Vestibular schwannoma is a clinically benign schwannoma that arises from the vestibulocochlear nerve that causes sensorineural hearing loss. This tumor is clinically and oncologically regarded as a benign tumor as it does not metastasize or invade surrounding tissues. Despite being a benign tumor, its management is difficult and controversial due to the potential serious complications, such as irreversible sensorineural hearing loss, of current interventions. Therefore, preventing hearing loss due to the natural course of the disease and complications of surgery is a challenging issue for an otologist. Improvements have been reported recently in the treatment of vestibular schwannomas. These include advances in intraoperative monitoring systems for vestibular schwannoma surgery where the risk of hearing loss as a complication is decreased. Precise genomic analysis of the tumor would be helpful in determining the characteristics of the tumor for each patient, leading to a better hearing prognosis. These procedures are expected to help improve the treatment of vestibular schwannomas. This review summarizes recent advances in vestibular schwannoma management and treatment, especially in hearing preservation. In addition, recent advances in the understanding of the molecular mechanisms underlying vestibular schwannomas and how these advances can be applied in clinical practice are outlined and discussed, respectively. Moreover, the future directions from the bedside to the bench side are presented from the perspective of otologists. Vestibular schwannoma is a clinically benign schwannoma that arises from the vestibulocochlear nerve  that runs through the internal auditory canal. The vestibulocochlear nerve comprises of the cochlear nerve, the superior vestibular nerve, and the inferior vestibular nerve. Most vestibular schwannomas originate from the inferior vestibular nerves between the other two nerves ,2. VestiThe incidence of vestibular schwannoma is estimated to be approximately 20 new cases per million people each year  with a lVestibular schwannomas are clinically and oncologically regarded as benign tumors. Despite this, the management of vestibular schwannoma is difficult and controversial because vestibular schwannoma interventions can cause complications. Considering the interventions for vestibular schwannomas, severe complications, including irreversible sensorineural hearing loss and facial nerve paralysis, must be considered. Therefore, while vestibular schwannoma is a benign tumor, when and how to treat it is not an easily solved clinical question and highly depends on several factors and conditions.Improving vestibular schwannoma management to prevent complications such as hearing loss and facial nerve palsy is desirable. In particular, from the viewpoint of an otologist, hearing preservation from the vestibular schwannoma is an essential but challenging subject, as well as preventing facial nerve paralysis. With recent advances in surgical equipment systems and the molecular understanding of the disease, vestibular schwannoma treatment has changed and improved. This review summarizes the recent advances in vestibular schwannoma management and treatment. Future directions from bedside to bench will be shown from the viewpoint of the otologist.Hearing loss caused by vestibular schwannoma is not always severe or permanent. This hearing loss can be mild to moderate ,11,12,13Thus far, Stangerup et al. reported that, while 53% of patients had good hearing and speech discrimination upon diagnosis, this became 31% after ten years of observation . RecentlConsidering the risk of gradual or sudden hearing loss in the natural course of disease for patients with vestibular schwannoma ,25, hearTherefore, if the tumor size is not life-threatening, non-hearing preservation surgery can be chosen once hearing loss sets in by natural course. This type of surgical decision making has been widely applied. However, the importance of hearing preservation has been underestimated in this context.Preserving residual hearing in vestibular schwannoma patients is necessary for several reasons. Hearing loss on the affected side due to either the natural course of the disease or the side effects of the interventions usually results in impaired sound localization and difficulty in understanding speech in the presence of background noise ,27. HoweThere are several management methods for vestibular schwannomas. A “wait-and-scan” policy, in which patients’ tumors are observed once or twice by MRI per year, is well applied to patients with non-growing tumors ,33,34,35There are several interventions available for a growing vestibular schwannoma, including radiotherapy and surgical resection. Stereotactic radiosurgery, such as Gamma-Knife ,38, has Although stereotactic radiosurgery has several merits and is widely used, it still has the disadvantage of hearing loss. It is believed that stereotactic radiosurgery has a high hearing preservation rate. However, recent long-term observations showed that patients’ hearing after stereotactic radiosurgery gradually decreased ,43,44,45Neurofibromatosis type II is often treated by a neurosurgeon and less often by an otolaryngologist, requiring a different treatment plan. In neurofibromatosis type II, special consideration should be given to the possibility of bilateral hearing loss due to bilateral vestibular schwannomas. Treatment strategies for sporadic vestibular schwannomas rarely apply to neurofibromatosis type II cases, as contralateral hearing levels and the possible presence of other brain tumors such as meningiomas affect the treatment strategy for neurofibromatosis type II.Surgical resection can be performed for all tumor sizes. Usually, large tumors, such as those associated with brainstem compression, are resected by neurosurgeons, and otologists treat relatively smaller tumors that are limited to the inner ear canal or those that slightly reach the brainstem. The middle fossa approach, translabyrinthine approach, and retrosigmoid approach are thought to be the three primary microsurgical approaches; however, other approaches are also used to remove vestibular schwannomas, each with benefits and limitations.Surgical interventions for vestibular schwannoma can be categorized into two types depending on the expected postoperative hearing results: non-hearing preservation surgery and hearing preservation surgery. Most non-hearing preservation surgeries are performed using the translabyrinthine approach . The traWhile the surgical approach can be easily divided into two groups, it is difficult to define “what is good and serviceable hearing” or “what is hearing worth to be preserved”. Therefore, several criteria have been used. Historically, Wade and House described the “50/50 rule”, which defined serviceable hearing as a pure tone average (PTA) of ≤50 dB with a speech discrimination score (SDS) of 50% or better . In 1988Based on these previous criteria, candidates for hearing preservation surgery have often been defined as patients with PTA ≤ 30 dB with SDS ≥ 70% ,57 or wiThe selection of the surgical approach is dependent on the degree of residual hearing, tumor size, tumor location, and whether hearing preservation is preferred. If hearing preservation surgery is selected, the central focus of the procedure is the preservation of auditory function. However, irrespective of which surgical category is selected, the surgeon must attempt to prevent facial nerve palsy, particularly in cases with no evident preoperative deficit. Intraoperative neural monitoring is a widely used method to facilitate postoperative hearing and prevent facial nerve function deficits.Since the first report of intraoperative ABR monitoring in vestibular schwannoma surgery in 1982 , it has However, intraoperative ABR monitoring has two major limitations. First, ABR detection is time-consuming. ABR measurement requires an average of 500–2000 stimulations and a duration of more than one minute. Although this time period is acceptable when applying ABR as a hearing test in an outpatient setting, it is problematic in intraoperative monitoring. Second, vestibular schwannomas impede acoustic neuron conduction. As a result, the amplitude of the ABR decreases and, in some cases, intraoperative ABR waveforms cannot be obtained. In the 2010s, a novel form of intraoperative monitoring for hearing function was developed, i.e., DNAP monitoring . In DNAPElectromyographic monitoring systems, such as the Medtronic NIM system, are widely used ,74,75,76The retrolabyrinthine approach is a surgical approach for vestibular schwannomas that can preserve patients’ hearing ,82,83,84However, there are several disadvantages of the retrolabyrinthine approach as well. First is that this approach cannot be applied to some patients because of certain anatomical features of the temporal bones. Patients with one or more of the following anatomical features may be poor candidates for this approach: high jugular bulb, less developed bony cells posterior to the labyrinth, less developed mastoid air cells, and less developed sigmoid sinus on the opposite side of the surgical site. The second disadvantage of the retrolabyrinthine approach is that the surgical field is relatively narrower than other approaches, and the fundus of the inner ear canal cannot be visualized by surgical microscopy alone. Although the use of the endoscope can overcome this limitation to some extent ,86,87, tPreviously, Bento et al. reported hearing preservation in 31.8% of retrolabyrinthine approach cases, all of whom presented with a minimum AAO-HNS level of Class B . RecentlAs discussed above, the hearing preservation rate has recently improved in patients with vestibular schwannoma. Therefore, there has been an increase in the number of patients with vestibular schwannoma who have undergone hearing preservation surgery. In particular, hearing preservation surgery has increased in younger patients where long-term postradiotherapy hearing loss would be a problem, or patients with normal hearing and smaller tumors who tend to avoid surgery due to the risk of postoperative hearing loss.BRAF gene variants in lung cancer and melanoma has been used to predict its clinical features and choices of treatment [Under such clinical situations, the precise prediction of tumor growth or the risk of hearing loss is required to determine the optimal timing of intervention. Moreover, the prediction of long-term prognosis after hearing preservation surgery is critical. However, a method to predict the clinical course of each patient has not been established. Recently, especially in the study of malignant tumors, the molecular biological investigation of surgically removed tumors from each patient has been thought of as being a feasible way to predict the clinical course of the patient. This approach has been broadly used in clinical settings for other tumors. For example, the investigation of reatment ,90.To date, several previous reports have suggested the possible use of these molecular biological approaches for vestibular schwannoma cases ,92,93. MClinical otologic surgeons await the unveiling of the molecular mechanisms underlying the tumorigenesis of vestibular schwannoma, which can be used to develop novel prognosis prediction methods based on somatic mutations of the tumors, for several reasons.First, this new prediction method would be helpful in postoperative management. If in the future, after hearing preservation, genomic testing of the resected tumor reveals a high probability of tumor regrowth surgery, radiation therapy for salvage can be considered early. In contrast, if the resected tumor is found to have a lower growth rate through somatic gene investigation, the postoperative management of the tumor will be easier, and even if a small residual tumor is detected, the surgeon can reassure the patient.Second, it would broaden the indications for surgery and possible surgical approaches. If the prediction of tumor growth or the sensorineural hearing loss risk is possible, a vestibular schwannoma biopsy can be considered along with complete tumor resection, especially under the reinforced monitoring of the facial nerve and hearing. Moreover, if rapid intraoperative diagnosis for these risks is possible, the results will help surgeons decide whether to focus on tumor resection or hearing preservation. In the case of a low-risk tumor, preservation of the hearing can be prioritized, and in the case of a high-risk tumor, the total resection of the tumor can be prioritized. In this context, the surgery starts with hearing preservation, such as via the retrolabyrinthine approach, and then, depending on the result of the rapid diagnosis made through intraoperative biopsy, the surgeon can convert to a non-hearing-preservation approach, such as the translabyrinthine approach, if total resection of the tumor is preferable. In such cases, concurrent cochlear implantation ,96,97,98Third, understanding the molecular mechanisms underlying the development of sporadic vestibular schwannoma may assist in developing new drug therapies. Neurological disorders such as sensorineural hearing loss caused by vestibular schwannoma usually result from tumor compression and impaired blood flow. The mechanism of neurological damage, however, has not yet been clarified, making it difficult to predict the progression of hearing loss or sudden hearing loss caused by vestibular schwannoma. However, novel therapies can act on this underlying molecular mechanism. Recently, several candidate drugs for the treatment of neurofibromatosis type II have been reported ,103,104.NF2 gene, a tumor suppressor gene located at 22q12 [NF2 encodes Merlin, a cytoskeletal protein [NF2 gene, combined with the acquired inactivation of this gene in somatic cells, leads to vestibular schwannomas, similar to the well-known “two-hit” theory for tumors caused by the inactivation of other tumor suppressor genes [Much of the knowledge on the molecular biology of vestibular schwannoma has been obtained from patients with neurofibromatosis type II, an autosomal dominant hereditary disease that manifests with bilateral vestibular schwannomas. Previous investigations have revealed that germline variants of the at 22q12 , can cauat 22q12 ,108,109. protein . Variantor genes   caused by partial or complete loss of chromosome 22, where the NF2 gene is located, can lead to sporadic vestibular schwannoma. Previously, it