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What Is Known and Objective: Evidence on whether the coronavirus disease 2019 (COVID-19) vaccination could cause hearing-related adverse events is still conflicting. This study aims to access the association between COVID-19 vaccine and hearing disorder., Methods: The Vaccine Adverse Event Reporting System (VAERS) was queried between January 2020 to November 2021. The disproportionality pattern for hearing impairment of COVID-19 vaccine was accessed by calculating the reporting odds ratio (ROR) and proportional reporting ratio (PRR). A further subgroup analysis based on the type of COVID-19 vaccine and the doses administered was performed. In addition, the disproportionalities for hearing dysfunction between COVID-19 and influenza vaccines were compared., Results and Discussion: A total of 14,956 reports of hearing-related adverse events were identified with COVID-19 vaccination and 151 with influenza vaccine during the analytic period in VAERS. The incidence of hearing disorder following COVID-19 vaccination was 6.66 per 100,000. The results of disproportionality analysis revealed that the adverse events of hearing impairment, after administration of COVID-19 vaccine, was significantly highly reported (ROR 2.38, 95% confidence interval [CI] 2.20-2.56; PRR: 2.35, χ 2 537.58), for both mRNA (ROR 2.37, 95% CI 2.20-2.55; PRR 2.34, χ 2 529.75) and virus vector vaccines (ROR 2.50, 95% CI 2.28-2.73; PRR 2.56, χ 2 418.57). While the disproportional level for hearing dysfunction was quite lower in influenza vaccine (ROR 0.36, 95% CI 0.30-0.42; PRR 0.36, χ 2 172.24)., What Is New and Conclusion: This study identified increased risk for hearing disorder following administration of both mRNA and virus vector COVID-19 vaccines compared to influenza vaccination in real-world settings., (© 2022 John Wiley & Sons Ltd.)

A 79-year-old man presented to the emergency department with a 1-week history of worsening confusion, falls and hearing impairment. An initial workup for infectious, metabolic and structural causes was unrevealing. However, further history discovered that he had been ingesting one to two bottles of Pepto-Bismol (bismuth subsalicylate) daily for gastro-oesophageal reflux symptoms. On his second day of admission, the plasma salicylate concentration was 2.08 mmol/L (reference range 1.10-2.20 mmol/L), despite no sources of salicylate in hospital. He was diagnosed with chronic salicylate toxicity and Pepto-Bismol use was discontinued. The patient was treated supportively with isotonic intravenous fluids only and plasma salicylate concentration fell to less than 0.36 mmol/L. Concurrently, all his symptoms resolved. This case highlights the potential adverse effects of over-the-counter medications. The diagnosis of chronic salicylate toxicity is challenging, specifically in the elderly and in undifferentiated presentations, as it can be missed if not suspected., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

As the first-line antidepressant drugs, selective serotonin reuptake inhibitors (SSRIs) have efficacy in controlling the symptoms of depression. However, adverse events such as anxiety and hearing disorders were usually observed in patients and even healthy volunteers during the initial phase of SSRI administration. Hearing disorders, including auditory hallucination and tinnitus, are not only highly comorbid with mental disorders but also acknowledged factors that induce psychiatric disorders. The pharmacological and neural mechanisms underlying SSRI-induced anxiety and hearing disorders are not clear. In particularly, the methods evaluating hearing disorders are not well established in animal models, limiting the pre-clinical research on its mechanism. In the present study, we examined the mismatch negativity (MMN), a cognitive component of auditory event-related potential (ERP), to evaluate the hearing process of auditory cortex in mice. Under the acute administration of citalopram, a widely used SSRI, the anxiety-related behaviors and reduced MMN were observed in mice. Serotonin transporter (SERT) is a potential target of SSRIs. The anxiety-related behaviors and reduced MMN were also observed in SERT knockout mice, implying the role of SERT in anxiety and hearing disorders induced by SSRIs. Meanwhile, the auditory brainstem response and initial components of auditory ERP were kept intact in SERT knockout mice, suggesting that hearing neural pathway is less affected by serotonergic system. Our study suggests that the SERT deficient mice might represent a useful animal model in the investigation of the anxiety and hearing disorders during the SSRI treatment., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: This study explores the current literature regarding associations between phosphodiesterase-5 (PDE-5) inhibitors and ototoxicity and provides a detailed summary and discussion of the findings., Data Sources: A comprehensive electronic search of PubMed/MEDLINE, Scopus, and Cochrane Library for studies published from database inception through March 21, 2018., Study Selection: Basic science articles, epidemiological studies, randomized controlled trials, cohort studies, case reports, reviews, meta-analyses, press releases, and newsletters were included. The PRISMA search strategy was used to select papers. Search terms are included in the appendix (http://links.lww.com/MAO/A733)., Results: Twenty-two articles met the inclusion criteria. Among case reports, there were a total of nine patients, all male, with an average age of 57.4 years (37-79 years, SD = 13.87 years). Of the cases of hearing loss, 25% (2/8 cases) were bilateral and 75% (6/8) were unilateral; 22% (2/9) were associated with tinnitus; and 33% (3/9) had accompanying vestibular symptoms (including vertigo and dizziness). Among multipatient studies, all prospective studies failed to find a significant association between ototoxicity and PDE-5 inhibitor use. Results of the retrospective studies were also heterogeneous. Many key molecules in the PDE-5 inhibition pathway have been demonstrated to exist in the cochlea. However, mirroring the clinical studies, the basic science mechanisms have suggested both ototoxic and otoprotective effects., Conclusions: Currently, the literature is inconclusive regarding the interaction between PDE-5 inhibitor use and ototoxicity. Future study such as a double-blinded placebo controlled randomized trial with audiometric assessment would provide more sound evidence. Similarly, a unified molecular model is necessary.

Background: As more children survive acute myeloid leukemia (AML) it is increasingly important to assess possible late effects of the intensive treatment. Hearing loss has only sporadically been reported in survivors of childhood AML. We assessed hearing status in survivors of childhood AML treated with chemotherapy alone according to 3 consecutive NOPHO-AML trials., Procedure: A population-based cohort of children treated according to the NOPHO-AML-84, NOPHO-AML-88, and NOPHO-AML-93 trials included 137 eligible survivors among whom 101 (74%) completed a questionnaire and 99 (72%) had otologic and audiologic examination performed including otoscopy (72%), pure tone audiometry (70%), and tympanometry (60%). Eighty-four of 93 (90%) eligible sibling controls completed a similar questionnaire., Results: At a median of 11 years (range, 4 to 25) after diagnosis, hearing disorders were rare in survivors of childhood AML and in sibling controls, with no significant differences. None had severe or profound hearing loss diagnosed at audiometry. Audiometry detected a subclinical hearing loss ranging from slight to moderate in 19% of the survivors, 5% had low-frequency hearing loss, and 17% had high-frequency hearing loss., Conclusions: The frequency of hearing disorders was low, and hearing thresholds in survivors of childhood AML were similar to background populations of comparable age.

Objective: Identify hearing effects of a single course of intravenous (IV) aminoglycoside antibiotics (AGs) therapy in adult cystic fibrosis (CF) patients. Determine whether the change is large enough to enable a proof-of-concept study of a new drug preventing AG-associated hearing loss., Design: Retrospective case review of CF patients with sequential audiograms ± an intervening course of IV AG therapy., Study Sample: 84 patients with no intervening IV AG treatment, 38 patients undergoing a single course of IV AGs., Results: Using ASHA ototoxicity metrics, 45% of adult CF patients in the Single-IV group met the criteria for ototoxicity compared to 23% of the No-IV patients. Other hearing metrics including the average maximal threshold shift (TS) and average high frequency TS showed highly significant differences between groups. Testing only participants with mild or greater pre-therapy high frequency hearing loss further increased the differences between the two groups by every metric tested., Conclusion: Adult CF patients exposed to a single course of IV AGs have significantly greater TS than patients without IV AG exposure. Patients with mild to moderate hearing loss prior to AG-IVs are at increased risk of developing ototoxicity from subsequent parenteral AG therapy.

