Age-related hearing loss has been related to a compensatory increase in audio-visual integration and neural reorganization including alterations in functional resting state connectivity. How these two changes are linked in elderly listeners is unclear. The current study explored modulatory effects of hearing thresholds and audio-visual integration on resting state functional connectivity. We analysed a large set of resting state data of 65 elderly participants with a widely varying degree of untreated hearing loss. Audio-visual integration, as gauged with the McGurk effect, increased with progressing hearing thresholds. On the neural level, McGurk illusions were negatively related to functional coupling between motor and auditory regions. Similarly, connectivity of the dorsal attention network to sensorimotor and primary motor cortices was reduced with increasing hearing loss. The same effect was obtained for connectivity between the salience network and visual cortex. Our findings suggest that with progressing untreated age-related hearing loss, functional coupling at rest declines, affecting connectivity of brain networks and areas associated with attentional, visual, sensorimotor and motor processes. Especially connectivity reductions between auditory and motor areas were related to stronger audio-visual integration found with increasing hearing loss. Age-related hearing loss, also known as presbycusis, is a form of bilateral sensorineural hearing loss typically affecting high frequencies from 2000 Hz onwards2. The degraded auditory input in that frequency range leads to difficulties in speech perception and makes conversations highly demanding, requiring additional attentional and cognitive resources4. Age-related hearing loss is also associated with an accelerated loss of cognitive abilities and a higher risk of dementia8 and may further result in depressive symptoms and social isolation9. Together with behavioural symptoms, changes in brain structure and neural activity patterns have been described in presbycusis patients. These involve decreased neural activity in temporal brain regions together with increased frontal activation in response to auditory stimuli10, as well as atrophy11 and cross-modal plasticity12 of auditory cortices. Moreover, functional coupling of several areas and networks are altered in participants with age-related hearing loss14. Respective investigations of functional coupling at rest are, however, scarce and revealed inconsistent results, which the present study aims to disentangle studying a large sample of elderly normal and hard of hearing participants who were not using hearing aids yet.Sensory impairments among elderly are a substantial health issue with increasing relevance in an ageing society. With respect to hearing difficulties, a prevalence of 75% has been described for hearing loss in the US population above an age of 7017. This way, brain regions are organized in several functional units such as the salience network, the default mode or the dorsal attention network. The salience network encompasses nodes in the cingulate cortex and the insula as well as prefrontal and supramarginal regions and is especially involved in the detection of salient events18. In elderly participants, weakened salience network connectivity has been related to cognitive decline and ageing19 and is possibly also influenced by hearing impairment4. For several other networks, connectivity modifications have been reported in hard-of-hearing individuals21. Specifically for age-related hearing loss, differences in network connectivity have been reported for the default mode network (DMN) and the dorsal attention network (DAN). The DMN is associated with internal thoughts and daydreaming as it is highly active during rest23. It includes prefrontal, temporal-parietal, and cingulate nodes25. In contrast, regions of the DAN, encompassing parts of the frontal eye fields and intraparietal sulci26, exhibit, like those of the salience network, reduced activity during rest, but elevated activity in attention-requiring tasks. The DAN is specifically recruited during demanding cognitive tasks as well as in guiding selective attention and stimulus responses27. Previous findings comprise increased coupling of the DMN to the middle frontal gyrus, but reduced connectivity of the DAN to the insula and postcentral gyrus in hard-of-hearing elderly16. Chen and colleagues14 reported a negative correlation of connectivity within the superior temporal gyrus and hearing thresholds. Findings from Rosemann and Thiel13 suggested that listening effort, rather than hearing thresholds, might be responsible for alterations of resting state connectivity in hard-of-hearing elderly. Reduced coupling of the DAN to the precuneus and superior parietal lobule as well as the auditory cortices to the inferior frontal gyrus were associated with subjective listening effort. In another study21, connectivity between auditory and visual areas (MT+) was positively related to hearing thresholds during both resting state and audio-visual processing. In summary, the literature provides evidence for changes in brain connectivity between several areas and networks associated with hearing loss. Existing results do, however, not yield a coherent picture which may be due to the small sample size of prior studies. Details about the directionality of the effect and its relation to behavioural changes remain unclear.Resting state functional connectivity measures temporal correlations of spontaneous, low-frequency neuronal activity between anatomically separated brain areas in absence of any task30. In line with the principle of inverse effectiveness31 the lacking accuracy in auditory perception and therefore increased ambiguity of stimuli leads to enhanced multisensory integration. Accordingly, particularly for older adults with decreasing hearing abilities, additional visual speech information conveyed via lip and mouth movements gains importance in order to increase speech intelligibility34. Integration can also occur for incongruent auditory and visual information. The McGurk effect36 constitutes a powerful example of this phenomenon. When presented with the visual image of a speaker producing lip movements of a syllable together with a different syllable presented for the auditory modality, listeners often perceive a sound that corresponds to a fused percept of both. For instance, if a 'ba' sound is added on a video sequence showing lip movements of someone producing a 'ga' sound, many people report to hear a 'da' sound37.Besides neural changes, audio-visual integration abilities are more pronounced among hard-of-hearing individuals compared to normal-hearing populations38. Additionally, areas crucial for speech production, including the lip area of the primary motor cortex, have been found to be involved in the perception of audio-visual speech stimuli42. Thereby, bottom-up sensory input is believed to be integrated with top-down information from frontal and motor areas in the posterior superior temporal sulcus (STS)44. Functional connectivity of the STS to sensory cortices was increased and depended on whether the reliability of the auditory or the visual stimulus part was less noisy and accordingly more reliable in audio-visual speech stimuli. However, when specifically considering McGurk susceptibility, connectivity between the STS and frontal, auditory or visual cortices was not modulated by illusion rates45. With regard to the McGurk illusion in hard-of-hearing subjects, electrophysiological evidence of cross-modal activity in auditory areas in response to the visual face stimulus of the paradigm was demonstrated30. Furthermore, audio-visual integration in hard-of-hearing participants has been linked to elevated activity in frontal brain regions and the left postcentral gyrus28 as well as task-based connectivity alterations of the auditory cortex to middle frontal, occipital and supramarginal gyri29. However, whether these connectivity modulations are persistent at rest and to what extent alterations in cross-modal activity patterns are mirrored in functional resting state connectivity remains unknown. In order to advance hearing aid fitting options, understanding neural adaptations of already mild stages of age-related hearing loss is of crucial relevance.Early auditory and visual areas are involved in the generation of the fused McGurk percept in healthy participants30. Concerning the neuroimaging data, we expected variability in resting state connectivity of the auditory cortices21 as well as the DAN20, DMN13, and salience network19 to be explained by progressing hearing loss. Further, we assumed that resting state functional coupling of audio-visual integration related areas, such as the primary motor cortex, STS, and auditory cortices, changes as a function of McGurk susceptibility45.To date, only a very limited number of studies investigated resting state connectivity in age-related hearing loss and research on the McGurk effect in this context is entirely lacking. The present research explores, for the first time, modulatory effects of hearing thresholds and McGurk susceptibility on resting state connectivity in a larger sample (n = 65) of elderly participants and thus aims to disentangle previous ambiguous findings. Based on existing literature, we hypothesised that audio-visual integration abilities correlate positively with high-frequency hearing lossn = 65 elderly participants  were analysed. Overall, participants’ age ranged from 52 to 80 years with a mean age of 66.82 years (SD = 5.89). Data of 36 subjects was recorded by Rosemann and Thiel28 and included 19 normal-hearing participants and 17 subjects with a mild-to-moderate hearing loss. Data of the remaining 29 mild-to-severe hearing-impaired subjects were measured within the project "Hearing aid use, audiovisual integration, and speech performance: probing the interplay", funded by the Hearing Industry Research Consortium (IRC) Grant 2017. Participants with a high-frequency hearing loss of more than 30 dB HL for the frequencies between 2000 and 8000 Hz were considered to have presbycusis . Hearing thresholds for the lower frequencies (125–1000 Hz) were within a normal range for all subjects and only subjects with a symmetrical hearing deprivation (less than 10 dB HL difference between both ears) were included in the analysis. All subjects were right-handed, German native speakers and reported no current or previous use of a hearing aid. Further eligibility criteria required individuals to have no current or previous neurological or psychiatric disorders (self-report) and no contraindications for the MRI, for instance pacemakers or stents. Both studies were approved by the local ethics committee of the University of Oldenburg and conducted in accordance with the Declaration of Helsinki 2008. All participants gave written and informed consent and were paid for their participation.Combining two samples from previous studies, data from 28, resting state and anatomical MRI was recorded after a task-based MRI session and was followed by questionnaires. Afterwards, further behavioural measures including the McGurk task and pure-tone audiometry were assessed.Both studies consisted of MRI measurements as well as neuropsychological assessments and the audiometric testing. In the subsample provided by Rosemann and ThielIn the IRC project, measurements took place on two independent testing days within 1 week. Amongst other assessments, the McGurk task and audiometry were conducted on one day, whereas MRI recordings together with additional questionnaires were conducted on the second date.In both projects, hearing thresholds were obtained using air conduction pure tone audiometry for the frequencies 125, 250, 500, 1000, 2000, 4000, 6000 and 8000 Hz.Stimulus material of the McGurk task was recorded in the Department of Media Production at the University of Oldenburg and contained audio and video files of a male speaker producing different syllables. The sound of the spoken syllable and visual information of the speaker’s face showing his articulatory lip movements were presented either in isolation , combined correctly (congruent conditions) or combined to incongruent audio-visual stimulus conditions . Only incongruent trials were evaluated in order to determine