potential of using antisense oligonucleotides to treat hereditary deafness caused by hair cell degeneration has also been established. Another research direction is related to stem cells being used for the development of in vitro 3D models of the human inner ear. Studies are also pursued to identify the mechanisms underlying the formation of cochlear organoids from pluripotent cells as well as determine the critical time points and events for cochlear sensory epithelial development and targeted hair cell differentiation.<b>Conclusions:</b> In summary, significant progress has been made over the past decade in the search for novel therapies for sensory hearing loss. This line of research remains an ambitious and important area for further exploration.

Exome sequencing reveals pathogenic mutations in the LARS2 and HSD17B4 genes associated with Perrault syndrome and D-bifunctional protein deficiency in Moroccan families.

BACKGROUND: Syndromic hearing loss (SHL) is characterized by hearing impairment accompanied by other clinical manifestations, reaching over 400 syndromes. Early and accurate diagnosis is essential to understand the progression of hearing loss and associated systemic complications. METHODS AND RESULTS: In this study, we investigated the genetic etiology of sensorineural hearing loss in three Moroccan patients using whole exome sequencing (WES). The results revealed in two families Perrault syndrome caused by LARS2, p. Asn153His; p. Thr629Met compound heterozygous variants in two siblings in one family; and p. Thr522Asn, a homozygous variant in two sisters in another. The patient in the third family was diagnosed with D-bifunctional protein deficiency (D-BPD), linked to compound heterozygous mutations p. Asn457Tyr and p. Val643Argfs*5 in HSD17B4. Molecular dynamic simulation results showed that Val643Argfs*5 does not prevent HSD17B4 protein from binding to the PEX5 receptor, but further studies are recommended to verify its effect on HSD17B4 protein functionality. CONCLUSION: These results highlight the effectiveness of WES in identifying pathogenic mutations involved in heterogeneous disorders and the usefulness of bioinformatics in predicting their effects on protein structure.

What are the neurodevelopmental outcomes of children with asymptomatic congenital cytomegalovirus infection at birth? A systematic literature review.

Congenital cytomegalovirus (cCMV) is among the most common congenital infections globally. Of 85%-90% cCMV-infected infants without symptoms at birth, 10%-15% develop sequelae, most commonly sensorineural hearing loss (SNHL); their childhood neurodevelopmental outcomes are less well understood. Embase and MEDLINE were searched for publications from 16th September 2016 to 9th February 2024 to identify studies reporting primary data on neurodevelopmental outcomes in children with asymptomatic cCMV (AcCMV), measured using assessment tools or as evaluated by the study investigators, clinicians, educators, or parents. The Newcastle-Ottawa scale was applied to studies to assess risk of bias. Of 28 studies from 18 mostly high-income countries, there were 5-109 children with AcCMV per study and 6/28 had a mean or median age at last follow-up of ≥5 years. Children with AcCMV had better neurodevelopmental outcomes than children with symptomatic cCMV in 16/19 studies. Of 9/28 studies comparing AcCMV with CMV-uninfected children, six reported similar outcomes whilst three reported differences limited to measures of full-scale intelligence and receptive vocabulary among children with AcCMV and SNHL, or more generally in motor impairment. Common limitations of studies for our question were a lack of cCMV-uninfected controls, heterogeneous definitions of AcCMV, lack of focus on neurodevelopment, selection bias and inadequate follow-up. There was little evidence of children with AcCMV having worse neurodevelopmental outcomes than CMV-uninfected children, but this conclusion is limited by study characteristics and quality; findings highlight the need for well-designed and standardised approaches to investigate long-term sequelae.

Hyperbaric Medicine in Pediatrics - reality of a Portuguese reference center.