has been reported that there is at least one allele of the NF2 gene mutation in 50–85% cases [NF2 gene has been reported in 30–62% cases [NF2 genes in sporadic vestibular schwannomas. They revealed “two-hit” alterations in the NF2 gene in every tumor [NF2 gene mutations might indicate that it may vary depending on the detection method and patient population. However, the mutation or inactivation of the NF2 gene is important for the tumorigenesis of sporadic vestibular schwannoma. Further investigation is required in future studies.It has been reported that somatic alterations in the wannomas ,116,117.wannomas ,118. Add5% cases ,128,129,2% cases . Recentlry tumor . This vaNF2 genes can explain many of the sporadic vestibular schwannoma cases. However, in a certain percentage of sporadic vestibular schwannoma cases, no mutations in the NF2 gene or mutations in only one allele were detected  found in the blood without an open biopsy. This new technology has been used to treat brain tumors . CombiniThis liquid biopsy is now possible by cerebrospinal fluid sampling from patients with vestibular schwannoma ,151,152.If a liquid biopsy is possible more easily and broadly, surgeons can propose early surgery to avoid irreversible hearing loss in high-risk patients and avoid unfortunate hearing loss due to an inappropriate wait and scan. To develop these ideal decision-making methods, the molecular mechanisms of sporadic vestibular schwannoma should be clarified.In this manuscript, we reviewed the recent advances in vestibular schwannoma treatment for hearing preservation from the viewpoint of otologists. We also summarized the latest understanding of the molecular biological mechanism of sporadic vestibular schwannoma. Combining understanding of the clinical viewpoint (Bedside) and molecular biological viewpoint (Bench) of vestibular schwannoma, a new treatment strategy is suggested . This neTo realize this personalized approach to surgery, in which the patients maintain their hearing ability after surgery while controlling local tumor growth, it is necessary to continue refining intraoperative monitoring technology and to further elucidate the molecular biological mechanism of vestibular schwannoma.


Auditory screening and early identification and management of patients with hearing loss improve the development prospects of infants.To analyze the outcomes produced by an Auditory Health Program in neonates managed in an intensive care unit.This prospective cross-sectional study enrolled neonates referred to the neonatal care unit at hospital CAISM/Unicamp with stays lasting for 48 hours and more within a period of 13 months.Automated monitoring of brainstem auditory evoked potentials was used in the auditory screening of neonates at the time of discharge. Children with poor BAEPs were sent to undergo audiological, otorhinolaryngological, and genetic tests.Auditory screening was performed for 84.7% of the live births; 39.7% were screened at 30 days or more of age. Diagnostic tests revealed that 63.8% of the children had normal hearing. Incidence of hearing loss was 4%; sensorineural hearing loss was observed in 1.4% of the subjects; 0.24% had auditory neuropathy spectrum disorder; and 2.2% had conductive hearing loss.Neonatal auditory screening was not offered universally, and nor was it carried out, in many cases, within the child's first month of life. Screening must be performed before neonates are discharged and in more than one stage. A high incidence of hearing loss was observed. Mortality rates in high-risk neonates have progressively dropped due to the advances in technology in neonatal intensive care units (ICU), medical devices, drugs, and the growing number of medical professionals specialized in this area.The advances in neonatology have led to higher survival rates among preterm low-weight babies. However, health care workers have been increasingly concerned with the quality of life these neonates will enjoy, as sequelae often set in after discharge.Hearing loss is a frequent alteration in children seen in neonatal ICUs, with incidences ranging between 1% and 4% in this populationSensory deprivation consequent to hearing loss, specifically in the early stages of language acquisition, introduces significant barriers to the overall development of the affected childrenUniversal neonatal auditory screening has been recommended as the main strategy to reduce the age at which hearing loss is diagnosedThe Neonatal Auditory Health Program encompasses a set of actions involving universal auditory screening for neonates accompanied by speech and hearing, otorhinolaryngological, and genetic tests for the subjects singled out during screening or speech and hearing tests. When performed early on, these procedures may improve patient development.Few studies have addressed the outcomes of children in need of intensive care.Therefore, this study aimed to analyze the outcomes produced by an Auditory Health Program including auditory screening and hearing loss diagnosis for neonates treated in an intensive care unit and/or intermediate care setting at Prof Dr. José Aristodemo Pinotti CAISM Hospital.This cross-sectional prospective trial was approved by the Ethics in Research Committee School of Medical Sciences, University of Campinas (FCM/Unicamp) and was given permit 1.085/2009. Subjects were enrolled voluntarily and their parents signed an informed consent term for their participation.The study included neonates seen in the ICU and/or intermediate care center at CAISM Hospital with stays lasting for 48 hours and more within a period of 13 months, between March of 2011 and March of 2012. Children born in other services, and patients who died or failed to complete all the stages of the study were excluded. Initially, the risk indicators on the JCIH and COMUSAAudiological assessment was carried out at the pediatric audiological diagnosis laboratory at Unicamp Cepre Pediatric Diagnostics Lab, FCM, Unicamp in a sound proof room. The test included the following steps: interview, middle ear examination, and BAEPs , in addition to transient otoacoustic emissions (TOAEs) and/or distortion product otoacoustic emissions (DPOAEs). The patients were sleeping during the administration of the test procedures.Electrophysiological thresholds, as well as auditory pathway integrity, were assessed through BAEPs on an Interacoustics Eclipse EP 25 with patients wearing ear buds. Auditory pathway integrity was tested with non-variable 80-dB clicks, to allow the assessment of the auditory pathway to the brainstem and identify possible alterations in its course. Electrophysiological thresholds were captured by offering patients stimuli at decreasing intensities until the V wave was triggered, using click and tone burst stimuli at 500 and 1,000 Hz. Stimulation was repeated twice to verify the reproducibility of the tracings and the presence of response. Responses were captured through surface electrodes with electrolytic paste placed on the right and left mastoid and on the frontoparietal position. Patients had their skin cleaned with abrasive paste on the sites on which electrodes were placed. The following parameters were analyzed: presence of waves I, III, and V; absolute latency of waves I, III, and V; interpeak latency I-V, I-III, III-V; amplitude of wave V in relation to amplitude of wave I; interaural differences in I-V interpeak latency or wave V latency. TOAEs and DPOAEs were captured using device ILO 292 USBII.Middle ear status was assessed through otoscopic examination (to verify whether patients were able to undergo impedance testing), tympanogram tracing, and ipsilateral acoustic reflex from 500 to 4,000 Hz, with the tone in the transducer set at 1,000 Hz. Impedance tests were carried out on a 235H-Interacoustics device.The responses obtained in the tests were recorded in a sheet. Normal hearing was attributed to infants with electrophysiological thresholds equal to or under 30 dB and absolute and interpeak latencies within the values expected for the subjects' ages and responses within expected ranges for the remaining test procedures.Patients with altered audiological test results were referred to an ENT physician for physical examination and imaging tests.o P10005340-6; testing method for hearing loss of genetic origin). PCR was used to analyze deletions D(GJB6-D13S1830) and Δ(GJB6-D13S1854) using previously described primersThe team's geneticist tested neonates underperforming in the screening tests by collecting DNA from the oral mucosa according to the protocol adopted in Laboratory Unicamp Cepre Pediatric Diagnostics Lab, FCM, Unicamp. DNA samples were collected by the examiner after the completion of the auditory tests. Oral mucosa DNA was used to analyze mutation 35delG by AS-PCR as standardized by the Human Molecular Genetics Lab at CBMEG ; 59% had two to four risk factors for hearing loss.p = 0.3963), gestational age (p = 0.3448), weight (p = 0.3291), number of risk factors (p = 0.4826), or age after birth at which the tests were carried out (p = 0.1654) were analyzed. Among risk factors, only hyperbilirubinemia was statistically significant in relation to the outcome of the auditory screening tests. Two thirds (66.7%) of the children with this risk factor failed auditory screening (p = 0.0002).No statistically significant difference was seen when pass/fail statuses and gender  completed the required diagnostic tests. The other patients were excluded from the program for not having completed the process after four attempts of scheduling visits for them.Mutation 35delG in the connexin 26 gene (GJB2) or deletions Δ(GJB6-D13S1830) and Δ(GJB6-D13S1854) in gene GJB6 were not seen in the genetic tests performed on the 44 patients who failed auditory screening tests. Two children had mutation A1555G in mitochondrial gene MTRNR. These children had normal hearing. p = 0.3477), gestational age (p = 0.2523), weight (p = 0.2491), and number of risk factors (p = 0.067). Statistically significant difference was seen (p = 0.002) between failed auditory screening tests for 35, 40, and 45 dB and patient diagnosis. Most of the children (90.9%) who failed the test at 40 dB had normal hearing.No statistically significant difference was seen when diagnosis of normal hearing and hearing loss were considered vis-à -vis gender  of the subjects had normal hearing. Hearing loss was observed in 36% (16/44) of the children; 20.4% (9/44) had conductive hearing loss; 13.6% (6/44) had sensorineural hearing loss; and 2.2%(1/44) had auditory neuropathy spectrum disorder .Most of the children who failed the screening tests had normal results in the hearing tests applied. There was a high rate of false positive results, i.e., children failing the auditory screening tests were deemed to have normal hearing in diagnostic evaluation. Automated monitoring of BAEPs in auditory screening has been claimed to reduce the need to refer patients to diagnostic assessment. The reduced rates reported in the literature are based on a two-stage auditory screening process (test-retest)Forty-three percent of the patients referred to diagnostic evaluation were lost in follow-up. Patient evasion in auditory health programs is a global reality. Compliance to auditory health programs must be improved to allow the early detection of individuals with hearing loss. Factors such as low number of prenatal care visits (one to three), having more than one child, being a single parent, and mothers with low levels of education impact infant health program compliance rates. It has been recommended that topics concerning the relevance of hearing for the development of children and the possibility of detecting early cases be discussed during prenatal care visits, so that parents become aware of the facts to consider on infant deafness and its adverse impacts. The importance of neonatal auditory screening should be more communicated to patients, health care workers, and pediatricians in particular, as neonates are part of the audience they serve, so as to encourage patient attendance to screening tests.The incidence of hearing loss in the studied sample was of approximately 4%; 1.4% of the subjects had sensorineural hearing loss, 0.24% had auditory neuropathy spectrum disorder, and 2.2% had conductive hearing loss . The incGenetic assays showed patients were normal for mutation 35delG in the connexin 26 (GJB2) gene. Although none of the individuals had mutation 35delG, it is present in 70% of the individuals with hearing loss in whom gene GJB2 is involved. A prevalence of 0.97% has been reported in Brazil for mutation 35delG, a rate of 1:103 heterozygotes, in a screening initiative carried out with 620 neonates in the region of CampinasThe children diagnosed with conductive hearing loss are being followed by the team's ENT physician and, whenever needed, they are referred for audiological evaluation. They will be followed by a multidisciplinary team, as the impact of conductive hearing loss upon the development of hearing, language, and school performance has been established. The patients with sensorineural hearing loss are currently having hearing aids fitted  and speech and hearing rehabilitation.The correlation between the studied variables and failure in auditory screening tests was not statistically significant. When risk factors are considered, only hyperbilirubinemia significantly affected the outcome of auditory screening tests. Diagnosis was statistically correlated with failing screening tests at 35, 40, 45 dB. Most of the children (90.9%) who failed the tests at 40 dB had normal hearing. More studies will be carried out to increase the size of the sample and verify this finding. The low number of children diagnosed with hearing loss may have affected the test results. The literature indicates higher incidences of hearing loss in children weighing 1,500 g and less and preterm babiesThe analysis of the results of this study indicated it was not possible to offer universal neonatal auditory screening in the studied sample or to screen patients within their first 30 days of life, given the long time for which neonates stay in intensive care. Whenever possible, auditory screening should be carried out before discharge. One-stage auditory screening led to a significant number of false-positive results. The overall incidence of hearing loss was 4%, including cases of sensorineural and conductive hearing loss, and auditory neuropathy spectrum disorder.


