Voice and speech are regulated by hearing. Vocal disorders in patients with hearing loss have not been evaluated yet as to the subjective degree of disability they cause in this group.to compare the results of the Voice Handicap Index (VHI) obtained for patients with normal hearing and moderate to profound bilateral sensorineural hearing loss. Study design: Controlled, cross-sectional.A total of 76 adult patients being treated on a University Otolaryngology center were enrolled (38 with and 38 without hearing loss), ages ranging between 19 and 59 years, were asked to complete the Portuguese version of the VHI.Total VHI score median values obtained were 23.5 and 4.0 for the study and control groups, respectively (p = 0.000). Significant differences between the two groups were found for all three VHI subscales  (p = 0.000).Our results lead us to infer a greater social and economical disadvantage as per assessed in the VHI of patients with moderate and higher bilateral sensorineural hearing loss. Voice and speech production is a complex process involving numerous regulatory mechanisms.The refinement and stabilization of such processes start in infancy; however they are only completed during adolescence, requiring motor information from the speech articulatory pathways  as well as sensorial information. Such sensorial information is also obtained from a hearing feedback mechanism still not completely understood, used as information for the correction and/or improvement of muscle commands associated with vocal production, in such a way as to be able to achieve the necessary modifications and reach a certain vocal objective .In the year 2000, Perkell et al. published an extensive review on voice and speech motor control obtained from studies with hearing impaired individuals in comparison with normal-hearing individuals, starting a theory on the influence of hearing on these processesVoice characteristics such as the utterance of vowels and consonants, fundamental frequency and its variations are parameters studied in numerous occasions in order to investigate the role hearing plays on our voices. In a study published in 1990, Waldstein showed alterations in these voice parameters in individuals with postlingual profound hearing loss, when the internal voice and speech model would have already been acquiredIn order to investigate the temporal characteristic of the voice change evolution caused by cochlear implants, five adult patients with profound postlingual hearing loss were analyzed at four different times: pre-implant; and at 1, 6 and 24 months after the implantHamzavi et al. published a paper about the effects cochlear implants have on the vocal emission of patients with postlingual hearing loss with 10.1 years of hearing loss duration average time, and hearing onset mean age of 35.7 years, showing an improvement on the fundamental frequency pattern and on the consonant emission patternSvirsky et al. assessed two patients with cochlear implants through speech and with the implants on and off, considering the alterations which happened during this fast change in the auditory conditions of the tested indi-vidualsThe characteristic of phoneme internal model maintenance is experimentally shown by Perkell through the analysis of the first and second voice forming factors emitted during vowel phonation by patients with postlingual hearing loss in situations of pre and post cochlear implantThe later the hearing loss establishes, the greater are the strength and permanence of the internal speech modelThe voice nasal pattern was also assessed as far as hearing is concerned. Nine patients with profound hearing loss submitted to cochlear implant were analyzed in five week intervals between implant activation and the second assessment, showing a significant improvement in F0 and its variation and that of nasality patternsHere we showed the huge array of voice and speech alterations caused by profound sensorineural hearing loss. We can state that voice alterations are frequent in patients with hearing loss of such characteristics, especially because of changes in the hearing-dependant regulatory mechanisms. Given such fact, it is pertaining to assess how much these voice and speech alterations impact the lives of these individuals, which is not evaluated by these objective voice analyses.Aiming at a better characterization and measuring of these difficulties experienced by the patients, many tools have been developed, mostly questionnaires involving voice-related quality of life. In a study published in 2005, the authors identified nine voice-related quality of life assessment toolsThe VHI is a questionnaire developed and published in 1997 by Jacobson et al. aiming at the self-assessment of the severity of the vocal alterations of patients with dys-phoniaVHI was initially developed for the English Language. In 2004, Guimarães and Abberton published one of the first papers on VHI for Portuguese, by adapting to Portuguese the questions written in EnglishVHI was used as a means to measure the voice-related handicap in different disease groups, such as organic dysphoniasNumerous authors compared other methods of vocal assessment. In 2002, Hsiung et al. did the spectrographic analysis, and found poor correlations after the statistical tests. The same results were also obtained by other authors27Despite the extensive publication on voice and speech alterations associated with hearing loss of such characteristics, there is no report on the use of VHI to assess these complaints from patients with hearing loss. Also, there are no reports of hearing evaluation in patients with moderate hearing loss.VHI analysis in patients with hearing loss could influence treatment: patients with higher VHI scores have to an early need to improve their audiometric thresholds, such as through the use of individual sound amplification devices (ISAD) or cochlear implants, depending on the intensity and cause of the hearing loss. Higher scores would also indicate the need for speech therapy, even in patients with moderate hearing loss. Such decisions must be made on a case-by-case basis, showing that VHI would also help in treatment customization and follow up of each individual, enabling a greater chance of treatment success and individual satisfaction.The present study aims at assessing the different Voice Handicap Index (VHI) scores among patients with normal hearing and those with sensorineural hearing loss at a moderate level, checking the degree of loss the vocal alterations were causing to the latter group.The present study was approved by the Ethics in Research Committee of the institution where it was done, under protocol # 234/06. This was a cross-sectional study, led between January of 2007 and July of 2008, with the individuals being recruited from the Otolaryngology outpatient ward.Inclusion criteria were: age between 18 and 60 years; altered tonal and vocal audiometry, showing a bilateral sensorineural hearing loss of moderate degree at frequencies equal to and higher than 500 Hz for the group of individuals with hearing loss; normal tonal and vocal audiometry (audiometric thresholds below 25 dB on the frequencies tested) for the control group; videolaryngoscopy without alterations and obtaining a signed informed consent form from the patients.Exclusion criteria involved: pre or perilingual hearing loss; alterations on voice auditory perception analysis; speech disorders ; professional use of the voice or its frequent use in an amateur way ; past of laryngeal surgery; hearing aid use at any moment prior to the assessment; past or current smoking habit and pulmonary or neurological disorders.During our study period, we analyzed 96 patients with the audiometric profile matching those required in the study. After employing the exclusion criteria, thirty-eight of these patients were actually included in the study. Another group of thirty-eight individuals with normal tonal audiometries matched the study group people in age and gender were included as control group.Videolaryngoscopy and the VHI were only carried out after the individual presented the researcher with the signed informed consent form. All the patients were submitted to vocal and tonal audiometry with the Intera-coustics CE10 audiometer, and the tritonal average was obtained for each ear separately through the mathematical average of the auditory thresholds in the frequencies of 500; 1.000 and 2.000 Hertz (Hz).The hearing loss was classified in levels, for each ear separately and for both ears together  aiming at the descriptive analysis: moderate (between 41 and 60 dB), severe (between 61 and 80 dB) and profound (higher than 81 dB) hearing loss. Considering the two ears together, we used the following classification: moderate, moderate-to-severe, moderate-to-profound, severe, severe-to-profound and profound.The laryngoscopy tests were done by the researcher with a 70 degree Storz rigid scope, Mini Xenon Storz light source, IK-CU43A Toshiba micro camera and 14 inch Sony monitor. In those cases in which the patients had an intense nauseous reflex preventing the test to be carried out, we used topical anesthesia with 10% lidocaine, if there were no contraindications related to it.The patient him/herself must fill out the VHI questionnaire after being instructed about its content and how to fill it out, without the presence of the researcher or escorts. Originally translated into Portuguese by Guimarães and Abberton in 2004The statistical analyses were carried out using the SPSS 16.0 Statistical Package for Windows . Results were presented as median (minimum - maximum) and standard deviation (SD). The Mann-Whitney non-parametric test was utilized in order to compare the numeric variables between the groups (control versus patient). In order to study the correlation among the numeric variables we used the Spearman correlation's test (regarded as “r”). A p-value below 0.05 - considered statistically significant.The age median value for the group of patients was 50.5 years (SD = 10.9 years), with extreme values of 19 and 59 years. In the control group, the median was 48.0 years (SD = 9.9 years), with extreme values of 20 and 58 years. The analysis between the two groups in relation to age did not show any statistically significant difference (p = 0.344), confirming efficiency of the pairing by age range. There was a positive and statistically significant correlation in the control group between age and the left tritonal mean value , the physical VHI subitem (r = +0.42 p = 0.009) and total VHI .The distribution between patients and controls regarding gender was: 28.9% of males and 71.1% of females, keeping the same ratios because of pairing by gender in the samples . There wFollowing, we used the box-plot graph in order to show the data related to the right and left tritonal mean values and scores of the subitems and VHI total between the two groups studied. The horizontal line crossing the box translates the median for each group. The boxes have upper and lower thresholds corresponding to p25 and p75 of the sample, with the upper and lower lines connected to the box tracing the limits at p90 and p10, respectively. The circles show the outliers and the asterisks show the extreme values in these samples.The tritonal mean for the left ear showed medians of 65 (DP = 18.9 dB) and 15 dB (DP = 5.0 dB) between patients and controls, respectively with extremes of 42 and 120 dB for the patients and 5 to 20 dB among controls. The comparative analyzes between the two groups showed a statistically significant difference between the groups (p = 0.000) . It is dThe tritonal mean value for the right ear also presented median values of 65 (SD = 19.9 dB) and 15 dB (SD = 5.1 dB) for patients and controls, respectively, with extremes of 42 and 120 dB for patients and 5 and 25 dB for controls. The comparative analysis between the groups showed a statistically significant difference between the two groups (p = 0.000) . It is dThe analyses of data correlation with the levels of hearing loss only showed statistically significant difference when associated with the right and left tritonal mean values. The data associated with the binaural hearing loss levels are shown on The hearing loss duration at the time of data collection showed a median of 14 years (SD = 11.1 years). The hearing loss duration extremes were from 1 to 40 years. The comparison between the groups showed an obvious statistically significant difference (p = 0.000). The correlation with the other issues analyzed within the group of patients with hearing loss did not show statistical significance.The VHI functional aspect showed a score median of 9.5  and 1  between patients and controls, respectively. The VHI physical aspect among patients showed a median score of 7.5 , while in the control group, the median was 0 . The emotional subitem had a median value of 5.5  for the group of patients; and it was 0  for the control group. The total score between the groups was 23.5  and 4.0  for patients and controls, respectively. The comparative analysis between the two groups showed a statistically significant difference for all VHI subitems, as well as for its total score: the functional, physical emotional and total aspects all showed a p-value of 0.000 .Graph 7DThe VHI