A fully implantable active middle ear device has been proposed and indicated for the rehabilitation of bilateral moderate or moderate-to-severe sensorineural hearing loss, assuming it would overcome the disadvantages of a conventional hearing aid. The indications have further been extended to severe or severe-to-profound forms of hearing loss in the case of an expected limited or null efficacy of hearing aids. While the literature has highlighted several positive aspects of the device, including a better quality of life related to its invisibility, the improvement of auditory and perceptual functions has not been controlled for throughout a long period of follow-up. The present study aimed to verify the behavior of the auditory threshold, especially the bone conduction (BC) component, in the implanted ear in a group of implantees affected by initial bilateral symmetric hearing loss of different severity grades. The BC threshold was assessed preoperatively at activation and at the last follow-up (ranging from 4 to 12 years) in the implanted ear, and preoperatively and at the last follow-up in the contralateral ear, to monitor eventual deteriorated values in both ears over time. The pure tone average , speech reception threshold (SRT) and the maximum word recognition score as a percentage (% WRS) and in dB HL were measured in the implanted ear to verify the efficacy of the device after the first fitting at device activation. A significant worsening of the BC threshold with respect to the baseline threshold was noticed during further follow-up. When comparing the implanted ear with the contralateral ear, a significant worsening of the bone PTA was assessed in the former with respect to the contralateral ear. Despite the worsened hearing found in the implanted ears, the beneficial gains in PTA and speech audiometry observed at the first activation remained constant at the follow-up, thus showing an extension of the efficacy of this device in aiding those with up to the most severe forms of sensorineural hearing loss. Active middle ear implants (AMEIs), either semi- or fully implantable, have been proposed as an alternative to conventional hearing aids (CHA) in subjects with moderate-to-severe hearing loss (HL) to overcome some of the issues observed with CHA, such as limited high-frequency amplification and incompatibility with a chronic inflammatory condition of the external auditory canal . One fulAfter the FI-AMEI application, the implantees' auditory conditions displayed some modifications that are not exclusively related to the device function. In fact, all the subjects showed a deterioration of the air-conduction thresholds that shifted the purely sensorineural into a mixed type of hearing loss. This finding is due to the interruption of the incudo-stapedial continuity by the partial removal of the incus long process, a necessary surgical step that allows for the minimization or elimination of possible distorted phenomena due to the piezoelectric bridge between the incus-cemented microphonic sensor and the stapes-cemented driver . ConsideConversely, the eventual deterioration of the bone conduction (BC) threshold should be considered to be an undesirable outcome that may occur just after surgery, analogous to other ear surgical procedures . When the BC decrease is of limited extent (<10 dB), it does not usually impact the functional output that is regulated at the first activation fitting. Conversely, a sensible loss of BC threshold may affect device function, as may be observed with any hearing rehabilitative tool, ultimately requiring alternative solutions . The likThe aim of the present study was to obtain evidence of eventual BC threshold deterioration in our FI-AMEI cohort, who were followed up for a long period of time, and to shed some light on possible correlations with some parameters, such as the initial degree of SNHL and the shape of the audiogram. In addition, we investigated the role played by SNHL etiology in a select cohort of implantees by comparing the implanted ear with the contralateral, non-implanted ear, when both were affected by the same initial degree of hearing loss. Finally, we investigated the possibility of either a persistent beneficial effect of the FI-AMEI despite BC threshold deterioration or the need for transitional rehabilitation by a cochlear implant.in-situ BC measurement was carried out by specific software provided by the manufacturer (Envoygram), which allows for the detection of lower (worse) levels of the BC threshold. Only patients with symmetric baseline SNHL (n = 20) so as presenting a mean threshold difference between the two ears <15 dB  is the first and, presently, the only fully implantable active middle ear implant (FI-AMEI) approved by the Food and Drug Administration  for the s <15 dB  were incThe absolute and mean values of baseline and last follow-up BC thresholds  in the ipsilateral and contralateral ears were assessed and compared. The auditory and perceptual gains at the last follow-up were assessed by PTA and speech audiometry and compared with the baseline fitting (activation) values to confirm the efficacy of the device. Visual Analog Scale (VAS) was also administered for the subjective evaluation of audiological benefit at 1 year after implant activation and at follow-up (4–12 years) to assess if the eventual bone threshold deterioration could have impacted on patients' satisfaction.n = 13) were distinguished from those with a severe-to-profound HL . The eventual influences of follow-up time and degree of BC worsening at the follow-up between the two subgroups were calculated after quantifying the statistical significance of the eventual deterioration in each subgroup.Among the study group, subjects with moderate-to-severe HL ; 1 patient was explanted after 6 years of continuous use for other medical problems (liver transplant program) and 2 patients had the implant removed due to post-operative complications . One patient was excluded because of unilateral hearing loss.Twenty of the 30 remaining patients  presenting preoperatively with symmetric sensorineural hearing loss and BC worsening at the follow-up, were the object of the study. Because none of these subjects showed BC worsening prior to 4 years post-surgery, this time limit was taken as the initial time (T0) for the follow-up, while the other time intervals were ≥5 years, between 5 and 10 years and >10 years.The baseline hearing threshold allowed us to distinguish moderate-to-severe and severe-to-profound hearing loss, which formed the basis of the two groups according to more (B) or less (A) severe hearing loss. A further distinction was made regarding the shape of the threshold that was identified as either flat or down-sloping.At the baseline evaluation, hearing loss was mild-to-moderate in one subject, moderate in 15 subjects, and moderate-to-severe in 4 subjects. The shape of the threshold curve was down-sloping in 5 subjects and flat in the remaining 15. A similar shape of the baseline threshold curve was found in the contralateral ear. All the operated ears showed a mean conductive type of loss of 35 dB . The minimum timing of the follow-up was 4 years, with a maximum of 12 years (mean 7.45 years). The follow-up time was <5 years in 7 subjects; >5 <10 years in 8 subjects; >10 <12 years in 5 subjects. At the last follow-up, the implanted ears showed moderate-to-severe HL in 10 subjects and severe-to-profound HL in 10 subjects; the contralateral ear showed mild-to-moderate HL in 1 subject, moderate HL in 14 subjects and moderate-to-severe HL in 5 subjects.p-value for the mean PTA as well as for each frequency (p < 0.0001) , with partial and total values of the BC threshold shown in  0.0001) .The mean BC threshold deterioration was 14 dB HL in the down-sloping curves and 21 dB HL in the flat-type curves . The worThe mean BC threshold level was 56.6 at the baseline and 62.55 at the last follow-up. The difference between the mean BC PTA at the last follow-up and the baseline threshold was 5.95 dB . The partial and total values of the baseline and last follow-up BC thresholds are shown in p = 0.0000).The comparison of the BC PTA value at the last follow-up with that of the baseline situation in the implanted and in the contralateral ear showed a mean worsening in the implanted ear of 18.6 