McGurk illusion rates. The ratio of perceived illusions in incongruent trials served as an indicator for individual audio-visual integration abilities.In both datasets, participants performed the McGurk task outside of the scanner using the same stimulus material, whereas the presented syllables and the timing of presentation differed slightly: The IRC study included auditory ‘ba’ sounds and visual ‘ga’ stimuli leading to the illusionary, fused percept of ‘da’. Participants were asked to indicate which sound they perceived in a three-alternative forced choice task including all three syllables as possible answers. In total, the experiment consisted of 200 trials: 90 incongruent and 90 congruent trials  and 10 auditory only and 10 visual only trials . The combined audio-visual stimuli were presented either simultaneously or with different Stimulus Onset Asynchronies (SOAs), in which the video sequence followed the auditory stimulus presentation. For both congruent and incongruent audio-visual stimuli, there were 10 trials with SOAs of 0, 70, 120, 170, 220, 270, 320, 370, 420 ms each. A previous analysis revealed that the effect of hard-of-hearing participants perceiving significantly more illusions than normal-hearing subjects is present across all SOAs and stronger for shorter SOAs . Approaching the trade-off of including preferably trials without SOAs only (to assimilate both datasets best possible), while ensuring a sufficient number of trials, trials with SOAs of 0, 70 and 120 ms were analysed, resulting in 30 congruent and 30 incongruent audio-visual trials. Sound intensity of the stimuli was adjusted by each subject individually. The default intensity of 70 dB SPL could be modified by the participant in steps of 1 dB SPL to maximally 90 dB SPL. Stimuli were presented with 69.41 dB SPL on average, ranging from 65 dB SPL to 78 dB SPL.28, in addition to the combination of auditory ’ba’ and visual ’ga’ syllables, auditory ’ba’ sounds were paired with visual ’ta’ stimuli, which could also lead to the perception of the phoneme ’da’. Moreover, an illusionary percept of ’ta’ was produced by using auditory ’pa’ and visual ’ka’ stimuli. Fifteen trials per syllable pair were presented resulting in 45 incongruent trials in total. No SOAs were used in this experiment. For all six syllables, there were seven congruent audio-visual trials, auditory-only and visual-only trials each, leading to 42 presentations for each condition and 171 trials in total. Answers were given in a four-alternative forced-choice task in which the illusionary syllable as well as the presented visual and auditory syllable were among the four response options for incongruent trials. Answers were selected using the numbers one to four on the keyboard with alternating response options across conditions and trials. Here, stimuli were presented at a constant level of 68 dB SPL for all subjects. Stimuli were presented using the Presentation software .In the study by Rosemann and ThielImaging data were acquired on a 3 T whole-body Siemens Magnetom Prisma MRI machine with a 20-channel head coil. Participants fixated a white dot, positioned centrally on a black screen, while resting state data was recorded with an ascending echo planar imaging sequence . A 3D T1-weighted sequence with MP-RAGE was used for co-registration to structural images. Note that the sequences differed slightly in the two underlying datasets .To assess the relationship between hearing-impairment and audio-visual integration abilities, a correlation analysis was computed. Additionally, a partial correlation analysis of hearing thresholds and McGurk illusion rates whilst controlling for age effects was performed. Pearson’s correlation coefficients were tested two-tailed and determined to be significant when passing a threshold of α = 0.05. Statistical analyses of behavioural data were performed using IBM SPSS Statistics 24.46 for SPM. Images were pre-processed in SPM including spatial realignment estimation, slice timing correction to the first slice of the volume and co-registration. These steps were followed by normalization to the Montreal Neurological Institute space using parameters obtained from segmentation of the anatomical T1-weighted image and spatial smoothing using a Gaussian kernel with a full width at half maximum of 8 mm. Next, data processing proceeded using the CONN toolbox. For a more thorough cleaning of the data, remaining physiological and movement artefacts were removed by linear regression. BOLD signal from white matter and cerebrospinal fluid as well as realignment parameters were used for denoising. Subsequently, a band-pass filter (0.008–0.9 Hz) and linear detrending was applied. First-level analyses revealed Fisher-transformed correlation coefficients for each subject. In second-level analyses, the individual seed-to-voxel connectivity maps of a specific seed to the whole brain were entered into regression models to test the hypotheses of changed resting state functional connectivity with hearing impairment or audio-visual integration abilities.Resting state fMRI data were analysed with the Statistical Parametric Mapping software package  based on MATLAB 2016b  and the CONN toolbox47 within the WFU Pickatlas48. An auditory seed, defined by both left and right Brodmann areas 41 and 42, was created. Connectivity as a function of hearing loss was tested for the auditory cortices as well as the three aforementioned network seeds. For correlation analyses of brain connectivity with McGurk illusion rates, the same auditory seed was used as well as two other areas related to audio-visual integration, the left motor lip area and the left STS. The seed coordinates for the lip area were based on the average individual activation peaks in response to the McGurk task from Murakami and associates41. For the seed in the left STS, coordinates from the same study, used in an effective connectivity measure, were adopted. The masks of these two seed regions constitute spheres of 8 mm radius around the coordinates provided by the literature (ibid.). All seed regions and networks investigated are listed in Table p < 0.001 and a cluster forming threshold of pFWE < 0.05 were calculated. Further, a Bonferroni-correction was applied resulting in adjusted significance thresholds of p < 0.0125 (divided by the four seed regions used) for the models with hearing loss as a regressor. Resting state connectivity analyses with respect to the McGurk task were performed for three seed areas resulting in a corrected significance threshold of p < 0.016.Relevant resting state networks included the DAN, DMN, and the salience network. Masks of these network seeds were provided by the atlas implemented in CONN . All nodes of a network were equally weighted, contributing jointly to the seed network's connectivity. Based on previous findings in the literature, additional seed areas were defined using the Automated Anatomical Labeling (AAL) ROI-LibrarySD = 15.83) when the entire sample was taken into account. The sample comprised 19 normal-hearing participants and 46 hard-of-hearing participants. Within the latter subgroup, twelve subjects exhibited hearing thresholds < 40 dB HL denoting a mild hearing loss, 26 subjects were considered to be moderately impaired (41–60 dB HL), and the remaining eight participants exhibited a severe form of age-related hearing loss (up to 80 dB HL) with a maximum hearing loss of 69.5 dB HL. Individual hearing curves for all participants can be found in Fig. r = 0.508, p < 0.001).Mean hearing thresholds for high frequencies (2000–8000 Hz) were 38.81 dB HL (SD = 33.02) of all incongruent trials. McGurk illusion rates correlated positively with high frequency hearing loss . In congruent trials, the correct syllable was perceived, on average, in 90.30% (SD = 19.53%) of the trials. Performance rates for auditory-only and visual-only conditions amounted to 87.01% (SD = 19.33%) and 56.99% (SD = 21.42%), respectively.In response to incongruent syllable pairs, the illusionary phoneme was perceived, on average, in 47.40% SD = 33.0 of all ir = −0.46, p < 0.001)  and r = − 0.50 (p < 0.001), respectively. No significant associations were found regarding the DMN and the auditory cortices, hence no significant seed-to-voxel correlations were obtained with the seeds in the DMN and the auditory cortices. All findings including the clusters’ peak MNI coordinates, cluster and effect sizes are summarized in Table Modulatory effects of hearing loss on resting state functional connectivity was investigated considering the DAN, DMN, and salience network as well as the auditory cortices as seed regions. To control for age effects, all analyses were performed with age as covariate. Multiple regression analyses of seed-to-voxel connectivity revealed significant results for two of the assessed seeds. Salience network connectivity to a cluster covering parts of the right cuneal, intracalcarine and supracalcarine cortex negatively correlated with hearing loss (01) Fig. a. Furthe01) Fig. b,c. Corrp < 0.001) and r = − 0.59 (p < 0.001), respectively. A similar relationship was ascertained for the seed situated in the lip area of the left primary motor cortex; higher McGurk susceptibility was related to reductions of functional coupling between the seed area in the primary motor cortex and a cluster comprising the left planum temporale and the left posterior superior temporal gyrus   was investigated for three brain regions that were consistently linked to audio-visual integration . Higher McGurk susceptibility was associated with reduced coupling of auditory cortex to the left and the right pre- and postcentral gyrus Fig. a,b. Corr01) Fig. c. DetailThe current study examined resting state functional connectivity with respect to age-related hearing loss and audio-visual integration abilities in a large sample of older adults. The two behavioural measures were positively correlated, irrespectively of any age effects. Hearing loss was found to have a negative modulatory effect on resting state functional coupling of the DAN to a cluster comprising parts of sensorimotor and primary motor cortices. The same relationship was obtained for the salience network and its connectivity to the visual cortex. Likewise, resting state functional connectivity between motor and auditory regions was negatively related to the strength of the McGurk effect.Functional connectivity at rest was influenced by age-related hearing loss. Higher hearing loss was associated with decreased functional coupling between the salience network and visual cortex and between the DAN and sensorimotor and motor regions (controlled for age effects).19, further reduced functional coupling of the salience network was also reported in fronto-temporal dementia and Alzheimer’s disease50. Our findings suggest that part of these changes may also be due to decreased hearing abilities with age. Cognitive decline associated with age-related hearing loss8 may, therefore, rest upon similar neural mechanisms of malfunctioning connectivity within resting state networks, as described in several neurodegenerative disorders51. The connectivity reductions involve the visual cortex, an area assumed to be increasingly important for hard-of-hearing elderly as they rely more strongly on visual cues52. The obtained reduction of coupling strength between salience network and cuneal cortex with progressing hearing loss in absence of any task might be—next to the assumed general dysfunction within the salience network—understood as a task-dependent downregulation. It is conceivable that tasks that require the detection of salient events increasingly involve the visual cortex in hard-of-hearing participants, which might be mirrored in a potential task-related increased synchronization between low-frequency fluctuations in nodes of the salience network and the visual cortex. At rest, however, when no alertness for the detection of salient events is needed, we assume that connectivity patterns reverse into anticorrelations as evident from the present analysis.Altered within-network connectivity of the salience network has been related to ageing and cognitive decline20 and Husain et al.16 reported between-group differences in resting state connectivity of the DAN for middle-aged participants. This is the first analysis, however, indicating