Each patient was evaluated four times: at baseline and after one week, one month, and three months of treatment. During each visit, each patient was subjected to full audiological history, otoscopic examination, basic audiological evaluations, and transiently evoked and distortion product otoacoustic emission (TEOAEs & DEOAEs).The hearing thresholds (frequency range 250–8000 Hz) and word recognition scores of patients with detectable TEOAEs and DPOAEs improved significantly, whereas no significant improvements were observed in those with no response.Hearing improvement is better in patients with detectable TEOAEs and DPOAEs. As a result, TEOAEs and DPOAEs are recommended as routine tests in all SSNHL patients to predict outcomes and monitor treatment as TEOAEs and DPOAEs reflect the cochlear OHCs activity. It is a common condition, affecting 1.5–1.7 per 100 new patients .Sudden sensorineural hearing loss (SSNHL) is defined as a 30 dB or more sensorineural hearing loss over at least three consecutive audiometric frequencies within 72 h . The cause and proper treatment are still unknown. Hearing threshold recovery may be total or partial regardless of the cause. Factors affecting recovery are the patient's age at hearing loss onset, severity and frequency ranges, vertigo, and the interval between hearing loss onset and the first contact with the treating physician .Most SSNHL patients are idiopathic . The differential diagnosis is extensive; infectious causes account for 13%, followed by otologic (5%), traumatic (4%), vascular or hematologic (3%), neoplastic (2%), and miscellaneous (2%) causes . Hearing loss occurs due to damage to hair cells or other cochlear structures in many of these etiologies and is permanent. More harm can be avoided if the underlying cause is determined and treated immediately .The underlying etiology is known in 7%–45% of SSNHL patients . Due to its potent anti-inflammatory action, systemic steroid therapy at high doses is the foundation of treatment . Additionally, steroids inhibit cytotoxic immune responses, enhance microvascular blood flow in the cochlea, and delay endolymphatic hydrops development. Antiviral medicines such as acyclovir or valacyclovir should be administered if a viral cause is suspected .SSNHL treatment should be prompt and focused on the conditions most likely to benefit. After 30 days, treatment may be ineffective since the acute disease may have subsided, and long-term harm may have occurred . Elicited OAEs may successfully distinguish between normal and hearing-impaired populations .Sounds originating in the cochlea can be detected and recorded using a microphone placed in the external auditory canal. Numerous studies evaluated the use of these emissions, termed otoacoustic emissions (OAEs). Transient evoked otoacoustic emissions (TEOAEs) and distortion product otoacoustic emissions (DPOAEs) are detectable in nearly all people with normal cochlear and middle ear function. In contrast, TEOAEs are absent in mild sensorineural hearing loss, and DPOAEs are absent in sensorineural hearing loss greater than 50 dB but detectable in inflammatory diseases associated with cochlear nerve involvement . However, changes in OAEs frequently precede changes in audiometric hearing thresholds. Otoacoustic emissions (OAEs) are derived from the electrochemical motility of the OHC. They indicate the integrity of the inner ear, particularly the cochlear amplifier, and thus they may be beneficial in evaluating the ISSNHL prognosis .Since TEOAEs and DPOAEs indicate outer hair cell (OHC) activity, it can be hypothesized that in the majority of ISSNHL patients, OHC function worsens as the hearing threshold increases and recovers when hearing improves According to Babich and Dunckly, 12 of 14 studies support using OAEs as a diagnostic method for predicting hearing improvement in ISSNHL patients. Some studies used TEOAEs or DPOAEs only, while others used both TEOAEs and DPOAEs.This study aimed to evaluate the predictive value of TEOAEs and DPOAEs in ISSNHL patients and monitor their changes during recovery.2This prospective study was conducted in the interval between March 2018 to January 2020 in the Audiology Unit, Mansoura University Hospital. Written informed consent was obtained from all patients following the Helsinki Declaration. The study was conducted following the standards of the Mansoura ORL Department Ethical Committee and was approved by the Faculty of Medicine Institutional Research Board.Thirty adult patients aged 20–50 years with idiopathic acute sensorineural hearing loss were included within the first week of the attack. All patients showed SNHL of at least 30 dB in three consecutive frequencies within three days.Patients with a medical or neurological condition affecting the auditory system, a family history of hearing impairment, otoscopic evidence of ear-drum abnormalities, ototoxic drug intake, noise exposure, vertigo, chronic middle ear pathology, or previous ear surgery were excluded.31Sound-treated room - locally made.2Pure tone audiometer: Madsen-Itera II (Denmark).3Impedance audiometer .4Otoacoustic emissions .All patients were evaluated four times, during the first week and after one week, one month, and three months of treatment.Once diagnosed, all patients received oral prednisone (1 mg/kg/day) for seven days, followed by another seven days to taper down the dosage. Intratympanic dexamethasone (10 mg/ml) was injected in the affected ear daily until no significant improvement was observed by pure tone audiometry (after every three intratympanic steroid injections). All patients were referred for a magnetic resonance imaging study of brain and cerebellopontine angle to rule out retrocochlear or brain lesions such as vestibular schwannoma. and word recognition score with Arabic phonetically balanced words . Immittancemetry included both tympanometries at varying pressures (+200 to −400 dapa). Then, they were elicited ipsilaterally at 1000 and 2000 Hz and contralaterally using pure tones of 500, 1000, 2000, and 4000 Hz.During each visit, each patient was subjected to full audiological history, otoscopic examination, and basic audiological evaluations such as pure-tone audiometry (PTA), speech audiometry, and immittancemetry. PTA included air conduction threshold ranging from 250 to 8000 Hz and bone conduction threshold ranging from 500 to 4000 Hz. Speech audiometry included speech recognition threshold (SRT) with Arabic spondee words TEOAEs were induced by clicks (80 dB pe SPL) and analyzed at 1, 1. 5, 2, 3, and 4 kHz in a 20-ms window and were considered present if the response signal to noise ratio (SNR) was 6 dB with reproducibility >70% at three frequencies, with an overall SNR of 6 dB SPL and an overall reproducibility >70%. DPOAEs were in the form of a DP-Gram over f2 750, 984, 1500, 2016, 3000, 3984, 6000, and 7969 Hz . They were considered present if SNR was 6 dB at four frequencies. DPOAE response levels were provided for f2 but were measured at 2f1-f2.This study was conducted on 30 patients with ISSNHL after excluding six patients . The patients' mean age was 42.33 ± 5.54 years and ranged from 20 to 50 years. Eighteen patients (60%) were males, and 12 (40%) were females. All patients were presented with unilateral ISSNHL; 14 (46.7%) in the right ear and 16 (53.3%) in the left ear.Hearing loss was mild in 14 patients (46.7%), moderate in 4 (13.3%), moderately severe in 4 (13.3%), severe in 6 (20%), and profound in 2 (6.7%). Audiometric configuration was high frequency ISSNHL in 18 patients (60%), flat in 8 (26.7%), and low frequency in 4 (13.3%).4Data were analyzed using SPSS version 23. Means with standard deviations (SD) were used for descriptive statistics. Repeated measures analysis of variance (ANOVA) or Friedman's test compared numerical data for more than two related groups, followed by post-hoc tests with Bonferroni correction. Pearson's and Spearman's correlation coefficients were used for correlation analysis. All P-values less than 0.05 were considered significant.5TEOAEs were detected in 18 patients during the initial evaluation but were not found in 12. They were detected in 21 patients after one week of treatment and 24 patients after one and three months. DPOAEs were detected in 20 patients at the initial evaluation but were absent in ten. They were detected in 22 patients after one week of treatment and 25 patients after one and three months.In fourteen mild ISSNHL patients, TEOAEs and DPOAEs were initially detected in 10 patients and were absent in four. In four moderate ISSNHL patients, TEOAEs were initially detected in two patients and were absent in the other two, while DPOAEs were detected in three of four patients. Also, in four moderately severe ISSNHL patients, TEOAEs were initially detected in two patients and were absent in the other two, while DPOAEs were detected in three of four patients. In severe ISNHL patients, TEOAEs and DPOAEs were initially detected in four patients and were absent in two. During the initial assessment, two patients were found to have profound ISSNHL with no TEOAEs or DPOAEs.Throughout the study, significant improvements in the hearing thresholds at 250–8000 Hz were observed. In contrast, no significant improvements were detected in the word recognition scores. The hearing thresholds at 500–4000 Hz improved significantly at one month and three months compared to the initial evaluation. No statistically significant changes in hearing