emotional subitem showed a significant correlation with the tritonal mean values for both ears of the control group . There was also a strong correlation between the emotional subitem and the functional  and physical  subitems in the group of patients with hearing loss.Other studies were published along the years with the VHI in Portuguese. As previously alluded to, Jotz et al. showed the VHI accuracy in differentiating patients with and without dysphoniaWe chose to include individuals between 18 and 60 years as a means to exclude the possibility of age-related vocal disorders - those associated with physiological vocal change and those associated with presbyphonia. The correlation between the total VHI score and the individual's age in the control group shows the trend towards a higher VHI score according to an increase in the age range found in the group of patients without hearing loss. Such data translates the natural trend of vocal pattern changes with age - expected in the control group since they are not affected by hearing loss.The gender of the individuals included in this paper was not a factor influencing any of the other data analyzed. By the same token, a study published in 2006 showed VHI score data separately for the two gendersThe tritonal averages were used in order to evaluate the group of patients with hearing loss for encompassing the 500; 1,000 and 2,000 Hz frequencies -concentrating most of the sound energy of complex sounds which characterize speechBased on Perkell's remarks on the role of hearing in vocal production1, in this paper we chose not to break the studied individuals down into ear sides. Not having any literature reference on the assessment of patients with unilateral hearing loss, nor comments on a possible laterality of the auditory feedback process, we included in this study only those patients with bilateral hearing loss.The literature on the hearing loss influence on voice is restricted to the assessment of patients with profound hearing loss. By enrolling patients with moderate hearing loss and their analysis as a group we were able to show, in a statistically significant fashion, that it is possible to have vocal alterations and related complaints also in this group of individuals.We also considered that, because of the major variability of responses obtained through using VHI in the group of patients (a variation of 94 points) and the subjective characteristic of the individual perception on vocal problems, there is no way to define a specific loss for patients with hearing loss, in other words, there is no way to describe a VHI score range such as a characteristic of patients with hearing loss, a comment which was also raised during the evaluation of laryngectomized patients with tracheoesophageal voiceThe influence of the hearing loss duration is only speculated on vocal alterationsThe results obtained by Jacobson in developing the VHI12 were groups according to the patient's perception on the intensity of their vocal problem in categories defined as normal voice; mild, moderate and severe dysphonia. The total average VHI scores obtained in each one of these categories were 33.69 for normal and mild , 44.37 for moderate and 61.39 for severe. In the present study, the total score of the patients with hearing loss showed a median value of 23.5, reasonably comparable with the group of mild dysphonia or with normal voice in the study by Jacobson; comparing the functional, physical and emotional subitem, his scores in this study are comparable only to the group with normal voice and mild dysphonia. The group studied by Jacobson in the development of the VHI was made up of patients with diagnosed laryngeal diseases, while the patients here analyzed had, necessarily, videolaryngoscopy without alterations. Such fact can justify the total VHI scores being less in our paper when compared to the group classified as mild dysphonia or no dysphonia by Jacobson.In the study published by Guimarães and Abberton we applied the same previous comments when comparing the results with those from Jacobson in 1997. The presence or absence of dysphonia was considered as defining the groups analyzed The total VHI score median value for the control individuals was 4.0 (SD: 6.0), matching the results from papers who assessed control groups made up of individuals without vocal alterations, even when considering the different distribution values used in the papers we analyzed. Very few studies involved the use of a control group when assessing the VHI in specific clinical situations: stressing the findings by Peeters in 2004, showing a total score of 2.331 for controls. The controls used by Khaintan had total mean score of 6.219, similar to findings reported by Pribuisiene (4.1 and 4.66)20. Guimarães and AbbertonAs to the results regarding the scores obtained from the group of patients with hearing loss, similar results to total VHI were also published by Behrman in 200429, in assessing patients with benign laryngeal alterations such as polyps, intracordal cysts and nodules. The median found in that study for the total VHI score was 30, not so far from the one found in the present paper (23.5). Similar scores were also found by Loughran in 2005 in patients submitted to endoscopic surgery or radiotherapy for initial laryngeal cancer The results obtained in patients with presbyphonia and post-radiotherapy of the T1a glottic cancer without disease recurrenceThe papers on patients with spasmodic dysphonia (in adduction and abduction) show results with total VHI scores varying between 63.46 and 102As we compare the results obtained in the VHI subitems and total scores to the studies published on the use of the same questionnaire in other clinical situations, we can see that the scores of the patients with hearing loss are usually lower than the ones already published in the literature. Thus, the disability caused by the hearing loss could be included as the ones with the lowest impact when compared to the other ones analyzed in the aforementioned studies.The analysis of the total and partial scores between the control and hearing loss groups showed a statistically significant difference (p = 0.000), which says that the patients with hearing loss had significant levels of voice-related disabilities when compared to the groups, corroborating the presence of vocal changes in these patients. The control group in this paper was strictly built, reinforcing even further the VHI score differences between the groups. The bivariate analysis of the VHI subgroup scores showed a positive correlation between each one of the subitems, saying that in the group of hearing loss patients there are not major differences as to the vocal disability pattern, in functional, physical or emotional aspects, which could be shown in the present study.As previously stated, objective methods of voice analysis, with vocal spectrograph, bear important information on the severity of the vocal involvement when compared to normal voices; however, they fail in indicating why and how patients with similar alterations have different social and personal impairment. The VHI questionnaire represents an important development on this issue. The comparison between such methods and VHI may not show strong correlations; however, it does not cancel out the analysis done in this paper because here we considered the level of perception of the vocal disability, which is a subjective parameter. The paper from Hsiung also shows and corroborates this fact, because they did not show a correlation between the objective method  and the subjective one (VHI)In this paper, we obtained a strong correlation between the VHI subitems from the hearing loss patients, indicating that the voice alteration affects multiple aspects of these individuals, including functional, physical and emotional aspects, besides the economic, affective and others. Thus, we must consider that the symptoms from a dysphonic syndrome include not only hoarseness or voice asthenia, for example, but also other issues which deeply influence the lives of patients and which are lived by each person in a different way.The patients hereby analyzed were collected among those referred to a tertiary care Otolaryngology service, causing possibilities of sampling bias because the population seen at our place is already selected from a population with hearing loss. Considering this selection bias, we believe that such share of the patients who came to a university care center would be a group already convinced of the need to treat their hearing problem. There is not a way to rule out a greater concern these patients have in relation to their hearing loss, including the vocal disorders, as already mentioned by other authorsThrough the results obtained in this study, we can state that patients with bilateral hearing loss starting from a moderate level have higher scores than patients with their hearing within normal ranges in a statistically significant fashion. Based on this analysis, the researcher points to this trend towards a greater social or economical disadvantage stemming from the disability or physical impairment specifically associated with the vocal alterations caused by such hearing loss.


Metasurfaces, the ultra-thin media with extraordinary wavefront modulation ability, have shown great promise for many potential applications. However, most of the existing metasurfaces are limited by narrow-band and strong dispersive modulation, which complicates their real-world applications and, therefore require strict customized dispersion. To address this issue, we report a general methodology for generating ultra-broadband achromatic metasurfaces with prescribed ultra-broadband achromatic properties in a bottom-up inverse-design paradigm. We demonstrate three ultra-broadband functionalities, including acoustic beam deflection, focusing and levitation, with relative bandwidths of 93.3%, 120% and 118.9%, respectively. In addition, we reveal a relationship between broadband achromatic functionality and element dispersion. All metasurface elements have anisotropic and asymmetric geometries with multiple scatterers and local cavities that synthetically support internal resonances, bi-anisotropy and multiple scattering for ultra-broadband customized dispersion. Our study opens new horizons for ultra-broadband highly efficient achromatic functional devices, with promising extension to optical and elastic metamaterials. This paper reports inversely designed metasurfaces with customized dispersion through bottom-up topology optimization to realize frequency-independent and ultra-broadband acoustic functionalities including directional energy transmission and convergence and ultrasound particle levitation. Metasurfaces have offered tremendous possibility in the fields of optical devices , carpet To achieve an arbitrarily defined broadband functionality, each metasurface element must provide the required local amplitude and/or phase modulation, which is controlled over the entire operating bandwidth. This modulation depends on the specific functionality and leads to the customization of the dispersion of each element. Recent studies have shown that broadband  optical To address the aforementioned challenges, we propose a systematic bottom-up inverse-design methodology for implementing ultra-broadband and customized metasurfaces, and explore the physics behind different functionalities. Our study demonstrates the feasibility of developing a systematic inverse-design model for constructing ultra-broadband achromatic metasurfaces, the dispersions of which can be tactically tailored. Optimized elements can be either non-dispersive or dispersive through customization, exhibiting many asymmetric scatterers and cavities within the elements. By combining these elements into specific patterns, we consistently achieve a class of metasurfaces that entail ultra-broadband, achromatic beam deflection, focusing and levitation, beyond the relative bandwidth of existing achromatic metasurfaces. Finally, we also reveal the ultra-broadband mechanism that results from a combination of integrated internal resonances, bi-anisotropy and multiple-scattering effects. We design three types of achromatic metasurfaces with customized microscopic and macroscopic dispersions, which entail ultra-broadband frequency-independent acoustic beam functionalities that have not been achieved before. The discovered asymmetric and bi-anisotropic microstructural topological characteristic and synthetical ultra-broadband achromatic mechanism offer a new basic platform for designing broadband frequency-independent metasurfaces. Meanwhile, we demonstrate a metasurface that supports ultra-broadband, stable and single-sided ultrasound levitation that can hardly be achieved with traditional ultrasound levitation technologies.The presented metasurfaces can simultaneously provide the customized specific dispersion of elements and non-dispersive nature of functionality within the ultra-broadband range, which leads to ultra-broadband achromatic metasurfaces, which, as expected, will allow them to be used in noise-control systems, medical ultrasonics and contactless particle control assembly. Meanwhile, the proposed ultra-broadband achromatic strategy can be extended to optical and elastic