that elderly individuals with presbycusis exhibit progressively decreased DAN connectivity with increasing hearing thresholds. Impaired DAN connectivity might explain attentional deficits that were described in hard-of-hearing individuals53. Aside from that, the resulting cluster in the pre- and postcentral gyri is closely situated to brain areas for tongue, mouth and lip representations55. Further, left sensorimotor and motor cortices are part of a distributed network for speech comprehension56. Thus, our results suggest that functional connectivity between the DAN and areas associated with speech comprehension and production is diminished in age-related hearing loss. This may imply that the attentional focus on lip and mouth movements is altered in hearing loss.For the DAN, reductions in functional resting state connectivity in participants with hearing impairment has been shown before. Luan et al.13, no effects of hearing loss on resting state functional connectivity were obtained while listening effort was found to modulate brain connectivity. This relationship was similar in normal-hearing as well as hard-of-hearing participants. Considering both studies in combination, they provide evidence for decreasing DAN connectivity with increasing hearing loss or listening effort and thus imply that different measures associated with hearing impairment (subjective listening effort as well as pure-tone audiometry) seem to impact neural coupling in similar ways. Rosemann and Thiel13 considered a reversal between positive and negative coupling, depending on task-based vs. resting state measures to be a possible explanation for their findings. However, not all resting state analyses reported a decline of functional connectivity in connection with hearing impairment. Increased coupling during resting state in hard-of-hearing compared to normal-hearing participants was reported by Husain et al.16 for the DMN and by Chen et al.14 for the cuneus. Puschmann and Thiel21 provided evidence for a continuous positive relationship of high-frequency hearing loss and resting state functional connectivity of the visual area MT+. With respect to the methodology of these investigations, it could be the case that transfer effects of directly preceding task-based recordings in Puschmann and Thiel21 were responsible for the persisting positive correlations during rest. Generally, comparability of the mentioned studies might be limited due to differences in sample size, age and degree of hearing loss of the group of participants. Additionally, it needs to be considered that functional connectivity of resting state networks is significantly influenced by age58, which was largely disregarded in the statistical analysis of previous investigations.Interestingly, in our previous investigation30, the behavioural analysis resulted in a positive age-corrected partial correlation between McGurk susceptibility and hearing loss. It can be inferred that regardless of effects by age, hearing loss is associated with a continuous increase of audio-visual integration abilities. The behavioural outcome of increasing McGurk susceptibility was found to be neurally mirrored in reduced functional coupling between the auditory cortices and bilateral pre- and postcentral gyri, covering the lip and tongue motor region55. This finding is complemented by the results of the reduced coupling of the lip area of the primary motor cortex to the left planum temporale with increasing McGurk susceptibility. The left planum temporale constitutes an area of early auditory processing59. The connectivity reductions reported here affect areas that are recruited during the performance of the McGurk task60. The involvement of the primary motor cortex substantiates the motor theory of speech perception based on Liberman et al.39 stating that areas relevant for speech production are involved in audio-visual speech processing, probably as part of the mirror neuron system40. Aside from the present investigation, other studies have also described altered resting state functional connectivity of the pre- and postcentral gyri in hearing-impaired individuals, however, independent of audio-visual integration abilities20. When using audio-visual stimuli in task-based fMRI recordings, hearing loss was found to be positively correlated to functional coupling between auditory and visual areas when processing matching audio-visual input with respect to motion and tone pitch21. Further, higher McGurk susceptibility was associated with increased activity in the right precentral gyrus as well as in stronger auditory cortex connectivity in hard-of-hearing compared to normal-hearing participants for incongruent McGurk trials29. The current findings of bilateral auditory cortices demonstrating connectivity reductions to both left and right-hemispheric pre- and postcentral gyri cover similar areas and thus support the relevance of these brain regions for enhanced multisensory processing in presbycusis. Considering the differences in the experimental design between the mentioned investigations29 and the current study, the increased neural activity and stronger connectivity of the involved areas during the integration of audio-visual stimuli seems to be reversed into decreased functional connectivity at rest, if no integration processes take place. This may constitute a compensatory mechanism for the enhanced co-activation during task performance.In line with our expectation and previous investigations61. However, studies in elderly participants have consistently shown higher illusion rates in hard of hearing compared to normal-hearing individuals30. We recently conducted another study in which a group of participants with mild to moderate age-related hearing loss (n = 16) was measured twice with a duration of 6 months between measurements. The number of perceived McGurk illusions was highly correlated across both measurement points (yet unpublished observations). Hence, it seems that the susceptibility to the McGurk illusion seems to be relatively stable in elderly hard of hearing participants, at least for a period of 6 months. Whether the susceptibility may change with progressing hearing loss within the same participants can only be answered in a longitudinal study.It should be noted that previous research has shown rather large variability in the McGurk illusion susceptibility, for instance based on differences in age, gender, culture or native language16 and Rosemann and Thiel13. In contrast, some other studies found altered connectivity of auditory seed regions in groups of people with a comparable hearing impairment62, however, they were inconsistent regarding the direction of effect (increased vs. decreased coupling). Based on the repeatedly reported structural and task-related changes in brain structure and activation of the auditory cortex10 as well as cross-modal reorganisations of the visual and auditory domains in age-related hearing loss63, we expected these relations to also be emulated on functional connectivity during rest. Nevertheless, in our large sample covering varying degrees of hearing loss, the hearing ability itself seems not to be linked to resting state functional connectivity in the auditory cortex. Instead, our study showed that McGurk illusion rates seem to be highly related to decreased functional connectivity. Probably, not the hearing abilities per se but rather the effect of the decreased auditory abilities on behavioural outcomes—for instance audio-visual integration abilities—seem to affect resting state functional connectivity of the auditory cortex.Functional connectivity of the auditory cortices was not observed to change as a function of hearing thresholds. This finding is consistent with the lacking between-group differences and correlations of auditory cortices resting state functional connectivity investigated by Husain et al.We here show in a large sample of elderly subjects with a wide range of untreated hearing loss that the degree of impairment is linked to changes in functional connectivity of two attention-related brain networks, the DAN and the salience network. The often observed increase in audio-visual integration, as measured with the McGurk susceptibility, was accompanied by changes in functional coupling between auditory and motor regions. For both, hearing thresholds as well as McGurk illusions, negative relationships with resting state functional connectivity were obtained. Hence, age-related hearing loss seems to be accompanied by an overall decline of connectivity affecting different brain areas and networks. Our research points out that with progressing hearing loss resting state functional connectivity continuously declines, starting already at early stages of hearing loss. The consequences of these alterations in presbycusis patients and its reversibility after hearing aid fitting are still unknown, but may become a major health concern as the prevalence of hearing loss will further increase in our ageing population.


Globally increasing number of elders is concerned. Hearing loss process in older adults cannot be avoided. An effective screening tool for hearing loss is essential for proper diagnosis and rehabilitation, which can improve QOL in older adults.This prospective-diagnostic test study evaluates the diagnostic value of Thai version of the Hearing Handicap Inventory for Elderly Screening (HHIE-ST) and the Thai Single Question (TSQ) surveys in screening hearing disability in 1109 Thai participants aged 60 years and older in communities in four provinces in Thailand. The HHIE-ST consisted of 10 selected questions from the validated HHIE-Thai version. A TSQ survey was developed to have the same meaning as an English Single Question survey. The participants answered both questionnaires, and a standard audiometry test assessed with air conduction from 250 to 8000 Hz was included as a gold standard.The prevalence of hearing disability was 38.34%. The HHIE-ST achieved a sensitivity of 88.96% (95% CI 85.77–91.64) and specificity of 52.19% (95% CI 48.24–56.13) for diagnosis hearing disability in Thai older adults, whereas the TSQ yielded a sensitivity of 88.73% and a specificity of 55.93%. A combined test including the HHIE-ST and TSQ achieved better performance with sensitivity of 85.29% and specificity of 60.13%.Either the HHIE-ST or the TSQ is a sensitive and useful tool for screening hearing disability in Thai older adults. Using the HHIE-ST together with the TSQ resulted in a better screening tool for detecting moderate hearing loss older adults who will benefit and recommended for hearing rehabilitation.TCTR20151015003. Date of registration October 14, 2015.The study is registered with the following number in the Thai Clinical Trials Registry:  Thailand, as well as most global nations, is now becoming an aging society given the rising number of older adults. In 2014, the Thai national health survey reported that 14.9% of the Thai population was over 60 years old and the prevalence of hearing disability in this population was 24.4% . TherefoThe standard method for the diagnosis of hearing impairment is standardized pure tone audiometry. The diagnostic criteria for diagnosing hearing impairment are a pure tone average hearing level in the better ear (PTA BE) of greater than 25 dB at 500, 1000, 2000 and 4000 Hz . The ThaTo achieve the standard diagnosis of and rehabilitation for hearing disability, a large budget, as well as time and expertise, are needed to perform the audiometric test. Due to the limited number of health care providers in many countries, including Thailand, it is difficult to access health services in rural areas, especially those used for hearing screening, diagnosis, and rehabilitation. Although in recent years, there has been the development of mobile or tablet-based hearing screening applications , none ofSeveral simple clinical tests have been proposed as methods for screening hearing loss. Whispered voice was one method where examiners whisper words from behind at varying distances, but the results of these tests are highly variable among examiners, possibly due to differences in the loudness of their whispering –15. A tuSeveral questionnaires have been developed and used as instruments for assessing hearing disability and handicap; these include the Hearing Handicap Inventory for