thresholds and word recognition scores were observed at three months compared to one month .Table 1PThroughout the study, the transient evoked otoacoustic emissions (TEOAEs) SNR significantly increased at 1, 1.2, 1.5, 2, 3.4, and 4 kHz. In contrast, no significant increase was observed at 3 kHz. Transient evoked otoacoustic emissions (TEOAEs) SNR significantly increased at 1, 1.2, 1.5, 2, and 3.4 kHz at one month and three months compared to the initial evaluation. In addition, it significantly increased at 2 kHz at three months compared to the first week. No significant changes were observed at three months compared to one month .Table 2TThere were negative correlations between hearing thresholds and TEOAEs SNR at 1 kHz at the initial evaluation, one week, one month, and three months. Furthermore, significant negative correlations were found at 2 kHz at the initial evaluation, one month, and three months, with an insignificant negative correlation at one week. In addition, statistically significant negative correlations were detected at 4 kHz at one month and three months, with an insignificant negative correlation at the initial evaluation and one week. Furthermore, negative correlations were noted between the average PTA and TEOAEs SNR at the initial evaluation, one week, one month, and three months .Table 3CCompared to the initial evaluation, patients with TEOAEs had improved hearing thresholds at 250–8000 Hz and word recognition scores at one month and three months. Also, significant improvements in the hearing thresholds at 2000 Hz and word recognition scores were noted at one week compared to the initial evaluation .Table 4PPatients with non-detectable TEOAEs had non-significant improvements in hearing thresholds at 250–8000 Hz and word recognition scores throughout the study .Table 5PDPOAEs SNR at 7969, 3984, 3000, 2016, 1500, 984, and 750 Hz demonstrated a significant increase throughout the study, with an insignificant change at 6000 Hz. Also, significant increases were reported at 7969, 3984, 3000, 2016, 1500, 984, and 750 Hz at one month and three months compared to the initial evaluation. In contrast, no significant changes were reported at three months compared to one month .Table 6DSignificant negative correlations were reported between hearing thresholds at 1000 Hz and DPOAEs SNR at 984 Hz at the initial evaluation, one month, and three months, with an insignificant negative correlation at one week. Also, significant negative correlations were observed between hearing thresholds at 2000 Hz and DPOAEs SNR at 2016 Hz at one month and three months, with insignificant negative correlations at the initial evaluation and one week. At the initial evaluation, significant negative correlations were reported between hearing thresholds at 4000 Hz and DPOAEs SNR at 3984 Hz, one week, one month, and three months. Furthermore, significant negative correlations were noted between hearing thresholds at 8000 Hz and DPOAEs SNR at 7969 Hz at the initial evaluation, one month, and three months, with an insignificant negative correlation at one week .Table 7CPatients with DPOAEs demonstrated significantly improved hearing thresholds at 250–8000 Hz and word recognition scores. Significant decreases (improvements) in hearing thresholds at 250–8000 Hz and increases (improvements) in word recognition scores were observed at one month and three months compared to the initial evaluation. Also, a significant decrease (improvement) in the hearing threshold at 1000 Hz and an increase (improvement) in speech discrimination scores were noted at one week compared to the initial evaluation. In addition, a significant decrease (improvement) in the hearing threshold at 500 Hz was reported at three months compared to one week .Table 8PThroughout the study, patients with non-detectable DPOAEs had non-significant decreases (improvements) in the hearing thresholds at 250–8000 Hz or increases (improvements) in word recognition scores .Table 9PThere was a significant positive correlation between TEOAEs and DPOAEs in almost all correlated frequencies at one week, one, and three months after treatment .Table 106, who stated the rarity of bilateral involvement (less than 2–5%).The current study included 30 patients with unilateral ISSNHL. No patient had bilateral involvement, which is consistent with ++ homeostasis in the OHCs of the cochlear base and apex. Three factors determine OHCs cytoplasmic Ca++ homeostasis; the first is Ca++ influx into OHCs via mechanotransducer (MET) channels; the second is the buffering of Ca++ cytoplasmic load by calcium-binding proteins and organelles like mitochondria; the third is Ca++ extrusion by the plasma membrane Ca ATPase pump. High-frequency basal OHCs are more susceptible to damage and apoptosis than apical OHCs due to their preferential increased risk of intracellular Ca++ overload. ue to the small membrane area, the basal ones have higher MET currents and lower Ca++ extrusion rates.The high-frequency SNHL was the most common audiometric configuration observed in the current study, followed by the flat and low-frequency types, and this finding is supported by several studies. ).The extrinsic factors are based on the hypothesis of different etiologies as acoustic trauma hits the basal turn of the cochlea with more energy load than the relatively protected apical region by the acoustic reflex. Furthermore, when viruses infect the middle ear or round window niche, they first reach the anatomically closed area of the basal part (, who reported improvement in PTA by 13.8 ± 16.6 dB for 31 patients treated within two weeks of ISSNHL onset by corticosteroids. Also, The current study has revealed statistically significant improvements in hearing thresholds at 250–8000 Hz. This finding is in line with ,.This study reported significant increases in TEOAEs SNR at 1, 1.2, 1.5, 3.4, and 4 kHz. In line with this finding, who revealed a concurrent increase in TEOAEs and DPOAEs amplitudes with the hearing threshold recovery in 15 patients with ISSNHL. These findings suggest outer hair cell function deterioration when the hearing threshold is elevated and recovery as hearing improves.Hearing thresholds and TEOAEs SNR at 1 kHz were found to have statistically significant negative correlations at the initial evaluation, one week, one month, and three months. In addition, statistically significant negative correlations were reported at 2 kHz at the initial evaluation, one month, and three months. In addition, statistically significant negative correlations were detected at 4 kHz at one month and three months. Furthermore, statistically significant negative correlations were reported between the average PTA and TEOAEs SNR at the initial evaluation, one week, one month, and three months. These findings are consistent with In contrast, In the current study, significant improvements were observed in hearing thresholds and word recognition scores in patients with TEOAEs. In contrast, no significant improvements were detected in patients with no TEOAEs. , small and large amplitude TEOAEs were measurable in normal and hearing-impaired ears, respectively. TEOAEs were more robust in some cases than expected at corresponding hearing thresholds, particularly at 1000, 1500, and 2000 Hz. Similarly, Nevertheless, according to In this study, DPOAE SNR significantly increased at 7969, 3984, 3000, 2016, 1500, 984, and 750 Hz. However, a non-significant increase was reported at 6000 Hz, which may be due to a more significant cochlear cell impairment at the mid frequencies than the higher ones.Significant negative correlations were reported between hearing thresholds at 1000 Hz and DPOAEs SNR at 984 Hz at the initial evaluation, one month, and three months. Also, hearing thresholds at 2000 Hz were negatively correlated with DPOAEs SNR at 2016 Hz at one month and three months. In addition, significant negative correlations were observed between hearing thresholds at 4000 Hz and DPOAEs SNR at 3984 Hz at the initial evaluation, one week, one month, and three months. Furthermore, hearing thresholds at 8000 Hz were negatively correlated with DPOAEs SNR at 7969 Hz at the initial evaluation, one month, and three months.The results of Significant improvements in hearing thresholds and word recognition scores were noted in patients with DPOAEs, whereas no significant improvements were detected in patients with no DPOAEs. In line with these findings, The findings of In the current study, the positive correlations between the TEOAEs and DPOAEs in ISSNHL patients at one week, one, and three months of treatment may be attributed to OHC and cochlear function recovery.OAEs are objective rapid tests with good reliability and stability . In the There were significant improvements in hearing thresholds throughout the study at 250–8000 Hz. After therapy, hearing improvement was more pronounced in patients with TEOAEs and DPOAEs than in others with no emissions. As a result, TEOAEs and DPOAEs are recommended as routine tests in all SSNHL patients to predict outcomes and monitor treatment as TEOAEs and DPOAEs reflect the cochlear OHCs activity.1- Aya El-sayed El-sayed Gaafar, Master.Clinical data collection, analysis and writing of the paper.2-Elshahat Ibrahem Ismail, MD.Clinical data collection, analysis and writing of the paper.3- Hesham Saad Zaghloul, MD.Clinical data collection, analysis and writing of the paper.All the authors declare that they have not any conflict of interest.