OBJECTIVE: To identify and characterize the population of Pediatric patients referred to our hyperbaric oxygen therapy center. METHODS: Retrospective and observational study, including pediatric patients treated with hyperbaric oxygen therapy, from 2006 to 2021, at the hyperbaric medicine reference center in the north of Portugal. Variables of interest were extracted from electronic medical records. RESULTS: Our study included 134 patients. The most frequent reasons for referral were carbon monoxide poisoning (n=59) and sudden sensorineural hearing loss (n=41). In 75 cases (56%), treatment was initiated in an urgent context. Symptom presentation at Emergency Department varied among patients, the most frequent being headache and nausea/vomiting. Concerning carbon monoxide poisoning, the most common sources were water heater, fireplace/brazier, and boiler. Regarding adverse effects, it was identified one case of intoxication by oxygen and four cases of middle ear barotrauma. CONCLUSIONS: The most frequent cause for referral was carbon monoxide poisoning. All patients evolved favorably, with few side effects being reported, emphasizing the safety of this therapy. While most pediatricians may not be aware of the potential benefits arising with hyperbaric oxygen therapy, it is of upmost importance to promote them, so that this technique is increasingly implemented.

Otology: Hearing Loss.

Hearing loss is the cause of significant morbidity throughout the United States and the world. Because of numerous factors, such as ongoing noise exposure, poorly controlled chronic disease, and an aging population, the burden of hearing loss is expected to continue to increase. Hearing loss commonly is categorized as conductive, sensorineural, or mixed. The type of hearing loss can be determined through a combination of patient history and physical examination, and then confirmed with audiometry and tympanometry. Advanced imaging is not typically necessary, but it may be helpful in specific instances. The presentation of sudden sensorineural hearing loss should prompt urgent referral to an otolaryngologist and audiologist. Management of this condition is selective but may initially include oral corticosteroids. Management for chronic hearing loss involves the use of hearing aids, which can offer a large benefit to users but historically have been expensive and not covered by many insurance plans. Recent US legislation has made hearing aids more accessible and affordable by allowing direct-to-consumer marketing and offering over-the-counter hearing aids without a clinical evaluation.

[Bibliometric visualization analysis of thiamine-responsive megaloblastic anemia syndrome].

Visual analysis of the current status, research hotspots, evolving trends, and future prospects in the field of thiamine-responsive megaloblastic anemia syndrome (TRMA), providing new insights and directions for subsequent research on the pathogenic mechanisms and prevention strategies of TRMA. Taking the core database of Web of Science as the literature source, selecting TRMA-related literature records published from 1997 to 2023 as the research object, and using R software and Citexs database to conduct visual analysis and discussion of the research content. The results showed that a total of 89 publications related to the topic were published from 1997 to 2023, with an average annual publication volume of 3 papers. Classified by country, it was found that the United States, and Israel among other countries and institutions, published a significant number of papers. Through keyword frequency analysis, high frequencies of keywords such as diabetes, deafness, thiamine-responsive megaloblastic anemia, and mutations in the solute carrier family 19 member 2 (SLC19A2) gene were observed, indicating that to date, these keywords have been the main research directions, highlighting a gradually reached consensus on the mechanism exploration of TRMA. In conclusion, TRMA research focuses on the mechanisms of hot topics such as diabetes, deafness, and thiamine-responsive megaloblastic anemia, and the core gene SLC19A2 research may currently become a new breakthrough point for future molecular studies.

[Prognosis of 109 cases of sudden sensorineural hearing loss in children].

Objective:To analyze the factors influencing the prognosis of sudden sensorineural deafness in children, and to provide theoretical basis for clinical prevention and treatment. Methods:The clinical data of 109 children with sudden deafness admitted to our hospital from 2016 to 2023 were retrospectively analyzed. The children were grouped according to eight related factors, including gender, age, climate, duration of hearing loss, concomitant symptoms, degree of hearing loss, sicken ear, and auditory curve. The chi-square test was used for univariate analysis, and logistic regression was employed to identify factors influencing prognosis. Results:After conventional treatment, 56 cases were ineffective（51.40%）, 30 cases were effective（27.5%）, 13 cases were effective（11.9%）, 10 cases were cured（9.2%）, and the total effective rate was 48.6%. Among concomitant symptoms, children with tinnitus had better treatment results（P<0.05）; In the degree of hearing loss, the effective rate of mild hearing loss was the highest（83.3%）, and the effective rate of very severe hearing loss was the lowest（40.0%）. The prognosis of low frequency decline and high frequency decline were better（P<0.05）; There was no significant correlation between gender, age, climate, duration of hearing loss, sicken ear and prognosis（P>0.05）. Conclusion:The auditory curve and the degree of hearing loss are the factors affecting the prognosis of children with sudden deafness. Additionally, children with tinnitus tend to have a better prognosis.