Elderly (HHIE), the Hearing Handicap Inventory for Elderly Screening Version (HHIE-S), A Single Question (Do you feel you have a hearing loss?) test and Three Single Questions and a 5-Minute Hearing Test –26. ThesThe Three Single Questions test has not been tested to determine its diagnostic value for screening hearing impairment in older subjects. The 5-Minute Hearing Test is composed of 15 questions with a wide range of sensitivities and specificities for screening hearing impairment in older subjects. The full version of HHIE has great specificity for identifying hearing impairment in older subjects, but it contains a total of 25 questions and is therefore not suitable as a screening tool due to the time required to complete it.The Hearing Handicap Inventory for Elderly Screening Version (HHIE-S) has been validated for screening hearing impairment in older subjects, is used as a study tool in various cultures and languages, and results related to its validity and sensitivity are acceptable , 29–32. The aim of this study was to assess and compare the performance of the Thai version of the HHIE-S instrument (HHIE-ST) and a Thai Single Question (TSQ) test in identifying older subjects with hearing loss against results obtained in measuring hearing loss using PTA, which is the gold standard in Thais over 60 years old.This study is a prospective diagnostic study conducted among older adult Thai subjects in four northeastern provinces, including Khon Kaen, Mahasarakham, Chaiyaphum, and Udon Thani from July 2015 to June 2016. The only inclusion criteria were volunteer Thais over 60 years old. The exclusion criteria were individuals who could not undergo a standard audiometry test, including those with profound otorrhea or difficulty in sitting or responding to sound and persons who could not cooperate with the test due to mental problems.The HHIE-ST was developed using 10 questions from the validated Thai version (HHIE-Thai) according to the original version of the HHIE-S. For the Thai Single Question (TSQ), we used the question in “The 2012 Disability Survey” , which wThe sample size was calculated using 77% for specificity  and 80% The following demographic data were collected: age, sex, underlying diseases, and educational level. An otologic examination was performed by an otorhinolaryngologist. No intervention was allowed before the hearing assessment was performed. PTA was assessed by an audiologist in a sound-proof booth using a calibrated diagnostic audiometer for hearing thresholds for air conduction from 250 to 8000 Hz.The audiometry results were interpreted according to WHO classification (1991) using the PTA BE at 500, 1000, 2000 and 4000 Hz. A PTA BE ≤ 25 dB indicated “normal hearing”, a PTA BE 26–40 dB indicated “mild impairment”, a PTA BE 41–60 dB indicated “moderate impairment”, a PTA BE 61–80 dB indicated “severe impairment”, and a PTA BE > 81 dB indicated “profound impairment, including deafness” .  High-fThe HHIE-ST consists of 10 questions with answers scored as “yes: 4 points”, “sometimes: 2 points”, and “no: 0 points”. The total score was calculated with a cut-off point score of “more than 8” considered to indicate hearing handicap according to the American Speech-Language-Hearing Association (ASHA) draft guidelines . The TSQFor volunteers who could not read, the interview was conducted by researchers. All data collection processes were performed on the same day, and the operators were blinded to the results of each process.We used the Chi-square test to analyze categorical data. The sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio were calculated using STATA software version 10 .This study was approved by the Office of the Khon Kaen University Ethics Committee in Human Research (project number HE581300). The study is registered under the following number at the Thai Clinical Trials Registry: TCTR20151015003.As shown in Fig. p < 0.001) as shown in Fig. P < 0.001).Regarding the audiometric results, 276 subjects (24.93%) had a normal PTA (PTA < 25 dB according to WHO criteria) in at least one ear, 166 (15.0%) had high-frequency hearing loss, and 426 (38.34%) had hearing disability. There was a significant difference in hearing level at each frequency between males and females and among the age groups  for moderate hearing impairment were 88.96% and 52.19%, respectively. The sensitivity and specificity of the TSQ and HHIE-ST for all severities of hearing impairment according to the WHO classification are shown in Table To compare the sensitivity and specificity of the HHIE-ST at different cut-off points ranging from 10 to 16, ROC curves were generated, and the AUC was calculated and is shown in Table Hearing loss in older adults, similar to most parts of the world, is not uncommon in Thailand. The prevalence of hearing disability, defined as a PTA > 40 dB in the better hearing ear in elder subjects, has been reported in different parts of the world to be approximately one-third of the older population , 39–42. Presbycusis is the most common cause of hearing loss in the older population . This prEnsuring that validated questionnaires are adopted and applied across different cultural contexts while retaining the reliability and validity of the original version is a challenge. For our study, we found that the reliability was very good for our Thai version and that our internal consistency was higher than that achieved by the Swedish version and comparable to that of the original version. The Cronbach’s alpha score for the HHIE-ST, the original version, the Japanese version and the Swedish version are 0.94, 0.82, 0.91 and 0.77, respectively , 27, 49.p < 0.001). There was no significant difference in HHIE-ST scores between sex or area of residence. However, there were significant differences in the total scores among groups with different levels of education, with higher scores received by participants with lower educational levels (p < 0.001). We suggest that this could be related to the ability to understand the true meaning of the questions and the possibility that there are differences in self-awareness between these groups. Average hearing levels were worse in men than in women at every frequency and worsened with age, as expected, although these trends were not statistically significant.Regarding HHIE-ST scores and demographic data correlations, we found that mean scores were significantly correlated with age group, with older individuals having higher scores  anFurthermore, a similar study in Thai population was done recently. Judee et al. reported the sensitivity of HHIE-ST at a cut-off score 10 for detecting hearing disability was 69.7% and specificity was 74.9 , which iGiven all the reasons outlined above and according to the ROC curves shown in Table The diagnostic value of the A Single Question survey has been reported to range from 48–90% for sensitivity and 50–91% for specificity , 52–54. We recommend that both the TSQ and the HHIE-ST are sensitive and useful for screening eligible hearing-disabled persons. However, we found that using the HHIE-ST in combination with the TSQ can increase specificity to 60.13% while sensitivity is still as high at 85.29%, as shown in Table The strength of this study is a large number of participants with varying educational levels and urban-rural community status. In addition, we conducted this study in a setting that accurately represents how the screening process would likely be done in a limited resource context. We performed the audiometry test in a sound-proof booth in the quietest area possible instead of using a sound-proof testing room, this could result in some error in the audiometry results. However, we conducted the test according to the WHO hearing measurement guidelines for nonclinical settings . Hence, Both the HHIE-ST and the TSQ are sensitive tools for screening eligible hearing disabled persons. However, a combination including the HHIE-ST with a cut-off score of 10 and the TSQ is a better screening tool for detecting Thai older adults with moderate hearing loss who will benefit and recommended for hearing rehabilitation.


Assessing infants’ hearing is of utmost importance, as hearing at this phase is required for the development of oral language. Through hearing, human beings are capable of developing communication. The Brainstem Auditory Evoked Potentials are an indispensable test to diagnose deafness in infants. This study aimed to analyze the results of the Brainstem Auditory Evoked Potentials in children with risk factors for hearing loss.This cross-sectional study analyzed the Brainstem Auditory Evoked Potentials in 123 infants aged 1 to 24 months at a hearing health care service. The Vivosonic Integrity V500 equipment, which enabled the child to be awake while the testing was carried out, was used in this study. The data were compared by gestational age and sex, according to the standards suggested in the equipment handbook.A significant difference was verified for age ranges 4 to 6 months, 13 to 15 months (waves I and V), and 7 to 9 months (wave V). The lower values in absolute wave latencies were comparable to data from the equipment handbook, justifying the need for standardization of the screening process.There are some differences between the standards in the equipment handbook and those observed in our study. These results will serve as a reference for the standardization of the equipment used in the hearing health care service. The hearing assessment in infants is of utmost importance, as hearing in this phase is required for the normal development of oral language and cognitive functions. Hearing allows human beings to identify, locate, and develop sensory experiences; this contributes not only to the maturation of the hearing system, but also the cognitive and emotional functions. It is also essential for acquisition and development of the oral and written language.Several organizations  and commNewborn Hearing Screening (NHS) aims for the early detection of cochlear hearing loss greater than 35 dB HL and may also comprise retrocochlear hearing loss among neonates and infants. Newborn Hearing Screening (NHS) is carried out by means of physiological and electrophysiological hearing measures used to assess the peripheral and central auditory pathways .The Brainstem Auditory Evoked Potentials (BAEP) is an important tool for the diagnosis of hearing impairment in neonates and infants, since it assesses the integrity of the auditory pathways and their maturation in relation to the infants’ age on the day of the test. A previous study  reportedBrainstem Auditory Evoked Potentials (BAEP), permits assessment of the integrity of the auditory pathway to the brainstem, and identifies electrophysiological threshold in neonates, allowing for the diagnosis of child cochlear or retrocochlear hearing loss .The Auditory Evoked Potentials (AEP) are electrophysiological responses to an acoustic stimulus and provide an objective measure of the integrity of the hearing system as a whole ,7. The AStudies ,6,9,10 rBased on literature and equipment features, the expected normality standards of the Brainstem Auditory Evoked Potentials (BAEP) devices for each subject’s age can be found in their handbooks and software. These data, provided by the handbooks, may not reflect normality of a different population on which the equipment is used. Thus, literature recommends a biological calibration of the equipment, according to the screened population ,8,12.This study aims to analyze the results of Brainstem Auditory Evoked Potentials (BAEP) in children with risk factors for hearing loss.This is a cross-sectional study, which analyzed the Brainstem Auditory Evoked Potentials (BAEP) results in 123 infants between 1 and 24 months of age at an accredited clinic of the Brazilian Unified Health System . The children were referred to the hearing health care service to undergo hearing diagnosis when they presented risk factors for hearing loss or failed the Newborn Hearing Screening (NHS).The study was approved by the Ethics Research Board under number 105.576. The free informed consent form was signed by parents/legal guardians before initiating the procedures.The inclusion factors for the research were as follows: children presenting a hearing assessment result within the normal standards based on Brainstem Auditory Evoked Potentials (BAEP), considering the electrophysiological threshold at 25 dBHL, tested with at least two wave markings, corresponding to waves I, III and V, in both ears, and disclosure of all anamnesis data. Testing was carried out by audiologists from the service, with the same standards as those used to carry out Brainstem Auditory Evoked Potentials (BAEP), result interpretation, and diagnostic report. Out of the 123 infants assessed, 57 (46.34%) were female and 66 (53.65%) were male.