Ctsk−/−) have a reduction in nocifensive behaviors in the formalin test. In addition, Ctsk−/− do not develop mechanical hypersensitivity after CFA injection for up to 7 days. Moreover, we found that inhibition of cathepsin K reduced mechanical hypersensitivity after CFA injection and mRNA levels, protein levels, and cathepsin K activity levels were elevated after CFA injection. Based upon our data, cathepsin K is indicated to play a role in the expression of chemically-induced cutaneous hypersensitivity, as Ctsk−/− mice do not develop mechanical hypersensitivity and show a reduction in nocifensive behaviors. Further research is needed to determine whether attenuating cathepsin K activity may generate a clinically relevant therapeutic.Persistent/chronic inflammatory pain involves multiple pathophysiological mechanisms and is far more complex than acute/momentary pain. Current therapeutics for chronic inflammatory pain are often not effective because the etiology responsible for the pain is not addressed by traditional pharmacological treatments. Cathepsin K is a cysteine protease that has mostly been studied in the context of bone and joint disorders. Previous work by others has shown that inhibition of cathepsin K activity reduces osteoarthritis-associated nociception in joints. However, the role of cathepsin K in cutaneous inflammation is understudied. We assessed the effectiveness of genetic deletion or pharmacological inhibition of cathepsin K in male mice on the expression of nocifensive behaviors after formalin injection or mechanical and thermal hypersensitivity after injection of complete Freund’s adjuvant (CFA) into the mouse hind paw. Our data demonstrate that cathepsin K knockout mice ( The “problem” with pain arises when acute/momentary pain becomes persistent/chronic due to maladaptations within the peripheral and/or central nervous systems2. Inflammation can play a critical role in the transition of acute to chronic pain, but our understanding of the underlying mechanisms is incomplete, and currently available analgesics do not address the underlying etiology8. Of particular interest to our group is the role of proteases that either directly or indirectly work in concert with inflammation to bring about these changes.Pain conveys information about our bodies when something may be awry, signals us when we need to protect body parts from further damage, and helps us make associations between stimuli that may be harmful and threatening to us10. While cathepsins are important in intracellular protein degradation, energy metabolism, and immune responses, they are also implicated in wide range of diseases including cancer, cardiovascular diseases, and inflammatory neurological diseases11. When secreted extracellularly under physiological conditions, cathepsins degrade protein components of the extracellular matrix12. In disease states, the role of cathepsins goes beyond simple proteolysis, as cathepsins participate in cytokine and chemokine processing during inflammation and mediate pain signaling17. Specifically, cathepsin S facilitates both inflammatory pain18 and neuropathic pain20. After nerve injury, cathepsin S takes part in the transition process from acute to chronic pain21. It exerts its effect by activating the protease-activated receptor (PAR) 222. Similarly, it has been shown that cathepsin B promotes chronic inflammatory pain after peripheral inflammation23, while cathepsin E (an aspartic proteinase24) contributes to the generation of neuropathic pain in autoimmune encephalitis25, and cathepsin G (a serine proteinase26) plays a role in the development of chronic post-surgical pain27. Therefore, a prominent role for cathepsins in various pain paradigms is beginning to emerge.Cathepsins are endogenous proteases mostly found within lysosomes29. However, there is growing evidence that cathepsin K has a critical role in chronic inflammatory pain signaling. For instance, in a guinea pig model for osteoarthritis in knees, prolonged cathepsin K inhibition reduced joint nociception30. Furthermore, inhibition of cathepsin K activity has been shown to have analgesic effects in a model of osteoarthritis30. We wanted to expand upon these studies and determine if cathepsin K has a role in models of cutaneous inflammation. To determine this, we assessed the effectiveness of genetic deletion or pharmacological inhibition of cathepsin K activity in male mice on the expression of nocifensive behaviors after formalin injection or mechanical and thermal hypersensitivity after injection of complete Freund’s adjuvant (CFA) into the mouse hind paw. Our data suggest that cathepsin K plays a role in the expression of inflammatory-induced hypersensitivity as cathepsin K knockout mice (Ctsk−/−) do not develop mechanical hypersensitivity and have a reduction in nocifensive behaviors. In addition, our data suggests that acute local pharmacological inhibition, unlike in models of osteoarthritis, produces an analgesic effect resulting in the attenuation of hypersensitivity after CFA injection. Furthermore, we observed increases in cathepsin K mRNA, protein, and activity after CFA exposure. Taken together, our data indicates cathepsin K is elevated after CFA injection and contributes to CFA-induced mechanical hypersensitivity. Further research is needed to determine the parameters by which inhibition of cathepsin K activity produces analgesia and whether attenuating cathepsin K activity may generate a clinically relevant therapeutic.Traditionally, cathepsin K has been studied in the context of bone and joint disorders31. In the formalin test, dilute formalin is injected subcutaneously into the hind paw. This test mimics a continuous chemical-induced tissue injury31. This causes the animal to display unprovoked nocifensive behaviors32. This display of nocifensive behaviors can be seen in two phases, the early phase, and the late phase. The response seen in the early phase is caused mostly by the activation of C-fibers. In the late phase, pain is thought to be produced by a combined effect of the inflammatory pain mediators released from the inflamed tissue and the functional changes in the dorsal horn31.Two chemically induced inflammatory models of pain were assessed to determine whether cathepsin K is necessary for the expression of inflammatory pain. The first model injected formalin into the hind paw. Formalin is the aqueous solution of 37% formaldehyde and is a chemical irritantCtsk−/−mice. Ctsk−/− mice exhibited a significant reduction in nocifensive behaviors compared to the WT mice 15–20-min (late phase) after formalin exposure  and a trend towards an attenuation in nocifensive behaviors in the early phase (0–5 min) in Ctsk−/− compared to WT mice , indicating that cathepsin K might be necessary for the expression of nocifensive behaviors during the late phase of the formalin test. Both Ctsk−/− and WT mice had similar paw diameters and weights after formalin injection, indicating both groups developed inflammatory edema and swelling (data not shown). To rule out that the reduction in nocifensive behaviors could not be attributed to a reduction in locomotor activity, general locomotor activity between the two groups was assessed.The formalin-evoked nocifensive response was compared amongst wild type (WT) and Ctsk−/− mice . However, we cannot rule out that Ctsk−/− mice do not have altered responding prior to formalin injection as we did not assess the effect of saline on basal responding prior to formalin injection.No difference in basal locomotor activity was found between the WT and 31, complete Freund’s adjuvant (CFA) was used to induce a more chronic inflammatory pain state in WT mice34. When CFA is injected intraplantar, it causes maximal swelling and inflammation of the paw ~ 24 h after injection and this inflammation remain persistent for 1–2 weeks37. A key characteristic of this inflammatory pain is hypersensitivity to various mechanical and thermal stimuli36. Hence, several behavioral paradigms were assayed to measure this hypersensitivity to stimuli. Hypersensitivity to mechanical stimuli causes a decrease in the mechanical paw withdrawal threshold (PWT) and can be termed as mechanical hypersensitivity38. In addition, hypersensitivity to thermal stimuli reduces the thermal latency and, therefore can be classified as thermal hypersensitivity38.Since formalin-induced pain manifests as more of a transient than chronic inflammatory pain stateCtsk−/− mice and WT mice after CFA injection were measured. In the first experiment using the traditional method of von Frey testing, a significant attenuation in CFA-induced mechanical hypersensitivity was found in Ctsk−/− mice compared to WT mice . This suggests that cathepsin K is necessary for the CFA-induced mechanical hypersensitivity.To determine the role of cathepsin K in chronic inflammatory pain, differences in the mechanical PWT between Ctsk−/− mice on day 1 and day 7 post-injection. CFA-injected WT mice had a trend towards a shorter latency to response than the saline-injected WT mice . Although we do not believe this changes the interpretation, especially given our pharmacological data, we cannot rule out the possibility of a floor effect and hence a confound in the ability of Ctsk−/− mice to adequately remove their paw any faster.Thermal hypersensitivity was assessed in a different cohort of mice at 53 °C in both WT and Ctsk−/− and WT mice showed similar amount of inflammatory edema and swelling in the paw on day 7 post-CFA injection after measurement of mechanical hypersensitivity (data not shown). This indicates that cathepsin K does not play a role in inflammation-induced edema but may be altering the transmission of the nociceptive signal.Interestingly, both Ctsk−/− mice, we wanted to see the effect of pharmacological inhibition of cathepsin K activity on the mechanical hypersensitivity in WT mice post-CFA injection. Before proceeding forward, a dose–response correlation study was performed to determine the ideal concentration of the inhibitor.After seeing no CFA-induced mechanical and thermal hypersensitivity in the 39. Therefore, for the dose–response study we chose concentrations less than 510 nM. The tested doses were 0.1 nM, 1 nM, 5 nM, 10 nM, 25 nM, 50 nM, 75 nM, 100 nM, 500 nM, and a vehicle control (0 nM). The data is graphed on a log scale; hence, the vehicle control cannot be seen on the graph.According to the manufacturer, this inhibitor is specific to cathepsin K, but at higher concentrations it can have off-target effects. For instance, the inhibitor has an inhibition constant of 510 nM for cathepsin BOn day 1, following CFA injection, but before testing the PWT all mice received the inhibitor injection at the same site as that of CFA injection the day before. The observed PWT for each concentration was used to plot a dose response curve Fig. B. Accord40. On the contrary, in SUDO method each mouse receives the same number of von Frey filaments, and therefore, moving forward, the SUDO method was used for all mechanical hypersensitivity experiments, except in Fig. Since the traditional method for detecting differences in von Frey sensitivity can result in mice receiving a varying number of von Frey filaments, it can lead to a different testing experience in each mouseBefore establishing whether there was a therapeutic effect of cKi (50 nM) we ruled out the possibility that there was an off-target effect of the cKi on the basal mechano-sensitivity  prior to testing on day 1 and day 7 after the CFA injection. Mann Whitney test showed that the vehicle-injected mice had a significant decrease in thermal latency from baseline on day 7, post-CFA . This shows that the inhibitor is not reducing the collective inflammatory edema and infiltration, is significantly reducing the inflammatory pain (expression and/or transmission).As in the We compared the cathepsin K mRNA, protein, and protein activity levels between CFA-injected mice and saline-injected mice on day 1 and day 7 post-CFA injection. Our biochemical analysis demonstrates that cathepsin K mRNA, protein and activity levels increase in the hind paw of WT mice 1 day and 7 days after CFA injection into the hind paw.Cathepsin K mRNA levels are higher in the paw of CFA-injected mice (n = 8) compared to saline-injected mice  induced model of painful osteoarthritis. Animals receiving L-006235 post-arthritis induction displayed less pain and there was no effect on the inflammation histologically. Therefore, it was suggested that L-006235 only reduced the pain signaling57. Finally, inhibition of cathepsin K with NC-2300, a potent orally active cathepsin K inhibitor was able to ameliorate CFA-induced paw swelling and improve locomotive activity suggesting cathepsin K participates in autoimmune inflammation58. Further studies are needed to determine why paw swelling was reduced with the orally active cathepsin K inhibitor, which we did not observe in Ctsk−/− mice or local inhibition within the hind paw.Like the cathepsin K inhibitor used for these studies, EMD 219379, the cathepsin G inhibitor TPCK also reduces the thermal hypersensitivity associated with CFA-induced inflammatory pain59 showed that inhibition of