[Advances in vestibular function and rehabilitation of large vestibular aqueduct syndrome].

Large vestibular aqueduct syndrome（LVAS） is a common recessive hereditary hearing loss disease, and some patients may also experience vestibular dysfunction. With the wide application of cochlear implant（CI） and the development of vestibular medicine, the pathophysiological mechanism of LVAS and the influence mechanism of CI on vestibular function are gradually elucidated. Consequently, the evaluation and rehabilitation of vestibular dysfunction function have also become research hotspots. This article reviews studies on vestibular function and related rehabilitation in patients with large vestibular aqueduct syndrome.

Diabetes mellitus, hearing loss, and therapeutic interventions: A systematic review of insights from preclinical animal models.

OBJECTIVES: The aim of this systematic review article is to evaluate the relationship between diabetes mellitus (DM) and sensorineural hearing loss (SNHL) utilizing preclinical animal models. The review focused on studies assessing SNHL in diabetic animal models, elucidating the mechanisms of DM-associated SNHL, and exploring the response of diabetic animal models to noise overexposure. We also discussed studies investigating the efficacy of potential therapeutic strategies for amelioration of DM-associated SNHL in the animal models. METHODS: A protocol of this systematic review was designed a priori and was registered in the PROSPERO database (registration number: CRD42023439961). We conducted a comprehensive search on PubMed, Science Direct, Web of Science, Scopus, and EMBASE databases. A minimum of three reviewers independently screened, selected, and extracted data. The risk of bias assessment of eligible studies was conducted using the Systematic Review Center for Laboratory Animal Experimentation (SYRCLE) tool. RESULTS: Following the screening of 238 studies, twelve original articles were included in this systematic review. The studies revealed that hyperglycemia significantly affects auditory function, with various pathological mechanisms contributing to DM-induced hearing impairment, including cochlear synaptopathy, microangiopathy, neuropathy, oxidative stress, mitochondrial abnormalities, and apoptosis-mediated cell death. Emerging interventions, such as Asiaticoside, Trigonelline, Chlorogenic acid, and Huotanquyu granules, demonstrated efficacy in providing otoprotection for preserving cochlear hair cells and hearing function. CONCLUSIONS: Our systematic review delves into the intricate relationship between DM and hearing impairment in animal models. Future research should focus on targeted therapies to enhance cochlear mitochondrial function, alleviate oxidative stress, and regulate apoptosis. The association between SNHL and social isolation as well as cognitive decline underscores the necessity for innovative therapeutic modalities addressing yet undiscovered mechanisms. Translating findings from animal models to human studies will validate these findings, offering a synergistic approach to effectively manage DM-associated co-morbidities such as hearing impairment.

A novel variant c.902C>A (p. A301D) in KCNQ4 associated with non-syndromic deafness 2A in a Chinese family.