™ V500  were placed as recommended by the handbook, on both mastoids (negatives - left M1 and right M2), high forehead (positive - Fz), and low forehead (ground - Fpz). The impedance between the electrodes was less than 5 KOhms; broadband rarefaction click stimuli were presented by insertion phones (ER 3) at an initial intensity of 80 dBHL with a repetition rate of 27.5 clicks/second and an average of 2.000 stimuli. The sweep duration was 12 ms, and the equipment used the Kalman weighted algorithm for signal processing. Duplicate recordings were made to examine reproducibility. The acoustic stimulus was later presented decreasing intensities, every 20 dBHL, up to the limit of 25 dBHL, a value considered normal.The protocol used to carry out the testing was as follows : the chiFor data analysis, such as absolute latencies of waves I, III and V, the interpeak intervals I-III, III-V and I-V were considered at an intensity of 80 dBHL and were also analyzed as interaural differences of wave V. Consider as age groups in months. These data were compared to equipment standards. Differences between the right and left ears and sex were analyzed. Preterm infants, born at less than 37 weeks, had their ages corrected using the Capurro method .Software Statística 13.3 and Mat Lab 6.0 and statistical procedures, such as the odds ratio test, Student’s t-test, and analyses of central tendency  of the findings were used. In addition, data were compared by gestational age and sex, based on the standards suggested in the equipment handbook. The adopted level of significance was 0.05 (5%).In In There was a statistically significant difference in interpeak intervals I-III, III-V, and I-V, which was greater among male infants between ages 1 and 3 months. In the age range between 4 and 6 months, a statistically significant difference was observed in absolute latencies of waves III and V, and interpeak intervals I-II and I-V, which was also greater among male infants. In addition, in the age range from 7 to 9 months, a statistically significant difference was observed in the absolute latency of wave III, and interpeak intervals I-III, which was also greater among male infants.We compared the sample means to the standard mean (equipment mean) using the Student’s t-test at significance level of 0.05 (5%) and verified a significant difference for age ranges from 4 to 6 months, 13 to 15 months at absolute latencies of waves I and V, and for the age range from 7 to 9 months at wave V. The test was not applied to ages ranging from 10 to 12 months, 15 to 18 months, and 18 to 21 months, since the samples for these age ranges were very small.The population in the study evidenced normal hearing at the time of data collection, identified by the behavioral assessment and Brainstem Auditory Evoked Potentials (BAEP), with the presence of absolute latencies of waves I, III, V, interpeak intervals I-III, III-V, and I-V, hearing thresholds up to 25 Dbhl.Notably, normative data based on the literature, is used in BAEP equipment for specific populations for correct identification of the hearing loss, early diagnosis, and early initiation of a rehabilitation program when applicable ,6,12.Regarding Brainstem Auditory Evoked Potentials (BAEP) standardization, in this study , a decreInstead of the expected latency decrease because of the maturation process, a significant increase in absolute latency of wave I was observed as infants grew older. Some factors may have influenced this finding, referring to the profile of the babies in the present study, because at the ages of 6 to 24 months of age, babies do not sleep easily for the proper examination, which may have influenced recording of wave I. However, a Brazilian study , which aStudies show a symmetry between the ears; therefore, results found in the right ear can be correlated to those in the left ear ,19,22. TAdditionally, at ages 7 to 9 months, a statistically significant difference was verified in the absolute latency of wave III and interpeak intervals I-III, which was also greater among male infants. Based on previous studies ,23,24, tA comparison between our study data and standard equipment data  revealedLimitations of this study include use of a sample with infants at risk of hearing loss.However, all infants underwent electrophysiological threshold assessment and those with hearing loss were excluded. In addition, gestational age was also corrected for premature infants, avoiding Brainstem Auditory Evoked Potentials (BAEP) distortions because of the immaturity of the auditory pathways. Some studies observed differences between Brainstem Auditory Evoked Potentials (BAEP) responses from neonates born preterm and at term, showing that responses generated between peripheral and central auditory pathways were influenced by the maturation process and gestational age ,7,9,14. Lower values were found in the absolute latencies of waves I and V compared to the standard equipment data and non-reported values in the equipment handbook were found in the absolute latencies of wave III, justifying the need for standardization of the service responsible for performing the assessment.By comparing the latencies of waves found in the study to those reported for the equipment, differences were verified in waves I and V at ages 4 to 6 months and 13 to 15 months, which was also verified in wave V at ages ranging from 7 to 9 months.The values ??found in this study, for waves I, III and V from one to three months will serve as a basis for the analysis of the results of the babies attended at the studied hearing health service.The results will serve as a reference for the standardization of equipment used in the hearing healthcare service, specifically for neonates with risk factors for hearing loss. Therefore, biological calibration is emphasized in the Brainstem Auditory Evoked Potentials (BAEP) test.However, further research with larger samples is needed to confirm our study findings.Bellia CGL contributed to the project and production of the article: research design, conceptualization, data curation, formal analysis, investigation, methodology, and writing. Junior HA contributed with data curation, investigation, methodology, visualization, and writing. Marques JM contributed with methodology, validation, and formal analysis. Lüders D contributed with methodology, formal analysis, writing-review, and editing. Gonçalves CGO contributed with project administration, conceptualization, formal analysis, supervision, methodology, writing, and review.


Individual differences and age-related normal and pathological changes in mental abilities require the use of cognitive screening and assessment tools. However, simultaneously occurring deficits in sensory processing, whose prevalence increases especially in old age, may negatively impact cognitive-test performance and thus result in an overestimation of cognitive decline. This hypothesis was tested using an impairment-simulation approach. Young normal-hearing university students performed three memory tasks, using auditorily presented speech stimuli that were either unprocessed or processed to mimic some of the perceptual consequences of age-related hearing loss (ARHL). Both short-term-memory and working-memory capacities were significantly lower in the simulated-hearing-loss condition, despite good intelligibility of the test stimuli. The findings are consistent with the notion that, in case of ARHL, the perceptual processing of auditory stimuli used in cognitive assessments requires additional (cognitive) resources that cannot be used toward the execution of the cognitive task itself. Researchers and clinicians would be well advised to consider sensory impairments as a confounding variable when administering cognitive tasks and interpreting their results. Over the past decades, there has been increasing interest in the role of cognition in (the decline of) speech processing across the adult lifespan see . Indeed,Presumably for reasons of convenience and universal usability, most cognitive tests require the administrator to provide verbal instructions, and a substantial number use at least some auditorily presented stimuli  to establish that none had any hearing impairment. The test consists of listening to diotically presented triple digits  in a fixed-level speech-shaped background noise  with the pure-tone average (PTA) for octave frequencies between 0.5 and 4 kHz  native-English-speaking volunteers were recruited from the undergraduate student population of Loughborough University (United Kingdom), and received course credit for participating in the study. All participants completed the internet version of the hearing-screening test offered by the British hearing charity “Action on Hearing Loss” (SD) = 1.1] formed the “normal-hearing” (NH) group that listened to unprocessed stimuli, and (ii) 26 participants  with a mean age of 19.3 years (SD = 1.3) formed the “simulated hearing loss” (SHL) group that listened to degraded speech. The small age difference between groups was not significant .Participants were randomly assigned to one of two experimental groups: (i) 30 participants  with a mean age of 19.1 years .All SHL participants correctly recognized the nine digits, but six of them (23%) failed to recognize two to four target words, representing 4 to 7% of the total number of words to be remembered in the LS test. Hence, all results of the LS test were reanalyzed, excluding those participants . However, there is converging evidence that sensitivity to temporal fine structure worsens with age and hearing loss  controlling experimentally  or (ib) statistically (by measuring sensory performance and using this information as a covariant) the effect of sensory decline, (ii) compensating for sensory deficits , and (iii) using a visual version of cognitive tests originally including auditory-based tasks  Sub-Committee. The participants provided written informed consent prior to participation in the study.CF designed the study, analyzed and plotted the data, and wrote the manuscript.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