dB compared with 6 dB in the contralateral ear, with a difference of 12.5 dB , 3, and The mean PTA implant values at activation were 25.5 dB HL at 250 Hz, 35 dB HL at 500 Hz, 39 dB HL at 1,000 Hz, 44 dB HL at 2,000 Hz and 72 dB HL at 4,000 Hz. The mean PTA implant values at the last follow-up were 43.25 dB HL at 250 Hz, 50.5 dB HL at 500 Hz: 57.25 at 1,000 Hz, 61.75 dB HL at 2,000 Hz and 79.25 dB HL at 4,000 Hz. The mean PTA implant gain at activation with respect to the BC threshold was 13 dB HL, and at the last follow-up, with respect to the follow-up BC threshold at the different frequencies, it was 19 dB at 250 Hz, 20 dB at 500 Hz, 18 dB at 1,000 Hz, 21 dB at 2,000 Hz, and 3 dB at 4,000 Hz , with a The mean SRT was 76.75 dB HL preoperatively, 57.75 dB HL at activation, and 69.25 dB HL at the last follow-up. The mean percent WRS was 81.5% preoperatively, 85% at activation, and 71% at the follow-up .p =0.0000), while the difference in percent of WRS was not significant. The comparison between the last follow-up and the preoperative speech audiometry values showed significant results only for WRS dB HL in the last follow-up data (p = 0.006). The comparison between the last follow-up and the activation speech recognition scores was significant for SRT (p = 0.00162) and for WRS dB HL in the last follow-up data (p = 0.023).The mean dB HL for the WRS maximum was 91.78 dB HL preoperatively, 74 dB HL at activation, and 82.5 dB HL at the follow-up . The meaVisual analog scale regarding implant benefit, administered at 1 year after implant activation and at the last follow-up, showed a mean value of 8.1 and 5.7, respectively .p > 0.05) in either ear (p = 0.02) but not in the contralateral ear (p = 0.17) (The different timings of follow-up were not significantly correlated with the degree of hearing loss (ther ear . The cor = 0.17) .because inclusion criteria did not require symmetric hearing loss, the postoperative hearing with the device was not compared with that of the contralateral aided ear because additional variables would have been introduced.” This assumption could be explained by the fact that the trial follow-up was limited to only 1 year from surgery.The Esteem® FI-AMEI has previously been reported to be beneficial not only for moderate and moderate-to-severe forms of SNHL  but alsoSince the primary goal of the present study was to monitor the BC threshold over time, using different follow-up periods, the assessment of the hearing threshold in the contralateral, non-implanted ear would appear to be crucial for shedding some light on the causes of eventual BC deterioration. First, in the immediate postoperative period, a change in the auditory pattern in all Esteem-implanted ears regarding the additional conductive component related to the interruption of ossicular chain continuity occurs, which is mandatory for a correct alternate action between the two implanted transducers , 17, 18.p = 0.000). Another interesting finding regards the role played by the baseline BC threshold morphology, showing that the flat-shaped curves presented a greater worsening than the down-sloping curves did. Worsening prevailed at 250 and 500 Hz for both curve shapes, without a statistically significant difference with respect to the other frequencies. The explanation for this finding could be related to the necessity of changing the fitting parameters during the follow-up times. In fact, in the case of an auditory decrease at high frequencies, the adopted fitting strategy involved cutting the frequencies between 8 and 12 kHz, considered the upper limit for a standard fitting session, to concentrate more energy toward the lower frequencies that could therefore be more solicited by the piezoelectric mechanical vibration. Another factor could be the minimal impedance improvement created during the surgery, with a bridge between the incus and stapes that should not impact the microphonic role of the tympanic membrane microphone. One important factor is related to the long observation time that allowed us to monitor the BC thresholds of both implanted and non-implanted ears over several years, with differences that did not statistically influence the severity of the final BC thresholds.The present study was designed as a retrospective, non-randomized, single center, clinically controlled study and included 20 Esteem implantees selected on the basis of bilateral symmetric SNHL. The implanted ear was initially chosen considering either an eventual greater degree of hearing loss or the favorable anatomical features of the mastoid size on the preoperative computed tomography (CT) evaluation. By following these patients over several years, it was possible not only to assess the efficacy of the implant after different durations of use but also to monitor the stability of the BC threshold, considering the contralateral ear as a control. The study group was heterogeneous for the severity of baseline hearing loss in the implanted ear since it included subjects who had moderate-to-severe SNHL (group A) and severe-to-profound SNHL (group B), and who had either flat or down-sloping curve shapes. The group was homogeneous for follow-up timing and for the symmetry of the baseline hearing threshold between the two ears in the same subject. Moreover, group B included mostly subjects with a down-sloping baseline auditory shape, which can be thought of as being on the border of an off-label indication, according to the manufacturer's recommendations. As mentioned before, the two groups were homogenous for the variables “follow-up timing” and “severity of the baseline hearing loss” of the implanted ear since no difference for these two variables was statistically demonstrated. Surprisingly, when assessing eventual differences in hearing loss deterioration as a function of the severity of baseline hearing loss, group A (moderate-to-severe) showed a more significant worsening than did group B (severe-to-profound) , despite the progressive bone conduction impairment. One may therefore assume that, if associated with a customized fitting program, the Esteem® device is able to provide an audiological benefit even in patients with severe hearing loss .The different degrees of deterioration between the two ears may allow us to rule out the importance of the etiology of SNHL. In fact, a certain degree of deterioration was also shown in the non-implanted ear without reaching the low levels shown by the FI-AMEI ear. In this regard, the duration of the follow-up showed no influence, with the same degree of threshold deterioration observed over both the minimum (4 years) and the maximum time (12 years). Likewise, the age of the patients and the severity of hearing loss did not influence the analysis, considering that the study group was formed of subject suffering from moderate-to-severe and severe-to-profound SNHL. In other words, a worse baseline threshold did not result in a greater likelihood of hearing deterioration than a milder threshold did. Therefore, the cause must be considered in other non-pathophysiological factors, such as the energy delivered by the device needing to be progressively increased to adapt to the new demanding situations related to deteriorated BC thresholds. This factor may also be the cause of an early depletion of the battery, which resulted in a mean life of 3.5 years instead of the 5–9 years predicted by the manufacturer . AnotherIt is possible to conclude that the BC threshold in some of the Esteem® implanted subjects can deteriorate over the time, but that its amplification properties could still provide a beneficial role for the implantees, with only a small percentage of them obliged to further rehabilitation with a cochlear implant.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Sapienza University. The patients/participants provided their written informed consent to participate in this study.