The burden of hearing loss among older adults could be mitigated with appropriate care. This study compares implementation of three hearing screening strategies in primary care, and examines the reliability and validity of patient self-assessment, primary care providers (PCP) and diagnostic audiologists in the identification of ‘red flag’ conditions .N = 500) from selected otolaryngology head and neck surgery clinics in a national practice-based research network to increase the likelihood of occurrence of medical conditions that might contraindicate hearing aid fitting. The primary outcome is the proportion of patients who complete the tele-HS within 2 months of the PCP appointment comparing Group 3  versus Groups 2 and 1 . The several secondary outcomes include direct and indirect costs, patient, family and provider attitudes of hearing healthcare, and accuracy of red flag condition evaluations compared with expert medical assessment by an otolaryngology provider.Six primary care practices will implement one of three screening strategies (2 practices per strategy) with 660 patients (220 per strategy) ages 65–75 years with no history of hearing aid use or diagnosis of hearing loss. Strategies differ on the location and use of PCP encouragement to complete a telephone-based hearing screen (tele-HS). Group 1: instructions for tele-HS to complete at home and educational materials on warning signs and consequences of hearing loss. Group 2: PCP counseling/encouragement on importance of hearing screening, instructions to take the tele-HS from home, educational materials. Group 3: PCP counseling/encouragement, in-office tele-HS, and educational materials. Patients from all groups who fail the tele-HS will be referred for diagnostic audiological testing and medical evaluation, and complete a self-assessment of red flag conditions at this follow-up appointment. Due to the expected low incidence of ear disease in the PCP cohort, we will enroll a complementary population of patients (Determining the relative effectiveness of three different strategies for hearing screening in primary care and the assessment accuracy of red flag conditions can each lead to practice and policy changes that will reduce individual, family and societal burden from hearing loss among older adults.NCT02928107; 10/10/2016 protocol version 1.Clinicaltrials.gov:  More than half a billion people worldwide are living with disabling hearing loss and prevalence increases with age . One in The financial burden of hearing loss is underestimated because screening for hearing loss is under-utilized resulting in an undetermined number of people affected. Financial burden at the individual level results from lost earnings, low productivity, the inability to secure and maintain employment, the need for premature retirement, and disability costs associated with hearing loss –12. FinaAlthough health-related and financial consequences of undetected and untreated hearing loss are expected to be significant, hearing screening is not a routine component of primary care. The United States (US) Preventative Services Task Force acknowledges the importance of identification and treatment of hearing loss for older adults but states that there is inadequate evidence to determine the balance of benefit and harm of screening for hearing loss in asymptomatic adults age 50 years and older . DespiteConflicting recommendations may explain below optimal hearing screening (HS) rates for older adults. Only 20% of physicians routinely screen for hearing loss and only 14% of adults 65–74 years and 16% of those 75+ years are screened , 18. OthUnfortunately, those who complete and fail a HS may not seek help for it, influenced by perceptions and attitudes of hearing loss and disability –21, 26. To address these challenges to hearing health care, we are conducting an implementation-effectiveness study aimed to (a) evaluate older adults’ uptake of HS and follow-up for audiologic testing if indicated, and (b) determine the accuracy of assessment and need for evaluation of ‘red flag’ conditions. We proposed to explore the patient, family and provider attitudes toward hearing loss, screening and medical care, and estimate the cost-benefit of three HS strategies in primary care practices. The three HS strategies for comparison include: (1) printed educational materials about hearing loss and access to at-home telephone-based HS (tele-HS), (2) PCP encouragement for HS plus printed materials and access to at-home tele-HS, and (3) PCP encouragement for HS plus printed materials and in-clinic tele-HS. Our primary hypothesis is that education and active encouragement by the PCP to perform and follow through on the screening in the office (Group 3) will result in higher HS rates than education, encouragement and instructions for home HS testing (Group 2) or education and instructions for home HS testing (Group 1). This pragmatic study intends to generate real-world evidence. Our collaboration with both a primary care practice-based research network and a NIH-funded nationwide network of community and academic otolaryngology practices is an effort to reduce the time lag from evidence to implementation and spread.Our goal is to develop evidence that can inform hearing health care for adults ages 65 to 75 years. In this implementation-effectiveness hybrid type 1 study (testing effects of the intervention while gathering data on implementation) we will determine the level of PCP involvement needed to inform and encourage older adults to follow through with routine HS and determine if providing the opportunity to complete the tele-HS in-clinic as part of the primary care appointment versus access to tele-HS at home increases HS completion. We study the costs associated with three different HS strategies and the patient, family and provider attitudes toward hearing loss and treatment. An implementation-effectiveness hybrid type 1 study as described here is best fit for examining HS in routine primary care because there is strong face validity for clinical intervention, minimal risk, and supporting evidence but not yet consensus for national HS recommendations . Our evaPrimary care practices for this study’s primary care cohort are from the 25 Family Medicine and Internal Medicine practices in the Duke Primary Care Research Consortium (PCRC). An initial query of data in our electronic data warehouse (DEDUCE) provide estimates per clinic for the number of unique patients age 65–75 seen between 8/1/15–7/30/16. Our site recruitment plan includes invitations to 8 of the 11 clinics with the highest numbers of potentially eligible patients ; of these, 6 clinics will participate in the study with 2 clinics per intervention group. Each group is balanced based on three factors: primary care specialty , practice size (number of providers and eligible patients), and ability/willingness to implement the intervention.Our study additionally includes otolaryngology head and neck surgery (OHNS) clinics in order to address our aim on accuracy of assessment of medical conditions and those which require evaluation. In addition to the local OHNS clinic that supports the patients seen in the PCP cohort, we will select at least ten OHNS clinics from Creating Healthcare Excellence through Education and Research (CHEER) Practice-based Research Network for participation in our study, with Duke serving as the Central IRB. CHEER is a multi-site national research network of physicians and allied health professionals specializing in disorders of the ear, nose and throat funded initially (in the 10 year start-up phase) by the NIH/NIDCD. OHNS clinics in the CHEER network are fully trained in regulatory and data quality standards, have together developed standard operating procedures, and have a multi-level governance structure that supports rapid study start up and patient recruitment .The total sample size for the PCP cohort is 660 study patients . The proposed sample to assess red flags in the OHNS multi-site CHEER research network is 500 patients. A CONSORT diagram of patient flow in the study is depicted in Fig. 65–75 years of ageBeing seen for non-acute follow-up or annual appointment for primary careInclusion criteria are:Current or prior history of hearing aid usePrior evaluation by an audiologist in the past 5 years and/or self-reports a hearing loss diagnosisBeing seen for an acute illness or hospitalizationExclusion criteria for this study are as follows:N = 600 for those patients eligible for analysis). The rationale for this is as follows: If 80% of patients in Group 3 undergo HS, we expect 25% may fail (N = 40); for Group 2 if 50% take the test, 25% or N = 25 will fail; for Group 1, we have hypothesized that a higher percentage of test takers may suspect hearing loss, and for this reason the failure rate may be higher than 25%. We estimate that 25% will take the HS test, and as many as half may fail, or N = 25. Thus, 40 + 25 + 25 = 90, and considered up to 100 might follow up for audiological diagnostic testing from the PCP cohort. If rates of test completion in the three groups are as expected , then, using standard methods for the calculation of power [n = 600, 200 per group. Indeed, if the rate is 80% as expected for Group 3, power will equal 80% to detect differences in rates of test completion, if the rate in Groups 1 and 2 is as low as 30%.Estimates of sample size for HS and audiology/OHNS follow up were determined as follows. Patients in Group 3 (in-office testing) may refuse to participate in the screening. Thus, although participation in that