GJB2) variants account for about 25.9% of familial hearing impairment (HI) cases. The GJB2-p.Arg143Trp (NM_004004.6:c.427C>T/OMIM: 121011.0009/rs80338948) variant remains the most frequent variant associated with congenital HI in Ghana, but has not yet been investigated in clinical practice. We therefore sought to design a rapid and cost-effective test to detect this variant. We sampled 20 hearing-impaired and 10 normal hearing family members from 8 families segregating autosomal recessive non syndromic HI. In addition, a total of 111 unrelated isolated individuals with HI were selected, as well as 50 normal hearing control participants. A restriction fragment length polymorphism (RFLP) test was designed, using the restriction enzyme NciI optimized and validated with Sanger sequencing, for rapid genotyping of the common GJB2-p.Arg143Trp variant. All hearing-impaired participants from 7/8 families were homozygous positive for the GJB2-p.Arg143Trp mutation using the NciI-RFLP test, which was confirmed with Sanger sequencing. The investigation of 111 individuals with isolated non-syndromic HI that were previously Sanger sequenced found that the sensitivity of the GJB2-p.Arg143Trp NciI-RFLP testing was 100%. All the 50 control subjects with normal hearing were found to be negative for the variant. Although the test is extremely valuable, it is not 100% specific because it cannot differentiate between other mutations at the recognition site of the restriction enzyme. The GJB2-p.Arg143Trp NciI-RFLP-based diagnostic test had a high sensitivity for genotyping the most common GJB2 pathogenic and founder variant (p.Arg143Trp) within the Ghanaian populations. We recommend the adoption and implementation of this test for hearing impairment genetic clinical investigations to complement the newborn hearing screening program in Ghana. The present study is a practical case scenario of enhancing genetic medicine in Africa.In Ghana, gap-junction protein β 2 ( GJB2) and gap-junction protein β 6 (GJB6) are the most common genes associated with the condition globally, with high prevalence reported in the European and Asian populations. However, recent data including the use of mouse models has indicated that mutations in the coding region of the GJB6 gene do not result in hearing impairment. The large genomic deletions in GJB6, especially GJB6-D13S1830, alters a cis-acting element and subsequently abolishes the expression of the cis-GJB2 allele [GJB6 gene itself plays no role in the development of hearing impairment but the surrounding sequences consisting of the cis-acting elements are responsible for the development of hearing impairment [GJB2 and GJB6 variants are rarely implicated in hearing impairment [GJB2 cases found in Morocco [GJB2 mutation (p.Arg143Trp) in the homozygous state accounts for 25.9% of cases in families segregating non-syndromic HI, as well as 7.9% of non-familial non-syndromic congenital HI cases . This Ghanaian exception, in the African context, is predominantly due to a GJB2 founder mutation (p.Arg143Trp), which was first reported in a village known as “the deaf village”, Adamorobe [Globally, the most prevailing sensorineural disorder is hearing impairment (HI) , which a2 allele ,5. Thus,pairment ,8 with s Morocco ,10, Suda Morocco , yet an  Morocco ,13,14. Idamorobe . As of 2damorobe . In thisGJB2 (p.Arg143Trp) variant in Ghana has created the need to develop a simple tool for testing in order to support appropriate informed counselling and planning for appropriate interventions. To develop molecular diagnostic tools for screening non-syndromic HI, there is a need for utilizing population and ethnic specific genetic markers due to the ethnically diverse nature of hearing impairment genes [GJB2 is prevalent. Specific genetic tests have been developed for carrier testing and prenatal diagnoses for GJB2-35delG variant in Caucasian populations [GJB2-p.Arg143Trp genotyping in Ghana.The exceptionally high proportion of nt genes ,18. Recent genes ,20. Thernt genes ,22,23, wulations ,25. In tThe study was performed in accordance with the Declaration of Helsinki. Ethical approval for the study was obtained from the Noguchi Memorial Institute for Medical Research Institutional Review Board (NMIMR-IRB CPN 006/16-17) and the University of Cape Town’s Faculty of Health Sciences’ Human Research Ethics Committee (HREC 104/2018). Written and signed informed consent was obtained from all participants who were 21 years of age or older, and from parents or guardians in cases of minors, with verbal assent from participants, including permission to publish photographs. Z through to 8000 HZ and the bone conduction from 250 HZ through to 4000 HZ. The pure tone average was determined using thresholds at 500, 1000, 2000, and 4000 HZ.Congenital hearing-impaired patients were recruited from schools for the deaf and from the Adamorobe community following procedures reported previously . BrieflyThe study participants were categorized into three groups: (1) deaf community-based familial cases, (2) nation-wide isolated/non-familial cases, and (3) control individuals without a personal or family history of HI. The first group was made of families segregating HI, with at least two affected individuals and with evidence of non-environmental causes. In this group, 30 study participants from 8 families segregating hearing impairment were recruited from the Adamorobe community in the Eastern Region of Ghana. Out of the 30 participants, 20 were hearing-impaired and 10 participants had normal hearing. Apart from the families with putative genetic etiology of hearing loss, an additional family was found to have a putative environmental etiology of the condition and was excluded from the study. The second group of participants was made up of 111 isolated/non-familial cases of unrelated probands with putative genetic causes of hearing impairment and were recruited from 6 schools for the deaf across Ghana. All the affected individuals  considered for the study had congenital non syndromic HI. The third group (the control group) was made of 50 normal hearing participants that were randomly recruited nationwide from the Ghanaian population. DNA extraction: Venous blood was collected from each participant and DNA was extracted from the blood samples using a QIAamp DNA Blood Maxi Kit  in the Laboratory of West African Centre for Cell Biology of Infectious Pathogens (WACCBIP), University of Ghana, Accra, Ghana. GJB2 (exon 2) and GJB6, as described by Bosch et al. in 2014. The annealing and extension temperatures for the PCR were 60 °C and 70 °C for 30 s and 1 min, respectively. The PCR amplicons were Sanger sequenced as described by Bosch et al. [GJB6-D13S1830) was performed as previously described, using primers and methods by del Castillo et al. [Polymerase chain reaction (PCR) and Sanger sequencing: At the Division of Human Genetics, University of Cape Town, specific primers  were useh et al.  using ano et al. . GJB2 gene was investigated using RFLP technique designed as follows. GJB2-specific primers [GJB2-p.Arg143Trp NciI-RFLP design including the cut sites is illustrated in Restriction fragment length polymorphism (RFLP) technique: The p.Arg143Trp variant in the  primers  were useGJB2-p.Arg143Trp genotypes. Tukey’s multiple comparisons test was used to compare between the GJB2-p.Arg143Trp genotypes. The specificity and sensitivity of the RFLP test were calculated as described by Schrauwen et al. [Data from the study was inputted into Microsoft Excel and analyzed with GraphPad Prism version 6. One-way analysis of variance (ANOVA) was used to determine the differences between the mean hearing measurements (pure tone average) of the different n et al. .In this study, 8 families from Adamorobe were found to have 2 or more family members living with hearing impairment , from whGJB2-p.Arg143Trp variant was PCR amplified for each participant  variant. In the eighth family were two individuals affected by HI, one was heterozygous (CT) and the other had the CC genotype .The molecular analysis using genotype B. In ordSeven (7) out of the 10 family members without hearing impairment were heterozygous (CT), thus having the p.Arg143Arg/p.Arg143Trp variant, while the rest had the p.Arg143 variant A. GJB2 variants [GJB2-p.Arg143Trp NciI-RFLP test. GJB2-p.Arg143Trp NciI-RFLP test was found to have 100% sensitivity compared to Sanger sequencing as the gold standard. To examine the clinical applicability of the test, 50 control participants with normal hearing were screened and found negative for the GJB2-p.Arg143Trp variant.A total of 111 individuals with non-familial isolated non-syndromic HI, whose samples were previously Sanger sequenced for variants , were anGJB2-p.Arg143Trp genotypic classification of the familial cases from Adamorobe, the pure tone average of homozygous mutant (TT) ranged from 97 to 108 dB with a mean of 105.4 and 107.3 dB in the left and right ears, respectively. The pure tone average range for the heterozygote (CT) was from 17 to 108 dB, with a mean of 43.6 and 40.6 dB in the left and right ears, respectively. The range for the homozygous CC genotype (p.Arg143Arg) was from 18 to 108 dB, with the mean 53 and 46.5 dB in the left and right ears, respectively. There was a statistically significant difference between the audiometric measurements of the TT and CT genotypes in both ears. Similarly, in both ears, there was a statistically significant difference between the TT and CC genotypes (On the basis of enotypes . GJB2-p.Arg143Trp (rs80338948). The GJB2-p.Arg143Trp variant results from a pathogenic point mutation (c.427C > T) in the exon 2 of the connexin 26 gene on chromosome 13 [GJB2-p.Arg143Trp, is the most common variant associated with hearing impairment in Ghana [This study designed a restriction fragment length polymorphism (RFLP) test for effective screening of in Ghana ,13,14. The use of next generation sequencing (NGS) has been proposed as the best tool for the discovery of hearing impairment genes , especiaGJB2-p.Arg143Trp) in Ghana. Accuracy, sensitivity, specificity, and predictive values are critical parameters considered for the clinical use of a test [GJB2-p.Arg143Trp NciI-RFLP test had good positive and negative predictive values for genotyping of the GJB2-p.Arg143Trp variant in the Adamorobe participants from Ghana, and also in a nationwide sample of unrelated affected individuals. Nevertheless, the test cannot differentiate between other variants within the recognition site of the restriction enzyme; hence, similar results would be obtained for the following pathogenic mutations: p.Phe142Leu (c.426C > A), p.Y142del (c.424_426delTTC), and p.Arg143Gln (c.428G > A). To confirm the specific mutation at the enzyme restriction site, Sanger sequencing would be needed. However, the high prevalence of the GJB2-p.Arg143Trp variant within the Ghanaian population makes the NciI-RFLP test relevant. A 100% sensitivity was obtained for the GJB2-p.Arg143Trp NciI-RFLP test when compared with the gold standard, Sanger sequencing. Although a single gene test for hearing impairment is inefficient for many populations [GJB2-p.Arg143Trp NciI-RFLP test would therefore be of great clinical value in Ghana. For the first time, we designed and tested the effectiveness of RFLP, using the NciI enzyme, to screen for the founder mutation , except in one family where one affected individual was heterozygous (CT) and the other without any variant (CC), suggesting that there are other genes still to be discovered to explain the HI in this family. Similar to a family from Japan [GJB2-p.Arg143Trp variant in the above family did not segregate with the HI phenotype  are now known to be pathogenic through the modification of GJB2 expression [GJB6 variant that might disrupt the cis-acting element. We therefore investigated GJB6 variants in particular; GJB6-D13S1830 and no GJB6 pathogenic variant was identified in this family. Hence, we propose the use of whole exome sequencing (WES) in future, or targeted panel sequencing, which has been shown to be efficient in Cameroonian families [GJB2-p.Arg143Trp variant in Ghana. The om Japan , the hethenotype B. Varianpression ,6. Hencefamilies , to furtGJB2-p.Arg143Trp variant is known to be associated with profound HI [GJB2-p.Arg143Trp homozygous individuals showed that they had profound HI. Previous studies by Brobby et al. from the same village indicated that GJB2-p.Arg143Trp homozygous individuals express profound hearing impairment [GJB2-p.Arg143Trp [found HI ,14,37. Tpairment . Similarpairment , we founrg143Trp ,13,14. GJB2-p.Arg143Trp founder mutation in Ghana. The GJB2-p.Arg143Trp NciI-RFLP test had 100% sensitivity when compared with Sanger sequencing, the gold standard. We therefore propose that testing for GJB2-p.Arg143Trp variant using the NciI-RFLP test should be implemented as part of the newborn hearing screening program in Ghana, a practical case scenario of enhancing genetic medicine in Africa. We developed a rapid and cost-effective NciI-RFLP test for the