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Fluorescence-guided visualization is a recently proposed technology in colorectal surgery. Possible uses include evaluating perfusion, navigating lymph nodes and searching for hepatic metastases and peritoneal spread. Despite the absence of high-level evidence, this technique has gained considerable popularity among colorectal surgeons due to its significant reliability, safety, ease of use and relatively low cost. However, the actual use of this technique in daily clinical practice has not been reported to date.This survey was conducted on April 2020 among 44 centers dealing with colorectal diseases and participating in the Italian ColoRectal Anastomotic Leakage  study group. Surgeons were approximately equally divided based on geographical criteria from multiple Italian regions, with a large proportion based in public (89.1%) and nonacademic (75.7%) centers. They were invited to answer an online survey to snapshot their current behaviors regarding the use of fluorescence-guided visualization in colorectal surgery. Questions regarding technological availability, indications and techniques, personal approaches and feelings were collected in a 23-item questionnaire.Questionnaire replies were received from 37 institutions and partially answered by 8, as this latter group of centers do not implement fluorescence technology (21.6%). Out of the remaining 29 centers , fluorescence is utilized in all laparoscopic colorectal resections by 72.4% of surgeons and only for selected cases by the remaining 27.6%, while 62.1% of respondents do not use fluorescence in open surgery . The survey also suggests that there is no agreement on dilution, dosing and timing, as many different practices are adopted based on personal judgment. Only approximately half of the surgeons reported a reduced leak rate with fluorescence perfusion assessment, but 65.5% of them strongly believe that this technique will become a minimum requirement for colorectal surgery in the future.The survey confirms that fluorescence is becoming a widely used technique in colorectal surgery. However, both the indications and methods still vary considerably; furthermore, the surgeons' perceptions of the results are insufficient to consider this technology essential. This survey emphasizes the need for further research to reach recommendations based on solid scientific evidence. Indocyanine green (ICG), approved for clinical use by the Food and Drug Administration (FDA) since 1959, is the most commonly used fluorescent probe. It is a low-cost molecule that is easy to use, widely available and negligibly toxic . In receThe Italian ColoRectal Anastomotic Leakage  Study Group comprises Italian surgeons particularly interested and experienced in colorectal surgery –9 workinThe aim of this study is to obtain a picture of how and to what extent ICG fluorescence-guided visualization is used in colorectal surgery to understand if the indications and the methods of use are sufficiently consistent and uniform to make prospective clinical studies unnecessary or outdated by daily clinical practice. The secondary aims are to analyze the availability of the technology, to detect organizational problems and highlight unsolved problems and to collect colorectal surgeons’ opinions about the actual usefulness and future developments of this technology.A questionnaire including 23 items was sent to 44 iCral study group centers. The study protocol was performed in accordance with the relevant guidelines. The Institutional Review Board of the University of Brescia, Department of Clinical and Experimental Sciences, approved the study protocol. A waiver of written informed consent was granted by the ethics committee of the University of Brescia.The questionnaire was structured in 4 sections: (1) hospital features , and surgical unit size (number of operating rooms and intensive care unit (ICU) hallmarks); (2) availability of fluorescence technology ; (3) indications for use, related to type of intervention, type of surgical approach, type of patient; (4) dosage, dilution, injection timing; and (5) personal opinion about usefulness of fluorescence technology and future developments. Maximum time granted to answer was 2 days.The datasets used and analyzed during the current study are available from the corresponding author on request.Questionnaire replies were received from 37 institutions (response rate 84.1%). Table From a technical perspective Table , there wParticipating surgeons were also asked for their opinion on the effectiveness of this method Table . Only 41Fluorescence-guided surgery allows enhanced real-time intraoperative visualization of anatomical structures and/or vascular perfusion –6. In thThe main goal of this paper is to describe protocols for handling ICG fluorescence imaging in colorectal interventions within Italian Departments of General Surgery participating in the iCRAL group. Fluorescence-guided surgery has forcefully entered daily clinical practice without being supported by high-level scientific evidence that certifies its usefulness . The impThe present questionnaire reliably represents a cross-sectional snapshot of Italian centers performing colorectal surgery. The composition of the iCRAL Group reflects the national public/private hospital and the academic/nonacademic hospital relationship. Most of the involved surgeons work in medium to large hospitals . Participating institutions should be considered colorectal medium–high volume centers, with scientific and cultural interest on the subject –9. PartiThe first consideration that emerges from the questionnaire analysis is that fluorescence technology is now extremely widespread: in 2019, only 21.6% of surgeons declared that they did not have the technology for fluorescence-guided surgery. Where it was available, in 69% of cases, there is more than one laparoscopic system; in 58.6% of cases, at least one column is always available; and in 62.1% of cases, multiple operations are possible at the same time. On the other hand, there is no consensus on the system brand; apart from a slight prevalence of Karl Storz devices, Stryker/Novadaq, Surgical Intuitive and Olympus units are equally distributed. We can therefore report a satisfactory diffusion of fluorescence technology, which makes it even more important to clarify the indications and techniques of use.Regarding the indications, 72.3% of surgeons use fluorescence by default in all laparoscopic interventions, while only 37.9% use it by default in open procedures. On the other hand, 27.6% of surgeons consider fluorescence only in selected cases, but there is no agreement on which these are . Few surgeons also take into account features different from perfusion evaluation, such as lymph node navigation (16.1%) and tumor labeling (35.5%). Basically, the most widespread practice involves the use of fluorescence for anastomotic perfusion evaluation in all laparoscopic colorectal surgeries.However, there is no agreement on the ideal timing for the perfusion assessment: for ileocolic anastomosis, approximately half of surgeons proceed with a single injection before the anastomosis, and half proceed with two injections one before and the second after the anastomosis . For colorectal anastomosis, the majority of surgeons (44.9%) perform the injection before the proximal colon section and before the anastomosis, while 27.6% perform it only before the proximal colon section; 10.3% perform 2 injections, one of which is made endoscopically after the anastomosis, and 17.2% perform 3 injections. Further discrepancies are also found in dilution and dose, as reported in Table A final interesting note relates to the perception of Italian surgeons of the efficacy of fluorescence in preventing anastomotic leaks: surprisingly, only 65.5% believe that this method should be implemented to the point of becoming a minimum essential requirement in colorectal surgery. However, this is understandable if we consider the subjective perception and statistical evidence relating to the reduction in anastomotic leaks: as many as 44.8% or 58.6% of the interviewed surgeons declared that they did not detect a subjective or statistical reduction in leaks, respectively.In conclusion, the assessment of visceral perfusion by means of fluorescence after an intravenous injection of ICG is an extremely widespread intraoperative technique yet is applied with considerable variability in protocols that prevents correct multicentric data collection aimed at a statistical demonstration of the usefulness of this procedure. Multilateral scientific action is required, coordinated and supported by the scientific societies of the surgical field to harmonize the application of the technique.