Interrupted speech and text are used to measure processes of linguistic closure that are important for recognition under adverse backgrounds. The present study compared recognition of speech and text that had been periodically interrupted with matched amounts of silence or white space, respectively. Recognition thresholds were obtained for younger and older adults with normal or simulated/impaired hearing and correlated with recognition of speech-in-babble. Results demonstrate domain-general, age-related processes in linguistic closure affecting high context sentences and domain-specific, hearing-related processes in speech recognition affecting low context sentences. Text recognition captures domain-general linguistic processes in speech recognition susceptible to age-related effects. Nevertheless, listeners can usually maintain high perceptual accuracy even when substantial portions of the signal are masked or deleted . SimilarIndeed, both speech and text provide modality-specific representations of the underlying modality-general linguistic structure. Their processing may thus be influenced by an overlapping set of modality-general perceptual, cognitive, and linguistic factors , 20 older adults with normal hearing , 21 older adults with hearing impairment  and 23 younger adults with normal hearing who listened to spectrally shaped speech and noise to simulate hearing loss . YNH and YSH adults had pure-tone thresholds ≤20 dB HL at octave frequencies from 0.25–8 kHz . ONH and2.2birch canoe slid on the smooth planks). Figure Experimental stimuli were sentences selected from the Harvard/IEEE corpus  with fiv2.3Stimuli were scaled to 70 dB SPL, prior to interruption, and then spectrally shaped, by increasing gain in 1/3 octave bands, according to the individual thresholds of the YNH, ONH, or OHI listeners to ensure at least 15 dB sensation level (SL) through at least 4 kHz. In practice, this resulted in minimal changes in the spectrum for YNH and ONH listeners  with an average speech level maintained at 70 dB SPL. The average speech level following OHI spectral shaping was 82 dB SPL. The YSH group listened to spectrally shaped speech that was identical to the shaped speech provided to individual OHI participants to which they were paired. In addition, speech was presented in the presence of a threshold matching noise with a spectrum that matched the hearing thresholds of the paired OHI listener in order to equate sensation levels between OHI and YSH listeners. Previous analysis with these same listeners has indicated that the combination of threshold matching noise and spectral shaping provided to the YSH group is sufficient to model the benefit OHI listeners obtain from glimpsing speech in speech-modulated compared to unmodulated noise  HDA 200 headphones following a TDT  System III digital-to-analog processor (RP2/RX6) and headphone buffer (HB7/HB5). Presentation was monaural to the right ear, unless target sensation levels were better obtained using the left ear . Text stimuli were displayed as full sentences for each condition, centered on an ELO  touchscreen monitor in a visual text window (1600 × 200 pixels).Participants completed testing in a sound-attenuating booth. Speech stimuli were presented at a sampling rate of 48.828 kHz A block of four familiarization trials was provided prior to testing that exposed participants to the range of duty cycles tested. Ten sentences were presented per duty cycle condition, with a total of 40 sentences for each modality. Testing proceeded from the smallest duty cycle  to the greatest  to minimize perceptual learning across trials.Open-set responses were live scored. Participants were encouraged to guess. No feedback was provided. A response was scored as correct if the participant repeated each key word exactly . Data across the duty cycle conditions for each participant were fit to individual logistic functions and the 50% recognition threshold for speech (SRT50) and text (TRT50) were calculated. These values reflect the duty cycle  required to obtain 50% correct speech/text recognition.3.3.1All participants had adequate hearing and visual acuity to perceive the speech and text stimuli, as indicated by obtaining at least 90% correct for uninterrupted speech and text , with the exception of one OHI who obtained 86% for uninterrupted speech.As a summary of performance, logistic functions fit to the group average for interrupted speech and text are displayed in Fig. p2 = 0.89, was found, confirming better recognition for interrupted speech with less perceptual information . Also, observed was a main effect of group, F = 14.6, p < 0.001, ηp2 = 0.35, with a significant interaction, F = 7.4, p < 0.001, ηp2 = 0.22. Regarding the group effects, post hoc paired t-tests between groups demonstrated an effect of simulated and actual hearing loss for SRT50 . However, the comparison among older adults did not reach significance following Bonferroni correction for multiple comparisons. As expected, no effect of simulated or actual hearing loss occurred for TRT50 . An effect of age was observed for both SRT50  and TRT50 . Thus, these results demonstrated that the group effect for SRT50 was mediated by both age and reduced hearing, whereas the effect of TRT50 was mediated by age-related factors alone.As can be observed from Fig. 3.2s) partial correlation analyses, controlling for age and PTA4. Results demonstrated a weak but nonsignificant positive correlation between speech and text thresholds . To assess the generalization of interrupted speech and text measures to more realistic speech-in-babble recognition, partial correlations were also tested with R-SPIN sentence recognition. As shown in Fig. s = −0.50, p < 0.001) and low  context sentences, accounting for around 30% of the variance of speech recognition in multitalker babble. TRT50 was weakly negatively correlated with high  and non-significantly with low  context sentences. Higher speech and text recognition thresholds, which indicated that participants required greater preservation of the stimulus, were associated with poorer speech-in-babble performance. Using All 84 participants were entered into Spearman rank order , reflecting shared variance in indexing general speech-in-babble recognition abilities. As TRT50 was only significantly associated with high context sentences, low content sentence recognition was added as a control variable along with age and PTA4. SRT50  and TRT50  were associated with the unique variance in performance on the high context sentences. In this case, the correlation coefficients for SRT50 and TRT50 on the unique variance in high context sentences were not significantly different .High and low context sentences were significantly correlated (r4.The present findings examined recognition of similarly interrupted speech and text to determine contributions of modality-general and modality-specific factors. The interruption parameters for speech and text were chosen to be analogous and provide matching signal representation in both modalities. Logistic functions were used to describe recognition performance and compare the proportion of preserved speech and text needed to reach an estimated 50% correct threshold. Results indicate only a weak association between interrupted speech and text, when controlling for age and hearing loss. This suggests an overall low modality-general effect of linguistic closure, even though the visual and auditory signal information is maximally matched between both modalities. Therefore, similarity between underlying linguistic elements achieved by matching interruption parameters for text and speech does not fully account for the domain-specific processing in each modality.The correlation analysis with R-SPIN sentences further highlight the role of domain-general and domain-specific processing of interrupted sentences. Specifically, the present results reveal significant correlations of both interrupted text and speech with high context masked R-SPIN sentences that have semantic cues that aid key word identification. Indeed, when controlling for general speech-in-babble abilities, SRT50 and TRT50 are similar in explaining linguistic closure abilities. In contrast, interrupted speech but not interrupted text scores also explain additional variance on low context masked R-SPIN sentences for which key word identification is much less constrained by contextual cues. This pattern of results suggests that the modality-general effect of linguistic closure facilitates key word recognition in semantically predictable contexts for both text and speech, while modality-specific factors of speech-in-babble processing play a greater role when contextual cues are limited, such as the case with low context R-SPIN sentences. Consistent with the purpose and design of the TRT task (The role of modality-general and modality-specific factors can be further examined in the effects of age and hearing loss. The comparison of performance across the four groups of the present study, which differ in participant age and hearing abilities, indicates that both age and hearing loss influence the perception of interrupted speech Fig. . HoweverOverall, the present findings indicate that both age and hearing loss have a negative influence on the perception of interrupted speech, while only age affects perception of interrupted text. Stronger correlations with sentences in babble with interrupted speech than text, while controlling for age and hearing loss, were likely due to these modality-specific factors. Although perception of both interrupted speech and text involves modality-general linguistic closure, which can compensate for missing linguistic elements in the sensory signal, other factors such as age, hearing ability, and signal quality may affect perceptual processing, leading to modality-specific differences in perceptual outcomes. Overall, the study findings indicate that the perception of interrupted speech is a stronger predictor than interrupted text for the recognition of speech in babble.


