This study aimed to select the optimal hearing aid compression speeds (fast-acting and slow-acting) for presbycusic patients by using auditory characteristics including temporal modulation and speech-in-noise performance.In total, 24 patients with unilateral or bilateral moderate sensorineural hearing loss who scored higher than 21 on the Montreal Cognitive Assessment (MoCA) test participated in this study. The electrocochleogram (ECochG) results, including summating potentials (SP) and action potentials (AP), were recorded. Subjects' temporal modulation thresholds and speech recognition at 4 individualized signal-to-noise ratios were measured under three conditions, namely, unaided, aided with fast-acting compression (FAC), and aided with slow-acting compression (SAC).p = 0.12). A decision tree analysis showed that the inclusion of the AP, unaided modulation thresholds, and unaided SRT75% may correctly identify the optimal compression speeds (FAC vs. SAC) for individual presbycusic patients with up to 90% accuracy.The results of this study showed that modulation discrimination thresholds in the unaided (−8.14 dB) and aided SAC (−8.19 dB) conditions were better than the modulation thresholds in the FAC (−4.67 dB) conditions. The speech recognition threshold (SRT75%) for FAC (5.21 dB) did not differ significantly from SAC (3.39 dB) (Both modes of compression speeds improved a presbycusic patient's speech recognition ability in noise. The SAC hearing aids may better preserve the modulation thresholds than the FAC hearing aids. The measurement of AP, along with the unaided modulation thresholds and unaided SRT75%, may help guide the selection of optimal compression speeds for individual presbycusic patients. Hearing affects people's quality of life. Presbycusis, or age-related hearing loss (ARHL), is a degenerative change of the auditory system associated with aging, often accompanied by decreased speech recognition of noise . Previous studies proposed that the reduced temporal processing ability of the elderly hearing-impaired listeners may account for some of the difficulties , namely, low SR fibers and high SR fibers, which accounted for 40 and 60% of the total nerve fibers, respectively  who were treated at Peking University First Hospital for hearing problems between March 2019 and June 2021. All patients have signed informed consent. Mandarin was their native language. Patients completed their medical case history intake and standard audiometry . The Montreal Cognitive Assessment (MoCA) was also administered to rule out significant cognitive impairment.The demographic details and audiometry results are shown in Two hearing aids with different modes of compression speeds were compared. The first was a 15-channel hearing aid that primarily uses SAC. It uses an adaptive attack time of <2 s and a release time of <20 s. The second was a 16-channel hearing aid that was used in the “syllabic compression” mode during this study . Other than the compression algorithm, all other features within the hearing aids were deactivated during the study. Both hearing aids were fitted to the NAL-NL2 target by the same experimenter and verified using real-ear measurement to ensure that the target output between the two hearing aids was matched to within 3 dB at 500–4,000 Hz.Because subjects were patients seeking hearing treatment, and binaural hearing aids, despite the clinicians' recommendations, were not a common practice in China, subjects were fitted and studied monaurally in the ear with a moderate-to-severe hearing loss. If both ears had moderate-to-severe sensorineural hearing loss, the test ear was randomly selected. The order of hearing aids tested was randomized. Subjects were blinded to the test hearing aids.Temporal resolution was measured using a temporal modulation discrimination test written by the School of Electronics Engineering and Computer Science at Peking University. The test stimuli were cosine modulated sinusoids with a carrier frequency at 1 kHz and a duration of 600 ms. The default modulation rate for the amplitude modulation was 4 Hz. The standard stimuli were modulated at a modulation depth of −15 dB. The target modulation depth was initially set to −3 dB and adaptively varied in 2 dB and then 1 dB steps using a two-down one-up rule. The RMS level of the standard and target stimuli was normalized and roved at ±2 dB. A three alternative forced choice (3AFC) paradigm was used in which subjects selected the interval that sounded different. A modulation threshold of “0” would suggest 100% modulation or poor temporal resolution, whereas a more negative modulation threshold  would suggest a better temporal resolution. The unaided modulation threshold was measured at 85 dB SPL, while the aided thresholds were measured at a stimulus level of 80 dB SPL.Speech recognition in noise was evaluated using the computer-aided Chinese speech audiometry platform  were first performed along with ECochG. MoCA was administered to ensure no significant cognitive impairment. The two test hearing aids were then fitted before their amplitude modulation discrimination thresholds and speech-in-noise performance was measured under three conditions, namely, unaided, aided with FAC, and aided with SAC, in random order. Patients are blinded to the identity of the hearing aids. After the initial decision tree analysis, another 10 listeners (see later) were enrolled to verify the accuracy of the decision tree prediction.Testing on speech recognition, amplitude modulation was conducted in a soundproof room with the stimuli presented directly in front of the subject by a soundbox. Stimuli intensity was measured by a sound pressure meter at 85 dB SPL during the unaided condition and 80 dB SPL in the aided condition with FAC and SAC (OTO suite was used as the test computer system). Subjects were tested monaurally with the non-test ear occluded with an earplug (made by OHRFRIEDEN with attenuation factor < 32 dB). Amplitude modulation discrimination thresholds were determined first, followed by a 10-min break before the speech in noise measurement was conducted. During each test, subjects were tested in the unaided, aided with FAC, and aided with SAC conditions in random order.t-tests were conducted. Python3.8 is used for statistical analysis based on sklearn and stats models. P < 0.05 is considered to be statistically significant.All the data were normally distributed, and standard independent All protocols for this study were conformed to the Declaration of Helsinki and approved by the Biomedical Research Committee of the Peking University First Hospital (2020-219). The patients/participants provided their written informed consent to participate in this study.The individual temporal modulation thresholds are summarized in t-test showed that the unaided modulation threshold and the aided modulation thresholds measured in the SAC were better than that using FAC. There was no significant difference in modulation thresholds between the unaided and aided SAC conditions. Thus, the acoustic changes resulting from different compression speeds can influence an individual's measured temporal resolution.The mean unaided and aided modulation thresholds were reported in Logistic functions were fitted to each individual subject's data at the 4 individualized SNRs for each test condition. In generating the logistic functions, we assigned a performance of 0% when the SNR was −10 dB and 100% when the SNR was 30 dB. The generated logistic functions, which represent the subjects' performance across a range of SNRs for each hearing aid condition , are summarized in Using this function, we estimated the speech reception threshold (SRT) at a criterion level of 75% (SRT75%) to reflect more closely on the SNR condition that subjects needed for successful daily communication in real life . A decision tree is a supervised learning algorithm intended to produce a classification for a new object whose characteristics are known. Every inner node of the tree is labeled as a test, which compares the input attribute to a threshold, and every terminal node is labeled as a category. To obtain a classification for a new object whose attribute values are known, we could put it in the tree from the top node. When a terminal node is reached, the object's classification would have been defined  and that using SAC (sSRT75%) to compare their relative efficacy. As the 95% confidence interval on the SRT75% data was estimated at 0.156, 1 ± 0.156 was taken as the upper and lower limit of the confidence interval. Thus, when fSRT75%/sSRT75% > 1+0.156, SAC yielded a lower SRT and was judged better. When fSRT75%/sSRT75% < 1–0.156, FAC yielded a lower SRT and was thus better. When 1 + 0.156 ≥ fSRT75%/sSRT75% ≥ 1–0.156, the efficacy of the two hearing aids was judged similar. Based on this analysis, 1 subject performed better (ratio < 0.844) with FAC, 12 subjects performed better with SAC (ratio > 1.156), and 11 subjects had similar hearing performance between two compression speeds (ratio between 0.844 and 1.156). This finding may also explain the non-significant difference in SRT75% measured between SAC and FAC.The decision tree analysis takes known factors that may affect the decision as inputs to generate the steps. According to previous studies, factors that may affect hearing aid performance include gender, age, cognitive level, cochlear ECochG (-SP/AP), SP, AP, PTA, unaided temporal resolution, and unaided SRT75%. These data were input to the model and the most significant factors that affected the decision included PTA, AP value, unaided modulation thresholds, and unaided SRT75%. The probable reasons for these factors were explained earlier in the methods. Of the 24 subjects included in the decision tree, 22 were correctly identified. The decision tree is shown in The decision tree starts with the individual's AP. If the individual's AP is >1.095 μV, the aided SRT75% obtained with SAC and FAC would be similar. Four subjects were identified in this step. When AP ≤ 1.095 μV, the unaided SRT75% should be further compared. When the unaided SRT75% is <7.813 dB, the aided SRT between SAC and FAC should be similar. Five subjects were identified in this step with 4 showing no difference in aided SRT75% between SAC and FAC and 1 better aided SRT75% using FAC. If the unaided SRT75% is ≥7.813 dB, one should proceed to examine the unaided modulation thresholds. When the unaided modulation threshold is ≤-8.062 dB, SAC should yield a better SRT75% than FAC. Seven subjects were identified, of which 6 had a better aided SRT75% with SAC, while the remaining subject performed equally well with SAC and FAC. On the contrary, if the unaided modulation threshold is >-8.062 dB, the impact of hearing loss emerged. When