Aminoglycosides, a class of clinically important drugs, are widely used worldwide against gram-negative bacterial infections. However, there is growing evidence that aminoglycosides can cause hearing loss or balance problems. In this article, we mainly introduce the main mechanism of ototoxicity induced by aminoglycosides. Genetic analysis showed that the susceptibility of aminoglycosides was attributable to mutations in mtDNA, especially A1555G and C1494T mutations in 12S rRNA. In addition, the overexpression of NMDA receptors and the formation of free radicals also play an important role. Understanding the mechanism of ototoxicity induced by aminoglycosides is helpful to develop new therapeutic methods to protect hearing. In this article, the prevention methods of ototoxicity induced by aminoglycosides were introduced from the upstream and downstream aspects. Hearing loss is the most common sensory disorder worldwide. The World Health Organization estimates that around 466 million people worldwide suffer from disabling hearing loss and that by 2050 more than 900 million people will have this condition. Disabled hearing loss is defined as a loss of more than 40 dB in the better-hearing ear of an adult and more than 30 dB in the better-hearing ear of a child. Hearing loss can affect an individual's quality of life, making it difficult to understand speech in life. And untreated hearing loss costs the world an additional $750 billion a year.Hearing loss has both congenital and acquired caused. Congenital causes are caused by hereditary or non-hereditary factors. Acquired deafness can be caused by noise, ear infections, age, and medication. It is worth noting that ototoxic drugs are an important factor in the induction of hearing loss. Ototoxic drugs mainly affect hair cells, causing permanent damage to hearing. Because hair cells in mammals are terminally differentiated and do not have the ability to regenerate spontaneously if they die, ototoxic drugs can have serious effects on hearing  and enters the inner ear through the stria vascularis. In topical administration, the drug can bypass the BLB into the middle ear and then through the round window into the inner ear. The drug is absorbed either by endocytosis on the apical surface , which provides organisms with the energy necessary for survival, and for the regulation of important function, including apoptosis and the production of free radicals  is a glutamate receptor, which exists at the synaptic site between cochlear hair cells and the radical dendrites of spiral ganglion afferents. Aminoglycosides may mimic the effects of polyamines on NMDA receptors Puel, . The assIt is generally accepted that ROS is involved in ototoxicity induced by aminoglycosides, and antioxidants can mitigate the effects of ototoxicity   synthesis inhibitor was found to have a protective effect against the ototoxicity of aminoglycoside. Dexamethasone acts mainly as a glucocorticoid, not a mineralocorticoid  family. Studies have shown that overexpression of Bcl-2 in transgenic mice can reduce hair cell loss and prevent hearing loss after aminoglycosides administration (Cunningham et al., The above protective agents are based on animal studies and have a preventive effect on ototoxicity. However, there are some limitations in animal research and there are some problems in the transition from animal research to human clinical research. On the one hand, we need to find suitable protective agents for clinical use, so that the protective agents will not affect the antimicrobial effect of aminoglycosides. Studies have shown that D-methionine does not interfere with antimicrobial effects of tobramycin (Fox et al., Aminoglycosides, a class of clinically important drugs, are widely used worldwide against gram-negative bacterial infections. However, there is growing evidence that aminoglycosides can cause hearing loss or balance problems. In this article, we mainly introduce the main mechanism of ototoxicity induced by aminoglycosides. Genetic analysis showed that the susceptibility of aminoglycosides was attributable to mutations in mtDNA, especially A1555G and C1494T mutations in 12S rRNA. In addition, the overexpression of NMDA receptors and the formation of free radicals also play an important role. Understanding the mechanism of ototoxicity induced by aminoglycosides is helpful to develop new therapeutic methods to protect hearing. In this article, the prevention methods of ototoxicity induced by aminoglycosides were introduced from the upstream and downstream aspects. It has been shown that the use of some antioxidants and inhibitors of caspase can prevent cell apoptosis and effectively prevent aminoglycosides-induced hearing loss. In addition, the delivery of mitochondria-targeted drugs is of great significance for treatment. However, recent reports have found that autophagy may also play an important role in the induction of ototoxicity by aminoglycosides, and autophagy may be protective mechanism of hearing (He et al., The mechanism of ototoxicity induced by aminoglycosides and prevention methods described above have been established from animal experiments and can be used as a potential means to prevent ototoxicity induced by aminoglycosides. We still have a lot of work to do in the transition from animal research to clinical use. The side effects brought by aminoglycosides to patients should not be ignored, and we should further develop new alternative or therapeutic drugs to treat hearing loss caused by ototoxic drugs.XF, PW, and PL: writing-original draft, investigation, software, and writing-review and editing. JP, SG, YZ, YA, CY, and ZY: investigation. JG, JY, and JF: writing-review and editing, supervision, and administration. RC writing-review and editing, funding acquisition, and supervision. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Cochlear implants have been used to restore hearing to more than half a million people around the world. The restored hearing allows most recipients to understand spoken speech without relying on visual cues. While speech comprehension in quiet is generally high for recipients, many complain about the sound of music. The present study examines consonance and dissonance perception in nine cochlear implant users and eight people with no known hearing loss. Participants completed web-based assessments to characterize low-level psychophysical sensitivities to modulation and pitch, as well as higher-level measures of musical pleasantness and speech comprehension in background noise. The underlying hypothesis is that sensitivity to modulation and pitch, in addition to higher levels of musical sophistication, relate to higher-level measures of music and speech perception. This hypothesis tested true with strong correlations observed between measures of modulation and pitch with measures of consonance ratings and speech recognition. Additionally, the cochlear implant users who were the most sensitive to modulations and pitch, and who had higher musical sophistication scores, had similar pleasantness ratings as those with no known hearing loss. The implication is that better coding and focused rehabilitation for modulation and pitch sensitivity will broadly improve perception of music and speech for cochlear implant users. Music is a powerful tool used to express and elicit emotion. It can be a deeply personal source of enjoyment. Hearing loss, however, can dampen or distort incoming sound, and thus greatly reduce music appreciation. Cochlear implants (CIs) restore hearing in people with sensorineural hearing loss and largely rehabilitate speech understanding without the need for visual cues. Despite having generally high levels of speech comprehension, music appreciation in CI users is largely diminished compared to their normal-hearing peers ,2. In paThe perceptual deficits that CI users face are largely caused by technological limits of the implanted electrodes. While the healthy auditory nerve contains around 30,000 fibers, cochlear implants use an array of no more than 22 electrodes. This limited range of electrodes along with the spread of electrical current reduces the resolution needed to resolve harmonics ,8,9. LikPoor representation of place and timing cues for pitch and timbre in CIs has a marked effect on music appreciation for CI users ,5,12,13.Timbre is also a vital component to enjoying music. It is described by the American Standards Association (1960) as “that attribute of sensation in terms of which a listener can judge those two sounds having the same loudness and pitch are dissimilar”, and is often associated with the character or brightness of a sound. While timbre is often defined by what it is not , it can be clearly described by several acoustic features. For instance, by extending the attack time of a trumpet, it becomes qualitatively like a violin; yet the two instruments can still be distinguished by their unique spectral content even if they were playing the same note. The timbre of the harmonic signal is comprised of three acoustic features that drive timbre perception, including the temporal envelope, the spectral envelope, and spectral flux ,28,29,30chords: musical structures formed by the simultaneous presentation of two or more harmonic sounds. Music’s perceived pleasantness is driven by how well the sources harmonize. The degree of harmony, however, varies with the interval distance between the combined harmonics. A single harmonic series will have overtones spaced at integer multiples of the fundamental. When played simultaneously with another harmonic series, the components of each series may fuse in pleasant consonance. In contrast, the overtones produced at more awkward intervals may sound