Background: A high level of occupational noise exposure has been noted in the fishing sector. Yet, less is known regarding other navigation groups, such as merchant seafarers, since a French study in the 1980s. This study assesses hearing impairment (HI) in a French merchant seafarers’ population. Methods: We collected data of all audiograms performed in 2018 and 2019 for French merchant seafarers. For each seafarer, hearing ability was measured in both ears using pure-tone audiometry at the following frequencies: 0.5, 1, 2, 3, 4, 6, and 8 kHz. Hearing threshold levels (HTLs), or the intensity of sound below which no sound is detected, were measured in decibels Sound Pressure Level (dB SPL) at each frequency and recorded in 5 dB increments. For HI, we used the validated definition of the American Speech–Language–Hearing Association (ASHA). Results: We were able to include statistical analysis results of 8308 audiograms. In a multiple logistic regression adjusted for age, experience, and class of navigation, we found that experience of more than 14 years Odds Ratio OR 1.28 (CI 95% 1.07–1.53), age 31–40 OR 2.2 (CI 95% 1.4–3.4), and >40 years OR 14, 3 (IC 95% 9.7–21) and marine engineers OR 1.26 (IC 95% 1.01–1.57) were still risk factors for HI. Conclusion: In 2018, Marine engineers were still the workers’ group with a higher risk of HI in merchant seafarers but, notch at 4 Hz, specific of noise-induced hearing loss, has improved. They have an HI close to the definition of socioacousis and mean deficit differences with deck and services’ merchant seafarers improved. Our results could be interpreted as a limitation of occupational noise exposure impact in a merchant seafarers’ population, needing an improvement in prevention measures and also encouraged to continue to improve onboard working conditions. Noise-induced hearing Loss (NIHL) is mainly linked to impulse and continuous noise exposure on the levels that can cause damage to the hearing system . World wFor a seafarers’ population, some risk factors of HI have been highlighted in the literature, including working in engine rooms, described in a Danish cohort published in 2008, which showed that fishermen and seafarers working in engine rooms were more likely to consult a hearing clinic than other seafarers and the general population . Indeed,A French study carried out by Jégaden in the 1980s on 222 seafarers found a level of noise exposure above the regulatory standards with a variable impact on the seafarers’ hearing.This study showed a typical hearing impairment with a notch at 4 kHz for marine engineers, while the deck crew had early presbycusis-like impairment which can be likened to socioacusis . SocioacIndeed, a study carried out in 2016 on 227 professional fishermen showed that a high rate of fishermen worked for long periods (more than 16 h), with noise levels ranging from 94.8 to 105.0 dBA. A distinction was made between the number of people with hearing impairment (which we could relate to presbycusis) and those with NIHL. The results showed, on one hand, that the number of people with NIHL was significantly correlated with the length of time in the fishing profession but not with age. On the other hand, the number of hearing-impaired people was significantly related to age but not to the number of years spent in the trade [Recommendations to limit occupational exposure levels have been published at the international and French levels ,12. New Hearing impairment studies in seafarers and fishermen are scarce and have only been conducted in a few geographical areas ,16,17,18The objectives are to investigate the hearing impairment prevalence in merchant French seafarers, to assess the impact of occupational noise exposure and the risk factors, and to follow the evolution in comparison to Jégaden‘study carried out in the 1980s up till now [We performed a cross-sectional observational study using retrospective data from the Health at Work file.In France, a specific occupational prevention unit called the Service de Santé des Gens de Mer (SSGM) oversees the medical examination of French seafarers. As part of the monitoring of occupational noise exposure and to assess the impact on the hearing capacities of seafarers, they carried out annual or biannual audiograms. The Labour Code stipulates that a worker whose daily exposure to noise exceeds 80 dBA or 135 dBC peak sound pressure level may, at his or her request or that of the occupational physician, undergo a screening audiometric test ,19,20. AThe data from audiometry are directly put into the seafarer’s occupational health file during medical examination at the SSGM. The data from the audiometric tests were anonymously extracted by the SSGM’s Informatics’ department. As audiometry is carried out at one or two-year intervals, we included all audiograms from 2018 and 2019. To avoid duplication, when two audiograms existed for the same file reference, most recent was included. Data from all the occupational health centers of the SSGM in France were included.Inclusion criteria: French registered merchant seafarer and audiometric test in 2018 or 2019 at the SSGM. As for the non-inclusion criteria: patients under judicial protection.During the examination at the SSGM, clear information on data extraction and used for research was given to seamen and they could decline it. These data are collected as part of mandatory health assessments. It is written in information form that non-identified data could be used for research. All data were de-identified before extraction and analysis. We ensured that the data were kept anonymous and secure.Hearing impairment (HI) was defined using American Speech–Language–Hearing Association (ASHA), as an average HTL among frequencies 1, 2, 3, and 4 kHz more than 25 dB SPL in either ear .The characteristics of the patients were described by number and frequency with percentage for the qualitative variables.Duration was divided into 2 classes , age into 3 classes , merchant seafarers’ population in 3 groups: marine engineer, deck, and service.Merchant seafarer’s group: international cabotage towing, international cabotage, pilotage, national cabotage towing, coastal navigation towing, national cabotage, coastal navigation, coastal navigation towing, long-distance towing, and long distance.For HI, we used a cut-off at 25 dB, with a class normal (≤25 dB) and abnormal .Descriptive statistics were calculated from the survey results and presented as counts and percentages. In total, 34,208 audiometric tests were extracted. After excluding due to incomplete or missing survey or audiogram data (6 or 8 kHz in majority) from other navigation groups, 8308 audiometric tests were included in the data analyses.For each audiometric frequency tested, mean HTLs were presented by age group and workplace categories. Chi-squared tests were used to examine the relation between NIHI and categorial variables such as workplace categories, experience, and age.p value less than 0.05 was considered statistically significant. Data analyses were conducted using XL stat software 2020 .Measures of association were computed from 2 × 2 contingency tables and reported as odds ratio (OR) with a 95% confidence interval (CI). Seafarers’ workplace categories  as independent risk factor for HI were examined, and these results were adjusted for age and years of experience to control for its confounding effect. For reference group, we used, respectively, HI ≤ 25 dB fo HI, age < 30 years for age, experience ≤ 13 years for experience, and service for workplaces’ categories adjusted OR and 95% CI were calculated according to the Cochran–Mantel–Haenszel method. A We collected data from 34,208 audiograms of all French seafarers. Tests with missing thresholds at 0.5, 1, 2, and/or 4 kHz were removed from the analysis, and we were able to include 8308 audiograms for merchant mariners in the statistical analysis.The main characteristics of the total population are summarized in Our results showed that most of our population is under 40 years of age and has been in the workforce for less than 13 years. As we know that the auditory impact of noise is most often revealed beyond the age of 40, and often even later, we will study, in more detail, the hearing losses of the latter age and seniority categories.The average hearing threshold levels at all tested frequencies, categorized by age and location, are summarized in Comparison of average HTLs of seafarers over a 40 year timespan (deck/marine engineers) between 1984 data (Jegaden), 2018–2019 data from our study, and the normal physiological audiometric curve according to ISO 7029 corresponding to the age class is shown in We note that the values of the deficits, at each frequency, are very close in each age group and in relation to workplace—deck, engine room, or service—the latter being slightly less impacted than the other two. For the HI analysis, univariate and multivariate analyses are reported in By analysing a large dataset from the routine medical examination of French merchant seafarers with audiometric measurements, we found that age, years of experience, and working in an engine room are risk factors for HI. These results show a very clear improvement, over time, in the hearing of the merchant marine engineers of merchant ships. The results confirm previous studies, showing a progressive hearing impairment with age and seniority, consistent with the fact that ship engine rooms are a very noisy place, which is attested by numerous sonometric studies .In one way, an interesting point of our study is to confirm, with a large number of audiograms, risk factors of HI in merchant seafarers. In another way, an interesting point of our study is to compare 1985 with ours. Our study is the only complete audiometric study on hearing loss in merchant seafarers comparable to the Jegaden study about 40 years ago . In a 19However, in our study, the audiogram-like presentation of the mean HTLs of French seafarers included between 2018 and 2019 no longer shows this typical notch at 4 kHz, but a curve similar for deck seafarers. It is, of course, difficult to compare studies that are very far apart in time based on different numbers of workers and done with different methodologies. Nevertheless, we have this approach between the audiometric graphs of Jégaden and ours, more specifically, by superimposing the curves of young seafarers aged 16 to 30 years and by comparing the age-related curve modifications for the other seafarers’ populations.We then see very clearly  that, onA major strength of our study is the inclusion of a large number of seafarers from a national database. The large number of data included allowed us to perform a multivariate analysis and increase the validity of our results.Comparison between two different time periods over a 40 year timespan, including the same type of merchant seafarers, highlighted the importance of HI evaluation in occupational groups with noise exposure. It also underlined the relevance of testing the impact on occupational health in the prevention program.Firstly, in order to eliminate any hearing fatigue, the audiogram must be performed without any occupational exposure to noise for at least 48 h, which is the case for the large majority of commercial seafarers. On the other hand, as not all SSGMs have soundproof booths to perform these measurements, we can question audiograms’ validity. We also do not know methods of result transcription into the computerized medical record. Nevertheless, the consistency of the overall results allows us to consider their good value.Second, there may be a confounding bias between the effects of noise on hearing and those of other factors, such as smoking, which is frequent among seafarers. Some studies have suggested that smoking directly affects the auditory system through nicotine and other ototoxic substances in cigarette smoke . A meta-Third, due to the large and representative population of French seafarers, our study results could be generalised to the global population of merchant seafarers. However, some countries still maintain very old and noisy ships and lack the use of hearing protection, having a noise health impact among seafarers, as suggested by Vukić et al.; we are not able to validate this hypothesis .Authors should discuss the results and how they can be interpreted from the perspective of previous studies and of the working hypotheses. The findings and their implications should be discussed in the broadest context possible. Future research directions may also be highlighted.If age, seniority in the profession, and the fact of working in the merchant ships engine room remain risk factors to noise-induced hearing loss, it is interesting to underline that this noise-induced hearing loss, typical in 40-year-old studies among marine engineers, has considerably improved. Stricter regulations in ship soundproofing and the change in the types of propulsion, in particular with less noisy new diesel-electric systems, could explain it. Engineers now have a hearing impairment, of the socio-acoustic type, very close to deck and service seafarers. Nevertheless, these results remain to be confirmed by other studies, due to limitations expressed about the uncontrolled and rigorous collection of data.


