The hearing gain was significantly higher in group I (33.3 ± 24.4 dB) than in group O . The “Recovery” ratio was significantly higher in group I (70.2%) than in group O (63.1%) (p < 0.05). A repeated measures ANOVA was performed to assess the statistical differences between hospitalization, treatment modalities, and pretreatment subgroups. The inpatient group showed a significant hearing improvement in all SSNHL patients (p < 0.05). There was a significant hearing improvement in the inpatient group with pretreatment hearing <40 and 40–70 dB (p < 0.05). There was no significant difference between the inpatient and outpatient groups in pretreatment hearing >70 dB (p > 0.05). Conclusions: This retrospective study showed that inpatient treatment for sudden hearing loss is more beneficial for hearing improvement than outpatient treatment. The positive effect of inpatient treatment appears to be significant in patients with a pretreatment hearing level of 70 dB or less.Objective: The primary treatment for sudden hearing loss is high-dose steroid therapy. In some countries, hospitalization has been taken for granted. Although most countries appear to treat sudden hearing loss on an outpatient basis, some other countries have considered hospitalization as necessary. Only a few studies have been conducted on the effect of hospitalization on hearing outcomes. Therefore, we compared the hearing outcome of inpatient- and outpatient-based treatments to determine whether hospitalization affects the recovery of sudden hearing loss. Methods: We conducted a retrospective case review of patients diagnosed with sudden sensorineural hearing loss (SSNHL). In total, 439 patients with SSNHL were enrolled and categorized as either inpatients (group I) or outpatients (group O). Pure-tone audiometry was initially performed before the treatment and 3 months post-treatment. “Recovery” was defined as a hearing gain of 15 dB HL and a final hearing of better than 25 dB. “No recovery” was defined as an improvement of hearing gain of <15 dB 3 months after treatment. To exclude the effect of the level of pretreatment hearing loss, we divided the patients into three subgroups based on their hearing level: <40 dB, 40–70 dB, and >70 dB. To assess the effect of the treatment modality, the patients were divided into three treatment subgroups: systemic steroids (SS), intratympanic steroids (ITS), and a combination of both (SS and ITS). Results: The pretreatment hearing level was significantly higher in group I (61.5 ± 25.4 dB) than in group O (50.3 ± 23.0 dB;  In many countries, including Korea, inpatient treatment has been considered helpful for the treatment of sudden sensorineural hearing loss (SSNHL). Therefore, hospitalization-based treatment has been given priority ,2,3. ThrThe treatment policy for SSNHL regarding inpatient- or outpatient-based treatment varies between countries. The German treatment guidelines state that the treatment of SSNHL is possible on an outpatient or inpatient basis, but inpatient treatment is recommended for patients with severe SSNHL . In JapaIn Korea, SSNHL has traditionally been treated with 7 to 10 days of high-dose systemic steroid administration with hospitalization. Medical insurance is provided to the entire nation of Korea, and in-hospital treatment had been available at relatively low prices without special restrictions, which allows for an extended period of hospitalization. Although inpatient treatment is recommended, several patients prefer outpatient treatment. Therefore, we wondered whether there was a difference in the effectiveness of the inpatient and outpatient treatments.To the best of our knowledge, there are only a few studies on the clinical evidence for the effectiveness of inpatient treatment for sudden hearing loss. Therefore, this study aimed to compare the effects of inpatient- and outpatient-based treatments for sudden hearing loss. We conducted a retrospective medical chart review of patients diagnosed with SSNHL between 2001 and 2017 in Incheon St. Mary’s Hospital, a tertiary hospital, the Catholic University of Korea. The institutional review board of Incheon St. Mary’s Hospital, the Catholic University of Korea approved this study (OC18RESI0067). In our patient cohort, meticulous history taking, physical and neurological examination, serological tests, and audiometric tests were performed. At the first visit, the tympanic membrane of all patients was examined under a microscope. Sudden hearing loss was diagnosed only when the tympanic membrane was normal, the air-bone gap (ABG) was less than 10 dB on the pure-tone audiometry (PTA), and the tympanogram was type A. Temporal bone computed tomography was performed to observe if there was any suspicion of middle ear disease by microscope examination. Inner ear magnetic resonance imaging was performed in patients with the following signs of suspected retrocochlear pathology: severe vertigo, balance problems, progressive hearing loss, neurological symptoms, low word discrimination score, or abnormal auditory brainstem response /4) were calculated. To determine treatment success, “Recovery” was defined as a hearing gain of 15 dB and a final hearing of better than 25 dB, and “No recovery” was defined as an improvement of a hearing gain of <15 dB HL at 3 months after treatment. To exclude the effect of the level of pretreatment hearing loss on the hearing outcomes, we divided the patients into three subgroups based on the hearing level of < 40 dB, 40–70 dB, and >70 dB. The patients were subdivided according to a previous study that reported that the hearing threshold of 40–70 dB was more responsive to steroid treatment . Hearingt-test for evaluating differences between unpaired groups. Qualitative variables were compared using crosstabs and Fisher’s exact test. The sphericity test is not possible when there are two repeated measurements. In order to confirm that the correlation between the two repeated measurements is low, a correlation analysis is performed. Since the correlation coefficient was 0.39 as low, a repeated measures analysis of variance (ANOVA) was used as the primary statistical analysis. The 0.05 level was selected for the F significance and 0.80 or better for power analysis. The analysis was conducted using SAS 9.4 . For all statistical tests, a p-value of <0.05 was considered statistically significant.The results are presented as means ± standard deviation. Continuous variables were compared using the Student’s p < 0.05). Tinnitus, vertigo, diabetes, and hypertension were not significantly different between the two groups (p < 0.05). The final hearing level did not show a significant difference between the two groups (28.3 ± 24.5 dB vs. 25.4 ± 22.5 dB) (p > 0.05), which is considered to indicate a positive effect of inpatient treatment  than in group O  as well as “Recovery” rate were also significantly better  in group I than in group O. . However, a repeated measures ANOVA analysis showed a significant effect between pretreatment subgroups and hospitalization (p < 0.05). Pretreatment subgroups and treatment modalities also showed a significant effect (p < 0.05). There was no significant interaction between hospitalization and treatment modalities in each pretreatment subgroups (p > 0.05)  . p < 0.05). There was a significant hearing improvement in the inpatient group with pretreatment hearing <40 dB and 40–70 dB (p < 0.05). There was no significant difference between the inpatient and outpatient group in pretreatment hearing >70 dB (p > 0.05)  . There were more than 500 articles in the literature, after searching PubMed for “sudden sensorineural hearing loss” and “systemic steroid” over the last 5 years, and only four studies addressed admission or outpatient-based treatment. An additional search for “sudden sensorineural hearing loss”, “admission,” and “outpatient” found two more articles . AlthougThe general advantages of inpatient treatment for sudden hearing loss are as follows: timely and accurate drug administration, monitoring and managing the adverse effects of steroid treatment, and care for accompanying dizziness or underlying diseases . Comprehensive management through hospitalization is expected to have a positive effect on the treatment outcome regardless of the disease. However, it is not yet known to what extent such management helps in the recovery of sudden hearing loss. Kim et al. suggested that rest and relief of social stress and anxiety through inpatient care might help recover the hearing . Most paIn terms of final audiograms, group I demonstrated significantly better hearing gain and recovery rates than group O, although group I showed worse pretreatment hearing levels than group O . To exclWhen all patients were analyzed, the hearing gain and recovery rates in group I were significantly better than those in group O, although pretreatment hearing was significantly worse than that in group O in our study. As observed in the results presented in The study by Kim et al., was the only one that compared the treatment outcomes between inpatient- and outpatient-based treatment. In their study, the disease duration, demographic factors, and comorbidities  were not significantly different between the two groups (inpatient vs. outpatient). Only the pre-treatment PTA was significantly worse in the inpatient group. Hearing recovery at 3 months post-treatment was compared and categorized into two groups: recovery (≥15 dB of hearing gain) and no recovery (<15 dB of hearing gain). The recovery rate was significantly higher for the inpatient group  than for the outpatient group . Through this result, Kim et al. suggested that admission must be strongly recommended for patients with SSHL [n = 57) was disproportionately small compared with the inpatient group (n = 244) in the study by Kim et al. To increase the power of statistical analysis and provide more reliable data, the compared groups must have a matched number of patients. Our study compared two groups with a fairly matched patient population (group I = 233 and group O = 185). However, the proportions of enrolled patients in each group were different. The total number of enrolled patients was similar in both studies, but the patient number in the outpatient group (The duration of time until the initiation of treatment was different in the two studies. Our study population initiated treatment earlier (group I: 3.6 ± 2.4 days and group O: 4.0 ± 2.4 days) than in the study by Kim et al. . Delay in treatment is one of the negative prognostic factors. For example, Cvorovic et al.  reportedPoor prognostic factors of idiopathic SSNHL have been reported as (1) profound hearing loss, (2) down-sloping audiogram shape , (3) verSeveral formulas for pure tone average have been employed for clinical or medicolegal purposes: the three-frequency average method , four-frequency average method , PTAs weighting 1 kHz , or 1 and 2 kHz . Based on Dobie’s research result that the 0.5, 1, 2, and 3 kHz PTA best correlated with communication performance, most tertiary hospitals in Korea use this four-frequency average method  ,29,30,31The degree of hearing loss may affect the outcome of steroid therapy. It has been reported that mild hearing loss (<40 dB) was recovered without treatment, and hearing loss of more than 70 dB was not effectively treated; hearing loss of 40–70 dB is known as a “steroid-dependent zone” as a pretreatment hearing level ranging from 40–70 dB shows marked response to steroid treatment ,21. The When the pretreatment hearing level and treatment modalities were included together, the final hearing and hearing gain were significantly better in group I than in group O with the patients with a pretreatment hearing level of 70 dB or less. Since the treatment modalities did not affect inpatient or outpatient treatment, the results of this study are considered to show a positive effect of inpatient treatment. The limitation of the present study is its retrospective nature, which may have introduced selection bias. A randomized clinical trial is necessary to confirm our result. However, we believe that our research can be of value for the physicians who treat patients with SSNHL and must make decisions regarding the treatment method.In this retrospective study, patients who received inpatient treatment for sudden hearing loss with a pretreatment hearing threshold <70 dB showed better hearing outcomes than those who received only outpatient treatment. Additional RCTs are required to support the result of this study.


