There is evidence that the factors contributing to the prevalence and aetiology of hearing impairment vary widely from one country to another. In South Africa, as in other low-income and middle-income countries, more context-specific information on the estimated prevalence of hearing impairment and the factors that contribute to its onset is required.The aim of this study was to provide decision-makers and hearing health professionals with local and accurate information on the prevalence of ear and hearing disorders in the Elias Motsoaledi Local Municipal (EMLM) area of the Limpopo province, South Africa.The World Health Organization (WHO) protocol for population-based surveys of prevalence and causes of deafness, hearing impairment and other ear diseases was utilised. A random multi-stage cluster sampling strategy, two-stage sampling, was utilised to select the seven municipal wards and 357 households through the probability proportional to size method. A total of 850 participants were included in the study.The overall prevalence of hearing impairment was 19.88%  and 8.94 (95% CI: 0.08–0.12) for disabling hearing impairment. The prevalence of ear disease was 13.19% (95% CI: 0.10–0.15), with impacted cerumen and otitis media reported most often. Associations with hearing impairment were established for age, gender and hypertension.The study has shown a higher prevalence of disabling hearing impairment in the rural EMLM area of the Limpopo province compared to global prevalence rates. In addition, known factors associated with hearing impairment were confirmed. The devastating consequences of disabling hearing impairmentSeveral factors contribute to the increased global prevalence estimates of disabling hearing impairment. Most notable is the significant association between hearing impairment and advanced age, which is attributed to increased mean life expectancy in many countries GBD, . The impApproximately 50% of hearing impairment can be prevented and most of the remainder can be treated successfully WHO, . DependiThe available estimates of the prevalence of hearing impairment and causes thereof in low-income and middle-income countries are limited WHO, , despiteTo reduce the burden of hearing impairment, the implementation of context-specific and targeted prevention programmes is vital. However, limited information is available on the prevalence and causes of hearing impairment as well as factors that contribute to the prevalence of thereof in the underserved, rural areas of South Africa  through the probability proportional to size (PPS) method. The first stage entailed the random selection of seven clusters using a rural sampling frame. This resulted in the exclusion of five wards (e.g. those where the two major towns were situated and those with a large number of residents). The second stage involved the selection of households by dividing the total number of households in the five selected wards by the total number of households to be tested. This indicated that every 35th household in each of the selected wards was to be included in the survey. The total number of households in each selected ward was divided by 35 in order to determine how many households to visit in each ward. In cases where the individuals in the selected households declined participation, the research team visited the household to the left of the household that refused.The required sample size of 1428 participants was based on the 10% estimated prevalence of disabling hearing impairment with precision of 3.4%   were between 15 and 64.11 years of age . The mean age of pilot study participants was 17.6 years . Following the pilot study, the role of the research assistants expanded to include pure tone audiometry and automated auditory brainstem response (AABR) screening (with the interpretation of testing findings made by the researcher). In addition, the protocol for entry into the households was changed to first approach the house to explain the purpose of the study and to determine equipment needs . This was more practical as the houses were too small to accommodate the research team and all the equipment.A pilot study was conducted in a randomly selected ward in the same area to refine the study protocol. Households were selected as per the sampling strategy and potential participants informed about the study in their home language. Forty participants from nine households  were included in the pilot study after giving written consent and/or assent. The same steps as outlined in the main study were followed and the study protocol completed with each participant. Data collected from these participants were not included in the main study. The majority of participants were female .Average ambient noise level measured during testing was 55.53 dBA (±2.5) (Bruel & Kjaer 2239 Type II integrating sound-level meter). No statistically significant relationship between the level of ambient noise during testing and different degrees of hearing impairment was found  was conducted. The study protocol for participants younger than 4 years included distortion product otoacoustic emissions (DPOAEs) (OtoRead), tympanometry (Titan) and AABR (Maico MB11). For participants older than 4 years, tympanometry (Titan) and pure tone audiometry (AS608 screening audiometer) were conducted. The screening results were recorded on the ear and hearing disorders survey form.Once ethical clearance for the research study was obtained from the Human Research Ethics Committee  of the University of the Witwatersrand (Protocol number: M130238) and permission granted by the Limpopo Department of Health and Social Development, data collection commenced.Community entry was made through permission sought from ward councillors and tribal authorities (e.g. village chiefs) prior to entry into the selected wards. The community was informed of the study by announcing the research project on Moutse FM, the local radio station.The research team visited each selected household and if permission was granted to enter the household, each individual was presented with the participant information sheet (if age appropriate) and the study was verbally explained to them. The participants were fully informed of the nature of the study and assured of confidentiality and their rights to withdraw from the study at any time without negative consequences. Only participants who gave written consent and/or assent were included in the study.The audiometric assessment was conducted as per the study protocol and participants who required ear and hearing health care were referred to their nearest health facility. All completed survey forms were verified for completeness by the audiologist and data transferred onto an Excel spreadsheet by the audiologist.Non-random errors were minimised as research assistants received comprehensive training on the study protocol under field conditions and had access to the comprehensive training manual throughout the study. The routine audiological test procedures used in the study are all valid measures with high sensitivity and specificity. All the equipment used in the study was calibrated prior to the start of the study . Daily listening checks and biological calibration were performed before each data collection session. The audiologist accompanied the research assistants on all visits and completed the same data collection forms as the assistants to determine the inter-rater reliability. Inter-rater agreement was 100%.t-test (p = 0.05) was used to determine the relationship between ambient noise levels and hearing thresholds obtained. Binomial proportion confidence intervals (p = 0.05) were used to estimate the probability (odds) of hearing impairment. The relationship of various factors associated with hearing impairment was analysed with binomial logistic regression (p = 0.05).SAS Version 9.3, a statistical software programme, was used to conduct data analysis. Descriptive statistics used included measures of central tendency and variability. An independent Approval was granted for this study with ethical clearance number: M130238.The prevalence of hearing impairment (>26 dB) in this population was 19.88% (95% CI: 0.15–0.21) .With the specific classification of hearing loss into various degrees, the prevalence of slight hearing impairment was 10.94% and that of disabling hearing impairment was 8.94% . The pren = 21) of the children in this age group obtained a ‘refer’ result. The majority of these participants were males .Because of the nature of the screening measures (DPOAE and AABR) used for children 0–3.11 years of age, it was not possible to differentiate between the degrees of hearing impairment. Instead, results were recorded as either ‘pass’ or ‘refer’. A ‘pass’ result indicated that they presented with normal middle ear and outer hair cell functioning. Only 37.5% , the majority  reported that the cause of their hearing impairment was unknown (undetermined).Of the participants who presented with disabling hearing impairment  was determined. The findings of the current study indicate that age and self-reported hypertension were associated with hearing impairment .n = 261) of the participants required referrals to the hospital or primary healthcare clinic for further management. Whilst the overwhelming majority of these individuals  required diagnostic audiometry to confirm the type and degree of hearing impairment, cerumen management was required for 35% (n = 92) and medical management was required for 10% (n = 26) of these participants.Thirty-one per cent (p < 0.0001) than the estimated prevalence rate (4.57%) reported for the Cape Town metropolitan area, South Africa  is higher than the reported global estimate of 6.12% WHO,  and otheThe high prevalence of ear disease reported in the current study was mainly because of impacted cerumen and otitis media. Globally, the prevalence of impacted cerumen varies widely. In the United Kingdom, between 2% and 6% of the general population present with cerumen impaction at any given time, whilst the diagnoses of 3.6% of emergency visits for otologic complaints in the United States were impacted cerumen  WHO,  as well n = 92) diagnosed with cardiovascular disease  and ear disease (cerumen impaction and otitis media) were confirmed. Although ototoxicity and noise-induced hearing loss were not associated with hearing impairment in this population, the importance thereof in causing hearing impairment should not be negated.The study was successful in providing the decision-makers in the national and provincial departments of health as well as hearing health professionals with information on the prevalence and causes of ear and hearing disorders in this rural area. The findings can be used to plan for and implement more accessible ear and hearing care services that are specifically tailored to the needs identified. The strategies outlined by Olusanya et al.  provide