The gut microbiota plays an important role in the early stages of human life. Our previous study showed that the abundance of intestinal flora involved in galactose metabolism was altered and correlated with increased serum bilirubin levels in children with jaundice. We conducted the present study to systematically evaluate alterations in the meconium metabolome of neonates with jaundice and search for metabolic markers associated with neonatal jaundice.We included 68 neonates with neonatal hyperbilirubinemia, also known as neonatal jaundice (NJ) and 68 matched healthy controls (HC), collected meconium samples from them at birth, and performed metabolomic analysis via liquid chromatography-mass spectrometry.Gut metabolites enabled clearly distinguishing the neonatal jaundice (NJ) and healthy control (HC) groups. We also identified the compositions of the gut metabolites that differed significantly between the NJ and HC groups; these differentially significant metabolites were enriched in aminyl tRNA biosynthesis; pantothenic acid and coenzyme biosynthesis; and the valine, leucine and isoleucine biosynthesis pathways. Gut branched-chain amino acid (BCAA) levels were positively correlated with serum bilirubin levels, and the area under the receiver operating characteristic curve of the random forest classifier model based on BCAAs, proline, methionine, phenylalanine and total bilirubin reached 96.9%, showing good potential for diagnostic applications. Machine learning-based causal inference analysis revealed the causal effect of BCAAs on serum total bilirubin and NJ.Altered gut metabolites in neonates with jaundice showed that increased BCAAs and total serum bilirubin were positively correlated. BCAAs proline, methionine, phenylalanine are potential biomarkers of NJ. In this study, we further investigated the possible mechanisms underlying the development of NJ and bilirubin encephalopathy by examining the differences in gut metabolomics between neonates with and without jaundice.22.1All patients were from a tertiary general hospital in Shenzhen, China. The diagnostic criteria for neonatal hyperbilirubinemia referred to the American Academy of Pediatrics Guidelines for Neonatal Jaundice Intervention 2.2LC-MS was performed as previously described 2.3https://www.metaboanalyst.ca/https://www.genome.jp/kegg/ commercial database to analyze the metabolite pathways.Regarding the methodology of metabolomic analysis, we mainly refer to our previous publication 2.4Machine learning was performed as previously described https://github.com/microsoft/dowhy) and EconML (https://github.com/econml/) libraries following the software manual as detailed in another manuscript Machine learning-based causal inference was performed using the Microsoft DoWhy  g, mean TBIL of (275.0 ± 64.0) umol/L.Sixty-eight matched HCs were also included: 35 males and 33 females, of whom, 44 were delivered vaginally, and 24 were delivered via cesarean section, mean birth weight of (3096 ± 466) g, mean TBIL of (150.6 ± 40.7) umol/L . There w2 and Q2 values were used to test the overfitting of the model and assess its statistical significance. The original model (R2Y) was closer to 1, indicating that the established model was more consistent with the real situation of the sample data. The original model (Q2) was close to 0.5, indicating that adding a new sample to the model yielded a more approximate distribution, and the original model better explained the differences between the two sample groups (A). Thus, the original model had good robustness, with no overfitting, and the fecal metabolomic analysis results showed good stability for the samples and instruments in both positive- and negative-ion mode. The metabolites clearly distinguished NJ from HC (B).The OPLS-DA model was built, and the Re groups A. Thus,  from HC B.Fig. 1OA), and the metabolite groups varied largely across the groups. The z-scores ranged from − 2 to 8 relative to those of the HC group.Based on the good robustness of the study model and the likelihood that metabolites can clearly distinguish the NJ group from the HC group, we further visualized the differential metabolites. First, we measured the relative levels of the metabolites at the same level based on z-scores A, and thWe constructed a volcano plot to visualize the metabolites that differed. 82 metabolites differed significantly between the NJ and HC groups, of which, 61 were significantly enriched in the NJ group, including valine, leucine, isoleucine, methionine, and phenylalanine, and 21 were significantly enriched in the HC group. 3.2A). After obtaining the pathway information for the differential metabolites by mapping them against metabolite databases such as KEGG and PubChem, we performed metabolic pathway enrichment analysis using MetaboAnalyst (B). ESI-positive-mode results showed high enrichment of histidyl tRNA biosynthesis; pantothenic acid and coenzyme A biosynthesis; and valine, leucine and isoleucine biosynthesis in the NJ group. ESI-negative-mode pathway enrichment results showed high enrichment of valine, leucine and isoleucine biosynthesis; pyrimidine metabolism; pyruvate metabolism; and valine, leucine and isoleucine degradation  was 0.874; the AUROC score for the combination of methionine and phenylalanine in addition to the above amino acids was 0.86, and the AUROC score for the combination of valine, leucine, proline, methionine, phenylalanine, and bilirubin was 0.969 . TherefoA–C), and the BCAAs, leucine and isoleucine, had a direct causal effect on serum bilirubin and thus an indirect causal effect on NJ (D–E).To further understand the biological significance of the metabolomic features of NJ, we evaluated the causal effect of treatment on outcomes based on a machine-learning causal inference approach using differential metabolites as the treatment and important clinical indicators, such as serum bilirubin levels, as outcomes. Notably, the branched-chain amino acids (BCAAs), valine, leucine, and isoleucine, were positively correlated with serum bilirubin A–C, and ct on NJ D–E.Fig. 4Bifidobacteria and gut bacteria involved in galactose metabolism and were positively correlated with increased serum bilirubin levels. To further investigate the roles and mechanisms of the gut microbiota in neonatal hyperbilirubinemia, we conducted the present study to know the gut metabolomics features of neonatal hyperbilirubinemia.LC-MS is used in metabolomic studies of stool, serum, and other samples to identify metabolites associated with diseases such as genetic metabolic disorders, autism, diabetes, and cancer We are aware that classical machine learning methods aim to find feature variables that can be used for disease classification and in this study we used a random forest model mainly because of its ability to rank metabolites. However, once metabolites have been found for disease classification, there is a need to further elaborate on whether there is a potential causal link between metabolites and neonatal hyperbilirubinemia/important clinical features, such as TBIL. The study of causal inference is becoming a current hot topic in artificial intelligence research, and we developed an algorithm for machine learning causal inference, which we found in a preliminary study to identify oral microbes with causal associations with autism from omics data We revealed the intestinal metabolomic profile of neonatal hyperbilirubinemia via LC-MS/MS and found that neonates with hyperbilirubinemia and HCs could be clearly distinguished based on their intestinal metabolome via OPLS-DA. For further analysis of differential metabolites, heat map of correlation coefficient of differential metabolites and KEGG annotation were made. Finally, pathway analysis was conducted ESI-positive-mode and negative-mode results both showed high enrichment valine, leucine and isoleucine biosynthesis in the NJ group. Notably, NJ group manifested as a significant elevation of intestinal BCAAs , proline, methionine, phenylalanine and were positively correlated with elevated total serum bilirubin.Previous studies have shown that elevated valine, leucine, lysine, isoleucine and alanine levels reflected abnormal amino acid metabolism in patients with neonatal jaundice BCAAs are involved in the synthesis of cholesterol, ketone bodies and glucose as the basic units of synthetic peptide chains So we performed an indepth analysis based on a random forest machine-learning model. Our study showed an AUROC score of 0.874 for the differential metabolites, valine, leucine, proline; and AUROC score of 0.969 for the combination of valine, leucine, proline, methionine, phenylalanine and bilirubin was reliable in diagnosing neonatal hyperbilirubinemia. Hence, the combination of valine, leucine, proline, methionine, phenylalanine and bilirubin was reliable in diagnosing neonatal hyperbilirubinemia. Based on machine learning, BACCs may play important roles in neonatal hyperbilirubinemia and the ROC value may predict the diagnosis.Here, we collected the first postnatal stool, which reflected the prenatal and immediate postnatal metabolic status. Starvation Since serum BCAA abnormalities are potential disease biomarkers. Previous studies show that high BCAA levels are associated with excitotoxicity, energy deficiency and oxidative stress in the brain And our previous study found that patients with NJ exhibited a reduction in bifidobacteria This study identified an alteration in branched-chain amino acid metabolism in neonatal jaundice and independent validation is needed to determine whether this alteration is a biomarker for neonatal jaundice. We will recollect samples and perform targeted metabolomic analysis in future.5Our results showed that the metabolome clearly distinguished the NJ group from the HCs, with a model AUROC score of 96.9 %. NJ manifests as an increase in intestinal BCAAs and was positively correlated with serum bilirubin. BCAAs have a potential causal effect on serum bilirubin and BCAAs  proline, methionine, phenylalanine are potential markers of neonatal hyperbilirubinemia.6The study was approved by the Ethics Committee of Longgang District Central Hospital of Shenzhen (NO.2019ECYJ026).All authors designed and executed the study and wrote the manuscript. All authors read and approved the final manuscript.Under supervision by Huixian Qiu and Mingbang Wang, Shujuan Zeng , Zhangxing Wang , Peng Zhang, Zhaoqing Yin performed data analysis manuscript drafting. Xunbin Huang,Xisheng Tang, Lindong Shi, Kaiping Guo, Ting Liu performed sample preparation and clinical evaluation.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.