Objective: To quantify reports made to the Food and Drug Administration Adverse Event Reporting System (FAERS), create a demographic of patient reports, and examine the cluster of symptoms to correlate consistency of postfinasteride syndrome (PFS) complaints. PFS is a provisional diagnosis encompassing a cluster of sexual, physical, and psychological and/or neurologic symptoms associated with 5-alpha reductase inhibitor use that emerge or continue after discontinuation of medication., Materials and Methods: FAERS dataset of 5-alpha reductase inhibitors from April 2011 to October 2014 was obtained. Each FAERS report had 16 categories for completion, but not every report was fully completed. Statistical analysis compared variables of interest between the 2 doses of finasteride (1 mg vs 5 mg)., Results: From FAERS, 2048 monotherapy cases were identified: 1581 of finasteride 1 mg, 240 of finasteride 5 mg, and 226 of unreported doses. Possibly related to labeling changes, from 2011 to 2014, there was a significant increase in adverse events (AEs) reported involving 1 mg dosing. Finasteride use was reported with many sexual AEs including diminished libido, erectile dysfunction, and ejaculatory complaints. Other common AEs included dermatologic, metabolic, and psychological and/or neurologic complaints. There were more AE reports with the 1 mg dose than the 5 mg dose. One case of dutasteride reported back pain, not generally attributed to PFS., Conclusion: FAERS data suggests that finasteride exposure is reported with a diverse collection of symptoms, particularly in younger men on 1 mg dosage compared to older men on 5 mg. Many of these complaints fall well out of the realm of previously established AEs from long-term controlled studies., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Systemic corticosteroids have been the mainstay of treatment for various hearing disorders for more than 30 yr. Accordingly, numerous studies have described glucocorticoids (GCs) and stressors to be protective in the auditory organ against damage associated with a variety of health conditions, including noise exposure. Conversely, stressors are also predictive risk factors for hearing disorders. How both of these contrasting stress actions are linked has remained elusive. Here, we demonstrate that higher corticosterone levels during acoustic trauma in female rats is highly correlated with a decline of auditory fiber responses in high-frequency cochlear regions, and that hearing thresholds and the outer hair cell functions (distortion products of otoacoustic emissions) are left unaffected. Moreover, when GC receptor (GR) or mineralocorticoid receptor (MR) activation was antagonized by mifepristone or spironolactone, respectively, GR, but not MR, inhibition significantly and permanently attenuated trauma-induced effects on auditory fiber responses, including inner hair cell ribbon loss and related reductions of early and late auditory brainstem responses. These findings strongly imply that higher corticosterone stress levels profoundly impair auditory nerve processing, which may influence central auditory acuity. These changes are likely GR mediated as they are prevented by mifepristone.-Singer, W., Kasini, K., Manthey, M., Eckert, P., Armbruster, P., Vogt, M. A., Jaumann, M., Dotta, M., Yamahara, K., Harasztosi, C., Zimmermann, U., Knipper, M., Rüttiger, L. The glucocorticoid antagonist mifepristone attenuates sound-induced long-term deficits in auditory nerve response and central auditory processing in female rats.

Ototoxicity diagnosis and management has historically been approached using a variety of methods. However, in recent years a consensus on useful and practical approaches has been developed through clinical guidelines of the American Speech Language Hearing Association, the American Academy of Audiology, and multiple clinical trials published in peer-reviewed literature. Some of the guidelines and approaches are used to detect and monitor ototoxicity, while others are used to grade adverse events. Some of the audiologic measures are primary, while others are adjunct measures and may be tailored to the specific needs of the patient or clinical trial. For some types of monitoring, such as drug-induced tinnitus or dizziness, validated paper survey instruments can be both sensitive and easy for fragile patients. This review addresses the characteristics of some of the most common clinical ototoxins and the most common methods for detecting and monitoring ototoxicity in clinical practice and clinical trials.

Unlike mammalian hair cells, which are essentially unable to regenerate after damage, avian hair cells have a robust capacity for regeneration. The prerequisite for understanding the above difference is knowing the genetic programming of avian hair cell regeneration. Although the major processes have been known, the precise molecular signaling that induces regeneration remains unclear. To address this issue, we performed a high-throughput transcriptomic analysis of gene expression during hair cell regeneration in the chick cochlea after antibiotic injury in vivo. A total of 16,588 genes were found to be expressed in the cochlea, of which about 1000 genes were differentially expressed among the four groups studied, i.e., 2 days (d) or 3 d post-treatment with gentamicin or physiological saline. The differentially expressed genes were distributed across approximately one hundred signaling pathways, including the Notch, MAPK (FGF), Wnt and TGF-β (BMP) pathways that have been shown to play important roles in embryonic development. Some differentially expressed genes (2-3 in each pathway) were further verified by qRT-PCR. After blocking Notch, FGF or BMP signaling, the number of regenerating hair cells and mitotic supporting cells increased. However, the opposite effect was observed after suppressing the Wnt pathway or enhancing BMP signaling. To our knowledge, the present study provided a relatively complete dataset of candidate genes and signaling pathways most likely involved in hair cell regeneration and should be a useful start in deciphering the genetic circuitry for inducing hair cell regeneration in the chick cochlea., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: To investigate early detection of amikacin-induced ototoxicity in a population treated for multidrug-resistant tuberculosis (MDR-TB), by means of three different tests: pure-tone audiometry (PTA); high-frequency audiometry (HFA); and distortion-product otoacoustic emission (DPOAE) testing., Methods: This was a longitudinal prospective cohort study involving patients aged 18-69 years with a diagnosis of MDR-TB who had to receive amikacin for six months as part of their antituberculosis drug regimen for the first time. Hearing was assessed before treatment initiation and at two and six months after treatment initiation. Sequential statistics were used to analyze the results., Results: We included 61 patients, but the final population consisted of 10 patients (7 men and 3 women) because of sequential analysis. Comparison of the test results obtained at two and six months after treatment initiation with those obtained at baseline revealed that HFA at two months and PTA at six months detected hearing threshold shifts consistent with ototoxicity. However, DPOAE testing did not detect such shifts., Conclusions: The statistical method used in this study makes it possible to conclude that, over the six-month period, amikacin-associated hearing threshold shifts were detected by HFA and PTA, and that DPOAE testing was not efficient in detecting such shifts.