metamaterials for highly efficient frequency-independent functional devices.Figure Unlike traditional top-down topology-optimization approaches, the proposed bottom-up inverse-design paradigm is based on achromatic dispersion tailoring and offers the following salient advantages: (i) it is based on the responses of metasurface elements rather than the entire physical field, thus simultaneously reducing the search space, optimization complexity and computational cost; (ii) it avoids the blindness of the empirical design; (iii) its element-based design philosophy embraces and combines multiple physical mechanisms, thus maximizing the ultimate performance such as broadband, high efficiency and achromatism, etc.; and (iv) it reveals novel topological configurations of the elements with broadband features.We start with anomalous refraction to validate the proposed inverse-design strategy. To achieve broadband negative refraction with a fixed angle of 20.2°, we perform topology optimization of 2D metasurface elements  based onHere we use the aforementioned inverse-design strategy to systematically construct a metasurface for ultra-broadband focusing at a constant depth of focus Fig. . The optAs shown in Fig. To understand the physics behind the achieved ultra-broadband operations, we closely examine phase, effective impedance matrices and multiple-scattering effects for representative metasurface elements Fig. . RegardlThe space-coiling and Helmholtz-resonator structures do not naturally accommodate bi-anisotropy and multiple scattering. However, all three mechanisms are important in our analyses , which further leads to achromatic functionality. On the one hand, most Helmholtz-resonator and space-coiling structures can only produce high transmissions near resonant frequencies. But our elements provide relatively high transmission over a broadband frequency range. This is the essential difference between our elements and traditional resonant ones. On the other hand, most of the existing Helmholtz-resonator and space-coiling metasurfaces are limited by a certain dispersion property—that is, the characteristic of the wave functionality  changes markedly with frequency. But our metasurfaces can support the non-dispersive nature of the wave functionality, which is another distinctive feature. Third, the effective metamaterial index of the space-coiling structure can be numerically characterized by the length of the propagation path. However, this approach fails to characterize the effective movements of our elements. In other words, the effective index is not directly related to the length of the propagation path. Therefore, we believe that the proposed elements differ from the previous ones using Helmholtz-resonator (HR) or coiling structures.In short, we believe that the physical mechanisms of our inverse-designed elements are different from previous Helmholtz-resonator and space-coiling structures. Only the synergistic effect of internal resonances, bi-anisotropy and multiple scattering can simultaneously contribute to the ultra-broadband achromatic wave functionalities with a high transmission that has never been realized before. This discovery would provide a way to achieve ultra-broadband functionalities of metamaterials (though not yet attempted) through the combined effects of multiple mechanisms described above.According to the acoustic intensity distributions , it is tBy integrating phase modulation, transmission, geometric features and wave functionalities into the design, we have methodically demonstrated the deflection of an ultra-broadband acoustic beam and the focusing and levitation of achromatic metasurfaces following a bottom-up topology optimization. All optimized structures can represent the new category of AMs, which can support asymmetric multiple scatterers, curve air channels and local cavities simultaneously. We have found that the optimized asymmetric metasurfaces can appropriately combine integrated internal resonances, bi-anisotropy and multi-scattering effects simultaneously, resulting in ultra-broadband customized dispersions. This highly efficient ultra-broadband mechanism is expected to become a new and versatile benchmark for broadband AMs. In view of the robustness and versatility of the proposed metasurfaces, the reported ultra-broadband topological features and tunable dispersion mechanisms can provide a new impetus to the entire field of optical  Supplem, acoustiBased on the intrinsic physical parameters, our constructed topology-optimization model enhances the existing design capability and the applicability of the AMs. The proposed design paradigm can be extended to other waves  for their manipulation as well as the realization of more diversified functionalities such as absorption, acoustic insulation, vibration control and underwater acoustic manipulation, etc. Whenever a target functionality requires the tuning of specific dispersion, the proposed approach should be applicable to generate various broadband achromatic meta-devices. Meanwhile, the principle of stable single-sided ultrasound levitation can be extended to the area of acoustic tweezers. The dispersion-based wave manipulation method can also be generalized to vortex acoustics, holographic, 3D acoustic field control, etc.A limitation of the proposed approach may be the complex geometry of inverse-designed structures. However, with the advent of advanced additive manufacturing capability, this could be mitigated in the foreseeable future. Limited by computational capacity, the current optimization process is applied to a 2D system. In terms of 3D design, dramatically increased design freedom will allow more complex wave functionalities with better performance and even wider bandwidth. Finally, combing our designs with existing active control and deep learning techniques will make large-scale, digital, reconfigurable and integrated achromatic metasurface devices available.3 and Young's modulus of 2370–2650 MPa. The metasurface for levitation was manufactured by a Micro Scale 3D Printing System nanoArch® S140  using a low-viscosity high-temperature resistant resin with a mass density of 1150 kg/m3 and Young's modulus of 4.2 GPa.Metasurfaces for deflection and focusing were manufactured using a UnionTech Lite800HD 3D-printing machine  using a low-viscosity photosensitive resin with a mass density of 1250 kg/mnwac030_Supplemental_FilesClick here for additional data file.


To check the rate of failure, hearing loss and its association with demographic variables and risk indicators for hearing loss in newborns submitted to the Newborn Hearing Screening in a secondary hospital.Cross-sectional and retrospective study, involving 1,570 newborns submitted to the different stages of the Newborn Hearing Screening Program. Initially, we carried out otoacoustic emission tests (ILO Echocheck) and the cochlear-eyelid reflex. Afterwards, we analyzed the demographic and clinical characteristics of the newborns, screening rate of failure, hearing loss and its association with demographic variables and risk indicators.Twenty-six newborns had failures in the first stages of the Program (1.7%), who were then referred to diagnostic evaluation. Of these, 16 (61.5%) did not come, two (7.7%) had normal results and eight (30.8%) were diagnosed with hearing disorders. The screening failure rate was 1.7% and the frequency of hearing disorders was 0.5%.Pre-term newborns of very low birth weights had higher rates of screening failures and a greater occurrence of hearing changes. The factors associated with screening failure and hearing changes were similar to the ones described in the literature. Hearing loss is one of the most common sensorial disorders. A clinically significant hearing loss may affect 1-3 for every 1000 low-risk newbornsAfter analyzing the literature, COMUSA , made up by otolaryngologists, pediatricians, speech and hearing therapists, and other professionals, made 21 recommendations for early identification, diagnosis and treatment of newborns and infants with hearing impairmentIn the present study we tried to analyze the demographic and clinical characteristics of the newborns who participated in the Neonatal Hearing Screening Program in a secondary level maternity, identifying the level of failure and the occurrence of hearing loss and its association with the following variables: gestational age, birth weight and neonatal clinical occurrences.This was a retrospective study in which we collected the results from the Neonatal Hearing Screening Program implemented in the Neonatal Unit of a Municipal Hospital located in the north of the city of São Paulo, SP. The annual number of live births, seen in the Neonatal Unit in this hospital is around 1,500; with rates of low-birth weight  of 11%; very low birth weight  rate of 1.6% and of extreme low birth weight (birth weight <1000g) rate of 0.8%.In the study, we included the newborns whose hearing screenings were done by the author, during 20 months, between February of 2004 and December of 2006.This project was submitted to and approved by the Ethics in Research Committee under protocol # 1332/06.The Neonatal Hearing Screening (NHS) was carried out by means of Transient Stimulus Evoked Otoacoustic Emissions (TEOE) and the Cochleo-eyelid Reflex (CER) by means of an agogô musical instrument (large campanula) at 100 dBSPL of intensity.TEOE was carried out in both ears using the ILO EchocheckT system, a portable device which uses click stimuli involving frequency bands between 1,500 Hz and 3,800 Hz. The click is presented at an intensity of 75 to 83 dBpeSPS. The response was considered positive (pass) when the otoacoustic emissions captured were 6 dB higher than the noise.CER happens in 100% of normal hearing children and its lack suggests bilateral hearing loss or central disorder. The study is carried out with an intense sound stimulus and the response is considered present when there is a contraction of the eye's orbicular muscle, seen by eyelid movement.® device with a click-type stimulus.The newborn who failed the screening was submitted to a complete audiological evaluation for diagnostic purposes. The assessment was based on the study of the TEOE, acoustic immittance measures obtained by the AZ7 immittance meter with a 226 hertz probe for the tympanometric curve, behavioral assessment and brainstem Hearing evoked potential (BAEP), with the Navigator Pro-Biologic Systems CorpThe children who had risk indicators for hearing impairment, even those who passed the hearing screening, were referred to Hearing development follow up.The hearing loss was classified as conductive when associated with middle or external ear disorders; or sensorineural, associated with cochlear disorders classified as mild to profound degreeAs far as the demographic characteristics of the children included in the study are concerned, we observed the following data: newborn gender, birth weight, gestational age and Apgar score.Concerning hearing impairment risk analysis, we collected the following variables: consanguinity, congenital malformations, perinatal asphyxia, hyperbilirubinemia, peri-intraventricular hemorrhage, meningitis, seizures, need for mechanical ventilation, use of ototoxic medication, congenital infections such as syphilis, rubella, toxoplasmosis, cytomegalovirus and human immunodeficiency virus (HIV) diagnosed during gestation or in the neonatal period, smoking, alcohol drinking or the use of illegal drugs during pregnancy; family with hearing loss, diagnosis or suspicion of genetic syndromes made by the pediatrician and/or geneticist, duration of neonatal ICU stay.We analyzed demographic and clinical characteristics of the newborns included in this study and the rate of failure in the screening, the occurrence of hearing loss and an association between failure in the test and gestational age, birth weight and the main neonatal complications.p<0.05 as significant.The results obtained were described as mean and standard deviation of the numerical variables and frequency for the categorical ones. The investigation concerning the factors associated with otoacoustic emission test failure was carried out by means of a univariate analysis, using the chi-squared or Fisher's test, considering During the study, 4,593 children were born at the maternity of this hospital. The NHS was carried out in 1,805 newborns (39.3%), 1,615 (89.5%) were born at term, 146 (8.1%) were preterm with birth weight higher than 1,500g and 44 (2.4%) preterm with birth weight lower than 1,500g.Of the 1,805 newborn evaluated, 235 did not come for the second stage of the NHS program; thus, only 1,570 newborns were evaluated.The 235 newborns who did not return, were compared to the 1,570 newborns of the study in relation to gestational age, birth weight and risk indicators, with the goal of checking for similarities between the groups for statistical purposes.p=0.821) and birth weight , when compared to the ones who did not return.The newborns who completed the second stage of the NHS had similar characteristics in relation to gestational age .Thus, we concluded that the children who did not return for an assessment at the second stage were similar to the ones who continued in the NHS program, except for the greater frequency of peri-intraventricular hemorrhage  females and 780 (49.7%) males; 1,401 (89.2%) born at term and 169 (10.8%) were premature.The children without TEOE and/or CER were considered as failure in this study. Therefore, the failure rate in this study's sample was 26 (1.7%). Of these, nine (0.6%) had one or more risk indicators for hearing loss.The mean gestational age and birth weight of the children in relation to the NHS are depicted on In regards of risk indicators for hearing impairment, 1,349 (85.9%) newborns, of the 1,570 included in the present study, did not have any risk indicator; and 221 (14.1%) had one or more risk indicators.In order to assess the failure rate at NHS in relation to the variables: gender, prematurity, ear tested, stay in newborn ICU, risk factors for hearing impairment, we considered the 1,570 newborns who made up the series investigated in this study.p=0.223) and ear side (p=1.000). There was a greater failure rate among preterm newborns (4.1%) in relation to those who were born at term (1.4%); p=0.017.The failure rate was not related to the child's gender (•At term Group (TG): at term newborns with birth weight equal to or higher than 1,500g.