GSDME gene are responsible for post-lingual, progressive, autosomal dominant hearing loss. This study aimed to characterize the genetic mutations and clinical features of a Chinese GSDME family.Hearing loss is considered one of the most common sensory nervous system defects, about 60% of which are caused by genetic factors. Mutations in the GSDME expression.After clinical evaluations, high-throughput DNA sequencing was conducted using DNA samples from this family. Sanger sequencing was performed to verify the suspected variants. A detailed genotype and phenotype analysis were carried out. Gene set enrichment analysis (GSEA) was performed to identify the signaling pathway associated with A known hotspot heterozygous splice-site variation (c.991-15_991_13delTTC) was identified and shown to segregate with the hearing loss phenotype in the family. This pathogenic splice-site variant results in skipping of exon 8. GSEA analysis identified changes in regulation of the cell cycle checkpoint, peroxisome, and amino acid metabolism signaling pathways.GSDME gene. Our findings support the 3 bp deletion (c.991-15_991-13del) was a hotspot variation, and it emerged as an essential contributor to autosomal dominant progressive hearing loss in East Asians. GSDME gene is closely associated with a range of signaling pathways. These characterized findings may provide new evidence for pathogenesis.We identified a reported mutation in the  Autosomal dominant non-syndromic hearing loss (ADNSHL) accounts for approximately 20% of non-syndromic hereditary hearing loss [Hearing loss is one of the most common clinically disabling diseases. According to the World Health Organization, more than 5% of the world’s population—466 million people—suffer from hearing loss of varying degrees . GeneticGSDME(MIM:600994) was mapped to chromosome 7p15 in 1995 and identified in 1998 in a Dutch family [GSDME had also been detected to play an essential role as an oncogene [GSDME could be activated by Caspase-3 cleavage, leading to apoptosis and cytokinesis transition [GSDME and the upstream pathways need to be further investigated. To date, several mutations in GSDME have been reported to cause ADNSHL [GSDME mutation, c.991-15_991_13delTTC, in a Chinese family. The TTC deletion in the polypyrimidine tract of intron 7 also led to exon 8 skipping in mRNA level and subsequently to non-syndromic sensorineural hearing impairment.Hereditary hearing loss exhibits a high degree of genetic heterogeneity. h family ,4. In laGSDMEMIM:00994 wase ADNSHL . These rAll procedures were approved by the Ethics Reviewing Committee of the Second Hospital of Hebei Medical University. All subjects or their parents provided written informed consent to participate in the study. A five-generation hearing loss-affected family from Hebei Province was collected  in 2019.All subjects received an otolaryngological clinical examination, including otoscopy, physical examination, pure tone audiometry (frequencies from 0.125 to 8kHz), acoustic conductance resistance, and computed tomography scans of the temporal bone. Hearing curves were drawn to determine the degree and type of hearing loss. The diagnosis of sensorineural hearing loss was made according to the WHO criteria.GSDME mutation. From these literature data, patient profiles containing age information and pure-tone audiograms  were selected. Only records from the first visit of each selected patient were included. In the collected dataset, there were 6 records from this study, 13 records for the delTTC pathogenic variant and 44 records for other pathogenic variants in GSDME. After calculating the binaural average air conduction thresholds from 0.25 to 8 kHz, we performed cross-sectional and longitudinal analyses with linear regression to evaluate the progression of hearing impairment for each frequency. Progression is considered significant if the 95% confidence interval of the slope does not include zero, expressed as annual threshold deterioration . We analyzed the progression rates for each frequency in the three groups: this study, delTTC variant, and other variants. As previously described [A literature search using the PubMed database retrieved published audiometric data for non-syndromic deafness families segregating the escribed ,16, age-GSDME mutation was verified by Sanger sequencing. Sequence alignment was performed after quality control of sequencing data to analyze whether the detected variants were consistent with co-segregation of hearing phenotypes and genotypes within the family. As for controls, DNA samples from 100 unrelated normal hearing individuals were also collected.According to the manufacturer’s guidelines, DNA was extracted from peripheral blood samples from all subjects using a blood DNA extraction kit . The proband was examined using a gene panel containing 415 genes related to deafness. The amplified DNA was captured using the GenCap deafness capture kit . We selected Exons, and the flanking 50 bp for capture and NGS sequencing was performed on an Illumina HiSeq2000 . The BWA software mapped the clean reads to the GRCh37/hg19 human reference genome. Variants were annotated by ANNOVAR and compared with multiple databases. Potential pathogenic variants were filtered with a minimum allele frequency threshold ≤0:001 for dominant inheritance. The Human Gene Mutation Database (HGMD) and the ClinVar database were searched for reported mutation, and reported benign variants were excluded. The pathogenicity was evaluated according to the American College of Medical Genetics and Genomics (ACMG) genetic variant classification criteria and guidelines. The detected GSDME by reverse transcription. A forward primer from exon 7 (5’–AACAGACAGCTTTGAGTGACA–3’) and a reverse primer from exon 10(5’–ATCCCAAACCTTTCTGTATCT–3’) was designed, followed by PCR amplification of cDNA fragments in this region. After the above PCR products were purified, we performed sequencing analysis; and the sequencing results were compared with the standard sequences(https://blast.ncbi.nlm.nih.gov/Blast.cgi).To observe the potential effect of this mutation on mRNA level,10ml of fresh peripheral venous blood was drawn from each family member, total RNA was extracted from peripheral blood, and RT-PCR was performed to synthesize the cDNA of GSDME gene mutation and explore its involvement in the molecular pathways, we downloaded the gene expression profile microarray data GSE70167 from the GEO database of NCBI (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE70167). The dataset was uploaded by Ken Op de Beeck in 2015 and included two HEK293T transfected cell populations: wild type and GSDME-knockout (KO) type. The knockout of the GSDME gene may affect the expression of specific associated genes and may impact molecular pathways. So we performed Gene Set Enrichment Analysis (GSEA) (v.4.2.3) to explore the signaling pathways between the two groups. The expression level of the GSDME gene was used as the phenotype label. The reference gene set was the c2.cp.kegg.v7.5.1.symbols.gmt, and the NES  was calculated. Gene set permutations were performed 1,000 times for each analysis to identify significantly different pathways. The gene set was significantly enriched if the normal p-value <0.05 and FDR  q value <25%.In order to investigate the potential mechanism of deafness caused by the The family exhibited a typical autosomal dominant inheritance pattern of hearing loss, which consists of 5 generations, 37 people . These aGSDME mutation was confirmed at a subsequent mutation screen, a young member of 10 years old (V:3) still exhibited a regular hearing curve pattern because the age of onset was not reached.Pure-tone audiograms of five patients showed moderate to severe sensorineural hearing loss bilaterally . The heaIncluding the results of this study, we divided the collected data into three groups: this study, delTTC variant, and other variants. We found there was no significant difference in the progression rates for each frequency  between the three groups P>0.05; . TherefoGSDME gene was found in the proband. A 3-bp deletion  was identified in intron 7 . The average sequencing depth on the targeted region was 505.10-fold, with 97.25% of the region covered by at least 20×, demonstrating the high quality of the sequencing data. Our study covered 751 loci for 147 genes in the deep intron region reported by HGMD. It increased probe coverage density for 29 genes  to facilitate Cap-CNV analysis and detection of deafness-associated genes in mitochondrial loop DNA. The results were all negative. After variant filtering and further prioritization for genes associated with ADNSHL, the mutation in the intron 7 . This muWe designed the primers from exon 7 and exon 10 to amplify the cDNA fragment. Sequencing analysis of the patient’s RT-PCR product revealed a deletion of the exon 8 sequence (exon skipping) in his mutant transcript, resulting in a direct linkage between exon 7 and exon 9 sequences . No mutaGSDME knockout upregulated acute myeloid leukemia, colorectal cancer, JAK/STAT signaling pathway, and hedgehog signaling pathway. We also found a significant downregulation in 11 signaling pathways involved in the peroxisome, valine leucine and isoleucine degradation, porphyrin and chlorophyll metabolism, pyruvate metabolism, selenoamino acid metabolism, base excision repair, propanoate metabolism, glycine serine and threonine metabolism, DNA replication, lysine degradation, and pyrimidine metabolism.In view of NES, FDR q-value, and nominal p-value, significantly enriched signaling pathways were selected . CompareGSDME deafness families reported in the literature [Hereditary hearing loss has been described as one of the diseases with a high degree of genetic heterogeneity, which is reflected in the diversity and complexity of deafness phenotypes, inheritance patterns, and pathogenic genes. In the present study, the graphical pedigree analysis exhibited that the inheritance pattern of deafness in this family is non-syndromic autosomal dominant, with late-onset, post-lingual, and progressive hearing loss. We found that the patients have an early onset of high-frequency hearing loss, and the decline was particularly significant between 1 and 8 kHz. Meanwhile, we observed that a young patient (V:3) shows no symptoms on all frequencies, which have no impact on hearing or speaking. This demonstrates that the clinical phenotype of this family is generally consistent with that of other terature .GSDME mutations that can lead to non-syndromic hearing loss. We found at least 23 GSDME families worldwide, including 6 from Europe and 14 from Asia  was detected in the family and reported in several East Asian families [GSDME mutations may be ethnically specific and that the c.991-15_991-13del mutation may be a more recurrent causative factor in autosomal dominant hearing loss in East Asians.We searched PubMed for all reported rom Asia . Fourteefamilies ,18,19. TGSDME mutation based on all available data previously reported, given the mechanism associated with all GSDME-related hearing loss. Progression at every frequency was fairly constant in the first two decades, in contrast to a more rapid progression in the third decade and particularly pronounced at high frequencies  and in-frame deletion of 126 amino acids in the reading frame. The final effect produces a truncated protein with a stop codon at position 372 [The GSDME mutation [GSDME knockout mice, only an increase in the number of the fourth row of cochlear hair cells was observed. No frequency-specific ABR examinations or vestibular function abnormalities were observed [Recent studies have shown that GSDME is mainly expressed in the placenta, brain, heart, kidney, and other human tissues, such as cochlear hair cells . The cocmutation . The mutmutation . In GSDMobserved . The resGSDME. These indicated that all these contributing factors, individually or interactively, led to apoptosis and cochlear damage.In combination with its association with deafness, it was found that the expression level of GSDME in tumor cells was significantly lower than that in normal cells, and enhanced GSDME expression had an inhibitory effect on the proliferation of hepatocellular carcinoma cells. The intrinsic mechanism was related to the apoptotic ability of GSDME . Therefothe GSDME gene may upregulate or downregulate some signaling pathways. GSDME is the first gene known to be involved in monogenic apoptotic deafness, and it is also a tumor suppressor gene with a critical role in major types of tumors. Although its knockout affects the signaling pathways in acute myeloid leukemia and colorectal cancer, many studies are still needed to confirm the association of GSDME-related hearing loss with the development of cancer and protection from cancer. The JAK-STAT signaling pathway takes part in many biological processes, including cell division, apoptosis, and immune regulation [. A study also found [GSDME was related to “valine leucine and isoleucine degradation” as our GSEA results. These three amino acids belong to the proteinogenic branched-chain amino acids (BCAAs), which have a possible pathophysiological relationship with human iron metabolism and are mediated by the mechanistic target of the rapamycin complex 1 (mTORC1) pathway [GSDME variant.Knockout of gulation . It playgulation . Peroxisgulation . A studyso found  peroxiso pathway . The chl pathway . All of GSDME mutation (c.991-15_991-13delTTC) leading to the skipping of exon 8 was identified through targeted genomic sequencing and co-segregation analysis, which was considered to be a hotspot mutation in East Asian populations. The reported GSDME mutations responsible for progressive hearing loss affect high and mid frequencies earlier and more severely than low frequencies. Further mechanistic studies are needed to better understand the role mutant GSDME plays in hearing loss.In conclusion, we described a five-generation Chinese family with late-onset, progressive, non-syndromic, sensorineural hearing loss. In this family, a S1 Table(DOCX)Click here for additional data file.S1 Fig(TIF)Click here for additional data file.S1 File(XLSX)Click here for additional data file.S2 File(XLSX)Click here for additional data file.S3 File(ZIP)Click here for additional data file.