harsh and dissonant. For example, complexes with a fundamental ratio of 1:1, 1:2, or 2:3 tend to sound consonant, whereas ratios of 8:9, 8:15, or 32:45 are often considered dissonant [Oftentimes, songs are not constructed out of single notes but composed of issonant ,34,35,36One factor that may impact music enjoyment for CI users may be their perception of consonance and dissonance. While CI users can rank or rate stimuli based on dissonance, performance is often poorer or less pronounced than in normal hearing listeners ,38,39. WStudies also demonstrate that previous levels of musical experience, including active music listening and engagement, can influence performance on musical tasks. For example, LoPresto (2015)’s work on consonance and dissonance demonstrates that normal hearing, musically trained participants were more likely than non-musically trained participants to indicate that they disliked the sound of dissonant intervals in comparison to consonant intervals . Music tThe purpose of this study was to characterize the pleasantness profile of CI users across harmonic intervals and to determine the aspects of modulation and pitch perception that influence the perception of consonance and dissonance. Furthermore, this study also investigates how levels of musical sophistication influence CI users’ performance in these tasks. Pleasantness ratings were obtained from participants with no known hearing loss and from CI users for harmonic intervals spanning an octave. We hypothesized that sensitivity to temporal pitch cues is a driving factor in pleasantness ratings. Specifically, we predicted that CI users with pleasantness profiles that are most like normal-hearing listeners and those with higher levels of musical sophistication would be those most sensitive to amplitude modulations.R = 36–83 years old, M = 65.5 years, SD = 13.7 years, females = 5) and eight individuals with no known hearing loss  took part in this experiment. Seven CI participants used Cochlear Corporation implants , one used an Advanced Bionics implant , and one used a Med-El implant . Complete CI participant information is provided in Nine total CI users . The TeamHearing web application includes a range of speech and pitch perception tests created to measure various aspects of hearing including musical judgements, psychophysical discriminations, and speech reception in various environments and noise conditions. The specific TeamHearing measures used for this study are described in the follow sections.People with no known hearing loss and CI users took part in an online listening experiment designed to characterize pleasantness ratings of musical dyads—pairs of musical notes presented simultaneously. All testing was done through TeamHearing assessments were accessed on a personal computer, personal tablet, or a mobile device. People with no known hearing loss used headphones to complete the task. CI users were asked to complete the task in a method that was most comfortable for them, either by listening to the task through speakers or receiving sound input directly to their processor via Bluetooth or through a Mini Microphone device . Calibration of sound levels were conducted using loudness adjustments and detection thresholds for pure tones. Participants completed five assessments: modulation detection, fundamental frequency discrimination, consonance identification, pleasantness ratings for musical dyads, and speech reception thresholds on a sentence completion task in multi-talker background noise. Total testing time was two to three hours. A permalink for this experiment can be found at https://www.teamhearing.org/82, accessed on 20 December 2021.Before completing the assessments, participants completed procedures to characterize relative loudness levels. First, participants adjusted a 1 kHz pure tone to be “soft”, “medium soft”, “medium”, and “medium loud”. Second, pure tone detection thresholds were measured for octave steps between 125 and 8000 Hz. Stimuli were 400 ms sinusoids with 20 ms raised-cosine attack and release ramps. At the beginning of a measurement run, participants set the stimulus volume to be “soft but audible”. Detection thresholds were then measured using a three-interval, three-alternative, forced-choice procedure in which two of the intervals contained silence and one interval contained the gain-adjusted tone. Participants were instructed via on-screen instructions to select the interval that contained the tone. The starting gain was set by the participant and thereafter reduced by 2 dB after correct responses and increased by 6 dB after incorrect responses. A run continued until three mistakes were made and the average of the last four reversals was taken as the detection threshold. This procedure converges to 75% detection accuracy .Modulation detection was measured for modulation frequencies near 10 and 110 Hz. These modulation frequencies were chosen as representative of a roughness cue relevant to harmonic distortion (10 Hz) and as representative of one of the relevant fundamental frequencies being examined for pleasantness ratings (110 Hz). Modulation detection was measured using a three-interval, three-alternative, forced-choice procedure where two of the intervals contained standard stimuli without modulation and one of the intervals was modulated with adaptively controlled modulation depth. The standard stimuli were 1 kHz pure tones that were 400 ms in duration with 20 ms raised-cosine attack and release ramps. The target stimulus was identically defined except being amplitude modulated. The initial modulation depth was set to 100%. The modulation depth was decreased by a factor of accuracy . A measuFundamental frequency discrimination was measured for fundamental frequencies near 110, 220, and 440 Hz. These fundamental frequencies were chosen as representative of the typical range of spoken speech and as indicative of the range over which discrimination typically deteriorates for CI users. Discrimination was measured using a two-interval, two-alternative, forced-choice procedure for which participants were asked which interval was higher in pitch. The stimuli were complex tones constructed in the frequency domain by summing all harmonics from the fundamental to 2 kHz with a low pass filtering function. The form of the low pass filtering function was:https://musescore.org/en, accessed on 20 December 2021; Musescore BVBA, Belgium). Stimuli were grand piano notes with a duration of three seconds. Before commencing a measurement run, participants were first provided with several examples of consonant and dissonant dyads. During piloting of the pleasantness ratings procedures, it was noted that some CI users who had extensive musical experience could clearly hear the difference between dyads that are typically labeled as consonant  and those typically labeled dissonant , though they were reluctant to assign the terms “pleasant” or “unpleasant” to this distinction.To test consonance identification, participants were asked to categorize dyads as either consonant or dissonant. Four-note dyads were examined including two dyads typically labeled as consonant  and two dyads typically labeled as dissonant . Consonance identification was measured for root notes near 110, 220, and 440 Hz with each dyad type measured with ten trials each. All musical stimuli were generated using MuseScore 3 composition and notation software  to an octave . Dyads were organized into experimental conditions with pleasantness ratings collected for pairings near 110, 220, and 440 Hz. Musical dyads were presented one at a time. Participants were asked to rate the pleasantness of the dyad on a Likert scale from 0 to 6 with 0 labeled as “dissonant or unpleasant”, 3 as “neutral”, and 6 as “consonant or pleasant”. For a measurement run, each of the thirteen dyadic pairings  were presented twice. A total of nine measurement runs were made including three repetitions of each of the three note ranges .Speech reception thresholds were measured for a sentence completion task using speech materials from the Speech Perception in Noise Test (SPIN) corpus in the presence of multi-talker background noise . The useX hours per day”). The perceptual abilities category includes questions about music listening skills . Musical training questions inquire about individuals’ formal and non-formal music practice experiences . Singing abilities questions inquire about individuals’ singing skills and activities . Questions under the emotion category reflect on instances of active emotional responses to music . These topics together consider an individual’s holistic musical ability, including instances of formal and non-formal music training and engagement. The composite score of these subscales makes up an individual’s general musical sophistication score. All items, except those assessing musical training, are scored on a seven-point Likert scale with choices that range from “completely disagree” to “completely agree” [Musical experience was measured using the Goldsmith Musical Sophistication Index Self-Report Inventory (MSI), a 39-item psychometric instrument used to quantify the amount of musical engagement, skill, and behavior of an individual . The quey agree” .d. Post-hoc Bonferroni adjustments were performed for significant main effects [Data processing and statistical analyses were performed in MATLAB 2021a programming environment . Results from each test were analyzed using a 2 × 3 mixed analysis of variance (ANOVA) with a between-subject factor of group (CI versus those with no known hearing loss) and a within-subject factor of measurement repetition (three repetitions per test). Effect size was calculated using Cohen’s  effects . PearsonFurther analysis of the similarities between pleasantness ratings were conducted by calculating the correlation between individual ratings with the average ratings from the group with no known hearing loss. p-values less than 0.1 and most less than 0.05. In summary, strong correlations were observed between measures with the strength of correlation generally persisting even when considering the participant groups separately.Correlation analyses were conducted to consider relationships between average results across procedures. Specifically, for each procedure, measures were averaged across repetitions and conditions to yield a single value for each participant. These participant averages were then used to calculate the correlation between results across procedures. For pleasantness ratings, the correlation between individual pleasantness ratings and the group average for participants with no known hearing loss was used as the procedural result. As an example of specific correlations, A final correlation analysis was conducted to compare MSI with performance on modulation detection, fundamental frequency discrimination, consonance identification, pleasantness ratings, and speech reception in noise. The composite general musical sophistication scores were used for correlations in data analysis. The perceptual measures are plotted against MSI for comparison in The hypothesis tested by this experiment is that low-level sensitivity to modulations and to pitch change are predictive of higher-level measures of consonance perception. We also predicted that higher levels of musical sophistication would be positively correlated with performance on music and speech perception tasks. The first hypothesis was supported by evidence of strong correlations between measures of modulation detection and fundamental frequency discrimination, along with higher-level measures such as consonance identification and speech reception in background noise. The second hypothesis was partially supported by strong correlations between musical sophistication scores and performance on fundamental frequency discrimination thresholds, consonance identification, and pleasantness ratings for both the no known hearing loss group and CI users. MSI scores for both groups were not significantly correlated with modulation detection or speech reception thresholds. Discussion is focused on the significance of these trends and how they relate to other aspects of hearing, such as audibility, pitch resolution, and speech comprehension in challenging environments.The present experiment was in part motivated by a study by Spitzer and colleagues (2008), who examined pleasantness ratings in people who had a cochlear implant in one ear and normal hearing in the other . In thatIn the present study, the relationships between modulation and pitch sensitivities with pleasantness ratings was explicitly considered. The results indicate that both low-level measures of modulation and pitch sensitivity are well correlated to consonance identification. Even when considering the CI users in isolation, the correlation between pitch discrimination with consonance identification and with pleasantness ratings profile was exceptionally strong. This evidence indicates that consonance perception amongst CI users is a broadly varying dimension of hearing, with the implant users who are most sensitive to modulations and pitch changes having the best access to consonance perception.Results demonstrate that musical sophistication level is another factor that is strongly correlated with CI users’ perception of consonance. This is supported by previous works by LoPresto and Firestone which conclude that increased music training and engagement can lead to improved consonance identification and pitch discrimination ,47. In cA further contribution of the present study is the precise characterization of how strongly the pleasantness ratings of CI users can align with those with no known hearing loss. Previous studies have not considered how the general shape of pleasantness ratings as a function of dyadic interval compares for cochlear implant users. In the present study, the correlation between pleasantness ratings for individual CI users with a template from those with no known hearing loss clearly indicates that CI users can have normal pleasantness ratings. More specifically, levels of musical sophistication for CI users and those with no known hearing loss were significantly correlated with pleasantness ratings. This indicates that music training plays a similar role in CI users as in normal hearing populations when it comes to pleasantness identification. However, some CI users have distinctly abnormal ratings with negative correlation to those with no known hearing loss, suggesting a possible reversal in which dyadic intervals sound pleasant and which sound unpleasant.Worth noting is that a strong correlation was also observed between pitch resolution and speech reception in multi-talker babble. The presumed mediating mechanism is that CI users who are more sensitive to pitch change can use this access to pitch to attend to target speech in the presence of competing talkers. While that mediating mechanism was not explicitly tested in the present study, the strong correlations support the conjecture. However, it is also possible that the best performing CI users are high performing on both pitch and speech tasks without the pitch mechanism necessarily facilitating speech recognition. Further evidence of the association, though not a causative relationship, was provided in previous work from our laboratory ,49. RetuThe present study demonstrates the importance of sensitivity to modulation and pitch detection in combination with music training in order to enhance consonance and dissonance identification abilities among CI users. With the ability to discriminate between consonant and dissonant sounds in music comes the potential to identify sounds that are more pleasant to an individual’s music listening . In addi


Background: Triclosan (TCS) is an environmental chemical with endocrine disrupting effects and can enter the body through the skin or oral mucosa. Human data about the effect of TCS exposure during pregnancy on neonatal birth weight and TCS exposure during childhood on children's growth are scarce.Objectives: To investigate the association between maternal urinary TCS level and neonatal birth weight, as well as children's urinary TCS level and children's body mass index (BMI).Methods: A systematic literature search was conducted using PubMed, Cochrane Library, and Web of Science. Finally, seven epidemiological articles with 5,006 participants from September 25, 2014 to August 10, 2018 were included in the meta-analysis to identify the relationship between maternal exposure to TCS and neonatal birth weight. On the other hand, three epidemiological articles with 5,213 participants from July 22, 2014 to September 1, 2017 were included in another meta-analysis to identify the relationship between children's exposure to TCS and children's BMI. We used Stata 16.0 to test the heterogeneity among the studies and calculating the combined effect value 95% confidence interval (CI) of the selected corresponding models.Results: TCS exposure during pregnancy was not significant associated with neonatal birth weight. The results of forest plots were as follows: ES (Estimate) = 0.41 (95% CI: −11.97–12.78). Children's urinary TCS level was also irrelevant associated with children's BMI: ES = 0.03 (95% CI: −0.54–0.60).Conclusions: This meta-analysis demonstrated that there was no significant association between maternal TCS level and neonatal birth weight, also there has no relationship between children's urinary TCS level and children's BMI. Triclosan (TCS) is a synthetic, broad-spectrum biocides, and it was first licensed for use in the 1960s .Currently, the relationship between exposure to TCS during pregnancy and neonatal birth weight as well as children's body mass index (BMI) is not clear. A previous study has found that females tended to have higher TCS exposure level than males . A studyTherefore, exploring the effects of exposure to TCS during pregnancy on neonatal birthweight and exposure to TCS during childhood on children's BMI are priorities. However, there is lack of a systematic studies about the topic. The purpose of our research is mainly to compare the effects of TCS exposure on growth indicators before and after birth. We also explored the heterogeneity of the included studies and make a subgroup analysis of involved factors that may affect the outcomes.In our study, we used the following search terms to retrieve the relevant literature in three electronic bibliographic databases: PubMed, Cochrane Library, and Web of Science.In this direction, we searched the published literature until December 2019.#1: (gestation) or (pregnancy) or  or (antepartum) or #2: (triclosan) or (TCS) or (phenols)#3: (birth weight) or  or (baby weight) or (birthweight) or (birth size) or #4: #1 AND #2 AND #3In this direction, we searched the published literature until December 2019.