the PTA is ≤ 50.833 dB, SAC yielded a better aided SRT75% than FAC. Six subjects were included in this step, and all had a lower SRT75% with SAC (than FAC). If the PTA is >50.833 dB, the effect of compression speed should be similar. Two subjects were included in this step, and both showed similar aided SRT75% for SAC and FAC.To verify the validity of the decision tree, 10 additional patients were enrolled . Their MoCA scores ranged from 21 to 28, and PTA ranged between 41.7 and 60 dB HL. The same experimental procedure, as mentioned earlier, was followed. The demographic characteristics and audiometric results of subjects are shown in The data of these 10 subjects were included in the decision tree for verification. Nine subjects were correctly identified by the decision tree, with a pass rate of 90%. The judgment process and results are shown in This study showed that the unaided temporal modulation thresholds were preserved using SAC but were degraded using FAC. Aided speech recognition threshold using a 75% criterion (SRT75%) was significantly better than the unaided SRT75%, but not so between SAC and FAC. The unaided SRT75%, unaided modulation thresholds, along with AP and PTA allowed us to perform a decision tree analysis that may help select the optimal compression speed for an individual listener reliably, using the aided SRT75% as a criterion of performance.The unaided modulation thresholds reflect the auditory system's ability to code temporal information. Aging and/or hearing loss alone or in combination can further damage this ability and make decoding of such temporal information difficult. In this study, we have shown that the compression speed could further alter or degrade such ability. In particular, the use of FAC smears the temporal contrast between louder and softer parts of the input sounds to result in poorer modulation thresholds. The use of SAC, on the contrary, preserved the modulation threshold measured in the unaided mode. As modulation thresholds have been reported to reflect speech in noise ability, it would suggest that speech in noise ability, measured as the SNR to reach 75% correct identification, would be poorer with FAC than with SAC. While better SRT75% was observed with SAC than FAC, the difference was non-significant.A plausible reason for the non-significant difference between SAC and FAC may be the mixture of subjects with different residual temporal resolution abilities in this study. If their residual ability is either good or poor, the results of the comparison may be more clear-cut in showing the advantage of one form of compression speed over the other. Indeed, the decision tree analysis revealed that only 11 subjects showed a clearer benefit with SAC and 1 subject showed a clearer benefit with FAC. Notably, twelve subjects were indifferent in their performance between SAC and FAC. Fewer subjects showing indifferent results or more subjects showing performance benefits with one compression speed would likely change our observations and conclusions.In that regard, the decision tree analysis provided good insights into the choice of optimal compression speeds on an individual basis. Rather than concluding that one form of compression speed is universally optimal for all listeners with presbycusis, the decision tree allows one to consider various individual factors  in order to select the most optimal compression speed on an individual basis. If the values reported in this decision tree are further validated in future studies, this could offer an avenue for finer selection of hearing aid parameters and ultimately further improve elderly patients' speech in noise performance with their hearing aids.In this decision tree, AP is taken as the first judgment criterion. Patients with high AP amplitude have a similar SRT75% between FAC and SAC, while in some patients with lower AP, SAC can achieve a better SRT75%. The low AP amplitude of ECochG reflects cochlear synaptopathy or low SR fiber dysfunction and is related to speech perception dysfunction in presbycusic patients. A study found that SAC can attain better speech recognition for children with auditory neuropathy, whose main lesion site is the auditory synapse  that we used. Additional patients could increase the power of our observations and likely provide more robust criterion cutoff values in our decision tree analysis. Second, compression speed is only one important parameter in a compression hearing aid. The compression ratio, or the availability of other signal processing algorithms like noise reduction and directional microphones, could also affect the reported benefit and/or satisfaction toward the hearing aids. A more robust decision tree may also consider those factors. Third, our criterion of “more benefit” is simply the ratio of the SRT75% measured with FAC and SAC. Indeed, a lower SRT75% reflects better speech understanding of noise and is a good measure of benefit. However, other measures of performance such as sound quality, or an SRT at other criteria such as 50% or 90%, may also be a good metric to examine relative performance/benefit. Finally, all participants in this study had moderate-to-severe hearing loss. This may limit the generalizability of the results of the decision tree to other degrees of hearing loss. More subjects with varied hearing levels may be helpful to determine the impact of hearing loss (PTA) on the decision.While we are motivated by the current findings of this study, we also recognized certain limitations to this study. First is the small sample size of patients (yizhangsyx@163.com).The data used to support the findings of this study were supplied by Peking University First Hospital under license and so cannot be made freely available. Requests for access to these data should be made to M.D. Zhang  and the National Natural Science Foundation of China (Grant No: 82071070).BS is employed by Widex Hearing Aid Shanghai Co., Ltd. The remaining 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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Of all the patients, 40.00% had a hearing average threshold that reached ≤25 dB HL after the clinical management period, among whom 27.27% were patients in stage 3. The restoration time was 2.5  months, with a range of 0.5–11.0 months, and the restoration time was longer for stage 3 than for stages 1 and 2 . The rising curves improved the most (p < 0.05), with most becoming peaks, whereas most peaks and flats remained the same. Patients who were initially in the earlier stages , have an increased odds ratio of hearing by an average of ≤25 dB HL. Age , peak curve , and flat curve , compared with the rising curve, increase the odds ratio of hearing on average by >25 dB HL. Most patients can have their hearing preserved or improved through strict clinical management, and sufficient follow-up is also essential. Stage 3 patients also have the potential for hearing improvement, although the restoration time is longer than in the early stages. The initial hearing stage, age, and audiogram pattern are related to the hearing benefits.Meniere’s disease is a progressive hearing–disabling condition. Patients can benefit from strict clinical management, including lifestyle and dietary counseling, and medical treatment. A prospective cohort study was carried out with 154 patients with definite Meniere’s disease, with an average age of 43.53 ± 11.40, and a male to female ratio of 0.97:1. The pure-tone thresholds of all 165 affected ears, over a one-year clinical management period, were analyzed. After one year, 87.27% of patients had improved or preserved their hearing at a low frequency, and 71.51% at a high frequency. The hearing threshold at frequencies from 250 Hz to 2000 Hz had improved significantly ( Meniere’s disease (MD) is a chronic unique inner ear disease associated with endolymphatic hydrops by histopathology, and is characterized by recurrent spontaneous vertigo, fluctuating sensorineural hearing loss (SNHL), tinnitus, and aural fullness . Though The Bárány society defines Meniere’s disease as episodic vestibular syndrome in the International Classification of Vestibular Disorders (ICVD) . The lesThe treatment for Meniere’s disease consists of reducing attacks, relieving symptoms, and preventing permanent damage to hearing. Lifestyle changes, diuretics, vasodilators, corticosteroids, intratympanic therapy, and surgical treatment methods are preferred. Although there is currently no complete cure for Meniere’s disease, clinical management, which includes lifestyle and dietary changes, medical treatment, psychological counseling, or minimally invasive procedures, such as intratympanic steroid therapy, helps most patients ,9,10. ClThe repeated attack, fluctuation, and progression of Meniere’s disease are consistent with the modality of chronic disease; therefore, it also needs to be managed according to the clinical practice of chronic diseases. The importance of lifestyle adjustment is put forward in the guidelines for MD. We conducted a study with a small series of patients and found that the hearing restoration of MD patients takes months; however, that observation period was only three months. A more extended observation was needed. During this observation period, strict clinical management and close follow-ups were needed for practice. In this study, the term “clinical management”, in its broadest sense, refers to the management of the core components of lifestyle adjustment and medical treatment.Moreover, hearing features have rarely been studied and reported in recent years after the treatment and criteria were updated; there is no clear consensus among different studies regarding the characteristics and evolution of audiometric thresholds and the morphology of the audiogram of patients at different stages of Meniere’s disease. In 1995, the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) devised a staging system based on the average hearing threshold of pure-tone audiometry (PTA) . This stThis is a prospective cohort study with pre- and post- intervention comparisons with the same group of patients. These patients were diagnosed with definite Meniere’s disease for whom audiological data were collected in the Hearing and Vestibular Clinic of the Department of Otorhinolaryngology of the tertiary hospital from August 2017 to November 2020. All procedures carried out in studies involving human participants were consistent with the ethical standards of the Ethics Committee of the Hospital.Inclusion criteria: 1) all patients were diagnosed with definite Meniere’s disease according to the diagnostic criteria approved by the Classification Committee of the Bárány Society (2015) [ all patiExclusion criteria: (1) the specified conditions to be