These issues will be discussed in this perspective article and a proposed remedy in the form of an inner ear therapeutics “moon shot” will be offered.Despite over 20 years of effort in academic research centers, start-up companies, and established pharmaceutical companies, there are no FDA-approved inner ear therapeutics for treatment of sensorineural hearing loss. There are a number of systemic barriers to creation of this new field of inner ear therapeutics. These include insufficient understanding of the particularity of different causes of hearing loss at the cellular and molecular level, lack of diagnostics of adequate sensitivity and specificity to discern these differences  Hearing loss is one of the most common treatable health conditions in the world. It is a problem with profound economic and social impact. The World Health Organization completed and released results of an extensive study of the problem in 2021 .The causes of hearing loss, the societal impact, and the potential remedies vary between the developed and developing world. Simple, relatively “low tech” interventions to detect and treat childhood ear infections, to monitor and protect against high noise exposure, and to screen for significant hearing loss for early intervention with medications and hearing aids are predicted to be dramatically successful across the world’s developing countries. Recognizing that cochlear implants do not restore natural hearing, cutting edge academic research institutions, and biotechnology and biopharmaceutical industries are seeking innovative remedies for genetic and degenerative conditions that have historically been considered irreversible. These include the most common modifiable hearing health risk of all, acoustic trauma, as well as age-related hearing loss. In addition, these companies are also taking aim at less common causes of hearing loss, including ototoxic drugs used to treat other conditions, such as cancer chemotherapy agents and some antibiotics, idiopathic sudden sensorineural hearing loss, and much rarer conditions of hereditary/genetic deafness. These cutting edge, innovative treatments are promising, both to prevent deafness and to reverse it. However, despite at least 20 years of research, only one drug has been approved, quite recently, by the U.S. Food and Drug Administration (FDA) for use in humans: sodium thiosulfate as an otoprotectant to reduce risk of cisplatin ototoxicity in pediatric cancer patients with non-metastatic solid tumors . And neiLiving with hearing loss presents many challenges. Regardless of whether symptoms arise early in life or late, gradually or suddenly, communication impairment is a heavy burden for hearing impaired people and their families, friends, and co-workers. If you have ever taken an airline flight, forgotten your headphones, and tried to watch a movie on someone else’s screen, across the aisle and two rows in front of you, you might have some small sense of the struggle hearing impaired people experience all the time. The cognitive load of coping with hearing loss is well-known . When suGreat breakthroughs in hearing restoration will rest, at a minimum, upon convergence of three critical lines of research: (i) Identification of “druggable” basic pathophysiologic mechanisms/disease targets, (ii) development of drug or other therapeutic agent to deliver, and (iii) identification or development of delivery system to get the agent to the target. Experts will offer differing assessments of the most promising avenues of hearing restoration research. However, all experts, both scientific and clinical, agree that they want these efforts to succeed. The literature in this field is abundant, and growing daily. What follows is a perspective of several systemic factors contributing to the failure, to-date, of these efforts to bring new pharmacologic and biologic treatments to our patients .In January, 1971, President Richard Nixon signed into law the US National Cancer Act of 1971, which called for commitment of $1.5 billion  over 3 years for cancer research. In January, 2022, an editorial in Nature reviewed the 50 year history of this “war on cancer” . Most noThe limits of our understanding of the “particular” nature of hearing loss at this granular level is also reflected in our clinical diagnostics. A behavioral audiogram is a blunt instrument. Pure-tone audiometry defines the psychophysical detection threshold for hearing at an array of frequencies believed to be clinically relevant when “modern” audiometers were invented 100 years ago. Likewise, speech audiometry measuring word recognition score gives only the crudest assessment of hearing clarity. Emerging and slowly spreading use of speech-in-noise metrics represents early attempts to adopt clinical practices that are sensitive to cochlear synaptopathy and other nuances of sensorineural hearing loss . DevelopThere is another good analogy for hearing restoration: Disaster relief. If you are a homeowner and a storm knocks off part of your chimney, it is a simple matter to call the mason and have them come over to do the repair. On the other hand, if your home has been devastated by a disaster, it matters little whether it was a flood, an earthquake, a tornado, or a fire. You will require an assortment of materials and workers in the building trades to reconstruct your home. In clinical otology and audiology, we may occasionally see a patient with a very “focal” lesion accounting for their hearing loss, for example, the monogenic COCH mutation of DFNA9 deafness  or the mIf we step away from the ear for a moment and reflect on the topic of drug development in other fields, such as hypertension, depression, or chronic lung disease, there is a mature ecosystem of large established pharmaceutical companies using high throughput methodologies to screen candidate compounds, building and utilizing collaborations with smaller companies to outsource many aspects of drug development and screening, carry out preclinical and clinical trials, seek regulatory approval, and bring drugs to market. This ecosystem is regularly disrupted by new discoveries, most often from academic research centers, leading to entrepreneurial efforts to start a new company, develop the new drug, and for this start-up enterprise to either elbow its way into the ecosystem as a new player or be absorbed into it when taken over by one of the larger companies. Whether brought by a young company or legacy pharmaceutical company, when the new drug comes to market in an existing field, the pathway to regulatory approval is generally well-known. The efficacy metrics for the new drug and the comparator tolerability issues are well-known. When a new drug comes to market in an existing field, the target patient population is clearly identified. When a new drug comes to market in an existing field, the mechanisms to educate prescribing physicians and to educate patients are well-known and in place. When a new drug comes to market in an existing field, the ins and outs of seeking insurance reimbursement for that drug are also well-known and understood.As noted in the introduction to this article, there are no FDA-approved inner ear therapeutics currently available for clinical use. There is no well-worn path to success for clinical trials design, selection of outcome measures, for regulatory approval, definition of target populations, dissemination of information to prescribing physicians and patients, or for negotiating reimbursement from health insurers. Developing “pipeline” drugs in other therapeutic areas often centers on increased potency compared to existing drugs. In the inner ear, where we are seeking to modulate developmental processes, increasing potency is more likely to cause catastrophic harm than improve control of complex events with critical sequencing and narrow concentration and timing parameters . These aOne does not have to go the million dollar drugs to encounter reimbursement challenges. Consider a drug that must be administered in the otolaryngology office by intratympanic injection followed by an additional 30–60 min on the treatment table for the drug to be absorbed and/or to monitor for adverse effects. If the otolaryngologist is reimbursed $150 dollars for that treatment that occupies the treatment room for 1 hour, during which they might have seen four other patients at $75–$100 each, there is strong financial disincentive for adoption of the new treatment in clinical practice. Start-up companies have an existential need to achieve profitability. Publicly traded pharmaceutical companies are obviously committed to profitability for their shareholders. Current estimates are that the average cost of bringing the new drug to market is in the range of $1.3 billion . In a toWhichever of the above analogies, warfare, disaster relief, or ecology, is most apt, they all share one critical feature: teamwork. Different units or branches of service in a military campaign seek to coordinate their efforts and pool their resources. Tradespersons on a construction project are not in competition. The plumber is not trying to out-do the electrician. In ecology, it is the complexities of interdependence that dictate success or failure. Serial entrepreneurs in the field of drug development who come into this new arena of inner ear therapeutics are likely to have finely honed competitive instincts and skills from their experiences in established fields, such as psychiatry or cardiovascular disease. Those are exactly the wrong instincts in this new field of inner ear therapeutics, which has yet to see any success. All the participants in the inner ear therapeutic space, the academic scientists, the entrepreneurs and start-up companies, the pharmaceutical industry giants, the clinicians in otology and audiology, are all in the same boat. If one company has a neurotrophin product and another company has a growth factor product and another company has a signaling molecule and another company grows hair cells, no one of them will succeed unless they all succeed. The infrastructure for successfully bringing an inner ear therapeutic agent to the patients who need it has not yet been built. We do not have the basic science understanding and control of normal developmental processes and pathologic processes leading to hearing loss. We do not have the diagnostics that are sufficiently granular and sufficiently sensitive to discern which patient has which problem. Likewise, we do not have the diagnostics to determine treatment efficacy. There is only limited success with regulatory approval to bring inner ear therapeutics into clinical trials and only one drug with primary inner ear mechanism of action  that has gained FDA approval. None have been brought to market. Thus, there is no experience with the physician and consumer education, distribution, or financing of such a treatment.We are in the “pre-competitive” phase of inner ear therapeutics development. As noted above, meeting all the needs to build an infrastructure – the basic science, the diagnostics, the regulatory approval pathways, the distribution and