The aim of the current study was to examine associations between depression and clinical functioning among a multi-ethnic sample.35 cognitively normal and Mild Cognitive Impairment (MCI) participants were included and self-identified as Hispanic or white non-Hispanic (WNH). The Hispanic group (n=18), had a mean age of 70.83 (SD=7.66) and 15.59 mean years of education (SD= 3.43). The WNH group (n=17) had a mean age of 71.76 (SD=6.9) and 16.81 mean years of education (SD=2.59). Subjects were given the Alzheimer’s disease Cooperative Study (ADCS) ADL inventory, the modified Clinical Dementia Rating scale (mCDR), and the Geriatric Depression Scale (GDS). Linear regressions were conducted to analyze the predictive associations between GDS scores and ADL functioning while controlling for the effect of diagnosis and age.Among Hispanics, the overall regression was significant = 12.32, p<.001). Higher GDS scores was found to significantly predict worse mCDR scores  when controlling for the effects other factors. When examining ADCS-ADL scores, the overall model was also found to be significant =5.28, p<.05). Higher GDS scores significantly predicted worse ADCS-ADL scores  when controlling for the effects of other factors. Diagnosis and age did not significant predict ADL scores. Among the WNH group, the regression model was not significant and depression was not a significant predictor of ADL functioning.The results suggest Hispanics are more vulnerable to the effects of depression on ADL function which has important implications for AD diagnosis.


Low-frequency interaural time differences and high-frequency interaural level differences (ILDs) are used to localize sounds in the horizontal plane. Older listeners appear to be worse at horizontal-plane sound localization to compared younger listeners, but little is understood about age-related changes to across-frequency binaural processing. This study investigated if the frequency dependence of across-frequency ILD processing is altered for older compared to younger listeners, which was done by using an across-frequency binaural interference task . It was hypothesized that as listeners experience advancing age and age-related high-frequency hearing loss , they will demonstrate worse binaural performance and experience more across-channel binaural interference , and will increasingly be affected by interferers at lower frequencies (because of age-related hearing loss) when compared to younger listeners. There were 11 older (>65 yrs) and 20 younger (<30 yrs) listeners with normal to near-normal audiometric thresholds up to 2 kHz. They were tested using a left-right ILD lateralization discrimination task. Single-tone ILD discrimination thresholds and across-frequency binaural interference were measured at 0.5, 1, 2, 4, and 8 kHz. ILD thresholds and interference were about twice as large for older compared to younger listeners. Interferers ≤1 kHz produced 2–3 times as much across-frequency binaural interference for older compared to younger listeners. Hearing thresholds were significant predictors of single-tone ILD thresholds; in addition, both target and interferer hearing thresholds were significant predictors of binaural interference. The results suggest a reweighting of binaural information that occurs with advancing age and age-related high-frequency hearing loss. This evidence of plasticity may help explain some of the age-related changes in spatial-hearing abilities. The prevalence of background noise in social situations is high. Communicating in non-quiet and acoustically complex listening environments is facilitated greatly by spatial hearing, particularly in younger listeners. In comparison, older listeners demonstrate diminished spatial-hearing benefits in background noise and report greater difficulty communicating in these situations  were tested. All older listeners had relatively good hearing for their age with audiometrically normal to near-normal hearing at octave frequencies from 0.25 to 2 kHz, which was defined as ≤30 dB HL with interaural asymmetries ≤15 dB. Larger hearing thresholds were allowed at 4 and 8 kHz, with interaural asymmetries ≤20 dB at these frequencies. Because these listeners had relatively good hearing for their age, particularly at low frequencies, they were called older normal-hearing (ONH) listeners despite some having larger hearing losses at ≥4 kHz. An additional ONH listener started the experiment, but did not finish it and their data was omitted from the analysis.Twenty younger normal-hearing (YNH) listeners  were tested as a control group; the data were previously reported in Rosen and Goupell . They meThe ONH listeners also performed a cognitive screening test  was applied to the entire stimulus; in other words, the level roving did not introduce overall level differences across frequency. A non-zero ILD was applied to the target tones by increasing the level in dB in one ear by ILD/2 and decreasing the level in the other ear by ILD/2. The interfering tone was diotic, meaning it had zero ILD. Both targets and interferers had zero ITD. The target stimuli were audible and all listeners could perform the task for all conditions at these levels, even at 8 kHz, where some of the older listeners had high-frequency hearing loss. Stimuli had a sampling rate of 48.828 kHz. The stimuli were the same as in experiment 1 of Rosen and Goupell .The experiment was completed in a double-walled sound-attenuating chamber . Listeners were presented stimuli and the experiment was controlled using MATLAB  on a personal computer. The stimuli were delivered by a real-time processor, programmable attenuator, and headphone buffer  to a pair of insert earphones . Insert earphones minimized issues with ear canal collapse for the ONH listeners. The equipment was the same as in experiment 1 of Rosen and Goupell .a priori probability. The task was to report the perceived direction that the sound moved from the first to the second interval. After each trial, correct answer feedback was provided. The adaptive staircase procedure had 14 reversals. The ILD decreased if there were three sequentially correct responses and increased for an incorrect answer  and five interferer frequencies  were tested. Control conditions tested the target frequencies in isolation. The across-frequency binaural interference conditions tested the target frequencies in the presence of a diotic (zero ITD and zero ILD) interferer, and every possible combination of the target and interferer frequencies was tested with the exception that the target and interference frequency could not be the same. At least three ILD thresholds were measured for each condition. This resulted in a total of 75 blocks in the experiment [5 ftar × 5 fint (including a no interferer control condition) × 3 blocks]. For one YNH listener who had more variability in their individual ILD thresholds, six thresholds were measured per condition because they had the time to do so. The order of conditions was randomized across the listeners and each condition was tested once before any condition was repeated, which helped minimize any order effects. Testing was ~6 h per listener, usually tested in 1- or 2-h sessions that occurred on 3–4 different days. Most listeners finished the study within 15 days, and one finished in 25 days. The procedure was the same as experiment 1 of Rosen and Goupell (Five target frequencies (f Goupell .buildmer (v2.3)  ]. The rationale for using 8 kHz as the reference was that the greatest variation in hearing thresholds were at that frequency (tar), was included as a frequency-specific predictor.The first analysis was a linear mixed-effect model, which was performed for the single-frequency ILD discrimination thresholds and random intercepts were included for each listener. The dependent variable was the ILD discrimination threshold (in dB), where thresholds from the individual tracks were included to predict the average . The independent categorical variables were age [2 levels: YNH (reference) and ONH] and frequency , target frequency , and interferer frequency . Independent continuous variables included the interaural average hearing thresholds for the target (θtar) and interferer (θint) frequencies.The second analysis started as a linear mixed-effect model, which was performed on the difference of the ILD thresholds in dB between conditions with no interferer and those with an interferer, called the binaural interference index .tar = 1 kHz or fint = 2 kHz), but there were also notable differences .To better understand the age-related and frequency-specific changes to the across-frequency binaural processing, The results of the multiple linear regression are shown in tar = 2 kHz  and ftar = 4 kHz . When examining the rows of int = 0.5 , 1 kHz , and 2 kHz . There were smaller binaural interference indices for ONH listeners at fint = 4 kHz . In addition, there were significant four-way interactions that depended on the target and interferer thresholds θtar and θint, suggesting both play a role in the amount of across-frequency interference that occurred.There were the numerous significant four-way interactions that were difficult to fully interpret together in Aging and hearing loss affect spatial-hearing performance, but little is understood about age-related changes to across-frequency binaural processing and its frequency dependence. Binaural processing requires temporal precision, which degrades with increasing age. Using an across-frequency binaural interference task, where remote diotic  interferers often cause elevated target thresholds, ILD discrimination thresholds were measured as a function of target and interferer frequency in younger and older adult listeners, all having normal hearing thresholds up to 2 kHz. Across-frequency ILD processing shows relatively large effects of frequency compared to single tones  were 3.9 dB on average for the ONH listeners, which was significantly higher than the 1.9 dB for the YNH listeners , Table 1Several studies have compared ILD discrimination thresholds for normal-hearing vs. hearing-impaired listeners, with some of the hearing-impaired listeners being older in age. These studies used narrowband noises (1/3rd-octave bandwidth), and include Gabriel et al. (One difference that might reconcile the different aging effects across studies is the stimuli that were used. The current study found a factor of two increase in ILD discrimination thresholds between age groups and used pure tones (a single frequency); the other studies found smaller or no increases and used wider bandwidth noise or click stimuli. Other studies have noted improved ILD and ITD performance with increasing stimulus bandwidth , and therefore was is not distinguishable from measurement noise. Hence, no measurement to date has provided convincing evidence of across-frequency ILD-based facilitation  could be similarly considered. It was not possible to use this approach in the current study because there were mostly interaurally symmetric listeners. It is common in binaural-hearing studies to recruit interaurally symmetric listeners with ≤10 dB interaural hearing threshold difference. Interaural threshold asymmetry might induce plasticity that could be age dependent. Listeners with asymmetric hearing appear to perceive centered images with equal sound pressure levels presented to the two ears instead of equal sensation levels  can be found at: The studies involving human participants were reviewed and approved by the Institutional Review Board in the Division of Research. The patients/participants provided their written informed consent to participate in this study.MG obtained funding for the study, designed the study, programmed the experiment, oversaw data collection, analyzed the data, and wrote the manuscript. All authors contributed to the article and approved the submitted version.Research reported in this publication was supported by the National Institute on Deafness and Other Communication Disorders of the National Institutes of Health under Award Number R01DC014948.The content is solely the responsibility of the author and does not necessarily represent the official views of the National Institutes of Health.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.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.