cathepsin K activity reduced nociception only after long-term treatment. The onset was said to be slow because of effects on pain mechanisms other than acute nociception57. Likewise, another cathepsin K inhibitor AZ12606133 also reduced the firing rate in osteoarthritic joint’s mechanosensory afferents but only 28 days after the onset of intrathecal administration and not 15 min after intra-arterial injection30. A possible explanation for why our treatment works acutely may be that in the arthritic joints, most probably the osteoclasts secrete the vast majority of cathepsin K. Therefore, initially most of the inhibitor molecules are bound to and utilized by the osteoclastic cathepsin K. Once the osteoclastic cathepsin K lowers the inhibitor can be more evenly distributed and more inhibitor molecules are available for binding to the cathepsin K in the other cell types that could be involved in producing the hypersensitivity. The fast onset seen in our study could also be due to fact that in our study we locally inhibited cathepsin K at the site of the inflammatory insult, rather than systemically or in the CNS. This is also important since Odanacatib, another cathepsin K inhibitor was withdrawn in phase 3 of clinical trials because it increased the number of adverse cardiovascular events and atypical fractures60. Odanacatib was being prescribed orally. Local inhibition by EMD 21379 will greatly reduce these side-effects if these adverse side-effects might be associated with this molecule as well. However, EMD 21379 does not have the same selectivity as Odanacatib and we cannot rule out the contribution of partially inhibiting cathepsin B, although minor (Ki apparent = 510 nM), and/or papain (Ki apparent = 1.2 µM) has on the inflammatory response23. In addition, whether EMD 21379 may inhibit cathepsin S and V has not been reported, which are both expressed in the epidermis61. Nevertheless, the pharmacological studies combined with the lack of a response in Ctsk−/− mice and the increases in cathepsin K mRNA, protein, and activity strongly suggest cathepsin K plays a role in inflammatory-induced nociception.However, in contrast to our study where acute injection of the inhibitor reduced nociceptive signaling, Nwosu et al.19 and differential expression of cathepsin S and X in the spinal cord of neuropathic pain models in rats has also been reported20. Therefore, future studies will see if cathepsin K also plays a role in neuropathic pain. Our data also suggest that cathepsin K could be involved in neuropathic pain, as Ctsk−/− mice showed almost no nociceptive behavior in the late phase of the formalin test and drugs that have been effective at attenuating the late phase have preclinically been shown to be effective at reducing neuropathic pain64.As seen above, some cathepsins like cathepsin S are known to be involved in neuropathic pain32. Since inhibition of cathepsin K activity after 7 days of persistent nociception was able to reverse the CFA-induced mechanical hypersensitivity this suggests that cathepsin K inhibitors may be used after the establishment of pain and provide a novel treatment strategy  and 45 male Ctsk−/− mice29 were used for these experiments. All mice were bred in-house and kept in a temperature-controlled room with a 12-h light/dark cycle and had free access to food and water and were age-matched between 8 and 16 weeks old during the experiment. Animals were socially housed in transparent boxes with bedding made of softwood shavings. All efforts were made to minimize the number of animals used in the experiments and to reduce the amount of pain and suffering. The number of mice per group for each experiment was determined a priori and is based on the statistical power needed to reliably detect the group differences given the measures to be made, the expected variance and size effect.All procedures were performed in accordance with the National Institutes of Health’s N-benzyloxycarbonyl-leucyl)-5-carbohydrazide)39 or its vehicle  1–2 h before testing. Cathepsin K inhibitor or vehicle injections were given locally (at the same site of CFA-induced inflammation).All behavioral experiments were performed during the light cycle. Mice used for behavioral analysis were handled/transported in cups to minimize the stress. They were also acclimatized to the experimental apparatus before the start of each study for a minimum of 1 h, at least twice prior to the initiation of the experiment. For mechanical hypersensitivity testing, mice were also acclimatized for an hour on each testing day. For studies spanning several days, testing was performed around the same time each day and was run in counterbalanced manner. In studies using different genotypes, age-matched mice were used. In studies using the same genotype, littermates were used as controls. For peripheral inflammation and inflammatory pain, either complete Freund’s adjuvant  or 5% formalin (Fisher Scientific#R31750004A) was injected into the right hind paw subcutaneously into the plantar surface. Saline  was injected as a control to account for possible mechanical trauma of the injection. In pharmacological studies, WT mice were injected with either 10 μL of cathepsin K inhibitor II  or in a simplified up-down fashion (SUDO method40). In the traditional method, von Frey filaments are applied in an ascending order starting from the bottom of the force range until the mouse displays a nocifensive response to more than five out of ten applications67. Whereas in the SUDO method, von Frey filaments are applied starting from the middle of the force range. Depending on whether a response is seen or not seen in five out ten applications of a filament, the next filament applied is of a lower or a higher force. In this manner a total of five filaments are applied in SUDO method40. Figure Ctsk−/− mice were performed by two independent experimenters using the two different methods described above. All pharmacological experiments, except the one shown in Fig. The minimal force in grams (g) needed to display an adequate pain response is termed as the mechanical paw withdrawal threshold (PWT). Mechanical PWT was measured to assess mechanical hypersensitivity after a chemical insult. To test the PWT, von Frey filaments  ranging from 0.16 to 4.0 g were used. The filaments were either presented in ascending order until the animal displayed a nocifensive response , when placed on a hot plate (IITC Life Science Inc.) at 53 °C, was measured and termed as the thermal latency. Transient Receptor Potential (TRP) channels are thermosensors in sensory nerves and since downstream TRP channel associated with cathepsin K is not known and all 4 TRP heat sensing channels are active at 53 °C, we choose to measure thermal latency at 53 °CCtsk−/− mice were habituated in the experimental chamber after which they received 20 μL of 5% formalin into the right hind paw. Immediately after the injection, the mice were put back in the chamber and were video recorded for 40 min. Formalin injection induced an unprovoked display of nocifensive behaviors such as licking, biting, and flinching of the paw. The total time spent displaying these responses during each 5-min window was noted70. Experiments were performed by a single experimenter, but the recordings were analyzed by a second person who was blinded to the genotype.WT and Change in paw diameter and weight due to swelling and edema was measured as a parameter of paw inflammation. Paw diameter was measured at the site of maximal swelling using a standard caliper, and paw weight was measured using a standard weighing scale after the removal of the paw at the hairline following the completion of the experimental study.−/− mice were acclimatized to the experimental apparatus for 5 min. After acclimation, beam breaks were measured for 15 min in one side of a three chambered conditioned place preference box (Med Associates). The experiment was performed similarly for 3 consecutive days. The total number of beam breaks on each day was used to determine the horizontal locomotor activity.WT and CKg for 15 min. The aqueous phase was shifted to a fresh tube. Isopropyl alcohol (1 mL) was added to it and incubated for 10 min, and then the sample was centrifuged at 12,000g for 10 min. The supernatant was discarded, and the RNA pellet was washed in 70% ethanol and centrifuged at 12,000g for 5 min. The supernatant was discarded, and the pellet was dried in air to remove any ethanol. The RNA pellet was dissolved in 50 μL of RNAase-free dH2O. The RNA was quantified by using a Nanodrop (Thermo Scientific).Paws were isolated from saline- or CFA-injected WT mice after 1 day or 7 days and cut into small pieces. Then the tissue was homogenized, lysed in Trizol reagent (Invitrogen#1559606), and the RNA was extracted for qRT-PCR. Briefly, 1 mL Trizol was added to cut tissues and homogenized using Dounce homogenizer. Next, chloroform (0.2 mL) was added to Trizol cell lysate, mixed, and incubated at room temperature for 5 min. The samples were then centrifuged at 12,000GAPDH (primer-qiagen#249900) was determined to normalize gene expression. The data was collected using Bio-Rad CFX manager and relative cathepsin K fold change is calculated using 2 (−ΔΔCT) method between CFA and Saline groups.The isolated RNA was transcribed into cDNA using RT2 First Stand Kit . Briefly, RNA (5 μg) was incubated with genomic DNA Elimination Buffer for 5 min at 42 °C in a Minicycler (Bio-Rad). RT Cocktail  was added to DNA Elimination mixture and incubated at 42 °C for 15 min. The reaction was stopped immediately by heating at 95 °C for 5 min and dH20 (91 μL) was added to each cDNA synthesis reaction. Cathepsin K expression was determined by qRT-PCR by mixing synthesized cDNA, cathepsin K primers , and SsoAdvanced Universal SYBR supermix  and placed in CFX connect (Biorad). The samples were heated at 95 °C for 10 min, and then 40 cycles were run at: 95 °C for 15 min, 55 °C for 40 s, and 72 °C for 30 s. Expression of housekeeping gene Paw was isolated from saline or CFA injected mice and cut into small pieces. Then the tissues were homogenized in RIPA buffer containing protease inhibitor cocktail  using dounce homogenizer. Protein concentration in the lysates was measured using Nanodrop (Thermo). Protein samples (40 µg) were then mixed with DTT containing Laemmli’s buffer and incubated at 99 °C for 10 min and were separated via Polyacrylamide Gel Electrophoresis (PAGE) using 4–15 gradient gel. After the separation, protein samples were transferred to PVDF membrane and probed using primary antibodies against cathepsin K mouse anti-cathepsin K  and Gapdh . The protein bands were visualized using freshly prepared Super-Signal West Femto Kit (Pierce) and Gel Doc XRS digital imaging system (Bio-Rad) was used to capture images. Once the images were captured, Restore PLUS western blot stripping buffer (Thermo Scientific) was used to strip the membrane before reprobing. Densitometry analysis was carried out using Quantity One software (Biorad). Cathepsin K protein was normalized to housekeeping protein GAPDH. Blots were compared by internally normalizing the blot to corresponding WT control  group.Cathepsin K activity was measured using cathepsin K Activity Assay Kit  following the manufacturer’s instructions. Figure 71. The remaining analyses for responses without these concerns were also conducted using a nonparametric approach for consistency. The nonparametric approach was more conservative than the parametric approach in this study as it confirmed the statistically significant differences for the parametric approach in all comparisons, except in a few cases.The responses in many of the data sets in this study involved counts which could be small or these responses involved ties where the values could be duplicated. As a result, there were legitimate concerns with the assumptions of normality that would be required of parametric analyses. Given these suspected violations of the assumptions, all analyses were conducted using a nonparametric approach72. Nevertheless, this approach is moderately robust to small deviations from this assumption of sphericity as it is a refinement of the Bonference adjustment that has been recommended in such circumstances72. Multiple Mann–Whitney tests were used for formalin, locomotor activity, mechanical hypersensitivity, cKi hot plate, mRNA, protein, and activity analysis experiments using GraphPad Prism software . Mann–Whitney test was used for WT vs. KO hot plate experiments using the same GraphPad Prism software. A p value of < 0.05 is considered statistically significant. There were no exclusions of any animal or data points.With the nonparametric approach, multiple comparisons were performed to evaluate group differences across each of the time points using the Holm–Sidak adjustment, which is a refined version of the Bonferroni adjustment . While this approach adjusts for the multiple tests, it assumes equal variances across the comparisons, which is in accordance with the assumption of sphericity