marketing, and the financing – will require extraordinary ingenuity and creativity, time, human and other resources, and money. There is no single academic site or group of academic sites able to accomplish this. Government agencies such as NIH and DoD will play important roles in certain stages of the science but our government is not in the business of financing product development. There is no single start-up company or group of start-up companies with the financial resources and long-term security to enable this work. Though it may not have been done before, except perhaps in the very earliest days of the war on cancer, the best chance of creating a successful field of inner ear therapeutics would be for established pharmaceutical industry giants to set aside their competitive instincts and come together in a collaborative “moon shot” effort.In 2021–22, Pfizer reported annual profits of approximately $66 billion, AstraZeneca $45 billion, Merck $41.5 billion, and Johnson & Johnson $63.8 billion. If each these companies pledged $1 billion annually for 10 years, and a consortium of experts from academe and industry was assembled to review applications and oversee disbursement of these funds, we would have our moon shot. We could expect to see rapid advancement in each of the domains necessary to establish an infrastructure for the field of inner ear therapeutics. By the end of this 10 year effort, there would be an expectation of transitioning to the competitive environment familiar in other fields.Is it worth it? Our patients would certainly tell you that it is. Clinicians will agree. But there are many thorny legal, financial, and other logistical reasons this has not been done before. It is an undeniable fact that the original moon shot that put Americans on the moon in the 1960s and 70s gave rise to many advances in science and technology that were not the primary target of the project yet paid off again and again over the years. There is every reason to believe that similar collateral benefits would accrue from an inner ear therapeutics moon shot. Obviously, the major pharmaceutical companies who enable this project would need assurance that they, as well as the public and participants in the programs, would share in those downstream benefits. It will be challenging to design, negotiate, and execute such a program. It will never happen without tireless effort by hearing loss patients and their advocates fighting to see it done. It will require deft leadership, ideally by an individual recruited from outside this field but with keen scientific, financial, business, political, and interpersonal skills. It will be a monumental challenge. However, without an inner ear therapeutics moon shot program, we are likely to see many more years of failure and frustration. There is an African proverb that captures the essence of this undertaking: “If you want to go fast, go alone. If you want to go far, go together.”All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.SA is the clinical advisory board member, Frequency Therapeutics, Inc., and the consultant, Spiral Therapeutics, Inc.The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


This study revealed elevated hearing thresholds at higher frequencies  in PTA and DPOEA with an increase in the severity of OSAS. All OSAS patients, especially with AHI > 30 should be regularly screened for hearing loss.Obstructive sleep apnoea syndrome (OSAS) is a condition that is characterised by frequent apnoea and hypopnoea attacks occurring during sleep. The blood supply to cochlea and acoustic nerves is from terminal arteries, thereby making them susceptible to hypoxia. To compare the audiological profiles in patients with OSAS according to Apnoea Hypopnoea index (AHI) score. Descriptive study was conducted in 32 patients diagnosed to have OSAS in a tertiary referral centre over two year period. The study group was divided into mild, moderate, severe OSAS based on AHI score. The hearing evaluation was done using pure tone audiogram (PTA) and distortion product otoacoustic emission test (DPOAE). Moderate and severe OSAS participants had elevated thresholds at higher frequencies in PTA , although this was not statistically significant. We also noticed, absent DPOAE responses at higher frequencies , with increase in the severity of OSAS at higher frequency, which was statistically significant ( Obstructive sleep apnoea syndrome (OSAS) is a condition that is characterised by frequent apnoea and hypopnoea attacks occurring during sleep. “Apnoea is characterised as termination of airflow for at least 10 s despite continuing respiratory effort”. “A hypopnoea is characterised as having one of these three characteristics either more than 50% airflow reduction or moderate reduction associated with oxyhaemoglobin desaturation or moderate with evidence of awakening on electroencephalogram; not for 10 s". In the general population, OSAS incidence varies from 2 to 4% [The apnoea attacks in OSAS can lead to reduced oxygen content in cerebrovascular circulation and in arteries supplying cochlea , 3. The In our study, we aim to evaluate the effect of OSAS on sensorineural hearing loss and find the correlation of hearing loss with the severity of OSAS. With this study, we hope to find a valuable test to diagnose early sensorineural hearing loss in OSAS patients.A descriptive study was conducted in 32 patients diagnosed to have OSAS in a tertiary referral centre over two year period. The study group was divided into mild, moderate, severe OSAS based on AHI score. The severity of OSAS is calculated using AHI score (apnoea-hypopnoea index), calculated as number of events divided by number of hours of sleep. Mild: AHI = 5–15, moderate: AHI = 15–30, severe > 30. Since hypertension, type 2 diabetes mellitus, hypercholesterolemia often accompanies OSAS and can themselves serve as risk factors for hearing loss with these conditions, they were excluded from the study. In order to reduce confounding effects of age induced hearing loss, patients above 55 years of age were excluded from the study. In addition, participants with any acute or chronic ear pathology, previous ear surgery, use of ototoxic drugs, previous trauma, congenital hearing loss, previous usage of steroids for extensive periods, history of noise exposure and malignant or benign tumours of brain were ruled out from the study.Demographic data and basic medical data were collected. A thorough examination of ear, nose and throat were done for all participants to rule out other causes of hearing loss. Pure tone audiometry and D.P.O.A.E. measurements were done to assess hearing. All participants underwent PTA evaluation at 250, 500, 1000, 4000 and 8000 Hz. Double channel clinical audiometer GSI 61  was used for PTA. In our study we considered hearing loss when the average of bone conduction threshold was greater than 25 dB HL. D.P.O.A. E assessment was done at 1000, 2000, 4000, 6000 and 8000 Hz and signal amplitude were measured. For OAE measurements, computer based DPOAE analyser GSI AUDERA was used. If signal amplitude was found less than − 10, it was considered as refer or fail response. If signal amplitude was found more than − 10, it was considered as present or pass response.The study was approved by institutional ethics committee.p value of < 0.05 was considered as significant.For analysis, the statistical programme Statistical Package for The Social Sciences version 17.0 was used. One-way ANOVA was performed to find the association between mean P.T.A at different frequencies and OSAS groups. In order to find the relation between D.P.O.A.E response and OSAS groups, Kendall's tau-b test was performed. All the participants were in 30–55 year age range. The mean age of the participants was 45.25, 43.4, 38.52 respectively in mild, moderate, severe OSAS groups. Statistically significance difference was not identified in any of the groups Fig. .Fig. 1AgP.T.A value was obtained for 250–8000 Hz. Comparison between mean hearing thresholds were done for all three categories. The mean hearing thresholds were elevated in participants with moderate and severe OSAS at higher frequencies i.e., 4000 Hz and 8000 Hz, although the results were not statistically significant. The mean hearing thresholds at 4000 Hz for moderate and severe OSAS were 26 ± 19.49 and 27.89 ± 10.45 respectively in right ear Fig. . The meap value < 0.05)  in the P.T.A evaluation in our research. This was primarily seen in moderate and severe OSAS patients, but the difference was not statistically significant.Deniz et al. study found that, relative to moderate and severe OSAS patients with varying degrees of sensorineural hearing loss, patients with mild OSAS and control groups had normal hearing thresholds . In a caOtoacoustic emissions are generated by outer hair cells of cochlea, hence can be used to establish if outer hair cells are operating normally. In OSAS, there is hypoxia which can interfere with normal functioning of outer hair cells, which can lead to reduced OAE levels. The damage of the hair cells outspreads to the whole cochlea, but it’s mostly at basal cochlea, where the higher frequencies are arranged as per the theory of tonotopicity; similar to what we see in noise exposure and ototoxicity .p value < 0.05). The study conducted by She et al. concluded that otoacoustic emission (OAE) levels were significantly lower in patients with OSAS than in the control group and that this was correlated with the sensitivity of cochlear hair cells to blood oxygen levels [In our study we found out that DPOAE response were absent in participants in severe OSAS patients at high frequency and this difference was statistically significant .Additional research is needed to elucidate the pathophysiological mechanism behind the development of hearing loss in OSAS patients. There is need to evaluate both peripheral and central auditory system in accordance with the severity of OSAS. Also, application of this study in a larger population can give additional information regarding the pattern of hearing loss as well as the pathophysiology behind the development of hearing loss. In addition, it is also important to study if management of intermittent hypoxia of OSAS patients by means of CPAP, Uvulopalatopharyngoplasty, mandibular advancement devices can prevent the development of or lead to improvement in hearing in OSAS patients. As some studies have shown that snoring loudness may itself be an etiological factor in the development of hearing loss in OSAS patients, it is possible to determine the advantage of simple treatments such as the use of ear plugs while sleeping.The findings of the study showed increase in hearing threshold on PTA  in moderate and severe OSAS patients. However, a study with large sample size is required to prove significance. Also, there is definite damage to outer hair cells of cochlea as indicated by absent or refer DPOAE response in moderate and severe OSAS patients in the higher frequencies . We recommend that recording OAEs could represent a valuable tool in spotting early cochlear damage that exemplifies OSAS patients.