excluded include, including vestibular migraines, superior semicircular canal dehiscence syndrome, sudden hearing loss, labyrinthitis, drug-induced deafness, posterior circulation ischemia, schwannoma, definite autoimmune inner ear disease, delayed endolymphatic hydrops, and intracranial tumor. (2) Patients with Meniere’s disease who had received an intratympanic gentamicin injection, endolymphatic sac surgery, semicircular canal occlusion, vestibular neurectomy, or cochlear implant surgery were excluded.Ultimately, a total of 156 patients were enrolled in the study, for two of whom follow-up data were lost for not coming back on time. Finally, the hearing of 165 ears in 154 patients was analyzed. There was unilateral Meniere’s disease in 143 ears and bilateral Meniere’s disease in 22 ears, with an average age of 43.53 ± 11.40 (19–70 years old), consisting of 76 males (49.35%) and 78 females (50.65%), with a male-to-female ratio of 0.97:1 .All the patients registered clinical information in detail, including sex and age. Medical histories were recorded in detail. Examination of otology was routinely performed. Pure tone audiometry was taken routinely. MRI of the internal auditory canal and posterior fossa was taken to exclude other diseases which can present vertigo and audiometrically verified asymmetric sensorineural hearing loss. Caloric and head impulse tests were used for the evaluation of the vestibular system’s status. The audiograms were analyzed as evidence.Regarding clinical management, when they received the diagnosis, all patients received education regarding a low-sodium diet, avoidance of particular foods and products, such as alcohol, caffeine, monosodium glutamate, excessive tea, and so on. Healthy lifestyle modifications and psychological counseling are needed, such as quitting smoking, avoiding allergy triggers, getting plenty of sleep, maintaining a good mood, taking part in appropriate physical activities, and so on. Patients were encouraged to make notes relating to their health. During the treatment course, patients were provided pharmacologic treatment with necessary steroids, betahistine, diuretics, or ginkgo preparation for the days or months of the trial, in order to control symptoms and maintain a stable state. When patients experienced an acute attack, systemic steroid therapy or local steroid injection were options for treating patients’ hearing loss. The systemic steroid was given prednisone 5 mg/kg/d as an initial dosage, for approximately 10–14 days with a slow tapering dose, and a local steroid injection was performed instead if there were contraindications with the systemic use of the steroid or when used as a supplementary treatment. Moreover, the patients temporarily used vestibular inhibitors during acute vertigo attacks and used betahistine with other medications for vertigo control at other times. We used betahistine 36 mg/d, for the attack and interval therapy. The treatment duration depends on patients’ symptoms, including vertigo and hearing loss. Hence, some patients used betahistine for several months, usually 3 to 6. Hydrochlorothiazide 25 mg/d as diuretics were used when patients were refractory to steroids and betahistine. Ginkgo biloba preparations at 57.6 mg/d, were not opposed to if needed. Vestibular rehabilitation exercise was performed during the non-acute period if needed. Patients were encouraged to keep a health diary. In addition, a one-year clinical follow-up was conducted.The pure-tone audiometric data were collected by professionals with a GSI 61 audiometer in a standard soundproof room, which limited the background noise to below 18 dB A. The audiometric thresholds for 250, 500, 1000, 2000, 4000, and 8000 Hz were determined by air and bone conduction, and narrow-band noise was used for masking.The poorest audiogram within six months of the interval before entering the study determined the patients’ onset hearing level, and their poorest audiogram at the one-year point (12 months ± 0.5 months) was taken as the hearing level after the one-year follow-up. For the criterion of clinical hearing improvement or deterioration, a greater than 5 dB change was used as an outcome measure . The purTo classify different types of the audiometric curve objectively, we referred to the function that Mateijsen and his colleagues  used to t-test and a chi-square test were used for comparisons between groups. Nonnormally distributed data were represented by quartile spacing and the Wilcoxon signed-rank test, whereas Spearman’s rank–order correlation test was used for comparisons between groups. Binary logistic regression was used to analyze risk factors. p < 0.05 was considered statistically significant.The database was established using Excel 2016, and statistical analysis was conducted using IBM SPSS Statistics for Windows, Version 24.0 . MATLAB was used for visualization. The data presented a normal distribution using the Kolmogorov–Smirnov test and are expressed as the mean and standard deviation; Student’s 2χ = 14.064, p = 0.08). There was a significant correlation between the average threshold of low and high frequencies , and the coefficient of high frequency:low frequency was 0.676:1.Affected ears at stage 3, and with a peak curve, represented the greatest proportion of all the collected hearing data. z = −8.330, p < 0.001), 500 Hz , 1000 Hz , and 2000 Hz . Notably, at 4000 Hz, there is no significant difference . In contrast, the 8000 Hz threshold showed a slight deterioration .Of the affected ears, 87.27% had improved or preserved hearing at a low frequency (66.06% improved and 21.21% preserved), and 71.51% at a high frequency (24.24% improved and 47.27% preserved). In u = −2.542, p = 0.011). The patients with hearing thresholds that reached ≤25 dB HL were younger than those with a hearing average >25 dB HL. Whether the hearing reached ≤25 dB HL or not had no relationship to sex, but there was a significant difference with regard to the initial audiometric curve patterns (The most striking result that emerged from the data is that 66 affected ears (40.00%) were restored to, or preserved at, a normal hearing level (average threshold ≤ 25 dB HL). The restoration time was 2.5  months, with a range of 0.5–11.0 months. The restoration time of the advanced stages (stages 3 and 4) ) was longer than that of the early stages (stages 1 and 2) ), and the differences were statistically significant (patterns .p < 0.001) and stage 3  improved significantly, whereas at stage 1  and stage 4 , it did not show a significant difference. At 2000 Hz, at stage 1 , hearing deteriorated, and at stage 3 , it improved, whereas the changes in the other two stages did not show a significant difference (p > 0.05). At the high frequency, at stage 1 , hearing deteriorated, and at stage 4 , it improved significantly, whereas the change in the other two stages did not show a significant difference (p > 0.05). In terms of average hearing threshold value, at stage 2 , hearing deteriorated slightly, and at stage 3 , it improved slightly. The hearing of patients at advanced stages (stages 3 and 4) improved more both at low  and high  frequencies than that of patients at an early stage (stages 1 and 2).The advanced stages still have potential for improvement. What stands out in p < 0.001), 42.41 dB HL to 35.29 dB HL , 44.79 dB HL to 35.49 dB HL , and 56.67 dB HL to 47.35 dB HL ) by means of rising, falling, peak, and flat curves, respectively. At the high frequency, there was a slight deterioration in the rising  and peak curves , and a slight improvement in the falling  and flat curves , but there was no significant difference between various types .What can be clearly seen in p < 0.001) had an increased odds ratio of hearing, on average, ≤ 25 dB HL. Age  increased the odds ratio of hearing to an average of > 25 dB HL. Compared with the rising curve, the peak curve  and flat curve  increased the odds ratio of hearing to an average threshold of >25 dB HL. There was no relationship between sex and hearing restoration.The dependent variable was defined as whether the average thresholds reached ≤25 dB HL after clinical management, and the independent variables and covariates included sex , age, audiometric curve (four types), and the initial stage . Patients at an earlier stage initially , patients’ hearing in advanced stages (stages 3 and 4) improved more at low and high frequencies. Patients in advanced stages should not be neglected, nor should they give up on rescuing their hearing. Instead, we emphasize that more attention should be paid to their symptoms, and they should attend follow-up appointments with their clinician to maintain their residual hearing. The hearing changes associated with Meniere’s disease need further observation to determine when to carry out an artificial hearing intervention or surgery, as irreversible hearing loss may occur.The importance of examining individual frequency thresholds is emphasized as one evaluates and monitors patients with Meniere’s disease over time . The proThe proportion of the peak curve was the greatest, which is similar to the findings of Paparella  and Lee We speculate that hearing loss appears in the low frequency initially, then in the high frequency, and then in the entire frequency, gradually deteriorating in this way. New studies report that the hearing loss profile does not only affect the low frequency in the early stages; however, a flat sensorineural hearing loss was observed in patients with familial Meniere’s disease and mutations in OTOG and MYO7A . In our More long-term follow-up studies are needed to investigate the progressive patterns of different patients and different treatment outcomes with Meniere’s disease. The hearing of the patients fluctuates alternatively between improvement and deterioration. The results of a five- or ten-year follow-up are expected in the future for more clinical information. Although vestibular migraines are excluded from the study, migraine symptoms are usually complex, and the influencing factors should be strictly limited when observing Meniere’s disease hearing changes. In the future, research needs to include more details. The influencing factors should be more strictly limited. Further in-depth comparative analysis should be conducted when the case numbers increase. Future research directions may also be highlighted in terms of predictive factors of listening outcomes.Most patients can have their hearing preserved or improved through strict clinical management, and sufficient follow-up time is also essential. Stage 3 patients also have potential for improvement, and their restoration time is longer than in the early stages. Initial hearing stage, age, and audiogram pattern are related to the hearing benefits.