There is a modest relationship between speech perception skills and perceived hearing handicap in individuals with hearing loss. In this study, an attempt is made at linking psychoacoustic results and speech perception skills to understand the subjective handicap and quality of life.To investigate how speech perception in noise , difference limen frequency, temporal modulation transfer function, hearing handicap inventory for adults, and quality of life in auditory neuropathy spectrum disorder differs from sensorineural hearing loss. Further we attempt to discern attributed factors of hearing handicap in auditory neuropathy spectrum disorder and sensorineural hearing loss.A cross-sectional study with comparative and correlational research designs were utilized. Eighty-four participants were grouped into sensorineural hearing loss (n = 49), and auditory neuropathy spectrum disorder (n = 35) was sub-grouped into mild, moderately severe, and severe. We evaluated signal to noise ratio-50, difference limen frequency, and temporal modulation transfer function. In addition, hearing handicap inventory for adults, and quality of life questionnaires were administered.Mild auditory neuropathy spectrum disorder showed impairment in speech perception and discriminating frequency, which were similar to the severe sensory neural hearing loss. Temporal resolution impairment in auditory neuropathy spectrum disorder mild was significantly higher than in each sub-groups of sensorineural hearing loss. The severity of the hearing handicap in was similar to severe sensorineural hearing loss, quality of life was equally affected in sensorineural hearing loss and auditory neuropathy spectrum disorder. In sensorineural hearing loss, signal to noise ratio-50 was positively related, and quality of life was negatively related to hearing handicap. In auditory neuropathy spectrum disorder, no contributory factors were related to hearing handicap.Mild auditory neural pathology demonstrates impairment in speech recognition and psychoacoustic skills similar to severe cochlear pathology. In sensorineural hearing loss, hearing handicap is predicted from quality of life and speech perception, but none of the contributory factors predicted hearing handicap in auditory neuropathy spectrum disorder. Hearing loss has a significant impact on hearing handicap and eventually affects the quality of life. Iwasaki et al.Auditory neuropathy spectrum disorder (ANSD) is a type of SNHL. The onset of hearing loss in ANSD at a later part of their life affects speech understanding ability,Psychoacoustics combines the study of acoustics and auditory physiology to determine the relationship between a sound’s characteristics and the auditory sensation that it provokes.Difference limen frequency (DLF) is another psychoacoustic test which assesses the ability to detect the smallest change in frequency between the two tones. GoldsteinNordvik et al.,The present study is focused on how the perceptual skill (SNR-50), psychoacoustic skills (TMTF and DLF), quality of life, and hearing handicap differed between ANSD and SNHL subjects. If the scores are different among groups, then to what extent auditory neural pathology subjects have impairment against their counterparts who have an auditory sensory pathology in the above-mentioned skills? Further, the relationship between hearing handicap and each of the measurements was ascertained in each group to determine the attributing factors for hearing handicap. It is hypothesized that mild pathology in the inner ear has impairment similar to the severe degree of auditory neural pathology, and each of the measured skills attributes for hearing handicap. The study aimed to investigate the potential attributing factors of hearing handicap in individuals with SNHL and ANSD. The following objectives were formulated: a) To compare each of the measured skills between the SNHL and ANSD group and b) To find the relationship between hearing handicap and measured skills and identify the potential attributing factors for hearing handicap.A cross-sectional study with comparative and correlational research designs was utilized. The study was a part of a research project which was approved by the ethics committee with the reference number SH/CDN/CC/ARF-59/2019-20. A purposive sampling method was used. The procedures involved in the study were explained to the participants, and informed consent was obtained before the data collection. A total of 84 participants were recruited in the study. We grouped into two based on the site of pathology. Group I (n = 49) included participants with confirmed cochlear hearing loss.1Hearing thresholds ranging from 30 dBHL to 90 dBHL in both ears symmetrically.2Normal middle ear functioning as indicated by type “A” tympanogram with elevated reflexes (ipsi- and contra-) at 500 Hz to 4 kHz (an octave) or absent reflexes.3Absent TEOAEs or DPOAEs based on hearing loss.4Tone decay test: patients who heard the tone for one complete minute without a change in loudness.5Native speakers of Kannada.Those participants who fulfilled the following conditions were included in the study:We sub-grouped these participants into three based on degree of hearing loss: mild , moderately severe  and severe .Group II included 35 individuals with confirmed auditory neuropathy spectrum disorder.1They complained of reduced hearing sensitivity and difficulty understanding speech.2They met the diagnostic criteria of auditory neuropathy spectrum disorder as per Starr et al.3Hearing thresholds ranging from 30 dBHL to 90 dBHL in both ears symmetrically.4Normal middle ear status indicated by type “A” tympanogram and robust otoacoustic emission.5Impaired neural response reflected in auditory brainstem response and middle ear reflexes were recruited in the study.6Native speakers of Kannada.All the participants met the following inclusion criteria:Further, the ANSD group was sub-grouped into three based on degree of hearing loss mild , moderately severe  and severe .Exclusion criteria for group I and II: participants having any history of systemic illnesses and complaints of any psychological or neurological problem were not included in the study.1A)Behavioral tests:Quantitative measures: The procedure of data collection included quantitative and qualitative tests. The quantitative tests included behavioral tests and psychoacoustic tests. Behavioral tests comprised of pure tone audiometry, speech perception in noise (SNR-50). Psychoacoustic tests included difference limen frequency (DLF) and temporal modulation transfer function (TMTF). In addition, we assessed hearing handicap inventory and quality of life under the qualitative tests.SNR 50Stimulus preparation: We prepared speech shaped noise having a spectrum similar to that of a standardized sentence. The procedure given by Shetty and MendhakarA)Psychophysical tasks:Ten sentences embedded at different SNRs were randomized. Each sentence was presented at most comfortable level through a loudspeaker at 0° azimuths. We instructed the participants to repeat the sentence heard. We noted the SNR level at which the testing started (L) and the number of correctly recognized target words in each sentence. The total number of target words from all sentences was added (T). We also documented the total number of words per decrement (W) and SNR decrement step size in each sentence (d). The obtained values were substituted to the Spearman–Karber equation, given below, to determine SNR 50%.We used the Maximum Likelihood Procedure (MLP) to estimate the thresholds for TMTF and DLF. The laptop loaded with MLP was connected to an auxiliary input of audiometer. The output of the audiometer was delivered bilaterally through headphones at the participants’ most comfortable level.Temporal modulation transfer function: The TMTF stimulus developed by Lorenzi et al.We obtained the modulation detection threshold (MDT) in dB in terms of the following equation. We utilized the method adopted by Zeng et al.A)Qualitative measuresDifference limen frequency: The stimulus developed by Micheyl et al.We administered the Kannada version of the Hearing Handicap Inventory for Adults (HHIA)Hearing handicap inventory for adults: The HHIA questionnaire consists of 13 questions in emotional and 12 questions in the social domain, constituting a total of 25 questions. Each question was rated on a three-point rating scale “yes” as 4, “sometimes” as 2, and “no” as 0. The maximum overall score is 100. The maximum number of points for social and emotional subsections is 48 and 52, respectively. A score of 0 implies no handicap, while a score of 100 implies total handicap. A score ranging from 0% to 16% indicates no handicap; a score of 18%–42% indicates mild-moderate handicap. A score of above 44% indicates a significant handicap. We obtained scores for each domain.World Health Organization — Quality of life: The Kannada version of the World Health Organization – Quality of Life BREF versionExperienced audiologists did the evaluation in the department. Later the data for this study was conducted by the research associate in the lab. It took 30 min to perform all the tests on each participant. The basic audiological evaluation and the data collected were on the same day.2(2) = 8.242; p = 0.016). Further, we performed a post hoc Mann–Whitney U test to check in which sub-groups of SNHL had caused a significant difference in SNR-50. The mild sub-group of SNHL required significantly lesser SNR to achieve SNR-50 than moderately severe  and severe sub-groups . Though the SNR required to achieve 50% recognition in noise was less in moderately severe than severe subgroup, it failed to reach a significant difference . In the case of ANSD, a measurable SNR-50 was obtained from 13/19 participants of the mild sub-group. The median SNR required to achieve 50% recognition in them was 9.5 dB . However, no measurable SNR-50 was obtained from either moderately severe or severe sub-groups of ANSD.To achieve 50% recognition of speech, the SNR required was less in mild hearing loss (n = 10) than moderately severe (n = 32), followed by a severe degree (n = 7) of SNHL group. The median SNR required to achieve 50% recognition in mild group was −1 dB , moderately severe was 3 dB , severe group was 4 dB . A Kruskal Wallis test showed a significant difference between sub-groups for SNR-50 in SNHL (χU test. It was observed that mild sub-group of ANSD (median = 9.5) required a significantly higher SNR to achieve 50% speech recognition than mild  and moderately severe  subgroups of ANSD. In addition, though mild sub-group of ANSD (median = 9.5) required higher SNR to achieve 50% recognition than severe , it failed to reach significance. It purports that the