This article describes key data sources and methods used to estimate hearing loss in the United States, in the Global Burden of Disease study. Then, trends in hearing loss are described for 2019, including temporal trends from 1990 to 2019, changing prevalence over age, severity patterns, and utilization of hearing aids.We utilized population-representative surveys from the United States to estimate hearing loss prevalence for the Global Burden of Disease study. A key input data source in modeled estimates are the National Health and Nutrition Examination Surveys (NHANES), years 1988 to 2010. We ran hierarchical severity-specific models to estimate hearing loss prevalence. We then scaled severity-specific models to sum to total hearing impairment prevalence, adjusted estimates for hearing aid coverage, and split estimates by etiology and tinnitus status. We computed years lived with disability (YLDs), which quantifies the amount of health loss associated with a condition depending on severity and creates a common metric to compare the burden of disparate diseases. This was done by multiplying the prevalence of severity-specific hearing loss by corresponding disability weights, with additional weighting for tinnitus comorbidity.An estimated 72.88 million  68.53 to 77.30) people in the United States had hearing loss in 2019, accounting for 22.2% (20.9 to 23.6) of the total population. Hearing loss was responsible for 2.24 million (1.56 to 3.11) YLDs (3.6% (2.8 to 4.7) of total US YLDs). Age-standardized prevalence was higher in males (17.7% [16.7 to 18.8]) compared with females . While most cases of hearing loss were mild , disability was concentrated in cases that were moderate or more severe. The all-age prevalence of hearing loss in the United States was 28.1% (25.7 to 30.8) higher in 2019 than in 1990, despite stable age-standardized prevalence. An estimated 9.7% (8.6 to 11.0) of individuals with mild to profound hearing loss utilized a hearing aid, while 32.5% (31.9 to 33.2) of individuals with hearing loss experienced tinnitus. Occupational noise exposure was responsible for 11.2% (10.2 to 12.4) of hearing loss YLDs.Results indicate large burden of hearing loss in the United States, with an estimated 1 in 5 people experiencing this condition. While many cases of hearing loss in the United States were mild, growing prevalence, low usage of hearing aids, and aging populations indicate the rising impact of this condition in future years and the increasing importance of domestic access to hearing healthcare services. Large-scale audiometric surveys such as NHANES are needed to regularly assess hearing loss burden and access to healthcare, improving our understanding of who is impacted by hearing loss and what groups are most amenable to intervention. The Institute for Health Metrics and Evaluation (IHME) produces results for the GBD study, the largest and most comprehensive attempt to quantify disease epidemiology worldwide . The mosHearing loss is linked to a reduction in several quality of life measures, including social wellbeing , cognitiModifiable risk factors for hearing loss and tinnitus such as occupational and recreational noise exposure underscore the need for preventive strategies to reduce burden . AlthougWhile several large-scale surveys  have beehttps://vizhub.healthdata.org/gbd-compare/).Estimates presented in this article are sourced from the Global Burden of Disease (GBD) study, which produces modeled estimates of global hearing loss prevalence and hearing aid use. The GBD study is a systematic analysis of the over 300 diseases, injuries, and risk factors in 204 countries and territories; details are described elsewhere . While tPrevalence is defined as the number of individuals who currently have a disease or condition, expressed either as a count or divided by the general population . In addition to prevalence, the GBD utilizes a custom measure to estimate the impact of a nonfatal condition: years lived with disability (YLDs). YLDs quantify the amount of disability associated with a condition and are calculated by multiplying the severity-specific prevalence of a condition by its associated disability weight. Disability weights range from 0  to 1 . Weights were derived from a series of representative multinational surveys that made pair-wise comparisons of the severity of different health states . Probit We defined hearing loss as measured by the softest sound an individual could hear in their better ear, taken as the pure-tone average of frequencies at 0.5, 1, 2, and 4 kHz. This definition aligns with the World Health Organization definition of hearing loss. We report the prevalence of hearing loss by six mutually exclusive severities Table .Hearing loss is also reported by the dimension of tinnitus status, which is characterized by being bothered by ringing, roaring, or buzzing in the ears lasting 5 min or more. This definition was obtained from U.S. National Health and Nutrition Examination (NHANES) surveys, which report the proportion of hearing-impaired respondents who self-report tinnitus . We utilEach severity of hearing loss is associated with a corresponding disability weight, used to reflect the relative impact of this health state on functional health. Disability weights increase with severity and tinnitus co-occurrence Table . For exaTo estimate the burden of hearing loss globally, we utilized survey data obtained through systematic review of published epidemiologic studies. Additionally, we deliberately include microdata sources and sources referred to IHME through collaborator input, such as NHANES surveys. Nonrepresentative surveys, surveys that did not report bilateral hearing loss, and surveys that did not employ pure-tone audiometry as a diagnostic tool were excluded. We used NHANES individual-level data to adjust data that did not report hearing loss prevalence by the reference categories employed by the GBD. This was done by pairing data that reported prevalence according to different severity categories, then running a model on the estimated logit difference between prevalence of the reference severity category and alternative severity category. Members of the core IHME research team for this topic area had full access to the underlying data used to generate estimates presented in this paper. All other authors had access to, and reviewed, estimates as part of the GBD study and research evaluation process, which includes additional stages of internal IHME and external formal collaborator review. Input data are publicly available through the Global Health Data Exchange .The key data source utilized to estimate hearing loss, hearing aid use, and tinnitus concurrence in the United States was the NHANES  Surveys for the years 1999 to 2000, 2001 to 2002, 2003 to 2004, 2005 to 2006, 2007 to 2008, and 2009 to 2010 . NHANES We utilized the following NHANES question to assess hearing aid use: “{Have you/Has SP} ever worn a hearing aid?” In addition to NHANES data, we utilized hearing aid use data from the Norway Nord-Trøndelag study  and U.K.To model hearing loss, we ran severity-specific models of hearing loss using a Bayesian meta-regression tool called DisMod-MR 2.1 . DisMod-We scaled severity-specific models of hearing loss prevalence (ranging from no hearing loss to complete) to sum to the entire population in a series of proportional scaling adjustments. We then adjusted global, national, and state-level prevalence estimates downward based on hearing aid use, assuming that individuals who use a hearing aid have better hearing acuity than those who do not. First, we calculated hearing aid use for each severity of hearing loss using NHANES and Nord-Trøndelag data by running a logistic regression on age, severity, and sex:We then calculated severity-specific hearing aid use for all by scaling regression outputs based on estimates of total hearing aid use from DisMod-MR 2.1:To adjust estimates of hearing loss prevalence for hearing aid use, we shifted the proportion of individuals who used a hearing aid in each location down one severity level of hearing loss. We conducted this adjustment due to an absence of data on the improvement in hearing acuity produced by hearing aid usage. We assumed that all individuals who use a hearing aid use one regularly. We assumed no improvement in hearing acuity from hearing aid use for individuals with complete hearing loss, under the assumption that amplification devices hold little utility on individuals with extensive cochlear or sensorineural damage .We additionally split estimates of hearing loss by four etiologies: congenital abnormalities, chronic otitis media, meningitis, and age-related and other factors. We maintained uniform disability weights for hearing loss across etiology. We assumed that all hearing loss occurring at birth was congenital, and estimated hearing loss due to chronic otitis media and meningitis based on models of total prevalence of chronic otitis media and meningitis (described elsewhere) . For ageFinally, we estimated the proportion of hearing-impaired people with tinnitus using data from NHANES and United Kingdom A.  surveys.Occupational noise exposure is a risk factor for age-related and other hearing loss in the GBD study. Occupational noise is defined as the proportion of the population exposed to 85 + dB of noise. Data from the International Labour Organization were used to model occupational noise exposure by year, age, sex, and location. We sourced input data on the population prevalence of hearing loss due to occupational noise exposure from published studies from Australia and the United Kingdom . Data onModeling of hearing loss due to occupational noise exposure is described in greater detail elsewhere .An estimated 72.88 million (68.53 to 77.30) people in the United States had hearing loss in 2019. This accounted for one in five people, or 22.2% (20.9 to 23.6) of the total population. Age-standardized prevalence was higher in males (17.7% [16.7 to 18.8]) compared with females (11.8% [11.2 to 12.5])  Americans with hearing loss that was mild to profound in severity, an estimated 6.97 million (6.11 to 8.01) utilized a hearing aid (9.7% [95% UI 8.1 to 11.0]). Moreover, an estimated 32.5% (95% UI 31.9 to 33.2) of Americans experienced hearing loss concurrent with tinnitus  YLDs produced by hearing loss in the United States in 2019, 23.0% (13.4 to 34.7) were attributable to mild cases and 25.0% (19.7 to 30.7), 24.1% (18.0 to 