Phosphodiesterase type 5 Inhibitors, such as sildenafil, vardenafil and tadalafil have been increasingly used today and some of the users have developed sudden sensorineural hearing loss.To present two patients with sudden deafness developed after an occasional use of the drug and review studies on the use of phosphodiesterase type 5 inhibitors and sudden hearing loss.Analytical study of two cases and review of the subject matter in the Pubmed/Medline and Bireme databases using the keywords: phosphodiesterase type 5 inhibitors and sudden deafness and its correlates in the English language.The patients analyzed are young without additional disorders, using phosphodiesterase type 5 inhibitors, and after combination treatment for sudden hearing loss only one had hearing improvement. We found nine scientific studies and reviewed preclinical studies, clinical trials, prospective and cross-sectional investigations.Increased occurrence in clinical practice and scientific reports in the literature suggest that the phosphodiesterase type 5 inhibitors are considered a risk factor for sudden deafness. Further studies with larger samples and control groups are needed for better assessing this association. Ototoxic drugs may cause balance and hearing disorders, modifying cochlear and vestibular functions. The most common known ototoxic drugs are aminoglycoside antibiotics; antineoplastic agents, particularly platinum-based (cisplatin and carboplatin); as well as some loop diuretics: furosemide, salicylic acid and quinineIn the first case report associating the use of phosphodiesterase type 5 inhibitor (PDE5i) with hearing loss in 2007, the authors attributed this disorder to a probable ototoxic effect of the drug used (sildenafil) and pointed out that there is an extensive list of ototoxic drugs such as aminoglycosides, antibiotics and other medications, and that was the first case correlating the use of sildenafil and sudden-onset hearing lossPhosphodiesterase type 5 inhibitors (PDE5i) such as sildenafil, vardenafil and tadalafil are drugs used to treat erectile dysfunction, but sildenafil is also indicated for pulmonary hypertension. Common adverse effects include headache, facial flushing, nasal congestion, dyspepsia and nausea. Recently, PDE5i have been associated with adverse effects involving vision, and there is emerging evidence suggesting that such drugs can be also responsible for hearing disorders, increasing the risk of sudden hearing lossRecent concerns about this class of drugs and the emergence of cases of sudden sensorineural hearing loss (SSNHL) resulted in a requirement of the FDA (Food and Drug Administration) - U.S agency that regulates food and pharmaceutical products - for a more rigorous labeling. Based on these reports, researchers stressed the need to investigate the potential relationship between sudden sensorineural hearing loss and use of this class of drugsSuch drugs are commercially known as sildenafil citrate , vardenafil , and tadalafil . Sildenafil was the first PDE5i licensed for erectile dysfunction treatment and has been widely prescribed since it was FDA-approved in the United StatesSudden deafness is characterized as a sensorineural hearing loss of sudden onset and unknown cause. There may be inner ear and/or central auditory pathways involvement, of variable intensity and frequency, ranging from a mild feeling of stuffed ear, total hearing loss, and tinnitus in approximately 80% of the casesThe hearing loss sensation can range from mild to very severe, and it may yield to spontaneous recovery in 25% or more cases. Sudden hearing loss progression behavior is quite variable, with total or partial spontaneous recovery; and it may leave irreversible auditory sequelaeIn a histopathological study of the temporal bone, after an episode of sudden hearing loss, there was great loss of cochlear neurons, and the organ of Corti and outer hair cells were missing in most of the cochlear basal turn, justifying, in that case, the hearing loss in the high frequenciesRecent evidence has suggested that phosphodiesterase type 5 inhibitors may be responsible for sensorineural hearing loss of sudden onsetGiven the relevance of the proposed topic and the fact that there are no publications in Portuguese, we became interested in carrying out this study, in order to present two cases of patients with sudden sensorineural hearing loss who were using phosphodiesterase type 5 inhibitors, and revisit studies on this correlation.We carried out an analytical study of two cases of young patients without other disorders, who were using phosphodiesterase type 5 inhibitors and developed sudden sensorineural hearing loss without hearing improvement after combination therapy , for hearing and tinnitus. Patients signed an informed consent form (ICF) and the study was approved by the Research Ethics Committee of the University of Brasília (UNB), under protocol number 132/12.The search strategy employed in the literature review was guided using the keywords indexed in DecS  in Portuguese and in MeSH  in English: sudden hearing loss and phosphodiesterase inhibitors and their correlates in English: sudden deafness and phosphodiesterase inhibitors. For this, we used the PubMed and Bireme/MedLine databases, and analyzed all papers published in indexed journals, including preclinical, clinical, prospective and cross-sectional studies.In this study, we considered only those papers published from 1998 to June 2013, a total of 15 years, and the last manual search conducted in electronic databases occurred in June 2013.For the two cases presented, Patient 1, aged 37, sought medical attention as soon as his mild vertigo and hearing loss symptoms started, and he was immediately subjected to treatment with the use of combination therapy for sudden hearing loss, that is, oral corticosteroids  associated with intratympanic steroid injection three times every other day , and the treatment was uneventful.In the first pure tone audiometry the patient did not have hearing thresholds in the left ear. He was also submitted to laboratory tests and MRI. He was submitted to distortion products evoked otoacoustic emissions and auditory evoked potential tests, and had results consistent with profound sensorineural hearing loss, or no response. There was no improvement even after combined therapy (OS + ITS) in audiometric tests performed one month after treatment.Patient 2, aged 43, presented hearing loss, tinnitus and severe vertigo as initial symptoms. He was submitted to laboratory tests and MRI, as well as hearing assessment by pure tone audiometry, otoacoustic emissions and Evoked Auditory Brainstem Response, with improvements in his hearing thresholds.On tinnitus, we used the Visual Analogue Scale (VAS) for discomfort and intensity as a subjective assessment and there was an improvement in score ; PatientWe found nine papers. The first publication correlating the use of phosphodiesterase type 5 and sudden hearing loss is from 2007 .Chart 1SThe effects of phosphodiesterase type 5 inhibitors in the cochlea are still uncertain due to the need for more studies with larger groups and a control group, and there is a need for otolaryngologists to add to their anamneses the possibility that patients with this type of hearing loss may be using this class of drugs, since there has been some evidence indicating that these drugs may be responsible for sudden sensorineural hearing loss.We also report that it is of fundamental importance to assess the mechanism of action of these drugs, to explain the possible causal association between their use and sensorineural hearing loss development, that even after the use of combination therapy , has been irreversible.Based on these results, we notice that in the two cases described, the sudden sensorineural hearing loss was unilateral, accompanied by tinnitus and dizziness. Patient 1 had hearing loss in all frequencies tested, and patient 2 had greater hearing loss in the higher frequencies. These findings are consistent with the literature, as described in a histopathological study of the temporal bone, after an episode of sudden idiopathic hearing loss, which revealed a large loss of cochlear neurons, mainly in the basal turn of the cochlea, explaining the hearing loss in the high frequenciesTinnitus represents a common complaint, perhaps the one most often associated with sudden hearing lossPatient 2 showed a significant change in hearing thresholds, given that his severe hearing loss changed to mild after combined treatment, and so had the tinnitus, it was severe and went on to be mild  and 2. TGiven the fact that the clinical history of patients did not mention comorbidities and, still, that sudden hearing loss can be idiopathic, it was possible to hypothesize that the use of phosphodiesterase type 5 inhibitors may have contributed to such occurrence, and recent studies have shown such correlationIt is of concern that young men, 37 and 43 years without other disease, using phosphodiesterase type 5 inhibitors have had this type of hearing loss, reinforcing the possible ototoxicity of this class of drugs and, in some cases, the irreversible hearing loss.Regarding the studies published on this subject, the first case report of the use of sildenafil and sudden hearing loss in the literature was published in 2007 by researchers from India. According to the authors, sildenafil is effective for oral treatment of erectile dysfunction syndrome and has been broadly used in view of relatively easy availability of such medications, including the fact that it can be acquired from the Internet. However, the authors emphasized that many patients are not aware of the harmful effects of sildenafil and use the drug without medical supervision. The case described is of a 44-year-old male patient, who had bilateral profound sensorineural hearing loss, which occurred after ingestion of 50 mg/day of sildenafil for 15 days. The patient reported that after 15 days of drug administration, he noticed hearing loss in the right ear and after two days of this initial symptom, the same occurred to the left ear. The patient was treated with 1mg/Kg/day of prednisolone for a month and his hearing data was documented by means of pure tone audiometry, Distortion Product Evoked Otoacoustic Emission and Auditory Brainstem Response (ABR)Still in 2007, after this case report, the FDA announced 113 hearing loss reports from patients who used PDE5i, and 84 of these cases were excluded from the number of cases for several reasons. The remaining 29 reports had a strong association between the use of PDE5 inhibitors  and sensorineural hearing loss. Besides hearing loss, there were still reports of tinnitus and dizziness. Given this, the FDA required manufacturers of these drugs to alert consumers about this possibility: sudden sensorineural hearing lossThe first experimental study was conducted in South Korea in 2008, in which the authors examined the hearing of lab animals that received high doses of sildenafil for 105 days and the rats were evaluated at baseline (0), on the fifth day (5), fifteenth (15), in the twenty-fifth day (25), in the thirty-fifth day (35) and the hundredth-and-fifth day (105). To assess the hearing, the authors used the Auditory Brainstem Response (ABR); middle latency auditory responses, as well as the evoked otoacoustic emissions. The authors reported that, in high doses, sildenafil caused changes to auditory evoked potentials, because it increased the latency duration of short latency potentials. The same kind of result occurred with the middle latency potentials. Otoacoustic emissions differ between the groups of