Background: Cisplatin-based concurrent chemoradiotherapy is currently considered to be the standard treatment regimen for patients with advanced nasopharyngeal carcinoma, but has well known side-effects such as gastrointestinal reactions, nephrotoxicity, and ototoxicity. Nedaplatin was developed to decrease the toxic effects induced by cisplatin, and in this trial we assessed whether a nedaplatin-based concurrent chemoradiotherapy regimen was non-inferior to a cisplatin-based regimen in patients with locoregional, stage II-IVB nasopharyngeal carcinoma., Methods: We did an open-label, non-inferiority, phase 3, randomised, controlled trial at two centres in China. Patients aged 18-65 years with non-keratinising stage II-IVB (T1-4N1-3 or T3-4N0) nasopharyngeal carcinoma, a Karnofsky score of at least 70, and adequate haematological, renal, and hepatic function were randomly assigned (1:1) to receive intravenously either nedaplatin 100 mg/m 2 or cisplatin 100 mg/m 2 on days 1, 22, and 43 for three cycles concurrently with intensity-modulated radiotherapy. Randomisation was done manually using a computer-generated random number code and patients were stratified by treatment centre and clinical stage. Patients and clinicians were not masked to treatment allocation. The primary endpoint was progression-free survival at 2 years; non-inferiority was shown if the upper limit of the 95% CI for the difference in 2-year progression-free survival between the two groups did not exceed 10%. Analyses were by both intention to treat and per protocol, including all patients who received at least one complete cycle of chemotherapy. This trial is registered with ClinicalTrials.gov, number NCT01540136, and is currently in follow-up., Findings: Between Jan 16, 2012, and July 16, 2014, we randomly assigned 402 patients to nedaplatin-based (n=201) or cisplatin-based (n=201) concurrent chemoradiotherapy. In the intention-to-treat population, 2-year progression-free survival was 89·9% (95% CI 85·8-94·0) in the cisplatin group and 88·0% (83·5-94·5) in the nedaplatin group, with a difference of 1·9% (95% CI -4·2 to 8·0; p non-inferiority =0·0048). In the per-protocol analysis (cisplatin group, n=197; nedaplatin group, n=196), 2-year progression-free survival was 89·7% (95% CI 85·4-94·0) in the cisplatin group and 88·7% (84·2-94·5) in the nedaplatin group, with a difference of 1·0% (95% CI -5·2 to 7·0; p non-inferiority =0·0020). A significantly higher frequency of grade 3 or 4 vomiting (35 [18%] of 198 in the cisplatin group vs 12 [6%] of 200 in the nedaplatin group, p<0·0001), nausea (18 [9%] vs four [2%], p=0·0021), and anorexia (53 [27%] vs 26 [13%], p=0·00070) was observed in the cisplatin group compared with the nedaplatin group. 11 (6%) patients in the nedaplatin group had grade 3 or 4 thrombocytopenia compared with four (2%) in the cisplatin group (p=0·065). Patients in the cisplatin group had a higher frequency of any grade or grade 3 or 4 late auditory or hearing toxicities than did patients in the nedaplatin group (grade 3 or 4: three [2%] in the nedaplatin group vs 11 [6%] in the cisplatin group, p=0·030). No patients died from treatment-related causes., Interpretation: Our findings show that nedaplatin-based concurrent chemoradiotherapy represents an alternative doublet treatment strategy to cisplatin-based concurrent chemoradiotherapy for patients with locoregional, advanced nasopharyngeal carcinoma. Further investigations are needed to explore the potential use of this treatment as induction or adjuvant chemotherapy or in combination with other agents., Funding: National Key R&D Program of China, National Natural Science Foundation of China, Sun Yat-sen University Clinical Research 5010 Program, Sci-Tech Project Foundation of Guangzhou City, National Key Basic Research Program of China, Special Support Plan of Guangdong Province, Sci-Tech Project Foundation of Guangdong Province, Health & Medical Collaborative Innovation Project of Guangzhou City, National Science & Technology Pillar Program during the Twelfth Five-year Plan Period, PhD Start-up Fund of Natural Science Foundation of Guangdong Province, Cultivation Foundation for the Junior Teachers in Sun Yat-sen University, and Fundamental Research Funds for the Central Universities., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The objective of the present study was the evaluation of the state of the auditory function in the premature children during the first year of life who underwent the neonatal treatment with various ototoxic antibiotics. A total of 232 newborn infants were available for the examination by the methods designed for recording distortion product optoacoustic emission (DPOAE) and short-latency auditory evoked potentials (SAEPs). The 'Statgraphics Centurion XV' program was used for the statistical treatment of the data obtained in the study. The results of recording DPOAE and SAEPs in 232 prematurely born children of different gestational age were used to evaluate their auditory function under conditions of treatment with various ototoxic antibiotics during the early neonatal period. It was shown that such treatment is likely to have an impact on the hearing function of premature children throughout the entire first year of life. Such influence can manifest itself as the enhanced threshold of the appearance of SAEPs peak V and the selective distortion of evoked responses recorded with the help of the DPOAE technique at a frequency of 4.6 kHz. It is concluded that all prematurely born children should be under observation of an otorhinolaryngologist-surdologist throughout the entire first year of life and, if appropriate, undergo the rehabilitative treatment at the earliest possible time. Moreover, the children with this condition must remain under the thorough follow-up care during at least 3 years including the yearly audiological evaluation and the comparative analysis of the results of previous observations for the timely identification of possible disturbances in the hearing function.

Objective: Possible therapeutic and protective benefits of intratympanic autologous serum application in amikacin-induced ototoxicity were investigated., Methods: Twenty-four guinea pigs were separated equally into two groups: therapeutic (group A) and protective (group B). Transient evoked otoacoustic emissions were recorded before and after autologous serum application. Apoptotic cells were identified in the organ of Corti, spiral limbus and spiral ganglion by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling ('TUNEL') method., Results: Transient evoked otoacoustic emission responses at 1, 1.4 and 2.8 kHz improved without significance after autologous serum application in group A (p > 0.05). A significantly protective effect of autologous serum was determined at 4 kHz in group B (p < 0.05). There were significantly fewer apoptotic cells at the spiral limbus in the therapeutic and protective groups compared to the control group (p < 0.05)., Conclusion: Autologous serum may offer protection against ototoxicity-induced hearing loss, but it cannot restore hearing. Immunohistochemically, autologous serum significantly decreases activation of the intrinsic pathway of pro-apoptotic signalling in mesenchymal cells compared to neurons and neurosensory cells.

Introduction: Cycloserine and Kanamycin are approved for treatment of multidrug-resistant tuberculosis with good tolerability in Tuberculosis patients and have various labeled adverse reactions but the neuropsychiatric adverse drug reactions with cycloserine are rarely explained., Case Report: We present a case report on Cycloserine induced Suicidal tendencies and Kanamycin induced decrease in hearing sensation in Indian MDR-TB patient. A 55-year-old male patient who was diagnosed with MDR-TB was prescribed with category IV anti-tubercular therapy. Within one month of initiation of therapy, he developed repeated suicidal thoughts, joint pain, restlessness, depression, constipation, insomnia, tinnitus and a decrease in hearing sensation., Results and Discussion: Cycloserine and kanamycin were closely associated with suicidal tendency and tinnitus followed by a decrease in hearing sensations respectively. On causality assessment using WHO-UMC Causality assessment scale, Adverse Drug Reaction with Cycloserine was found to be certain and for kanamycin, ADR was found to be possible., Conclusion: Early management of such fatal ADR can improve the compliance, thus preventing the relapse of infection as well as improving therapeutic outcome in Tuberculosis patients., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Background: Ototoxicity from treatment with the anticancer drug cisplatin remains a clinical problem. A wide range of intracellular targets of cisplatin has been found in vivo., Aim: To investigate cisplatin-induced change of the serum metabolite profile and its association with ototoxicity., Material and Methods: Guinea pigs (n = 14) were treated with cisplatin (8 mg/kg b.w., i.v.) 30 min after administration of the otoprotector candidate sodium thiosulfate (group STS; n = 7) or sodium chloride (group NaCl; n = 7). Ototoxicity was evaluated by ABR (3-30 kHz) before and 4 d after drug treatment, and by assessment of hair cell loss. A blood sample was drawn before and 4 d after drug treatment and the polar metabolome in serum was analyzed using LC-MS., Results: Cisplatin-treatment caused significant threshold elevations and outer hair cell (OHC) loss in both groups. The ototoxicity was generally lower in group STS, but a significant difference was reached only at 30 kHz (p = .007). Cisplatin treatment altered the metabolite profile significantly and similarly in both groups. A significant inverse correlation was found between L-acetylcarnitine, N-acetylneuraminic acid, ceramide, and cysteinylserine and high frequency hearing loss in group NaCl. The implication of these correlations should be explored in targeted studies.