Lassa fever (LF) is a neglected tropical disease that is caused by Lassa virus (LASV), a human hemorrhagic fever-causing mammarenavirus. A notable sequela of LF is sensorineural hearing loss (SNHL) that can develop in about 33% of the patients. Animal models of LF-associated SNHL have been limited in size and scope because LASV is a biosafety level 4 (BSL4) pathogen that requires its handling in a high biocontainment laboratory. In this report, we describe the development of an alternative arenavirus hearing loss model by infecting outbred Hartley guinea pigs with a virulent strain (rP18) of the Pichinde virus (PICV), which is a guinea pig-adapted mammarenavirus that has been used as a surrogate model of mammarenaviral hemorrhagic fevers in a conventional (BSL2) laboratory. By measuring auditory brainstem response (ABR) throughout the course of the virulent rP18 PICV infection, we noticed that some of the animals experienced an acute but transient level of hearing loss. Cochleae of hearing-impaired animals, but not of controls, had demonstrable viral RNA by quantitative RT-PCR, indicating the presence of virus in the affected inner ear with no overt histopathological changes. In contrast, neither the outbred Hartley guinea pigs infected with a known avirulent strain (rP2) of PICV nor those that were mock-infected showed any evidence of hearing loss or viral infection of the inner ear. This is the first report of an immunocompetent small animal model of mammarenavirus-induced hearing loss that can be used to evaluate potential therapeutics against virus-induced hearing impairment under a conventional laboratory setting. Lassa virus (LASV) is an Old World mammarenavirus  that is endemic to west Africa and causes a severe form of hemorrhagic disease known as Lassa fever (LF). It is estimated that as many as 300,000 infections and 5,000 deaths occur annually as a result of LF . LF incuAn under-addressed consequence of severe LF is the onset of sensorineural hearing loss (SNHL), which by some estimates may occur in up to 33% of LF patients . SNHL diDue to the inherent difficulties of studying the specific molecular mechanisms responsible for hearing loss in humans, animal modeling is necessary to conduct deeper and more regimented studies of LASV-induced hearing loss. Several animal models currently exist to model human LASV infection , but modOryzomys albigularis rodents in Colombia [An alternative (surrogate) animal model of human mammarenaviral hemorrhagic fevers, including LF, that can be conducted in a conventional (BSL2) laboratory involves outbred Hartley guinea pigs infected with a virulent strain of the Pichinde virus (PICV) . PICV isColombia . PICV waColombia . Our labColombia . OutbredColombia , and canColombia . As suchTo this end, we set out to determine whether rP18-infected outbred Hartley guinea pigs can experience hearing loss in addition to other known disease signs that overlap with human mammarenaviral hemorrhagic fevers. We found that a significant portion of the outbred Hartley guinea pigs infected with rP18 experienced hearing loss, while outbred Hartley guinea pigs that have either been mock-infected or infected with a known avirulent rP2 virus did not experience hearing loss, as determined by auditory brainstem response (ABR). However, we did not find any consistent and significant histopathological changes in cochleae associated with hearing loss but were able to detect PICV RNAs in some hearing-impaired cochleae of the virulent rP18-infected animals.The plasmids that contain the PICV genome and the methods used for generating rP18 and rP2 viruses have been described previously ,32. BabyThe methods for generating rP18 and rP2 viruses have been described previously ,32. Supe6 pfu (plaque-forming unit) of the virulent rP18 strain of PICV was used to inject intraperitoneally (IP) into 6–14-week old outbred Hartley guinea pigs (n = 8) to generate a uniform level of virulent PICV infection, whereas IP injections of 1 × 106 pfu of the avirulent rP2 strain of PICV into each of the outbred Hartley guinea pigs (n = 6) were not known to cause any significant disease signs. Additionally, three outbred Hartley guinea pigs were injected with phosphate-buffered saline (PBS) as mock-infected controls. The animal’s bodyweights and rectal temperatures were monitored daily following the injections. The phenotypic differences between the rP2- and rP18-infected animals were described in our previous reports [We used the approved protocol of the Institutional Animal Care and Use Committee (IACUC) at the University of Minnesota to conduct animal studies. Briefly, outbred male Hartley guinea pigs were obtained from Elm Hill Breeding Labs (USA). Based on our extensive historical data and analysis ,31,33,34 reports ,31,33,345 cells/well). In the following day, cells were infected with 500 µL of either serially diluted rPICV stocks or serum of virus-infected animals (in PBS) for 1 h at 37°C. After washing once with PBS, cells were incubated in MEM supplemented with 0.5% agar and cultured for an additional 4 days at 37°C and 5.0% CO2. Plaques were stained overnight with a diluted neutral red solution (0.01%) in 0.5% agar-MEM medium.Vero cells were seeded into 6-well plates at 60%–70% confluency , hearing was measured in all animals by auditory brainstem response (ABR) method as previously described . Brieflyparies labyrinthicus housing the cochlea was exposed after a dissection of the temporal bone bulla from the skull. Following the removal of the otic capsule, the left and right cochleae were fixed overnight in 4% paraformaldehyde (PFA) at 4°C followed by an overnight incubation in PBS at 4°C. Cochlea underwent decalcification for 2–3 weeks in the decalcification solution (10% EDTA in PBS) until the cochlea was translucent. Cochlea then underwent sucrose infiltration by washing in 10% sucrose for 30 minutes at room temperature followed by washing in 15% sucrose for 30 minutes at room temperature and an overnight incubation in 15% sucrose at 4°C. Cochlea was incubated in 1:1 15% sucrose/OCT compound  at 4°C for about 24 h, and then again overnight in degassed OCT at 4°C. Cochlea in OCT was snap frozen in liquid nitrogen the following day. Tissue sections were prepared by cutting 10 μm sections of the tissue in a cryostat. Hematoxylin and eosin (H&E) staining was performed by the veterinary diagnostic laboratory at the University of Minnesota.Cochleae were prepared for tissue sectioning as described previously . The parCochleae frozen in OCT were homogenized, and total RNA was extracted from the cochlea using TRIzol reagent . Single-stranded cDNAs of the bi-segmented PICV genome were generated using random hexamers  and the MMLV reverse transcriptase enzyme  following the manufacturer’s protocol. Quantitative RT-qPCR was conducted using primers that were specific to the PICV nucleoprotein (NP) gene, whose sequence was conserved between the rP2 and rP18 strains, as well as primers that were specific for the cellular GAPDH as a control. The sequences of the primers used for RT-qPCR are as follows: PICV NP F 5’-CCCGGACAGAGAAATCCTTATG-3“+), PICV NP R 5’-CTCCCTTGAACTTGAGACCTTG-3”), Guinea pig GAPDH F 5’-ACAGTGACAGCCATTCTTCC-3“+), Guinea pig GAPDH R 5’-AGCCGAACTCATTGTCATACC-3”). The IQ SYBR Green supermix  was used for the DNA amplification in a Bio-Rad CFX quantitative PCR machine  at 95°C for 3 min, followed by 40 cycles of DNA amplification at 95°C for 10 s and 60°C for 30 s. The absolute concentration of viral RNA was determined by performing a standard curve using a PICV-NP containing plasmid  and was t-test for each individual time point. For t-tests, ANOVA, and linear regression were performed using GraphPad PRISM  and mixed model analysis was performed using R .For To investigate the initiation and development of hearing loss and other disease signs and mortality during the course of the virulent rP18 virus infection, some of the rP18-infected outbred Hartley guinea pigs were sacrificed at 8 dpi, 12 dpi, and 16 dpi, which coincided with the predetermined terminal point of the rP18 virus infection ,31 as deTo assess whether guinea pigs experienced hearing loss during rP18 infection, we recorded hearing levels by ABR for five sound frequencies at various timepoints following the infection. We found that, when averaged as a group, the rP18-infected animals had significantly increased hearing threshold levels post infection (when compared to their baseline levels) than the mock or rP2-infected groups . These tVirus-induced hearing loss can have a number of causes ranging from temporary inflammatory ear-canal blockages to damages to the auditory nerves, hair cells, and/or support structures found in the cochlea ,40. To dAs previous studies have determined that LASV can be detected in the cochleae of some of the LASV-infected animals ,27 we wiThere are some similarities and differences between the various animals used to model human LF in terms of hearing loss. A major challenge in working with LASV is that it is a BSL4-level pathogen that requires the necessary high biocontainment laboratory. As such, there have only been three studies done to date, to the best of our knowledge, to examine the important issue of hearing loss in LASV-infected animals . Here, w4 pfu of recombinant LASV-Josiah, and monitored them for up to 42 days post infection [Huynh and colleagues examined hearing loss in inbred strain 13/N guinea pigs  that arenfection . In our nfection . LASV annfection . They alnfection  either bnfection . Unfortunfection .3pfu of LASV-Josiah intramuscularly (IM) as determined by the brainstem auditory evoked response communication (BAERCOM) method, which is similar to the ABR method used in our current study [The findings of the presence of viral materials in the cochlea of some of the animals in our current study and in the published report  likely unt study . The autnt study  despite nt study . Unfortunt study . It is int study  did not 4pfu or 1 × 105pfu of LASV strains isolated from fatal (LV2384) and non-fatal (LV2350) human LF cases obtained during an outbreak in Sierra Leone in 2012 [5pfu LV2350 were designated as deaf, which was defined as showing no behavioral changes to two or more click stimuli, by day 60 postinfection. In comparison, none of the IFN α/βγ receptor KO mice infected systemically (IP) with 1 × 105 pfu of LV2350 developed any signs of deafness by day 60 postinfection [In a separate study, Yun and colleagues used the STAT1 knock-out (KO) immunodeficient mice as a model for LASV infection, which differs from other immunodeficient mouse strains  in their in 2012 . These v in 2012 . Hearing in 2012 . All surnfection . The autnfection . Finallynfection . The cocnfection ,54. WhilThe findings of inflammation and vasculitis in or surrounding the cochlea either at the late stage of virus infection  or well In summary, in our current study, we found that a significant portion of outbred Hartley guinea pigs infected with the virulent rP18 PICV show acute hearing loss . However