high-dose sildenafil and the control group with long-term treatment. The authors stated that these results indicated a decrease in the number of outer hair cells of the organ of Corti and that the probable cause of this is the toxic effect due to excess nitric oxide in the auditory organs such as the cochlea and the auditory nerve. Based on these results, the authors demonstrated that the administration of large doses of sildenafil in the long term, may contribute to the development of sensorineural hearing lossIn 2009, two more cases were reported and there was also a review of post-marketing data from the FDA, through a retrospective analysis and found the following results: of 25 patients analyzed, 15 (88%) had hearing loss within 24 hours after taking PDE5 inhibitor. Eight patients (32%) reported dizziness associated with hearing loss. In 96% of reported cases, the hearing loss was unilateral. Complete hearing recovery was observed in five patients (20%), while the other three patients (12%) had at least a partial improvement. Therefore, of the 15 patients with initial hearing loss, only eight patients (32%) reported improvement compared to the initial complaint. The authors concluded that, although the data was not conclusive, there seems to be a potential link between the use of PDE5 inhibitor and sudden sensorineural hearing loss. Thus, the authors stressed that otolaryngologists should include it in their anamneses and among possible causes of sudden sensorineural hearing loss, an inquire about the use of any of the PDE-5 inhibitors. Although there is currently no direct evidence of a mechanism behind this side effect, the authors postulated that it is related to the prolonged effects of cyclic guanosine monophosphate (GMPc) within the cochleaIn 2009, the first prospective observational study was carried out in humans. Eighteen patients who were using a PDE5 inhibitor for erectile dysfunction treatment were studied. Threshold Audiometry was performed in all patients at frequencies from 250 to 16,000 Hz before and after 1, 5 and 72 hours after ingestion of 10 mg of vardenafil. Four patients showed a statistically significant increase in the hearing threshold in one ear, consistent with the criteria of ototoxicity within 72 hours of ingestion of the drug. Furthermore, all patients showed a significant unilateral decrease in the threshold at 10,000 Hz. However, with the discontinuation of the drug, there was improvement in hearing thresholds and all the hearing loss disappearedIn an epidemiological study carried out in 2010, the researcher compared subjects with and without hearing loss, who were using the PDE5i. The author points out that this was the first epidemiological study that evaluated the association between the use of PDE5 inhibitors and sensorineural hearing loss. The cohort consisted of 11,525 men aged 40 years or older and chosen from the Medical Expenditure Panel Survey between 2003 and 2006. During a period of two years, participants provided data in five interviews about their demographic information, health, healthy postures and drug prescription. They also reported no difficulty hearing or the use of hearing aids. The results showed that the incidence of hearing loss was 17.9% - a percentage which increased with age. Approximately 2% of the patients had taken some kind PDE5i, and 80.3% of them used sildenafil (Viagra).The results showed that the hearing loss was twice as common among those who made use of PDE5 inhibitors (3.0% versus 1.4%). No significant hearing loss was seen with tadalafil or vardenafil. However, the author attributed this result to the fact that the limited use of tadalafil and vardenafil by the participants may have limited their ability to find a possible association with hearing impairment. The author also highlighted that the relationship between the use of PDE5i and hearing loss can result from a tendency of drugs that promote the congestion of nasal erectile tissue, raising middle ear pressure, as well as concerns that PDE5i works by blocking cGMP breakdown and its buildup induces gene expression through transcription factor protein phosphorylation by specific kinases, which have been associated with damage to the hair cells of the cochlea. Finally, the author points out that the irreversible nature of hearing loss and its impact on quality of life underscores the need for more research on the etiological role of PDE5i use, and because it was a cross-sectional study, it provides only a limited view on the relationship between the use of PDE5i and hearing loss; and therefore requiring further investigationIn 2010 there was a report on a patient who developed unilateral sensorineural hearing loss of sudden onset, possibly related to the use of vardenafil for erectile dysfunction treatment. They described their case study as a patient of 57 years who came to the ER with hearing loss from mild to moderate in the right ear, in the range 500–3000 Hz, confirmed by pure tone audiometry and occurred after ingestion of vardenafil. The authors described that such patient was hospitalized two days later for the administration of intravenous dexamethasone, followed by oral prednisone and an improvement in hearing occurred on the fourth day of hospitalization and he was discharged three days later, continuing prednisone in an outpatient basis. Audiometry performed 10 days after treatment with corticosteroids, confirmed that the hearing in the range of 500–3000 Hz was within normal limits.The authors considered that there was a possible association of sudden sensorineural hearing loss associated with the consumption of vardenafil. The authors also undertook an analysis of cases of hearing loss associated with PDE5i in the United States with the FDA's Adverse Events Notice System database, to compare the characteristics of their patient with those of other cases of adverse events reported and based on the temporal relationship of sudden sensorineural hearing loss and the use of vardenafil by this patient, they propose that vardenafil is a probable cause of hearing loss. According to the authors, this case provided new evidence that the use of PDE5 inhibitor should be considered as a possible cause in patients with sensorineural hearing loss of sudden onsetA study was conducted in 2011 in order to review and analyze the current literature on the correlation between the use of PDE5i and hearing loss and suggests possible physiological mechanisms, as well as investigate the global communication of this side effect. The authors pointed out that the use of sildenafil and other PDE5i has grown rapidly since its launch in 1998 and a growing body of evidence indicates significant morbidity associated with the side effects brought about by this class of drugs vis-à -vis hearing loss.For this study, pharmaceutics surveillance agencies in North America, Europe and Australia were contacted and were requested to provide reports of hearing loss associated with the use of PDE5i. Thereafter, the reports were examined to exclude those for whom there were other possible causes to justify the hearing loss. The authors found 47 cases of sensorineural hearing loss with a temporal association with the intake of PDE5 inhibitors, based on the literature and on data obtained from pharmaceutic surveillance agencies. Patients had a mean age of 56.6 years. Eighty-eight percent of unilateral hearing loss were reported with a uniform distribution between the left/right sides. Hearing loss occurred within 24 hours after ingestion of a PDE5 inhibitor in 66.7% (n = 18) of the cases, and the use of sildenafil accounted for over 50% of the cases. Given these results, the authors concluded that there is growing evidence that PDE5 inhibitors may induce sensorineural hearing loss. And on these results, there needs to be more awareness of this disabling side effect among the health professionals responsible for prescribing this medication. The authors also emphasize that with the expiration of sildenafil patents between 2011–2013, generic drugs are more affordable and may cause a significant increase in the use of these drugs, as well as an increase in the number of sensorineural hearing loss casesIn Turkey, in 2012, researchers analyzed the histopathological effects of sildenafil use in the long term on the cochlea in an animal model. For that, the authors studied adult male Wistar albino rats. The control group was fed with a standard laboratory diet. The study group received sildenafil 1.5 mg/kg once daily orally for 45 days. Each temporal bone was dissected and the cochleae were removed en bloc. The rats were divided into two experimental groups: Group 1 (n = 10) was the control group, to which no medication was given, and Group 2 (n = 10) received sildenafil. They used 50 mg of sildenafil , ground into fine powder and dissolved in 0.9% NaCl. The dose of sildenafil citrate administered in this study was 1.5 mg/kg, a dose compatible with the doses normally used in humans. Sildenafil therapy was administered orally via an orogastric tube, once a day for 45 days, until 12 hours prior to surgery. To evaluate their hearing, the authors used the Transient Evoked Otoacoustic Emissions (TEOAE) test. The authors observed that the hematoxylin and eosin stain showed no difference between the groups. With respect to immunohistochemical analysis, caspase-3 immunostaining was observed in the group taking sildenafil. In the control group, the caspase 3 immunoreactivity was not observed. Thus, the authors concluded that caspase-3 immunostaining in the sildenafil group was strongly associated with an increase in apoptotic events in the cochlea, and the long-term use of sildenafil may cause hearing loss by increasing apoptosisp > 0.05). However, three patients used 20mg of tadalafil and had significant increase in their hearing thresholds in the higher frequencies. There was no incidence of sudden sensorineural hearing loss in the study group.In 2013, we performed the first prospective observational study using tadalafil in the auditory function, through an objective hearing evaluation. It was a prospective observational study in a tertiary hospital. Twenty-five patients who had not used tadalafil and had erectile dysfunction and pulmonary arterial hypertension underwent pure tone audiometry and Evoked Auditory Brainstem Response (ABR) prior to drug therapy, and 3 and 30 days after drug therapy. The authors found that 15 patients used 10 mg of tadalafil for erectile dysfunction, and 10 patients were taking 20 mg of tadalafil once daily for pulmonary arterial hypertension. There was no statistically significant difference in the hearing threshold at baseline and at follow-up (The authors stated that this was the first prospective observational study that evaluated the effect of tadalafil on the auditory function with objective evidence. Although they did not find a statistically significant result to confirm or refute the association between tadalafil and hearing impairment, raising the threshold at higher frequencies after the use of tadalafil supports the results of previous studies and suggests a possible relationship between the two. Finally, the authors suggest that further studies should be conducted with larger similar samples to understand the exact impact of type 5 phosphodiesterase inhibitors on auditory functionsThe increased occurrence of sudden hearing loss in patients using PDE5i and scientific reports in the literature suggest that the use of phosphodiesterase type 5 inhibitors is regarded as a risk factor for hearing, indicating the need for further studies on the possible ototoxicity of this class of drugs.