30.4), and 8.1% (5.4 to 11.1) were attributable to moderate, moderately severe, and severe cases, respectively  in 1990 to 22.2% (20.9 to 23.6) in 2019, a 28.1% (25.7 to 30.8) increase. This difference was statistically significant . Moreover, the number of hearing loss cases increased from 43.99 million (41.61 to 46.49) in 1990 to 72.88 million (68.53 to 77.30) in 2019, an increase of 65.7% (62.6 to 69.2). Much of this increase was driven by mild cases, which increased 64.4% (60.5 to 68.7) from 28.50 million (26.84 to 30.22) in 1990 to 46.85 (43.88 to 50.07) in 2019. In contrast to all-age prevalence, age-standardized prevalence remained constant, at 14.6% (13.8 to 15.3) of the population in 1990 and 14.7% (13.9 to 15.5) in 2019  Americans with mild to profound hearing loss utilized a hearing aid, indicating high unmet need for healthcare services in groups most likely to benefit from intervention . Other sAn objective of Healthy People 2030 is to increase the number of adults with hearing loss who use a hearing aid by 2 percentage points (24.4% in 2018 to 26.4%)—a goal which will require commitment at the federal level to make it easier to acquire a hearing aid. The Medicare Audiologist Access and Services Act introduced in the U.S. House and Senate includes direct access to audiologists without requiring an order from a physician and streamlines coverage such that, if passed, audiologists will be able to provide the full range of diagnostic and treatment services within their scope of practice. Streamlining Medicare services is expected to save taxpayers $108 million over 10 years (Jong 2021). Though a step in the right direction to reducing barriers to care, unfortunately, coverage for hearing aids remains limited.As the United States suffers from an audiologist shortage in many regions , it is iThere are several strengths of our paper. First, our global modeling approach leveraged information on the severity, etiology, and distribution of hearing loss from varied analyses, included adjustment for hearing aid utilization, and incorporated severity-specific disability weights, which permit rigorous comparisons of disability between age groups, locations, time, and other causes of disease or injury.While the GBD’s linkage between hearing loss audiometric thresholds, descriptions of functional health, and quantitative disability weights permit a systematic view of health loss produced by hearing impairment, it is important to note that these classifications may not capture the full range of functional health outcomes for each individual living with hearing loss. As audiometric measurements do not map directly onto real-world hearing acuity for every individual, depending on the type of hearing loss, even individuals with “normal” audiometric thresholds may experience functional limitations . ConversIn this study, we were interested in reporting the burden of hearing loss among the US population. Considering tinnitus is often comorbid with hearing loss, and tinnitus is associated with increased mental distress and decreased quality of life , disabilA key limitation of our modeling approach was data sparsity, both globally and in the United States. Our models of hearing loss prevalence in the United States were primarily informed by NHANES surveys, which provide age-, sex-, and severity-specific information on loss, as well as data on the proportion of survey participants who utilized a hearing aid or experienced tinnitus. While NHANES surveys were valuable sources of information on hearing loss in the United States, NHANES data in our models were not reported at the state level, which reduces our capacity to make inferences about hearing loss burden by state. Moreover, due to the cyclic nature of data-seeking in the GBD study, NHANES data from 2011 to 2012 and 2015 to 2016 were not included in GBD 2019 estimates. These rounds of data were included in GBD 2020 estimates, and future rounds of NHANES surveys will be readily incorporated in future iterations of the GBD study. Although our modeling methods allow estimates to borrow strength from other high-income countries with more recent data, this impacts the ability to accurately estimate the burden of hearing loss in the United States over time, particularly in years after 2010. In conjunction with modeling methods that leverage temporal data from other locations in regions where new data are not available, this lack of newer data may mask temporal trends in NHANES data which suggest decreases in age- and sex-specific hearing loss prevalence over time . Our modWhile NHANES data provided audiological information on individuals over 5 years old, it did not include similar information for young children or infants. There was a lack of specific information on bilateral hearing loss in children in the United States, making it particularly difficult to produce accurate estimates of hearing impairment prevalence in younger ages. Sources such as the CDC Early Hearing and Detection program provide comprehensive estimates of hearing loss in American infants, but report information by ear instead of by person, and therefore were not included in our modeling approach.Moreover, our estimates of hearing loss burden assume reduced burden of hearing loss in individuals who use a hearing aid, in the absence of data on the decibel-level improvement in hearing acuity produced by hearing aid usage. Our adjustment methods may be crude in nature, neglecting other components of hearing aid usage that may impact hearing acuity, including hearing aid fit, daily hours of use, technology style, and upkeep.Due to insufficient information at the country level, a major limitation of the occupational noise methodology is that industry and occupation are primarily used as proxies for exposure, and we only included limited information on noise exposure levels within different industries. Further, use of hearing protection was only considered to a limited degree and with rather general assumptions regarding differences in exposures between low/middle-income and high-income countries. Additional data gaps included state-level data, information on the usage of hearing devices such as cochlear implants and other technologies, and information on the etiology of hearing impairment, which are not commonly assessed in surveys of hearing loss prevalence. More data in these areas are needed to rigorously assess the burden of hearing impairment in the United States, providing relevant information for domestic policymakers and hearing healthcare providers.Hearing impairment is a growing problem that has detrimental impacts on language development, communication, and social wellbeing. Estimates indicate that hearing impairment is a leading source of disability in the United States. Despite high burden, hearing aid use is low, indicating unmet need for healthcare services that will grow in coming years if not complemented by health system scale-up. As populations age and prevalence rises, new data sources on the severity, etiology, and prevalence of hearing loss are needed to strengthen national estimates and target healthcare services toward key populations.L.M.H. and P.S.B. report personal fees from the World Health Organization from a contract to conduct an analysis for the World Hearing report, paid directly to them. K.M.R. reports grants or contracts from the US Department of Defense , and US Veterans’ Affairs , payments made to institution to support salary, and from US National Institutes of Health (NIH-NIDCD 1R13DC020098-01), outside the submitted work. T.W.B. reports grants or contracts from the European Union , German Research Foundation (DFG), US National Institutes of Health, German Ministry of Education and Research, Alexander von Humboldt Foundation, Else-Kröner-Fresenius-Foundation, Wellcome Trust, Bill & Melinda Gates Foundation, KfW, UNAIDS, WHO, consulting fees from kfW on the OSCAR initiative in Vietnam, participation on a Data Safety Monitoring Board or Advisory Board with NIH-funded study “Healthy Options” , Chair, Data Safety and Monitoring Board (DSMB), German National Committee on the “Future of Public Health Research and Education,” Chair of the scientific advisory board to the EDCTP Evaluation, Member of the UNAIDS Evaluation Expert Advisory Committee, National Institutes of Health Study Section Member on Population and Public Health Approaches to HIV/AIDS (PPAH), US National Academies of Sciences, Engineering, and Medicine’s Committee for the “Evaluation of Human Resources for Health in the Republic of Rwanda under the President’s Emergency Plan for AIDS Relief (PEPFAR),” University of Pennsylvania (UPenn) Population Aging Research Center (PARC) External Advisory Board Member, and leadership or fiduciary role in board, society, committee or advocacy group, paid or unpaid as Cochair of the Global Health Hub Germany ; outside the submitted work. I.M.K. reports supposed for the present manuscript from the Bill & Melinda Gates Foundation and the World Health Organization. A Singh reports consulting fees from Crealta/Horizon, Medisys, Fidia, Two labs, Adept Field Solutions, Clinical Care Options, ClearView Healthcare Partners, Putnam Associates, Focus Forward, Navigant Consulting, Spherix, MedIQ, UBM, Trio Health, Medscape, WebMD, and Practice Point Communications; and the National Institutes of Health and the American College of Rheumatology; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Simply Speaking; support for attending meetings or travel, or both from OMERACT, an international organization that develops measures for clinical trials and receives arm’s length funding from 12 pharmaceutical companies, when traveling to OMERACT meetings; participation on a data safety monitoring board or advisory board as a member of the FDA Arthritis Advisory Committee; leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid, with OMERACT as a member of the steering committee, with the Veterans Affairs Rheumatology Field Advisory Committee as a member, and with the UAB Cochrane Musculoskeletal Group Satellite Center on Network Meta-analysis as a director and editor; stock or stock options in TPT Global Tech, Vaxart Pharmaceuticals, Atyu Biopharma, Adaptimmune Therapeutics, GeoVax Labs, Pieris Pharmaceuticals, Enzolytics Inc., Seres Therapeutics, Tonix Pharmaceuticals, and Charlotte’s Web Holdings, and previously owned stock options in Amarin, Viking, and Moderna Pharmaceuticals; all outside the submitted work.