Background: Several instruments are used for measuring functional limitations among rheumatoid arthritis (RA) patients. However, these instruments are incongruously assessed for their psychometric properties. The National Health and Nutritional Examination Survey (NHANES) uses a generic questionnaire to assess the activities of daily living (ADL) to measure functional limitations among its participants. The psychometric properties of the NHANES-ADL scale were evaluated using a patient examination and survey data. Methods: NHANES-ADL scale was assessed for its internal consistency and factor structure. Scale reliability was assessed with Cronbach’s alpha reliability coefficient. Principal component analysis with Promax rotation was used to obtain factor structure. Confirmatory factory analysis was used to calculate fit indices. The graded item response theory model was used to estimate item discrimination, difficulty, and test information. Results: Our sample included 1132 individuals with RA. Exploratory factor analyses of 19-item NHANES ADL scale produced one factor solution and accounted for 35% of variance. The Cronbach alpha of this scale was 0.92. The results of graded item response model indicated items performing well discriminating high and low level of functional ability. A higher slope (α) reflected stronger ability of items to discriminate across the continuum. Conclusions: The NHANES ADL scale showed good reliability, single dimensionality, and validity in RA patients. Studies should explore its test-retest reliability and its ability to reliably measure functional change over time in the future. Approximately 1% of the world population and about 1.5 million people in the United States suffers from rheumatoid arthritis (RA) . AccordiRA is an inflammatory chronic progressive disease. Despite the progressive nature of RA, patients experience high and low levels of functional ability. Chronic pain and functional limitations are the most severe effects of RA ,5. RA paInability to perform usual activities was reported by nearly 43% of 50 million adults that are diagnosed with arthritis. Similarly, 31% of working-age adults report similar limitations. About 40% of adults with RA found it very difficult or impossible to do at least one of the following nine activities of daily living (ADL): stooping, bending, or kneeling; standing more than 2 h; walking a quarter of a mile; pushing a heavy object; climbing a flight of stairs; lifting or carrying 10 pounds; siting for more than 2 h; reaching above your head and grasping small objects .It is evident that, future health outcomes and treatment response in RA patients can be best predicted by subjective patient and physician measures. Functional status impacted with bone and joint conditions is commonly assessed using various health assessment instruments or questionnaires. These questionnaires or instruments assess ADL including self-care, mobility, housework, and transportation, etc. The Short Form-36 (SF-36) has been a widely used, multidimensional non-disease-specific ADL instrument. The Health Assessment Questionnaire Disability Index (HAQ) is considered to be the gold standard for measuring functional activity in RA patients . HoweverThere are several generic and disease specific instruments used in measuring functional status among RA patients, such as the Barthel index for activities of daily living, the Groningen activity restriction scale (GARTH), the World Health Organization Disability Schedule-II (WHODAS-II), the Health Assessment Questionnaire Disability Index (HAQ-DI) Health Assessment Questionnaire II (HAQ-II), the shortened arthritis impact measurement scales (AIMS), the Multidimensional Health Assessment Questionnaire MDHAQ-10-ADL), MDHAQ-14-ADL, and the Sickness Impact Profile (SIP-RA) to name few -ADL, MDH,17,18,19The National Health and Nutritional Examination Survey (NHANES) uses a generic questionnaire to assess ADL. Its psychometric properties were assessed in patients with cervical pain, low back pain, severe headache, stroke, and general population previously ,22,23,24The NHANES assesses the health and nutritional status of children and adults in the United States. A cross-section of nationally representative non-institutionalized US civilian population is surveyed on health and nutrition . The surOut of 10,714 participants who reported having arthritis, 2032 of whom reported having RA, a total of 1132 participants with RA who completed the ADL questionnaire and responded to all of the items were included in our final analyses. Participants < 18 years of age and with missing responses to ADL items were excluded.The NHANES survey on functional abilities includes questions related to performing ADLs . This quWe analyzed the NHANES-ADL scale for its internal consistency, factor structure, and item characteristics with the graded item response theory (G-IRT) model. Statistical analyses were performed using the SPSS 27  and the STATA 14 . Data were reported as means, frequencies, and percentages. Scale reliability was assessed by the Cronbach’s alpha reliability coefficient and its value of 0.7 was considered acceptable . MaximumICCs were also plotted, where each figure represented a single item, whereas the curves represented four Likert-type responses to the individual items. The x-axis represented the latent constructs of ADL, with a z-score of −3 to +3. A negative score on the x-axis translated to high level of ADL ability. In contrast, an increasingly positive or higher score represented a lower ADL ability. Each of the ICC response had four curves, the first one indicates “no difficulty”, the second “some difficulty”, the third “much difficulty”, and the fourth “unable to do”. Item difficulty, also known as horizontal threshold parameter estimate (β), indicate the likelihood of each Likert-type response between each item. The positive correlation of the individual responses with the latent construct of ADL difficulty was indicated by any value above zero .Our study sample included 1132 individuals with RA. The respondents mean age was 58.2 ± 0.6 years and 664 (58.7%) were female. Most respondents were non-Hispanic white (35.1%), had a college/associate degree (31.3%), were married (47%) and had an annual family income of <$25,000 (44.2%). Additionally, 89.3% of the respondents reported having some form of health insurance .A 19-item NHANES ADL scale produced one factor solution accounting for 35% variance on exploratory factor analysis using Promax rotation. This suggests most of the items were related to the latent construct of ADL. The largest single factor loading  strongly suggests the relationship between RA and the disruption of physical and social activity. The Cronbach alpha of 0.92 of the single dimensional scale was well above the accepted value of 0.70 .The results of the item response theory, using the graded response model, indicated that all items discriminated well between respondents with a high and low level of functional ability in performing ADLs. The majority of items showed stronger discrimination, which included: difficulty doing chores around the house, preparing meals, walking from one room to the other, standing up from an armless chair, getting in and out of bed, difficulty using silverware or holding a cup, dressing up or doing buttons, standing for extended intervals of time, going out to attend events or participating in social activities, leisure activities, and difficulty moving large objects .All the items and Likert-type responses were located above zero, indicating high levels of ADL limitations and an increased level of sensitivity for the ADL’s latent construct. Our analysis showed the majority of the NHANES-ADL questionnaire items exhibited a stronger performance to discriminate across the scale as indicated by higher slope, α. The ICC of items 9, 10, 13, 15, and 18, had the highest level of endorsement for the response “much difficulty”. In all other curves, except for items 2, 13, and 14, the highest level of endorsement was demonstrated by “some difficulty”. This further suggested the highest probability of being associated with ADL limitation. The ICCs for items 2, 13, and 14, were less discriminating as reflected in the relative flattening of item curves. However, the values of slope were less convincing, but still acceptable .The NHANES-ADL questionnaire revealed singular dimensionality and strong internal reliability at scale level . Using iPatients are considered the best and most accurate source for quantifiable data related to functional limitations, pain, fatigue, and mental health etc. Functional limitation is the most significant prognostic clinical measure of long-term outcomes in RA patients measured by self-reported questionnaire. The NHANES uses a generic questionnaire to measure the functional limitation (ADL) among its participants . High anMost of the items in our study showed stronger discrimination, which included item 5 (difficulty doing chores around the house), item 6 , item 7 , item 8 (standing up from an armless chair), item 9 (getting in and out of bed), item 10 (difficulty using silverware or holding a cup), item 11 (dressing up or doing buttons), item 12 , item 16 , and item 19 (difficulty moving large objects). All the items and Likert-type responses indicated high levels of ADL limitations and an increased level of sensitivity for the ADL’s latent construct.Similarly, most items were sensitive to a mild to moderate ADL limitation level. All of the parameter estimates were to the right of z score “0”. Our results were also consistent with finding that items such as difficulty in stooping, crouching, kneeling, standing for long periods, and moving large objects, had a parameter estimate value below zero, indicating that these items were less sensitive to ADL limitation for lower Likert selection ,21.The Likert scale of the NHANES-ADL questionnaire provided greater information distinguishing ADL difficulty level compared to when these responses were transformed into binary and tested using a graded response model in other study . Our stuIRT have been employed to assess item discrimination, test information, and the sensitivity of questionnaires used in national datasets, including the National Health and Aging Trends Study (NHATS) and the Health and Retirement Study ,38. The Our study has several limitations. This was a cross-sectional study, therefore, participants measured functional ability as a snapshot of their ADL at one point in time. Thus, the longitudinal impact of RA on ADL could not be examined. Furthermore, test-retest reliability and the responsiveness of the questionnaire items was not assessed. Additionally, the results cannot be generalized to the individuals with greater levels of functional limitations, or who are institutionalized. Disabled individuals living in institutional settings were excluded in this study. This may have limited the normality of the distribution of the ADL score. Other methodological biases such as non-response, question order, or misclassification, may have underestimated the severity of ADL. In addition, the severity of ADL was self-reported and was not confirmed clinically. The presence of other co-morbidities among participants may have also influenced our results. Individuals with RA accounted for only 2.9% of the total participants, despite the large number of individuals who participated in the NHANES survey. Despite these limitations, our findings suggest a few modifications in this scale may help improve the clinician’s ability to examine and measure functional status more efficiently.The NHANES ADL scale showed good reliability, single dimensionality, and validity in RA patients. Strong sensitivity and discrimination across the entire spectrum of functional ability was observed with most of the scale items. The NHANES-ADL scale seems to be a useful tool in measuring ADL among RA patients. Studies should explore its test-retest reliability and its ability to reliably measure clinical change over time in the future.