Retinal diseases are very difficult to treat. So, early diagnoses and preventions are very important. But, few eye doctors can treat patients with retinal diseases in Nepal. Retina Eye Care of Nepal (RECON) project was designed to strengthen retina eye care services in Nepal.RECON was implemented from May 2016 to February 2019 in Nepal. Four Master Eye Doctors (MED) received Training of Trainers (TOT) from Tokushima University, Japan. MEDs developed training materials for different cadres of ophthalmic human resources, enhanced retina eye care facilities, and conducted retina-screening camp in Nepal.Twenty ophthalmologists, 16 optometrists, 48 ophthalmic assistants and 17 ophthalmic nurses, 76 physicians and 28 health workers were trained in retina care. Eight outreach retina camps were conducted.The project was a novel approach to strengthen retina services in Nepal. The aim of the project was accomplished with the ultimate benefits to the needy retina patients who otherwise were going to miss the retina services. Recently causes of blindness are changing in Nepal. The number of people blind due to retinal diseases is increasing. Age-related macular degeneration (AMD), diabetic retinopathy (DR), hypertensive retinopathy, and retinal vein occlusion are the major retinal problems in Nepal. As the prevalence of vitreoretinal disorders is increasing with age, it indicates that retinal disorders will be a major public health issue with longevity in future .A rapid assessment of blindness conducted in 2010 had reported posterior segment problems as the second common cause of blindness, after cataract in Nepal . So, earThe projected population of Province 3 and 4 in Nepal were 60, 26,626, and 24, 72,494 respectively in the year 2016 . There aRetina Eye Care of Nepal (RECON) project was a joint program of BP Eye Foundation, Kathmandu, Nepal, and Tokushima University, Japan to strengthen 3 retina centers in Province 1 and 1 retina center in province 4. The project duration was from May 2016 to February 2019. The purpose of RECON was to strengthen retina eye care services in Nepal by training ophthalmic human resources, enhancing retina eye care facilities, and conducting retina-screening camp.RECON established a unique approach to accomplish its objectives Fig. .Fig. 1AFour eye institutes, Hospital for Children, Eye, ENT & Rehabilitation Services (CHEERS) located at Bhaktapur district, Himalaya Eye Hospital (HEH) located at Kaski district, Nepal Eye Hospital (NEH) and BP Koirala Lions Club of Ophthalmic studies (BPKLCOS), located at Kathmandu district were selected as the partner retina centers. CHEERS and HEH had one retina specialist each and NEH and BPKLCOS had two retina specialists each at the time of project execution. Four Retina specialists, one from each partner retina center of Nepal received one-month Training of Trainers (TOT) in retina care from Tokushima University of Japan in the first year of the project and got a certificate of Master Eye Doctor (MED).MED also received advanced retina training for 2 weeks at Kindai University and the Tokushima University of Japan at the beginning of the 3rd year of the project.All partner retina centers already had vitrectomy machines and laser facilities. Vitreoretinal procedures were already in functional states at all retina centers except at CHEERS. Moreover, BPKCLOS and NEH located at the capital city already had residency programs. HEH is located outside of the capital city while CHEERS is a new hospital at Bhaktapur, within close premises of the capital city. The project supported fundus photography machines, ophthalmic ultrasonic imaging, wide-angle viewing system, and cryo machine to these partner eye institutes. MEDs started strengthening of retina clinics with knowledge and skills gained during TOT in retina care from Tokushima University.MEDs conducted first continuing medical education (CME) on retina eye care with facilitators and visiting retina experts from Tokushima University to the targeted ophthalmologists with a focus on retina force networking. Second CME was on developing vitrectomy in Nepal.These MEDs prepared training materials on retina management for different cadre of ophthalmic human resources including general ophthalmologists, optometrists, ophthalmic assistants, ophthalmic nurses, and female community health volunteers. These MEDs already provided two weeks retina training for ophthalmologists, one-week training for optometrists, ophthalmic assistants, and ophthalmic nurses from different eye institutes of Nepal. The training included early detection and prompt referral of retinal diseases from the community to the retina training centers.Portable fundus camera, binocular and monocular indirect ophthalmoscope with 20 dioptre convex lenses were used to screen the retinal diseases at eye camps. The patients with retinal diseases found at eye camps were sent to the respective retina centers for further treatment. Retina camps were conducted in partnership with local health clubs, municipalities, or nongovernment organizations. Each camp shared the task among different cadres of health care workers including MED, optometrist, ophthalmic nurse and ophthalmic assistant. MED performed fundoscopy and advised for further treatment, optometrist performed fundus photography, ophthalmic nurses helped in counseling and ophthalmic assistant helped in taking vision, pupil dilation, and history taking.Table Recently, retinal disease is also regarded as a public health concern in the developing world. There have been improved and cost-effective treatment options available for retinal problems even in a developing world. However, a significant challenge still is the shortage of skilled human resources. There is an observed and felt need for more ophthalmic health force with subspecialty training in retinal disease who can train future generations of eye workers in this mid and low-income countries .A significant barrier was the practice of setting up a screening system without adequate treatment facilities being in place . In our The general practitioners and physicians are often the first medical personals to see the patients with diabetes. There are varying levels of awareness about diabetic retinopathy among physicians. This is very crucial as they are the ones referring patients with diabetes to ophthalmologists. It is not surprising to see an unsatisfactory level of knowledge and awareness of physicians about the importance of diabetic retinopathy evaluation. Physician’s low level of awareness about diabetic retinopathy is found even in resource-rich settings, and further training is recommended –9.Most Eye camp is widely practiced in all over Nepal. To add the retinal disease screening at eye camps is very useful for the prevention of retinal diseases. Retina camps were the means of eye health education, eye examinations, fundus photography to patients in our project.The conclusion from Bhakapur retina study in Nepal highlighted the real world scenario about retinal diseases in Nepal. The high prevalence of retinal diseases, low awareness on major blinding retinal diseases in the population and high risk groups warrants the prompt attention for awareness campaigns, retinal diseases screening, using allied ophthalmic personnel and allied medical personnel using fundus cameras, proper referral network to tertiary eye hospitals, cross referral with the physician for diseases like diabetes, and hypertension and facilities for treatment of these diseases are required for the prevention of avoidable blindness from these major retinal disorder .In our retina camps, apart from direct beneficiaries who got free consultation in retina camps, there were many indirect beneficiaries in the community. Awareness of diabetic and hypertensive retinopathy and other retinal diseases were the main aims of retina camp. This is a good step of advocacy for early detection and prompt treatment to prevent retina related visual blindness in Nepal.The comprehensive campaigns are necessary to promote increased awareness in a community by involving people from various walks of life in collaboration with community eye centres and eye hospitals. Improving awareness will help in early detection of diseases and reduction in visual impairment and blindness .RECON was a novel approach to strengthen retina services in Nepal. The aim of the project was the ultimate benefits to the needy retina patients who otherwise were going to miss the retina services. There was a strengthening of retina eye care of all these retina centers. The project focused on the training retina workforces, enhancing retina care by easy access and improved services and awareness to even grass root level in the community by conducting retina-screening camp. We recommend further similar type of strategy in different provinces of Nepal to combat retinal-related blindness in the future.


It is well-known that aminoglycoside antibiotics can cause significant hearing loss and vestibular deficits that have been described in animal studies and in clinical reports. The purpose of this review is to summarize relevant preclinical and clinical publications that discuss the ototoxicity of non-aminoglycoside antibiotics. The major classes of antibiotics other than aminoglycosides that have been associated with hearing loss in animal studies and in patients are discussed in this report. These antibiotics include: capreomycin, a polypeptide antibiotic that has been used to treat patients with drug-resistant tuberculosis, particularly in developing nations; the macrolides, including erythromycin, azithromycin and clarithromycin; and vancomycin. These antibiotics have been associated with ototoxicity, particularly in neonates. It is critical to be aware of the ototoxic potential of these antibiotics since so much attention has been given to the ototoxicity of aminoglycoside antibiotics in the literature. Aminoglycoside antibiotics are well-known to cause ototoxicity, particularly hearing loss. Other antibiotics can also cause significant ototoxicity but the effects of these drugs on hearing and balance have not received the same widespread attention as have the aminoglycosides. This paper reviews the ototoxicity of other antibiotics to emphasize that these drugs also can cause hearing loss and balance disturbances. The antibiotics included are capreomycin, erythromycin, azithromycin, clarithromycin and vancomycin. This review was carried out by searching PUBMED using the following search terms: capreomycin ototoxicity, erythromycin ototoxicity, azithromycin ototoxicity, clarithromycin ototoxicity, macrolide ototoxicity, vancomycin ototoxicity and chloramphenicol ototoxicity.Streptomyces capreolus  compared with capreomycin (4.2%) . IncreasA prospective and retrospective study of 60 patients treated for MDR-TB with aminoglycosides or capreomycin at two hospitals in India from 2011 to 2016 found that 20% of capreomycin treated patients demonstrated permanent high frequency sensorineural hearing loss. Ototoxicity was associated with a large cumulative dose and older age . RecordsThe Uppsala Monitoring Center (UMC) is the World Health Organization Collaborating Center for international drug monitoring. It maintains a repository of data on adverse drug reports from around the world known as VigiBase®. This database contains individual case safety reports (ICSRs). The UMC conducted a study of patients treated with aminoglycosides or capreomycin for the treatment of drug-resistant TB who developed ototoxicity related to treatment. They analyzed all ICSRs in VigiBase® from 56 countries, mostly from Asia and Europe between 1968 and June 2014 where these drugs were administered. Authors utilized logistic regression analysis to determine the association between the administration of parenteral antibiotics in the treatment of tuberculosis and the reports of ototoxicity. The magnitude of the association was expressed as the reporting odds ratio (ROR), with 95% confidence intervals (CI). The ROR was used to determine relative risks for ototoxicity. RORs of ototoxicity and the suspected drug revealed that capreomycin administered to 117 patients showed an ROR for deafness of 1.4 (CI = 0.4–4.5) relative to streptomycin, which was the index drug for comparison. Amikacin and kanamycin were found to have much higher RORs than capreomycin . OverallA recent large scale meta-analysis of 35 studies comprising 9,178 patients with reports of significant adverse events associated with treatment of rifampin-resistant or MDR-TB was carried out using data from 53 centers in more than 30 countries. The highest rates of adverse effects leading to permanent drug discontinuation were found in patients treated with injectable antibiotics including aminoglycosides, capreomycin, amino-salicylic acid and linezolid. Of 1,932 patients treated with capreomycin, 161 experienced adverse events that resulted in stopping treatment. Only 71 cases reported specific adverse effects resulting in discontinuation of treatment. Twelve of 71 (17%) of those treated with capreomycin suffered hearing loss . ConsideEarly animal studies showed that long-term treatment with capreomycin in dogs and cats resulted in deafness in both species and vestibular injury in cats, demonstrated by reduction in post-rotatory nystagmus and severe ataxia just prior to death . The exaStreptomyces erythreus  and cochlear