Sometimes there is no hearing impairment, but it is possible to have an auditory disorder. This is known as a central auditory processing disorder (CAPD). Speech dichotic tasks are useful tools to evaluate CAPD, but there is almost no tool to assess this for Azeri people in their native language. The aim of this study was to evaluate central auditory processing of Azeri participants by Azeri dichotic digit test (ADDT).Participants were 52 normal Iranian Azeri students  in the Department of Audiology, School of Rehabilitation Sciences, Iran University of Medical Science, Tehran, Iran in 2016. They were chosen by convenient sampling. ADDT was constructed and administered in free recall conditions along with a Persian dichotic digit test (PDDT). After two to four weeks, reliability was performed. P>0.05). The results showed a significant difference between both ears’ scores in PDDT (P<0.02) as well as in ADDT (P=0.00). The right ear advantage was seen in both tests.The mean of the right ear score of PDDT and ADDT was 98.90% and 99.09%, respectively. ADDT was reliable in almost all scores. There was no significant difference in performance between men and women in any score of both tests (All participants performed significantly better on digits presented in the right ear than the left ear in both tests. Central auditory processing of Azeri participants for Azeri is similar to that for Persian. Central auditory processing (CAP) is the perceptual processing of auditory signals in the central nervous system (CNS) and the neurobiological mechanisms which are substraiting of electrophysiological auditory potentials. CAP encompass sound localization and lateralization; sound discrimination; auditory pattern recognition; temporal characteristics of auditory signals. Central Auditory Processing Disorder (CAPD) is problems with the perceptual processing of auditory signal in the CNS, which reflects by deficiency in one or more of the above mentioned central auditory behaviors . ChildreDichotic listening procedure was introduced in 1954, in which the competing pairs of digit series are presented simultaneously into the two ears . The folDDT is a fast and simple test, developed to evaluate central auditory processing system in dichotic conditions , 11 in bA study was conducted at the development and standardization of Persian double PDDT on 81 normal Persian adults aged 18 to 32 in Iran and found that DDT was a useful tool to assess the auditory processing system in Persian adults . A reseaToday, the number of bilingual speakers is more than monolingual speakers in the world's population . The firDDT is available in different forms, including single, double and triple . The PerIn this study, double Azeri Dichotic Digit Test (ADDT) was constructed and administered along with a double Persian Dichotic Digit Test (PDDT) for Azeri people to study their central auditory processing characteristics. The right ear score, the left ear score and the REA of each test were calculated and analyzed and the results of the PDDT were compared with the results of the ADDT. The objective of the present study was evaluation of central auditory processing of Azeri-Persian bilinguals with dichotic listening tasks in both Azeri and Persian stimuli. This cross-sectional comparative study was conducted with feasibility and reliability measuring tools which included two main steps of construction and administration.The Persian stimuli in digit level are currently available and include twenty unique double sets of nine 1-10 monosyllabic digits , 17. SinRecording of digits was done in a studio by an Azeri-Persian bilingual broadcaster. He had a clear and standard Tabrizi accent and repeated each digit six times with an interval of two seconds with equal tonality and intensity. After completing the recording, the recorded materials were written on CD at 8x by an SBW-06D2X-U CD ROM (ASUS).. Six seconds of silence between each item was considered for the subject's response. Each item consists of four monosyllabic digits presented to the ears simultaneously. No digit was repeated in an item and each digit had a relatively equal chance to be selected. Between two digits a 500 ms interval was considered. The signals were arranged in such a way that the onset of stimulation was simultaneous to the onset of the signal and a silence interval was considered at the end of each signal to make the duration of each pair of digits was equal Detailed assessment was carried out to ensure that the onset and offset of stimuli were equal. The resulting wave was written with Wave format. At the beginning, a calibration tone with 30 sec duration and frequency of 1000 Hz was recorded on a CD with intensity equal to the average intensity of digits  and the total score for each ear was 100%. Ethics considerationAll participants were selected from Azeri students of Iran University of Medical Sciences (IUMS) and Tehran University of Medical Sciences (TUMS) in Tehran, Iran. All participants completed informed consent form. The ethical aspect of this study was approved by the Research Ethics Committee of IUMS in letter 94/1809/105/d. Inclusion criteria: An Azeri participant was considered as one born in East or West Azerbaijan or Ardabil Provinces of Iran, acquired Azeri language first, but the Persian language (L2) learn relatively early in childhood before the age of five to seven years old and had no interaction with other languages; no history of otologic, neurologic, and audiology disorders, bilateral normal hearing and normal word recognition score; threshold asymmetry less than 15dB (33)  and right handedness assessed through Persian version of Edinburg Handedness Scale. The handedness score ranged from –100  to +100 .Hearing assessment and dichotic tests were conducted in Audiology Clinic in the Rehabilitation Science School of IUMS in Tehran, Iran in Oct 2015 until May 2016. Dichotic tests were performed in binaural mode using headphones . Since all dichotic tests should be implemented at the most comfortable level (MCL) before performing the test, the volume level of the computer was set at 60 dB SPL as the MCL of normal hearing people (33) and calibration was performed in 4152 artificial ears (B&K) using 2235 Sound Level Meter (B&K). Signal presentation conducted via CD player through the laptop using a laptop . At the beginning of each session the device was calibrated and to ensure the leading signal integrity, channel balance, and volume settings, the sound was heard through the headphone, half of the numbers were presented to the right ear and the other half to the left. Both dichotic tests were conducted in free recall format. During free recall, participants were asked to repeat all the digits of both ears in any order . Using pStatistical AnalysisThe Kolmogorov-Smirnov test was used for comparing the data distribution against the normal distribution. Spearman correlation coefficient was used to assess the reliability. We Utilized paired t-test to compare the two test scores between the test and the re-test. Independent t-test was used to investigate the effect of gender on the results of each test. We used paired t-test to compare both test scores between both ears to evaluate the ear effect. The data were processed in SPSS 21  at the significance level of 0.05.Participants were 52 Azeri students . Frequency descriptive of gender of all participants was seen in Figure 1. The range of age was 18 to 35. The means of pure tone average of right and left ears were 4.33 dBHL. The mean lateral preference value based on Edinburgh Handedness Scale was 9.01±1.74. The amounts of mean, Standard Deviation, median, minimum, maximum of scores for both tests in test and re-test are summarized in P>0.05) with the exception of the left ear score of ADDT (P=0.02). To investigate the reliability of both tests, Spearman correlation coefficient was also used. Total scores in bilinguals were repeatable (P<0.05), but the right ear score of ADDT and the REA score of PDDT were not reproducible (P=0.019). Significant difference between the two ears confirmed an REA in PDDT. The comparison of the scores of right and left ears for ADDT in bilinguals also showed a highly significant difference (P=0.001). The obtained value approved a significant REA in Azeri stimuli.Test-retest reliability was surveyed by comparing the mean scores of the first and the second run. All scores of both tests were reliable . The mean of the right ear, the left ear and REA scores for PDDT in the present study  are consistent with another result . Their rReliabilityThe reliability was assessed using correlation coefficients and paired t-test. Total scores based on Spearman correlation coefficient were repeatable but the right ear score of ADDT and REA score of PDDT were not reproducible. In this way, four out of six calculated scores showed repeatable results. Results are reliable . Test-retest reliability indicated that five out of six calculated scores are repeatable. Thus, almost all results are reliable. Reliability of test-retest can somehow show the learning effect on the results. There was no learning effect on any score of any tests except the left ear score of ADDT . Left eaGender effectIn the present study, the gender did not affect the results of PDDT and ADDT. This finding is in agreement with other studies -38 in whADDT vs. PDDT:The results of the present study clearly indicated REAs for PDDT and ADDT, presented stimuli were processed in the left hemisphere. This finding is in line with the several previous studies , 23-25, Greater REA of Azeri (L1 compared to REA of Persian (3.41 vs. 0.82), is the inequality of the left ear scores (95.67 vs. 98.03) and similarity of the right ear scores (99.09 vs. 98.90). Increasing the left ear score and decreasing the left ear score in Persian are indicative of the effect of bilingualism on results. The findings of the present study showed different REAs for Azeri and Persian stimuli, this finding was also reported in Chinese-English  and ItalSince dichotic test results do not change after the age of 12 -12, the In conclusion, Azeri version of double DDT is a reliable tool in almost all scores. Gender has no effect on any score of ADDT. Although the values of REA for PDDT and ADDT were not the same, REAs were observed for both ADDT and PDDT. Using ADDT to assess central auditory processing of Azeri people in dichotic listening seems to be useful.