Beauveria bassiana is a well-known insecticidal biocontrol agent. Despite its broad field applications, its survival, colonization, and stability under field conditions remained unclear, mainly due to the lack of a quick and reliable detection method. In this study, we developed a quantitative real-time PCR technology to monitor the stability and population dynamics of B. bassiana in different substrates , different spores of B. bassiana applied on Chinese cabbage leaves surface, and the lethality of Pieris rapae spraying with different spores of B. bassiana. Our results showed a decreased concentration of B. bassiana DNA in all three substrates from the 1st day till 9th day of post inoculation (dpi) period, possibly due to the death of B. bassiana. After this decrease, a quick and significant rebound of B. bassiana DNA concentration was observed, starting from the 11th dpi in all three substrates. The B. bassiana DNA concentration reached the plateau at about 13th dpi in water and 17th dpi in the soil. On cotton leaves surface, the B. bassiana DNA concentration reached the highest level at the 17th dpi followed by a small decline and then stabilized. This increase of DNA concentration suggested recovery of B. bassiana growth in all three substrates. We found that the most suitable killing effectiveness of P. rapae was the 1.0 × 107 spores/mL of B. bassiana. In summary, we have established a detection technology that allows a fast and reliable monitoring for the concentration and stability of B. bassiana under different conditions. This technology can benefit and help us in the development of proper management strategies for the application of this biocontrol agent in the field. Beauveria bassiana is an entomopathogenic fungus that can infect more than 700 insect species belonging to 149 different families in 15 different orders by causing white muscardine disease in them [B. bassiana is the most well studied entomopathogenic fungi and has been frequently used as a commercial mycoinsecticide in the field [B. bassiana was used to control insect pests, including Pissodes castaneus, Ostrinia nubilalis, and Rhynchophorus ferrugineus, infield through direct spraying [B. bassiana is safe to human, natural beneficial insects, and beneficial microorganisms. During field applications, it can also be used together with other commercial chemical pesticides [B. bassiana. Currently, B. bassiana is widely used to control insect pests in the order of Lepidoptera and Coleoptera, including many forest pests [ in them . To datehe field . For exasticides –12. Morest pests , 14.B. bassiana could secrete many biologically active compounds like lactide and poisonous proteases during its infection in insect hosts [B. bassiana is also known to hijack nutrients and water from the infected insects to accelerate their death process [B. bassiana spores can be formulated to produce wettable powder for commercial use in agriculture as well as in forests [B. bassiana in field depended largely on environmental factors [It was reported that ct hosts , 16. B.  process . B. bass forests –21. A se factors . We reas factors , 24.Metarhizium anisopliae in oriental migratory locust [B. bassiana in various substrates  at 28°C. With this new technology, we can now monitor B. bassiana population dynamics and regrowth in field samples and develop more effective management strategies using this and other biocontrol agents.Peng and coworkers investigated the growth and survival of y locust . In thisB. bassiana was originally isolated from a tomato field in Yueyang, China  and then maintained in the laboratory. Before use, this fungus was grown till a concentration of 1.0 × 1012 spores/g·mass. The liquid growth medium used for B. bassiana was potato dextrose agar (PDA-Medium), and the carbon-to-nitrogen (C : N) ratio was at 10 : 1 (Vega. 2003). Cotton plants used in this study were grown in a greenhouse and the soil was from Chunhua in Changsha, China , which contained 10% water, and the water used was the natural water from a lake in Changsha, China .B. bassiana containing water, soil, and plant leaf samples using a DNA extraction kit . Concentration and quality of each DNA sample were measured by using a spectrophotometer . For each DNA sample, three technical replicates were analyzed during real-time fluorescent PCR with a SYBR Green I reagent  as instructed by the manufacturer (TransGen Biotech).DNA was extracted from B. bassiana. The resulting PCR products were cloned and sequenced by the TSINGKN Biotech . Conserved DNA sequences obtained from the PCR products were analyzed using the DNAMAN software, and six pairs of real-time PCR primers were designed based on the obtained sequences using the Primer 5.0 software in the DNAMAN . In the subsequent real-time PCR assays, diluted B. bassiana genomic DNA or double distilled water (ddH2O) were used as the positive and negative control sample, respectively. The six designed primer sets were first tested by gradient PCR with three different annealing temperatures  and later by PCR amplifications. The resulting PCR products were visualized in agarose gels through electrophoresis. The primer set giving a single specific PCR product was considered to be the optimal B. bassianareal-time PCR primer set and was used in further experiments.The initial PCR amplification was carried out using a set of bacterial universal primers (Baker. 2003) and the DNA isolated from B. bassiana genomic DNA and then measured its concentration using a spectrophotometer. The copy number of the recombinant plasmid DNA was calculated as previously reported [According to a previously described method , we firsreported  and thenB. bassiana was homogenized, dried, and diluted 1 : 99 (w/v) in sterilized water. The diluted sample was incubated at 28°C inside an incubator and sampled once every two days (one mL sample per sampling time) till the 29th day of postincubation (dpi) period. The collected samples were centrifuged at 12,000 rpm/min for 1 minute and the supernatants were discarded prior to the extraction of DNA from the pellets. For real-time PCR reactions, three technical replicates were analyzed and used to represent a specific DNA sample.B. bassiana powder was mixed with 99 grams sterilized black soil, incubated at 28°C in an incubator and then sampled once every two days (1 g soil sample per sampling time) as described above. The collected soil samples (0.1 g each) were used for DNA extraction as described above. Real-time PCR was then performed using three technical replicates per sample.One gram dried B. bassiana powder was diluted in 99 grams sterilized water and then spread onto the surface of cotton leaves. After air drying, three to four cotton leaf pieces were randomly collected once every two days. The sampled cotton leaf tissues were grounded in liquid nitrogen and 0.1 g powder from each leaf sample was used for DNA extraction. For real-time PCR, three technical replicates were used to represent a specific sample.One gram dried B. bassiana with 1.0 × 102 (A), 1.0 × 104 (B), 1.0 × 106 (C), 1.0 × 107 (D), and 1.0 × 108 (E) spores/mL were sprayed evenly on Chinese cabbage leaves at the same growth level at 28°C and 60% humidity. The buffer solution used for the dilution of the spores of B. bassiana was set as a blank control. The leaf samples were analyzed for B. bassiana DNA concentrations by real-time PCR after 24 hours of spraying, three to four pieces of cabbage leaf were randomly collected once every two days. For real-time PCR, three technical replicates were used to represent a specific sample.The B. bassiana with 1.0 × 102 (A), 1.0 × 104 (B), 1.0 × 106 (C), 1.0 × 107 (D), and 1.0 × 108 (E) spores/mL were used to spray uniformly on the cabbage leaves. After spraying 12 hours, cabbage leaves were fed to 40 heads of P. rapae selected at normal active fourth stage larvae, the P. rapae larvae were cultured in a net cage at 28°C and 90% humidity. The buffer solution used for the dilution of the spores of B. bassiana was set as a blank control. After feeding for 24 hours, one P. rapae were randomly collected to check for the B. bassiana DNA concentrations by real-time PCR. The selected P. rapae was rinsed with water to avoid the presence of B. bassiana outside the body, which will affect the experimental results. For real-time PCR, three technical replicates were used to represent a specific sample.The In this study, all the experiments were repeated twice to ensure the repeatability of the results.Data obtained from three independent experiments were combined and analyzed by using one-way ANOVA program in Excel  and the SPSS 13.0 statistical software package . Post hoc multiple comparisons were conducted at the 5% level of probability using Duncan's multiple range test (DMRT).μL = (6.0 × 1014 copies × plasmid concentration (g)/μL)/. The efficiency of each primer set was determined through PCR reactions and the resulting PCR products were visualized in agarose gels through electrophoresis. Results of the assay showed that, when the annealing temperature was set at 54°C, four of the six primer sets gave strong and correct sized PCR product bands. At 52°C, three primer sets gave positive PCR products of different size, and at 56°C, only two primer sets gave positive PCR products  was used for the following real-time PCR assays. Through PCR amplification assays, a standard curve of PCR was determined as Y = −3.26X + 11.25, R2 = 0.99965, and the PCR amplification efficiency = 1.03   . The amoB. bassiana DNA in soil was also determined by real-time PCR. Results shown in B. bassiana DNA concentration declined quickly from the 1st dpi (5.253 × 106 copies of B. bassiana DNA/μL) to the 9th dpi (4.530 × 105 copies of B. bassiana DNA/μL). As shown in B. bassiana DNA concentration rebound at the 11th dpi and continued to increase till 17th dpi (4.776 × 106 copies of B. bassiana DNA/μL). After this increase, B. bassiana DNA concentration remained relatively stable till 29th dpi, suggesting a reestablishment of B. bassiana population in soil samples. This experiment was repeated twice.Stability of B. bassiana powder was diluted in water and sprayed onto the surface of cotton leaves. After incubation at 28°C for several days, the leaf samples were analyzed for B. bassiana DNA concentrations by real-time PCR. The results shown in B. bassiana DNA was at 3.202 × 105 copies of B. bassiana DNA/μL at the 1st dpi and then declined to 2.777 × 104 copies of B. bassiana DNA/μL at the 9th dpi. The concentration of B. bassiana DNA rebound at the 11th dpi and reached 2.975 × 105 copies of B. bassiana DNA/μL at the 17th dpi. The B. bassiana DNA concentration decreased slightly again and reached 2.126 × 105 copies of B. bassiana DNA/μL at the 21st dpi, and then remained stabilized. This experiment was repeated twice. B. bassiana DNA was not detected in the negative control samples.Dried B. bassiana spores over time, we selected different concentrations of spores to spray on Chinese cabbage leaves and then detected the stability of B. bassiana DNA. Results shown in B. bassiana DNA was at 7.976 × 107 (A), 1.100 × 108 (B), 1.308 × 108 (C), 1.391 × 108 (D), and 1.460 × 108 (E) copies of B. bassiana DNA/μL at the 1st dpi and then declined to 1.724 × 107 (A), 5.261 × 107 (B), 1.021 × 108 (E) copies of B. bassiana DNA/μL at the 9th dpi and 8.292 × 107 (C), 9.076 × 107 (D) copies of B. bassiana DNA/μL at the 7th dpi. The concentration of B. bassiana DNA rebound at the 11th dpi and reached 5.381 × 107 (A), 1.156 × 108 (B), 1.474 × 108 (C), 1.553 × 108 (D), and 1.615 × 108 (E) copies of B. bassiana DNA/μL at the 21st dpi and then remained stabilized. Although the concentration of B. bassiana was different, the stability of B. bassiana DNA on Chinese cabbage leaves surface showed roughly the same