#1: (triclosan) or (TCS)#2: (obesity) or (fat) or (plump) or (obese) or (corpulent) or (overweight) or (weight) or (axunge)#3: #1 AND #2The inclusion criteria for the studies were:Able to search the full text of literature;Pregnant women as the subject, not experimental animals;Explicitly specified the substance that pregnant women were exposed to TCS during pregnancy;The data showing the correlation between TCS concentration and neonatal birth weight were provided, such as estimate (ES) and 95% confidence interval (95% Cl);If the same population was used in different studies, we selected the recent one with larger sample size;The research design had no defects and the literature quality was high.The inclusion criteria for the studies were:Able to search the full text of literature;Infants or children as the subjects, not experimental animals (population);Explicitly specified the substance that infants or children were exposed to TCS (ES);The data showing the correlation between TCS concentration and children BMI were provided, such as ES and 95% CI (outcome);If the same population was used in different studies, we selected the recent one with larger sample size;The research design had no defects and the literature quality was high.The exclusion criteria for the studies were:(1) Not conform to the research topic;(2) Animal studies, conference abstract, lecture literature, editorial materials or comments, and so on;(3) Studies had design defects and poor quality;(4) The research objects exposure to multiple environmental endocrine disruptors;(5) Raw data was unavailable;(6) Unpublished studies.At first, the titles and abstracts of all identified publications were independently reviewed by two authors based on the inclusion criteria and exclusion criteria for the eligibility of the included articles. Then, further screening of the remaining full retrieved papers were implemented, and the references of the selected articles were evaluated. We identified the literature that were finally adopted. Studies were exported in Endnote X7, and duplicates were automatically removed. To ensure the accuracy of the results, the two authors have also checked and corrected for duplicates manually. According to literature inclusion criteria, we used a predefined template to extract information . Any disReferring to the Newcastle Ottawa Scale (NOS) standard, the two authors independently evaluated the quality of each literature . NOS conAll data acquisition and analysis were processed in the software Stata 16.0. We inserted appropriate information extracted from related literature in the spreadsheets and used the meta-analysis module to perform statistical analysis. We used the adjusted 95% CI in both birth weight and children's BMI as the effect value for TCS exposure during pregnancy on neonatal birth weight and children TCS exposure on children's BMI, respectively.P < 0.05, i2 ≥ 50%, the articles were regarded to have high heterogeneity. Considering that heterogeneity will drive different statistical methods to summarize the data, if heterogeneity is expected, random effects models will be preferable to fixed effects models (Specific steps: (1) Subgroup analysis: We explore the characteristics of the original studies and performed a hierarchical analysis based on different adjusted methods of TCS, different gender of infants, and different trimester that TCS was detected, and calculate the 95% CI of each subgroup; (2) Sensitivity analysis: We used a one-by-one elimination method for sensitivity analysis and chose a random effects model to analyze potential instability factors in meta-analysis, and evaluate the impact of publication bias of the overall results; (3) Heterogeneity test: If s models . OtherwiA total of 658 studies were initially included, and 435 records were obtained after eliminating the duplicate. By searching for the keyword (TCS) of the full text, 30 records were remaining. By reading titles and abstracts, 10 records were excluded due to irrelevant exposures or outcomes and eight records were experimenting on animals. The remaining 12 records were selected through reviewing the full papers. Among 12 full papers selected, five records were not considered since two had too small a sample size, and the other three records took the change in z-values as the results. Finally, seven articles were identified and included in our study , 17–20 . All sevA total of 862 studies were initially included, and 475 records were obtained after eliminating the duplicate. By reading titles and abstracts, 361 records were excluded due to irrelevant exposures or outcomes, 88 records were experimenting on animals, eight records on plants, and 15 records on microbes. Finally, three articles were identified and included in our study –31 Figu. In the The methodological quality of included studies was assessed by using the NOS. The characteristics of these studies are displayed in P = 0.196, i2 < 50%. The forest plot graph , P = 0.140, i2 < 50%, respectively, which manifested that whether use urine creatinine or SG as the adjusted method of TCS, the maternal urinary TCS level had no significant effect on neonatal birth weight. Meta-analysis forest plot was shown in We divided included studies into two groups based on the adjusted methods of TCS of either urine creatinine or specific gravity (SG). The results were as follows: ES = 2.28 (95% CI: −50.97–55.53), In the meta-analysis of the association between maternal urinary TCS level and neonatal birth weight as well as urinary TCS level of children and children's BMI, several articles were combined, which may lead to heterogeneity between studies. However, the results showed that the pooled ES values before and after the exclusion of a study were essentially the same as the 95% CIs, indicating that the original meta-analysis was reliable , 7.P = 0.754; p = 1.000; Publication bias was observed for TCS exposure during pregnancy and birth weight as well as TCS exposure during childhood and children's BMI using Begg's test and funnel plots  except for one study that TCS was not converted.In summary, in our meta-analysis, there was no significant association between exposure to TCS during pregnancy and neonatal birth weight, as well as TCS exposure during childhood on children's BMI. We recommend a broader, larger prospective cohort study to assess the relationship between prenatal TCS exposure and neonatal birth outcomes. In addition, we should pay more attention to TCS exposure during childhood and reduce children's exposure to TCS.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.JL carefully read and screened the literature related to the research direction and collected the data. DC made figures and tables and they were all the main authors of the manuscript. YH polished the language and optimized the format of the first draft. In the process of reviewing the manuscript, the language was checked and polished by FB. TC reviewed and revised the final manuscript and gave advice during the submission process. XW was the final reviewer. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The predominant hearing impairment in this case was sensorineural (SNHL). Of the patients diagnosed with AMD, SNHL was found in 88.89% of those with exudative macular degeneration and in 67.74% of those with atrophic macular degeneration. In contrast, we found that a significant proportion of the control group had normal hearing. Conclusion: One possible explanation for the association between retinal and cochlear impairment may be due to a melanin disorder.The pathogeneses of age-related macular degeneration (AMD) and age-related hearing impairment are not yet fully understood. If AMD and age-related hearing impairment are correlated, the cause of both may be a result of a common vulnerability. The aim of this study was to assess the interrelation between age-related macular degeneration and age-related hearing loss. Material and methods: In our case-control analysis, the hearing conditions of 40 subjects with AMD were compared with 40 age-matched healthy controls. In all patients, retinal changes were certified by clinical examinations, optical coherence tomography (OCT), and fluorescein angiography (FA). All subjects were inspected with pure tone audiometry (PTA), impedance audiometry, and speech audiometry. Results: A significant correlation ( Macular degeneration is a multifactorial disorder of the retina and a major cause of central vision loss in the elderly. The prevalence of age-related macular degeneration (AMD) varies in different racial and ethnic groups around the world and rises with each decade after the age of 50. The etiology of AMD is not well-established; however, the main role has been assigned to retinal pigment epithelium (RPE) illness. Melanin in the RPE protects photoreceptor cells against light-related toxicity and plays a crucial role in the pathogenesis of AMD ,2. MelanThe study protocol was approved by the ethics committee of “Victor Babes” University of Medicine and Pharmacy, Timisoara, Romania . All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.In our case-control study, the hearing conditions of 40 patients with age-related macular degeneration (AMD) were compared with 40 age-matched healthy controls. The studied population was referred to Ocularcare Eye Clinic during one year from March 2019 to March 2020. In all patients, retinal changes were confirmed by posterior pole eye exams, fluorescein angiography, and optical coherence tomography.The diagnosis of retinal lesions was performed by a retinal specialist in every case. Due to the variety of retinal lesions, optical coherence tomography (OCT) was followed by fluorescein angiography (FA). Nine types of lesion components were established. Drusen was defined as a white-yellow retinal lesion located at the interface between the Bruch membrane and retinal pigment epithelium. On the fluorescein angiography, multiple hyperfluorescent spots of small size and round shape were detected with poorly defined contours and a tendency to confluence. Geographic atrophy (GA) was recognized by some patterns, including drusen regression and progression of the atrophy in areas with pigmentary changes. FA was detected in atrophic areas with a window defect and with good visibility of the choroidal vessels. Choroidal