The OCT and OCTA images showed displacements of the fovea and choroidal intermediate vessels postoperatively. The degree of displacement of the choroid was significantly less than that of the retina (P < 0.001). The displacements of the choroidal bifurcations were significantly correlated to their preoperative distance from the optic disc  and they were significantly correlated with the retinal displacements . The retina was displaced inferiorly and centripetally, but these localized displacements were not observed in the choroid. In conclusion, clinicians need to be aware of these displacements when evaluating the subfoveal choroid following the surgery because the displacement is different between the retina and the choroid.It has been reported that the macular region of the retina is displaced after vitrectomy with internal limiting membrane (ILM) peeling in eyes with macular hole (MH), but the displacements of the deeper layers of the eye, e.g. RPE and choroid are unclear following the surgery. We used optical coherence tomography (OCT) and OCT angiography (OCTA) to obtain 3 mm × 3 mm  Analyses of pre- and postoperative fundus photographs have shown that the retina is displaced in the macular region following the MH closure by vitrectomy with ILM peeling10. Displacement of the retina is also caused by vitrectomy with ILM peeling in other retinal diseases11.Earlier studies have shown that an idiopathic macular hole (MH) can be treated by vitrectomyin situ repeatedly in short intervals13. Akahori et al. evaluated the displacements of the retina using the OCTA en face images of the superficial retinal capillary plexus (SCP), and they concluded that the retina was displaced nasally, inferiorly, and centripetally in the macular region10.Optical coherence tomography angiography (OCTA) is noninvasive and safe and has enabled clinicians to investigate the retinal vasculature en face images is located in the inner retina10. This indicated that the macula displacements are displacements of the inner retina. However, the displacements of the deeper layers of the retina, e.g. RPE and choroid following vitrectomy with ILM peeling are unclear.The retinal vessels observed in the fundus photographs are mostly those of the inner retina, and the SCP observed in the OCTA 15 and its blood flow17 are altered by retinochoroidal diseases. Other studies have reported that the choroidal thickness is reduced in both the affected and the unaffected contralateral eye compared to that of age- and sex-matched control eyes in eyes with an idiopathic MH19. In addition, the retinal and choroidal thicknesses in the OCT images were reduced following vitrectomy with ILM peeling for a MH20. If the choroid is displaced following vitrectomy with ILM peeling, the displacement would probably affect the postoperative choroidal thickness and blood flow.It has been reported that the thickness of the choroiden face images at different retinal depths including the intermediate choroidal plexus (ICP)13, which can be used to measure the displacements of the choroid following vitrectomy with ILM peeling. The displacements have been measured for the SCP10 but not for the ICP.The OCT instruments can obtain Thus, the purpose of this study was to determine whether the retina and choroid in the macular region are displaced following the vitrectomy with ILM peeling in eyes with a MH.The procedures used in this cross-sectional retrospective study were approved by the Ethics Committee of the Nagoya University Hospital, Nagoya, Japan, and they conformed to the tenets of the Declaration of Helsinki. All of the patients signed an informed consent form before the surgery.®, Heidelberg Engineering, Heidelberg, Germany) images were obtained before, and 2, 4, and 8 weeks following the surgery. The exclusion criteria included eyes with severe cataract, macular diseases, history of other ocular diseases, and high myopia of more than −5 diopters (D).We reviewed the medical records of patients with a unilateral, idiopathic MH who had undergone successful MH closure by vitrectomy at the Nagoya University Hospital from October 2017 to September 2018. Comprehensive ophthalmic examinations were performed on all the patients. In addition, OCTA, fundus autofluorescence (FAF), and SD-OCT  to obtain the 3 × 3 mm10. In brief, we first selected an easily identifiable retinal vessel bifurcation in the SCP image and choroidal vessel bifurcation in the ICP image. The distance between the bifurcation and the center of the optic disc was measured  or 12% perfluoropropane (C3F8) into the vitreous cavity. The patients were instructed to maintain a prone position until a closure of the MH was confirmed with OCT following the surgery.We performed a standard three-port PPV with the Alcon Constellation 25-gauge (G) system . Core vitrectomy was performed, and if necessary, a posterior vitreous detachment was created. Then, the ILM was peeled circumferentially from the retina using ILM-peeling forceps in all cases. Then, we performed a peripheral vitrectomy with shaving and inspected carefully the periphery over 360 degrees carefully in all cases. Finally, fluid-air exchange was performed followed by the injection of 20% sulfur hexafluoride  to evaluate the significance of the relationship between the displacements in the four quadrants and the chronological data. We used Pearson’s correlation coefficient test to evaluate the significance of the associations between the changes in the displacement of each bifurcation and the angle formed and the preoperative distance and angle. All statistical analyses were performed using the Statistical Package for Social Sciences for Windows 21.0 .Thirty-eight eyes of 38 patients with a MH underwent the successful MH closure surgery during the period. Sixteen eyes were excluded; 2 for prior vitrectomy, 1 for macular degeneration, 10 for high myopia, and 3 for severe cataract that prevented an acquisition of high quality OCTA images. Finally, 22 eyes of 22 patients  were studied. The demographics of the patients and the surgical procedures are shown in Table The fovea was displaced following the surgery, and the changes in the average distance between the fovea and the optic disc were shortened by 0.14 ± 0.06 mm and the angle was rotated downwardly by an average of 0.89 ± 0.73°.P < 0.001) at 2 weeks postoperatively. The mean distances were also reduced significantly in all four quadrants, and the reduction was maintained throughout the postoperative period  at 2 weeks postoperatively. The mean distances were also reduced significantly in all four quadrants, and the reductions were maintained throughout the postoperative period. No significant differences were observed in the distances during postoperative periods in the both of retina and choroid in all of the quadrants . A significant difference was observed in the angle among the 4 quadrants at Week 2 following surgery  of the choroid at Week 2 was significantly and positively correlated with that of the retina at Week 2  following surgery in eyes with a rhegmatogenous retinal detachment (RRD). dell’Omo et al. reported that displacements of retina were observed in 44 of 125 (35.2%) eyes following a retinal reattachment in eyes with a RRD25. These findings indicated that hyperfluorescent lines can be observed after the inner retinal layer is displaced laterally from the RPE layer as in eyes with a RRD. Our results suggest that the inner retinal layer was not displaced from the RPE layer, and the RPE layer was displaced together with the inner retinal layer following the surgery.We were not able to find any studies reporting on the presence of hyperfluorescent lines following the surgery. Shiragami 26. The sensory retina adheres strongly to the RPE which allows the RPE to transport subretinal fluid at a very high rate against a substantial gradient of hydrostatic or osmotic pressure27. This would be related to the observation that the RPE layer was displaced along with the inner retinal layer.The Müller cells are believed to maintain the structural integrity of the retina as an important role28. The choriocapillaris is approximately 10 µm thickness in the foveal region, and it is a highly anastomosed network of capillaries28. The choriocapillaris can be detected by OCTA, but it is difficult to evaluate the displacements of the choriocapillaris layer because its hexagonal and lobular shapes resembles that of the RPE. However, the choriocapillaris layer is presumably not displaced from the RPE layer because the choriocapillaris layer is apposed to the outermost layer of Bruch’s membrane which adheres to the RPE.The choroid is comprised mostly of blood vessels histologically and is divided in five layers; Bruch’s membrane, the choriocapillaris, Haller’s layer, Sattler’s layer, and the suprachoroiden face image can detect the vasculature in the choroidal vessels of Haller’s and Sattler’s layer. However, the choroid has the stroma containing extravascular tissue, e.g. elastic fibers and collagen. This means that the choroidal vessels are not adhesively connected in these layers and to the choriocapillaris layer which might cause the gap in the displacement of the choriocapillaris layer and the choroidal vessels in the OCT images. The gap might lead to the differences in the displacements between the retina and choroid following surgery.OCT Taken together, the peeling of the ILM probably causes the displacement of the inner retina and the degree of displacement would be related to the displacement of the RPE and choroid. However, there is no adhesive connection between the intermediate choroidal vessels causing a gap in the displacement between the choroid and the inner retina following the surgery.Our result showed that the choroid was not displaced centripetally, i.e., toward the fovea, following the MH closure which was reasonable because if the choroid and the RPE were displaced toward the fovea, then some wrinkling should be observed in the RPE layer over the fovea following the surgery. The distance between the fovea and the bifurcations of the choroidal vessel was in opposite directions between the superior, temporal quadrants and nasal, inferior quadrants. These differences should be related to the fact that the fovea was displaced nasally and inferiorly following the surgery. The displacement of the choroid was less than that of the retina which can cause the distance to be shorter between the fovea and the nasal and inferior bifurcations of the choroid.There have been many reports about the choroidal thickness and blood flow at the fovea. However, the choroid is displaced following the surgery, and the degree of the displacement in choroid is different from that in retina. This means that the subfoveal choroid following surgery is different from that before surgery, and it can cause differences of the measured area of the subfoveal choroid between before and following surgery. Accordingly, we need to pay attention to the results of the subfoveal choroid, e.g. thickness and blood flow following the vitrectomy with ILM peeling in any kind of retinochoroidal diseases.2en face OCTA image would enable us to analyza a wider field of view. However, the resolution is better with the 3 × 3 mm2en face images. Thus, we used the 3 × 3 mm2en face images to determine the displacements. Further prospective studies on analyses of the different choroidal vascular layers using a larger number of subjects will be necessary for clarification of the mechanism of the choroidal displacements.This study has several limitations. First, this was a retrospective study on a limited number of participants, which might be the reason why no significant differences were found in the angle and the distance to the fovea in the choroidal displacement. Second, the displacement of choroid was compared with that of retina in each quadrant, and because it is rare that the location of retinal bifurcation is coincident with that of choroidal bifurcation, we did not compare the displacement of retina and choroid directly for each bifurcation. Third, although we confirmed the choroidal displacement in the OCT B-scan images, and we did not measure the distance of displacement using the images because it is difficult to find a fixed point on the image to measure. Fourth, analyses of the 6 × 6 mmIn conclusion, the choroid was displaced toward the optic disc following the vitrectomy with ILM peeling in eyes with a MH. Clinicians need to be aware of this when evaluating the subfoveal choroid following the surgery because the displacement is different between the retina and the choroid.