group is expected to be high, it will likely not equal 100%. Rates of Tele-HS completion are estimated at: 25% for Group 1, 50% for Group 2 and 80% for Group 3. We estimate that no more than a total of 100 patients will fail HS and be referred on for further testing  yielded 3424 unique patients in 1 year, confirming that the proposed sample size of 500 recruited over 3 years is feasible.Duke University serves as the study coordinating center for all research activities and is responsible for communicating across all sites and patients. Study approval from the Duke University Institutional Review Board (IRB) includes a waiver of consent due to participation having minimal risk and that it would not adversely affect individual welfare or patient rights. Study information provided to participating patients includes all elements of informed consent; however, written or verbal consent are not obtained or required. Personal identifiers are not stored with study data to protect confidentiality of patient during and after the trial. The pragmatic study design is dependent on preserving clinical flow. Obtaining written consent is not practical due to the large sample size per primary care practice.N = 220 patients per group). Prospective enrollment is scheduled at each site based on the number of patients age 65–75 years, and participating provider schedules on a given day, until a total of 110 patients are enrolled. A member of the clinical care team first introduces the study to prospective patients. Either a member of the clinical care team or the study coordinator then gives the study informational consent page along with the self-screening study eligibility form to the patient. Patients have the option to participate; completing the study eligibility form implies patient consent. Patients who meet eligibility based on responses in the form are considered enrolled and receive a study packet appropriate for the intervention group to which that practice site is assigned.A total of 955 subjects will be screened for eligibility to enroll 660 patients for the PCP aim. These 660 patients will be across six sites, 110 per practice in each of the six participating practice sites, two practices per intervention arm  of all screened patients are recorded. No compensation is provided for study participation as all activities are considered standard of care. The hearing screening is provided free of charge, whether performed in the office or at home. All data collected clinically are managed electronically centrally at Duke University. Patients with a HS failure are referred for audiological assessment as described below.Eligible and enrolled patients in all groups receive printed information about hearing loss, a questionnaire packet, and tele-HS specifics for their intervention group. The three tele-HS intervention groups are depicted in Table Although several HS methods are available and in use , optionsGroup 3 in-office use of the tele-HS is completed on a ‘land line’ telephone. Patient information packets for Groups 1 and 2 instruct patients to complete the HS at home from a land line (versus mobile device or cell phone) in their own home or that of a family member or friend. Patients who conduct the tele-HS receive results at the end of the call , either in the office (Group 3) or home (Groups 1 and 2).Failure rate of those completing the tele-HS test are tracked but this is not considered an outcome of the study. A study coordinator contacts patients who fail the tele-HS either in the PCP office or by phone and asks patients to follow up with an appointment for diagnostic audiological testing and medical evaluation with a specialty provider at the Duke Head and Neck Surgery and Communication Disorders Clinic. The follow-up visit is described as part of routine care for hearing loss and it is recommend to be completed within 4 months following the tele-HS failure. The number of patients who schedule and who attend the follow-up visit are documented.PCPs complete a questionnaire during their evaluation of the patient to assess for ‘red flag’ conditions during the index office visit. While in the audiologist’s office, and prior to audiological testing, patients who failed the tele-HS complete a short questionnaire to indicate their awareness of whether they have any of the ‘red flag’ conditions. The patient self-assessment of medical contraindications is especially important with the 2016 change by the FDA no longer requiring medical evaluation for red flag conditions. Hearing aid dispensers rely on prospective users to review information to make an informed decision on the purchase of a hearing aid but patient/purchaser awareness of risk is unclear.Audiological diagnostic assessment for patients who failed the tele-HS is performed in a sound-treated booth utilizing earphones. It includes pure tone audiometry for air and bone conduction (audiogram), speech testing, and tympanometry, per standard of care for hearing diagnostic testing. Audiologists document their findings, including whether or not a red flag condition or other significant non-red flag condition is present and should be considered a medical contraindication to hearing aid fitting.Of the eight red flag conditions, cerumen impaction is expected to be present in up to 30% of older adults with hearing loss . In ordeEvaluation of red flag conditions on hearing and implications for hearing aid fitting are being studied with participation of patients in the PCP study and also with patients recruited from OHNS clinics in the CHEER network across the US. This approach of expanding enrollment from the CHEER network clinics is essential for increasing the likelihood of occurrence of medical conditions that might contraindicate hearing aid fitting. Procedures similar to the main study will be followed with at least 10 participating sites in the CHEER. The proposed sample is 500 adults  ages 65–75 years who present for evaluation of hearing loss, either as a new patient or at follow-up, and do not currently or in the past use a hearing aid. A CHEER site study coordinator approaches patients who meet enrollment criteria upon clinic check-in, informs them about the study, the purpose and any time requirements, and obtains informational consent. Tele-HS will not be conducted. CHEER site studies then followed steps 2–7 as depicted in Fig. In order to approximate ‘real world’ audiology expertise in community-based and academic Otolaryngology Head and Neck Surgery clinics, we do not offer training or skills verification for the red flag study. We acknowledge that this subset of audiologists is not representative of all dispensing audiologists or hearing aid dispensers, and that findings are not imminently generalizable. However, this study and its design sought to provide important preliminary data for future research with a wider population of providers.Printed materials on study procedures are provided as guidance and to ensure documentation standardization across sites . Per patient site payments are offered to offset the costs of repeat audiograms in the case of cerumen impaction. Repeat audiograms are not standard of care and sites would otherwise have sent patients to otolaryngology providers without performing audiometry, have cerumen removed, and then return for testing. No compensation is provided to patients as the burden of participation is low.The PCRC Research Advisory Board will review our proposal and advise on the study procedures, budget, and approach to recruitment. Practice managers and PCPs work closely with the study team to design the tools and standard operating procedures compatible with the workflow in the clinic and to optimize provider involvement and patient recruitment and participation. Protocol training is provided at each site with additional 1:1 training for clinic staff prior to patient recruitment. No specific training in performing an ear exam is provided unless requested. Evaluation is to reflect the exam of a general practitioner. Each intervention arm is piloted with 15 patients in three of the six participating primary care practices . Using operations management expertise, we gather data and feedback on implementation of encouragement protocols, medical evaluation of the ears, the administration of the HS, data collection in the office setting, and office flow to inform refinement of the protocol to assist in implementation.percent of patients who schedule follow-up diagnostic testing,percent of patients with an identify hearing loss with the tele-HS who attend the specialty visit for follow-up diagnostic audiologic testing,percent of patients with an identified hearing loss with the tele-HS who completed a plan for appropriate hearing loss intervention if indicated, andaccuracy of assessment for red flag conditions comparing PCP and audiologist evaluations versus an otolaryngology provider evaluation (gold standard).The primary outcome measure is the percent of patients who complete the tele-HS within 2 months of their PCP visit. Although in-office tele-HS may have a higher compliance rate than at-home tele-HS, the failure rate may be greater among those who proceed with in-home HS as their compliance to complete the HS at home could be motivated by suspected hearing loss. Our secondary effectiveness outcomes measured within 4 months of the failed tele-HS include the:We will also explore the association of cerumen impaction with pure-tone thresholds.Data are sought to describe the attitudes of patients and the perceived attitudes of communication partners regarding hearing