trend, which showed a decreasing trend from the 1st dpi to the 9th dpi (except (A), (B), and (E)), all concentrations showed an increasing trend from the 11th dpi to the 19th dpi and then remained stabilized at 21th dpi to the 29th dpi. This experiment was repeated twice. B. bassiana DNA was not detected in the negative control samples.To investigate the dynamics of different amounts of B. bassiana spraying on cabbage leaves at 12 hours, the treated leaves were fed to P. rapae. Then, the assayed P. rapae were analyzed for B. bassiana DNA concentrations by real-time PCR. Results shown in B. bassiana DNA were 1.633 × 108 (A), 2.854 × 104 (B) copies of B. bassiana DNA/μL at the 7th dpi; 4.574 × 108 (C), 5.276 × 108 (D), and 6.063 × 108 (E) copies of B. bassiana DNA/μL at the 9th dpi. The concentration of B. bassiana DNA rebound at the 11th dpi and, respectively, reached 2.638 × 108 (A), 6.953 × 108 (B), 8.839 × 108 (C), 8.887 × 108 (D), and 9.263 × 108 (E) copies of B. bassiana DNA/μL at the 21st dpi. The mortality rate of P. rapae treated with different spores at 21st, respectively, reached 15% (A), 50% (B), 65% (C), 90% (D), and 95% (E), the concentration of 1.0 × 106 (C) spores/mL reached 65% at the 19th dpi; the concentration of 1.0 × 107 (D) spores/mL reached 50% at the 13th dpi and reached 90% at the 21st dpi; the concentration of 1.0 × 108 (E) spores/mL reached 50% at the 14th dpi, and reached 90% at the 19st dpi. This experiment was repeated twice. B. bassiana DNA was not detected in the negative control samples.After the different number of spores of B. bassiana 16s rDNA and established a sensitive and reliable PCR and a real-time PCR method for the detection of B. bassiana in various substrates. The sensitivity of the detection technology was 4.337 × 104 copies of plasmid/μL. Using this method, we can now reliably monitor B. bassiana population dynamics in B. bassiana preinoculated soil or cotton leaves samples. Our results indicated that during the 1st to the 9th dpi, B. bassiana DNA concentration declined in all substrates. According to our understanding, this decline was caused by the massive death of initially inoculated B. bassiana. The DNA concentration started to increase sharply after the 9th till 11th dpi. It is possible that this increase represents a rapid regrowth of B. bassiana, survived from the treatments. From the 11th to the 29th dpi, B. bassiana DNA concentrations remained high in all three substrates, suggesting that the B. bassiana population had reached the maximum level under the assayed conditions. In this study, B. bassiana DNA was not detected in any negative control samples and thus, the identified PCR primers produced the B. bassiana DNA specific bands when electrophoretically analyzed.In this study, we identified a pair of PCR primers specific for the B. bassiana applied on Chinese cabbage result shown that the stability of B. bassiana DNA are consistent when plants treated with 1.0 × 106, 1.0 × 107, and 1.0 × 108 spores/mL. But the mortality rate of P. rapae treated with different spores at 21st, respectively, reached 15%, 50%, 65%, 90%, and 95%, the concentration of 1.0 × 106 spores/mL reached 65% at the 19th dpi; the concentration of 1.0 × 107 spores/mL reached 50% at the 13th dpi and reached 90% at the 21st dpi; the concentration of 1.0 × 108 spores/mL reached 50% at the 14th dpi, and reached 90% at the 19st dpi. With the increase in the initial spores of B. bassiana, the mortality of P. rapae gradually increased. At low spores (1.0 × 102 spores/mL and 1.0 × 104 spores/mL), the death rate was approximately 15–50%. At high spores , the death rate was 65–95%. The results indicated the effect of killing insects was obviously increased with increasing the concentration of B. bassiana, whereas considering the cost-effectiveness, the 1.0 × 107 spores/mL of B. bassiana was the most suitable.Different number spores of B. bassiana field applications focused mainly on the development of antibiotic-resistant strains [B. bassiana is, however, time-consuming and the resulting resistance strain(s) might become attenuated after a few generations. In contrast, understanding the environmental impacts on B. bassiana stability and recolonization behavior in the field can facilitate the design and establishment of more effective insect pest management strategies and thus achieving a better control effect. This PCR detection technology may also be modified for other biocontrol agents. In summary, this study has established a fast, low-cost, and reliable method for the determination of B. bassiana stability and recolonization in various substrates under the controlled conditions.Since the invention of real-time PCR, this technology has been widely applied to molecular biology studies . Current strains –33. The


Listening and communication difficulties can limit people’s participation in activity and adversely affect their quality of life. Hearing, as well as listening and communication difficulties, can be measured either by using behavioural tests or self-report measures, and the outcomes are not always closely linked. The association between behaviourally measured and self-reported hearing is strong, whereas the association between behavioural and self-reported measures of listening and communication difficulties is much weaker, suggesting they assess different aspects of listening. While behavioural measures of listening and communication difficulties have been associated with poorer cognitive performance including executive functions, the same association has not always been shown for self-report measures. The objective of this systematic review and meta-analysis is to understand the relationship between executive function and self-reported listening and communication difficulties in adults with hearing loss, and where possible, potential covariates of age and pure-tone audiometric thresholds.Studies will be eligible for inclusion if they report data from both a self-report measure of listening difficulties and a behavioural measure of executive function. Eight databases are to be searched: MEDLINE (via Ovid SP), EMBASE (via Ovid SP), PsycINFO (via Ovid SP), ASSIA (via ProQuest), Cumulative Index to Nursing and Allied Health Literature or CINAHL (via EBSCO Host), Scopus, PubMed and Web of Science . The JBI critical appraisal tool will be used to assess risk of bias for included studies. Results will be synthesised primarily using a meta-analysis, and where sufficient quantitative data are not available, a narrative synthesis will be carried out to describe key results.No ethical issues are foreseen. Data will be disseminated via academic publication and conference presentations. Findings may also be published in scientific newsletters and magazines.CRD42022293546. This systematic review is the first to investigate the relationship between self-reported listening and communication difficulties and executive function using meta-analysis to synthesise the available evidence.It uses an established framework  and taxonomy (Cattell-Horn-Carroll-Miyake) to define target domains and measures of listening and communication difficulties and executive functions, respectively.Grey literature (including unpublished study results) will be included.This protocol has been reported in accordance with the PRISMA-P statement.Only studies available in English are eligible for inclusion.Listening and communication are crucial for a healthy life and difficulties in communication can limit people’s participation and adversely affect their quality of life. Hearing loss plays a fundamental role in determining a person’s ability to listen and communicate, although research over the years has shown that there are other factors, beyond hearing loss, that are also important. Both hearing and listening and communication can be measured using behavioural measures such as pure-tone audiograms and speech-in-noise tests, or via self-report questionnaires. Behavioural and self-report measures of hearing are generally well correlated, and behavioural measures of hearing are often well correlated with both behavioural and self-report measures of listening and communication, that is, questionnaires. When a listener has a behaviourally measured hearing loss, it is likely that they will also experience and report difficulties with listening and communicating.et al proposed a cascade linking hearing to effective communication, which in turn can be mapped to the International Classification of Functioning and Disease (ICF) framework (core set for hearing loss).Effective communication, which relies on good hearing, is instrumental for a high level of functioning and good quality of life.On the other hand, considering the activities and participation domain of listening and communication, behavioural and self-report measures are less robustly correlated. This is highlighted by the fact that two individuals who experience the same pure-tone average audiometric thresholds can experience and report substantially different degrees of listening and communication difficulties.4Cognition has a complex relationship with auditory function depending on whether it is considered at the function (hearing) or activities/participation (listening/communication) level. Specifically, hearing loss, both behaviourally measured and self-reported, has been shown to be associated with poorer cognitive performance across a range of cognitive domains including global cognition, episodic memory, processing speed, semantic memory, visuospatial ability, executive functions, and cognitive impairment and dementia.7For listening and communication, on the other hand, the type of assessment appears to play a role. For behavioural measures, the role of cognition for the ability to perceive speech  has been reliably demonstrated for individuals with hearing loss, and this relationship is robust even when taking into consideration individuals’ age and objective hearing levels (pure-tone average audiometric thresholds).executive functions may play a key role in the variation of individual experiences of listening and communication difficulties, regardless of absolute hearing levels.For self-report measures of listening or communication difficulties in quiet and in noise on the other hand, the role of cognition is much less clear and a clear link with cognition is not always shown.shifting), information updating and monitoring (updating), and inhibition of prepotent responses (inhibition). Indeed, there is emerging evidence from large-scale cohort studies that individuals with self-reported hearing loss exhibit significantly poorer performance on tests of flexibility, psychomotor speed and executive function.14Executive functions refer to ‘higher order cognitive processes that control lower level cognitive processes in the service of goal-directed behaviour’ (p.186).In this review, we aim to synthesise the evidence assessing the relationship between self-reported listening and communication difficulties and objective measures of executive function, while controlling (where possible) for the potentially confounding factors of age and pure-tone audiometric hearing thresholds. To our knowledge, this independent relationship has yet to be extensively examined, despite data pertaining to both executive functions and self-reported listening and communication difficulties often being reported as part of wider research study methods.activity limitations and participation restrictions arising from hearing loss, and narrow our focus to self-report measures that align with ICF core set for hearing loss domains of listening (d115), communicating with – receiving – spoken messages (d310) and conversation (d350). Similarly, to definitively identify executive function domains and classify behavioural measures of executive