BACKGROUND: Deafness autosomal dominant 2A (DFNA2A) is related to non-syndromic genetic hearing impairment. The KCNQ4 (Potassium Voltage-Gated Channel Subfamily Q Member 4) can lead to DFNA2A. In this study, we report a case of autosomal dominant non-syndromic hearing loss with six family members as caused by a novel variant in the KCNQ4 gene. METHODS: The whole-exome sequencing (WES) and pure tone audiometry were performed on the proband of the family. Sanger sequencing was conducted on family members to determine if the novel variant in the KCNQ4 gene was present. Evolutionary conservation analysis and computational tertiary structure protein prediction of the wild-type KCNQ4 protein and its variant were then performed. In addition, voltage-gated channel activity of the wild-type KCNQ4 protein and its variant were tested using whole-cell patch clamp. RESULTS: It was observed that the proband had inherited autosomal dominant, non-syndromic sensorineural hearing loss as a trait. A novel co-segregating heterozygous missense variant (c.902C>A, p.Ala301Asp) of the KCNQ4 gene was identified in the proband and other five affected family members. This variant was predicted to cause an alanine-to-aspartic acid substitution at position 301 in the KCNQ4 protein. The alanine at position 301 is well conserved across different species. Whole-cell patch clamp showed that there was a significant difference between the WT protein currents and the mutant protein currents in the voltage-gated channel activity. CONCLUSION: In the present study, performing WES in conjunction with Sanger sequencing enhanced the detection of a novel, potentially causative variant (c301 A>G; p.Ala301Asp) in exon 6 of the KCNQ4 gene. Therefore, our findings contributed to the mutation spectrum of the KCNQ4 gene and may be useful in the diagnosis and gene therapy of deafness autosomal dominant 2A.

Serum lipid metabolism characteristics and potential biomarkers in patients with unilateral sudden sensorineural hearing loss.

BACKGROUND: Glycerophospholipids (GPLs) are essential for cell membrane structure and function. Sphingomyelin and its metabolites regulate cell growth, apoptosis, and stress responses. This study aimed to investigate lipid metabolism in patients experiencing sudden sensorineural hearing loss across all frequencies (AF-SSNHL). METHODS: The study included 60 patients diagnosed with unilateral AF-SSNHL, among whom 30 patients had a level of hearing improvement ≥ 15 dB after 6 months of follow-up. A propensity score-matched (2:1) control group was used. Liquid chromatography‒mass spectrometry based untargeted lipidomics analysis combined with multivariate statistics was performed to investigate the lipids change. The "lipidome" R package and weighted gene co-expression network analysis (WGCNA) were utilised to assess the lipids' structural features and the association between lipids and hearing. RESULTS: Lipidomics successfully differentiated the AF-SSNHL group from the control group, identifying 17 risk factors, mainly including phosphatidylcholine (PC), phosphatidylethanolamine (PE), and related metabolites. The ratios of lysophosphatidylcholine/PC, lysophosphatidylethanolamine/PE, and lysodimethylphosphatidylethanolamine/PE were upregulated, while some glycerophospholipid (GPL)-plasmalogens were downregulated in the AF-SSNHL group, indicating abnormal metabolism of GPLs. Trihexosylceramide (d34:1), PE (18:1e_22:5), and sphingomyelin (d40:3) were significantly different between responders and nonresponders, and positively correlated with hearing improvement. Additionally, the results of the WGCNA also suggested that partial GPL-plasmalogens were positively associated with hearing improvement. CONCLUSION: AF-SSNHL patients exhibited abnormally high blood lipids and pronounced GPLs metabolic abnormalities. Sphingolipids and GPL-plasmalogens had an association with the level of hearing improvement. By understanding the lipid changes, clinicians may be able to predict the prognosis of hearing recovery and personalize treatment approaches.

A novel start-loss mutation of the SLC29A3 gene in a consanguineous family with H syndrome: clinical characteristics, in silico analysis and literature review.