loss. PCPs record patients’ subjective assessment of the presence or absence of significant hearing impairment. All patients in primary care are asked to complete two questionnaires either during the index office visit or at home, returning them with a pre-addressed and stamped envelope. The Attitudes towards Loss of Hearing Questionnaire for Non-Hearing Aid Users (ALHQ) is a 22-item instrument that measures attitudes on five subdomains: denial of hearing loss, negative associations, negative coping strategies, manual dexterity and vision, and hearing-related esteem –37. EachSixteen focus groups are planned to collect data that will to provide context to the questionnaire results from the main study. These groups will include 128–160 patients, communication partners, clinic staff and healthcare clinicians across study groups and clinical sites. Discussions aim to understand attitudes and perceptions that may support or impede pursuit of hearing health care.PCPs are asked to assess cognitive function and comment on functionality using a 3-point scale . We will examine if successful completion of the tele-HS is possible for those with mild or moderately-severe cognitive impairment.Direct costs for each primary care intervention group and the individual strategies are calculated with costs of the educational material, tele-HS, and estimated cost of PCP time to educate and encourage the patient using a guided script (designed to be less than 3 min). Indirect costs for in-clinic HS include cost of the space used and staff time to direct patients to the room for the tele-HS.N = 220 patients in each group). Due to the anticipated high rate of screen failures and withdrawals, we plan to approach up to 2000 patients (completed self-screening study eligibility forms) to meet the goal of 660 study packets distributed to eligible patients.The primary analysis is based on the anticipated 660 patients who are deemed eligible and receive a study packet in the main study (R33 phase). In each of six practices, it is expected that 110 patients will receive a study packet, with two practices per intervention arm  schedule, b) complete the visit for diagnostic audiologic testing, and subsequently, c) complete a plan for appropriate hearing loss intervention, if indicated, within 4 months of initial hearing screening.The difference in the Group proportions in test completion will be examined for the primary outcome by a test of proportions. If there is an overall difference in rates of test completion, follow-up pairwise contrasts will be conducted to assess which groups differ significantly, comparing Group 3 vs. Groups 1 and 2, and, secondly, Groups 1 vs 2. Although every effort will be made to balance practice populations, we realize that practices may differ in the attributes of recruited patients. To control for baseline group differences, in follow-up sensitivity tests, we will assess if the differences in site, demographic, and comorbid conditions impact the observed group differences by multinomial logistic regression.This study is designed to answer real-world questions in hearing health care: what primary care model is best for motivating adults ages 65–75 years to complete a tele-HS and follow-up for medical evaluation and care if warranted, and how accurate are assessments of red flag conditions from patient, PCP and audiologists? We further assess barriers to implementation including attitudes, perceptions, cognitive impairment and costs in order to guide future implementation research that could test discrete implementation strategies . We desiNASEM convened an expert committee to study and provide recommendations in 2016 for improving the affordability and accessibility of hearing health care for adults in the US. Institutional, technological and regulatory changes are recommended [This study will establish evidence for conditions that should be contraindicated for hearing aid fitting and the impact of the most common red flag condition, cerumen, on hearing thresholds. Although the FDA has eliminated the requirement for medical evaluation of red flag conditions as it was in place without evidence to support it, we are still without research on these conditions as contraindications. The ‘red flag’ requirement for education of potential hearing aid users remains in place to ensure users are aware that there may be a medically treatable cause of their hearing loss. Our findings will help inform both practice and policies for audiologists, hearing aid dispensers and labeling of amplification devices.As part of our implementation-effectiveness design, we chose not to randomize the patients or the sites for pragmatic reasons. Patient randomization to the intervention would mean that all clinics would have to be able to employ each screening strategy. In a real-world scenario, clinics will likely implement only one screening strategy. Clinic randomization is also not performed due to budget limitations for involving a high number of clinics and an unknown intra-class correlation for an adequately-powered cluster randomized trial, which would require at least 10 clinics per intervention arm. Site-level implementation allows us to train providers and measure costs of implementing a new approach as part of standard of care for this patient population. A site-level design increases pragmatism, feasibility of PCP engagement, and simplifies the patient recruitment process in comparison with a patient-level or patient-randomized design. We aim to achieve balance in site-level characteristics  and the number of patients is held constant across sites and interventions arms. However, we will plan to evaluate for imbalance in patient characteristics  of study participants and non-participants between groups, and demographics of the study sample  to the overall practice demographics for this age group.In conclusion, our study addresses critical gaps in hearing health care. If successful, we will identify a primary care-based approach that increases uptake of tele-HS and medical follow-up. The design of our study will accelerate translation into practice and establish the foundation for widespread large implementation and future research to reach medically underserved populations. Hearing is vital to daily function and participation at home, in the workplace and in the community; it is a public health imperative that research continues to advance access and accessibility to hearing health care services and technologies.


Platinum compounds are a group of chemotherapeutic agents included in many pediatric and adult oncologic treatment protocols. The main platinum compounds are cisplatin, carboplatin, and oxaliplatin. Their use in clinical practice has greatly improved long-term survival of pediatric patients, but they also cause some toxic effects: ototoxicity, myelosuppression, nephrotoxicity, and neurotoxicity. Hearing damage is one of the main toxic effects of platinum compounds, and it derives from the degeneration of hair cells of the ear, which, not having self-renewal capacity, cannot reconstitute themselves. Hearing loss from platinum exposure is typically bilateral, sensorineural, and permanent, and it is caused by the same mechanisms with which platinum acts on neoplastic cells. According to available data from the literature, the optimal timing for the audiological test during and after treatment with platinum compounds is not well defined. Moreover, no substances capable of preventing the onset of hearing loss have been identified. Platinum compounds are a group of chemotherapeutic agents included in many pediatric and adult oncologic treatment protocols. Their use in clinical practice has greatly improved long-term survival of pediatric patients .The main platinum compounds are cisplatin, carboplatin, and oxaliplatin. They exert their action by covalent binding to purine DNA bases, resulting in interference with normal DNA function ,3.Cisplatin was the first compound discovered in 1965 by Rosenberg and colleagues during an experiment on electric fields and cell division of bacteria, and was introduced in clinical practice in the first years of the 1970s . Its cytAfter intravenous infusion, 90% of cisplatin binds to plasma proteins and has a high capacity to penetrate into the liver, kidneys, testicles, colon, and small intestine, but does not normally pass into the central nervous system (CNS) .About 90% of the drug is eliminated from the body through the kidneys, thanks to the glomerular filtration and tubular secretion processes, whereas 10% is eliminated by biliary excretion. Generally, 25% of cisplatin is eliminated from the body within 24 h after administration , howeverChemotherapy with cisplatin is used in the treatment of several pediatric cancers, such as germ cell tumors, hepatoblastoma, medulloblastoma, medulloblastoma/primitive neuroectodermal tumor (PNET), neuroblastoma, high-risk osteosarcoma, and refractory lymphomas ,8.The main adverse effects associated with cisplatin are nephrotoxicity, neurotoxicity, and ototoxicity; to try to avoid them, the dose of subsequent administrations of the drug must be reduced ,11,12,13Carboplatin is an analogue of cisplatin that was developed to reduce the dose-limiting toxicity of cisplatin. Carboplatin is less toxic than cisplatin because it reacts less with DNA due to its greater chemical stability .2 of cisplatin, a dose of 400–500 mg/m2 of carboplatin is required, approximately four times higher.Previous studies have proven that carboplatin is 8–45 times less potent than cisplatin and, to obtain a comparable