Quadrupedal mammals have fore-aft asymmetry in their body structure, which affects their walking and running dynamics. However, the effects of asymmetry, particularly in the transverse plane, remain largely unclear. In this study, we examined the effects of fore-aft asymmetry on quadrupedal trotting in the transverse plane from a dynamic viewpoint using a simple model, which consists of two rigid bodies connected by a torsional joint with a torsional spring and four spring legs. Specifically, we introduced fore-aft asymmetry into the model by changing the physical parameters between the fore and hind parts of the model based on dogs, which have a short neck, and horses, which have a long neck. We numerically searched the periodic solutions for trotting and investigated the obtained solutions and their stability. We found that three types of periodic solutions with different foot patterns appeared that depended on the asymmetry. Additionally, the asymmetry improved gait stability. Our findings improve our understanding of gait dynamics in quadrupeds with fore-aft asymmetry. Because mediolateral ground reaction forces (GRFs) are much smaller than vertical forces during trotting of quadrupedal mammals  is the angle of Body i relative to the horizontal line. Lij  is the length of Leg ij. The mass and moment of inertia around the COM of Body i  are Mi and Ii, respectively. The body joint has a torsional spring with a spring constant of KB that produces the body torsional movement. The body spring is at the equilibrium position when the bodies have the same posture (θF = θH). The spring constants of the forelegs (Legs FL and FR) and hind legs (Legs HL and HR) are KF and KH, respectively. All the legs have the same nominal length L0. The distance between the COM of the bodies and the root of the leg spring is D for both the fore and hind bodies. The gravitational acceleration is Each leg of a quadrupedal mammal has only 10% or less of the total mass . The mai mammals , we igno mammals  and focuij  is in the air, it remains vertical and maintains the nominal length (Lij = L0). When the tip touches the ground, the leg spring starts to compress to receive a GRF. When its length returns to the nominal length (Lij = L0) after compression, the tip leaves the ground. Because touchdowns and liftoffs occur at the nominal length, our model is energy conservative.When Leg The equations of motion of the model are given byLij = Z + Dj sin θi. Leg ij touches the ground when its tip reaches the ground and leaves the ground when its length returns to the nominal length. These conditions are both given byMF + MH, length scale D, and time scale To generalize the dynamics of the model, we non-dimensionalize the governing equations using the mass scale μi = Ii/((MF + MH)D2), ki = KiD/((MF + MH)i = F, H), kB = KB/((MF + MH)D), dL = 1, dR = −1, and hereafter, τ. The dimensionless condition for the touchdown and liftoff of Leg ij is given byDuring trotting, the four legs work in two pairs. Specifically, the diagonal legs  are paired. These two pairs touch the ground alternately. In this study, we focus on the motions during which one pair of legs touches and leaves the ground and then the other pair does the same. We assume that each leg touches the ground only once in a single gait cycle. Additionally, when one leg of a pair touches the ground, it never leaves the ground until the other leg of that pair touches the ground, that is, a double stance phase exists for each pair. We define the following four phases: flight (F), fore stance (FS), hind stance (HS), and double stance (DS) phases. In the flight phase, all the legs are in the air. In the fore (hind) stance phase, only the fore (hind) leg of a pair is in contact with the ground. In the double stance phase, both legs of a pair are in contact with the ground.q+ = BLRq− at the apex . In this study, *+ and *− indicate the states immediately after and before reversing, respectively. Therefore, we focus on the touchdowns and liftoffs for only one pair of legs, specifically using the pair of legs FL and HR.Because the model is left-right symmetric, the motion during which one pair touches and leaves the ground, and the motion during which the other pair touches and leaves the ground can be expressed using the same expression when the left and right sides of the model are reversed. Specifically, we use rA = 0 to represent the condition where the COM reaches an apex, rF = 0 to represent the condition where the fore leg of the pair touches and leaves the ground, rH = 0 to represent the condition where the hind leg of the pair touches and leaves the ground, and rD = 0 to represent the condition where both legs of the pair simultaneously touch and leave the ground. Specifically, Condition i  is given byrF(q) = rFL(q), and rH = rHR(q).The motion from one apex to the next apex is obtained from the phase transitions between the four phases , as illustrated in Based on these phase transitions, the motion from one apex to the next apex can be explained using nine sequences (Sequences 1–9), as illustrated in xi+1 = P(xi), where xi is the state immediately after the reversal at the ith apex. A fixed point x* on the Poincaré section, which satisfies x* = P(x*), corresponds to a periodic solution. We search the periodic solutions numerically by solving the following:z* by comparing the simulation results and measured data of animals as described in We search the periodic solutions using a Poincaré map by taking a Poincaré section immediately after the reversal of the left and right sides of the model at the apex δxi to the obtained solutions immediately after the reversal at the ith apex. The linearization of the Poincaré map P around x* yieldsJ is the Jacobian matrix of P. If all eigenvalues of J are located inside (inside and on) the unit circle on the complex plane, the periodic solution is asymptotically  stable; otherwise, the solution is unstable. Because the model is energy conservative, no asymptotically stable solutions exist. Therefore, we simply refer to marginally stable as stable. We define Λ = maxi=1,…,5|λi|, where λi  are the eigenvalues of J. If Λ = 1 is satisfied, the periodic solution is stable; otherwise, the solution is unstable.We add a perturbation μF and μH) and leg stiffnesses (kF and kH). To highlight the fore-aft asymmetry between these parameters, we define the averaged values of the moments of inertia and leg stiffnesses between the fore and hind bodies as μ0 and k0, respectively, and represent these four properties using asymmetric parameters ɛμ and ɛk as follows:Although we used the same physical parameters between the fore and hind bodies in the model in our previous study , quadrupɛμ = ɛk = 0 corresponds to the symmetrical model used in our previous work , which have a short neck, and warmblood horses, which have a long neck. For dogs, we use nd limbs , which yɛμ = ɛk = 0) in our previous study  to determine k0, κ, and z* so that the half cycle duration τ* (duration from an apex to the next apex), magnitude of the vertical movement δz, and duty ratio averaged among the four legs β0 of the periodic solution minimize c1, c2, and c3 are the coefficients and τ*, δz, and β0, respectively, during fast trotting in animals . In particular, we use c1 = 0.1 and c2 = c3 = 1. Using the obtained values of k0, κ, and z*, we then introduce asymmetry  in the model (ɛμ = 0.12 and ɛk = 0.21 in dogs and ɛμ = 0.14 and ɛk = 2.5 in horses). For the symmetric model , which yielded k0 = 1.5, κ = 0.2, and z* = 0.06. By changing ɛμ and ɛk based on the symmetric periodic solution, we uniquely obtained the periodic solution for each set of . ɛμ and ɛk, the curve of z is sinusoidal and those of θF and θH are parabolic. When ɛμ = ɛk = 0, the magnitudes of θF and θH were identical and flight–double stance phase transition directly occurred , which never changed the profiles of θF and θH from those in the symmetric model (ɛμ = ɛk = 0) and maintained Sequence 1 (ɛμ < aɛk and Sequence 9 appeared for ɛμ > aɛk (ɛμ = 0.12 and ɛk = 0.21) satisfied ɛμ < aɛk and thus generated Sequence 5. We compared the locomotion characteristics  between simulation results using the estimated parameters of dogs and the measured data of dogs in We obtained a periodic solution uniquely through the optimization in the symmetric model for dogs . When changing ɛμ and ɛk, we also achieved Sequences 1, 5, and 9 depending on ɛμ⋚aɛk, where a = 0.69 (see ɛμ = 0.14 and ɛk = 0.25) also satisfied ɛμ < aɛk and generated Sequence 5. We compared the simulated locomotion characteristics using the estimated parameters of horses with the measured data of horses in Similar to the dog model, we obtained a periodic solution and 0.69 see . The estμ0, k0, and κ by ± 50% from the dog parameter set  in ɛμ = aɛk, ɛμ < aɛk, and ɛμ > aɛk, respectively. Although the coefficient a changed slightly when μ0 and k0 increased  =  by calculating the maximum eigenvalue Λ of the Jacobian matrix of the Poincaré map (ɛμ = aɛk was satisfied (including ɛk = ɛμ = 0), Λ was much larger than 1 and the periodic solutions were highly unstable (the instability increased as ɛk increased). As the distance of  from ɛμ = aɛk increased, Λ decreased. The solutions became stable with Λ = 1 when  moved across two parallel lines ɛμ = aɛk ± b, where b = 0.02. This means that the trotting of the symmetric horse model was unstable, whereas fore-aft asymmetry stabilized it. The estimated asymmetric parameters of horses (ɛμ = 0.14 and ɛk = 0.25) satisfied ɛμ < aɛk − b, which indicates that the trotting of horses was stable. By contrast, the periodic solutions for the dog parameter set  =  were always stable for 0 ≤ ɛμ ≤ 0.3 and 0 ≤ ɛk ≤ 0.3, including the symmetric case ɛk = ɛμ = 0 .We investigated the stability of the obtained periodic solutions for caré map . When ɛμ = 0 . This reɛk, ɛμ ≥ 0) by independently changing μ0, k0, and κ from the parameter sets of dogs and horses. We found that ɛμ = aɛk ± b determined the stability for both cases in the same manner as that for the above results. Specifically, if b = 0, the periodic solutions were stable regardless of ɛμ and ɛk. By contrast, if b > 0, while the periodic solutions were unstable when ɛμ = ɛk = 0, they became stable when ɛμ ≥ aɛk + b or ɛμ ≤ aɛk − b. Therefore, although large asymmetry was necessary as b increased, fore-aft asymmetry stabilized the periodic solutions. We examined whether b depended on μ0, k0, and κ in the same manner as a in b by independently changing μ0, k0, and κ by ± 20% from the parameter sets for dogs  and horses  in μ0 exceeded a certain value, b increased from 0. When k0 or κ fell below a certain value, b increased from 0.Next, we investigated the stability of the periodic solutions in the asymmetric model (ɛμ = ɛk = 0), we demonstrated that k0 hardly affected the stability of the periodic solutions, and μ0 and κ mainly determined the stability. Specifically, the periodic solutions were stable when μ0 ≤ κ + 0.5 and unstable when μ0 > κ + 0.5. We investigated b around this stability boundary (μ0 = κ + 0.5) with k0 = 1.5, 1.85, and 2.2 in k0 = 1.5 and k0 = 2.2 correspond to the dog and horse parameters, respectively. For each value of k0, the boundary between b = 0 and b > 0 existed around μ0 = κ + 0.5.In our previous study  using thɛμ and ɛk. Specifically, Sequences 1 (flight–double stance–flight), 5 (flight–fore stance–double stance–fore stance–flight), and 9 (flight–hind stance–double stance–hind stance–flight) appeared when ɛμ = aɛk, ɛμ < aɛk, and ɛμ > aɛk, respectively  as shown in θ = (θF + θH)/2) and torsional angle (ϕ = (θF − θH)/2) is crucial. Sequence 1 requires simultaneous touchdowns and liftoffs by the paired fore and hind legs. In our previous study (ɛμ = ɛk = 0), we demonstrated that Sequence 1 appeared only when θ = 0, that is, the fore and hind bodies always rotated in the opposite direction (θF = −θH). In the present study, we demonstrated that even if the model had asymmetric properties ɛμ and ɛk, the relationship ɛμ = aɛk produced θF = −θH (θ = 0), which resulted in Sequence 1. This relationship was analytically obtained using perturbation theory (see ɛμ ≠ aɛk caused θF ≠ −θH (θ ≠ 0), other sequences appeared. In particular, when θ and ϕ had the same sign, the rotation of the fore body (θF = θ + ϕ) became larger than that of the hind body (θH = θ − ϕ), which induced Sequence 5. When θ and ϕ had opposite signs, the rotation of the hind body became larger than that of the fore body, which induced Sequence 9.Regardless of the dog and horse models, we found periodic solutions, which had several types of phase transitions depending on the asymmetric parameters ectively , where aus study  using theory see . By contɛμ = ɛk = 0 in the transverse plane was unstable, it was stabilized by introducing ɛμ and ɛk to satisfy ɛμ < aɛk − b or ɛμ > aɛk + b  as shown in In previous studies , the resk + b , where bb = 0 and b > 0 existed near μ0 = κ + 0.5 in the μ0-κ plane  in the symmetric model (ɛk = ɛμ = 0), as achieved in . Therefore, we expect that the boundary between b = 0 and b > 0 is identical to μ0 = κ + 0.5 in the μ0-κ plane. However, our results had some differences between them, as shown in In this study, the boundary between -κ plane , which cieved in . When μOur results showed that the fore-aft asymmetry improves gait stability during trotting. Although our model incorporated only passive forces using springs, unstable gait can be stabilized by additional control inputs. However, when the system has passive stability, it needs less control inputs and sensory feedbacks. This results in low energy consumption, which is therefore beneficial for quadrupedal animals.Because the front part of the body is generally heavier and has larger moment of inertia in the transverse plane than the hind part in quadrupeds , the forμ0 = 0.62 and ɛμ = 0.12) and μ0 < κ + 0.5 was satisfied . As a result, we achieved b = 0 and the periodic solutions were stable even when we introduced the asymmetries ɛμ and ɛk. Additionally, ɛμ < aɛk was satisfied for the estimated values in dogs, which yielded Sequence 5 (μ0 = 0.72 and ɛμ = 0.14). The periodic solution of the symmetric horse model with ɛμ = ɛk = 0 was unstable. However, that was stabilized by making the fore legs stiffer , such as gnus, do not use trotting, but do use walking and cantering , where the fore leg of the pair touches the ground earlier and leaves it later than the hind leg. Although horses show Sequence 5 during trotting , they baantering . This isIn this study, we examined the effects of fore-aft asymmetry on trotting by quadrupedal mammals in the transverse plane using a simple model. Our results demonstrated that the asymmetry gives different foot patterns and improves gait stability. Our findings improve our understanding of gait dynamics in quadrupeds with fore-aft asymmetry.