This study aimed atinvestigating the relationship between speech-frequency hearing loss (SFHL), high-frequency hearing loss (HFHL), and cognitive impairment (CI) and then to determine whether there are any differences in gender among older community dwellers in China.1012 adults aged ≥ 60 years  and living in Chongming District, Shanghai were enrolled in the study. We used the audiometric definition of hearing loss (HL) adopted by the World Health Organization (WHO). Speech-frequencies were measured at 0.5 kHz, 1 kHz, 2 kHz, and 4 kHz; high-frequencies were measured at 4 kHz and 8 kHz. Pure tone average (PTA) was measured as hearing sensitivity. Cognitive performance was measured using the mini mental state examination (MMSE).P < 0.05) in MMSE was associated with speech- and high-frequency hearing sensitivity.Our studies demonstrated a 37.6% prevalence of HL in males and a 36.0% prevalence of HL in females. Adjusted for confounding variables, the results from a multivariate analysis showed that SFHL was associated with CI in females  and males . However, HFHL was associated with CI only in females . HL was associated with poorer cognitive scores (P < 0.05). “Registration” (The associations between HL and CI varied according to gender in older community-dwellers, suggesting that different mechanisms are involved in the etiology of HL. Moreover, hearing sensitivity was negatively associated with cognition scores; therefore, early screening for HL and CI among older community-dwelling adults is advised. Cognitive impairment (CI) is prevalent among older people, with nearly 43.8 million people having CI worldwide . In ChinIn recent years, more studies have concentrated on the relationship between HL and cognitive decline. Some researchers have proposed a strong correlation between HL and CI in older adults , 9; howeThe purpose of this study was to analyze the associations between HL at different frequencies and CI in community-dwelling adults in China, in order to allow early screening for HL and CI to play a warning role and investigate whether there is a gender difference between HL and CI. Because HL and CI are two major geriatric health issues and are related to the quality of late life, determining gender differences in these associations will be helpful in developing gender-specific health policies that can contribute to the well-being of older adults.This cross-sectional study was conducted in four different communities in Chongming District, Shanghai. We collected the physical examination data of older adults living in four different communities from June to July 2019, including demographic and health-related parameters . Air conduction thresholds (dB) were measured for both ears at seven frequencies , and across an intensity range of 0 dB to 100 dB, but we did not measure 6 kHz for the limited time. The speech-frequency pure tone average (PTA) was computed as mean thresholds at 0.5 kHz, 1 kHz, 2 kHz, and 4 kHz, which are most important and represent speech perception . The higCognitive performance was measured using the mini mental state examination (MMSE). The MMSE items assess several cognitive domains, which are summed to a maximum total score of 30 points. The items may be clustered in six domains measuring different cognitive processes: orientation to time (5 points), orientation to place (5 points), registration (3 points), attention (5 points), recall (3 points), and language (9 points). Considering the participants’ education, CI was defined as MMSE ≤ 17 for illiterates; MMSE ≤ 20 for primary school graduates; and MMSE ≤ 24 for junior high school graduates or those with higher-level education [All of the participants were asked to complete a questionnaire by face-to-face interviews, physical examination, and blood sample collection during baseline. The data on sociodemographic characteristics, behavioral characteristics, and medical history were obtained with questionnaires. The sociodemographic characteristics included sex, age, education level, monthly income, living status, and marital status. Height and weight were measured, and body mass index (BMI) was calculated as weight in kilograms divided by the square of height in meters. Education level was categorized as illiterates, primary school graduation, high school graduation and above. Monthly income was categorized as < 1000 yuan, 1000–3000 yuan, 3000–5000 yuan, and > 5000 yuan. Living alone was categorized as yes or no. Marital status was categorized as married, widowed, single, and divorced. The behavioral characteristics included smoking history, drinking history, PA situation, Activity of daily living scale (ADL), and Instrumental activity of daily living (IADL). Smoking history was categorized as follows: nonsmokers, former smokers, and current smokers. Drinking history was also categorized as follows: nondrinkers, former drinkers, and current drinkers. PA and sitting time in the most recent week were assessed using the short form of the International Physical Activity Questionnaire (IPAQ) . Activit2 test. Continuous variables were summarized as mean ± SD or median (interquartile range) values, and comparisons were performed using the t-test. A multiple logistic regression model was used to examine the association of different frequency hearing loss with CI. The model was stratified according to gender and age, respectively. We generated a model adjusted for BMI, marital status, living alone, monthly income, education, IPAQ, ADL, IADL, diabetes, hypertension, hyperlipidemia, and stroke. The linear regression models were adjusted for age and above; the association of different frequencies of hearing sensitivity with cognitive domains  was evaluated. All of the tests were two-tailed, and the differences were considered to be statistically significant at P < 0.05.All statistical analyses were performed using the SPSS 25.0 edition for Microsoft Windows . The descriptive characteristics for categorical variables were summarized as percentages, and significant differences were evaluated using a χA total of 1,136 participants were evaluated in person by study personnel. Of these, 124 were excluded: 47 had incomplete questionnaire information at baseline, 34 had incomplete hearing assessments data, 40 had incomplete MMSE data, 2 had incomplete education level data, and 1 had maximum data of 4 m walking speed , and had lower MMSE scores . These characteristics were also evident in females. Moreover, there are different associations by gender. For example, the HL in females showed a relationship with marital status (P < 0.001), living alone , education level (P < 0.001), and drinking history (P = 0.010), but these results are not significant in males . Meanwhile, compared to those with normal hearing, those with HL did not demonstrate differences in terms of smoking history among males and females (P > 0.05).The demographic characteristics and the distribution of different covariates between the normal hearing and HL groups are described in Table Table P < 0.05), and HFHL were significantly associated with CI between ages 65 and 69 (P = 0.009); no similar results were observed in the 75 years and older group. However, in males, none of the models showed significant associations of HFHL or SFHL with CI in all age groups.In order to ensure the reliability of our research results, we conducted a stratified analysis by age to assess possible effect modification on the association between SFHL, HFHL and CI. Table P < 0.05) in model 1. In addition, there was a significant negative correlation between hearing sensitivity and cognitive domains  . After adjusting for covariates , the association had changed in some cognitive domains. Table P < 0.05) in model 2. High-frequency PTA negatively affected all cognitive domains in model 2, except the orientation of place (P = 0.099) and time (P = 0.065). In addition, Table P = 0.001) in model 2, while speech-frequency PTA affected the cognitive domains in model 2, except the orientation of place (P = 0.597) and language function (P = 0.072). Table P < 0.05) in the unadjusted model, but after adjusting for confounding variates, these correlations disappeared. Moreover, there was an association in speech-frequencies PTA involving the orientation of place (P = 0.003), attention/calculation (P = 0.003), and registration (P = 0.003). Obviously, registration was associated with high- and speech-frequency PTA in all models. It is worth noting that this also existed in males.To determine the independent associations between cognition and hearing sensitivity of different frequencies, Tables e P = 0.05. In addThe purpose of our study was to investigate the relationship between SFHL, HFHL, and CI, then to determine whether any association differs by gender among older community dwellers in China. Our cross-sectional study results showed that SFHL and HFHL may be associated with a higher risk of CI. Furthermore, we found that SFHL was more strongly associated with CI in males and females, while HFHL had a different association with CI among males and females. Hearing sensitivity was negatively and independently related to MMSE scores, regardless of gender. We explored which cognitive domains on the MMSE are more strongly associated with hearing sensitivity stratified by gender. As far as we know, this is the first study to explore the different relationship in different-frequency HL and CI by gender variance in older Chinese community-dwelling adults.P = 0.050; P = 0.010, respectively), but not in males or females after stratified by gender . To some extent, our study showed that there is no independent correlation between hearing and language function in males and females. It is worth noting that we are conducting a large cohort study on older adults in Chinese community. Except for those in hospital, nursing homes and other facilities, as well as the bedridden seniors, older adults in the community who could come in for a medical examination were all included in the study. So participants who have communication difficulties or severe cognitive impairment were excluded at recruitment stage, and they were invited to a face-to-face interview with our experienced examiners in quiet environments.Our research shows a significant correlation between HFHL and CI, and the significance still exists after adjusting for confounding factors. As the most common type of HL in older adults, the incidence of HFHL increases with age, and older people are more likely to have decreased cochlear blood supply and loss of outer hair cells at cochlear basal . HL is oMoreover, several studies have shown that females have a lower hearing threshold and an increased sensitivity compared to males , 32. AltOur research also shows a significant correlation between SFHL and CI, and the significance still exists after adjusting for confounding factors. Our results are in line with previous research showing significant associations between greater HL and poorer cognitive function in both cross-sectional and prospective studies , 42. On P < 0.001; data not shown); their speech-frequency PTA also worsened with each older age group. In females, we found similar results. However, those 75 years and older, SFHL and HFHL were not significantly associated with CI in males and females. Because our study population was older and the hearing function of old adults is generally weakened not continuously getting worse in aging which described as the ceiling effect [In our study, male’s high-frequency PTA worsened with each older age group (40.66 ± 11.72 vs 43.59 ± 12.58 vs 49.40 ± 14.50; g effect . Our oldg effect . Their cWe found that impairment on the MMSE overall is independently and significantly negatively related to hearing sensitivity after adjusting for confounding variables. Hearing sensitivity is also negatively related to hearing status. Similarly, one report by Lin et al. demonstrated that those with HL performed worse in MMSE scores than those with normal hearing . In the This study had several limitations. First, as this was a cross-sectional study design, although correlations among SFHL, HFHL, and CI were found in older adults, the causation is still unknown. Second, all of our subjects are from four communities in Chongming District, Shanghai, and we required them to arrive at the prescribed place of physical examination by themselves and provide their informed consent; hence, subjects with severe CI were not included in our study. In the future, we will improve our research design and more accurately ascertain the association between CI and HL at different frequencies among older community dwellers in China.Our study suggests that SFHL and HFHL are associated with CI, but males and females demonstrate different results, suggesting that different mechanisms are involved in the etiology of HL. Moreover, we found that hearing sensitivity is negatively associated with cognitive domains, and that registration is most significant. The associations between hearing frequencies and cognitive health may vary according to gender. Gender-specific strategies in healthcare policies are needed. In view of our limited ways to assess cognitive function, future research should focus on a more comprehensive approach to assessing cognition and implementing a longitudinal study in order to explore the causal relationships between HL and CI.