•Preterm Group : premature babies with birth weight equal to or higher than 1,500g.•Preterm with very low birth weight Group (PT MBP): premature babies with birth weight lower than 1,500g.In order to analyze failures in relation to the gestational age and birth weight, the children were broken down into three groups:p<0.001.The rate of NHS failures in the PT MBP (15.0%) group was higher than that from the GT (1.2%) and PT >1,500g (1.6%) groups, In order to analyze the influence of risk indicators concerning hearing impairment, the sample was broken down according to the number of risk factors presented (from one to five).We analyzed 15 risk indicators for HL. After diagnostic assessment, two children (0.1%) had normal results, which were considered false-positives. 16 (1%) children did not show up for their return visit and eight (0.5%) had a hearing impairment diagnosis - four being sensorineural hearing loss (0.25%), one conductive hearing loss caused by craniofacial malformation (0.06%); and three children with suspected retrocochlear disorder (0.2%).p=0.625) and it was significantly higher in pre-term babies , when compared to their term newborn counterparts. Among premature babies, such disorder was more frequency among those of very low birth weight, when compared to those which birth weight higher than 1,500g .The hearing impairment frequency analysis was similar for both genders , recommended that failures in the first stage should not surpass 10%. Such result may be explained by the age in which the first NHS was carried out, since most of the children were assessed within 48 hours of life, before being discharged from the hospital.The rate of failure in the NHS (25.3%) for newborns with and without risk indicators for hearing impairment was higher than those in some studies present in the literatureDespite the possibility of capturing TOAEs already after 24 hours of life, it is also known that middle ear effusion is also very common in the first 48 hours of lifeMoreover, factors such as an excess of environment noise or routine procedures which make the child more restless , the external auditory meatus being obstructed by vernix or by wax may contribute to the high rates of retests in NHS programsThe high rate of evasion found in the present study and also described in the literature is still a major challenge for audiology professionalsThere is a huge lack of information for parents and the professionals who care for these newborns concerning the importance of NHS in the early detection of congenital hearing disorders and of late or progressive onsetThere has been a great difficulty concerning the mothers' understanding of the importance of NHS in the early diagnosis and treatment of babies with hearing disorders. Many mothers have reported financial difficulties in commuting to the hospital for the follow up visits.We must stress that our hospital cares for many teenage mothers, some with difficulties in coping with the situation of an unplanned pregnancy and without much interest in NHS. We also have a lot of immigrant patients whom, besides having the difficulties aforementioned, also have some worsening factors such as: communication challenges, some illegally living in the country and who do not return to the hospital in fear of being identified.Thus, studies which have focused the causes for high rates of evasion, considering the social and demographic factors of the population considered, are needed in order to overcome this challenge.JCIH (2007), the rate of false-positives should not be higher than 3.0% in relation to the total number of children assessed. The rate of false-positives found in the present study (0.1%) is within recommended levels.According to the Brazilian Committee on Hearing Loss During Childhood (1999) and the From our sample, 221 newborns (14.1%) had one or more risk indicators, and such index was similar to the ones found by other authorsThe most frequent risks found were similar to the ones found in the literature. Risk indicators associated with ICU stayJCHI (2007), which suggest that such index should not be higher than 4% of the individuals assessed.The percentage number of children who failed and were referred to diagnosis was 1.7%. Such figure is in agreement with what is recommended by the Brazilian Committee on Hearing Loss (1999) and the Based on the publications compiled, we noticed that the percentage of failures can be impacted by many factors: environment noise or baby noise during the screening itself, sleepiness or awareness state of the newborn, examiner's experience with the equipment being used, time of NHS program existence, number of newborns assessed, protocol and procedure utilized, besides the demographic traits of the newborn, complications and risk indicators for hearing impairment, which will be discussed belowIn the present study, there were no statistically significant differences in the gestational age mean value among the children who passed and those who failed the NHS.Now, birth weight was a relevant variable. The children who failed the NHS had the lowest mean weight.Many studies have shown associations between birth weight and NHS failure and/or hearing disordersAs far as the gender variable is concerned, we did not find significant differences, which is in agreement with some studies in the literatureConcerning the ears tested, failures in the newborn hearing screening were similar in both ears, which are different from what was obtained from one of the compiled studiesComparing the frequency of failures in the newborn hearing screening program among babies born at term and pre-term, a higher rate of failures was found among pre-term newborns, a result which was similar to the ones found in the literature studiedIn the present study, besides the gestational age, birth weight was also important considering NHS failures. The statistical analysis showed that the rate of failures was higher among those pre-term babies with very low birth weight. Many studies have reported this same findingFailures in the newborn hearing screening program were the most prevalent in the group of children with the most risk indicators.Numerous studies have described that the more risk indicators a person has, the higher will be the likelihood of this person developing some sort of hearing disorderRisk indicators: cranial malformation, hyperbilirubinemia, mechanical ventilation, use of ototoxic drugs, peri-intraventricular hemorrhage, ICU stay longer than 48 hours were variables associated with NHS failure.Craniofacial malformation has been considered a risk factor associated with hearing disordersIt is known that hyperbilirubinemia is toxic to the hearing apparatus and to the central nervous system, and it can cause sequelae such as hearing loss, hearing neuropathy and encephalopathy. Numerous studies have described the correlation between hyperbilirubinemia and hearing disordersRisk indicator: mechanical ventilation, also seems to be associated with hearing disorders in the literatureThe effect of ototoxic drugs in the hearing of high-risk newborns has been compared by many authorsStudies have showed the presence of peri-intraventricular hemorrhage in children with hearing disordersThe greater need to send to the ICU those newborns who failed NHS shows that such babies have a greater risk of failing NHS, since, in general, they have other factors associatedThe rate of hearing disorders, considering the 1,554 babies who completed the NHS stages and the audiologic diagnostic was 0.5%. The hearing loss rate in the present study was similar to that reported by studies carried out in populations with similar traits to the ones studiedThere were no differences between males and females insofar as the diagnosed hearing disorders are concerned. However, in relation to gestational age and weight at birth, it has been noticed a greater percentage of very low birth weight premature babies with hearing disorders. Some studies have reported a greater rate of hearing loss in premature childrenIt is worth stressing the importance, not only of doing the NHS in premature babies, but also to follow up on their hearing and language development. Premature children may present a delay in their Hearing behavior when compared to their counterparts born at termIn regards of the number of risk indicators presented by the group of term newborns diagnosed with hearing loss, one child did not have any risk factor, and another one had craniofacial malformation; in the group of premature babies with birth weights higher than 1,500g, the child diagnosed with sensorineural hearing loss had only the risk of family history for HL; and in the group of premature babies with birth weight below 1,500g, besides the very low birth weight risk, all the children diagnosed with hearing disorders remained in the ICU for a period longer than 48 hours, four needed mechanical ventilation, four used ototoxic drugs and two had peri-intraventricular hemorrhage. A proper interview made by the NHS team is fundamental to identify the risks associated with hearing loss and the need to follow these children up, even if they had normal results in the NHS.It is recommended that all children who spent over five days in the ICU be referred to hearing assessment by means of the BAEP, in order to detect children with hearing neuropathy spectrum.Many studies have shown an association between hearing disorders and risk indicators for hearing lossAlthough children with a risk for hearing loss have a greater likelihood of having disorders, there are a considerable number of children diagnosed with hearing loss who do not have any risk factors. In the present study, one of the eight children diagnosed with hearing disorders did not have any risk factor.Compiled studies in the literature report significant rates of children diagnosed with hearing loss who did not have risk indicators for hearing disordersThere was a statistically significant association among risk indicators for hearing disorder: family history for hearing loss, craniofacial malformation, need for mechanical ventilation, use of ototoxic drugs, peri-intraventricular hemorrhage, ICU stay for over 48 hours and very low birth weight.Based on the results found in the present study we can make many suggestions to the NHS team. Besides being a well-trained and well-structured team, it must me committed to performing NHS every day of the week, have a proper and effective follow up of these babies who failed NHS and those who had risk indicators for hearing loss and must invest in practice and experience in order to increase the efficacy of the ProgramThe importance and implementation of the NHS programs in Brazil has grown substantially; however, there are numerous challenges preventing it from being effective, especially in maternities which serve the low income population, since the rate of evasion among this population during the NHS program is high. Studies which analyze the best method to bring mothers awareness about the importance of the audiological diagnosis and the minimization of evasion factors in the NHS process are valid in order to make the NHS program more effective.1The rate of detected failures by otoacoustic emissions and the use of the cochleo-eyelid reflex was 1.7%;2The prevalence of hearing disorders found in the present study was 0.5%;3The very low birth weight newborns have higher newborn hearing screening failure rates and hearing disorders;4The failure rate in newborn hearing screening was associated in a statistically significant fashion with the risk indicators: craniofacial malformation, hyperbilirubinemia, need for mechanical ventilation, use of ototoxic drugs, presence of peri-intraventricular hemorrhage, stay in middle to high risk the neonatal ICU for more and 48 hours and birth weight below 1,500g;5Hearing disorders were significantly associated with the variables: family history for hearing loss, craniofacial malformation, use of ototoxic drugs, need for mechanical ventilation, presence of peri-intraventricular hemorrhage, stay in middle to high risk neonatal ICU for over 48 hours and birth weight below 1,500g.