Many cancer patients and survivors experience permanent and life-debilitating effects, such as ototoxicity, from treatment. Ototoxicity manifests as high-frequency hearing loss and tinnitus, which can have a detrimental effect on the quality of life (QoL) of those affected. Currently, there is little information and support offered to these patients who experience ototoxicity, potentially leading to many being undiagnosed and untreated.The aim of this study was to explore the extent of ototoxic side effects, such as hearing loss and tinnitus, and their impact on cancer patients following chemotherapy treatment. Secondary objectives included detecting the time periods of onset and duration of the ototoxicity and identifying what support was available to this population.Posts from publicly available online forums were thematically analyzed using the guidelines by Braun and Clarke. A coding manual was iteratively developed to create a framework for the analysis of the ototoxicity experience among the cancer population.bottom-up thematic analysis, 6 major themes were identified: nature of ototoxicity, time of experienced ototoxicity, information on ototoxicity, quality of life, therapies, and online social support.A total of 9 relevant online forums were identified, consisting of 86 threads and 570 posts from 377 members. Following the There was a significant number of reports expressing concerns about the lack of information on the risk of ototoxicity. More support for those suffering is needed; for example, improved interdepartmental communication between oncology and audiology services could optimize patient care. Patients should also be encouraged to communicate with their health care professionals about their ototoxicity and relay how their QoL is impacted by ototoxicity when accessing support. Tinnitus was the most common concern and was associated with distress. Hearing loss was less common; however, it was associated with fear and employment issues. Those who reported preexisting conditions were fearful about worsening their condition as their QoL was already impacted. Although there are an estimated 17.5 million cancer cases per year worldwide, the development of screening programs and improved diagnostics have contributed to an increase in survival rates . The curThese effects can potentially have a significant impact on quality of life (QoL). Tinnitus, for example, is associated with sleep difficulties, and hearing loss is associated with dementia ,9. A deeThere is a lack of information on the prevalence and effect of ototoxicity because of the underreporting of ototoxic events, and few longitudinal studies have been carried out ,13. The The increase in popularity of using the internet allows anyone to access health care information instantly and can potentially improve patients’ knowledge and help with treatment decisions ,17. TechApproximately 14.2% of long-term cancer survivors live with disabilities directly caused by their cancer treatment and its toxic nature ,25. ClinEthical approval for the study was obtained by the University of Nottingham, School of Medicine Ethics Committee. Although informed consent was not required in this study as the information was available in the public domain, all members’ personal details were kept anonymous to maintain confidentiality and protect privacy .Quotes used were extracted as part of a longer original post. Details that would allow the member to be traced were excluded. Risk to forum users was deemed to be minimal.Relevant and representative forums were identified using the 4 most common search engines: Google, Yahoo!, AOL, and Bing . Search The data extraction and the thematic coding strategy were based on the Gao et al  and Braubottom-up strategy, open coding was performed by making initial comments on the first 100 messages, from which a pilot coding manual was produced. For example, the quote “The most worrying thing I have come across is that I may suffer changes to my hearing, I am petrified.” was described as a fear of developing ototoxicity. This was followed by grouping similar descriptions together into codes which fit into categories, and finally, arranging these into clearly defined themes , but as you probably know, when you become aware of it, it is hard to ignore. I hope you are lucky and yours goes away.User H, Forum 5day-to-day life (n=62) was affected by ototoxic effects. Many members shared concerns over how their hearing loss affected their relationship with their partners and family members, which could be distressing and isolating:However, most users reported in abundance how their I'm three years post chemo and now have tinnitus in my left ear which is getting worse. I don't recall being told chemo could damage ear and it drives me mad. Will it ever go? Sound sets it off so if I sit in silence its okay but it's affecting my relationship now. I don’t know what to do.User F, Forum 2Research has been conducted on how tinnitus and hearing loss affects QoL; however, it has not been expanded into the population facing cancer treatment and survivorship -45. In aI cannot hear at all in my left ear ever since having chemotherapy. I have been fitted, aged 39, with a hearing aid but I have very short hair as a result of chemo, so they show and it affects my self-esteem. I don't sleep with the aids in so I can’t hear my baby when she wakes at night which I find really distressing. I feel about 90.User S, Forum 2employment (n=14). Specifically, professional musicians shared their fear over losing the ability to play music. Members spoke of the risk of losing their hearing being catastrophic for their employment and even mentioned early retirement. Most of the questionnaires used to assess QoL and ototoxicity do not mention the impact on employment. This area needs to be explored clinically, specifically in those who critically rely on hearing to be employed, such as musicians:Another concern among members was the effect ototoxicity had on Better than dead? At this point, I'm wondering. I cannot work with this condition because my job requires proper hearing. Hearing loss and this constant tinnitus is life-changing, far more than having cancer is. This has me worried more than living with cancer. I'm wondering if I'll ever have another day where I can hear clearly and be a productive member of society.User Z, Forum 4reminder of cancer (n=9). Although members mentioned successfully managing the tinnitus and hearing loss, it acted as a permanent reminder of what difficulties they had been through. There was a sense of general fear (n=49) experienced across the forums, as members frequently discussed being fearful of losing their hearing and how this could affect their life. In fact, many people discussed concerns over safety and how this gave them anxiety. As mentioned previously, these aspects of life are rarely included in questionnaires, and therefore, are rarely reported in the literature:Of the main issues faced with ototoxicity, one was how it acted as a I cannot hear the door opening, food cooking, the television or radio and comprehend what they're saying. It's dangerous. I never realized how much we rely on the sounds of cooking. No more multi-tasking in the kitchen, I have to stand and watch the stove top now.User A, Forum 9fear of permanence (n=36) of the ototoxic effects. There were frequent concerns over how long the hearing loss and tinnitus would last and if they would ever recover normal hearing. Currently, there is little knowledge about the duration of ototoxicity and no predicting factors, which could further induce this fear in patients:Within this sense of fear, there was a specific I completed all of my chemotherapy cycles and since then I have lost a lot of hearing and also have ringing in my ears. Has anyone experienced this and gained hearing back? I am hoping since I only finished a month ago I will improve, but no one is telling me anything. If anyone has a positive story I would love to hear about it, to give me hope.User F, Forum 3distress and severe impact on QoL (n=53). There were messages that described hearing loss and tinnitus as “unbearable, severe and extremely bothersome,” which is consistent with the current literature on how tinnitus and hearing loss affect QoL in the general population [Associated with fear was pulation . HoweverTinnitus is controlling my life right now and I don’t know what to do. I am suicidal and keep thinking of the best way to end this misery once and for all. I don’t know how long I can keep this up. I wish I was strong like all of you in this forum but I am so weak and fragile right now. I gave up on God ever existing cos if he did exist then none of us would be suffering like this right now and diseases such as cancer would not exist.User E, Forum 6coping mindsets subtheme: acceptance of ototoxicity (n=23), survival mindset (n=33), and the inability to cope (n=9). Messages on acceptance and having to learn to live with tinnitus varied from being positive to resentful:How members coped with ototoxic effects varied greatly throughout the forums. A total of 3 codes formed the I'm afraid I do not know how to say this without being blunt, but would you really rather die than live with some permanent tinnitus from your cancer? Most of us have a few souvenirs from cancer, I think that is better than dying.User G, Forum 4I finished all my chemotherapy 6 months ago and I am still suffering from side effects. Numbness in my fingers and toes, pain in my feet and calves and hearing loss. I AM happy to be alive, but I can't shake off the dissatisfaction I have with the body treatment left me with.User D, Forum 3coping mindset was the survival mindset. People shared thoughts such as “worry about the cancer now and the side effects later” within this survival mindset and tended to promote this view of ignoring any side effects until after the cancer was in remission. This mindset could in fact be partially responsible for the underreporting of toxicities in clinical trials, therefore, having negative clinical implications on research. Patients should be encouraged to speak openly about their experienced toxicities:The most frequent The most important thing is that the chemotherapy worked, it just seems silly for us to be moaning about a bit of tinnitus.User P, Forum 5inability to cope. These members appeared to be extremely depressed and seemed to need urgent care and advice, such as counseling:Although not many, there were members with an I have had the Cisplatin dose reduced 20 percent for the second round due to the ringing and hearing loss. I can't seem to find anything positive to report. Most say it’s permanent, including my oncologist and audiologist. I may be forced to stop treatment if mine gets any worse because I'd rather be dead than deaf.User I, Forum 4By supporting these patients before their tinnitus and hearing loss worsens, the health service and patients alike could potentially save on mental health costs. Moreover, aspects such as sleep, employment, and relationships are all major parts of life, and when these are affected, it can have a devastating effect on a whole population. It has been reported that those with more comorbidities seem to experience a higher incidence and severity of tinnitus, which could factor in to having a lower QoL . Researcdrug (n=239) treatment regimens they were on, such as cisplatin (n=143), carboplatin (n=56), oxaliplatin (n=2), and nonplatinum drugs (n=38). Some messages expressed simply their regime and their adverse effects, without mentioning how it affected their QoL. It is difficult to conclude how these members cope and are affected by ototoxicity:Members discussed which I have severe hearing loss and osteoporosis from carboplatin. I am only 21.User G, Forum 3diagnostics (n=12) they experienced, with an almost equal number of members stating they had no baseline test (n=5) compared with having had a baseline test (n=7). This correlates with studies having found that baseline tests are not as frequently carried out as suggested [There were few members discussing the uggested :I had a baseline reading before chemo. Showed mild age related hearing loss, but I could still hear compared to now!User H, Forum 9I didn't have a baseline test before starting chemo because no one suggested it.User L, Forum 4medical adjustments (n=96). This involved many of the members having to wear hearing aids (n=51) because of the ototoxic effects, and others adjusting treatment regimens because of ototoxicity (n=45), which involved anything from changing the drug and lowering the dose to stopping treatment altogether to prevent any further hearing loss or tinnitus. This code was heavily associated with fear of permanence and distress:A subtheme that was relatively abundant within the OHFs was The hearing test I had told the audiologist it was permanent. I got hearing aids about 3 months after treatment was over. I wasn't told hearing loss was a possibility. Every time I went to a doctor, I asked the doc to look at my ears. Finally, one said, see the audiologist. I was crushed - I was only 45 at the time. I did get the hearing aids, and they help so much.User C, Forum 3online social support (n=478), which included support expressed by members to create a community and develop friendships. From the 570 different forum messages, only 1 message was interpreted as negative. The advice and Tips (n=299) subtheme involved members asking for advice (n=99) and offering general advice (n=200) from how to ignore tinnitus to which hearing aid to use. There were many messages that offered positive support (n=132) and used terms such as “you’re not alone” (n=47):Finally, there was a sense of I hadn't realised how many others have developed Tinnitus too—nice to be in good company.User D, Forum 9A significant number of patients expressed concerns over not being adequately informed about the true risk of ototoxicity. Although some members expressed having been warned of the risks, they reported that the information given to them was vague and unclear. Some spoke about referrals to audiology departments and seemed satisfied with this level of support. It could be suggested that more interdepartmental communication be made to optimize patient care. Furthermore, information available to patients on ototoxicity could be improved by updating the chemotherapy leaflets. Patients may feel overwhelmed with the amount of information given to them; thus, the information should be shared on a case-by-case basis. It is noteworthy, however, that from the 570 messages analyzed, only 1 message expressed feeling overwhelmed by the information about ototoxicity.Members who were fearful of losing hearing were those who had preexisting conditions. This could be because their QoL has already been impacted, whereas those posting who had no previous experience with hearing loss or tinnitus would not know how exactly their QoL may be affected. For many, ototoxicity is not an immediate concern when thinking of chemotherapy. However, once the immediate adverse effects subside, ototoxicity remains as a distressing reminder of their cancer. Patients should be encouraged to communicate with their health care professionals about their ototoxicity and relay how their QoL is impacted to access the appropriate support.There were more reported concerns over tinnitus than any other ototoxic effect. Tinnitus was also associated with distress and the inability to cope. Members posted concerns over sleep, their relationships, and their mental health. More clinical interventions, such as cognitive behavioral therapy, should be readily available to this population. Furthermore, hearing loss was common within the OHFs but was more associated with fear of losing hearing, fear over personal safety, and fear of hearing loss impacting employment.As this research was observational and exploratory, there was no way of quantitatively measuring QoL. The posts were subject to misinterpretation, even though 2 researchers were involved in analysis to minimize the risk of this potentially occurring. Although OHFs are popular within communities, this sample is not necessarily representative of the population, as only 2 of the forums had information on number of members and active threads; therefore, it is difficult to draw conclusions on the exact population. Only those who have internet access and are inclined to voluntarily share personal information participated. It is also possible that those who post on forums are those with the most severe worries, and those whose questions have not been answered by health care professionals, meaning they seek advice on the Web. Furthermore, gender, age, and geographical location of the members were mainly unknown. Therefore, no analysis could be undertaken on these factors.In conclusion, ototoxicity has a significant burden on the QoL of those suffering from cancer. More information and support should be available to this population to help manage these long-term symptoms. Tinnitus was the most frequently reported ototoxic effect within the OHF, followed by hearing loss. The ototoxic effects were associated with lower QoL, fear, isolation, depression, and frustration that patients were not warned enough about these effects.