Hearing loss is highly prevalent but disparities exist in hearing care. Delivering care in partnership with community health workers (CHWs) is an established approach to addressing disparities but has not been robustly studied in hearing care. We recruited older adults with hearing loss from community sites in Baltimore, MD. The 2-hour intervention consists of fitting a low-cost amplification device and counseling.151 participants were randomized. The primary outcome was change in communication function . Communication function significantly improved in the intervention group, with an intention to treat estimated average treatment effect of a -12.98 point change . In the first randomized control trial of a CHW-delivered hearing care intervention for older adults using low-cost amplification devices, participants receiving the intervention demonstrated a treatment effect comparable to prior studies of conventional hearing aids fit by audiologists.


In recent years, there has been a growing body of literature highlighting the relationship between presbycusis and consequences in areas other than hearing. In particular, presbycusis is linked to depression, dementia, and cognitive decline. Among this literature, the effect of hearing aids, currently the most common method of treating presbycusis, is also a growing research topic. This pilot study aims to explore the effects of hearing aids on the cognitive and multisensory consequences of presbycusis. To that purpose, saccades and vergences eye movements were studied, towards visual and audiovisual targets, of a presbycusis population wearing hearing aids for an average of two years. These measurements were done whether or not participants were wearing their hearing aids. Eye-movement characteristics, particularly latencies (the reaction time taken to initiate an eye movement), allows one to measure attentional and multisensory characteristics. Previous studies showed that presbycusis was linked with an increase of saccade latencies and an improvement in audiovisual interaction capacities, i.e., latencies for audiovisual targets are shorter than those for visual targets. Eye movements are measured and analyzed with REMOBI and AIDEAL technologies. Results show a shortening, with hearing aids, of right saccade latencies to visual targets, suggesting an increase in attention and/or engagement. Yet, saccade latencies are not shorter for audiovisual vs. visual targets alone, neither when wearing hearing aids, nor without. Moreover, convergence latencies are particularly slow for any type of target and with or without hearing aids. The results suggest deficits for audiovisual interactions and the initiation of convergences in that population. These deficits could be part of the factors triggering the need to wear hearing aids. These results therefore show interesting relationships between hearing-aid wearing in a presbycusis population and oculomotricity and invite further research in this area. Presbycusis is a progressive, age-related hearing loss beginning around the age of 50. Its auditory consequences are a decrease in detection thresholds of high frequencies and a degradation of speech understanding, especially in noise . AccordiAlongside this issue is the question of the effectiveness of hearing aids on these cognitive aspects. Presbycusis is caused in particular by a loss of the inner hair cells and the auditory nerve, allowing the creation of the auditory neural signal . These dOur previous studies have investigated the links between presbycusis and eye movements allowing us to explore our three-dimensional environment, in order to better understand the cognitive and multisensory consequences of presbycusis. Oculomotricity is an ideal tool to study the mechanisms of action orchestrated by our brain, in particular through these reaction times, associated with attentional cognitive processes ,18. IndeThe neural networks underlying oculomotor movements have been extensively studied in the past and are among the best-known networks. The study of eye movement has been used in the literature to assess the effects of age, mostly for saccades. Regarding saccades, there is an increase in latencies and a decrease in speed and accuracy with age ,20,21,22For a population of older adults, these studies have found that age-related hearing loss is associated with (i) an increase in saccade latencies  and (ii)The present pilot study was designed to investigate the effect of hearing aids on these relationships. The purpose was to develop this new field of research exploring the cognitive consequences of presbycusis, looking for results concerning the wearing of hearing aids, as well as new methods of measurement to evaluate the cognitive consequences of hearing rehabilitation via hearing aids. To this end, the oculomotor latencies of saccades and vergences, towards visual and audiovisual targets, were studied in a presbycusis population that had been wearing hearing aids for an average of two years. These latencies were compared according to whether or not hearing aids were worn. They were also compared to those of a senior population of the same age who had never worn hearing aids. In order to better target the cognitive processes involved, we also compared these results with performance on the Stroop test, which also measures cognitive executive processes, including selective attention and inhibition ,29,30,31The study was conducted in accordance with the Declaration of Helsinki, and approved by Ethics Committee “Ile de France II” .A group of hearing-aided seniors with presbycusis (group Senior_HA) and a group of seniors who have never worn hearing aids (group Senior) were tested. The group Senior_HA was composed of 21 participants (mean age 75.4 ± 6.7). Participants in this group had been wearing their hearing aids for an average of 2.21 ± 1.5 years. The group Senior was composed of 20 participants (mean age 72.05 ± 8.4). They all completed a short questionnaire at the beginning of the tests to report if they had good vision in their daily life (with or without correction), if they took medications that could damage their sensory and motor functions, or if they had neurologic, psychiatric, auditory, or oculomotor disorders. Those who had cataracts were treated. All the participants had good sight or wore visual correction. During the tests, none of the participants complained about not seeing the visual target. Thus, the participants were considered to be representative of a normal aging population. Informed consent was obtained from all of the participants after the nature of the procedure had been explained. The search for participants was conducted during a period of confinement of the COVID-19 pandemic. Participants were recruited mainly through the cognitive research network RISC and by advertising in associations that may have senior participants.A professional audiometrist was in charge of performing two kinds of audiometry, in a sound booth calibrated cabin, with an audiometer of the brand Interacoustics . The outer ear canals of all the participants were all checked before the hearing tests.This test aims to assess the audibility, i.e., the minimum intensity required for a sound to be heard. It was realized, for each ear separately, with the headset TDH-39P. For each ear was determined the lowest intensity in dB HL needed by the participant to detect the following pure tone: 250, 500, 750, 1000, 2000, 3000, and 4000 Hz. The final score is called the Pure Tone Average (PTA) and represents, for each ear, the mean of all these thresholds. Only the best PTA between the two ears was retained to match to the hearing-loss definition of the World Health Organization. They consider a hearing loss when the best PTA between the two ears is bigger than 20 dB HL .This test aims to assess speech comprehension in silence. Lists of words with differing intensities are sent to the participant, enabling them to calculate a comprehension score for a given intensity. It was performed with a loudspeaker situated at 1 m in front of the participant (azimuth 90°). Thus, the two ears were tested simultaneously. The different intensities with which the lists were sent were 70, 60, 50, 40, 30, 20, or 10 dB SPL. The lists used were the Lafon cochlear lists, composed of 17 monosyllabic words of 3 phonemes (51 phonemes) . The comThe hearing tests were performed with and without hearing aids.Divergence, convergence, left saccade, and right saccade were elicited with the REMOBI device, which is a visio-acoustic device developed by our laboratory .REMOBI  is a plane surface upon which are disposed red LEDs . Each LED is equipped with a buzzer delivering a 2048 Hz pure-tone of 70 dB SPL. Participants were sitting and the REMOBI was placed at their eye level. The instructions given to them were to look at the only LED that was on, as quickly and accurately as possible, and then to maintain the fixation as the LED was still on, all of which without moving the head. Thus, the localization and patterns of LEDs allowed the testing of the desired eye movements.During this sequence were elicited 20 trials of a saccade to the right and 20 trials of saccade to the left, randomly interleaved. For each trial, participants first fixated a central LED, situated at 70 cm in front of them (same distance from his two eyes). The right and left saccades were elicited by lightning a peripheral LED, also at 70 cm, but at 20° to the right or to the left from the central LED.During this sequence were elicited 20 trials of convergence and 20 trials of divergence, randomly interleaved. All the LEDs were situated in front of the participant (same distance between the left and right eye) and varied only in depth. For each trial, participants first fixated a central LED, situated at 40 cm from them. The divergence and convergence were elicited by lighting a peripheral LED, situated at either 20 cm (Convergence) or 150 cm (Divergence) from the participant.The normal proximal point of convergence is supposed to be less than 10 cm . It shouFor saccade and vergence sequences, the central LED was switched on during a random time between 1200 and 1800 ms. The peripheral LED was lit for 2000 ms. There was an overlap time of 200 ms where the two LEDs were lit at the same time (overlap paradigm). The trials were separated by a blank period of 300 to 700 ms. The total duration of a sequence was approximately 150 s.The hearing tests were performed with and without hearing aids. The score extracted is the latency, expressed in ms, and representing the time between the activation of the peripheral LED and the initiation of the movement. The saccade and vergence sequences were tested for visual targets and for audiovisual targets. For the visual targets, the LEDs turned on without activation of their adjacent buzzer. For the audiovisual targets, an auditory signal was sent with the adjacent buzzer of the LED 50 ms before the activation of the LED. This auditory signal was activated for a duration of 100 ms.The eye movements were captured with the head-mounted video-oculography device, Pupil Core , and the data acquired were analyzed with the AIDEAL software . It derived the signal by calculating the difference between the two eyes from the individual calibrated eye position signals . The total saccade movement was measured by defining its onset and offset when the velocity of the movement was above or below 10% of its peak velocity. The movement of vergence was divided into two components, following the double mode control of the vergence model. This model divides the dynamic of vergence into two chronological steps: i) an initial step of enhanced speed without visual feedback (open-loop) and then ii) a sustaining step, slower and driven by visual feedback (closed-loop) ,36,37. TThe French version of Stroop Victoria was used in the current study . It is cThe selective attention and inhibition capacities are evaluated by comparing the performances during the Dot and Interference Conditions. The Dot Condition assesses the baseline capacity of color recognition and enumeration. The Interference Condition also assesses these capacities but with the interference of the words. The information given by the instinctive reading of the word is more protruding than its actual color, and it has to be inhibited by the brain.The