This study aimed to determine the characteristics of sound localization in children with unilateral microtia and atresia (UMA) and the influence of a non-surgical bone conduction device (BCD). Hearing benefits were evaluated by the word recognition score (WRS), speech reception threshold, the international outcome inventory for hearing aids (IOI-HA), and the Speech, Spatial, and Qualities of Hearing Test for Parent (SSQ-P). Sound localization was measured using broadband noise stimuli randomly played from seven loudspeakers at different stimulus levels . The average unaided WRS and speech-to-noise ratio (SNR) for UMA patients was 18.27 ± 14.63 % and −5 ± 1.18 dB SPL, and the average aided WRS and SNR conspicuously changed to 85.45 ± 7.38 % and −7.73 ± 1.42 dB SPL, respectively. The mean IOI-HA score was 4.57 ± 0.73. Compared to the unaided condition, the mean SSQ-P score in each domain improved from 7.08 ± 2.5, 4.86 ± 2.27, and 6.59 ± 1.4 to 8.72 ± 0.95, 7.61 ± 1.52, and 8.55 ± 1.09, respectively. In the sound localization test, some children with UMA were able to detect sound sources quite well and the sound localization abilities did not deteriorate with the non-surgical BCD. Our study concludes that for children with UMA, the non-surgical BCD provided a definite benefit on speech recognition and high satisfaction without deteriorating their sound localization abilities. It is an efficient and safe solution for the early hearing intervention of these patients. Hearing loss is a major global problem and was described as an epidemic of the twenty-first century by the Microtia and atresia, a developmental malformation of the middle and external ear, is a common cause of congenital conductive hearing loss. Two-thirds of patients with microtia and atresia experience the unilateral form  with unilateral conductive hearing loss (UCHL) . Common Sound localization is a complex process that relies on the computation and integration of multiple spatial cues at the level of the auditory pathway . For patCurrently, there is no research investigating the characteristics of sound localization and the effects of non-surgical BCDs in school-aged children with UMA. This study had three primary objectives: to detect the hearing benefits of a BCD on speech perception and subjective satisfaction in children with congenital UMA; to compare characteristics of sound localization in children with congenital UMA and children with NH, as well as acquired UCHL; to investigate whether the use of BCD would be detrimental to the original sound localization of children with UMA and reveal predictive factors for the improvement of sound localization accuracy after using a BCD.Ethical approval was given by the medical committee of Beijing Tongren Hospital, Capital Medical University (TRECKY2018-067). Written informed consent for participation was obtained from the parents and guardians of the participants.Eleven children (mean ± SD: 7.45 ± 1.81 years) who had UMA and congenital UCHL were included. All patients had NH in one ear  and pure conductive hearing loss in the impaired ear . For comparative purposes, eight boys and three girls aged 6–12 years who had bilateral NH were recruited as control listeners. All control listeners had bilateral air and BC hearing thresholds ≤ 25 dB HL across frequencies of 0.5–4 kHz. Detailed demographic data are summarized in The BCD used in the current study was a non-surgical adhesive device . All devices were set in the omnidirectional mode for all experimental conditions, and the volume was adjusted based on patients’ preferences. The system fittings of the ADHEAR did not change during all experiments.Children with UMA were tested with the BCD off (unaided condition) and on (aided condition) . ChildreFor the UMA group, unaided audiological tests were performed on the day they received the BCD and aided audiological tests were measured after a mean period of 9.27 ± 1.85 weeks. For the NH group, all tests were performed in one visit.All tests were conducted in a double-walled soundproof laboratory. Participants sat in a chair placed 1 m in front of seven loudspeakers. Sound field hearing thresholds were obtained by warble tones for octave frequencies across 0.25–4 kHz in dB HL. Speech perception under quiet was measured by the word recognition score [WRS (%)] of the Mandarin speech test materials (MSTMs)  at 65 dB°, azimuth)  . BroadbaTo familiarize the participants with the experiment before the formal sound localization tests, a brief block of 12 broadband stimuli was presented. They were instructed to localize the stimuli as fast as possible, and no feedback was provided throughout the training to avoid the influence of learning in the formal test.The subjective satisfaction was measured with two questionnaires, the Chinese version of the International Outcome Inventory for Hearing Aids (IOI-HA)  and the RESP and αTARG referred to the response azimuth and target azimuth (both in degrees). Additionally, the best linear fit of the target-response relationship for each participant was also computed using Equation 2, where g is the response gain , and b is the response bias (offset in degrees). In this study, the right side was defined as the impaired side; therefore, azimuth coordinates for patients with left ear impairment and controls with NH with left ears plugged were inverted.The mean absolute error (MAE) was calculated using Equation 1 to assess the sound localization accuracy under different conditions, where the αt-tests were conducted to evaluate differences under different test conditions. The Mann-Whitney U-test was used to compare the difference in the unaided, aided, and delta MAEs (delta MAE = aided MAE - unaided MAE) between the groups of different sexes, sides of impairment, and etiologies. Spearman correlation analysis was conducted to analyze the correlations between continuous variables (age and follow-up time) and the unaided, aided, and delta MAEs, respectively. The p-values of < 0.05 and < 0.01 were considered statistically significant. SPSS version 26.0  and GraphPad Prism version 8.0  were used to analyze the data and draw diagrams.Paired and independent p < 0.01). For the NH comparison group, the mean hearing threshold was 15.36 ± 3.88 dB HL. The aided mean hearing threshold of the UMA group was still higher (worse) than the mean hearing threshold of the NH group (p < 0.01). Detailed outcomes across 0.5–4 kHz are depicted in For patients with UMA, the mean hearing threshold of the healthy ear was 14.82 ± 3.82 dB HL. The unaided hearing threshold was 51.36 ± 5.02 dB HL and significantly improved to 27.64 ± 2.38 dB HL with a mean functional hearing gain (FHG) of 23.73 ± 3.47 dB HL . The mean WRS and SNR of the comparison group were 99.27 ± 1.35 % and −10.55 ± 2.77 dB SPL, respectively. p < 0.01; SNR: p < 0.05).The average unaided WRS and SNR for patients with UMA were 18.27 ± 14.63 % and −5 ± 1.18 dB SPL, respectively, whereas the average aided WRS and SNR conspicuously changed to 85.45 ± 7.38 % and −7.73 ± 1.42 dB SPL, respectively (WRS: p < 0.01).The mean overall IOI-HA score was 4.57 ± 0.73. A score > 3 per item, defined as a benefit from the BCD, was found for nearly all participants. The mean score for items 1–7 were 3.86 ± 0.31, 3.57 ± 0.25, 4.29 ± 0.19, 3.79 ± 0.24, 4.14 ± 0.14, 4.64 ± 0.13, and 4 ± 0.23, respectively. The results of the SSQ-P without (unaided) and with (aided) BCD are presented in r2 for all participants are presented in p = 0.104, MAE: p = 0.436). Control listeners showed good sound localization performance in the UP condition. All exhibited considerable deterioration after being plugged , with most of them being unable to localize the stimuli presented from the plugged side. Although no significant difference was observed between the unaided and P conditions , the results indicated that children with UMA showed better sound localization performance  than the stimulated acquired UCHL listeners. This phenomenon might be related to the adaptation to congenital unilateral asymmetric hearing loss; however, the benefit of this adaptation was insufficient for children with UMA to localize sound as accurately as the normal controls did.Individual data on sex, age, MAE, gain, bias, and To further explore the influence of BCDs on the localization ability of patients with UMA. The localization accuracy of the patients with UMA and the controls were calculated on the impaired (including the atretic and plugged) and the contralateral  side, respectively.p < 0.05) on the impaired side than in controls in the P condition (p = 0.303) or the contralateral side , indicating that the BCD use was not detrimental to the original sound localization ability of the patients with UMA  and poor performers  according to the criterion in p < 0.05, Our results showed that some patients with congenital UCHL have relatively good monaural directional hearing without any hearing intervention . All 11 children with UMA were divided into two subgroups of good performers , indicating that children with UMA who have poor sound localization performance (lower gain) showed more improvement in sound localization after being fitted with BCDs . The results revealed an evident relationship between gain and delta MAE  . Better Consistent with the findings of previous studies , our resIn our study, no significant improvement in sound localization accuracy was observed in children with UMA aided with BCDs. Similar results have also been obtained in previous studies  regardinAs shown in One main limitation of the study is that the factors influencing sound localization accuracy amongst listeners with congenital UCHL are not entirely clear. The small age span in the present study (we mainly included children aged 5–11 years) may be attributed to the absence of a significant correlation between patient characteristics and individual sound localization differentiation. Thus, more factors influencing sound localization performance conflict and the optimal age of BCD use need to be investigated in further studies that include more participants of different ages.In conclusion, some children with UMA were able to compensate using the remaining distorted binaural cues to detect sound sources, unlike the children with stimulated acquired UCHL; however, this compensating ability was still far worse than children with NH and varied across individuals. As the application of BCD provided a definite benefit on speech recognition abilities and high participant satisfaction, it is recommended that children, particularly those with poor sound localization performance, should be fitted with non-surgical BCDs at an early age.The original contributions presented in this study are included in the article/The studies involving human participants were reviewed and approved by the Medical Committee of Beijing Tongren Hospital, Capital Medical University (TRECKY2018-067). Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.YJL, SZ, CZ, and SG: conceptualization. YJL, PC, and LY: data curation. JY: formal analysis. SZ and CZ: funding acquisition. LY, RR, and YL: methodology. SZ and DW: project administration. YJL, RR, and YL: visualization and writing-original draft. LY, DW, CZ, and SZ: writing-review and editing. All authors contributed to the article and approved the submitted version.