Salicylate is the active ingredient in aspirin, and in high-doses it is used as an experimental tool to induce transient hearing loss, tinnitus, and hyperacusis. These salicylate-induced perceptual disturbances are associated with tonotopic-map reorganization and neural activity modulation, and such neural correlates have been examined in the central auditory pathway, including the auditory cortex (AC). Although previous studies have reported that salicylate induces increases in noise-burst-evoked neural responses and reorganization of tonotopic maps in the primary AC, little is known about the effects of salicylate on other frequency-organized AC subfields such as the anterior auditory, secondary auditory, and dorsomedial fields. Therefore, to examine salicylate-induced spatiotemporal effects on AC subfields, we measured sound-evoked neural activity in mice before and after the administration of sodium salicylate (SS, 200 mg/kg), using flavoprotein auto-fluorescence imaging. SS-treatment gradually reduced responses driven by tone-bursts with lower (≤8 kHz) and higher (≥25 kHz) frequencies over 3 h, whereas evoked responses to tone-bursts within middle-range frequencies (e.g., 12 and 16 kHz) were sustained and unchanged in the four subfields. Additionally, in each of the four subfields, SS-treatment induced similar reorganization of tonotopic maps, and the response areas selectively driven by the middle-range frequencies were profoundly expanded. Our results indicate that the SS-induced tonotopic map reorganizations in each of the four AC subfields were similar, and only the extent of the activated areas responsive to tone-bursts with specific frequencies was subfield-dependent. Thus, we expect that examining cortical reorganization induced by SS may open the possibility of new treatments aimed at altering cortical reorganization into the normative functional organization., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Medical students acquire latent tuberculosis (TB) infection at a rate of 23 cases/100 person-years. The frequency and impact of occupational TB disease in this population are unknown., Methods: A self-administered questionnaire was distributed via email and social media to current medical students and recently graduated doctors (2010 - 2015) at two medical schools in Cape Town. Individuals who had developed TB disease as undergraduate students were eligible to participate. Quantitative and qualitative data collected from the questionnaire and semi-structured interviews were analysed with descriptive statistics and a framework approach to identify emerging themes., Results: Twelve individuals (10 female) reported a diagnosis of TB: pulmonary TB (n=6), pleural TB (n=3), TB lymphadenitis (n=2) and TB spine (n=1); 2/12 (17%) had drug-resistant disease (DR-TB). Mean diagnostic delay post consultation was 8.1 weeks, with only 42% of initial diagnoses being correct. Most consulted private healthcare providers (general practitioners (n=7); pulmonologists (n=4)), and nine underwent invasive procedures (bronchoscopy, pleural fluid aspiration and tissue biopsy). Substantial healthcare costs were incurred (mean ZAR25 000 for drug-sensitive TB, up to  ZAR104 000 for DR-TB). Students struggled to obtain treatment, incurred high transport costs and missed academic time. Students with DR-TB interrupted their studies and experienced severe side-effects (hepatotoxicity, depression and permanent ototoxicity). Most participants cited poor TB infection-control practices at their training hospitals as a major risk factor for occupational TB., Conclusions: Undergraduate medical students in Cape Town are at high risk of occupationally acquired TB, with an unmet need for comprehensive occupational health services and support.

This study aims to assess whether geranylgeranylacetone (GGA) could reduce ototoxicity induced by cisplatin through upregulation of not only heat shock protein(HSP)-70, but also HSP-27 and HSP-40, and to study if GGA would reduce cisplatin-induced increase in oxidative stress. 48 guinea pigs were used in this study and treated with the following regimen: 0.5% CMC (sodium carboxymethyl cellulose) control for 7days, GGA (600mg/kg/d) for 7days, a combination of GGA (600mg/kg) for 7days and then one dose of 10mg/kg cisplatin (GGA+Cis), and a combination of CMC for 7days and then 10mg/kg cisplatin (cisplatin group). Auditory brainstem response (ABR) measurement was performed in each animal at time before treatment and 7days after the last dose. Additionally, HSPs, nitric oxide (NO), and lipid peroxidation (LPO) levels in cochlear membranous tissues were assessed. The mean ABR thresholds in the cisplatin group were significantly (p<0.05) increased when compared to the other three groups. In guinea pigs receiving both GGA and cisplatin, the mean threshold shift (TS) were smaller (p<0.05) than those of the cisplatin group, but larger (p<0.05) than those of the CMC control or GGA only group with statistical significance. Compared to the GGA only group or the group treated with GGA+Cis, the cisplatin group had the highest (p<0.05) oxidative stress (NO and LPO levels), and the lowest (p<0.05) mean HSPs expression levels. It can be concluded that GGA attenuate ototoxicity induced by cisplatin through upregulation of HSP-27, -40, and -70. Moreover, increased oxidative stress induced by cisplatin in the cochlea membranous tissue could be reduced by pre-treatment of GGA., (Copyright © 2017. Published by Elsevier Inc.)

High dose of salicylate, the active ingredient in aspirin, has long been known to induce transient hearing loss, tinnitus and hyperacusis making it a powerful experimental tool. These salicylate-induced perceptual disturbances are associated with a massive reduction in the neural output of the cochlea. Paradoxically, the diminished neural output of the cochlea is accompanied by a dramatic increase in sound-evoked activity in the auditory cortex (AC) and several other parts of the central nervous system. Exactly where the increase in neural activity begins and builds up along the central auditory pathway are not fully understood. To address this issue, we measured sound-evoked neural activity in the cochlea, cochlear nucleus (CN), inferior colliculus (IC), and AC before and after administering a high dose of sodium salicylate (SS, 300 mg/kg). The SS-treatment abolished low-level sound-evoked responses along the auditory pathway resulting in a 20-30 dB threshold shift. While the neural output of the cochlea was substantially reduced at high intensities, the neural responses in the CN were only slightly reduced; those in the IC were nearly normal or slightly enhanced while those in the AC considerably enhanced, indicative of a progress increase in central gain. The SS-induced increase in central response in the IC and AC was frequency-dependent with the greatest increase occurring in the mid-frequency range the putative pitch of SS-induced tinnitus. This frequency-dependent hyperactivity appeared to result from shifts in the frequency receptive fields (FRF) such that the response areas of many FRF shifted/expanded toward the mid-frequencies. Our results suggest that the SS-induced threshold shift originates in the cochlea. In contrast, enhanced central gain is not localized to one region, but progressively builds up at successively higher stage of the auditory pathway either through a loss of inhibition and/or increased excitation., (Copyright © 2016. Published by Elsevier B.V.)

Background: The primary goal of chemotherapy is to cure cancer and its symptoms. Hence, in recent years, there has been an increase in cancer paediatric survival rate. However, there have also been adverse side effects such as ototoxic hearing loss because of chemotherapy. Therefore, this study aimed at exploring whether the parents of children undergoing chemotherapy are aware of ototoxic effects of chemotherapy., Methods: A non-experimental quantitative study was conducted to collect data through questionnaires, one for paediatric oncologists and the other for parents. A convenience sampling strategy was employed to recruit 11 paediatric oncologists and 7 parents from two public hospitals in Gauteng. The questionnaires were analysed quantitatively, using descriptive statistics., Results: About 55% of paediatric oncologists indicated informing parents about the ototoxic effects of chemotherapy. On the contrary, 71% of parents reported having been informed by paediatric oncologists about the possible hearing loss because of chemotherapy; however, 57% of the children are receiving a combination of cisplatin and cyclophosphamide despite being aware of their ototoxic nature., Conclusion: This study paves the way for qualitative studies to ascertain how parents are informed about the possible side effects such as hearing loss because of chemotherapy treatment. The mode in which parents are informed about the possible side effects related to chemotherapy is critical, considering that a high number of children are still receiving chemotherapeutic drugs that are directly linked to hearing loss.