scores extracted from the Stroop test were: Stroop_D, representing the time taken to finish the Dot Condition; Stroop_I, representing the time taken to finish the Dot Condition; Stroop_I/D, representing the ratio of the time taken to finish the Dot Condition on the time taken to finish the Interference Condition. Higher Stroop_I/D reveals a lower capacity of inhibition.The results for the hearing scores are grouped in p = 0.002).Wearing hearing aids significantly improved hearing scores, i.e., PTA and SI50. With their hearing aids, the hearing-impaired seniors had a similar PTA as the unimpaired seniors. However, their SI50 was still significantly higher , similar in age, had similar cognitive performances, but differed in their hearing, especially on the parameter of speech understanding in silence (SRT50).p = 0.036). However, there was no significant effect of hearing aids for eye-movement latencies to audiovisual targets.First, the latencies of the group Senior_HA are compared when their participants were wearing or not their hearing aids. The results in The only impact of wearing hearing aids, in a population with presbycusis and wearing hearing aids for several years, was therefore the shortening of the latency of saccades to the right.The results are also shown in For visual targets, the latency of the convergences was significantly longer for the group Senior_HA, with or without their hearing aids, than for the group Senior (395 ± 70 ms for Senior_HA0 and 403 ± 73 ms for Senior_HA1 vs. 342 ± 69 ms for Senior).For audiovisual targets, the latency of the right saccades was significantly longer for the group Senior_HA with or without their hearing aids, than for the group Senior (327 ± 73 ms for SA0 and 329 ± 64 ms for SA1 vs. 274 ± 41 ms for SnA_2). The same phenomenon was observed for the leftward saccades, but only when the participants of the group Senior_HA wore their hearing aids (324 ± 58 ms for SA1 vs. 268 ± 51 ms for SnA_2).There was an audiovisual facilitation for saccades in the group Senior, i.e., a significant reduction in latency when presenting audiovisual targets compared to visual targets . This result can be considered as the origin of the previous result, showing shorter saccade latencies towards audiovisual targets for the group Senior. This facilitation was not found in the group Senior_HA, with or without their hearing aids.The results suggest a decrease in the latency of right saccades to visual targets with the wearing of hearing aids in a presbycusis hearing-aided population. The auditory amplification of the background noise of the room (not soundproofed for the oculomotor tests) and of the noises coming from the participants  could induce a more important state of alertness and concentration, resulting in the reduction of the latency.There are studies evaluating the influence of background noise on detection tasks or various cognitive tasks. This literature presents numerous contradictory results, depending in particular on the nature of the sound used and the test situation. Some studies have shown an improvement in performance in the presence of background noise. Davies et al.  and PoulIt is interesting to note that this result was not found for movements towards audiovisual targets: the wearing of hearing aids no longer accelerated the latency. The sound of the audiovisual target could itself act as an arousal factor. Adding sound may have counterbalanced the effects found with visual targets.It is interesting to find these results only for rightward saccades, not for leftward ones. This bias may be related to the overtraining of rightward saccades which are the motor basis of reading activity. Wearing the hearing aids would act as a general warning effect improving the latency of the most frequently made saccades to the right.In the senior hearing-aided population, the difference between the latency of saccades to visual targets and the latency of saccades to audiovisual targets remains the same with or without hearing aids. This result suggests that wearing hearing aids does not improve the audiovisual facilitation of saccade latencies in a presbycusis-impaired population. Given that hearing aids amplify the sound of the audiovisual target, this issue is similar to that of the influence of sound intensity on audiovisual facilitation: does decreasing or increasing the intensity of the sound of an audiovisual target alter the audiovisual facilitation observed on saccade latency?Few studies in the literature can provide answers concerning this particular context. There are indeed studies assessing multisensory facilitation as a function of the intensity of different sensory modalities ,45,46,47It is possible that the amplification via hearing aids of the audiovisual target sound was not significant enough to improve the audiovisual facilitation. This amplification is not exactly known. In the senior hearing-aided population, the average gain given by the hearing aids for the 2000 Hz detection threshold  was 16 ± 7 dB. However, hearing aids have different amplification depending on the intensity received. In general, the louder the sound is received by the hearing aids, the less it will be amplified. Since the sound of the audiovisual target is well above the detection thresholds, its amplification via the hearing aids is therefore less than 16 dB on average.Note also that, in our study, sound appears 50 ms before diode activation. This interval was chosen because it causes the greatest audiovisual facilitation ,50,51. HIn summary, our results do not show an improvement of audiovisual facilitation with the wearing of hearing aids, in a presbycusis population wearing hearing aids for several years. However, this issue should be addressed with new paradigms, for example by controlling the amplification of the hearing aids on the audiovisual target, or by simultaneously activating the sound and the diode of the audiovisual targets.Furthermore, it is very important to note that the senior hearing-aided population seemed to have deficits in audiovisual facilitation. This point is developed below in The results show a significant decrease in saccade latencies for audiovisual versus visual targets in the senior population. This audiovisual facilitation is a well-known result in the literature , 52,53,,55,56. HThus, the lack of audiovisual facilitation could be one of the characteristics and reasons why seniors with presbycusis decide to wear hearing aids. The results of our previous study  also indThese results therefore question the role of decreased multisensory abilities as a trigger for the desire for a hearing aid. Audiovisual facilitation for saccade latency could become an indicator of the need for a hearing aid for a person with hearing loss.Another possible biomarquer is the abonrmal sloweness of vergence initiation (long convergence latency) in such a population present in both testing conditions with or without hearing aids. Reacting rapidly to a target coming towards and closer to a participant is vital and seems to be delayed by about 50 ms relative to the population with no hearing aids. This results is surprising and needs further investigation; a possible interpretation would be a side effect of hearing aids emphasizing the left–right auditoty perception at the expense of the near–far axis.This study shows several relationships between auditory rehabilitation in a presbycusis population and their oculomotor and multisensory abilities, leading to various interpretations, and opening the way for further studies on this unexplored topic.The results suggest an immediate effect of hearing aids on concentration and alertness. There also appear to be deficits in multisensory and convergence initiation abilities in presbycusis patients with hearing aids. These deficits could be part of the factors leading to the willingness to start hearing rehabilitation. It would be interesting to discover the mechanisms modulating these deficits. It is possible that the hearing aid users tested were fitted too late to recover their multisensory compensation abilities.It is important to remember that these results were extracted from a small cohort. They should be confirmed with more data. In addition, only significant results were reported. We might have missed effects that were only trends in our study that would prove significant with more data. It would also be important to better control for certain variables, such as the amount of time hearing aids were worn on a daily basis, the length of time the participants had been wearing their hearing aids, or the length of time they had been hearing. Indeed, the amount of time worn and the length of time the hearing aids have been in use affect their effectiveness ,59,60.REMOBI: US885 1669, WO2011073288. AIDEAL: PCT/EP2021/062224 7 May 2021.


Internal auditory meatus stenosis is defined as a loss of 3mm or more in the vertical diameter of the internal acoustic meatus, or even as a meatus smaller than 2mm.Inner ear abnormalities may occur in about 20% of the cases of patients who have sensorineural hearing lossThis loss may happen because of alterations in the VIII cranial nerve (vestibulococlear).In most cases, it happens as an isolated congenital manifestation, and other systemic abnormalities are rarely found. The major alteration happens due to a constriction caused by impaired bone growth, resulting in an abnormal internal acoustic meatus. The stenosis etiology may be explained as being secondary to an aplasia or hypoplasia of the vestibulocochlear nerve. The embryologic events involved in fetal growth between the 4th and the 8th weeks are crucial for bone growth, and may cause such disease. The labyrinth may be also involved, being aplastic or with a deformed or incomplete cavity. It is not uncommon to have a completely normal labyrinth, though.3An acquired bone disease may also result in stenosis of the internal acoustic meatus .Clinical manifestations involve especially hypoacusis, there may also be tinnitus and vertigo in the side affected. When there is facial nerve involvement, there may be paresthesia and even paralysis.,The physician should investigate the patient's obstetric, natal and post-natal history in order to rule out malformations during this period.Otorhinolaryngological exam involves otoscopy, which is usually normal, and also tests that investigate the patency of the VIII cranial nerve's vestibular branch .Among complementary tests, Audiometry may show a sensorineural hearing loss that varies as to the degree of hearing loss (from mild to profound), depending on the level of nerve involvement.Diagnosis of certainty is made by CT scan, which shows a narrow acoustic meatus, thus pointing to the disorder. MRI can be used in order to see the structures that involve the VIII cranial nerve, which may be aplastic.As treatment modalities, the cochlear implant offers very promising results, as well as hearing aids, which help patients recover their hearing.R.N., 18 years, female, came to our service complaining of right side hearing loss, noticed about one year ago, of unknown onset. She did not complain of tinnitus, vertigo, otalgia and otorrhea. She said she had not undergone any neonatal hearing screening test. Her hearing pattern did not get worse along the years. She also did not have learning disorders during childhood.She did not show any evidence of pre-natal, natal and postnatal infection, nor of using ototoxic drugs.She has essential hypertension and is being treated with propanolol (40mg) BID; nifedipine (20mg), administered once a day and hydrochlorothiazide also once a day.She did not have relatives with hearing loss.Her ear drums were intact and translucid. Her nose and throat exams were normal. Balance tests were also within the normal limits.We followed the investigation protocol of hypoacusis in our service. We ordered: audiometry and immitanciometry, PEATE and OAE.Her tests showed severe sensorineural hearing loss on the right side. PEATE did not show evidence of retrocochlear alterations.Afterwards, we ordered ear CT scan and MRI, which showed stenosis of the internal acoustic meatus and vestibulocochlear nerve hypoplasia, respectively.As treatment, we referred the patient to a hearing aid fitting, speech and hearing therapy and otorhinolaryngological follow up in our institution.