antitumor effect, higher doses of carboplatin are necessary ,15. LokiCarboplatin is commonly used in the treatment of pediatric tumors such as hepatoblastoma, brain tumors, germ-cell tumors, neuroblastoma, Ewing sarcoma, osteosarcoma, and relapsed or refractory Wilms tumor .Veal et al. (2007) reported that about a third of all children with solid tumors receive chemotherapy with carboplatin . Unlike Oxaliplatin (trans-L-diaminocyclohexane (DACH) platinum oxalate II) is a third-generation platinum compound ,20. OxalIn addition, oxaliplatin shows no cross resistance with cisplatin or carboplatin, and this is due to two types of mechanisms. The first one is related to the drug structure; the DACH ring is large enough to prevent the mismatch–repair enzyme complex from binding to the oxaliplatin adducts . The secOxaliplatin has pharmacokinetic characteristics similar to cisplatin and carboplatin. After intravenous administration, initially about 70% of the drug binds to plasma proteins, especially albumin, and subsequently up to 95% of the drug is bound to proteins. When bounded to plasma proteins, the drug loses some of its anti-tumor activity. Furthermore, oxaliplatin is able to penetrate erythrocytes and remains there longer than in plasma. On this basis, O’Dwyer et al. (2000) reported that red blood cells can probably represent a drug reservoir .The main route of oxaliplatin elimination is represented by the glomerular filtration of the kidney, and only 2% of it is eliminated in the feces. There is no correlation between renal function and platinum exposure (AUC). Unlike the other platinum compounds, oxaliplatin is better tolerated by the human body, and it causes hearing damage in less than 1% of the patients and renal toxicity in less than 3%. Moreover, although oxaliplatin can determine neurotoxicity affecting the peripheral sensory nerves, this is rapidly reversible because the drug does not accumulate even after multiple cycles of treatment .As reported in several studies ,25, oxalCisplatin, carboplatin, and oxaliplatin are all compounds obtained from platinum and have some similar pharmacodynamic characteristics; nevertheless, they each present specific antineoplastic activity and are therefore used in different treatment protocols for tumors both of pediatric and adult population.Hearing damage is one of the main toxic effects of platinum compounds. It derives from the degeneration of hair cells of the ear, which, not having self-renewal capacity, cannot reconstitute themselves . HearingSometimes, hearing loss can be perpetuated even after the suspension of therapy with platinum compounds, manifesting itself after many years ,28,29.Platinum ototoxicity is due to the degeneration of mechanosensory hair cells in the organ of Corti, the spiral ganglion, and the lateral wall cells  . About 3The mechanisms at the basis of the described damage are presumably the same with which platinum acts on neoplastic cells. The platinum compound interacts with cell DNA, inducing monoadducts at nucleophilic sites, which can subsequently lead to intrastrand and interstrand crosslinks in the DNA . The resThese events can be realized only if platinum compounds cross the blood labyrinth barrier (BLB), where inner ear sensory cells reside. The passage of platinum compounds through the BLB can occur in the event that cell integrity is altered or if the paracellular permeability between adjacent endothelial cells increases. Another mechanism is provided by transport systems that include megalin (LRP2), the organic cation transporter 2 (OCT2) (SLC22A2), or the high affinity copper uptake protein 1 (Ctr1) SLC31A1) [A1 31,3939,40.Moreover, indirect mechanism of damage by platinum compounds on hair cell function can be caused by magnesium deficiency. Magnesium is necessary to maintain hair cell permeability  and cochThe described damage mechanisms cause hearing loss from platinum compounds, but not all children undergoing chemotherapy with these drugs show the same extent of hearing impairment. This could be explained by the existence of a genetic predisposition to platinum-induced hearing loss. In recent years, many study groups have focused their attention on the search for genes involved in platinum ototoxicity, identifying the genes involved in transport and metabolism of platinum compounds and in DNA repair as possibly responsible . Among sGenes associated with hereditary deafness have also been studied as possible culprits genes, but their polymorphisms do not seem to be involved in hearing loss from platinum compounds ,53.A recent study of Clemens et al. (2020)  evidence2 is considered the threshold for significant ototoxicity [2 [2 [Hearing loss from platinum compounds is also different according to the total dose and the type of compound used. Cisplatin is the most ototoxic platinum compound, whereas oxaliplatin is the least ototoxic. In the pediatric age group, a cumulative cisplatin exposure exceeding 400 mg/mtoxicity ,45, whericity [2 . In facticity [2 . For carIn addition to the total dose administered, the mode of administration may also facilitate platinum acoustic damage. Bolus infusions are more ototoxic compared to short or continuous infusions . Up to nOther risk factors involved in hearing loss caused by platinum compounds are represented by tumor site, concomitant CNS irradiation, and the association with other ototoxic medications.Central nervous system tumor site is associated with the highest rate of hearing loss. This high incidence is conditioned by several factors, among which is the higher dose of platinum compounds used in this type of tumor and the direct damage the tumor can cause in this area , particuAs previously mentioned, platinum compounds are eliminated by the renal system, and impaired renal function may delay excretion of platinum agents facilitating hearing impairment . MedicatPresence of co-existing ear pathology such as chronic otitis, middle ear effusion, or cerumen impaction can further worsen auditory impairment .A complete evaluation of the auditory function is necessary before starting treatment with platinum compounds, as it allows for the obtaining of a basal assessment that can be compared to subsequent evaluations, during treatment and after the end of it. The baseline assessment can be undertaken with different audiological tests in relation to patient’s age.Audiometry is the easiest test to use and allows for the detection of the minimum audibility threshold of the patient. A complete audiometric exam includes pure tone audiometry and speech audiometry .Pure tone audiometry allows for the identification of the auditory threshold, the minimum intensity of a sound that the subject is able to sense. It consists of administering to the patient, in an environment free of noise pollution, tones with an increasing frequency and then asking the subject to signal the presence of a sound through a behavioral response. This type of test requires collaboration from the patient, and therefore is strongly influenced by his or her age, and thus can only be used in children over 7–8 years of age. In younger children, it is necessary to use alternative methods . ChildreSpeech audiometry, on the other hand, allows clinicians to evaluate the patient’s ability to understand spoken language, and consists of asking the patient to repeat specific words. In younger children, speech audiometry can be carried out by asking them to indicate an object or a drawing that corresponds to the communicated word. This type of test does not allow for the evaluation of hearing damage in the initial phases, which typically involves high frequencies, but allows us to estimate its impact on the child’s daily life .Pure tone audiometry typically includes the frequency range of 0.25 to 8 kHz. A further form of audiometry, which can be useful in the early diagnosis of hearing damage from platinum compounds, is represented by high frequency audiometry. It is an audiometry that evaluates the hearing threshold for sounds with a frequency higher than 8 kHz and up to a maximum of 20 kHz . BecauseAs already mentioned, the acoustic damage from platinum compounds is sensorineural and not conductive. Therefore, before performing the audiometry test it is useful to exclude the presence of pathologies affecting the structures of the external ear through the execution of a tympanogram. This will make it possible to eliminate any confounding factors in estimating the auditory function.In children younger than 7–8 months, audiometry is not applicable. At this age, the otoacoustic emissions (OAEs) measurement could be useful to evaluate normal ear function. OAEs measurement specifically evaluates cochlear outer hair cell function. Differently from pure tone audiometry, OAEs cannot estimate severity of hearing loss. When OAEs are altered, it is possible to use a second line test, which is the auditory brainstem response (ABR). This test allows for the estimation of the normal function of all auditory structures by measuring the transmission of the nerve impulse generated by the administration of sounds, and is applicable when behavioral testing is not possible due to young age, uncooperation, or medical conditions . Table 1After having obtained a basal assessment of auditory function, it is necessary to repeat it during treatment. The frequency of the tests is strongly connected to the cumulative doses of platinum administered and to the presence of other risk factors. At present, there is not much scientific evidence regarding the best time to repeat audiological tests