Introduction: Long-term daily azithromycin therapy reduces the frequency of exacerbations in chronic obstructive pulmonary disease (COPD) in a randomized controlled clinical trial setting. Concerns exist regarding arrhythmic and auditory toxicities from chronic use in the real-world setting. We hypothesized that risk factors for adverse drug reactions to azithromycin would be more frequent than previously reported, that certain specific subgroups would have different frequencies of these risk factors and that the whispered voice test would be a useful test with which to test for hearing deficits., Methods: Following ethical approval, 47 consecutive hospital-based patients with a mean age 69 years ± 8.2, and with physician-diagnosed COPD (mean FEV 1 45.1 ± 18 % predicted), were screened for subjective hearing impairment (screening questions and whispered voice test) and by electrocardiogram for prolonged QTc. Other potential risk factors and contraindications to long-term daily azithromycin were sought., Results: In total, 38 patients (80.9 %) had at least one risk factor or contraindication to azithromycin treatment. 19 patients (40.4 % of total) had subjective hearing impairment. 17 (36.1 %) had prolonged QTc intervals. 4 patients (8.51 %) had contraindicating co-morbidities. Those on long-term oxygen therapy were significantly more likely to have at least one risk factors or contraindications to azithromycin (p = 0.0025)., Conclusion: In a COPD population who would otherwise potentially be candidates for long-term daily azithromycin therapy, over 80 % had risk factors for complications from long-term daily azithromycin. Preventative treatment with long-term daily azithromycin may be appropriate for fewer COPD patients than previously thought, especially in those on long-term oxygen therapy.

Cisplatin is a commonly used antineoplastic agent that produces ototoxicity that is mediated in part by increasing levels of reactive oxygen species (ROS) via the NOX3 NADPH oxidase pathway in the cochlea. Recent studies implicate ROS generation in mediating inflammatory and apoptotic processes and hearing loss by activating signal transducer and activator of transcription (STAT1). In this study, we show that the adenosine A1 receptor (A1AR) protects against cisplatin ototoxicity by suppressing an inflammatory response initiated by ROS generation via NOX3 NADPH oxidase, leading to inhibition of STAT1. Trans-tympanic administration of the A1AR agonist R-phenylisopropyladenosine (R-PIA) inhibited cisplatin-induced ototoxicity, as measured by auditory brainstem responses and scanning electron microscopy in male Wistar rats. This was associated with reduced NOX3 expression, STAT1 activation, tumor necrosis factor-α (TNF-α) levels, and apoptosis in the cochlea. In vitro studies in UB/OC-1 cells, an organ of Corti immortalized cell line, showed that R-PIA reduced cisplatin-induced phosphorylation of STAT1 Ser(727) (but not Tyr(701)) and STAT1 luciferase activity by suppressing the ERK1/2, p38, and JNK mitogen-activated protein kinase (MAPK) pathways.R-PIA also decreased the expression of STAT1 target genes, such as TNF-α, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) and reduced cisplatin-mediated apoptosis. These data suggest that the A1AR provides otoprotection by suppressing NOX3 and inflammation in the cochlea and could serve as an ideal target for otoprotective drug therapy., Significance Statement: Cisplatin is a widely used chemotherapeutic agent for the treatment of solid tumors. Its use results in significant and permanent hearing loss, for which no US Food and Drug Administration-approved treatment is currently available. In this study, we targeted the cochlear adenosine A1 receptor (A1AR) by trans-tympanic injections of the agonist R-phenylisopropyladenosine (R-PIA) and showed that it reduced cisplatin-induced inflammation and apoptosis in the rat cochlea and preserved hearing. The mechanism of protection involves suppression of the NOX3 NADPH oxidase enzyme, a major target of cisplatin-induced reactive oxygen species (ROS) generation in the cochlea. ROS initiates an inflammatory and apoptotic cascade in the cochlea by activating STAT1 transcription factor, which is attenuated byR-PIA. Therefore, trans-tympanic delivery of A1AR agonists could effectively treat cisplatin ototoxicity., (Copyright © 2016 the authors 0270-6474/16/363962-16$15.00/0.)

Amikacin is a semi-synthetic aminoglycoside widely used to treat infections caused by gentamicin-resistant gram-negative organisms and nontuberculous mycobacteria. However, the use of this agent often results in ototoxicity due to the overproduction of reactive oxygen species (ROS). Galangin, a natural flavonoid, has been shown to play a protective role against mitochondrial dysfunction by reducing mitochondrial ROS production. In this study, the effect of galangin on amikacin-induced ototoxicity was examined using cultures of cochlear explants. Immunofluorescent staining showed that treatment of inner hair cells (IHCs) and outer hair cells (OHCs) with galangin significantly decreased damage induced by amikacin. Moreover, pretreatment with galangin resulted in decreased amikacin-provoked increase in ROS production in both types of hair cells by MitoSOX-red staining. Attenuation of apoptotic cell death was assessed immunohistochemically using active caspase-3 antibody and with terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, compared to explants exposed to amikacin alone (P<0.05). These results indicate that galangin protects hair cells in the organ of Corti from amikacin-induced toxicity by reducing the production of mitochondrial ROS. The results of this study suggest that galangin can potentially be used as an antioxidant and antiapoptotic agent to prevent hearing loss caused by aminoglycoside induced-oxidative stress., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Purpose: To identify the effects of alcohol intake during pregnancy on the central auditory nervous system in relation to their possible diagnosis, Fetal Alcohol Syndrome, partial Fetal Alcohol Syndrome, Alcohol-Related Birth Defects and Alcohol-Related Neurodevelopmental Disorder, his extension and the hearing assessment method., Research Strategy: Systematic and integrative review searched the databases PubMed, LILACS and SciELO, with terms in Portuguese and English "fetal alcohol syndrome", "alcohol-related disorders" associated with "hearing". Selection criteria: We identified 123 abstracts, six were selected and published until May 2015., Data Analysis: Were listed topics to be answered, characterization of the sample; the diagnosis result of fetal exposure; method of hearing assessment and described results., Results: Among the behavioral assessments, Verbal Dichotic Tests with syllables and sentences and Speech in Noise Test, were used. Among the electrophysiological tests, the Brainstem Auditory Evoked Potential was detected change neural synchrony, and Long-Latency Auditory Evoked Potential - P300, early latency values., Conclusion: There is evidence that children exposed to alcohol in utero present central auditory nervous system involvement signals, but it was not possible to identify the influence of different subtypes and their losses. Cortical auditory pathways were the most investigated and the electrophysiological method as used with an unexpected result in two of them, early N2 and P300 latency.

Objectives: Occupational exposure to anaestethic gases has been suggested to induce auditory damages. The aim of this study is to investigate high-frequency audiometric responses in subjects exposed to anaesthetic gases, in order to highlight the possible effects on auditory system., Methods: The study was performed on a sample of 30 medical specialists of Messina University Anaesthesia and Intensive care. We have used tonal audiometry as well as high-frequency one. We have compared the responses with those obtained in a similar control group not exposed to anaesthetic gases. Results were compared statistically., Results: Results show a strong correlation (p = 0.000) between left and right ear responses to all the audiometric tests. The exposed and the control group run though the standard audiometry analysis plays different audiometric responses up only to higher frequencies (2000 HZ p = 0.009 and 4000 Hz p = 0.04); in high-frequency audiometry, as all other frequencies, the attention is drew to the fact that the sample groups distinguish themselves in a significantly statistic way (10,000 Hz p = 0.025, 12,000 Hz p = 0.008, 14,000 Hz p = 0.026, 16,000 Hz p = 0.08). The highest values are the ones related to exposed subjects both in standard (2000 Hz p = 0.01, 4000 Hz p = 0.02) and in high-frequency audiometry (10,000 Hz p = 0.011, 12,000 Hz p = 0.004, 14,000 Hz p = 0.012, 16,000 Hz p = 0.004)., Conclusion: Results, even if preliminary and referred to a low-range sample, show an involvement of the anatomic structure responsible for the perception of high-frequency audiometric responses in subjects exposed to anaesthetic gases., (© The Author(s) 2012.)