The process of hair cell damage and death as a result of exposure to noise and ototoxins seems to be mediated by reactive oxygen species.Aim: To investigate the relationship between genetic polymorphisms in the Glutathione S-transferase and the susceptibility to hearing loss induced by aminoglycosides.Materials and Methods: Null genotypes were analyzed by multiplex-PCR in the DNA samples from 50 patients and 72 controls. The patients were divided into 3 groups, 10 with hearing loss using aminoglycosides (group A), 20 with hearing loss without exposure to the drug (group B) and 20 hearing individuals who used the antibiotic (group C).Study Design: Experimental.Results: Polymorphisms in the GSTM1 and GSTT1 genes were found in 16% and 42% of patients and in 18% and 53% of the control group, respectively. After statistical analysis no significant difference was observed between the control groups and A (p=0.86) and (p=0.41), controls and B (p=0.27) and (p=0.24), controls and C (p=0.07) and (p=0.47), controls and A + C (p=0.09) and (p=0.47), C and A (p=0.32) and (p=0.75), GSTT1 and GSTM1, respectively.Conclusion: Our data show that polymorphisms in GSTM1 and GSTT1 genes have no influence on the ototoxicity of aminoglycosides. Many are the factors responsible for hearing impairment (HI), and they include the environment, infections, noise and ototoxic agents – which damage the auditory nerve; or genetics2 and H2O reduction. Thus, enzymes belonging to the antioxidant system, which act on the metabolism of glutathione and on the decomposition of superoxide anions and hydrogen peroxide, are activated on an attempt to neutralize these molecules which potentially damage the cochlear tissueOxygen reactive species (ORS) are involved in a growing number of diseases, including hearing loss – in a lesser frequency. Nonetheless, oxidative stress is strongly related to ototoxic-induced hearing deficiency caused by aminoglycosides or the noise-induced hearing loss type. In these cases, the toxic components are converted into hydroxyl radicals, causing the death of cochlear hair cellsGlutathione (GSH) detoxifies a number of exogenous and endogenous substances, by a non-enzymatic pathway and by enzymatic conjugation of the metabolites catalyzed by S-Transferase Glutathione (GST)In humans, two of these subclasses GSTM1 and GSTT1, have genetic variability. About 30-50% of the individuals had a null genotype for gene GSTM1, depending on the raceChanges to the antioxidant system and an increase in the oxidative stress can potentialize the toxicological responses associated with glutathione reduction. This indicates that the radicals generated modulate the activity and the expression of the antioxidant enzymesThe study was carried out in individuals with hearing impairment (HI) who used or did not use aminoglycoside ototoxic antibiotics, and in hearing newborns, premature and high-risk babies who remained at least 48 hours in the neonatal ICU and were exposed to the antibiotic. The patients were broken down into three groups: group A, individuals with hearing impairment and who used amino-glycosides (n=10); group B, with hearing impairment and who did not use aminoglycosides (n=20); and group C, hearing individuals who used aminoglycosides (n=20). The control group was made up of 72 individuals, randomly selected from the general population.Samples of genomic DNA were extracted from the peripheral blood after obtaining the signed consent form approved by the Ethics Committee . In order to extract the DNA from individuals from the general population we used the DNAzol reagent, according to instructions from the manufacturer (Invitrogen®). In the samples from the other groups we used the phenol-chloroform standard.The polymorphic sequences of genes GSTM1 and GSTT1 were established by a multiplex PCR, including the b-globin gene as internal control of the 630pbThe statistical significance differences between the groups were calculated by c2 followed by the Yates correction with a 5% significance level .The genotypes were grouped by hearing normality, presence of hearing impairment and exposure to aminoglycoside antibiotics. The null GSTT1 was found in 16% (08 of 50) of the patients and in 18% (13 of 72) of the control individuals (p= 0.009). Null GSTM1 alleles were found in 21 (42%) of the 50 patients studied and in 38 (53%) individuals from the general population (p= 0.049). The frequency of homozygote GSTT1 and GSTM1 genotypes was significantly lower in patients assessed when compared to control individuals.The frequency of null GSTT1 and GSTM1 genotypes and the comparison of the results among the groups are shown on Antioxidant and detoxifying reactions related to glutathione are essential for intracellular protection. Nonetheless, it is known that the treatment with some drugs and time affect the inner ear defense system of mammals. Noise exposure and treatment with gentamicin do not affect tissue glutathione levels. Nonetheless, the antioxidant system is being influenced by aging and by the use of cisplatinMany studies suggest that the antioxidant activity can impact the hearing loss susceptibility. There are reports of genetic polymorphism on GSTM1 which act against the ototoxicity of cisplatinThe availability of information on GSTT1 and GSTM1 polymorphisms in the Brazilian population is still scarceNonetheless, we know that there are numerous environmental factors which can cause hearing loss, such as glutathione S-transferase that have an important role to play on the defense against oxidative stress caused by these factors.Our data strongly suggests that the null GSTT1 and GSTM1 genotypes are not associated to aminoglycoside-induced hearing loss.


Dementia is a disease in which memory, thought, and behavior-related disorders progress gradually due to brain damage caused by injury or disease. It is mainly caused by Alzheimer’s disease or vascular dementia and several other risk factors, including genetic factors. It is difficult to treat as its incidence continues to increase worldwide. Many studies have been performed concerning the treatment of this condition. Rho-associated kinase (ROCK) and phosphodiesterase-5 (PDE-5) are attracting attention as pharmacological treatments to improve the symptoms. This review discusses how ROCK and PDE-5 affect Alzheimer’s disease, vascular restructuring, and exacerbation of neuroinflammation, and how their inhibition helps improve cognitive function. In addition, the results of the animal behavior analysis experiments utilizing the Morris water maze were compared through meta-analysis to analyze the effects of ROCK inhibitors and PDE-5 inhibitors on cognitive function. According to the selection criteria, 997 publications on ROCK and 1772 publications on PDE-5 were screened, and conclusions were drawn through meta-analysis. Both inhibitors showed good improvement in cognitive function tests, and what is expected of the synergy effect of the two drugs was confirmed in this review. Dementia refers to a significant decrease in an individual’s cognitive level accompanied by memory, thought, and behavior-related disorders caused by brain damage due to injury or disease, and it hinders the patient’s social function . AlthougThere are two main types of dementia: Alzheimer’s disease (AD) and vascular dementia (VD). AD is a neurodegenerative disease and accounts for 60–70% of patients with dementia . AD causThe other type of dementia, VD, is caused due to issues with the brain blood supply, which usually worsens cognitive performance and gradually decreases due to minor strokes . VD alsoCurrently, more than 55 million people worldwide live with dementia, and nearly 10 million new patients are identified every year. In 2020, the prevalence of AD in the United States was estimated at 5.3% in the 60–74 year age group, 13.8% in the 74–84 year age group, and 34.6% in the ≥85 year age group ,15. In aSeveral considerations have been proposed to treat AD . The goaAD is characterized by NFTs of extracellular Aβ plaque and highly phosphorylated tau . AccordiVD is associated with several cerebrovascular risk factors . Some faA mechanism of ischemic VD involves a major vascular disease in which blood flow in the brain decreases because of arterial stenosis. However, this has not been sufficiently investigated clinically, and the large vessel disease associated with VD is unclear. However, small changes in blood vessels cause damage to brain tissue and are potentially responsible for cognitive impairment. Another possible mechanism influencing small blood vessel changes is incomplete ischemia and selective tissue necrosis, causing selective neurological necrosis due to decreased functioning of neuroglial cells and microvessels ,36,37.ROCK is the downstream effector protein of RhoA, a GTP-binding protein ,39. It bMutation of presenilin (PSEN) was confirmed in cases of early-onset AD . The APPIn addition, hyperphosphorylation of tau, a characteristic of AD, seems to be associated with ROCK. Although no specific mechanism has been identified, ROCK activation activates tau kinase and inhibits tau phosphatase, increasing the expression of P-tau and oligomeric tau. It also reduces the microtubule-binding of tau and increases the formation of NFTs in neurons .2+ increases through guanine nucleotide exchange factors, the increased ROCK phosphorylates MLC [ROCK is involved in vascular remodeling, which starts with RhoA. Downstream targets of ROCK include MLCP, LIMK, Ezrin/Radixin/Moesin (ERM) intermediate filaments, and other factors affecting intracellular processes that are important for cell contraction, movement, proliferation, and morphology . RhoA biates MLC . The incROCK is also related to endothelial NOS (eNOS): it is the upstream negative regulator of eNOS, and its expression reduces eNOS expression . eNOS haNeuroinflammation is an inflammation of nerve tissue and can begin as a response to various signals, including infection, traumatic brain damage, toxic metabolites, or autoimmune. Neuroinflammation is a common feature observed in many neurodegenerative disorders and is an important factor in neurodegenerative progression. The involvement of local innate immune responses contributes greatly to central nervous system (CNS) damage .Activation of the RhoA/ROCK pathway increases the permeability of inflammatory factors in response to inflammatory stimuli . The RhoROCK also directly increases the inflammatory response. Cyclophilin A (CyPA) is a protein belonging to the immunophilin family. When ROS is induced in a hypoxic state, it stimulates CyPA secretion along with ROCK activity. CyPA secreted from VSMCs binds to basigin, a receptor outside the cell, to regulate the cell signal pathway  and actsThe PDE superfamily consists of 11 subtypes, PDE1-PDE11, and classification is based on sequence homogeneity . PDE-1, The relationship between PDE-5 and AD focuses on the NO pathway. The NO/sGC/cGMP signaling pathway appears abnormally in the AD brain ,81,82,83PDE-5 breaks down cGMP produced from NO/sGC/GTP signals. cGMP acts on blood vessels and contributes to vascular relaxation. When the cGMP in the VSMCs is reduced by PDE-5, the blood flow to the brain may reduce due to vasoconstriction .cGMP regulates intracellular inflammatory responses. Monocyte chemoattractant protein-1 (MCP-1) is a chemokine that contributes to the inflammatory response by recruiting monocyte, memory cells, and dendritic cells at the inflammatory site ,88. NO rAstrocyte is a neuroglial cell of the brain and spinal cord. It is involved in blood-brain barrier formation and function , neurotrOverexpression of ROCK has been shown to cause an increased inflammatory response, increased oxidative stress, high oxidation of tau, and cognitive decline due to β-amyloid accumulation. In such a situation, ROCK inhibitors are a good choice for treating dementia. Fasudil is a typical ROCK inhibitor with potential neuroprotective effects that can cause neurogenesis and increased neuronal viability ,96. InhiPDE-5 suppression is another possibility to improve dementia. PDE-5 inhibitors increase the cGMP concentration by blocking the cGMP decomposition of PDE-5 described above, and the increased cGMP expands blood vessels and improves blood flow through smooth muscle tissue relaxation. Typical PDE-5 inhibitors include sildenafil, vardenafil, and tadalafil. Subsequent animal studies with sildenafil demonstrated long-term retention of an inhibitory avoidance response in mice. In an in vitro study using N9 microglia, it was shown that cGMP accumulated because of regression of PDE-5 following sildenafil treatment could contribute to inhibiting microglia activation. In addition, injection of PDE-5 inhibitors into the ischemic stroke rat model with reduced cognitive function through middle cerebral artery occlusion (MCAo) improved neurological deficits and anxiogenic disorder and improved locomotion .In this study, a meta-analysis was performed to investigate the relationship between cerebrovascular disease and drug effects of ROCK and PDE-5 inhibition in animal models. A meta-analysis is a quantitative, formal, epidemiological study design used to systematically assess previous research studies to derive conclusions about that body of research. It can be performed when there are several scientific studies addressing the same problems, and each study reports measurements that are expected to be somewhat error-prone. The efficacy of ROCK inhibitors and PDE-5 inhibitors as drug treatments for dementia in animal models is analyzed and presented here.Multiple comprehensive databases, such as PubMed, EMBASE, and the Cochrane Library, were used to search studies on ROCK inhibitors and PDE-5 inhibitors. The search was conducted on all manuscripts published so far without restriction on the year of publication. MeSH keywords were searched and are specified in the attached supplementary data: Keywords for ROCK inhibitors and PDE-5 inhibitors. The searched publications were evaluated for quality using the Newcastle-Ottawa scale , and datThe Morris water navigation task, also known as the Morris water maze (MWM), is a behavioral technique mostly used with rodents . It is pTwo reviewers (D.H.L. and J.S.O.) independently extracted data according to a predetermined data extraction form. Duplicate data was removed using Endnote. Features extracted from each study include the first author’s name, publication year, pathology induction method of the disease group, drugs used in the experimental group receiving pharmacotherapy, gender, age, pharmacotherapy method, drug dosage, disease classification (AD or VD), MWM—mean value of time spent in the target quadrant (TSTQ), SD values (%), and mice participating in the experiment .Meta-analysis was performed using a random effect model. The results were presented according to the 95% confidence interval (CI). A heterogeneity test was performed using the Cochran Q test, and a publication bias test was performed using the Egger’s test. Statistical analysis was conducted using Revman (version 5) software.Because of the high heterogeneity, each group was sub-classified into a subgroup, and a meta-analysis was performed.A total of 997 publications on ROCK inhibitors were identified through the search formula. According to the screening criteria, 11 publications were finally selected  after 1. FinallyA total of 414 mice participated in the 23 finally selected studies. Both male and female mice were included in these studies. Their age was widely distributed from 8 weeks to 18 months .Of these, 330 (79.8%) mice had AD, and 84 (20.2%) mice had VD. Methods that induced AD included drug administration and genetic mutations. The intracerebroventricular streptozotocin (ICV-STZ) method, which induces AD in animals without transformation, shows mitochondrial abnormalities , decreasMice with conditions imitating VD-induced arteriosclerosis with cholesterol crystals, ischemic stroke with bilateral common carotid artery occlusion (BCAO), or bilateral common carotid artery ligation had hypoxic damage to the brain.Ganoderma lucidum triterpenoids, Edaravone, and Clitoria ternatea have also been verified to inhibit the ROCK pathway. PDE-5 inhibitors (12 out of 23), including sildenafil, tadalafil, vardenafil, CM-414, and KJH-1002 have also been verified in each publication. The drugs were either stereotaxic, orally-administered, injected into the left lateral ventricle, administered through gavage, or through intraperitoneal or intracerebral vascular injection. Of all mice, a total of 205 (49.5%) mice were treated with either ROCK inhibitors or PDE-5 inhibitors, 98 (23.7%) of which were treated with ROCK inhibitors, and 107 (25.8%) were treated with PDE-5 inhibitors.ROCK inhibitors for pharmacological treatment of dementia (11 out of 23) include Fasudil and Y-27632. Considering that the scales of all studies are not the same and the heterogeneity is high, the analysis was divided into standardized mean difference SMD,  and meanI2 64%) more cognitive improvement than before treatment. Among them, mice treated with PDE-5 inhibitors had 1.80% SMD (95% CI 1.25–2.34 I2 61%) cognitive improvement before treatment, while mice treated with ROCK inhibitors had 1.87% SMD (95% CI 1.25–2.49 I2 66%) cognitive improvement than before treatment. The biggest SMD improvement among publications with ROCK inhibitor treatment was found in the report of Yun AD ROCKI 2013, showing a difference of 4.69% (95% CI 3.44–5.94) SMD. Conversely, the smallest SMD difference was 0.97% (95% CI 0.26–2.19), as reported by K.H. Reeta AD ROCKI 2017. Among the reports receiving PDE-5 inhibitor treatment, the most obvious difference in SMD was 3.28% (95% CI 1.98–4.57), which was reported by Mohamed Cognitive PDE5I 2021. On the other hand, the PDE-5 inhibitor treatment with the smallest SMD difference was Garcia Cognitive PDE5I 2013, which reported 0.35% (95% CI 0.54–1.23).Mice, who received all treatments, had an average of 1.83% SMD  more cognitive improvement. Among them, mice treated with PDE-5 inhibitors had 10.73% MD (95% CI 9.21–12.26 I2 16%) cognitive improvement, while mice treated with ROCK inhibitors had 12.70% MD (95% CI 8.55–16.85 I2 84%) cognitive improvement. The biggest MD improvement noted among publications on ROCK inhibitor treatment was in the report Cuadrado Cognitive PDE5I 2011, showing a difference of 33.63% (95% CI 13.63–53.63) MD. Conversely, the least MD difference was 6.65% (95% CI −1.42–14.72), which was reported by Zhu Cognitive PDE5I 2015. Among the reports on PDE-5 inhibitor treatment, the most obvious difference in MD was 31.79% (95% CI 19.88–43.70), as reported by Manish AD ROCKI 2018. On the other hand, the PDE5I treatment with the smallest MD difference was YU AD ROCKI 2020, which reported an improvement of 5.67% (95% CI 1.67–9.67).Mice, who received all treatments, had an average of 11.78% MD  results of animal models were compared based on the SMD and MD through meta-analysis, confirming that both ROCK inhibitors and PDE-5 inhibitors helped improve cognitive function.Therefore, the results of this analysis expect synergistic treatment effects for the combined administration of both drugs. Both ROCK and PDE-5 inhibitors showed good effects on improving cognitive impairment, and many factors share both mechanisms. ROCK suppresses eNOS and PDE-5 suppresses NO, leading to a downward adjustment of NO/cGMP. And they share several factors that can affect neuroinflammatory responses, such as MCP-1, NF-kB, and VCAM-1. So we conclude that the combined administration of both inhibitors is worth studying in anticipation of the treatment effect of synergy.