BACKGROUND: The SLC29A3 gene, which encodes a nucleoside transporter protein, is primarily located in intracellular membranes. The mutations in this gene can give rise to various clinical manifestations, including H syndrome, dysosteosclerosis, Faisalabad histiocytosis, and pigmented hypertrichosis with insulin-dependent diabetes. The aim of this study is to present two Iranian patients with H syndrome and to describe a novel start-loss mutation in SLC29A3 gene. METHODS: In this study, we employed whole-exome sequencing (WES) as a method to identify genetic variations that contribute to the development of H syndrome in a 16-year-old girl and her 8-year-old brother. These siblings were part of an Iranian family with consanguineous parents. To confirmed the pathogenicity of the identified variant, we utilized in-silico tools and cross-referenced various databases to confirm its novelty. Additionally, we conducted a co-segregation study and verified the presence of the variant in the parents of the affected patients through Sanger sequencing. RESULTS: In our study, we identified a novel start-loss mutation (c.2T > A, p.Met1Lys) in the SLC29A3 gene, which was found in both of two patients. Co-segregation analysis using Sanger sequencing confirmed that this variant was inherited from the parents. To evaluate the potential pathogenicity and novelty of this mutation, we consulted various databases. Additionally, we employed bioinformatics tools to predict the three-dimensional structure of the mutant SLC29A3 protein. These analyses were conducted with the aim of providing valuable insights into the functional implications of the identified mutation on the structure and function of the SLC29A3 protein. CONCLUSION: Our study contributes to the expanding body of evidence supporting the association between mutations in the SLC29A3 gene and H syndrome. The molecular analysis of diseases related to SLC29A3 is crucial in understanding the range of variability and raising awareness of H syndrome, with the ultimate goal of facilitating early diagnosis and appropriate treatment. The discovery of this novel biallelic variant in the probands further underscores the significance of utilizing genetic testing approaches, such as WES, as dependable diagnostic tools for individuals with this particular condition.

Toward parametric Bayesian adaptive procedures for multi-frequency categorical loudness scaling.

A series of Bayesian adaptive procedures to estimate loudness growth across a wide frequency range from individual listeners was developed, and these procedures were compared. Simulation experiments were conducted based on multinomial psychometric functions for categorical loudness scaling across ten test frequencies estimated from 61 listeners with normal hearing and 87 listeners with sensorineural hearing loss. Adaptive procedures that optimized the stimulus selection based on the interim estimates of two types of category-boundary models were tested. The first type of model was a phenomenological model of category boundaries adopted from previous research studies, while the other type was a data-driven model derived from a previously collected set of categorical loudness scaling data. An adaptive procedure without Bayesian active learning was also implemented. Results showed that all adaptive procedures provided convergent estimates of the loudness category boundaries and equal-loudness contours between 250 and 8000 Hz. Performing post hoc model fitting, using the data-driven model, on the collected data led to satisfactory accuracies, such that all adaptive procedures tested in the current study, independent of modeling approach and stimulus-selection rules, were able to provide estimates of the equal-loudness-level contours between 20 and 100 phons with root-mean-square errors typically under 6 dB after 100 trials.

A preoperative dose of the pyridoindole AC102 improves the recovery of residual hearing in a gerbil animal model of cochlear implantation.

Sensorineural hearing loss (SNHL) is the most common sensory deficit worldwide. Due to the heterogeneity of causes for SNHL, effective treatment options remain scarce, creating an unmet need for novel drugs in the field of otology. Cochlear implantation (CI) currently is the only established method to restore hearing function in profound SNHL and deaf patients. The cochlear implant bypasses the non-functioning sensory hair cells (HCs) and electrically stimulates the neurons of the cochlear nerve. CI also benefits patients with residual hearing by combined electrical and auditory stimulation. However, the insertion of an electrode array into the cochlea induces an inflammatory response, characterized by the expression of pro-inflammatory cytokines, upregulation of reactive oxygen species, and apoptosis and necrosis of HCs, putting residual hearing at risk. Here, we characterize the small molecule AC102, a pyridoindole, for its protective effects on residual hearing in CI. In a gerbil animal model of CI, AC102 significantly improves the recovery of hearing thresholds across multiple frequencies and confines the cochlear trauma to the directly mechanically injured area. In addition, AC102 significantly preserves auditory nerve fibers and inner HC synapses throughout the whole cochlea. In vitro experiments in an ethanol challenged HT22 cell-line revealed significant and dose-responsive anti-apoptotic effects following the treatment of with AC102. Further, AC102 treatment resulted in significant downregulation of the expression of pro-inflammatory cytokines in an organotypic ex vivo model of electrode insertion trauma (EIT). These results suggest that AC102's effects are likely elicited during the inflammatory phase of EIT and mediated by anti-apoptotic and anti-inflammatory properties, highlighting AC102 as a promising compound for hearing preservation during CI. Moreover, since the inflammatory response in CI shares similarities to that in other etiologies of SNHL, AC102 may be inferred as a potential general treatment option for various inner ear conditions.