Ototoxicity describes reversible or irreversible disorders of inner ear functions due to the influence of chemical, biological, or physical substances. Ototoxicity should be kept in mind during differential diagnosis of hearing loss, tinnitus, dizziness, and vertigo. In clinical practice, drug-induced ototoxic effects play a major role. The otorhinolaryngologist should also be involved in interdisciplinary cooperation, e.g., during treatment with antineoplastic chemotherapeutic agents with potential ototoxic side effects. In clinical practice, multimedication and interactions between different agents can complicate precise correlation in individual cases. Recent studies also show that noncellular components, such as otoconia, are extremely sensitive to chemical attacks.

Objective: This study adopted an inner ear test battery comprising audiometry, and ocular vestibular-evoked myogenic potential (oVEMP), cervical VEMP (cVEMP) and caloric tests to assess inner ear function in patients with long term exposure to organic solvents., Methods: Eighteen patients exposed to organic solvents and another 18 non-exposed controls from the same environment were enrolled in this study. Each subject underwent an inner ear test battery., Results: The percentages of abnormalities identified by the oVEMP test, cVEMP test, audiometry and caloric test for the exposed group were 85%, 54%, 50% and 33%, respectively, which showed significant differences when compared with the respective 8%, 8%, 6% and 0 for the non-exposed group. Additionally, a significantly declining trend of inner ear deficits from the utricle to the saccule, cochlea, and semicircular canals was noted in the exposed group, but not in the non-exposed group., Conclusion: Ototoxicity was identified in those exposed to organic solvents, with the sequence of abnormal inner ear function from the utricle to the saccule, cochlea, and semicircular canals.

The aminoglycoside antibiotic gentamicin can cause both ototoxicity and nephrotoxicity, the severity of which varies with circadian time of daily treatment. However, it is not yet resolved if such drug-induced adverse effects are independent or interdependent phenomena. Two groups of 9 female Sprague-Dawley rats (200-250 g), each housed separately and entrained to a 12 h light (06:00-18:00 h) - 12 h dark cycle, received a daily subcutaneous injection of 100 mg/kg gentamicin. One group was treated at the beginning of the activity span, 2 Hours After Lights On (HALO), and the other at the beginning of the rest span, 14 HALO. Global toxicity was gauged by both body weight loss relative to the pre-treatment baseline and number of deaths. Ototoxicity, i.e., hearing loss, was assessed by changes in auditory brainstem response (ABR) for pure tone stimuli of 8, 16, 24, and 32 kHz before and after 2 and 4 weeks of gentamicin treatment. Renal toxicity was evaluated by changes in urinary N-acetyl-β-glucosaminidase (NAG)/creatinine (CR) concentration ratio before and after each week of treatment. In a complementary substudy of separate but comparable 2 and 14 HALO groups of rats, blood samples were obtained before and 30, 60, 120, and 240 min post-subcutaneous injection of 100 mg/kg gentamicin. Number of animal deaths was greater in the 2 (4 deaths) than 14 HALO (1 death) group, mirroring more severe initial (first two weeks of treatment) body weight losses from baseline, being more than 2-fold greater in animals of the 2 than 14 HALO group. Ototoxicity progressively worsened during the treatment; although, the extent of hearing loss varied according to circadian time of treatment across all frequencies (p < 0.05), particularly the 24 and 32 kHz ones (both p < 0.005), both at the 2 and 4 week assessments. At 32 kHz after 4 weeks of gentamicin dosing, the 2 HALO group showed an average 42 dB hearing loss, while the 14 HALO group exhibited only an average 10 dB loss. ABR response latencies were longer for the 2 than 14 HALO rats. The time course of nephrotoxicity differed from that of ototoxicity. The mean urinary NAG/CR ratio peaked after the first week of treatment, averaging 13.64-fold greater than baseline for the 2 HALO-treated animals compared to 7.38-fold greater than baseline for the 14 HALO-treated ones. Ratio values declined thereafter; although, even after the second week of dosing, they remained greater in the 2 than 14 HALO group (averaging 8.15-fold greater and 2.23-fold greater than baseline, respectively). Pharmacokinetic analysis of the blood gentamicin values revealed slower clearance, on average by ∼25% (p < 0.001), in the rats of the 14 than 2 HALO group (x ± S.E.: 3.22 ± 0.49 and 4.53 ± 0.63 mL/min/kg, respectively). The study findings indicate robust difference of the time course in rats of both treatment groups of gentamicin-induced ototoxicity and nephrotoxicity, supporting the hypothesis these organ toxicities are independent of one another, and further suggest the observed treatment-time differences in gentamicin adverse effects may be more dependent on local cell, tissue, or organ circadian (chrono) pharmacodynamic than (chrono) pharmacokinetic mechanisms.

Neuropsychiatric and gastrointestinal side effects of opioids are well documented, but self-reported hearing disturbance from opioids is often unrecognized. Two cases are presented illustrating a possible association between auditory symptoms and opioid toxicity. Possible mechanisms are discussed.

Objective: Cochlear implants (CIs) have provided some auditory function to hundreds of thousands of people around the world. Although traditionally carried out only in profoundly deaf patients, the eligibility criteria for implantation have recently been relaxed to include many partially-deaf patients with useful levels of hearing. These patients receive both electrical stimulation from their implant and acoustic stimulation via their residual hearing (electro-acoustic stimulation; EAS) and perform very well. It is unclear how EAS improves speech perception over electrical stimulation alone, and little evidence exists about the nature of the interactions between electric and acoustic stimuli. Furthermore, clinical results suggest that some patients that undergo cochlear implantation lose some, if not all, of their residual hearing, reducing the advantages of EAS over electrical stimulation alone. A reliable animal model with clinically-relevant partial deafness combined with clinical CIs is important to enable these issues to be studied. This paper outlines such a model that has been successfully used in our laboratory., Approach: This paper outlines a battery of techniques used in our laboratory to generate, validate and examine an animal model of partial deafness and chronic CI use., Main Results: Ototoxic deafening produced bilaterally symmetrical hearing thresholds in neonatal and adult animals. Electrical activation of the auditory system was confirmed, and all animals were chronically stimulated via adapted clinical CIs. Acoustic compound action potentials (CAPs) were obtained from partially-hearing cochleae, using the CI amplifier. Immunohistochemical analysis allows the effects of deafness and electrical stimulation on cell survival to be studied., Significance: This animal model has applications in EAS research, including investigating the functional interactions between electric and acoustic stimulation, and the development of techniques to maintain residual hearing following cochlear implantation. The ability to record CAPs via the CI has clinical direct relevance for obtaining objective measures of residual hearing.