function as either shifting, updating or inhibition, we will use the Cattell-Horn-Carroll-Miyake (CHC-M) taxonomy.16When considering measures of self-reported listening and communication difficulties, it is important to clearly define what we mean, as there are well over a hundred self-report measures pertaining to listening,Is there an association between self-reported listening and communication difficulties and performance on behavioural measures of executive function in adults with hearing loss?Is any association moderated by age and/or hearing loss (as measured using average pure-tone audiometric thresholds)?To review and synthesise evidence for the association between self-reported listening difficulties and performance on behavioural measures of executive function, in adults with hearing loss.Adults with hearing loss (with or without hearing devices), aged 18 years and over with no reported cognitive decline. We will accept a qualitative definition of hearing loss as ‘mild’, ‘moderate’, ‘severe’ or ‘profound’, or a quantitative definition where the group average pure-tone audiometric threshold is classed as mild hearing loss or greater using the WHO definition of mild (26–40 decibel [dB] hearing level [HL] inclusive); moderate (41–60 dB HL inclusive); severe (61–80 dB HL inclusive) and profound (81+dB HL).A correlation coefficient between self-reported listening or communication difficulties and executive function, either reported or calculated from other reported data.Self-reported listening and communication difficulties can be measured by a single item or a questionnaire assessing the following ICF core set for hearing loss domains of listening (d115), communicating with—receiving—spoken messages (d310) and conversation (d350).At least one behavioural measure of executive function must be included, defined according to the CHC-M taxonomy as tasks that measure updating , shifting  and inhibition .16Where available, demographic information about the population  and objectively measured hearing loss (average pure-tone audiometric thresholds) will also be examined as subgroup descriptors and/or potential moderator(s).Cross-sectional, longitudinal, experimental, quasi-experimental and observational studies will be included.Articles must be available in English. No restrictions on publication dates will be applied.Databases to be searched (see Box 1MEDLINE (OVID) exp=explode the search term to include narrower more specific terms, .af. = search all fields in the documentexp Hearing Loss/exp Hearing/exp Self Report/(self report* or self-report* or questionnaire).af.exp Cognition/(cogniti* or executive or attention* or memory).af.(inhibit* or updat* or shift*).af.1 or 23 or 45 or 6 or 78 and 9 and 1010.1136/bmjopen-2022-071225.supp1Supplementary dataTwo reviewers will independently screen titles and abstracts, and full texts of retrieved records, against the inclusion and exclusion criteria. If insufficient information is provided in the titles and abstracts to know if it should be included or if there is disagreement between the two reviewers, the article will be included in the full-text screening. Disagreement at the full-text screening will be resolved by a third reviewer.https://www.covidence.org/).A data extraction form will be created and improved by pilot testing before data extraction starts. The data from each study will be extracted separately by two reviewers and then compared. A third reviewer will be involved if there is any disagreement. Article selection and data extraction will be carried out using Covidence review management software (http://arohatgi.info/WebPlotDigitizer/app/) will be used to extract data. A third reviewer will be involved if there is any disagreement between data extracted.The data to be extracted are the aim, study design, setting, conflicts of interest, demographic information about the population , sample size, bibliographic information , correlation coefficients between self-reported listening difficulties and executive function (and (if reported) between pure-tone audiometric thresholds and self-reported listening difficulties/executive function), type of executive function measure, type of self-reported listening difficulty measure and (where relevant) procedure of pure-tone audiometric assessment, as well as documenting any missing outcome data. We will note if both self-report and behavioural measures have been completed while wearing a hearing device. The authors will be contacted via email if sufficient detail is not reported. If data are only reported via figures, then WebPlotDigitizer . For each criteria, studies will be assessed for fulfilment .Key study characteristics will be described, including study design, sample size and type of executive function measures used. The effect to be synthesised is the relationship between self-reported listening difficulties and behavioural measures of executive function defined by correlation coefficients. If correlation coefficients cannot be calculated or extracted for meta-analysis, study authors will be contacted to request the required information. Subgroup analyses will examine (where reported) key factors of age, category/measure of self-reported listening difficulty, type of executive function measure, and type of hearing device, and pure-tone audiometric thresholds. Meta-analyses will be conducted for subgroups where data for a minimum of n=5 effects are available.The meta-analysis will be carried out using the correlation coefficient as the outcome measure. A random-effects model will be fitted to the data. We will calculate at maximum one correlation coefficient per type of executive function by type of listening difficulty. If a study reports multiple different correlations, there is likely to be some level of dependency in the data that needs to be dealt with. To handle any dependency between effect sizes in the analyses, a multilevel random-effects meta-analysis approach, as recommended by Assink and Wibbelink, will be applied.2 statistic will be reported.24 25The amount of heterogeneity  will be estimated using the restricted maximum-likelihood estimator.The analysis for the secondary research question will be carried out in the same way as above, with the difference that meta-regressions will be used to investigate potential moderator effects. The moderators will be evaluated one by one, and if both get significant effects, they will be evaluated together. The meta-regression procedure will follow the tutorial for meta-regression on the metafor package home page.26Funnel plots will be used to assess reporting bias. In addition, the funnel plot asymmetry will be evaluated with the rank correlation test and the regression test, using the SE of the observed outcomes as predictor.27 28This review does not raise any ethical issues. Results will be disseminated via scientific peer-reviewed journal articles, scientific magazines and conference presentations.Patients or the public were not involved in the creation of this review protocol.MeSH terms will be used in relevant databases.


In the squelch setting, group 1 showed a difference of 2.42 dB compared to 1.53 dB of group 2 (p = 0.85). In the head shadow setting, patients of group 1 reported a difference of 7.5 dB, compared to 4.61 dB of group 2 (p = 0.34). As for the APHAB questionnaire, group 1 reported a mean global score difference of 11.10% while group 2 showed a difference of −4.00%. Conclusions: Bilateral BCI in patients affected by bilateral conductive or mixed hearing loss might show more advantages in terms of sound localisation, speech perception in noise and subjective satisfaction if compared to unilateral BCI fitting in patients affected by unilateral conductive hearing impairment. This may be explained by the different individual transcranial attenuation of each subject, which might lead to different outcomes in terms of binaural hearing achievement. On the other hand, patients with unilateral conductive or mixed hearing loss fitted with monaural BCI achieved good results in terms of binaural hearing and for this reason, there is no absolute contraindication to implantation in those patients.Background: To assess and compare binaural benefits and subjective satisfaction of active bone conduction implant (BCI) in patients with bilateral conductive or mixed hearing loss fitted with bilateral BCI and patients with monaural conductive hearing loss fitted with monaural BCI. Methods: ITA Matrix test was performed both on patients affected by bilateral conductive or mixed hearing loss fitted with monaural bone conduction hearing implant  before and after implantation of contralateral bone conduction hearing implant and on patients with monaural conductive or mixed hearing loss before and after implantation of monaural BCI. The Abbreviated Profile of Hearing Aid Benefit (APHAB) questionnaire was administered to both groups of subjects and the results were compared with each other. Results: Patients of group 1 reported a difference of 4.66 dB in the summation setting compared to 0.79 dB of group 2 ( Binaural rehabilitation of patients affected by conductive hearing loss has been strongly discussed over the years and is still lined with criticality about its effectiveness and benefit. In fact, as demonstrated by Stenfelt, due to the individual TA , any BCI (bone conduction implant) stimulation through the so-called “cross hearing” not only the ipsilateral ear but also the contralateral cochlea leads to interfering in binaural cues .0N0) and no further settings were analysed [With regard to binaural restoration of patients affected by monaural conductive hearing loss, in the past many authors tried to demonstrate binaural benefits after fitting with BCI in such patients and their results turned out to be conflicting: in some works, BCI seemed not to improve sound localisation under noise conditions  and was analysed . Some auanalysed .The efficacy of binaural rehabilitation through BCI in patients affected by bilateral conductive hearing loss, on the other hand, has been strongly demonstrated over the years and found favourable consensus in many authors ,10,11,12Given these assumptions, the question remains whether unilateral BCI in patients affected by monaural conductive hearing loss might provide satisfactory outcomes in terms of binaural hearing if compared to an additional BCI in patients affected by bilateral conductive hearing loss already fitted with a unilateral implant. The aim of the presented study is to demonstrate whether bilateral amplification with BCI in patients affected by bilateral conductive hearing loss could provide better results in terms of speech perception under noise conditions and subjective satisfaction compared to benefits gained by unilateral BCI in patients affected by monaural conductive hearing loss.This study has been performed in accordance with the ethics standards laid down in the 1964 Declaration of Helsinki and informed written consent was obtained from all patients. Committee approval was taken from University of Turin .TM, Med-El, Innsbruck, Austria) in the Otolaryngology Division of Molinette Hospital, Turin. Group 2 included 7 patients  affected by monaural conductive or mixed hearing loss who underwent surgery implantation of monaural bone conduction hearing aid  in the Otolaryngology Division of Molinette Hospital, Turin. The main age at implantation was 30 years  for group 1 and 48 years  for group 2. Participation in the study was voluntary. All the surgical procedures were performed by the same surgeon. Inclusion criteria for all groups were patients older than 18 affected by bilateral (group 1) or monaural (group 2) conductive or mixed hearing loss fitted with bilateral (group 1) or monaural (group 2) BCI. Exclusion criteria were age under 18 years, learning disability and attention disorders. Information for each subject in both groups including age at implantation, gender, aetiology of deafness , side of implantation and pre-implantation audiometric scores are summarised in The cohort included two different groups of patients (group 1 and group 2) whose audiometric results were compared. Group 1 included 7 female patients affected by bilateral conductive or mixed hearing implanted with bilateral bone conduction hearing aid  to measure bilateral hearing thresholds in daily life before implantation. The audiological pattern of all groups is reported in 0N0); in the squelch setting the signal was frontal, and the noise was presented to one ear (S0N90); in the head shadow setting, the speech was presented to one side and the noise to the contralateral ear (S90N−90). For group 2, in the summation setting speech and noise were both presented from the front of the patient (S0N0); in the squelch setting speech was presented from the front and noise on the side affected by conductive hearing loss (S0N90); in the head shadow setting, speech was presented on the side affected by conductive hearing loss and noise on the better ear (S90N−90). The Matrix test was performed on both groups at two different times (time 0 and time 1) in order to compare the gain in terms of binaural benefits of each group:-Group 1. Time 0: tests were performed using only the BCI in the worse ear, without wearing the contralateral one for 1 week. In fact, in case of patients affected by bilateral hearing loss implanted with bilateral aids, the ear that underwent surgery first was the one that showed lower verbal perception, so the worse ear was chosen to be aided first. Time 1: tests were performed with bilateral BCI.