Valeriana jatamansi Jones is a traditional Chinese herb and possesses antiviral effects. In this study we investigated the potential mechanisms of V. jatamansi Jones in RV-induced diarrhea. MTT assay was performed to evaluate cell proliferation and the diarrhea mice model was constructed using SA11 infection. Mice were administered V. jatamansi Jones and ribavirin. Diarrhea score was used to evaluate the treatment effect. The enzyme-linked immunosorbent assay was performed to detect the level of cytokines. Western blot and quantitative reverse transcription-PCR were used to determine protein and mRNA levels, respectively. Hematoxylin-eosin staining was applied to detect the pathological change of the small intestine. TdT-mediated dUTP nick-end labeling was conducted to determine the apoptosis rate. The results showed V. jatamansi Jones promoted MA104 proliferation. V. jatamansi Jones downregulated phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT) in protein level, which was consistent with the immunohistochemistry results. Moreover, V. jatamansi Jones combined with ribavirin regulated interleukin-1β (IL-1β), interferon γ, IL-6, tumor necrosis factor α, and IL-10, and suppressed secretory immunoglobulin A secretion to remove viruses and inhibit dehydration. V. jatamansi Jones + ribavirin facilitated the apoptosis of small intestine cells. In conclusion, V. jatamansi Jones may inhibit RV-induced diarrhea through PI3K/AKT signaling pathway, and could therefore be a potential therapy for diarrhea.Rotavirus (RV), as the main cause of diarrhea in children under 5 years, contributes to various childhood diseases.  Rotavirus (RV) is the main reason for severe diarrhea among infants and children under 5 years old worldwide , especiaValeriana jatamansi Jones is a perennial herb mainly found in China and India and can be used as a substitute for European V. officinalis  were designed as 5’-CTTCTACCAGACGCGGAAAG-3’ (forward) and 5’-ATTCGGCCTGAGAATCACTG-3’ (reverse).Total RNA was extracted from cells using TRIzol method. The extracted RNA was reversely transcribed with a Transcriptor First Strand cDNA Synthesis Kit . The PCR was performed using a Real-Time PCR System  under the following conditions: 95°C for 10 min, followed by 40 cycles of 95°C for 10 s, 55°C for 30s, and 72°C for 60 s. Results were analyzed with the 2Total RNA was extracted by a single-step isolation procedure using Trizol . Total RNA were synthesized into cDNA using the Transcriptor First Strand cDNA Synthesis Kit (Roche Diagnostics GmbH). Semi-quantitative RT–PCR was performed to determine expression levels. GAPDH was used as a loading control. All primers were synthesized by SANGON (China). The sequences of the primers used were listed as follows: phosphatidylinositol 3-kinase (PI3K): Forward, 5’-CATCACTTCCTCCT GCTCTAT-3’, Reverse, 5’-CAGTTGTTGGCAATCTTCTTC-3’; protein kinase B (AKT), Forward: 5’-GGACAACCGCCATCCAGACT-3’, Reverse: 5’-GCCAGGGACACCTCCATCTC-3’; GAPDH: Forward, 5’-GGAGCGAGATCCCTCCAAAAT-3’, Reverse, 5’-GGCTGTTGTCATACTTCTCATGG-3’.V. jatamansi Jones) medium-dose group , high-dose group , RV+H+ribavirin group .Three-day-old suckling specific BALB/c male mice were purchased from the Model Animal Research Center of Nanjing University (China) and housed at 25°C with a 12 h light/dark cycle. The study was approved by the Ethics Committee of Jiangsu Agri-animal Husbandry Vocational College. All the mice were randomly divided into six groups: normal group , RV infection groups , low-dose group  to DPI7 and homogenized in 0.01 mol/l phosphate-buffered saline (pH 7.2) in a 10% (w/v) solution or suspension and centrifuged at 1200 × g for 20 min. The supernatants were collected and RV shedding was determined through RV antigen detected by PCR according to the manufacturer’s instructions. The test was considered positive if the optical density at 450 nm (OD450) ≥ 0.1.The severity of diarrheal illness was assessed by fecal material. Stools were scored from 1 to 4 based on color, texture, and amount. Normal feces were scored 1, exceptionally loose feces scored 2, loose yellow-green feces scored 3, and watery feces scored 4. Stools with a score of ≥ 2 were considered to be diarrhea. The percentage of diarrhea was calculated each day. Mice with no stool were considered as mice with no diarrhea. The diarrhea severity was determined.The serum levels of interleukin 1β (IL-1β), interferon γ (IFN-γ), IL-6, tumor necrosis factor α (TNF-α), and IL-10, secretory immunoglobulin A (sIgA) were determined with an ELISA kit (China) according to the manufacturer’s instructions. The results were detected with a microplate reader at the wavelength of 450 nm.Protein samples of mouse small intestine were extracted by M-PER Mammalian Protein Extraction Reagent  and quantified by Bio-Rad Protein Assay  according to the manufacturers’ instructions. The protein samples were separated with 12% sodium dodecyl sulfate polyacrylamide gels and transferred to polyvinylidene fluoride membranes. The membranes were blocked with 5% skimmed milk for 2 h at room temperature and then incubated in rabbit monoclonal primary antibodies for PI3K p85 beta , p-PI3K p85 beta , AKT , p-AKT  overnight at 4°C. After washing in PBS for 5 times, the blots were incubated in goat anti-rabbit horse-radish peroxidase-conjugated secondary antibody  for 1 h at room temperature. The protein level was determined with an ECL Detection Kit (Thermo Scientific) and analyzed by ImageJ 1.49 software .Small intestines were removed and fixed in 4% polyoxymethylene. The slices (5 mm) were secreted and deparaffinized. Then, the slices were stained by hematoxylin and eosin and observed under a light microscope. Crypt depth and villi height were measured with software Image Pro Plus 5.1 (IPP5.1). The villus length was measured from the base to the top of the villi, and the crypt depth was measured between the crypt-villus junction and the base of the crypt.2O2 for elimination of endogenous peroxidase activity. After blocking with goat serum, the slides were incubated with primary antibodies: anti-PI3K p85 beta , anti-p-PI3K p85 beta , anti-AKT ,anti-p-AKT  and then with goat anti-rabbit horse-radish peroxidase-conjugated secondary antibody  at room temperature for 1 h. The image was visualized with a microscope (Nikon).Tissues were deparaffinized and blocked with 0.3% HCell apoptosis in the mouse small intestine was detected by TUNEL assay with the In Situ Cell Death Detection Kit  according to the manufacturer’s instructions. Briefly, the small intestine of each mouse was embedded in paraffin and cut into 5-μm slices. Then, the slices were incubated with Fresh TUNEL mix (50 μl) for 1 h at 37°C and then with converter-POD at 37°C for 30 min. Afterwards, the slices were added with 50 μl of diaminobenzidine (DAB). Then the slices were washed with PBS thrice and then dehydrated, mounted, and captured with an optical microscope . Five fields were randomly chosen for each individual, and apoptotic cells were counted.p < 0.05 was considered statistically significant.All experiments were performed in triplicate and data were presented as the mean ± deviation standard (SD). Statistical analysis was performed by a one-way ANOVA followed by a Student-Newman-Keul’s test. 50 value was 41.17 μM for 48 h treatment, indicating that under 41.17 μM, V. jatamansi Jones had no significant inhibitory effects on MA104 cell proliferation  and ribavirin. Additionally, V. jatamansi Jones plus ribavirin was more potent in regulating cytokines involved in inflammation response. These results suggested blocking PI3K/AKT signaling pathways with V. jatamansi Jones may be an efficient therapy for RV-induced diarrhea.In previous studies, PI3K/AKT signaling pathways were shown to be intensively involved in the initiation and progression of intestinal diseases -18. Vira in rats , 22. Imp in rats . Ribavir in rats . Additio in rats . TherefoV. jatamansi Jones on RV in vivo. Diarrhea score results suggested V. jatamansi Jones and ribavirin improved diarrhea symptoms in RV-induced mice.Moreover, this study also evaluated the effect of V. jatamansi Jones played an anti-virus and protective role in RV-induced diarrhea through inactivating PI3K/AKT pathways. The combination of V. jatamansi Jones and ribavirin was more potent in inhibiting RV-induced diarrhea. V. jatamansi Jones could be used as a new drug and serve as a novel strategy for RV-induced diarrhea.Collectively,


GJB2 gene mutations, 30 patients were identified with STRC mutations, and 16 patients had pathogenic or likely pathogenic USH2A mutations. The presence of at least one GJB2 non-truncating variant in genotype led to less severe hearing impairment. The flat and gently sloping audiogram profiles were mostly revealed in all groups. The follow-up revealed the stability of hearing thresholds. GJB2, STRC, and USH2A pathogenic variants were detected in most patients in our cohort and were congenital in most cases.Congenital and early onset bilateral sensorineural hearing loss (SNHL) is mainly caused by mutations in numerous genes. The introduction of universal newborn hearing screening (UNHS) has increased the number of infants with mild, moderate, and moderate-to-severe sensorineural hearing loss (SNHL) detected in the first year of life. We aimed to evaluate the audiological features in patients with mild, moderate, and moderate-to-severe SNHL according to genotype. Audiological and genetic data were analyzed for 251 patients and their relatives with congenital bilateral mild, moderate, and moderate-to-severe SNHL. Hearing loss severity, audiogram profile, interaural symmetry, and dynamics of hearing thresholds were analyzed. In this case, 165 patients had  GJB2 gene are the most frequent cause of congenital SNHL. The screening of the GJB2 gene has recently turned into a routine clinical tool for neonates and infants with bilateral SNHL [GJB2, STRC, USH2A genes was demonstrated in the cases with mild and moderate congenital or early childhood SNHL [The majority of congenital sensorineural hearing loss cases (SNHL) are associated with mutations in numerous genes encoding the structures of the inner ear. The introduction of universal newborn hearing screening (UNHS) has increased the number of children with mild to moderate congenital SNHL detected in the first year of life ,2. Mutatral SNHL ,4,5. Theood SNHL ,7,8.GJB2-related hearing loss is mostly congenital or prelingual, stable, with a severe degree in the majority of cases [GJB2 genotypes, the reason of the phenotypic variability especially in 35delG homozygous patients remains unknown and cannot be explained by the effect of one major modifier gene. SNPs significantly associated with milder phenotype may produce a small modifying effect on the phenotype [GJB2-related hearing loss. The frequencies of non-penetrant at birth cases come to 3.8% and 6.9% that emphasize the importance of the genetic newborn screening for GJB2 mutations simultaneously with UNHS [It is well-known that of cases ,10. As aof cases ,12,13. Ahenotype . Not allhenotype ,16,17. Tith UNHS ,20,21,22GJB2-related hearing loss has a significant prevalence in the Russian Federation. The prevalence of hereditary hearing impairment due to mutations in the GJB2 gene is 1 per 1000 newborns. The carrier frequencies of the c.35delG mutation in a healthy population vary significantly between different regions from 2.5 to 6% [GJB2 gene have been identified in more than 65% of neonates with non-syndromic SNHL detected in the first year of life. Infants with GJB2-related hearing loss have mild and moderate SNHL in 31 out of 110 cases (28%) [GJB2 mutations demonstrate stability of auditory brainstem evoked response (ABR) thresholds during the first year of life in 66 out of 73 infants (90%), while in infants without biallelic GJB2 mutations, ABR thresholds were stable in 24 out of 35 infants (68%) [.5 to 6% ,24,25. Mes 28%) . The dynts (68%) ,28.