Cisplatin is a widely used anti-cancer drug. Ototoxicity is a major dose-limiting side-effect. A reproducible mammalian in-vitro model of cisplatin ototoxicity is required to screen and validate otoprotective drug candidates. We utilized a whole organ culture system of the postnatal mouse inner ear in a rotating wall vessel bioreactor under "simulated microgravity" culture conditions. As previously described this system allows whole organ culture of the inner ear and quantitative assessment of ototoxic effects of aminoglycoside induced hair cell loss. Here we demonstrate that this model is also applicable to the assessment of cisplatin induced ototoxicity. In this model cisplatin induced hair cell loss was dose and time dependent. Increasing exposure time of cisplatin led to decreasing EC50 concentrations. Outer hair cells were more susceptible than inner hair cells, and hair cells in the cochlear base were more susceptible than hair cells in the cochlear apex. Initial cisplatin dose determined the final extent of hair cell loss irrespective if the drug was withdrawn or continued. Dose dependant otoprotection was demonstrated by co-administration of the antioxidant agent N-acetyl l-cysteine. The results support the use of this inner ear organ culture system as an in vitro assay and validation platform for inner ear toxicology and the search for otoprotective compounds., (Copyright © 2014 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Objective: To evaluate auditory function in a group of workers exposed to organic solvent mixture at a paint factory., Design: Cross-sectional study., Study Sample: One hundred and sixty-one workers were studied, 77 exposed to solvents and 84 unexposed. Fourteen solvents were measured, including toluene, xylene, and n-hexane. Pure-tone audiometry and brainstem auditory-evoked potentials (BAEP) were performed. Industrial noise was < 85 dBA and exposure levels to organic solvents were low., Results: The exposed group showed a hearing impairment in both ears compared with the unexposed workers. Multiple linear regression models adjusted by age, chronic pathologies, and environmental noise for frequency means between 125 and 8000 Hz produced the following results: for the left ear, R(2) = 33.3%, exposed vs. unexposed β = 4.1 (p < 0.001); and for the right ear, R(2) = 38%, exposed vs. unexposed β = 4.8 (p < 0.001). Adjusted for age and chronic pathologies, waves III and V, and interpeak interval latencies were increased (p < 0.05) in both ears in the exposed group., Conclusions: Although solvent mixture concentrations and noise levels were low, our results demonstrate that there may be a concurrent ototoxicity and neurotoxicity condition and emphasize the importance of including BAEP analysis for comprehensive assessments. Future studies that include otoacoustic emissions assessments to monitor cochlear function and central auditory processing tests are imperative.

Objectives: Audiologists regularly use serial monitoring to evaluate changes in a patient's auditory function over time. Observed changes are compared with reference standards to determine whether further clinical action is necessary. Reference standards are established in a control sample of otherwise healthy subjects to identify the range of auditory shifts that one might reasonably expect to occur in the absence of any pathological insult. Statistical approaches to this seemingly mundane problem typically invoke 1 of 3 approaches: percentiles of the cumulative distribution, the variance of observed shifts, and the "standard error of measurement." In this article, the authors describe the statistical foundation for these approaches, along with a mixed model-based alternative, and identify several necessary, although typically unacknowledged assumptions. Regression to the mean, the phenomenon of an unusual measurement typically followed by a more common one, can seriously bias observed changes in auditory function and clinical expectations. An approach that adjusts for this important effect is also described., Design: Distortion product otoacoustic emissions (DPOAEs) elicited at a single primary frequency, f2 of 3175 Hz, were collected from 32 healthy subjects at baseline and 19 to 29 days later. Ninety percent test-retest reference limits were computed from these data using each statistical approach. DPOAE shifts were also collected from a sample of 18 cisplatin patients tested after 120 to 200 mg of cisplatin. Reference limits established according to each of the statistical approaches in the healthy sample were used to identify clinically alarming DPOAE shifts in the cisplatin patient sample., Results: Reference limits established with any of the parametric methods were similar. The percentile-based approach gave the widest and least precisely estimated intervals. The highest sensitivity for detecting clinically alarming DPOAE shifts was based on a mixed model approach that adjusts for regression to the mean., Conclusions: Parametric methods give similar serial monitoring criteria as long as certain critical assumptions are met by the data. The most flexible method for estimating test-retest limits is based on the linear mixed model. Clinical sensitivity may be further enhanced by adjusting for regression to the mean.

Introduction: INF- α is a common drug for the treatment of hepatitis B and C. Although a variety of related complications are discussed, possible ototoxic effects of this mediation are not well described., Methods and Materials: In a before-after control study, 24 patients who received INF- α for the treatment of hepatitis B and C and 30 normal controls were included. Subjective and objective ototoxicity evaluations via questionnaire, high frequency audiometry, and measuring transiently evoked otoacoustic emissions (TEOAEs) were performed one week before and one month after the prescription of the drug. Results. Subjective hearing complaint, tinnitus, and vertigo were seen in just 3 cases, which was not statistically significant (P = 0.083). In the frequency range of 4000 to 8000 Hz before (9.38 ± 1.0 and 10.7 ± 1.2, resp.) and after (17.9 ± 2.6 and 17.6 ± 2.6, resp.) one month of treatment, a significant difference (P = 0.083) was detected. Progressive decreases in amplitude of the OAE during TEOAE measurement in 1, 2, and 4 frequencies among 41.66%, 18.75 %, and 43.75% were observed, respectively. The hearing loss was seen more among older and male cases significantly. Conclusion. The results showed ototoxicity of INF- α that may encourage planning hearing monitoring in patients receiving this drug.

A variety of drugs in veterinary use have side effects that can potentially damage the senses of hearing or balance in animals. A large body of literature exists on the incidence and mechanisms of ototoxicity in experimental animals and in humans, but little is documented in domestic dogs and cats. However, the generality of these adverse actions across species allows one to extrapolate and provide the veterinarian with insight into possible complications of chemotherapy., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: A cisplatin ototoxicity monitoring protocol was recently proposed using distortion-product otoacoustic emissions (DPOAEs) measured in 1/48th octave steps over the highest obtainable quarter octave ( Dille et al, 2010 ). This protocol can take up to 40 minutes to complete in both ears among seriously ill patients in a potentially noisy test environment. The goal of the current study was to contrast the diagnostic accuracy of ototoxicity monitoring protocols based on changes in DPOAE levels at wider, more rapidly tested, primary frequency step sizes., Design: Measure DPOAE levels in 1/48th octave steps over the highest half-octave of obtainable DPOAEs prior to treatment and at each ototoxicity monitoring session during the course of treatment with cisplatin., Study Sample: Nineteen cancer patients being treated with cisplatin at the Portland Veterans Affairs Medical Center were observed over 56 monitoring appointments. Hearing thresholds in the sensitive region for ototoxicity (SRO) were measured concurrently with DPOAE levels., Results: DPOAE levels measured in 1/24th octave steps provided comparable accuracy, and half the testing time, to the 1/48th octave step protocol previously described., Conclusions: DPOAE level shifts measured in 1/24th octave steps may provide a basis for rapid ototoxicity monitoring among adult cancer patients treated with cisplatin.

Purpose: Most patients with epithelial ovarian cancer have a poor overall prognosis. Therefore, one of the main therapeutic aims after cytoreductive surgery for these patients is to identify, delay and relieve chemotherapy-induced side effects and optimise the quality of life, especially after first-line therapy., Methods: Twelve ovarian cancer patients undergoing carboplatinum-containing chemotherapy were assessed using validated tests for olfactory, gustatory, and hearing functions before, during, immediately after, and 3 months after chemotherapy., Results: All chemosensory functions decreased during and after carboplatinum-containing chemotherapy, but recovered 3 months after treatment ended. For olfaction, this decrease was significant, affecting odour identification minimally, and odour threshold the most. For taste, the decrease was not significant, but could be observed in total scores and in each quality (sweet, sour, salty, and bitter). For hearing, the decrease was not significant, but a recovery of the deep and middle frequencies was clearly evident 3 months after chemotherapy., Conclusions: Patients must be informed about transient declines in chemosensory functions during chemotherapy. Symptomatic relief provided by the use of more spices, a small amount of glutamate, or additional flavouring might help to compensate for decreased functions during chemotherapy and increase patient quality of life.