It is increasingly agreed upon that cognitive and audiological factors are associated with self-perceived hearing handicap in old adults. This study aimed to compare self-perceived hearing handicap among mild cognitive impairment (MCI) subgroups and a cognitively normal elderly (CNE) group and determine which factors  are correlated with self-perceived hearing handicap in each group. A total of 46 MCI patients and 39 hearing threshold-matched CNE subjects participated in this study, and their age ranged from 55 to 80 years. The MCI patients were reclassified into two groups: 16 with frontal-executive dysfunction (FED) and 30 without FED. All subjects underwent audiometric, neuropsychological, and self-perceived hearing handicap assessments. The Korean version of the Hearing Handicap Inventory for the Elderly (K-HHIE) was administered to obtain the hearing handicap scores for each subject. After controlling for age, years of education, and depression levels, we found no significant differences in the K-HHIE scores between the MCI and the CNE groups. However, after we classified the MCI patients into the MCI with FED and MCI without FED groups, the MCI with FED group scored significantly higher than did both the MCI without FED and the CNE groups. In addition, after controlling for depression levels, significant partial correlations of hearing handicap scores with frontal-executive function scores and speech-in-noise perception performance were found in the MCI groups. In the CNE group, the hearing handicap scores were related to peripheral hearing sensitivity and years of education. In summary, MCI patients with FED are more likely to experience everyday hearing handicap than those without FED and cognitively normal old adults. Although educational level and peripheral hearing function are related to self-perceived hearing handicap in cognitively normal old adults, speech-in-noise perception and frontal-executive function are mainly associated with hearing handicap in patients with MCI. Hearing impairment does not necessarily parallel self-perception of hearing handicap in everyday life . AccordiBoth audiological and non-audiological variables are associated with self-perceived hearing handicap. Several studies indicate an association between self-perceived hearing handicap and patient outcomes on speech-in-noise measures –8. A recThe aforementioned studies suggest that non-audiometric factors may play an important role in self-perceived hearing handicap in old adults. Thus, factors other than the degree of hearing impairment may contribute to self-perceived hearing handicap in old adults. One recent study on the impact of cognitive function on self-perceived hearing handicap indicates that old adults with high working memory capacity have more hearing difficulties in their daily lives, and the results contradict the authors’ initial hypothesis . AccordiTo overcome such limitations, this study was carefully designed in order to account for the effect of cognitive function on hearing-related difficulties. We hypothesized that old patients with mild cognitive impairment (MCI) would have more hearing-related difficulties than their hearing threshold-matched peers with normal cognitive function would. Specifically, we hypothesized that MCI patients with frontal-executive dysfunction (FED) would report greater hearing handicap than those without FED. Because previous studies have demonstrated that frontal-executive function strongly impacts speech-in-noise perception in patients with MCI ,14 and sth edition; and 4) normal activities of daily living. Exclusion criteria included a history of major medical, neurological, or psychiatric illness. The MCI patients were further classified into patients with FED  and patients without FED . The FED patients had to meet the following criteria: 1) age- and education-adjusted scores below -1.0 SD on the animal naming or phonemic-letter naming tests in the Controlled Oral Word Association Test (COWAT) [We recruited 46 MCI patients, aged 55 to 80 years, at the Memory and Dementia Clinic at the Dong-A University Medical Center. MCI was diagnosed according to the Petersen’s criteria : 1) subj (COWAT) . If patiWe recruited 39 cognitively normal old adults (14 men and 25 women) as a control group. The cognitively normal old adults had to meet the following criteria: 1) no significant underlying medical, neurological, or psychiatric illness; 2) normal performance as defined by age- and education-adjusted scores above -1.0 SD on the Korean version of the Mini-Mental State Examination (K-MMSE) , digit sFor hearing acuity, all subjects had to meet the following inclusion criteria: 1) no conductive components on tympanometry and pure tone audiometry; 2) hearing threshold levels at 0.5, 1, and 2 kHz ≤ 25 dB HL; 4 kHz ≤ 40 dB HL; and 8 kHz ≤ 70 dB HL for each ear; 3) no greater than 10 dB HL of inter-aural asymmetry on pure-tone averages (PTAs) ; 4) a speech discrimination score ≥ 80% for each ear; and 5) no previous use of hearing aids. The elderly subjects were recruited at a relatively early stage of age-related hearing impairment, which is characterized by threshold elevation beginning at high frequencies. This study was approved by the Institutional Review Board of the Dong-A University Medical Center, Busan, Korea (IRB#: 16–048). Written informed consent was obtained from every participant before the experimental procedures. The capacity of participants to give informed consent was assessed using the Clinical Dementia Rating (CDR) scale . It has All participants underwent pure-tone audiometry, speech audiometry, tympanometry, and speech-in-noise perception tests. Air and bone conduction thresholds were measured with a clinical pure-tone audiometer . We calculated the PTAs at 0.5, 1, 2, and 4 kHz for each ear. We measured the speech reception threshold, speech discrimination score, and most comfortable loudness level for each ear. Speech-in-noise perception was measured via sentence recognition tests with speech-spectrum and multi-talker babble background noise at a signal-to-noise ratio of -5 dB. The means or medians of the binaural average of the pure-tone audiometric thresholds at each frequency are shown in pure-tone audiograms for each group .All participants underwent a standardized neuropsychological test, the Seoul Neuropsychological Screening Battery (SNSB) . The SNSAll participants completed the Korean version of the Hearing Handicap Inventory for the Elderly (K-HHIE) ,26. SelfP = 0.05, and statistical analyses were carried out using SPSS 23.0 software.All continuous variables were first tested for normality using the Shapiro-Wilk test. Continuous variables not normally distributed, presented as medians and interquartile ranges, were analyzed using the Kruskal-Wallis test. However, the continuous variables normally distributed, presented as mean and SD, were analyzed using the one-way analysis of variance. Second, because normality was rejected for the hearing handicap scores, nonparametric analysis of covariance based on Quade’s test in SPSS was used to compare the hearing handicap scores among groups after adjusting for age, years of education, and depression levels. Post-hoc analyses were conducted using pairwise comparisons with Bonferroni corrections to examine the differences among groups. Additionally, multiple regression analysis using the backward elimination approach was performed in order to determine which independent variables, including cognitive impairment, age, years of education, and depression levels, were predictors of the K-HHIE total scores for the entire sample. Third, for nonparametric partial correlation, Spearman rank correlation coefficients (rho) were computed by controlling for depression levels in each group to examine the correlations of self-perceived hearing handicap with demographic, audiometric, and neuropsychological variables. Alpha levels were set at F1,83 = 2.590, P = 0.111), emotional , and total scores  on the K-HHIE. In addition, multiple regression analysis was performed using the backward elimination approach in order to determine which independent variables, including cognitive impairment , age, years of education, and depression levels, were predictors of the K-HHIE total scores for the entire sample. In the final model , depression levels  and years of education  remained significant while age (P = 0.917) and cognitive impairment (P = 0.273) were eliminated from the analysis. Simple linear regression analysis confirmed that the years of education and depression levels were significantly correlated with the K-HHIE total scores, respectively .After controlling for age, years of education, and depression levels, we found no significant main effects of group on social/situational , emotional , and total scores  on the K-HHIE. Post hoc analysis revealed that the MCI with FED group scored significantly higher than did both the MCI without FED (P < 0.001) and the CNE (P < 0.001) groups on the social/situational section. In addition, the MCI with FED group scored significantly higher than did the MCI without FED (P < 0.001) and the CNE (P < 0.001) groups on the emotional section. Moreover, the MCI with FED group scored significantly higher in total scores than did the MCI without FED (P < 0.001) and the CNE (P < 0.001) groups. No significant differences were found between the MCI without FED and the CNE groups on the social/situational, emotional, and total scores on the K-HHIE , CNE (dummy variable) , MCI without FED (dummy variable) , and depression levels  remained significant while age (P = 0.537) and years of education (P = 0.143) were eliminated from the analysis.In addition, we also performed multiple regression analysis using the backward elimination approach in order to determine which independent variables, including cognitive impairment , age, years of education, and depression levels, were predictors of the K-HHIE total scores for the entire sample. Dummy coding was conducted for cognitive impairment with the MCI with FED group as the reference group. In the final model (P = 0.041), color reading time per item , or interference scores  in the K-CWST. In the MCI without FED group, we found a significant correlation between the K-HHIE total score and the sentence recognition score in the multi-talker babble noise