Prognostic Factors in Idiopathic Sudden Sensorineural Hearing Loss: The Experience of Two Audiology Tertiary Referral Centres.

Background and Objectives: Although different hypotheses have been proposed over time, there is a dearth of information on factors able to predict the response to treatment for idiopathic sudden sensorineural hearing loss (ISSNHL) and hearing recovery. The aim of this study was to apply univariate and multivariate statistical models in a retrospective clinical setting of patients given therapy for ISSNHL at our tertiary academic audiological centers to investigate the prognostic value of clinical signs, symptoms, and comorbidities in relation to hearing recovery. Materials and Methods: The inclusion criteria were: history of ISSNHL diagnosed and treated at the Padova or Modena tertiary academic audiological centers; age ≥ 18 years; availability of clinical and audiological outcome data. The exclusion criteria were: hearing loss in acoustic schwannoma, endolymphatic hydrops, meningitis, trauma (head trauma, temporal bone fracture, acoustic trauma), barotrauma, perilymphatic fistula; exposure to noise levels ≥ 80 dB in the work environment; any unilateral or bilateral hearing loss (except for presbycusis) prior to ISSNHL diagnosis; any disorders affecting the external or middle ear; any previous ear surgery; refusal to make medical data available for research purposes. Eighty-six consecutive patients (38 females, 48 males; median age: 58 years; interquartile range: 47.00-69.00 years) were included. A systemic steroid therapy was administered to all patients, either orally with prednisone or intravenously with methylprednisolone. Second-line therapy included intratympanic steroid injections and/or hyperbaric oxygen therapy. Results: A multivariate logistic regression model was used, including the non-multicollinear clinical and audiological variables, which showed a p-value < 0.10 at the univariate analyses (namely age at diagnosis, time to diagnosis, oral steroid dose, and PTA on the affected side). Only PTA on the affected side retained its statistical significance (OR: 1.0615, 95% CI: 1.0185-1.1063, p = 0.005). Conclusions: The analysis of our data showed an association between the hearing threshold before treatment and the recovery from ISSNHL. Further studies on larger cohorts (especially in a prospective setting) are needed to shed more light on the prognostic role of clinical parameters in patients with ISSNHL. In a correct counseling setting, with regard to the patient's concern about not being able to recover hearing, it is important to offer perspectives of appropriate hearing rehabilitation approaches.

Useful Clinical Criteria for Identifying Neonates with Congenital Cytomegalovirus Infection at Birth in the Context of an Expanded Targeted Screening Program.

Cytomegalovirus (CMV) is the leading infectious cause of brain defects and neurological dysfunctions, including sensorineural hearing loss (SNHL). Targeted screening in neonates failing the hearing screen is currently recommended in Italy according to national guidelines. However, SNHL may not be present at birth; also, congenital CMV (cCMV) may manifest with subtle signs other than SNHL. Therefore, the inclusion of additional criteria for cCMV screening appears clinically valuable. Starting January 2021, we have implemented expanded targeted cCMV screening at our center, with testing in case of maternal CMV infection during pregnancy, inadequate antenatal care, maternal HIV infection or immunosuppression, birthweight and/or head circumference < 10th centile, failed hearing screen, and prematurity. During the first three years of use of this program (2021-2023), 940 (12.3%) of 7651 live-born infants were tested. The most common indication was birthweight < 10th centile (n = 633, 67.3%). Eleven neonates were diagnosed as congenitally infected, for a prevalence of 1.17% (95%CI 0.48-1.86) on tested neonates and of 0.14% (95%CI 0.06-0.23) on live-born infants. None of the cCMV-infected newborns had a failed hearing screen as a testing indication. Implementation of an expanded cCMV screening program appears feasible and of clinical value.