% . The dGJB2, STRC, USH2A genes associated with mild, moderate, and moderate-to-severe SNHL.The aim of our study is to evaluate the audiological features in patients with hearing loss caused by mutations in the Audiological and genetic data were obtained for 251 patients (233 unrelated persons and 18 relatives) with congenital or early childhood bilateral non-syndromic SNHL of which 121 were males and 130 were females. All patients were observed in the National Research Centre for Audiology and Hearing Rehabilitation between February 2009 and February 2019 in the frame of observational longitudinal study. The median age at the enrollment was 7 years . Medical and family history, clinical data, including onset and progression of hearing loss, and the UNHS results were obtained from patient’s medical records. Our group was consisted of mild, moderate, and moderate-to-severe subgroups selected based on average hearing threshold levels (HTL) at 0.5, 1, 2 and 4 kHz in the better hearing ear. All patients had the results of their genetic tests.Based on the UNHS results, our group was divided into two subgroups. The first one was the group of 168 children born in the period after introduction of UNHS from 2008 till 2019 (UNHS group) . The criInformed written consent was obtained from all patients. Regarding family history, most patients had no relatives with hearing loss and no signs of the syndromes. In our study group only 28 patients (12%) had positive family history (one or more relatives with hearing impairment) and 18 relatives were included in the study.A number of audiological tests were performed in all patients. It included tympanometry, acoustic reflexometry, and transient evoked otoacoustic emission (TEOAE) registration using a standard protocol for all patients. The 1000 Hz tympanometry was used for testing infants in the age up to 6 months and 226 Hz tympanometry was applied when child was older than 6 months . Auditory brainstem evoked response (ABR) and auditory steady-state response (ASSR) recordings were performed in infants and toddlers (thresholds were obtained in dB nHL) with further hearing threshold confirmation using age-appropriate behavioral testing . ABR and ASSR thresholds (in dB nHL) were compared with behavioral thresholds (dB HL) using relevant frequency specific correction factor. Click- and tone-burst evoked ABR and ASSR were registered during patients’ natural sleep in a sound-proof and electrically isolated room. Pure tone threshold audiometry (PTA) has been used for all patients in the frequency range of 125–8000 Hz for air conduction and 250–4000 Hz for bone conduction stimuli , which was possible, since the follow-up period in our study was more than 5 years and all children have reached the age for PTA. The severity of hearing loss was estimated based on average hearing threshold levels (HTL) at 0.5, 1, 2 and 4 kHz in the better hearing ear and classified as normal, with thresholds ≤25 dB; mild hearing loss-26–40 dB; moderate hearing loss-41–55 dB; moderate-to-severe-56–70 dB, severe hearing loss-71–90 dB; and profound hearing loss with thresholds ≥91 dB ,30. The The analysis of audiological data included the onset of hearing impairment, an assessment of the degree of hearing loss in the better ear, the type of audiometric curve, the symmetry of the hearing loss and the dynamics of hearing thresholds.The frequencies of different audiogram profiles in each genotype were analyzed. The audiogram profile was evaluated by the ratio of hearing thresholds at frequencies of 0.5, 1, 2, 4 kHz according to the following criteria : (1) flaThe follow up period for most patients was more than 5 years and most patients had more than two audiograms.GJB2 gene. DNA analysis of GJB2 was carried out for all patients as previously described [GJB2 sequence variants was based on the cDNA reference sequence of the NM_004004.5 transcript.The genetic testing for DNA samples was carried out in the DNA Diagnostics laboratory at the Research Centre for Medical Genetics. The study included children and adults with bilateral SNHL, who previously underwent a molecular genetic analysis for mutations in the escribed . BrieflyGJB2-negative patients were tested using a custom targeted massive parallel sequencing panel, which includes 33 genes , TPRN, WHRN, ALMS1, POU3F4, SMPX), reported to cause non-syndromic and syndromic SNHL. For each sample, a library was created using the AmpliSeq™ Library Kit 2.0 commercial kit . Next generation sequencing was carried out on the Ion S5™ device . The processing of sequencing data was performed using an automated standard algorithm offered by Termofisher Scientific  as well as the Gene-Talk software. The clinical significance of the detected variants was assessed based on recommendations for the clinical interpretation of DNA sequence variants [USH2A gene the gross deletion/duplication analysis was carried out using the SALSA MLPA REAGENT KIT and original probes P361-A2 and P362-A2 for the USH2A gene . The obtained data were analyzed using the Coffalyser V8 program. To search for single-nucleotide variants, the presence of gross deletions and duplications in the STRC gene was also analyzed as it was described in our previous report [STRC gene, we used the SALSA MLPA REAGENT KIT and original probes P461-A1 for the STRC, CATSPER2, CKMT1B, PPIP5K1, PDIA3 genes . All patients underwent genetic counseling after obtaining the results of genetic testing.DNA samples of variants . For alls report . To conf2 test, in three or more groups by quantitative indicators using the Kruskal-Wallis test. The differences were considered statistically significant at p < 0.05.The collection and statistical processing of information was carried out using the Snailbase Medical Data storage and analysis system developed at the National Research Centre for Audiology and Hearing Rehabilitation and the Statistical Package R. For each variable, the median, quartiles, minimum, and maximum values were calculated. The statistical significance of differences in the values of signs in two groups was determined using the nonparametric Mann-Whitney test, differences in the frequencies of signs-using the χThe UNHS results were available for 118  patients. In this case, 94 infants failed UNHS, 83 of them were examined under the age of 12 months , 11 chilThe proportion of patients with “not performed” or “not available” result was higher among patients with moderate and moderate-to-severe hearing loss  than with mild degree (17%). Generally, 80% (94/118) patients failed UNHS, and 20% (24/118) were not detected by the screening. The distribution of patients according to the degree of SNHL showed that the detection level was better for moderate-to-severe (93%) and moderate (78%) phenotype than for the mild degree-72%. The median age of SNHL detection after UNHS for the “Failed” group was 5.5 months for the mild degree, 7 months-for moderate and 6 months-for the moderate-to-severe degree. The median age of SNHL detection for “Pass” group was 44.5 months for mild and moderate phenotype, and 24.5 months for moderate-to-severe impairment. If UNHS was not performed, the median age of diagnostics for mild SNHL was 69 months (5.5 y), and for moderate-to-severe 42 months (3.5 y).GJB2 mutations were found in 159 unrelated patients and 6 relatives with mild, moderate, and moderate-to-severe SNHL . Among them, 87 patients had truncating variants in both alleles , 49 patients had truncating and non-truncating variants in alleles (genotype T/NT), 29 patients had non-truncating variants in both alleles (genotype NT/NT) , 12 patients and 4 sibs had more than one the pathogenic or likely pathogenic variant of the USH2A gene , and mutations in the TECTA and ALMS1 genes were found in two patients.e NT/NT) . In the Among patients with mild, moderate, and moderate to severe SNHL the allele frequency of GJB2 variants differed from our previous whole group with bilateral SNHL of all severities . The allp = 0.00001, Kruskal-Wallis test t = 14.3 and p = 0.000, Kruskal-Wallis test t = 24.92, respectively). The c.358_360delGAG variant was found in 7 patients with moderate hearing loss.Patients with a homozygous c.35delG genotype prevailed in the group with the T/T genotype (61 vs. 26) and demonstrated moderate SNHL in 46% of cases, moderate-to-severe-in 40%, and mild-only in 14%. There was no difference in severity between c.35delG homozygotes and patients with the compound T/T genotype . PatientThe audiogram profiles in our cohort were predominantly flat and gently sloping and depended on genotype. In A gently sloping profile of the audiogram was observed in 21% of patients with the T/T genotype, in 19% of patients with the T/NT genotype, and in 33% of patients with the NT/NT genotype. Most often, this profile was found in the subgroups with NT/NT genotype: p.Met34Thr homozygotes  and other variants  D. A steeA non-specific audiogram profile was observed in all groups between 22% (T/T) and 29% (T/NT). The highest frequency of this profile was detected in the T/NT subgroups with the p.Val37Ile variant , T/NT with heterozygous p.Met34Thr  and NT/NT with homozygous p.Met34Thr  B,D.GJB2 gene are characterized by a flat and gently sloping profile of the audiograms . Clinically, this is characterized by higher speech intelligibility and a more favorable option for hearing aid fitting. The follow up revealed the stability of hearing thresholds in 85% (140/165) of cases.In the study group there were no audiograms with a U-shaped and ascending profile. Thus, patients with pathogenic variants of the STRC and USH2A patients are mostly flat and gently sloping, though USH2A cases had more hearing thresholds difference between high and middle frequencies  of cases were caused by mutations in the STRC gene and 5% (12/233) of cases were linked to the USH2A gene. The inclusion criteria were based only on the severity of hearing loss, and most cases were presumably congenital and non-syndromic, no environmental or other causes were excluded except for severe neurologic pathology. These results demonstrate the high frequency of genetic etiology in cases of mild, moderate, and moderate-to-severe non-syndromic SNHL in our area. We can only explain such a high percentage by the prevalence of the GJB2 mutations in our country. The frequency of other genes is consistent with data from other studies. Recently, some works have appeared that indicated a high proportion of hereditary cases in the group of patients with mild and moderate hearing loss. Approximately two-thirds of sporadic pediatric mild-to-moderate SNHL have a clear Mendelian genetic etiology, and one-third is associated with CNVs involving STRC in Korea [In this study, the detection capabilities of a pathological genotype in patients with mild, moderate, and moderate-to-severe congenital bilateral SNHL were 83% in our cohort without relatives (193/233): 68% (159/233) of cases were caused by mutations in the in Korea .GJB2 gene were higher than in the total group. The c.35delG was most frequent variant for hearing loss of different severity. The p.Met34Thr variant was the