condition . In the total MCI group, we found significant correlations between the K-HHIE total score and the sentence recognition score in the multi-talker babble noise condition , word reading time per item , or color reading scores  in the K-CWST. In the CNE group, we found significant correlations of the K-HHIE total score with the PTA  or years of education   . ScatterIt is increasingly agreed that cognitive factors and audiological factors are associated with self-perceived hearing handicap, especially in old adults, suggesting that old adults with cognitive impairments may have more hearing-related difficulties than their hearing threshold-matched peers with normal cognitive function. As old adults with hearing handicap experience emotional distress and restrictions on social engagement in everyday life, which ultimately reduce their quality of life ,27, it iFirst, MCI patients with FED are more likely to experience hearing difficulties in their daily lives compared with those without FED or cognitively normal old adults. Considering the relationship between working memory capacity and executive functioning , the finIn the present study, among measures on frontal-executive function, variables related to the K-CWST were specifically correlated with hearing handicap scores in the MCI groups. In the MCI with FED group, hearing handicap scores were positively correlated with the color reading time per item and interference score, which is calculated by subtracting the time per item of the word reading from the time per item of the color reading. Moreover, in the total MCI group, hearing handicap scores were positively correlated with the word reading time per item and were negatively correlated with the color reading scores. The Stroop test mainly assesses the ability to inhibit cognitive interference and the processing speed by measuring the accuracy and speed of performance . BecauseSecond, speech perception performance is significantly correlated with self-perceived hearing handicap in patients with MCI. Specifically, hearing handicap scores were negatively correlated with the sentence recognition scores in the multi-talker babble noise condition in the MCI without FED and total MCI groups and in the speech-spectrum noise condition in the MCI with FED group. However, it should be noted that only the correlation between the K-HHIE total score and the sentence recognition score in the multi-talker babble noise condition in the total MCI group remained significant after applying a Bonferroni correction for multiple comparisons. Several previous studies indicate an association between self-perceived hearing handicap and outcomes on speech-in-noise measures –8. The fThird, peripheral hearing sensitivity explains little of the variance in MCI patients’ self-reported hearing handicap. The degree of peripheral hearing loss was not one of the factors correlated with subjective hearing difficulties in the MCI patients. In the CNE group, we found a relatively low correlation between hearing sensitivity and self-perceived hearing handicap. In addition, although numerous studies have shown that peripheral hearing sensitivity is correlated with self-perceived hearing handicap in old listeners, the correlations are only weak to moderate ,10. MoreThe fourth discussion point is that we found a significant positive correlation between hearing handicap scores and years of education in the CNE group. Although no such correlations were found in the MCI groups, old adults with higher education reported greater hearing handicap than those with lower education in the CNE group. The results are somewhat consistent with those in a previous study, which demonstrates that less than 12 years of education is an associated factor for less self-perceived hearing handicap . The assInterestingly, multiple regression analysis for the entire sample revealed that years of education and depression levels were possible predictors of the hearing handicap scores, but the correlation between hearing handicap and years of education was negative. This negative correlation for the entire sample was in the opposite direction from that for the CNE group. This result could suggest that educational level may affect hearing handicap differently in cognitively normal old adults and in cognitively impaired old patients. As shown in Finally, multiple regression analysis for the entire sample confirmed that depression level was also a significant positive predictor of hearing handicap scores. That is, the more that older listeners showed symptoms of depression, the more they had hearing difficulties. It is well known that depression symptoms adversely impact cognitive function in elderly people . SymptomNotably, this study suggests that MCI patients with FED experience more hearing difficulties than do their peers with normal cognitive function or MCI patients without FED in daily life. Cognitive function, especially frontal-executive function and speech-in-noise perception performance, is correlated with self-perceived hearing handicap in elderly patients with MCI. This study indicates that, in clinical practice, the self-assessment of hearing handicap, in addition to audiometric assessments, needs to be conducted in order to evaluate each individual’s hearing difficulties in daily life. If old adults report more hearing problems than do their hearing threshold-matched peers, they may have cognitive impairments, especially in frontal-executive function. Therefore, those old adults should be considered for assessment and intervention on neuropsychological function. In audiological settings, clinicians can provide proper intervention services to these patients by early referral to neuropsychology and/or aural rehabilitation specialists.Despite the strengths of our study, it also has some limitations. First, in the present study, we controlled for hearing thresholds, age, years of education, and depression levels to investigate the effect of cognitive function on self-perceived hearing handicap. Although participants’ depressive symptoms were evaluated and adjusted in this study and the relations between depression and self-perceived hearing handicap were indicated in the literature –38, otheS1 Table(DOCX)Click here for additional data file.


The selective iNOS inhibitor 1400W (150 μg.10 μl-1) was administered twice a day by eye-drops during the second week of diabetes. The retinae were collected 2 weeks after diabetes induction to assess the protein and gene expression of markers by Western blot and qRT-PCR, the distribution of iNOS and B1R by fluorescence immunocytochemistry, and the vascular permeability by the Evans Blue dye technique. Diabetic retinae showed enhanced expression of iNOS, B1R, carboxypeptidase M (involved in the biosynthesis of B1R agonists), IL-1β, TNF-α, vascular endothelium growth factor A (VEGF-A) and its receptor, VEGF-R2, nitrosylated proteins and increased vascular permeability. All those changes were reversed by treatment with 1400W. Moreover, the additional increase in vascular permeability in diabetic retina induced by intravitreal injection of R-838, a B1R agonist, was also prevented by 1400W. Immunofluorescence staining highlighted strong colocalization of iNOS and B1R in several layers of the diabetic retina, which was prevented by 1400W. This study suggests a critical role for iNOS and B1R in the early stage of diabetic retinopathy. B1R and iNOS appear to partake in a mutual auto-induction and amplification loop to enhance nitrogen species formation and inflammation in diabetic retina. Hence, B1R-iNOS axis deserves closer scrutiny in targeting diabetic retinopathy.Compelling evidence suggests a role for the inducible nitric oxide synthase, iNOS, and the bradykinin type 1 receptor (B1R) in diabetic retinopathy, including a possible control of the expression and activity of iNOS by B1R. In diabetic retina, both iNOS and B1R contribute to inflammation, oxidative stress, and vascular dysfunction. The present study investigated whether inhibition of iNOS has any impact on inflammatory/oxidative stress markers and on the B1R-iNOS expression, distribution, and action in a model of type I diabetes. Diabetes was induced in 6-week-old Wistar rats by streptozotocin (65 mg.kg DR is a major complication of diabetes mellitus and the leading cause of blindness in working-age adults . Most paCurrent therapeutic interventions are used only for the late stage of DR when microvascular complications have already resulted in irreversible structural changes. These treatments, including the intravitreal injections of anti-VEGF and laser photocoagulation, are invasive, need to be repeated regularly and are only able to stop the progression of DR without restoring the loss of vision . TherefoUnder physiological situation, NO produced at low amounts by the constitutive isoforms of NOS, endothelial NOS (eNOS) and neuronal NOS (nNOS), plays, however, an important role in ocular hemodynamics and cell viability , being iEarlier studies have shown that the iNOS inhibitor, aminoguanidine, inhibited NO production, protein nitration, iNOS expression, vascular dysfunction, and retinal cell death in diabetic rats , 2004. A9-BK and Des-Arg10-KD) are the preferred agonists of the inducible B1 receptor (B1R)  . Kinin ror (B1R) . B2R plaor (B1R) . The indor (B1R) , notablyor (B1R)  and its or (B1R) . It was or (B1R) . It is wor (B1R)  and B1R or (B1R) . These sTo better understand the B1R-iNOS relationship in DR, we investigated the expression and distribution of B1R and iNOS in 2 weeks STZ-diabetic retinae to enable comparison with previous studies using B1R antagonists . The impad libitum. Diabetes was induced by a single intraperitoneal injection of Streptozotocin . Age-matched control rats were injected with vehicle used to solubilize STZ; 0.1M citrate buffer pH 5.All experimental methods and animal care procedures were approved by the animal care committee of the Université de Montréal , in accordance with the Canadian Council on Animal Care. Animal studies are reported in compliance with the ARRIVE guidelines . Six-wee-1 with a commercial blood glucose analyzer  (Glucose concentrations and body weight were recorded every 3 days and on the day of the experiments. Diabetes was confirmed by the measurement of a blood glucose concentration greater than 