Background: The Carina system  is a totally implantable device providing acoustic amplification in adult patients with moderate-to-severe sensorineural or mixed hearing loss. One of the main concerns about such a totally implantable device has been represented by the subcutaneous battery lifespan. The aim of this article is to report the analysis of battery performances in a series of Carina-implanted patients after a long follow up. Methods: In this retrospective study, the technical data of a series of patients implanted with the Carina middle ear implant in our clinic have been analysed, extracting the data from the log of telemetric measures. Results: The mean lifespan cutback was 0.43 h/years (from 0 to 0.71 h/year), with a strong negative significant correlation between the follow-up period and the percentage of battery residual lifespan. Conclusion: The lifespan of the Carina’s battery seems consistent with the manufacturer statement of a pluri-decennial lifespan, avoiding the need of an early surgical substitution and providing a full day of use of the system even after up to 12 years from the implantation. Totally implantable hearing devices are indicated as a treatment for moderate-to-severe hearing loss in patients who can not benefit from conventional hearing aids . In particular, the Carina system  is a totally implantable device providing acoustic amplification in adult patients with sensorineural hearing loss (SNHL) or mixed hearing loss (MHL) . All theThe Carina is nowadays indicated for adult patients with moderate-to-severe SNHL or MHL with an audiometric threshold of 30–85 dB, especially in the high frequencies ,6,7. CanThe Carina device was used in patients with ossicular chain malformations and conductive hearing loss. In these cases, the device must impart its mechanical energy to the cochlea via pathways other than the normal middle ear conductive pathway, such as the round window or the stapes footplate after a stapedotomy. In this regard, Siegert et al., in 2007, implanted a device in subjects with congenital auricular atresia, using a modified transducer system, with satisfactory results, whereas Tringali et al., in 2008, successfully treated a case of severe conductive hearing loss by directly stimulating the stapes footplate with a MET™ V transducer for conductive applications, in a child with Franceschetti syndrome and bilateral auricular atresia associated with middle ear malformation . MoreoveExclusion criteria are a history of recurrent middle ear infections or a known middle ear malformation, inner ear disorders, retro-cochlear or central hearing impairment .Even if other middle ear implants can be placed through minimally invasive approaches, such as the exclusive transcanal approach, the usual surgical technique for Carina implantation involves a posterior atticotomy after a 3–5 cm post-auricular incision ,12.Even if there is no consensus on the optimal placement of the subcutaneous microphone, three possible locations sites are convenient for the positioning: anteriorly and superiorly to the external auditory canal, posteriorly to the external auditory canal, and on the mastoid tip .Even if this system has been recently discontinued in some countries, it has been previously confirmed as a valid alternative to hearing aids, especially in patients that are unable to wear the traditional hearing prosthesis for psychological problems or external auditory canal issues.All the main components of the Cochlear Carina are implanted under the skin, including the microphone, the sound processor, and even the rechargeable batteries. The subcutaneous microphone collects sound from behind the ear and sends it to the processor. The signal, then, is amplified, processed, and forwarded to the actuator as mechanical movement. The transducer can be coupled to the stapes, oval window, or round window.Through a telemetric arrangement, the programming system permits the fitting of the implanted device, similarly to a cochlear implant. The charging system has a base station, a charging coil, and a battery charger. To charge the battery of the system, the charging coil is placed over the skin in magnetic contact with the implanted device. A full charging takes approximately 45 min. Through a remote control, the recipient can turn the system on and off and adjust the volume [One of the main concerns about such a totally implantable device has been represented by the subcutaneous battery lifespan.The battery, indeed, is charged with a coil placed on the skin over the implant. The procedure should be performed daily and it lasts about 1 to 1.5 h. The manufacturer asserts that, as new, the battery could last more than 30 h with a single cycle of charge ,14.With normal use, then, the battery span should decrease gradually. From the manufacturer testing, indeed, considering a daily use of at least 16 h, the Carina’s battery lifespan is supposed to be 25–30 years, with a gradual decrement of performance  see Fig.Then, since the battery is implanted under the skin, a substitution would require a surgical intervention for the electronic capsule replacement. The middle ear transducer, however, should not be removed during the battery change procedure.The aim of this article is to report the analysis of battery performances in a series of Carina-implanted patients, submitted to surgery, and followed up in the Otolaryngology Audiology and Phoniatric Operative Unit of Pisa University Hospital, defining the useful lifespan of the subcutaneous batteries and assessing a mean rate of the performance’s decrement. The results, then, will be compared with those reported from the manufacturer from experimental accelerated testing.Technical data of a series of patients implanted with the Carina middle ear implant in a national referral centre for otosurgery from 2009 to 2019 were retrospectively reviewed.Then, the mean dB gain with Carina, comparing the pure tone average (PTA) (250–2000 Hz) of a free field audiometry with and without the system switched on, was calculated.The subjective benefit of the intervention was assessed collecting the Glasgow Benefit Inventory (GBI) questionnaire  for eachAll the recipients received the third generation of the Carina prosthesis  or newer versions. All the implants, therefore, own the same type of battery.The follow up was calculated as the period between the activation and the last telemetric measure in months.The data were extracted from the log of telemetric measures. All the measures were ruled out by the same specialist with the same software, released by the manufacturer.The percentage of residual battery lifespan was calculated as 100% of battery health corresponding to a single cycle charge duration of 30 h. The single charge lasting decrement was expressed as a percentage.p values < 0.05 were considered as statistically significant.The data obtained were analysed using the Pearson correlation through SPSS statistics for Windows, Version 23.0 . Since 2009, 19 patients were submitted to Carina implantation. One of those patients received a bilateral implantation; therefore, the number of Carina systems implanted in our centre was 20.In all cases, the device was implanted through a surgical procedure under general anaesthesia. The surgery was conducted through a slightly curved post-auricular incision, two flaps, cutaneous and muscular, to visualise the spine of Henle and the mastoid region. So, a small superior atticotomy was created, about 2 cm wide, to expose the body of the incus. The arm of the mounting bracket of the device was modified to perfectly place the device on the incus. The mounting bracket was then fitted securely to the mastoid cortex using bone screws. Bone beds for the device were drilled posterior and superior to the atticotomy. The transducer was mounted in the retaining ring. The tip of the transducer was advanced into the hole on the incus and the positioning was evaluated using the TLA. The device was placed on the bone bed and the microphone was placed under the skin in the retroauricular region.(a)Explantation for extrusion after prosthesis infection in two cases;(b)Explantation for patient’s wish in one case;(c)A stopping of prosthesis use, due to hearing loss progression over time and subsequent lack of benefit from the amplification through the implanted device in three cases;(d)Moving to other centres for follow up in two cases ;(e)Death of the recipient in one case;(f)Unknown reasons in two cases.Eight of the implanted patients attend regular annual follow-up procedures, by mean telemetric measures, fitting and audiological evaluations. The lost-to-follow-up patients was due to:The mean follow-up time of the study population was 91.25 months .The mean postoperative functional gain with the device switched on was 27.5 dB (12.50–36.25 dB). The mean GBI total result was 30.9 (21.0–38.7). For the General subsection of the GBI, the mean result was 35.5 (25.5–42.8); for the Social Support subsection, the mean result was 5.8 (0.5–11.3); for the Physical subsection, the mean result was 5.2 (0.3–10.0).The mean lifespan percentage of the battery was 86.88% (from 71% to 100%), equivalent to an estimated mean maximum single cycle of charge duration of 26.06 h (from 21.3 to 30 h).The mean lifespan cutback was 0.43 h/years (from 0 to 0.71 h/year).p < 0.001)  see .The advantages of a totally implantable hearing aid are several: e.g., a higher acceptance by the user, as it would be an invisible prosthesis; the prevention of atmosphere exposition, leading to a lower rate of damage from temperature and moisture; the protection from water, permitting a full aquatic experience; and the comfortable use while sleeping and moving or doing exercise, preventing damage from dislodgement and perspiration ,17.The Carina system is a fully implantable middle ear prosthesis. It was previously reported that this system can provide a substantial benefit in improving hearing performances in different environmental conditions ,12, valiThe published audiological results showed a good hearing gain using the Carina system, with a mean functional gain of 24–29 dB ,19. In oIn addition, the subjective benefit in terms of quality-of-life perception, assessed with a GBI questionnaire, confirm what was reported in literature, with a mean total post-implant result of 30.9. This value, indeed, is in line with what was previously reported by many authors, confirming a good subjective satisfaction from middle ear implantation surgery .However, a fully implantable device presents some drawbacks. Firstly, the subcutaneous microphone can present an attenuation of signals and reduced sensitivity because of the above skin flap, and it can record issue-transmitted sounds such as blood flow, muscular contractions, or the user’s own voice ,21. A caIn all our cases, the surgical procedure was performed through general anaesthesia, in about 3 h, without any relevant surgical complication in any of the patients. In the patients reported in the present paper, we did not record any significant postoperative variation in hearing thresholds, for either air or bone conduction thresholds, with a mean deterioration of the thresholds of circa 3 dB, indicating the absence of surgical damage to the cochlea. A very useful tool for the surgeon, certainly, is the transducer loading assistant (TLA), i.e., the telemetric system, created by the parent company, to evaluate the correct position and the coupling of the transducer. The TLA makes possible the excellent results of the device. Moreover, in order to improve the evaluation of the coupling of the device, Cebulla et al. recommends the use of the intraoperative auditory evoked potentials in place of the TLA system .Further, a totally implantable system requires an implantable battery capable of a full day of energy supply that can be recharged rapidly wirelessly and with a sufficient lifespan that permits the avoidance of further surgeries to back it up; moreover, it should not heat significantly, and it must be safe ,24,25,26The Carina’s battery is a 50 mAh lithium-ion battery. Like all batteries with lithium-ion technology, it goes through a certain decrement of performance related to the use and the subsequent cycles of charge. The manufacturer declares a useful battery lifespan of 25 to 30 years, assuming a daily use of the implant of at least 16 h. After that period or whenever the mean duration of a full cycle of charge does not permit a full-day utilization, the Carina’s implanted battery should be substituted surgically. These data were calculated from the manufacturer, according to lab testing procedures of accelerated life-testing, and supposing a complete discharge of the battery at every cycle . AccordiOver their lifespan, lithium-ion batteries tend to degrade gradually . A varieThanks to the telemetric system, it was possible to estimate the battery lifespan of our cohort of Carina recipients. In our study population, after a mean follow-up period of 91.25 months (7.6 years), the mean lifespan percentage of the batteries was 86,88%, corresponding to a mean estimated duration of a single cycle of charge of 26 h, with an annual lifespan cutback of 0.43 h see . Those rFurther, our data seem to confirm the experimental finding of the manufacturer, with a progressive decrement of the batteries’ performances, but with the capacity to guarantee enough run-time hours for an all-day long use of the system for decades.Furthermore, despite the need for some explantations and some patients lost to follow up in our casuistry, none of these adverse events were related to battery issues.In our opinion, the present article can add knowledge in the field of totally implantable hearing devices, since it is the only paper in scientific literature that reports pluri-decennial in vivo results of totally implantable batteries.The limitations of our study are related to the relative paucity of the casuistry, even due to the considerable amount of lost-to- follow-up patients.The Carina middle ear implant system, despite being recently discontinued in some countries, represents a valid amplification system for adult patients with moderate-to-severe sensorineural or mixed hearing loss. Despite some drawbacks that are common in totally implantable devices, we can state from the present study that the batteries are safe, and their lifespan is good, providing a full day of use of the system even after up to 12 years from the implantation.In our study population, with a significant follow-up period, none of the patients needed a revision surgery for a too-low battery status or battery failures.The lifespan of the Carina’s battery, even in vivo, seems to stick to the manufacturer statement of a pluri-decennial lifespan, avoiding the need of an early surgical substitution.