Objective: Ototoxicity is a frequent adverse event of cisplatin treatment. No therapy is currently available for cisplatin-induced ototoxicity. A systematic review of experimental animal studies and in vitro experiments was conducted to evaluate gene therapy as a potential future therapeutic option., Data Sources: Eligible studies were identified through searches of electronic databases Ovid MEDLINE, Ovid MEDLINE In-Process, Embase, PubMed, Biosis Previews, Scopus, ISI Web of Science, and The Cochrane Library., Study Selection: Articles obtained from the search were independently reviewed by 2 authors using specific criteria to identify experimental animal studies and in vitro experiments conducted to evaluate gene therapy for cisplatin-induced ototoxicity. No restriction was applied to publication dates or languages., Data Extraction: Data extracted included experiment type, cell type, species, targeted gene, gene expression, method, administration, inner ear site evaluated, outcome measures for cytotoxicity, and significant results., Results: Fourteen articles were included in this review. In vitro and in vivo experiments have been performed to evaluate the potential of gene expression manipulation for cisplatin-induced ototoxicity. Twelve different genes were targeted including NTF3, GDNF, HO-1, XIAP, Trpv1, BCL2, Otos, Nfe2l2, Nox1, Nox3, Nox4, and Ctr1. All of the included articles demonstrated a benefit of gene therapy on cytotoxicity caused by cisplatin., Conclusion: Experimental animal studies and in vitro experiments have demonstrated the efficacy of gene therapy for cisplatin-induced ototoxicity. However, further investigation regarding safety, immunogenicity, and consequences of genetic manipulation in the inner ear tissues must be completed to develop future therapeutic options.

Aminoglycosides, such as gentamycin, are well known ototoxic agents. Toxicity occurs via an activation process involving the formation of an iron-gentamycin complex with free radical production. Antioxidants like Q-ter (a soluble formulation of coenzyme Q(10), CoQ(10)), can limit or prevent cellular ototoxic damage. The present study was designed to investigate the possible protective effects of Q-ter on gentamycin ototoxicity in albino guinea pigs (250-300 g). Animals were divided into five experimental groups: I, a sham control group given an intra-peritoneal (I.P.) injection of 0.5 ml saline (SHAM); II, gentamycin group (GM), treated with an injection of gentamycin (100 mg/ kg); III, gentamycin + Q-ter group (GM+Q-ter), treated with gentamycin (same dose as group II) and an I.P. injection of coenzyme Q(10) terclatrate (Q-ter) at 100 mg/kg body weight; IV, injected with gentamycin (100 mg/kg) plus saline; V, treated with Q-ter alone (100 mg/ kg). All animals were treated for 14 consecutive days. Auditory function was evaluated by recording auditory brainstem responses (ABR) at 15 and 30 days from the beginning of treatment. Morphological changes were analyzed by rhodamine-phalloidine staining. Gentamycin-induced progressive high-frequency hearing loss of 45-55 dB SPL. Q-ter therapy slowed and attenuated the progression of hearing loss, yielding a threshold shift of 20 dB. The significant loss of outer hair cells (OHCs) in the cochlear medio-basal turn in gentamycin-treated animals was not observed in the cochleae of animals protected with Q-ter. This study supports the hypothesis that Q-ter interferes with gentamycin-induced free radical formation, and suggests that it may be useful in protecting OHC function from aminoglycoside ototoxicity, thus reducing hearing loss.

Purpose of Review: Various medications can modify the physiology of retinal and cochlear neurons and lead to major, sometime permanent, sensory loss. A better knowledge of pathogenic mechanisms and the establishment of relevant monitoring protocols are necessary to prevent permanent sensory impairment. In this article, we review main systemic medications associated with direct neuronal toxicity on the retina and cochlea, their putative pathogenic mechanisms, when identified, as well as current recommendations, when available, for monitoring protocols., Recent Findings: Pathogenic mechanisms and cellular target of retinotoxic drugs are often not well characterized but a better knowledge of the course of visual defect has recently helped in defining more relevant monitoring protocols especially for antimalarials and vigabatrin. Mechanisms of ototoxicity have recently been better defined, from inner ear entry with the use of fluorescent tracers to evidence for the role of oxidative stress and program cell death pathways., Summary: Experimental and clinical studies have elucidated some of the pathogenic mechanisms, courses and risk factors of retinal toxicity and ototoxicity, which have led to establishment of relevant monitoring protocols. Further studies are, however, warranted to better understand cellular pathways leading to degeneration. These would help to build more efficient preventive intervention and may also contribute to understanding of other degenerative processes such as genetic disorders.

Objective: Good test-retest reliability of high frequency (≥ 8 kHz) pure-tone audiometry (HFPTA) is essential to detect significant changes in hearing threshold caused by ototoxicity. While the test-retest reliability of HFPTA in adults has been extensively studied, such investigations in children are scant. This study aimed to evaluate the test-retest reliability of the HFPTA in normal-hearing children with particular reference to the criteria for ototoxicity., Design: Participants were 125 children aged between 4 and 13 yr, with normal hearing in the 0.25 to 4 kHz range and normal tympanometric findings. The participants were divided into three age groups, 4 to 6 yr (16M; 16F); 7 to 9 yr (22M; 30F); and 10 to 13 yr (24M; 17F), for investigating possible age effects in the test-retest reliability of HFPTA. The instrumentation for the HFPTA procedure was an Interacoustics AC40 audiometer with Koss R/80 high-frequency headphones, calibrated to meet Australian standards. Hearing thresholds at 8, 9, 10, 11.2, 12.5, 14, and 16 kHz were measured in a sound-treated chamber using a modified Hughson-Westlake procedure with a 5 dB step size. Testing began with an ear and test frequency selected at random; the subsequent test frequencies were randomly selected. After acquisition of hearing threshold data at all frequencies, the other ear was tested using the same procedure. After the first HFPTA test, the headphones were removed and carefully replaced. A second HFPTA test was performed with the ear order reversed. The order of testing the ear for the next participant was reversed., Results: Good test-retest reliability of HFPTA was achieved with no significant difference in mean HFPTA thresholds across test and retest conditions for all age groups. An age effect in the test-retest reliability of HFPTA was evident with the 4- to 6-yr-old, 7- to 9-yr-old, and 10- to 13-yr-old children demonstrating normal variability of thresholds (within ±10 dB) in 89.9%, 93.0%, and 97% of ears tested, respectively. When the variability of test-retest thresholds was assessed at each frequency, the 4 to 6 yr group showed significantly lower percentage of normal variability at 14 kHz. In identifying significant deterioration of hearing thresholds across test-retest conditions in relation to the ASHA (1994) ototoxicity criteria, the three age groups (youngest to oldest) demonstrated false-positive rates of 24.6%, 11%, and 7.6%, respectively., Conclusion: : Overall, this study demonstrated high test-retest reliability of HFPTA in all but the 4 to 6 yr group. With a false-positive rate of 24.6% for ototoxicity for the youngest group, it is recommended that the HFPTA should not be used alone in assessing the possibility of a genuine threshold shift for this age group. If possible, the HFPTA should be supplemented with an objective test of auditory function to confirm the diagnosis. For children aged 7 yr or older, the HFPTA test is promising as a useful tool to identify hearing impairment in the extended high-frequency range (>8 kHz). However, interpretation of HFPTA findings in serial testing for monitoring hearing in a child should be made with due attention being given to the frequency of the stimulus, age of the child, and the associated nonzero false-positive rates.

Numerous investigations of cortical crossmodal plasticity, most often in congenital or early-deaf subjects, have indicated that secondary auditory cortical areas reorganize to exhibit visual responsiveness while the core auditory regions are largely spared. However, a recent study of adult-deafened ferrets demonstrated that core auditory cortex was reorganized by the somatosensory modality. Because adult animals have matured beyond their critical period of sensory development and plasticity, it was not known if adult-deafening and early-deafening would generate the same crossmodal results. The present study used young, ototoxically-lesioned ferrets (n = 3) that, after maturation (avg. = 173 days old), showed significant hearing deficits (avg. threshold = 72 dB SPL). Recordings from single-units (n = 132) in core auditory cortex showed that 72% were activated by somatosensory stimulation (compared to 1% in hearing controls). In addition, tracer injection into early hearing-impaired core auditory cortex labeled essentially the same auditory cortical and thalamic projection sources as seen for injections in the hearing controls, indicating that the functional reorganization was not the result of new or latent projections to the cortex. These data, along with similar observations from adult-deafened and adult hearing-impaired animals, support the recently proposed brainstem theory for crossmodal plasticity induced by hearing loss.