20 mmol.L Canada) .versus eNOS and nNOS (-1) was prepared daily with sterile saline 0.9% and filtrated (0.20 μm mesh). This dosage was chosen based on a pilot dose-response study where 10 μL of 5 mg.mL-1 failed to affect the increase of vascular permeability in STZ-retina. The latter inflammatory response was slightly decreased with 10 μL of 10 mg.mL-1, and completely reversed with 10 μL of 15 mg.mL-1. In the present study, 10 μL of the 15 mg.mL-1 solution  was administered twice a day on the surface of the eye using a pipette. To make sure that the drop effectively remained on the surface of the eye, animals were hand-restrained for 60 s. The presence of ocular irritation such as redness, porphyrin secretion or corneal opacity was verified daily.One week after diabetes induction, rats were treated twice a day (8 AM and 5 PM) with one eye drop application of the selective iNOS inhibitor 1400W for a 7-day period. N-(3-(aminomethyl) benzyl)acetamidine  is an extremely slowly reversible inhibitor for human and rat iNOS with a 5000-fold selectivity for iNOS and nNOS . In a prand nNOS . In a moand nNOS , 2002. FTo assess the contribution of iNOS in B1R-induced vascular permeability, twenty rats were randomly divided into two control groups and two STZ-diabetic groups of 5 rats per group. Control groups and STZ-diabetic groups were treated either with the vehicle or with 1400W by eye-drops. Pupils of isoflurane anesthetized rats were dilated with 0.5% tropicamide to allow intravitreal injections on day 10 and 12. Under a dissecting microscope, a small incision of 1mm was done behind the limbus using a 30-gauge needle to facilitate the intravitreal injections. A sterile solution of the B1R agonist R-838 synthesized at the Research Institute of Biotechnology, National Research Council of Canada   was injected into the vitreous through the incision using a glass micropipette sealed at the tip of the Hamilton microsyringe (10 μL)  according to our previous study . The con-1). A catheter  was inserted into the right femoral vein and Evans blue dye   was injected i.v. over 10 s. The rats were kept on a heating pad for 2 h to allow the dye to circulate, while the body temperature was monitored at every 10 min. Thereafter, the rats were infused with a 25 mL of sterile saline 0.9% through the left heart ventricle, to wash out intravascular dye. Both eyes were then enucleated, and the retinae were dissected out and immediately weighed. Evans blue dye was extracted by incubating each retina in 1 mL formamide  for 18 h at 70–75°C. The fluorescence of Evans blue was measured using a spectrofluorometer  at 620 nm (excitation) and 680 nm (emission). Based on a standard curve, data were calculated in μg of Evans blue and then expressed per g of fresh tissue.Retinal vascular permeability was measured using Evans blue dye extravasation technique as previously described . Rats un-1, i.p.) and the retinae were dissected out and put in RNAlater stabilization reagent . Total RNA was extracted from retinae using a commercial kit . First-strand cDNA synthesized from 400 ng total RNA with random hexamer primers was used as template for each reaction with the QuantiTect Rev Transcription Kit (QIAGEN). SYBR Green-based real-time quantitative PCR using Mx3000p device for signal detection  was performed as previously described . Quantitative analysis of specific bands was performed by densitometry using the MCID-M1 system .The measurement of protein expression of retinal inflammatory mediators was done using the Western Blot technique as previously described . 40 μg o164 . Secondary antibodies were horseradish peroxidase (HRP)-linked with: goat anti-mouse (SC-2005) or goat anti-rabbit (SC-2004) or donkey anti-goat (SC-2020) and HRP-linked used at dilution of 1:25000 (for B1R and B2R), 1:4000  and 1:3000 (nitrotyrosine). The nitration of protein tyrosine residues generating 3-nitrotyrosine has been used as a footprint for the formation of peroxynitrite in-vivo  and then perfused with a paraformaldehyde solution (4% PFA). Dissected retinae were then post-fixed in 4% PFA for 2 h and kept in 70% alcohol overnight at room temperature for a paraffin embedding. The retinae were then cut into 10-μm-thick sections and placed onto glass slides and kept at 4°C till the day of experiment. For proteins detection, the sections were deparaffinized prior to the immunofluorescence experiment. First, glass slides were incubated in sodium citrate buffer at 95°C for 45 min. Sections were then allowed to cool down for 20 min. Sections were then washed 3 times (5 min each) with 0.1 M PBS buffer (pH 7.4) and incubated for 1 h at room temperature in blocking buffer (PBS containing 10% donkey serum and 0.25% triton X-100). Sections were left incubated overnight at room temperature with the blocking buffer containing primary antibodies: polyclonal rabbit antiserum to rat B1R (1:200), mouse monoclonal anti-iNOS . The following day, slides were washed 3 × 5 min in PBS 0.1M and then incubated for 2 h at room temperature with Alexa Fluor 488 donkey secondary anti-rabbit IgG  to visualize B1R, with Alexa Fluor 555 donkey anti-mouse IgG  to visualize iNOS. At the end, the slides were washed and mounted using glycerol solution. Images were obtained with a confocal microscope Zeiss-LSM800 equipped with an argon laser  and transferred to a computer and analyzed using NIH ImageJ 1.36b Software . Images were obtained at 20x and 40x objective. Semi-quantification of immunofluorescence staining intensity was made on 5 randomly selected surface areas of each retina from four STZ-diabetic rats, four controls and four STZ-diabetic treated rats. Background intensity (gray intensity) was subtracted from each individual value.At day 15, rats were anesthetized with sodium pentobarbital . Results are expressed as the mean ± SEM and n represents the number of rats used in each experiment. One-way ANOVA followed by Tukey’s post hoc test was used for all the measurements. Results were considered significant at a value of P < 0.05.Statistical analysis was performed using PrismAt the time of sacrifice, blood glucose concentration was significantly higher in STZ-diabetic groups compared with control rats, but no statistical difference was seen between non-treated and treated STZ-diabetic rats with R-838 and/or 1400W . Body weAn increase of iNOS expression was seen concomitantly with an elevated expression of B1R and CPM in STZ-diabetic retina. In comparison to control retina, iNOS expression was increased by six-fold at protein level, and by 2.5-fold at mRNA level in diabetic retinae . B1R expWestern blot analysis revealed that the intensity of several nitrosylated protein bands, notably at 200, 180, and 100 kDa, increased in the retina of STZ-diabetic rats compared to control . The eye164, which is one isoform of VEGF-A, was increased by four-fold while the mRNA level of VEGF-A was increased by 3-fold in diabetic retina .VEGF-A plays a key role in increasing vascular permeability and promoting the angiogenesis in DR. Thus, intravitreal injections of anti-VEGF are one of the treatments used to stop DR progression. The protein expression of VEGFc retina . The enhc retina . Similarc retina . This cyc retina , was alsThe immunofluorescence staining confirmed the enhanced levels of iNOS and B1R in the STZ-diabetic retina. In contrast, iNOS and B1R immunostaining was slightly detectable in control retina and no colocalization was evidenced . STZ-indFollowing the upregulation of B1R and iNOS in the STZ-diabetic retina, we determined whether B1R was functional and could interact with iNOS in an inflammatory response such as the breakage of blood-retinal barrier. The 1-week treatment with 1400W reversed the STZ-induced increase in vascular permeability and reduced significantly the response to the B1R agonist in diabetic retina . The iNOIn the present study, we showed that iNOS plays an important role in the development of vascular damage linked to DR and in B1R-induced vascular permeability. We found that eye-drops application of the selective iNOS inhibitor, 1400W, reversed inflammatory response, nitrosative stress and vascular hyperpermeability in the retina of STZ-diabetic rats. Importantly, this study provides the first evidence that B1R is colocalized with iNOS throughout the retina and that B1R activates iNOS to enhance vascular permeability in this model of DR. A positive loop is suggested between iNOS and B1R to amplify and perpetuate the retinal inflammatory process. This is keeping with earlier data showing that B1R antagonism  had simiThe increase of the oxidative stress is considered as an important factor in the pathophysiology of DR. Chronic hyperglycemia induces oxidative stress, which can consequently damage proteins, lipids, and DNA . RetinalUnlike the constitutive NOS, iNOS is activated under hypoxic and inflammatory conditions leading thus to excessive amounts of NO, which might contribute to the pathogenesis of DR . TherefoIn a model of type 2 diabetes, iNOS was found expressed in the GCL, the INL, and at the ONL . Also, aWe have previously shown that B1R is implicated in the very early stage of DR  and thatThis study shows that iNOS and B1R play a critical role in the early stage of DR. B1R and iNOS appear to partake in a mutual auto-induction and amplification loop to enhance nitrogen species formation and inflammation in diabetic retina. Hence, targeting the B1R-iNOS axis can represent a promising and non-invasive therapeutic approach in DR. However, further studies are needed to confirm the concentration and any potential side effect of 1400W reaching to the retinal, corneal and choroidal compartments.The datasets generated for this study are available on request to the corresponding author.RO, EV, and RC conceived and designed the experiments. RO performed the experiments, analyzed the data, and drafted the manuscript. RC and EV supervised the study, edited, and wrote the final version of the manuscript. All authors approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Congenital cytomegalovirus (cCMV) infection is a common congenital infection that causes sensorineural hearing loss (SNHL). Despite its substantial impact on public health and cost burden, epidemiology and clinical features of CMV-related SNHL have never been reported in the Korean populations. This