microphonics (CM) in the basal turn of the cochlea. Complete recovery of both EP and CM within 20 min after erythromycin dose was completed. In contrast to the effects of intravenous injection, the perilymphatic perfusion of erythromycin resulted in nearly complete loss of the CM and the decrease of both CM and EP was irreversible . These fnner ear . Some henner ear .The only published human temporal bone study of erythromycin ototoxicity presents findings that are consistent with the experimental findings in guinea pig cochlea discussed above. The finding of strial edema in all cochlear turns in the human temporal bone specimen suggests that strial dysfunction resulting from inhibition of K+ secretion could account for the observed hearing loss. Stria vascularis dysfunction could explain the flat threshold loss with good speech discrimination that is frequently found in patients with erythromycin ototoxicity, and it can also account for the reversible nature of the hearing loss .Guidelines have been issued for prevention of erythromycin ototoxicity: (1) elderly individuals and patients with reduced liver or kidney function should have pretreatment audiograms and follow-up testing during or after treatment if symptoms occur; (2) care should be taken when erythromycin is treatment is combined with other ototoxic drugs; (3) doses of erythromycin should not exceed 1.5 g daily if serum creatinine is >180 mol/L .The decline in the reported incidence of ototoxicity from erythromycin in recent years may result from adherence to the above guidelines and the development of new macrolide antibiotics like azithromycin and clarithromycin that have probably supplanted the use of erythromycin to a large extent.Azithromycin and clarithromycin are alternatives to conventional macrolides like erythromycin in the routine treatment of many dermatologic, upper respiratory, and lower respiratory tract infections. They are tolerated better, less toxic, and more convenient to take. Their use may provide better patient compliance .A clinical trial of 29 HIV negative patients, receiving only azithromycin 600 mg daily for 4 months followed by 2 months of azithromycin plus streptomycin for the treatment of MAC-associated lung disease. Three patients treated with azithromycin alone complained of hearing loss confirmed by audiograms. Hearing loss resolved after reducing the dose of azithromycin. Another 9 patients suffered hearing loss. However, they were also receiving streptomycin for 2 months . A groupMycobacterium avium infections related to acquired immunodeficiency syndrome (AIDS). An HIV positive patient was treated with azithromycin 500 mg daily for several months for Mycobacterium avium complex (MAC) and Mycobacterium kansasii-associated pneumonia. He developed decreased hearing, bilateral tinnitus, and dizziness. An audiogram showed moderate to severe SNHL that improved over 3 weeks after stopping azithromycin (Many patients experienced reversible SNHL following prolonged high-dose therapy for hromycin . Among ahromycin . A retrohromycin .p = 0.04). Hearing improved to baseline in 21/61 (34%) patients who discontinued azithromycin . They were treated with azithromycin 250 mg daily for 1 year to test the hypothesis that this drug would decrease the frequency of acute exacerbations. SNHL was confirmed by audiogram in 142 (25%) of subjects receiving azithromycin, compared with 110 patients who received placebo (20%)  was 1.168 ) . An analCaution is advised in the treatment of SARS-CoV-2 with the combination of azithromycin with hydroxychloroquine, since both drugs have been shown to be ototoxic .The ototoxicity of azithromycin was tested in guinea pigs. Oral administration of azithromycin caused a reversible reduction in transient evoked otoacoustic emissions (TEOAEs). These findings suggest that azithromycin may exert transient ototoxic effects on outer hair cells. The use of TEOAE monitoring may be helpful in clinical studies of patients receiving prolonged or high doses of azithromycin .Another study utilized topical application of various concentration of azithromycin solutions to the middle ear. Inner hair cells in the basal turn were severely damaged to a greater extent than were the outer hair cells in a concentration-dependent manner .Very little is known about the mechanisms of ototoxicity of azithromycin. Animal studies discussed above suggest that azithromycin may act on outer hair cells to cause transient dysfunction with systemic treatment. Topical middle ear application resulted in severe preferential damage to inner hair cells. No mechanisms have been proposed for azithromycin ototoxicity.Mycobacterium avium complex (MAC) infections  demonstrated a mild, persistent SNHL on audiometric testing during the 2nd week of treatment. The authors attributed the ototoxicity to the high dose of clarithromycin  (Clarithromycin (6-O-methyl-erythromycin A) was developed in Japan in 1980 to improve upon the profile of erythromycin. It is acid stable, causes fewer gastrointestinal side effects, and has a longer half-life than erythromycin. It can be administered twice a day instead of four times a day . This infections . A studyhromycin . One hunts (22%) .M. avium-associated lung disease received treatment with clarithromycin  either alone or in combination with rifampin, an aminoglycoside (one patient), a quinolone, clofazimine, isoniazid, ethambutol, pyrazinamide, or minocycline. Twelve of these patients demonstrated baseline hearing impairment. Several had been previously treated with streptomycin. Four of the 12 (33%) patients developed additional hearing loss during treatment that was not severe enough to discontinue drug therapy . The drug was discontinued in one patient whose hearing problem had been diagnosed clinically, and his hearing was restored. The drug regimens of the remaining seven patients with hearing loss were not changed since the impairment was not severe  disease were treated with clarithromycin (0.75–2g/day), minocycline and clofazamine for 15 months. Three patients (3/22) developed ototoxicity requiring a reduction in the dose of clarithromycin by 50% after a short interruption of treatment. Audiograms were performed before treatment and after 1, 2, 3, and 6 months of treatment and when patients showed signs of hearing deterioration  in the group treated with clarithromycin suffered hearing loss >25 dB and no patient had vestibular toxicity  pediatric patients receiving prolonged clarithromycin therapy for the treatment of non-tuberculous mycobacterium (NTM) cervicofacial lymphadenitis. Hearing loss developed between 25 and 63 days after initiation of treatment. HL was unilateral in two children and persisted in one child after treatment was discontinued . Based oA recent study analyzed ADR reports of ototoxicity from the Italian spontaneous reporting system (SRS) from 2001 to 2017. The authors measured disproportionality by calculating the reporting odds ratios (RORs) and 95% confidence intervals (CIs) with a case/non-case methodology. Clarithromycin  demonstrated a statistically significant disproportionality for the onset of hearing loss . Thus, cp < 0.05). The temporary diminution of TEOAE could likely be attributed to the transient dysfunction of outer hair cells (OHCs) (The mechanism of ototoxicity associated with clarithromycin is unknown. Experiments in the guinea pigs administered clarithromycin 75 mg/kg i.v. reversible reduction of transient evoked otoacoustic emissions (TEOAEs) (s (OHCs) .Publications dealing with ototoxicity risk from macrolides searched large data bases and came to opposite conclusions. A retrospective nested case-control study of a health claims database, the LifeLink  was carried out. A random selection of patients aged 15–60 years old from 2006 to 2014 was performed. The authors found an association between SNHL and macrolide. However, a similar risk was found for case controls treated with non-ototoxic antibiotics. The authors concluded that there did not appear to be an increased risk of SNHL in patients treated with macrolide antibiotics . HoweverA systematic review of the literature was accomplished. The authors reviewed 44 publications, describing patients of all ages. Three were prospective and 41 were retrospective studies. The authors summarized 120 cases of hearing loss associated with macrolide drug administration. Seventy-eight cases were SNHL confirmed audiometrically. Nine additional publications described 42 cases of subjective patient-reported hearing loss that was associated with oral or intravenous macrolide administration at standard and elevated doses. The authors concluded that SNHL may follow macrolide exposure, even at standard oral doses . It appeA recent review of ototoxic drugs in Italy showed a significant association of ototoxicity with the individual macrolides azithromycin and clarithromycin . These aThis has been covered s under erythromycin, azithromycin and clarithromycin.Staphylococcus aureus (MRSA) infections . Three of these patients were receiving ototoxic medications (one on gentamicin and two on furosemide), but this incidence was not significantly different than that for the group of patients without audiometric testing . Regression tree modeling revealed that for patients <53 years old, no patients had detectable hearing loss. However, among patients >53 years old, the incidence was 19%  exhibited SNHL Two patients had mild hearing loss. Two suffered mild to moderate loss and three showed moderate to severe SNHL. No variables were correlated with SNHL, including age >40, pretreatment SNHL, vancomycin doses >4 g/day or elevated serum levels of vancomycin . Serum cClostridium difficile colitis  cochlear potential showed a small change after gentamicin 50 mg/kg alone. However, when the same dose of gentamicin was combined with vancomycin, a highly significant diminution of the AC cochlear potential occurred. Animals treated with 100 or 200 mg/kg had no significant loss of OHCs, nor did those guinea pigs receiving 50 mg/kg of gentamicin sulfate alone. However, combinations of 100 or 200 mg/kg of vancomycin with gentamicin had a dramatic increase in the loss of cochlear OHCs.Vancomycin combined with gentamicin did not increase the serum or perilymph levels of gentamicin. The authors postulated that vancomycin may cause a selective accumulation of gentamicin in hair cells by increasing the permeability of these cells . This hyChloramphenicol was isolated from soil bacteria, an actinomycete, from compost soil. It was later synthesized . ChloramA case report described a patient who suffered gradually progressive sensorineural hearing loss after systemic treatment with chloramphenicol. It began in one ear, but when the course of treatment was repeated, the second ear became involved. Hearing loss progressed to profound bilateral SNHL in this patient .Additional cases have been reported. Forty-nine cases of ototoxicity were reported from the University of Benin in Nigeria. Almost half of these patients received chloramphenicol (21/49 or 43%). Most of the chloramphenicol treatments were parenteral. Hearing loss was severe to profound, bilateral and permanent in 66% of these cases . A laterChloramphenicol ototoxicity has been studied in guinea pigs and in cats. In guinea pigs that had the drug applied to the round window membrane, permanent loss of cochlear microphonics of up to 30 dB was recorded . ChloramCats treated with saturated chloramphenicol solution on gelatin sponge on the round window demonstrated a permanent reduction of CM responses. However, the threshold elevations were not as severe as in the guinea pig .The mechanism of chloramphenicol ototoxicity is unknown.It is important to be aware that antibiotics other than aminoglycosides can cause hearing loss. These antibiotics can play a critical role in the treatment of life-threatening infections in patients with infections caused by bacteria that are resistant to standard therapy. Additional research is needed to determine the mechanisms by which these drugs can cause ototoxicity.LR conceived the idea for the review presented in this article and wrote the main text. VR and DM helped with research and compilation of the manuscript. All authors contributed to the article and approved the submitted version.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.