We conducted a systematic review and meta-analysis to compare round window (RW) and cochleostomy (C) surgical approaches for the placement of cochlear implants (CIs). After obtaining the Institutional Review Board (IRB) approval, 213 peer-reviewed articles published between January 1, 2000, and August 1, 2021, comparing RW and C approaches were identified via a search on Google Scholar, Cochrane, and PubMed. The inclusion criteria were articles having an English version and involving only human subjects . Statistical analysis of compiled electrode-to-modiolus distances was performed with two-sample independent t-tests. Live patients were categorized as having complete hearing preservation (<10 dB threshold shift), partial hearing preservation (10-20 dB shift), or minimal hearing preservation (>20 dB shift). Chi-squared testing was used to compare the distribution of hearing preservation categories between surgical approaches. Due to the heterogeneous nature of the data, only summative information was provided on the effects of approaches on trauma, electrical impedance, speech perception, vestibular dysfunction, ease of scala tympani insertion, and scalar shift. A total of 3,797 CI patients were evaluated. The RW approach resulted in a smaller  electrode-to-modiolus distance when compared to the C approach. The RW approach (93.0%) led to statistically better hearing preservation than the C approach (84.3%) (p<0.05). The RW approach was also associated with better outcomes in terms of speech perception, ease of scala tympani insertion, and reduced scalar shift. No difference between approaches was found with regard to trauma, electrical impedance, and vestibular dysfunction. Based on our findings, the RW approach appears to have several benefits compared to the C approach. A cochlear implant (CI) is a device used to restore hearing in patients who cannot be helped with a hearing aid . CIs havSurgeons continue to debate as to which technique is superior. Even though some systematic reviews/meta-analyses on the topic are available in the literature, there are many outcomes to consider when comparing the two surgical approaches, including trauma, hearing preservation, and speech perception.We conducted a systematic review to compare surgical approaches in the context of trauma, electrical impedance, speech perception, vestibular dysfunction, ease of scala tympani insertion, and scalar shift. In the context of this review, we carried out statistical testing of homogenized data to identify which surgical approach yields better hearing preservation and electrode-to-modiolus distance.MethodsEthical ApprovalInstitutional Review Board (IRB)-exempt status was obtained from our institution to conduct this review.Literature SearchA systematic review of available literature on Cochrane, PubMed, and Google Scholar published between January 1, 2000, and August 1, 2021, was conducted. The methodology is summarized in Figure Electrode-to-Modiolus Distance AnalysisFor the analysis of electrode-to-modiolus distance, the only literature available for review used the Med-EL standard 12-electrode arrays, and hence only those papers including data about Med-EL standard 12-electrode contact arrays were specifically included. Further, all included studies had to determine the electrode-to-modiolus distance in a consistent manner, specifically via combined flat-panel CT (FPCT) and curved multiplanar reconstruction (MPR). In total, this approach yielded two papers for analysis ,7.Extracted data were made comparable by analyzing RW and C approach electrode-to-modiolus distances for the 12-electrode positions common to all studies. Electrode distances were pooled and compared with two-sample independent t-testing.Hearing Preservation AnalysisFor the analysis of hearing preservation, only those papers that reported hearing preservation in decibels were included. Although 18 papers reviewed hearing preservation, not every paper reported preservation in decibels. In total, our inclusion criteria yielded three papers for analysis .Extracted decibel readings were pooled and used to classify patients into the following categories: patients having complete hearing preservation (mean hearing threshold increasing ≤10 dB), those with partial preservation (increasing between 10 dB and 20 dB), and patients with minimal preservation to complete loss of residual hearing (increasing ≥20 dB). A chi-squared test was used to compare the distribution of hearing preservation categories between the two surgical approaches.Other AnalysesEight papers were analyzed for ease of scala tympani insertion ,7,11-16.ResultsSample Size and DemographicsIn total, 36 studies met our criteria for inclusion Figure . The incElectrode-to-Modiolus Distance AnalysisAnalyzing the two papers regarding electrode-to-modulus distance yielded 48 electrode arrays with a mean patient age of 26 years. Patient ages ranged from 0.8 to 64 years. Of note, 60% of the patients were male.Two-sample independent t-testing revealed that the RW approach provided a significantly smaller electrode-to-modiolus distance when compared to the C approach. Specifically, the distance was 0.15 mm smaller on average with significant differences favoring the RW approach identified in electrodes 1-3, 5-10, and 12. No significant difference was found in electrodes 4 or 11  to assess residual hearing loss. Two of the studies measured hearing preservation with PTA thresholds between 125 and 500 Hz. The third study measured hearing preservation with PTA thresholds at 250, 500, and 1000 Hz.Of the patients analyzed for hearing preservation, 141 and 115 underwent the RW and C approaches, respectively. One of the studies included was a systematic review from 2013 and did not specify the average age of the participants. The remaining two studies included in the analysis were from 2014 and were not included in this systematic review. These latter studies had an average patient age of 42 years.Of the RW-approach patients, 93% (n=77) had less than a 20-dB shift in their hearing threshold with 7.1% (n=10) having greater than a 20-dB shift. Of the C-approach patients, 84.3% (n=36) had less than a 20-dB shift in their hearing threshold with 15.7% (n=18) having greater than a 20-dB shift  difference between these distributions, suggesting that the RW approach leads to significantly better outcomes with respect to hearing preservation.TraumaSeven of the included studies evaluated intraoperative trauma ,6,22-26.Electrical ImpedanceThree of the included studies evaluated electrical impedance -21. One Speech Perception Five of the included studies evaluated speech perception ,27-30. TVestibular Dysfunction Three of the included studies evaluated vestibular dysfunction -33. One Ease of Scala Tympani InsertionEight of the included studies evaluated the ease of insertion into the scala tympani ,7,11-16.Scalar ShiftTwo of the included studies evaluated the presence of scalar shift ,18. BothDiscussionHearing preservation is an integral outcome to consider when determining which surgical approach to use. Our data suggest that the RW approach leads to optimum hearing preservation in pediatric and adult populations. While this may lead surgeons to consider the RW over the C approach, it is also important to understand other differences in outcomes between these approaches.Electrode-to-modiolus distance is a crucial consideration. The importance of electrode-to-modiolus distance remains controversial, but decreased distance appears to be associated with decreased current levels for suprathreshold simulation ,35. AlthA more clinically useful outcome that we evaluated was intraoperative trauma to the cochlea. Minimizing intracochlear trauma is pivotal for residual hearing preservation . Our anaElectrical impedance is a measure indicative of the integrity and function of electrodes. It reflects the status of the tissue-to-electrode interface . Lower eSpeech perception is a measure of CI integrity. Speech perception is defined as the ability to identify and understand human speech and discriminate between monosyllabic words. Our analysis did not reveal the superiority of either the RW or C approach in maximizing speech perception with 60% of the studies we reviewed regarding speech perception revealing no difference between the approaches ,27,29. TVestibular dysfunction and dizziness are common side effects associated with CIs . Our anaEase of scala tympani insertion is critical as patients with electrodes in the scala tympani experience better overall hearing outcomes, less postoperative vertigo, and preservation of residual hearing when compared to those with electrodes in the scala vestibuli -42. Our The scalar shift is a strongly unwanted complication in CI surgery, which results in damage to the cochlear microstructure with loss of hair cells and spiral ganglion neurons ,43. PrevBiasThe results of this systematic review may be limited by the innate risk of selection bias, implementation bias, as well as attribution bias associated with systematic reviews.Level of evidenceThe studies included in the meta-analysis had a level of evidence of 2. LimitationsOur review is limited primarily by the lack of homogenous data and small sample size, meaning that we were able to perform statistical analysis on only two of the eight desired surgical outcomes/complications. Furthermore, there is no consensus as to which variables carry the most weight when determining which surgical approach is better, and hence we assigned equal weight to all variables.Our meta-analysis revealed that when compared to the traditional C approach, the RW approach for the placement of cochlear implants is associated with better hearing preservation and reduced electrode-to-modiolus distance. The clinical significance of the reduced electrode-to-modiolus distance is yet to be elucidated, but the reduced distance may correlate with longer-lasting batteries in these devices.Our systematic review indicated that the RW approach can lead to better outcomes of speech perception, more ease of scala tympani insertion, and reduced scalar shift. Regarding trauma, electrical impedance, and vestibular dysfunction, other factors like surgeon experience and patient anatomy may be more predictive of success than the choice of surgical approach. Taken together, we recommend the RW approach over the C approach for new surgeons without a preferred operative approach seeking to optimize patient outcomes and ease of insertion. We believe further studies can reveal other differences in short- and long-term outcomes between these approaches.