mild degree of neural pathology in speech recognition has a similar problem with that of the severe degree of cochlear pathology.Further, to know the severity of impairment in the SNR-50 between the cochlear and neural site of the lesion, we compared the mild subgroup of ANSD (n = 19) with each of the subgroups of SNHL on SNR-50 using the Mann–Whitney 2(2) = 2.62, p = 0.270), 1000 Hz (χ2(2) = 3.141, p = 0.208), 2000 Hz (χ2(2) = 1.26, p = 0.53), 4000 Hz (χ2(2) = 2.22, p = 0.328). Similarly, for the ANSD group, there were no significant differences between subgroups on DLF at 500 Hz (χ2(2) = 5.29, p = 0.071), 1000 Hz (χ2(2) = 8.022, p = 0.051), 2000 Hz (χ2(2) = 1.938, p = 0.379), 4000 Hz (χ2(2) = 2.672, p = 0.263).The median and SD of DLF at each frequency from sub-groups of SNHL and ANSD are tabulated in U test revealed a significantly better frequency resolution in SNHL than ANSD on DLF at 500 Hz , 1000 Hz , 2000 Hz , and 4000 Hz .We combined the DLF data at each frequency as there was no significant difference between the sub-groups. This is true in case of SNHL and ANSD. Further a Mann–Whitney U test result revealed that the mild subgroup of ANSD required a significantly larger DLF for 500 Hz than each of the mild , moderately severe  and severe  subgroups of SNHL. In addition, a significantly larger DLF was observed in mild ANSD for 1 kHz than mild , moderately severe  and severe  sub-groups of SNHL. Further, a significantly larger DLF was required by the sub-group of ANSD for 2 kHz than mild , moderately severe  and severe  subgroups of SNHL. We observed a similar result for 4 kHz as the mild group of ANSD required larger DLF to discriminate the primary tone from its variable tones than mild , moderately severe  and severe  subgroups of SNHL. It infers that frequency resolution in the mild sub-group of ANSD was affected more than the severe subgroup of SNHL. To sum up, the individuals with ANSD required a significantly higher difference in frequency to differentiate two tones compared to those with SNHL  = 3.529, p = 0.129), 64 Hz (χ2(2) = 2.81, p = 0.245), and 128 Hz (χ2(2) = 3.65, p = 0.161). Unlike the SNHL group, there was a measurable score on temporal resolution only at 8 Hz and 64 Hz in mild sub-groups of ANSD.The median scores and SD on TMTF in individuals with SNHL and ANSD are tabulated in U test result revealed that mild subgroup of ANSD required a significantly higher modulation detection threshold for 8 Hz modulation frequency than each of the mild , moderately severe  and severe  subgroups of SNHL. Similarly, a significant higher modulation detection threshold was observed in mild ANSD for 64 Hz modulation frequency than mild , moderately severe  and severe  sub-groups of SNHL. It infers that the temporal resolution in mild ANSD was affected more than the severe subgroup of SNHL.In addition, we compared the mild subgroup of ANSD with each of the sub-groups of SNHL on modulation detection threshold at 8 Hz and 64 Hz. A Mann–Whitney 2(2) = 3.49, p = 0.175), the emotional domain of HHIA (χ2(2) = 1.497, p = 0.473) and total score of HHIA (χ2(2) = 2.757, p = 0.252).2(2) = 2.40, p = 0.301) and total score of HHIA (χ2(2) = 0.682, p = 0.711).U test result revealed a significantly higher severity of hearing handicap in ANSD than SNHL (χ2(1) = 6.347, p = 0.012) (2(1) = 7.842, p = 0.005) and emotional domain (χ2(1) = 4.249, p = 0.039).The scores in each domain of HHIA obtained between sub-groups were combined in each of the groups as there were no significant differences in them. This was done to compare the scores of each domain of HHIA between SNHL and ANSD. A Mann–Whitney = 0.012) . This waU test. We performed these comparisons to determine the severity of handicap in the mild sub-group of ANSD compared to which subgroups of SNHL. The mild sub-group (median = 68) of ANSD showed a significant higher hearing handicap than mild  and moderately severe  subgroups of SNHL. Also, though the total hearing handicap in the mild subgroup of ANSD (median = 68) had a higher score on total hearing handicap than the severe sub-group of SNHL (median = 54), it failed to reach significance .Further, we compared the mild subgroup of ANSD with each of the subgroups of SNHL on the total hearing handicap index using the Mann–Whitney 2(2) = 0.838, p = 0.658), health (χ2(2) = 0.014, p = 0.993), physical (χ2(2) = 0.091, p = 0.955), psychological (χ2(2) = 0.243, p = 0.885), environmental (χ2(2) = 1.72, p = 0.422), social (χ2(2) = 1.623, p = 0.444), and total QOL (χ2(2) = 0.743, p = 0.690) (2(2) = 0.468, p = 0.792), health (χ2(2) = 4.212, p = 0.122), physical (χ2(2) = 2.16, p = 0.340), psychological (χ2(2) = 2.383, p = 0.304), environmental (χ2(2) = 0.082, p = 0.960), social (χ2(2) = 0.006, p = 0.997), total QOL (χ2(2) = 0.130, p = 0.937)  . Further= 0.937) .Table 4M2(1) = 4.454, p = 0.035). In addition, though each domain of quality of life was affected more in ANSD than SNHL, it failed to reach significance in health (χ2(1) = 0.075, p = 0.785), physical (χ2(1) = .238, p = 0.626), psychological (χ2(1) = 0.238, p = 0.626), environmental (χ2(1) = 0.644, p = 0.422), social (χ2(1) = 2.899, p = 0.089) and total score of quality of life (χ2(1) = 0.486, p = 0.486).We combined the scores in each domain of quality of life obtained between sub-groups of SNHL, as there were no significant differences in them. Similarly, it was done for ANSD subgroups. Further, we compared the quality of life between SNHL and ANSD groups. The total score of quality of life was affected more in ANSD than SNHL , which wU test. We performed these comparisons to know the severity of quality of life in the mild sub-group of ANSD compared to which subgroups of SNHL. Though the quality of life was worse in the mild sub-group of ANSD than ieach of the sub-groups of SNHL, it failed to reach significance.We compared the mild subgroup of ANSD with each subgroup of SNHL on the total score of quality of life using the Mann–Whitney p = 0.022). In addition, we found a significant mild degree of negative correlation between total hearing handicap and a total score of quality of life . However, no correlation was found between total hearing handicap scores and an average of pure tone averages ., DLF at 500 Hz , 1000 Hz , 2000 Hz , 4000 Hz ; and TMTF scores at 8 Hz , 64 Hz  and 128 Hz .The attributing factors such as hearing thresholds, speech perception in quiet, SNR-50, modulation detection thresholds, difference limen of frequency, and quality of life in individuals with SNHL and ANSD were utilized to correlate with hearing handicap. This relationship was performed separately for SNHL and ANSD. We performed a Spearman's sign rank correlation coefficient between hearing handicap scores and attributing factors. In individuals with SNHL, we found a significant mild degree of the positive correlation between the total hearing handicap scores and SNR 50 , SNR 50 , DLF at 500 Hz , 1000 Hz , 2000 Hz , 4000 Hz  and TMTF scores at 8 Hz , 64 Hz , and 128 Hz . However, there was a significant mild degree of negative correlation between total handicap scores and total quality of life .In individuals with ANSD, no correlation was found between hearing handicap and any of the attributing factors: average of pure tone averages . It purports that the hearing handicap is equally affected irrespective of scores in the measured test from the samples of ANSD participants. This is because they tend to compare the present listening problem with their listening abilities prior to the hearing loss.Deterioration of the temporal processing begins by forth decade of life in individuals with normal hearing.The mild subgroup of ANSD participants required significantly higher SNR to achieve 50% recognition of speech than the mild subgroup of SNHL. However, there was no measurable SNR for 50% recognition in moderately severe and severe sub-groups of ANSD. In addition, the mild ANSD sub-group has a speech perception impairment similar to that of the severe sub-group of SNHL. Larger DLF was required as a function of frequency. This was true for each of the sub-groups of SNHL and ANSD. A significantly larger DLF was required in ANSD than SNHL for each frequency. Also, the severity of impairment in discriminating frequency in the mild subgroup of ANSD was similar to the severe sub-group of SNHL. In TMTF, there was no measurable modulation detection threshold for moderately severe and severe groups of ANSD in each of the modulation rates. Whereas mild sub-group of ANSD required a higher modulation detection threshold than the mild sub-group of SNHL at 8 Hz and 64 Hz, respectively. Besides, temporal resolution impairment in the mild sub-group of ANSD was significantly higher than in each of the sub-groups of SNHL. The hearing handicap was more significantly affected in ANSD than SNHL. The severity of the hearing handicap in the mild sub-group of ANSD was similar to the severe sub-group of SNHL. Quality of life was equally affected in both SNHL and ANSD groups. In the SNHL group, the SNR-50 was positively related, and QOL was negatively related to hearing handicap. Speech perception and quality of life were the contributory factors for hearing handicap in the SNHL group. Whereas, in ANSD, none of the factors are related to hearing handicap.Speech perception in noise, psychoacoustic skills, hearing handicap, and QOL was significantly affected more in ANSD than SNHL groups. Also, the severity of the mild sub-group of ANSD was similar to those participants of the severe sub-group of SNHL in each of the behavioral skills, psychoacoustic skills, hearing handicap, and QOL assessed. Further, the hearing handicap in SNHL was attributed to SNR-50 and quality of life. In ANSD, the hearing handicap is not related to any of the attributor factors undertaken in the study. The study provides insight into how much the mild ANSD subject suffer against their counterparts who have a sensory impairment. The finding purports that “mild” ANSD subjects have listening impairment similar to that of “severe” degree of SNHL subjects. The limitation of the study is the fact that in the sample of each group, we were unable to categorize their hearing handicap or QOL based on the scores of tests measured in the present study. This is because the sampled population rated the same degree of hearing handicap or QOL irrespective of the degree of hearing loss.This study provides insight into how much the mild ANSD subject suffers against their counterpart who has a sensory impairment. The finding purports that “mild” ANSD subjects have listening impairment similar to that of “severe” degree of SNHL subjects.All India Institute of Speech and Hearing, Mysuru.This study was funded by the The authors declare no conflicts of interest.