TMC1) gene has been linked to autosomal recessive (DFNB7/11) and autosomal dominant (DFNA36) non-syndromic hearing loss, and it is a relatively common genetic cause of SNHL. Here, we report eight Finnish families with 11 affected family members with either recessively inherited homozygous or compound heterozygous TMC1 variants associated with congenital moderate-to-profound hearing loss, or a dominantly inherited heterozygous TMC1 variant associated with postlingual progressive hearing loss. We show that the TMC1 c.1534C>T, p.(Arg512*) variant is likely a founder variant that is enriched in the Finnish population. We describe a novel recessive disease-causing TMC1 c.968A>G, p.(Tyr323Cys) variant. We also show that individuals in this cohort who were diagnosed early and received timely hearing rehabilitation with hearing aids and cochlear implants (CI) have reached good speech perception in noise. Comparison of the genetic data with the outcome of CI rehabilitation increases our understanding of the extent to which underlying pathogenic gene variants explain the differences in CI rehabilitation outcomes.Sensorineural hearing loss (SNHL) is one of the most common sensory deficits worldwide, and genetic factors contribute to at least 50–60% of the congenital hearing loss cases. The transmembrane channel-like protein 1 ( In addition, hearing loss is associated with at least 400 different syndromes [Congenital moderate-to-profound bilateral sensorineural hearing loss (SNHL) affects at least 1 in 1000 infants . InheritTMC1) gene encodes a transmembrane protein that acts as a component of the mechanotransduction channel in the auditory and vestibular hair cells of the inner ear [TMC1/2 mutant mice have no mechanosensitive current [TMC1 alter the biophysical properties of hair cell mechanosensory transduction [TMC1 has been linked to autosomal recessive non-syndromic severe-to-profound hearing loss  and autosomal dominant late-onset progressive hearing loss  [TMC1 is a relatively common genetic cause of SNHL and accounts for 0.5–8.1% of patients with autosomal recessive SNHL (ARSNHL) in different ethnic populations [The transmembrane channel-like protein 1 .All individuals and their family members with pathogenic or likely pathogenic The patients were recruited from the departments of clinical genetics in Oulu University Hospital (Patients 1–8) and Turku University Hospital (Patients 9–11). In both clinics, genetic testing is offered to all children receiving a diagnosis of hearing loss, and to adults with hearing loss of unknown cause as a part of diagnostics.The available medical records, as well as familial and clinical history, were evaluated. Eight (N = 8/11) affected individuals underwent an audiometry at 125–8000 Hz. Otoacoustic emission (OAE) testing (N = 6/11), transient evoked OAE (TEOAE) (N = 2/11), auditory brainstem response (ABR) (N = 6/11), and automated auditory brainstem response (AABR) (N = 2/11) were performed for the young individuals. These were not performed for the older individuals due to availability of the screening and different practices. Seven (N = 7/11) affected individuals underwent a speech-in-noise test. Speech perception was evaluated using spoken language; the adults conducted the Finnish matrix sentence test (FMST) and the children conducted the simplified Finnish matrix sentence test (FINSIMAT). Computed tomography (CT) scans and magnetic resonance imaging (MRI) were performed on those patients who had cochlear implants (CIs). The patients were subsequently referred to the Department of Clinical Genetics for pedigree construction and genetic evaluations.GJB2 testing is performed before large gene panels. Six affected individuals were screened for pathogenic variants of GJB2 by Sanger sequencing, with negative results.Peripheral blood samples were collected from available and consenting individuals, and genomic DNA was extracted using automated QIAsymphony device and Qiagen Qiasymphony DSP DNA Midi kit . Traditionally, TMC1 variants, Sanger sequencing of parental samples was performed to confirm that the variants are in trans in patients. No other clinically relevant variants were found in the genetic testing.Exome based hearing loss gene panels have been conducted over a period of last six years as part of clinical diagnostics. The gene panels performed vary depending on the laboratory where the test is conducted and the year the test is ordered. An exome-based next generation sequencing (NGS) hearing loss gene panels were performed in the Laboratory of Genome Diagnostics in Nijmegen, the Netherlands (gene panel versions DG-2.5 and DG-2.8) for two patients; Blueprint Genetics, Espoo, Finland  for two patients; Tyks Genomics, Laboratory medicine, Turku, Finland for two patients, and Nordlab Oulu, Finland for two patients. In three families  with multiple participating affected individuals, targeted variant testing by Sanger sequencing was performed after the pathogenic variant was identified in the proband. In families with compound heterozygous The clinical characteristics of the affected cases for each family included in this study are summarized in In the families with a recessive pattern of inheritance (Families 1–7), the hearing loss was congenital. Three individuals (Patients 3–5 from Families 3 and 4) were born before the start of the newborn hearing screening program, and before CIs were available. Their hearing aid benefit was limited, and they all use sign language as their primary mode of communication. The newborn screenings were abnormal in all tested cases , the OAE and TEOAE showed no responses , and the ABR was abnormal in all tested cases . An audiogram revealed a bilateral profound SNHL in all the affected individuals A–F. One In family 8, with dominant inheritance, the onset of hearing loss was postlingual and was diagnosed at the age of 7 years. The hearing loss was progressive, and audiograms revealed down-sloping curves G,H. The TMC1 (NM_138691.3) c.1534C>T, p.(Arg512*)  variant, which was classified as pathogenic according to the ACMG guidelines  [TMC1 (NM_138691.3) variants c.1534C>T, p.(Arg512*) and c.968A>G, p.(Tyr323Cys) . The latter is classified as likely pathogenic, according to the ACMG guidelines , and, to the authors’ knowledge, this variant has not yet been reported in the literature. Parental testing revealed that the variants were in different alleles. Two affected individuals from families 6 and 7 were compound heterozygous for the TMC1 (NM_138691.3) variants c.1534C>T, p.(Arg512*) and c.1763+3A>G, p.(?) . The latter is classified as pathogenic according to the ACMG guidelines . TMC1 c.1763+3A>G has previously been reported in the medical literature [Five individuals from families 1 to 4 were homozygous for the TMC1 NM_8691.3 c.and PP5) . Two indTMC1 (NM_138691.3) c.1714G>A, p.(Asp572Asn), . This heterozygous TMC1 variant and severe hearing loss segregated dominantly in this family. TMC1 c.1714G>A, p.(Asp572Asn) is classified as pathogenic according to the ACMG guidelines .Two individuals from family 8 were heterozygous for the In this study, we reported nine individuals from seven Finnish families with congenital ARSNHL and biallelic TMC1 variants. We also reported two individuals from one Finnish family with autosomal dominant SNHL (ADSNHL) and a heterozygous TMC1 variant. All the affected individuals with recessively inherited TMC1 variants displayed severe-to-profound congenital hearing loss associated with down-sloping audiograms, where higher frequencies are the most severely affected. This is consistent with previous publications demonstrating that pathogenic recessive TMC1 variants cause moderate-to-profound hearing loss ,18,19,20TMC1 variants [TMC1 variants demonstrating excellent functional outcome after Cis [TMC1 c.1534C>T, p.(Arg512*) variant [TMC1 variants with variable auditory outcome after Cis [Previous work has shown variable auditory outcome in patients with pathogenic biallelic variants ,21,22,23fter Cis . In the GJB2-associated DFNB1 [In our study population, the individuals who had access to CIs in early childhood, and received timely hearing rehabilitation with hearing aids and CIs, have reached a good speech perception in quiet and in noise. No age-specific reference values have been established for children for the FINSIMAT, but the two youngest individuals in the present study had SRTs in a range similar to that of typically performing early implanted CI users of their age . The older, early implanted CI users also reached good speech perception. The average SRT for a bilateral CI user with the FMST was −5.4 dB SNR in a large, unselected group of Finnish CI users . Two of ed DFNB1 . Both inEven though CIs have been highly successful in restoring hearing in severe and profound hearing loss, the rehabilitation results remain highly variable with a significant proportion of the variance still unexplained ,27. ImplTMC1 c.1534C>T, p.(Arg512*) is enriched in the Finnish population, with a minor allele frequency (MAF) 24 times higher in Finns (0.003344) than in non-Finnish Europeans (0.0001395)  [TMC1 c.1534C>T, p.(Arg512*) homozygote patients in Finland is (0.003344)2 × 5.5 million or approximately 62, and the carrier frequency of this pathogenic variant is approximately 1/300 in the Finnish population. In this cohort, the TMC1 c.1534C>T, p.(Arg512*) variant was identified in 14 of the 18 alleles (78%) of the ARSNHL patients, and was in either a homozygous or a compound heterozygous state in all patients. Based on the gnomAD and clinical data, we suggest that the TMC1 p.(Arg512*) variant is likely a Finnish founder variant. As hearing loss is genetically highly heterogeneous, additional similar variants will possibly be identified as enriched in the Finnish population.The ry 2022) . The expTMC1 c.1534C>T, p.