More than half (58.7%) of the transplant patients had at least one hearing problem. Hearing loss was observed in 50%, 60.9% and 76.1% of the transplant patients at 8,000, 16,000 and 20,000 Hz. Hearing thresholds of transplant and hemodialysis patients increased from 4,000 to 20,000 Hz and was higher than that of controls. Hearing thresholds were higher at 1,000–2,000 Hz in patients using tacrolimus and at 16,000–20,000 Hz in patients using mTOR inhibitor. No correlation was found between hearing threshold and blood tacrolimus or mTOR inhibitor levels. Most kidney transplant and hemodialysis patients have hearing loss at higher frequencies than medium frequencies. Hearing loss in chronic kidney patients is likely to be permanent and kidney transplantation may not improve hearing problems. Hearing problems may be more pronounced at medium frequencies in patients receiving tacrolimus but at higher frequencies in patients receiving mTOR inhibitors.It is not known whether hearing disorders improves with kidney transplantation. One of the neurotoxic effects of immunosuppressive drugs may be unrecognized hearing loss. In this study, our aim was to evaluate the hearing disorders in kidney transplant patients. Hearing problems in 46 kidney transplant patients [eGFR ≥ 60 ml/min/1.73 m  Kidney transplantation is the most preferred treatment method for end-stage renal disease. According to the World Health Organization data, in 2019, 100,097 kidney transplants were performed all over the world . CalcineWe have observed that some kidney transplant patients, albeit very few, experience hearing problems after transplantation. Advanced age, diabetes, ototoxic drug use, and uremia can partially explain this situation; it is possible that the immunosuppressive drugs used, especially tacrolimus, may also have ototoxic effects. It is accepted that mTOR inhibitors do not have neurotoxicity -9. ThereIn this study, our primary aim was to determine any hearing problems in kidney transplant patients in kidney transplant patients using questionnaire and EHFA. Our second goal was to determine whether there was a relationship between the hearing problem, if any, and the type of immunosuppressive drug used.This cross-sectional case-control study was conducted at the Department of Nephrology and Department of Ear-Nose, and Throat Clinics of Kahramanmaras Sutcu Imam University Medical Faculty Hospital, and Izmir Bozyaka Training and Research Hospital. A total of 89 patients; 46 kidney transplant recipients (TX group), 23 hemodialysis patients (HD group) and 20 healthy controls (C group) were included in the study. Ethical approval was obtained from the local ethics committee of Kahramanmaras Sutcu Imam University . Written informed consent was obtained from all patients.2 , between the ages of 18–50 years, that have passed at least 6 months after kidney transplant, and have been using tacrolimus or an mTOR inhibitor (Everolimus) in their immunosuppressive regimen were included in the TX group. Nondiabetic patients aged 18–50 years and that have received maintenance hemodialysis treatment three sessions/week for at least 6 months were included in the HD group. Healthy subjects who matched with kidney transplant patients for age and gender distribution were included in the control group.Nondiabetic kidney transplant recipients with an estimated glomerular filtration rate (eGFR) > 60 ml/min/1.73 m2, kidney transplant patients using regimens that do not contain tacrolimus or mTOR inhibitors were not included in the study.Patients under the age of 18 and over 50, were diagnosed with Alport syndrome, had a known or newly developed diabetes mellitus (DM), have used ototoxic drugs within the last 3 months , had a history of hereditary or acquired hearing loss problems due to several reasons , have had ear trauma or surgery, have intracranial pathology that may cause hearing loss, have malignancy and been receiving chemotherapy, and those in whom the time elapsed since the start of dialysis or after kidney transplant was less than 6 months, HD patients whose Kt/V value was less than 1.2 within the last 3 months, kidney transplant patients with eGFR < 60 ml/min/1.73 mData such as patients’ age, gender, presence of comorbidity , the etiology of chronic kidney disease (CKD), the number of years they have been receiving HD treatment, duration of RRT  before transplantation, the time elapsed after kidney transplant, and the immunosuppressive drugs used were obtained from their medical records. Systolic and diastolic blood pressures (SBP and DBP), height and weight were measured before the midweek dialysis session for HD patients and during the examination for TX and C groups. Body mass index (BMI) was calculated by dividing body weight in kilograms divided by square of height in meters.Fasting blood glucose (FBG), blood urea nitrogen (BUN), creatinine (Cr), sodium (Na), potassium (K), calcium (Ca), phosphorus (P), LDL cholesterol, triglyceride (TG), uric acid (UA), serum albumin levels were measured with the standard methods. A blood sample of the HD patients was taken just before the midweek dialysis session. The patients’ Kt/V values and urea reduction ratios (URR) were retrieved from their medical records, and the arithmetic average of the last 3 months was calculated. The blood of TX patients was taken during outpatient control and tacrolimus or mTOR inhibitor blood levels (C0) were measured.Audiometric measurements and the examinations of the external and middle ear and the throat were performed by a single otolaryngology specialist in each centre. Lavage and aspiration were performed on patients who required plug aspiration. All audiological evaluations were performed in a standard double-wall, soundproof booth . Airway hearing tresholds at 250, 500, 1,000, 2,000, 4,000 and 8,000 Hz frequencies using the Telephonics TDH 39P headphones  with the Interacoustics AC-40 audiometer , bone conduction hearing thresholds at the 500, 1,000, 2,000 and 4,000 Hz frequencies using the Rodioear B-71 bone transducer , and high frequency airway hearing thresholds  using Harward HR H903 headphones were determined. The mean and standard deviation of air and bone conduction thresholds were calculated for each frequency for all patients. The actual hearing levels were determined by masking in patients with a hearing level difference of more than 40 dB between both ears and an air-bone conduction difference of >10 dB. Apart from audiometric examinations, immitance measurements were made using Interacoustics AZ26 and AT235h clinical tympanometry devices. Middle ear pressur and ipsilateral and contralateral acoustic reflex thresholds of all participants were evaluated. In addition, Speech Reception Treshold (SRT), Speech Discrimination (SD) tests were performed on all patients.1. Did you have a hearing problem before the transplant?2. Did your hearing decrease after the transplant?3. Do you feel the need for a hearing aid?4. Do you have any ear pain or a feeling of pressure in the ear?5. Do you have ringing in the ear (Tinnitus)?6. Do you have dizziness?7. Did you experience sudden hearing loss after the transplant?8. Have you had ear surgery?9. Have You had an Ear/Head Trauma?To define hearing problems, TX and HD patients were asked the following survey questions appropriate to the patient’s group.p value of less than 0.05 was considered statistically significant. Bonferonni correction was applied to evaluate which group caused the difference; the groups were compared in pairs, and a p value of less than 0.016 was considered significant. The categorical variables were evaluated with the Chi-square test. The Mann-Whitney U and chi-square test were used to compare patients using tacrolimus or an mTOR inhibitor according to data type. A p value of less than 0.05 was considered significant.The power analysis of the study was performed with the G*Power 3.1.9.7 for Windows  softwareMore than half (58.7%) of the TX patients had evolved at least one hearing problem. A great majority (93.5%) said that they had no hearing problems before the transplantation. Among the TX patients, 31.1% had pressure sensation in the ear, 41.3% had tinnitus, and 19.6% had dizziness. While 97.8% of the patients said they did not need help for hearing, only 2.2% stated otherwise. None of the patients had sudden hearing loss after kidney transplantation. On the other hand, 8.7% of HD patients had pressure sensation in the ear, 17.4% had tinnitus and 26.1% had dizziness. Ear ache-pressure sensation and tinnitus complaints were more common among the TX patients than HD patients .Chronic kidney disease etiologies observed in HD patients were hypertension (HT) in 21.7%, chronic glomerulonephritis (CGN) in 13.3%, unknown/other causes in 65%. In the TX group, 26.1% had HT, 6.5% had polycystic kidney disease (PKD), 10.9% had CGN, and 56.5% had unknown and other causes.p = 0.13) and gender distribution . The SBP of TX and HD patients was higher than that of healthy controls . Other laboratory parameters are summarised in The TX, HD, and C groups were similar in terms of age   .p = 0.02)  .p > 0.05 for all).Hearing thresholds in all groups were similar between the 1,000–2,000 Hz range   .The first test of immittance testing was tympanometry, which returned normal values for middle ear pressure levels in all patients. The second test was the acoustic reflex test, which revealed that the stapedius reflexes were bilaterally normal for all participants.p = 0.04) (p = 0.005)  . The SD = 0.005) .The normal hearing thresholds was accepted as 20 dB for the 250–8,000 Hz frequency range and 30 dB for the 16,000 and 20,000 Hz frequency range. The percentage of patients with hearing defects in all are given in p = 0.001; and 58.43 ± 12.74 dB vs. 39.00 ± 17.97 dB at 20,000 Hz for the right ear; p < 0.001) (p < 0.001), had passed a longer time after transplantation  and had lower eGFR . Since these parameters are known to affect hearing, when the analysis was repeated after excluding some patients so that the two groups were matched in terms of age, eGFR and the time elapsed after kidney transplantation, it was observed that the hearing thresholds at 1,000–2,000 Hz in the patients receiving tacrolimus continued to be significantly higher than those receiving an mTOR inhibitor, and the hearing thresholds at 16,000–20,000 Hz in the patients who received an mTOR inhibitor were still higher than the patients who received tacrolimus   . However< 0.001) .p > 0.05). However, patients who received an mTOR inhibitor had higher SD values in both ears than the patients who received tacrolimus . When both groups were matched, the mean SD value of the patients receiving mTOR inh was still higher than those receiving tacrolimus . The hearing threshold was inversely correlated with eGFR and serum p values   .This study is the first to evaluate the hearing function of kidney transplant patients with EHFA and evaluate the effect of immunosuppressive agents on hearing. Our main findings can be summarized as follows. The majority of kidney transplant patients have hearing-related abnormalities. Kidney transplant patients have hearing loss that does not affect the middle frequencies but is evident at high frequencies, and their hearing level is as bad as HD patients. Hearing loss in CKD patients is likely to be permanent and a kidney transplant may not improve their hearing problems. The SRT and SD values were impaired with hearing loss. The use of tacrolimus seems to cause auditory deficit in the 1,000–2,000 Hz range, and the use of mTOR inhibitor mostly at high frequencies such as 16,000 and 20,000 Hz.The frequency of sensorineural hearing loss in CKD patients ranges from 28 to 77%, and hearing function declines as the stage of CKD increases –14. The Unfortunately, there is not sufficient evidence that these abnormalities improve after kidney transplantation. In two studies conducted by Mitschke et al in 1975 and 1977, it was suggested that audiometric abnormalities returned to normal after kidney transplantation. The authors showed that 7 of 10 HD patients’ hearing thresholds within the range of 256–8192 Hz returned to normal after kidney transplantation. The three patients in whom the hearing defect did not improve had hereditary nephritis . HoweverThe SRT values were higher while the SD values were lower for the study groups than the control group. These results are in close agreement with pure tone threshold results and confirm the validity of the pure tone thresholds. The immittance testing returned normal results in all groups. This may be expected since HD, kidney transplantation or the drugs used had no effects on the middle ear pressure and acoustic reflex.Our study had some limitations. Since it was conducted in two different locations, the measurements made by two audiologists may partially affect the results. Its cross-sectional design rather than being a prospective one may be another limitation. However, there are only three studies in the literature evaluating hearing problems in kidney transplant patients with audiometry, while few others have evaluated the condition using questionnaires only. Our study is the first of its kind to make analyses with EHFA. In addition, there is no other study in the literature that evaluates the relationship between hearing problems and the immunosuppressive drug type used. The number of patients in our study was determined by power analysis, and the power of our study was over 80%.In conclusion, there are defects in hearing and cochlear functions in kidney transplant patients due to permanent hearing defects because of CKD and the additive effects of immunosuppressive drugs. Hearing defects probably do not improve after a kidney transplant. This issue needs to be investigated with prospective studies.