study investigated the detailed audiologic phenotypes of cCMV infection to see if a specific SNHL pattern is associated with a particular clinical setting. A total of 38 patients with cCMV infection were studied retrospectively. Patients were classified into three groups with distinct demographics: clinically driven diagnosis (n=17), routine newborn CMV screening according to the NICU protocols (n=10), or referral to ENT for cochlear implant (CI) (n=11). The incidence of cCMV infection was 3.6%, showing 33.3% of SNHL among cCMV patients, 38% of asymmetric hearing loss, 29% of late-onset hearing loss, and diverse severity spectrum in patients with CMV-related SNHL. CI recipients with CMV-related SNHL showed a significantly improved speech perception. Surprisingly, in 36.4 % of CI implantees, initial audiological manifestation was significant asymmetry of hearing thresholds between both ears, with better ear retaining significant residual hearing up to 50dB. CMV turns out to be a significant etiology of SNHL, first to date reported in the Korean pediatric population. Analysis of audiologic phenotypes showed a very wide spectrum of SNHL and favorable CI outcomes in case of profound deafness. Especially for the patients with asymmetric hearing loss, close surveillance of hearing should be warranted and CI could be considered on the worse side first, based on the observation of rapid progression to profound deafness of better side. Congenital cytomegalovirus (cCMV) infection is a common congenital infection with an incidence rate ranging from 0.5 to 2% of all live births , 2. ChilSince CMV was first identified as a cause of deafness in 1964 . The remPreviously, maternal seroprevalence of CMV has been shown to be able to predict the prevalence of cCMV in infants; every 10% increase in maternal seroprevalence corresponds to 0.26% in CMV at birth , the incTo date, diagnosing CMV-related SNHL has been a challenge to many clinicians due to the short time window for making the correct diagnosis and relatively low awareness of disease entity by pediatricians and otolaryngologists. However, CMV-related SNHL is one of the few etiologies of preventable and treatable hearing loss in children. Here, we investigated the epidemiology of cCMV infection-related SNHL and demonstrated its clinical manifestations, specifically detailed audiological features in the Korean pediatric population.A total of 38 patients diagnosed with cCMV infection were recruited in Seoul National University Hospital (SNUH) and Seoul National University Bundang Hospital (SNUBH). Children were ascertained either by clinically driven diagnosis (45%) or as a part of routine newborn CMV screening process in the neonatal intensive care unit (NICU) at SNUH (26%), or as a referral to the SNUBH ENT clinic for cochlear implant (CI) (29%). Congenital CMV infection was diagnosed via urine PCR identification of the virus DNA within the first two weeks of life in infants.Patients who were diagnosed based on clinical suspicion between 2005 and 2016 were enrolled as having been clinically diagnosed with cCMV infection . Patients with positive results from CMV screening in neonates born at or below 32 weeks/ or less than 1.5kg at birth (SNUH NICU protocol) were recruited from the NICU between 2014 and 2016 . Additionally, eleven patients with confirmed cCMV infection from another hospital, who had undergone CI in SNUBH, were also enrolled . These three groups were mutually exclusive. A retrospective study of 27 patients (groups 1 and 2) was performed to review the medical records, including the clinical and laboratory test results, hearing outcomes evaluated by multiple modalities, and any association with other developmental delays. As for group 3, given that their detailed medical documents regarding the diagnosis of cCMV infection at another hospital were unavailable and their audiologic characteristics were uniformly profound deafness, they were only analyzed for the postoperative CI outcomes and progression of hearing loss, which were collected from SNUBH medical archives.This retrospective cohort study was approved by the institutional review boards of SNUBH (no. B-1612/376-106) and SNUH (no. J-1704-109-847). >20 dB was indicated as asymmetric. The pre- and postoperative CI outcomes were evaluated with the Category of Auditory Performance (CAP), which is a global outcome measure of auditory abilities [Audiologic evaluations were made by Auditory Brainstem Response (ABR), Automated ABR (AABR), Pure Tone Audiometry (PTA), and Otoacoustic Emissions (OAE), including both Distortion Product OAE (DPOAE) and Transiently Evoked OAE (TEOAE). AABR was used for newborn hearing screening. Hearing level by threshold was classified as normal (0-25 dB), mild hearing loss (26-45 dB), moderate hearing loss (46-70 dB), severe hearing loss (71-90 dB), and profound hearing loss (≥91dB) –12. Hearbilities . P < 0.05 was deemed to indicate statistical significance.The data are expressed as the means ± SD. Mann–Whitney test was used to compare the means of postoperative speech perception outcomes at each time point with preoperative speech perception outcome, and Fisher's exact test was performed to examine the association of risk factors with SNHL. Statistical analyses were performed and graphs were plotted with GraphPad prism 5.0 software .Among 27 patients diagnosed with cCMV infection (groups 1 and 2), fifteen patients were male (55.6%) and twelve patients were female (44.4%), and mean follow-up time was 39.8 months, ranging between 1 and 145 months. Demographics, including prematurity, low birth weight, hyperbilirubinemia requiring exchange transfusion, and NICU care for greater than 5 days are summarized . Group 3To investigate the incidence of cCMV infection, we used the data from group 2, which was prospectively recruited according to the NICU protocol. Group 2 was selected among 276 screened neonates who were born at or below 32 weeks/ or less than 1.5kg at birth, resulting in an incidence rate of 3.6% for cCMV infected neonates meeting such criteria.Among 27 patients, hearing assessment by AABR, ABR, OAE, or PTA was performed in 24 patients, where the NBHS was performed in 21 patients. Among 3 patients who were not evaluated in NBHS, one showed hearing loss at first hearing evaluation at the age of 7 months (1-2). Two patients who passed the NBHS developed hearing loss at 2- and 7-month-old (1-4 and 1-5); the rate of late-onset hearing among CMV-related SNHL was 29% (2/7) in our cohort. In total, eight out of 24 patients presented hearing loss; the proportion of hearing loss in Korean cCMV infection patients was calculated to be 33.3% (8/24) . HoweverNo patient had severe hyperbilirubinemia that required exchange transfusion, and seven hearing-impaired patients whose OAE results were available demonstrating abnormal OAE findings, consistent with increased ABR thresholds, which excluded the possibility of auditory neuropathy spectrum disorder due to severe hyperbilirubinemia Tables  and 2.Sixteen patients out of 27 patients received antiviral therapy by intravenous Ganciclovir or oral Valganciclovir, or both. Among them, one patient suffered from bone marrow suppression, although his viral status became negative after a 3-week administration of IV Ganciclovir. Another patient had ganciclovir permanently discontinued due to severe neutropenia. Among eight patients with hearing loss, seven patients received antiviral therapy; three patients showed improved hearing while 2 patients demonstrated no change, and, for the remaining two patients, follow-up hearing test result was not available . NotablyRegarding the progression of hearing loss, sixteen patients, comprising 5 patients from group 1 and 11 patients from group 3, with available follow-up audiologic assessments, were analyzed . Three pP < 0.0001)  .Our Korean cohort showed that 33.3% of patients with cCMV infection had SNHL, 38% of asymmetric hearing loss, 29% of late-onset hearing loss, and a diverse spectrum of SNHL severity, ranging from mild to profound among CMV-related SNHL patients. Interestingly, there was no hearing-impaired patient in group 2. However, this should be interpreted very cautiously given the relatively high incidence of delayed-onset hearing loss among cCMV infection patients, with the onset mostly within 5 years of birth . The incP=0.006 and P=0.008, respectively) as opposed to the previous study [Several risk factors for CMV-related deafness were proposed by the Joint Committee on Infant Hearing. Among the risk factors, severe neonatal jaundice was shown to cause neurotoxicity, impairing the auditory system, which is known to be highly sensitive to overt bilirubin-induced toxicity , 19. Infus study . HoweverOur study has several limitations. We included three groups with distinct demographic features. Hence, our study may suffer from selection bias, hindering the generalizability. For example, patients in group 2 were recruited from the NICU, which included more preterm patients. Therefore, when analyzing our data, we used each group selectively to reduce selection bias. Moreover, due to the nature of retrospective study, incidence of cCMV infection and CMV-related hearing loss could not be deduced accurately, limiting the usefulness of the epidemiologic data.CMV turned out to be a significant cause of neonatal and infant SNHL, first to date reported in the Korean population. Our analysis showed diverse audiologic features but with favorable CI outcomes. Moreover, in our study, three patients developed late-onset SNHL after passing NBHS, and four patients with asymmetric audiologic configuration progressed to bilateral profound deafness as late as the age of 5 years. This indicates that periodic audiologic evaluations should be mandatory, at least up to early childhood, for those with positive CMV results, regardless of the NBHS results. Additionally, for those who have asymmetric hearing loss with one side of profound hearing loss, we could advise them to consider CI on the worse side first without delay, eventually benefitting the patient from the CI for better auditory rehabilitation. We hope that the findings highlighted in this study could help physicians to acquire better understanding of audiologic phenotypes of CMV-related hearing loss according to a particular clinical setting.