(Arg512*) causes a premature stop codon. It is predicted to cause a loss of normal protein function either through protein truncation (512 out of 760 aa) or nonsense-mediated mRNA decay. TMC1 c.1763+3A>G, p.(?) is predicted to cause a splice site defect leading also to a loss-of-function of normal TMC1. TMC1 c.968A>G, p.(Tyr323Cys) was identified in two affected individuals in a compound heterozygote state with a known pathogenic TMC1 c.1534C>T, p.(Arg512*). The mother of these two affected individuals was a healthy heterozygous carrier of this TMC1 c.968A>G, p.(Tyr323Cys) variant suggesting that TMC1 c.968A>G, p.(Tyr323Cys) is a recessive variant leading to a functional null allele.The TMC1 c.1714G>A, p.(Asp572Asn) is a well-known dominantly acting TMC1 variant [TMC1 is a critical functional residue for pathogenic dominant variants [TMC1 is located within the hypermutable CpG context, thereby explaining its location as a mutational hot spot and its occurrence in different populations [TMC1 variants create a functional null allele and lead to recessive inheritance through a loss-of-function mechanism. It has been proposed that two mechanisms link pathogenic TMC1 channel variants and deafness: decreased Ca2+ permeability to all pathogenic variants, and decreased resting open probability in low Ca2+ confined to pathogenic dominant variants [In contrast,  variant ,20,29,30variants .TMC1 variants c.1534C>T, p.(Arg512*), c.968A>G, p.(Tyr323Cys), and c.1763+3A>G, p.(?) with profound congenital ARSNHL in seven Finnish families, and TMC1 c.1714G>A, p.(Asp572Asn) with postlingual progressive ADSNHL in one Finnish family. To the authors’ knowledge, the TMC1 c.968A>G, p.(Tyr323Cys) variant is a novel variant expanding the knowledge of the genotypic spectrum of pathogenic TMC1 variants. We also showed that the TMC1 c.1534C>T, p.(Arg512*) variant is the most prevalent variant enriched in the Finnish population, suggesting a founder effect. To the authors’ knowledge, these are the first reported cases of TMC1-related SNHL in Finland.We identified Our study demonstrates that the individuals who had access to CIs in early childhood, and received timely hearing rehabilitation with hearing aids and CIs, have reached a good speech perception in quiet and in noise. Comparison of the genetic data with the outcome of CI rehabilitation increases our understanding of the extent to which underlying pathogenic gene variants explain the differences in CI rehabilitation outcomes. It is even possible that in the future patients can be stratified based on the underlying gene defect into categories that can predict their rehabilitation outcomes.


However, little research has been done on human beings, especially in eastern countries. To assess the effects of TCS exposure on male fecundity, we recruited couples who planned to conceive and went to the preconception care clinics for physical examination in Shanghai, China. TCS was quantified in male urine samples collected at enrollment. For this study, 443 couples were included in the cohort, and 74.7% of couples (n = 331) were prospectively followed 12 months later. The outcomes of interest included the pregnancy status of their wives and time to pregnancy. Elevated male urinary TCS concentrations were found to be associated with diminished fecundability (fecundability odds ratio (FOR) 0.77; 95% CI, 0.62–0.97). The risk of infertility significantly increased  as TCS levels elevated. Besides, we divided TCS concentration into tertiles a priori, and there tended to be a dose-response pattern in both analyses. Our findings suggest that environmental exposure to TCS may have an adverse impact on male fecundity.Triclosan  is widely used in personal care and household products. It is ubiquitous across the ecosystem nowadays. Several  Triclosan  is a broad spectrum biocide added routinely in a wide array of antiseptic wash products, laundry detergents, cosmetics, and household products . Many anvia two main routes, namely dermal contact and oral route (ingestion of contaminated drinking water and food) (The uptake of TCS in humans occurs nd food) , 5. Besind food) .In vitro study by Kumar et al.  –9. Resear et al.  demonstrr et al.  found thr et al.  found TCr et al. .Several studies of TCS exposure in men take semen quality as the primary outcome. Many reported a significant statistical association between TCS exposure and semen parameters. Nassan et al.  reportedThis study recruited couples who went to male preconception care clinics in a university affiliated teaching hospital for pre-pregnancy eugenic check from November 2013 to March 2014. Enrolled couples were married (men ≥ 22 years old and women ≥ 20 years old) and planned to conceive recently. Couples who had continuously tried to conceive over 12 months but failed were excluded. All couples signed written informed consent. A trained interviewer obtained information on couples' demographic characteristics, living and working environment, sexual and reproductive status, health-related behaviors, and medical history that may affect reproductive health through a face-to-face interview. The male participants were asked to provide urine and semen samples. The study was approved by the Ethics Committee of Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China (XHEC-C-2013-001).via a telephone interview after 12 months. Information collected included contraceptive use, pregnancy status, hospital visit (if any), and time to pregnancy (TTP). TTP is an epidemiologic metric widely used for studies of human fecundity (The couples were then prospectively followed ecundity . TTP wasr2 = 0.998). All the intra- and inter-batch precisions were <15%. The recovery was 91.1%. We also measured each urine sample's creatinine level using an enzymatic method on an automatic chemical analyzer  to correct the fluctuations of TCS concentrations caused by urine concentration or dilution. Analysts were blinded to all information during the tests.A single spot urine sample (100 ml) was collected in a sterile polypropylene cup from each male participant, dispensed into polypropylene tubes , and stored at −80°C until measurement. Total urinary TCS concentration (free and conjugated) was measured using the method reported previously . After tAll data collected were doubly entered into the EpiData database. Urine TCS values less than the LOD were imputed as LOD/sqrt2 , 20. Takt-test was used for continuous variables with normal distribution and the Wilcoxon rank-sum test for non-normally distributed continuous variables. The chi-square test was used to examine differences in categorical variables. The association between the urinary TCS level and infertility was examined by Logistic regression, while the association between TCS level and fecundability was examined by the Cox model modified for discrete-time data.The student's Factors that may impact the relationship between TCS exposure and the interest outcomes were considered as confounders . Age, smThe baseline characteristics were comparable among pregnant, infertile, and not pregnant couples, except for male reproductive history and corrected TCS concentration . Comparer = 0.66), only male ages were adjusted in the following analyses. Higher TCS concentrations were positively associated with reduction in fecundability . Moreover, a significant (P = 0.02) trend was observed when we divided the TCS concentrations into tertiles.P = 0.06).Multivariable logistic regression models were used to study the effect of pre-pregnancy urinary concentrations of TCS on male infertility. Among the remaining 329 couples, 71 tried to conceive for <12 months and the wives were still not pregnant at the end of the follow-up. Therefore, they were excluded from this analysis. As shown in We found a positive association between TCS concentration and infertility as well as a negative association between TCS concentration and fecundability in this study. The findings suggest that environmental exposure to TCS may have an adverse impact on male fecundity.Male fecundity refers to the male component in the biological ability for reproduction, which could be evaluated by the time it takes for the female partner to conceive . To our in vivo and in vitro studies through three perspectives. Firstly, TCS was revealed to bind to estrogen and androgen receptors exhibiting estrogen, and anti-androgenic activities  in our study seem to be similar to Asian levels (GM = 1.29 ng/ml) in Japan; GM = 0.99 ng/ml in Korea , but lowr = 0.31)  , which mOur prospective study suggests that environmental exposure to TCS adversely impacts male fecundity. But in light of the limitations of this work, our results await corroboration by more large-scale prospective cohort studies of repeated preconception urinary measures of couple's TCS exposure in the context of couple fecundity.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Ethics Committee of Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China (XHEC-C-2013-001). The patients/participants provided their written informed consent to participate in this study.WZ designed the study, analyzed and interpreted the clinical data, and drafted the manuscript. CX collected clinical data and managed the database. SZ measured the level of TCS creatinine concentration in urine. DZ and HZ supervised the project and critically revised the manuscript. All authors read and approved the final manuscript.This study was supported by the National Natural Science Foundation of China (82003470 and 81401253), the China Postdoctoral Science Foundation (2012M520910), Projects of Shanghai Municipal Health Commission (201840140), and Projects of Shanghai Stomatological Hospital (SSDCE-2016-02).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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.