during treatment. According to Durrant et al. (2009), follow-up evaluations should be performed 24 h prior to each course of platinum-based chemotherapy ,67.In our clinical practice, we perform an audiometry test before each course of chemotherapy containing platinum compounds and whenever there is a clinical sign of hearing impairment, even though it is not always possible due to patients’ clinical conditions. This strategy allows us to identify the onset of hearing damage earlier on, thus giving us the ability to carry out measures to reduce its extent.Different evaluation scales of hearing damage caused by chemotherapy have been standardized. Among these are the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), the American Speech-Language Hearing Association (ASHA) ototoxicity criteria, the Brock criteria, Chang and Chinosornvatana’s grading system, and the New International Society of Pediatric Oncology (SIOP) Boston Ototoxicity Grading Scale.The Brock criteria was the first and most widely used pediatric-specific ototoxicity scale. This scale is based on absolute hearing thresholds unrelated to the baseline test. It has four grades (1–4) to categorize the severity of platinum induced hearing loss .Chang and Chinosornvatana’s grading system is a modified Brock scale to include both 20 and 40 dB HL cut-offs; it is complicated to apply and requires additional threshold data that may be difficult to obtain in an ill or uncooperative patient .The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) has been typically used in cancer treatment studies; this rating scale, in its latest version of 2017, specifically considers pediatric patients and distinguishes five degrees of severity of hearing damage with a cut-off of 20 dB HL.The American Speech-Language Hearing Association (ASHA) ototoxicity criteria can be used for extended high frequencies (>8000 Hz) and allows for the monitoring of the auditory threshold during treatment. In addition, these criteria require a complete baseline assessment, which is difficult to obtain in children; moreover, the major limitation of the ASHA criteria is the lack of a grading scale to evaluate the severity of hearing loss .The New International Society of Pediatric Oncology (SIOP) Boston Ototoxicity Grading Scale takes into consideration the possibility that the child may present with middle ear disease (rather common in children), and requires bone conduction thresholds in case a problem with sound conduction through the middle ear is suspected, or in the presence of abnormal tympanometry. The scale is based on absolute thresholds and uses 20 and 40 dB HL cut-off, with greater importance given to hearing loss in the medium frequencies compared to the high frequencies .This scale of evaluation for hearing loss is useful in clinical practice in identifying the severity of the damage in order to undertake possible protection strategies. Knight et al. (2017) compared different ototoxicity classification systems and evidenced that the SIOP scale may be superior to ASHA, Brock, and CTCAE scales for classifying ototoxicity in pediatric patients who were treated with cisplatin .At the end of treatment with platinum compounds, every patient has to be tested for hearing loss.As previously mentioned, ototoxicity is proportionately higher in survivors treated with high cumulative cisplatin doses than with low doses and in survivors treated with platinum-based drugs who were younger at the time of diagnosis ,67,68,70Recently, Clemens et al. (2019) systematically reviewed the scientific literature available to date, and drafted a document that outlines the necessary steps in the follow-up of patients undergoing chemotherapy protocols that include platinum compounds .In this work, they stated that according to the published available data, it is not possible to define a surveillance time interval during which patients have to be tested. In particular, it is unclear how long-term survivors who have no hearing loss at the end of treatment should undergo hearing assessment tests .According to data available in the literature, surveillance in survivors should begin at the end of treatment and should be performed annually for children under the age of 6 years, every 2 years for children aged between 6 and 12 years, and every 5 years for teenagers and young adults over the age of 12. This long surveillance is important due to the possible appearance of hearing damage, even long after the end of treatment .Surveillance must be carried out with closer controls until completion of language development, and for this reason the indications of Clemens et al. (2019) provide for an annual check up to 6 years of age .Usually, survivors are tested at frequencies of 8000 Hz or less and, if no losses of more than 15 dB are measured, hearing function is considered to be unaffected and surveillance is discontinued.For routine surveillance of cancer survivors aged 6 years or older, pure-tone audiometry at 1000–8000 Hz is the gold standard. If equipment is available, additional testing with high-frequency audiometry at more than 8000 Hz is also recommended for its usefulness in the pediatric age .The use of high-frequency audiometry increases the number of diagnoses of asymptomatic hearing loss in children treated with cisplatin-based chemotherapy .In our experience, monitoring of the auditory function during platinum-derived treatment significantly improved our ability to detect patients with early hearing impairment. With reference to a previous work , our proEducation, amplification or hearing-assistive technology, cochlear implantation, hearing aids, tactile aid, frequency-modulated system, communication approaches, or intervention programs (such as early and consistent speech therapy) are all strongly recommended by Clemens et al. (2019) to minimize the social and intellectual impact of hearing loss in children ,79,80,81N-acetylcysteine, sodium thiosulfate, or other antioxidants has been evaluated in adult clinical trials without conclusive results, as reported in the U.S. clinical trials website . Therefore, in the past, some treatment protocols have considered the possibility, in the event of hearing loss, of reducing the dose of cisplatin or replacing it with a less ototoxic compound such as carboplatin [The prevention of hearing damage is certainly a challenge for all those who deal with childhood cancer. The integrity of the auditory function is a fundamental prerequisite for the development of language and in general for the psychological and social maturation of the individual. Thus, the development of effective strategies is a major goal to protect or rescue auditory function from platinum-induced ototoxicity without affecting or decreasing the antitumor activity of these compounds. Several preclinical studies using both the transtympanic route and systemic administration indicate that antioxidant molecules, such as tiopronin, Vitamin E, curcumin and others, can rescue reactive oxygen species and improve hearing ,82,83,84Amifostine  has beenAnother substance that acts in a similar way to amifostine, by binding derivatives of platinum compounds and acting as a ROS scavenger, is sodium thiosulfate . This haD-Methionine acts with a mechanism similar to the previously mentioned substances and has been studied as an otoprotective agent not only against platinum derivatives but also against other drugs with ototoxic action, showing good efficacy in preclinical animal studies, although human efficacy data are not yet available .N-acetylcysteine, which can be administered trans-tympanic and has shown good ear protection capacity [The systemic administration of these compounds, however, could cause a reduced therapeutic response to chemotherapy. Consequently, in recent years, some studies have placed their attention on substances that can be administered locally into the ear. Among these compounds there is capacity . The admcapacity .Considering that the main limitations for cisplatin treatment are chemoresistance and side effects, recently two different polyphenols, curcumin and ferulic acid, have been studied as adjuvant chemotherapeutics. Thanks to their biphasic antioxidant activity in normal cells undergoing stressful conditions, such as the hair cells, as well as pro-oxidant activity in cancer cells, these molecules are promising tools in counteracting chemoresistence and ototoxicity . Taken tIn 2017, Crabb et al. analyzed the possible use of aspirin as an otoprotective drug against cisplatin; their hypothesis was based on the fact that aspirin protected from hearing damage caused by aminoglycosides . HoweverAlthough many studies are focusing on the research of substances with otoprotective function, at present, none of them have shown real efficacy and safety against hearing loss caused by platinum compounds .Platinum compounds represent a cornerstone in the treatment of many different childhood cancer types, and their use has dramatically improved survival. However, they can determine toxic effects including hearing damage, which is an important problem for patients in the pediatric age group. The knowledge available to date has highlighted the need to carry out a careful audiological follow-up in survivors of childhood cancer that have undergone treatment with platinum compounds. The search for agents that can reduce hearing damage derived from platinum compounds represents a challenge that is still open, and its victory would allow the achievement of significant improvements in the quality of life in this group of patients.