most common mutation in our study group. The presence of at least one non-truncating variant caused milder course of hearing loss. The non-truncating mutations p.Met34Thr, p.Val37Ile, p.Leu90Pro were more common for the mild and moderate hearing loss. Patients with the c.35delG homozygous genotype demonstrated all degrees of severity but the mild phenotype was rare (14%). At the same time patients with non-truncating variants in both alleles (NT/NT) had mild phenotype in most cases and very rare moderate-to-severe phenotype. Several of the common genotypes associated with mild and moderate phenotype were described in detail earlier and complete GJB2 mutation screening was offered to all children with non-syndromic SNHL, regardless of severity [It was shown that in patients with mild, moderate, and moderate-to-severe SNHL, the allele frequencies of non-truncating mutations in the severity ,36,37,38STRC- and USH2A-related SNHL are detected by UNHS. In this case, 8 out of 11 children with the USH2A biallelic mutations failed UNHS and initially were diagnosed as having the bilateral non-syndromic hearing loss before the detection of a molecular cause [Due to UNHS, more children with mild to moderate hearing loss are diagnosed in the first year of life . Generalar cause .Medical genetic counseling for various forms of hereditary hearing loss is carried out to explain the cause of hearing loss, the recurrence risks of the disease, and the course of hearing loss. However, the difficulty of genetic data interpretation or the lack of expected results in some cases leaves the patient and family without an answer to these questions. Despite this, molecular genetic studies can help most families with known genetic disorders. Prenatal and pre-implantation diagnosis allow for the assistance of the family in the birth of a healthy child.GJB2 gene are the major cause of mild, moderate, and moderate-to-severe hearing loss in our cohort. Among patients with mild, moderate, and moderate-to-severe bilateral SNHL the allele frequency of GJB2 variants were different from our previous group with SNHL of all severities. The presence of at least one non-truncating GJB2 variant causes a milder course of hearing loss. Hearing loss associated with the GJB2, STRC, and USH2A genes are characterized by congenital and early onset, symmetrical hearing impairment with mild and moderate severity, stable hearing thresholds in the first or second decade of life in most cases.In this study the group of patients with mild, moderate, and moderate-to-severe congenital, SNHL demonstrates a high frequency of the pathological genotypes. Generally, 80% of patients of our cohort with known results failed UNHS. Mutations in the


A cochlear implant is a neuroprosthetic, electrical device that is developed for the treatment of patients who have sensory hearing loss. It directly stimulates the hearing nerve by bypassing the injured or damaged sensory receptors, the hair cells. This implant is directly placed in the inner ear. It is an electronic device which is proved to be very useful in patients with sensorineural hearing loss. This implant consists of a speech processor , which takes up the sound; transforms it into digital signals, and then internal components take it to convert it into electrical energy, which stimulates auditory nerves, and the brain perceives it and hears it as a sound. This is one of the most successful surgeries, which happens very frequently nowadays. Although, many complications are mostly associated with this implant. This paper deals with the preoperative, operative, and postoperative complications associated with cochlear implant surgery. That includes tinnitus, Meniere's disease, unilateral hearing loss, musical ear syndrome, infections; flap necrosis, facial nerve palsy, improper electrode placement, magnet displacement; failure and re-implantation, cholesteatoma, and pneumocephalus. These are just a few of the complications; there are much more complications which are associated with cochlear implants. The cochlea is a structure of coiled nature present in the ventral area of the inner ear and is the main organ for perceiving sound. The Organ of Corti lines throughout the spiral of the cochlea, the sensory epithelium, which is highly derived and rigorously patterned which helps in converting stimuli of auditory into impulses of the nerve . A prevaWhen a person is unable to hear, cochlear implants (CI) can be used, which are the best solution for the perception of speech for most users . The objCochlear implant surgery is a routinely done surgery that is performed under general anesthesia. Behind the ear, a small incision is made by the surgeon. The cochlear implant is kept under the skin, and the electrodes are inserted into the inner ear. Tests for measuring the response to the implant are done by a team of surgeons. Further, they would close the incision using disposable stitches. Cochlear implants and hearing aids are two different devices. Amplification of the sound is the main function of a hearing aid. This amplified sound is detected by the ear, which is damaged. Many people recognize warning signals with the help of this device. Implant users can understand other sounds present in the environment. They understand what the other person is saying .Indications of cochlear implants are bilateral (B/L) sensorineural hearing loss (SNHL), B/L deafness , B/L loss of hearing for frequency in higher ranges whilst maintaining frequency of lower ranges, in aids of hearing absence - stimulation of electroacoustic nature and asymmetrical hearing loss with deaf ears having serious tinnitus, which other hearing aids cannot treat, like the bone conduction implant or bi-contralateral routing of signals system (biCROS/CROS), treatment should be done one by one. There are various special cases in which we need fast intervention with implantation . These cMethodologyStructural components of an implant are a magnet, controller and battery compartment, sound processor, and ear hook Figure  17]. . 17]. Mechanism of actionThe Cochlear implant takes the sounds present in the environment with the sounds of a person speaking, using microphones that are integrated within the speech processor. Acoustic signals, which are recorded by the processor, are then transformed into the digital domain for pre-processing . th cranial nerve (cochlear part)  Figure  17,18].,18.th crComponents of a cochlear implantThe implant consists of the following parts: A speech processor, transmitter, receiver, and electrode array Table  15]. . 15]. Cochlear implant surgery has various advantages and disadvantages when performed on patients with complications. These are listed in Table Pre-operative indicationsTinnitus is a condition in which the patient experiences a ringing sensation in the ear. Before performing the surgical operation of putting the cochlear implant, tinnitus is a condition that is commonly indicated. There are studies in which it has been found that there are noticeable changes in the perceptivity of tinnitus after a cochlear implant . StimulaMeniere’s disease (MD) is another clinical indication for cochlear implantation. It is an inner ear disorder in which certain clinical features have been observed, including loss of hearing, ringing sensation in the ear (tinnitus), and spinning sensation (vertigo). In most cases, it is a gradually progressive condition that has a remarkable impact on the person's social life . The preApart from these major complications, it is also observed in the pediatric population that the application of CI in unilateral hearing loss is a newly approved treatment modality by FDA (Food and Drug Administration) in 2019 . StudiesOperative complicationsWhile performing the operative procedures of a cochlear implant, multiple complications can be observed. Anatomical malformations of the middle ear can cause complexity in cochlear implant surgeries. These abnormalities could be inner ear malformations which include cochlear aplasia, hypoplasia of the cochlea, incomplete partition with a prevalence of 40%-100%, hypoplastic mastoid with 55.2% prevalence, aberrant facial nerve course with 36% prevalence rate, aplastic round window with 71% prevalence and malformation of the vestibuli . These aIt has been estimated that around 46.58% is the actual exposure of the facial nerve in iatrogenic (physician-induced) dehiscence . The anaFlap necrosis is another major surgical complication observed during cochlear implant surgery, which has a rate of 1.4% . It causAnother complication during surgery is improper placement of the electrode. It is one of the major complications during cochlear implant surgery, with a rate of 3.8% . While iThere could be another type of complication seen in cochlear implants, magnet displacement . A studyPostoperative complicationsIn virtue of failure and re-implantation of the implant, the process of CI is a secure rehab surgical intervention for hearing with a low rate of complication. There are minor postoperative complications that rightly cause infection in children, such as acute otitis media. In the case of adults, it is cochleovestibular, i.e., tinnitus and vertigo. Major complications include re-implantation after due surgery or in case of failure of the device . Other operative complications of cochlear implants may include Gusher syndrome, which means profuse amounts of CSF  observed while performing cochleostomy in CI. As per a study, which included 415 patients, it was found that 39 gushers were observed to have an incidence rate of about 9.39% . This syApart from these significant postoperative complications, Injury to the facial nerve has been another postoperative complication. The prevalence rate of transient facial nerve palsy in cochlear implant patients has been observed to be around 1.4% . PostopeAnother major complication that is also followed by an implant surgery is musical ear syndrome (MES). This is a syndrome in which there is the perception of musical sensations in the auditory system without any external stimulus. It is described as a rare situation called musical ear syndrome . Prevaleth August 2022 [Pneumocephalus is another rare postoperative condition that causes seizures and is rarely seen to happen weeks after post-surgery. Only five cases for this have been reported as searched on PubMed as on 8ust 2022 . They arust 2022 . The occurrence of cholesteatoma (0.95%) has also been observed in CI patients . There iThe critically classified surgical complications, as well as the indications, since pre-operative indications, operative, and postoperative complications are illustrated in Figure Cochlear implants are one of the most effective treatment options for the rehabilitation of patients who have sensorineural hearing loss. Our study included preoperative indications and operative and postoperative complications in which it was noted that there are multiple complications with high prevalence rates, which are associated with cochlear implants. These complications could range from simple infections like otitis media, incision infections, or wound infections; to facial nerve palsies. We have also included certain rare complications in our study, which include pneumocephalus, anatomical malformations of the ear, electrode displacements, and implant failure.Proper indications for the use of implants, highly sensitive imaging modalities, and thorough knowledge about the anatomy of the ear and nearby structures may prove a boon in reducing complications.