-Group 2. Time 0: tests were performed without any BCI. Time 1: tests were performed after implantation of BCI.Speech intelligibility in noise with the BCI was tested using ITA Matrix test . ResultsThe difference between the results obtained at time 0 and those obtained at time 1 was calculated for each group in all three patterns and scores of the two groups were compared with each other to calculate the benefit in terms of binaural cues. Furthermore, each patient of both groups was administered a self-assessment questionnaire (APHAB—Abbreviated Profile of Hearing Aid Benefit—questionnaire), consisting of 24 questions to evaluate the perceived satisfaction of the subject itself with the bilateral or monaural BCI. The scores obtained provide the surgeon and the audioprothesist information regarding 4 sound properties under noise conditions: the ease of communication (EC), defined as communication under quiet conditions; the reverberation (RV), defined as communication under reverb conditions; the background noise (BN), defined as communication in places with different noise levels; the aversiveness (AV), defined as the discomfort deriving from environmental sounds. The difference between the GS obtained with bilateral or unilateral BCI resulted in the global benefit achieved by each patient from the implantation of the BCI. The subjects of the study were asked not to wear the BCI for 1 week and to fill in the questionnaire. Afterwards, they filled in the same questionnaire after at least 1 week of continuous use of the hearing aid. A global score (GS) obtained from the average of the four parameters’ scores for the two listening modes (without and with BCI) was calculated for each patient. All scores of APHAB questionnaire were expressed in the form of percentages. All surveys regarding APHAB questionnaire were carried out 2 months after BCI implantation for every subject of the study and all subjects used the implant correctly all day until our evaluation.U test, a non-parametric test used to compare the means between two groups. The test allowed us to evaluate the significance of the difference between test results of patients belonging to group 1  and patients belonging to group 2 . The statistical significance was set at p < 0.05.Categorical variables are reported as frequency and percentage; continuous variables are reported as mean ± standard deviation (SD). Due to the small sample size of the study, the statistical analysis was performed using Mann–Whitney U test non-parametric test to highlight differences in subjective hearing and quality of life without and with BCI for all four categories  in the two groups of patients.As for the APHAB questionnaire results were analysed using Mann–Whitney Statistical analysis was performed using IBM SPSS Statistics for Macintosh software, Version 28.0.p < 0.05). In the squelch configuration, patients of group 1 obtained a mean SNR of −0.60 dB  at time 0 and an average SNR of −2.84  at time 1. The difference between the results is 2.42 dB. Patients of group 2 showed a mean SNR of −3.06 dB  at time 0 and an average SNR of −4.59 dB  at time 1. The difference between obtained scores is 1.53 dB. In this setting, the differences obtained in the two groups resulted as not statistically significant (p = 0.85). In the head shadow setting, subjects of group 1 showed a mean SNR of 5.47 dB  with unilateral BCI, compared with a mean SNR of −2.03 dB  with bilateral BCI. The difference between time 0 and time 1 was 7.50 dB. Subjects of group 2 obtained an average SNR of 0.63 dB  without BCI and an average SNR of −3.99 dB  with the BCI. The difference between time 0 and time 1 was 4.61 dB. Also in this setting, the differences of the two groups resulted as not statistically significant (p = 0.34). In the summation setting, patients of group 1 showed a mean SNR of 3.73 dB  with unilateral BCI (time 0), compared with an average SNR of −0.93 dB  with bilateral fitting (time 1). The difference between the results was 4.66 dB. Subjects of group 2 obtained a mean SNR of −2.11 dB  without BCI (time 0) and a mean SNR of −2.90 dB  with the BCI (time 1). The difference between results is 0.79 dB and resulted as statistically significant compared to the difference in SNR obtained by patients of group 1 (p < 0.05). All the items of the questionnaire resulted in a non-statistically significance of the differences between the two groups  except for the AV item, which showed a statistical significance in terms of subjective satisfaction between the two groups (p < 0.05). In particular, the AV scores’ average of group 1 was 21.29%  at time 0 and 36.41%  at time 1 with an increase in the perceived discomfort of 15.12% . On the other hand, the AV score’s average of group 2 was 25.67%  at time 0 and 69.00%  at time 1, with a difference of −43.33%. Concerning the APHAB questionnaire in terms of GS, patients of group 1 reported a mean score of 33.00%  at time 0 and of 21.90%  at time 1, with a difference of 11.10%. Group 2 reported a mean score of 39.91%  without BCI and of 43.92% (SD 12.09%) with the BCI; the gain between time 0 and time 1 was −4.00% for group 2, so showing a statistical significance as compared to the score obtained by group 1  started from lower hearing thresholds at baseline condition before treatment if compared to group 2 , resulting in a difference between group 1 and group 2 of 5.84 dB for the summation setting, 2.46 dB for the squelch setting and 4.84 dB for the head shadow setting at time 0. In fact, the implantation of a single BCI in subjects affected by bilateral conductive hearing loss results necessary in a disadvantaged starting condition if compared to subjects affected by unilateral hearing loss who received normal hearing input from the contralateral normal-hearing ear since their birth .-In our work, both groups showed a substantial decrement in the signal-to-noise ratio (SNR) at the speech recognition threshold (SRT) for all tested settings. However, group 2 obtained higher absolute scores in all analysed settings and, in contrast, a lower gain of benefit in terms of binaural cues if compared to group 1. There are several possible reasons that could explain these results. First of all, patients of group 2 were implanted when they were already adults and, as a result, they experienced binaural hearing deprivation for many years. Moreover, Stenfelt demonstrated that the so-called “transcranial attenuation” is responsible for affecting binaural hearing with a BC aid due to the additional stimulation of the cochlea contralateral to the BC device side [-p < 0.05) only in the summation setting. In fact, the different “starting condition” of group 1 and group 2  means that when signal and noise were presented both from the front, the gain of benefit obtained by group 1 with both BCI was much more consistent if compared to the gain of advantages obtained by fitting patients who already showed good ability to perceive sounds through to the non-aided ear (group 2). Indeed, bilateral BCI in patients affected by bilateral conductive hearing loss (group 1) led to symmetrical hearing thresholds and resulted in a great audiological improvement over the starting condition.According to Agterberg et al., who investigated binaural summation scores in patients affected either by bilateral conductive hearing loss implanted with bilateral BAHA or unilateral BC hearing loss fitted with unilateral BAHA, concluded that the former reported better scores in terms of binaural hearing ; our res-Patients of group 2 reported heterogeneous scores in terms of binaural benefits but showed a real binaural achievement also in the squelch setting, with a mean of −4.59 dB at time 1 and a difference of 1.53 dB if compared to the baseline situation. Since all patients in this group have been implanted in adulthood, we may assume that they experienced the same binaural hearing deprivation. For this reason, this heterogeneity in scores might be ascribed to the different individual TAs of each subject of the study.Scores obtained in our work lead us to make some considerations:Our audiometric results find some correspondence in the APHAB questionnaire which shows that patients of group 1 reported higher satisfaction with respect to their initial condition if compared to subjects of group 2, whose subjective performances seemed to be even better without than with the BCI (GS benefit: −4.00 dB). This suggests that, due to the different individual TA, the stimulation of the contralateral cochlea might cause disturbance in some patients affected by unilateral BC hearing loss fitted by unilateral BCI. Moreover, Priwin et al. found that some children with unilateral hearing loss used the BCI only in the classroom, thus revealing that unilateral BC hearing might show benefits in the school environment but seemed not to represent a subjective fundamental tool for patients in their everyday hearing life .In conclusion, despite the limits given by the low sample size, our data suggest that bilateral BCI in patients affected by bilateral conductive or mixed hearing loss might show more advantages in terms of speech perception in noise and subjective satisfaction if compared to unilateral BCI fitting in patients affected by unilateral conductive or mixed hearing impairment. This may be related both to the different transcranial attenuation of individuals which was considered to be responsible for the discomfort experienced by some patients fitted with unilateral BCI, and to the asymmetrical hearing thresholds obtained by such subjects. On the other hand, patients with unilateral conductive hearing loss fitted with monaural BCI achieved good results in terms of binaural hearing and for this reason, there is no absolute contraindication to implantation in these patients. Compared to the pre-existing literature, a pre-operative trial with softband or adhesive devices may be of value in patients affected by unilateral conductive hearing impairment in order to priorly select those who would benefit most from the procedure.