Octodon degus in which Aβ peptides accumulated in the brain and retina as a function of age. This current study investigated microglial morphology, expression of PSD95, synaptophysin, Iba-1 and choline acetyltransferase (ChAT) in the retina of juvenile, young and adult degus using immunolabeling methods. Neurotransmitters glutamate and gamma-aminobutyric acid (GABA) were detected using immunogold labeling and glutamate receptor subunits were quantified using Western blotting. There was an age-related increase in presynaptic and a decrease in post-synaptic retinal proteins in the retinal plexiform layers. Immunolabeling showed changes in microglial morphology characteristic of intermediate stages of activation around the optic nerve head (ONH) and decreasing activation toward the peripheral retina. Neurotransmitter expression pattern changed at juvenile ages but was similar in adults. Collectively, the results suggest that microglial activation, synaptic remodeling and neurotransmitter changes may be consequent to, or parallel to Aβ peptide and phosphorylated tau accumulation in the retina.Accumulation of amyloid-beta (Aβ) peptides is regarded as the hallmark of neurodegenerative alterations in the brain of Alzheimer’s disease (AD) patients. In the eye, accumulation of Aβ peptides has also been suggested to be a trigger of retinal neurodegenerative mechanisms. Some pathological aspects associated with Aβ levels in the brain are synaptic dysfunction, neurochemical remodeling and glial activation, but these changes have not been established in the retina of animals with Aβ accumulation. We have employed the  Octodon degus (degus) have confirmed a role for Aβ peptides in diseases, including increased Aβ peptides and phosphorylated tau levels in the adult retina (Elevated levels of amyloid beta (Aβ) proteins and the associated cell damage have been described in the aging eye and opened up the possibility of Aβ being a key constituent of age-related ocular pathologies . Severalt retina  or altert retina . Other st retina , and modt retina . The degt retina . As an at retina . Other pt retina . Inbreedt retina . TherefoIn a previous publication , greaterA prominent feature of the aging process in the retina and brain is inflammation . In thisad libitum. Young and adult degus were housed in groups of 2–4 animals in metal cages with a chip wood-based bedding floor. Food consisted of commercial rabbit pellet, hay cubes or Prolab rat diet (RMH 3000 LABDIET). Water ad libitum was provided. No material for nest or social enrichment was provided to adults. Animal ages were: juvenile 4–10 months (n = 25), young 12–24 months (n = 8), adult 36–56 months (n = 5) and aged adult ≥ 60 months old (n = 15). Only animals that had behavioral testing to infer their neurological status were included in this manuscript. Animals with cataracts, usually developing in degus secondary to diabetes, were not included in this study. Representative images of the brain Aβ labeling in some animals is shown in Degus were born and raised in the animal facility at Universidad de Valparaiso, Chile. Animals were bred under a 12:12 light/dark cycle in a controlled temperature environment (23 ± 1°C) with water and food Octodon degus at various ages were euthanized by intraperitoneal pentobarbital overdose injection. All experiments were in accordance with the bioethics regulation of the Chilean Research Council (CONICYT) and in accordance with the Association for Research in Vision and Ophthalmology statement for the use of animals in ophthalmic and vision research. The University of Auckland Animal Ethics Committee (permit number: AEC 001138) also approved the collection of tissues for these experiments.The eyes were dissected from the orbit, and fixed in 4% paraformaldehyde (PFA), 0.01% glutaraldehyde in 0.1 M phosphate buffer saline (PBS) for 30 min followed by several 10 min PBS washes. After fixation the tissues were submerged in sucrose solutions for cryoprotection and then were embedded in optimum cryosectioning medium (OCT) and were sectioned at 12 μm and collected on Superfrost Plus glass slides. Sections were maintained frozen at −20°C until immunohistochemistry proceeded. All tissues were processed under the same conditions. Retinal sections were incubated in a blocking solution containing 6% donkey or goat serum, 1% bovine serum albumin (BSA), and 0.5% Triton X-100 for 1 h, and then incubated in primary antibody  diluted The procedure for post-embedding silver-intensified immunogold detection has been previously described . Briefly® conjugated secondary antibody  was used to detect the primary antibody. The detection was enhanced using silver intensification of the nanogold tag as previously described , with the excitation wavelengths set for Alexa 488, and Alexa 594 fluorochromes and for DAPI. A z-stack  was acquired using 0.9 μm step-size to go through a total thickness of ∼9 μm per tissue. Six retinal images acquired from different animals were analyzed for each group, and the representative images shown in the figures. Retinal sections with silver-intensified amino acid immunoreactivity were imaged under the same lighting and contrast parameters, using Brightfield microscope  with an attached Leica DFC495 camera and a LASV4.8 Leica Microsystems software used for taking the images.All fluorescence retinal images were acquired using an Olympus FluoViewSix images from each animal per age group were analyzed to obtain the percentage area labeled by the antibody, using Image J . Images were split into RGB channels and the single channel that corresponded to the secondary antibody fluorochrome was used in the quantification. Retinal cell counting was performed in 1 μm thickness confocal images. A fixed size area was selected on each image and the number of labeled cells in that area was counted. Number of Iba-1 positive microglial cells were counted in central retina. Values per retina were averaged and plotted as mean ± SEM (standard error of the mean).Immunogold labeling was quantified in grayscale images. Using the auto-threshold modality, minimum and maximum threshold values were selected. The labeled area was calculated by determining the mean pixel number in selected retinal areas.post hoc test was performed to determine significant differences in the expression of retinal markers between age groups. A p < 0.05 was considered to be statistically significant.Statistical analyses were performed using SPSS . One-way ANOVA and Bonferroni p = 0.996). However, there was a marked increase in SYN expression in adult degus . There was no statistically significant difference between adult and the aged adult group . However, SYN labeling pattern showed retraction of photoreceptor synaptic end , which remained high in adults (4.07 ± 0.8) but was significantly different from young animals (p < 0.05). Interestingly, a significant decrease in protein expression was found in aged adults (2.60 ± 0.22) compared with adult animals (p < 0.01). The decrease in PSD-95 protein expression was found even in aged adults that had a reduction in size of both the outer nuclear layer (ONL) and the OPL (The post-synaptic density protein 95 (PSD-95) was detected in the OPL and IPL . PSD-95  the OPL ’.To determine if the changes in synaptic layer protein expression were associated with neurotransmitter changes, Western blotting of synaptic proteins and glutamate receptor subunits was conducted . Shank wp < 0.05), suggesting an age-related effect on expression of the subunit.GluN1, a subunit present in NMDA receptors was also quantified as a function of degus’ age. GluN1 expression was not significantly different between juvenile and young animals but a significant decrease was detected between young and adults  type glutamate receptors was also found at all ages. There was a non-significant decrease in GluA2 expression when comparing juvenile with young retina. A significantly higher expression was seen in the adult degus group (1.31 ± 0.02) compared with the young group (0.61 ± 0.05), but the GluA2 value in the adult group was not significantly different from the juvenile group  followed by increase (p < 0.05) in the OPL of the old adult degus  in This investigation confirmed the presence of synaptic changes with aging in degus retina. We proposed that synaptic remodeling is the consequence of abnormal accumulation of Aβ peptides and hyperphosphorylated tau, found in degus at a young age (∼12 months old) . This isIn the AD-like brain, altered neuritic growth and synapse formation are associated with abnormal processing of amyloid precursor protein (APP) and Aβ aggregation. This results in degeneration of sprouting cholinergic neurites into dystrophic forms similar to what is observed in mature AD plaques. There was differential PSD-95 expression with age in the degu’s retina. PSD95 was the least abundant in the juvenile degus, and peaked in the young degus, followed by a decrease in protein expression from adult age. PSD is a complex network of neurotransmitter receptors, regulators of synaptic electrical activity, and links to cytoskeletal elements. PSD95 has been previously described to strongly label the rod spherules and cone pedicles in the OPL. It is also found at BC ribbon synapses in the IPL, and co-localizes with the NR1 subunit of the NMDA glutamate receptors . The lowSYN is a membrane protein of the synaptic vesicles, and has multiple functions in synaptic vesicle formation, exocytosis and delivery of neurotransmitters. It is also thought to be closely related to synaptogenesis and synaptic plasticity during neural tissue development . In the area centralis region ∼2.8 mm dorso-temporal to the ONH and measures about 1.0 mm2. In the area centralis the peak RGC density is 6,384 cells/mm2  of the degus, and these layers are the axonal, nuclear, and dendritic processes of the GCL respectively, it is possible that active microglia were the most numerous in the central retina due to relatively greater density of RGCs, and greater amount of Aβ and NFT accumulation. Very few completely amoeboid cells were observed, suggesting that the increased number of microglia around the ONH may be associated with local changes rather than an active state of inflammation. It was also interesting to note that the microglia in the IPL seemed intermediately activated over the microglia in the OPL, which stayed inactive (flat cell morphology with few cell processes). This may be because the inner retina was exposed to relatively more cellular stress, possibly due to the Aβ and NFT deposition.Microglial cells showed morphological intermediate forms of activation through the retina at an adult age (≥36–48 months), which coincided with the same age groups that have Aβ and Tau protein changes, and showed the greatest increase in previous investigations . One of ells/mm2 . The areAβ accumulation in the retina is a sign of amyloidosis associated neurodegeneration , and is Degus have been described as a novel AD-like animal model . HoweverBy employing degus at different ages we demonstrated that there is an age related increase in Aβ accumulation in the retina that is associated with synaptic changes and neurotransmitter imbalance. The aged adult degus showed variability in expression of AD markers, as expected in a non-transgenic natural animal model. This reiterates that degus are a close representation of the aging process and sporadic/late-onset AD, as these animals share 97.5% protein homology with human Aβ.All datasets generated for this study are included in the article/The animal study was reviewed and approved by bioethics regulation of the Chilean Research Council (CONICYT) and the University of Auckland Animal Ethics Committee (permit number: AEC 001138).LC, MA, and AP conceptualized the study. LC contributed to the acquisition, analysis and interpretation of data, contributed to the conception of the work, drafted the manuscript, and revised it critically for intellectual content. AP, MA, and NI assisted with funding acquisition. AA and CT-R contributed to the acquisition of data, analysis and interpretation of data, contributed to the conception of the work, and revised the manuscript critically for intellectual content. JA contributed to the processing of tissue samples and acquisition of data. All authors contributed to writing, reviewing and editing the final version. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The purpose of this study is the evaluation of post-operative hearing threshold after revision surgery and obliteration of troublesome canal wall down mastoidectomy cavities (CWDMCs). The ability to use and tolerate conventional hearing aids (CHAs) was also evaluated.A retrospective chart analysis of 249 patients with chronically draining CWDMCs who underwent revision surgery including obliteration of the mastoid cavity between 2007 and 2017 at the AMC location of the Amsterdam University Medical Centers (Amsterdam UMC) was performed. Patient characteristics, pre- and post-operative Merchant grade, surgical outcomes, pre- and post-operative hearing thresholds, and the ability/necessity to use a CHA or the ability/necessity to use a Bone Conduction Device (BCD) were recorded.p < 0.05). For all types of ossicular chain reconstruction, a significant improvement in mean Pure Tone Average was observed (p < 0.05). The percentage of patients with an indication for CHA was similar pre- and post-operatively (67% both pre- and post-operatively). The ability to use a CHA improved from 3% pre-operatively to 57% post-operatively (p < 0.001).Dry ears were found in 95% of the total cohort. Residual disease was detected in 1.6% during MRI follow-up with no residual cholesteatoma in the obliterated area. In 3.2% of the patients, recurrent disease was found. A significant improvement in mean air conduction level, mean bone conduction level, and mean air-bone gap (ABG) was found post-operatively (This study shows that revision surgery and obliteration of CWDMCs enable successful CHA rehabilitation post-operatively. Upon this type of surgery, hearing thresholds improve significantly, but the need for rehabilitation with a CHA remains necessary in most cases. It is well known that chronically draining and troublesome canal wall down mastoidectomy cavities (CWDMCs) have a profound negative effect on those inflicted –3. Due tA retrospective chart analysis was performed of all patients with troublesome CWDMCs who underwent revision mastoid cavity surgery with partial obliteration of the mastoid and reconstruction of the ear canal at the AMC location of the Department of Otolaryngology of the Amsterdam University Medical Centers, between 2007 and 2017. Operations were performed by six different surgeons. A more detailed description of this technique has been published previously . In brie® partial ossicular replacement prosthesis (PORP), (3) Fisch II Spandrel® total ossicular replacement prosthesis (TORP), and (4) cartilage interposition on intact stapes.Pre- and post-operative audiometric results were analysed for all patients. The thresholds of both bone and air conduction of both ipsi- and contralateral ear were reviewed. Pure Tone Averages (PTAs) at 0.5, 1, 2, and 4 kHz were used to determine the air conduction thresholds of the affected and non-affected ear. Bone conduction levels were determined using averages at 0.5, 1, and 2 kHz. In cases where one of the frequencies was not measured or no threshold was present, this was accounted for as missing data. In addition to audiometric results, data regarding type of ossicular chain reconstruction were acquired. We identified four categories: (1) no ossicular chain reconstruction, (2) Kurz ClipThe indication for a CHA was somewhat arbitrarily defined as a PTA of equal or more than 35 dB HL. This level was chosen as the Dutch reimbursement system for CHAs requires a PTA of at least 35 dB HL. Patients with hearing losses of more than 80 dB HL were assumed to be better off with a cochlear implant and, therefore, excluded from our study. A subgroup comprised of patients who had both pre- and post-operatively a CHA indication and from whom it was registered if they used a CHA pre- and post-operatively , was created. This subgroup enabled comparison of hearing rehabilitation and CHA tolerance pre- and post-operatively. Reasons for non-usage of CHAs as well as cases with bilateral hearing rehabilitation were identified. The use of BCDs was separately evaluated in the entire cohort.t test was used to determine differences between pre-operative and post-operative hearing thresholds . p values < 0.05 were considered to be statistically significant. A violin plot was used to illustrate the change of hearing threshold within the population of all participants. A Chi-squared test was performed to determine whether a significant difference could be observed in the use of CHA pre- and post-operatively.Statistical analyses were performed in SPSS 25.0 . Data are expressed as number (%) and mean (SD). The Student’s n = 4) of all cases, residual cholesteatoma was found, located in the tympanic space and detected during MRI follow-up. Of these cases, the mean time to detection was 43 months post-operatively (range 34–52 months). No residual disease was found in the obliterated area. Recurrence formation of cholesteatoma was found in eight patients (3.2%). Concerning the Merchant classification, changes are depicted in Table A total of 249 patients were included. The male to female distribution was 148 (59%) to 101 (41%), respectively, with a median age of 45 years (ranging from 6 to 86 years). Median time to follow-up was 52 months with a range between 1 and 139 months. One hundred and six patients (43%) had a follow-up time of more than 5 years. In 1.6%  towards better hearing  is observed. A total of 29 patients (12%) with an indication for a CHA did not need a CHA post-operatively because of improved hearing level (< 35 dB HL). Sixteen patients (7%) who had no indication for a CHA pre-operatively because of hearing > 80 dB HL were able to get a CHA post-operatively because of improved hearing (35–79 dB HL). A counselling model for expected post-operative CHA indication was proposed derived from the changes in PTA pre- versus post-operatively , hearing data were complete and could be used for analysis. Pre- and post-operative PTAs of both air and bone conduction are shown in Table 1 level < 5 dB HL. n = 20) of cases demonstrated a contralateral normal hearing ear (e.a. PTA < 35 dB HL). Only 7 (18%) cases did not wear a CHA due to occlusion problems post-operatively.We included 106 patients for analysis of hearing rehabilitation as they had both an indication for CHA before and after surgery and a complete data set. Clear differences were seen when comparing pre-operative and post-operative CHA usage Table . Nearly We plotted the final hearing rehabilitation solutions against bilateral hearing thresholds to evaluate a possible predictive value of the PTA of the contralateral ear. It appeared that the contralateral hearing threshold does influence the choice for wearing a hearing aid on the operated ear, the contralateral ear, or bilaterally. However, cluster analysis did not support our hypothesised predictive models.Of the 249 patients in this cohort, 22 patients wore BCD pre-operatively due to the troublesome cavity. Post-operatively, 9 (41%) patients still preferred a BCD over a CHA, whereas 13 patients (59%) preferred using a CHA.Instable CWDMCs have been reported in 10 up to 40% of all cases . We repoIt remains debatable whether hearing thresholds of canal wall down mastoidectomy are worse when compared to canal wall up cases . OssiculAlthough hearing thresholds improved for the group as a whole, we also demonstrate that the group eligible for hearing rehabilitation remains nearly unchanged. In addition, one should note that some individuals demonstrate a deterioration in hearing thresholds and, therefore, the need for hearing rehabilitation remains pivotal.Troublesome cavities are likely to result in a difficulty to wear CHAs. Other factors such as: a large post-operative meatus, altered resonance frequency of the ear canal, and inadequate aeration due to occlusion all complicate CHA usage in CWDMCs , 24. OneWe found a slight shift in BCD rehabilitation toward CHA. Our data suggest that one should consider to primarily perform revision surgery in troublesome cavities to enable CHA usage before advising BCD. We potentially introduce an inclusion bias as we performed our analysis regarding CHA usage and tolerance in a selected subgroup of the total cohort as this subgroup of patients had a complete data set. We still feel that this subgroup is representable of the whole group. In our center, a CHA is the favored device for hearing rehabilitation due to lower costs and no need for further intervention. However, some have advocated a BCD in large ABGs to perform better in case of speech recognition , 26. ComFor counselling of an individual patient, we now can present the chance of hearing threshold change in regard to CHA indication (within the Dutch reimbursement system) Fig. . One shoOur study supports and strengthens the hypothesis that revision surgery and obliteration of CWDMCs enables successful CHA rehabilitation post-operatively. Hearing threshold improves significantly after such surgery, but the need for hearing rehabilitation remains necessary in most cases. Performing ossiculoplasty in troublesome CWDMCs seems to be beneficial. We supply a counselling diagram of the expected need for CHA rehabilitation postoperatively.


To scope current service provision across England for management of otitis media with effusion and hearing loss in children with Down syndrome; to explore professional decision‐making about managing otitis media with effusion and hearing loss; and to explore patient and public views on the direction of future research.NHS clinical practice through a structured telephone survey; a qualitative study of professional decision‐making with in‐depth interviews collected and analysed using grounded theory methods; patient/public involvement consultations.Mixed methods including a service evaluation of Twenty‐one audiology services in England took part in the evaluation; 10 professionals participated in the qualitative study; 21 family members, 10 adults with Down syndrome and representatives from two charities contributed to the consultations.There was variation across services in the frequency of routine hearing surveillance, approaches to managing conductive hearing loss in infancy and provision of hearing aids and grommets. There was variation in how professionals describe their decision‐making, reflecting individual treatment preferences, differing approaches to professional remit and institutional factors. The consultations identified that research should focus on improving practical support for managing the condition and supporting decision‐making about interventions.There is system‐level variation in the provision of services and individual‐level variation in how professionals make clinical decisions. As a consequence, there is inequity of access to hearing health care for children with Down syndrome. Future research should focus on developing core outcomes for research and care, and on improving decision support for families. Alongside, we ran patient, parent and public involvement groups to explore future research topics.This was a mixed3.1A telephone survey was conducted with clinicians in England who had responsibility for hearing services for children with DS. Clinicians were recruited through professional contacts as well as through a short online questionnaire to members of the Down Syndrome Medical Interest Group and British Academy of Audiology asking about the range of interventions for OME and hearing loss offered to children with DS in their department  and willingness to take part in a 30‐minute telephone survey. Services were sampled to include those providing bone‐anchored auditory devices and air conduction hearing aids. The survey was structured to cover: protocols for hearing surveillance, criteria for intervention, types of interventions provided, outcome measures, the level of multidisciplinary involvement and parent involvement in decision‐making in their service.3.2We used grounded theory methodsThe researcher (AH), who is also an audiologist, conducted in‐depth interviews guided by a topic guide Table . They la3.3Over the course of the study, PPI groups were held. These involved parents and carers of children with DS, people with DS, a charitable organisation representing people with DS and a charitable organisation representing children with hearing loss. The aim of the groups was to identify research topics and priorities relating to OME and hearing loss that are important to them as service users, to present the topics arising from the research and to discuss future research priorities. The findings which arose are grouped according to common topics and a narrative summary presented.3.4The service evaluation was conducted with agreement from University Hospitals Bristol NHS Foundation Trust Research and Innovation department 2015). R&D approval and NHS Permission for Research were obtained for the qualitative study through the University Hospitals Bristol NHS Trust (16/6/2015) and informed, written consent was obtained from all research participants. In line with National Institute of Healthcare Research guidance,. R&D app4Data were obtained on the service provision for children with DS of 21 audiology services across the South West, London, East Midlands, Yorkshire and Humber, North East, South East and East of England.Ten professionals working with children with DS and hearing loss, covering a range of professional groups, took part in qualitative interviews. The participants worked in, or with, five different NHS services in England. Due to the small sample size, no further details are given to protect their anonymity.Three PPI groups were held and attended by a total of twelve mothers and one grandmother; additionally, eight parents provided feedback outside the groups. One group was held and attended by ten adults with DS. Consultation with representatives from two charities also took place.4.1There was variation in key aspects of service delivery for children with DS Table . All ser4.2There was variation in how professionals describe their decision‐making about OME and hearing loss in children with DS. These variations reflect individual preferences, differing approaches to professional remit and institutional factors. The key theme, labelled “focus,” refers to how the child's life is viewed by the professional and whether their focus is primarily on a child's ears and hearing or on their health, development, family and school life. This is influenced by how they viewed their professional remit, how the relative burdens and benefits of interventions and treatments were perceived and ultimately how decision‐making was described Figure . Key the4.2.1Views on professional remit varied from those who viewed ears and hearing loss alone as being within their remit, to those who viewed their remit as encompassing the interaction of hearing loss with a child's health and development. Although views on remit were related to the professional role of the participant with Audiologists and ENT surgeons more likely to have an ear and hearing focus, variation in viewpoint was also observed within participants of the same professional group.4.2.2There was variation in how the impact of OME and hearing loss on a child with DS was viewed. Some participants primarily focused on the ear and hearing impact of the condition, whereas others considered the impact on speech and communication and the wider impact on the child and family. Those who focused on ears and hearing described decision‐making as primarily focused on alleviating the OME or hearing loss, viewing hearing aids or surgery as the solution. This contrasted with those who took an approach to decision‐making focused on developing listening, communication and participation. Views on treatment and intervention success varied from a focus on curing OME or wearing hearing aids to those who viewed success as improving or maintaining quality of life or developmental outcomes, not always involving hearing aids or surgery and including sign language and other communication tactics.4.2.3There was evidence of preferences amongst many of the professional participants for particular treatments and interventions for children with DS, with some preferring grommets and others hearing aids. This was not related to professional group, and there was variation in preference within groups. Participants described observing colleagues having preferences. A smaller number of participants did not identify a preference and described how they present the pros and cons about different options to families.4.2.4Many of the participants described the difficulty of being able to differentiate between the impact of hearing loss and the inherent learning disabilities of children with DS, of knowing “what's the ears and what's not?” The approach to this issue varied according to the focus on the child with DS. For those whose focus extended beyond ears and hearing, determining the impact of the hearing loss on the child was fundamental to decision‐making. Decision‐making involved, for example, deciding whether a child's behavioural difficulties were the result of hearing loss or a characteristic of DS. Decision to refer for treatment or to treat was made when hearing loss was felt to be having a negative impact on the child. For those participants who primarily focused on ears and hearing, understanding the impact on the child with DS was less important. Decision‐making for these participants was made primarily on diagnostic ear and hearing information, with hearing aids and grommets more likely to be prescribed. Those who considered other aspects of the child, such as their sensory sensitivity or likely tolerance, were more nuanced in their discussion around decision‐making.4.2.5The context in which decisions were made was influenced by availability of professional expertise, access to treatments and interventions, the health service set‐up and the child's educational setting. Having highly skilled professionals within a service provided a context in which decisions could be made effectively, such as having access to surgical expertise in children with DS and therefore ability to refer for grommet intervention or audiologists with experience of working with a range of hearing aids.4.3Parents discussed their ideas for future research through relating their personal experiences, both positive and negative. Parents were asked to discuss their views on the importance of future research on improving decision support and improving service provision and management of OME and hearing loss. Adults with DS attended a group workshop on the topic of ears and hearing; they discussed their personal experiences and knowledge about hearing, hearing loss and audiology services. Charity representatives gave their perspectives  developing tools for SDM and supporting parents in managing the condition; (b) deciding on the core outcomes for future research; (c) deciding on the key patient, clinical and quality outcomes for clinical services and commissioners; and (d) developing evidence: what works for which children with DS, to inform future management guidelines.All authors have completed the conflict of interest disclosure form and declare AS was previously supported through an NIHR Research Professorship at UCL and is now supported in part by the NIHR University College London Hospitals Biomedical Research Centre; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; and no other relationships or activities that could appear to have influenced the submitted work.