neovascularization (CNV) was clarified by a blood vessel complex that expands through the Bruch membrane from the choriocapillaris into the sub-RPE (type 1) or subretinal space (type 2). Classic CNV was defined as a well-defined laced pattern during early transit with subsequent leakage and late staining of fibrous tissue. Occult CNV was described as an elevated, irregular area of hyperfluorescence in the middle phase and with persistent hyperfluorescence in the late phase of FA. Retinal pigment epithelial detachment (PED) from the inner collagenous stratum of Bruch membrane was identified as a round-ovalar lesion with smooth edges that showed early hyperfluorescence and leakage. Four types of PED were observed: serous, drusenoid, fibrovascular, and haemorrhagic. Serous PED was identified by a well-circumscribed area of hyperfluorescent pooling. Drusenoid PED was identified by an early diffuse hypofluorescence and irregular late staining. Fibrovascular PED showed irregular, stippled hyperfluorescence, leakage, and late staining on FA. Haemorrhagic PED was identified by an abundant masking of background fluorescence but with visibility of the overlying vessels. A disciform scar was recognized by a prompt staining and a strong hyperfluorescence without leakage.All patients were investigated with audiological tests comprising pure tone audiometry (PTA), speech audiometry, tympanometry, the measurement of the Stapedius reflex, and otomicroscopic examination. Audiometry was effectuated by using an AMPLIVOX Model 240 Portable Diagnostic Audiometer by an otologist. The cases of congenital hearing damage and any auditory conditions related to ototoxic drugs or noise exposure were eliminated from the study. The examination of hearing-impaired subjects and audiometry analysis were performed in close collaboration with an otolaryngologist.The measurements of air and bone pure-tone thresholds were obtained to provide information regarding hearing sensitivity and the type and severity of hearing impairment.Pure-tone thresholds were evaluated in concordance with the International Organization for Standardization (ISO). Pure tones for the frequencies 125, 250, 500, 1000, 2000, 4000, and 8000 Hertz (Hz) were obtained for the air conduction test, and the frequencies 250, 500, 1000, 2000, 4000, and 8000 Hz were obtained for the bone conduction test .The audiological screening was performed by speech audiometry, tympanometry, the measurement of the Stapedius reflex, and otomicroscopic examination, in accordance with international reference standards.The type of hearing impairment was classified as normal hearing, conductive hearing loss, sensorineural hearing loss, and mixed hearing loss in accordance with the World Health Organization (WHO). Therefore, the normal hearing range was <20 dB HL. A conductive hearing loss was defined as air-bone gaps ≥15 dB at one frequency or ≥10 dB at two frequencies. A sensorineural hearing loss was defined as a hearing threshold ≥20 dB HL with an air-bone gap <15 dB at one frequency or <10 dB at two frequencies. Mixed hearing loss was defined as a combination of both conductive and sensorineural hearing loss.p value of less than 0.05 was taken as statistically significant. We used statistical tests such as the Kruskal–Wallis test, the Mann–Whitney test, ANOVA, t-test, chi-squared test, and the Wilcoxon signed-rank test. The distribution of variables was validated using the Shapiro–Wilk test. The Kolmogorov–Smirnov test was used to verify the assumption of normality.The statistical analysis was performed using SPSS software version 22.0. Pearson’s correlation analysis was used, and a t-test analysis. The average degree of hearing loss in varied subtypes of AMD  was notably different from the control group , especially sensorineural hearing impairment (SHI). A significantly higher percentage of SNHL was noticed in AMD patients compared with the control group  and uveal melanoma. Uveal melanocytes in eyes with dark-colored irises have more eumelanin compared with light-colored eyes and thus can protect the eye from light toxicity. Because eumelanin is less photoreactive than pheomelanin, the elevated level of eumelanin in dark-colored eyes is associated with a smaller frequency of uveal melanoma and age-related macular degeneration, as epidemiological studies suggest. Furthermore, choroidal melanin is an antioxidant, it neutralizes reactive oxygen species injury, and it defends the retina from oxidative stress. The distribution of the RPE melanin is also very important in considering the toxicity of drugs related to it. In contrast to the choroidal layer, RPE melanin has a zonal allotment, with decreasing levels from the equator but with a peak concentration at the macula lutea. In the macular region the cytoarchitectonics of the RPE cells is narrower. Therefore, melanin concentration is greater in the macular area where light is focused.The protective functions of melanin on the eye tissues seem to be performed by biochemical and physical mechanisms. The pigment has antioxidant and photo-screen effects. The photo-screening effect prevails in the anterior pole of the eyeball, which is vulnerable to sunlight and UV radiation. The posterior pole of the eye is exposed to a limited quantity of light and ultraviolet waves. Therefore, antioxidant properties are the main way of protection ,9.In the human ear, the melanin pigment is mostly present in the cochlea, in the vestibular organ, and in the endolymphatic sac. Melanin-containing cells of the cochlea are located in the stria vascularis and the modiolus. Melanin is abundant in the intermediate layer of the three-layered vascularized epithelial tissue. The literature suggests that all phases of local melanogenesis occur in the intermediate cells. In the modiolus, melanocytes are distributed in the perineural and perivascular spaces.In the vestibular organ, melanocytes are distributed in two sectors: (1) in the utricle and the ampulla and (2) in the saccule. The melanocytes of the ampulla and utricle are found subepithelially, below the basement membrane among the connective tissue cells. In the saccule, melanin pigment is found in the membranous wall. In the endolymphatic sac, the melanocytes are located in properly vascularized areas, bordering with the cells responsible for the support of the endolymphatic ionic content. Melanin protects the inner ear against oxidative damage. Low levels of melanin make the cochlea vulnerable to oxidative stress and lipofuscin aggregation ,11,12.Through aging, the quantity of melanin in RPE cells and the cochlea decreases, and lipofuscin depositions rise. Small melanin concentrations seem to be one of the most important factors leading to AMD and SNHL development.Several studies emphasize the correlation between age-related hearing impairment and age-related macular degeneration. The study conducted by Ghasemi et al. denoted a clear association between simultaneous macular and cochlear impairment. Bozkurt et al. underlined that age-related hearing loss is more common in patients with age-related macular degeneration.Our study denotes a significant association between age-related macular degeneration and sensorineural hearing loss. We would like to emphasize the possibility of a common melanin impairment in RPE cells and the inner ear. Therefore, melanin degradation may account for a major cause for simultaneous hearing and visual damage in the elderly. Further studies are necessary to conclude a causal association between age-related macular degeneration and sensorineural hearing loss.


It remains unclear to what extent newborn hearing screening (NHS) detects congenital cytomegalovirus (cCMV)-associated sensorineural hearing loss (SNHL) in Japan. This study aimed to clarify the NHS results and audiological characteristics of patients with cCMV-associated SNHL. A total of 541 individuals with unilateral or bilateral hearing loss of unknown etiology were examined for cCMV infection. cCMV infection was defined by the presence of CMV DNA in the dried umbilical cord detected using real-time quantitative PCR. NHS results and audiological data were retrospectively obtained from medical records. Forty-four cases (8.1%) were positive for cCMV infection. Of them, 33 cases underwent NHS and 13 cases (39.4%) passed NHS bilaterally. The pure-tone audiograms of 21 patients were obtained. There were seven cases of unilateral SNHL, five cases of asymmetric bilateral SNHL, and nine cases of symmetric bilateral SNHL. cCMV-related hearing loss is highly heterogeneous, and there is a high risk of missing this condition through NHS. Hearing loss due to congenital cytomegalovirus (cCMV) infection was first reported in 1964 . Among tInfants are often infected with CMV via birth canal secretions, breast milk, their siblings, and the surrounding environment immediately after birth; consequently, CMV infection diagnosed using specimens collected after 21 days of age cannot be identified as congenital. Therefore, the detection of CMV DNA by isothermal nucleic acid amplification using urine within 21 days after birth is the gold standard for diagnosis of cCMV infection and has been covered by insurance policies since 2018 in Japan . Dried bEarly hearing detection and early intervention have positively impacted the outcomes of children who are deaf or hard of hearing and their families across the world. Universal newborn hearing screening (NHS) has significantly lowered the average age of identification . NHS is This study was approved by the ethical committee of the National Hospital Organization Tokyo Medical Center and by the ethical committees of all research institutes who collaborated in this study. Informed consent was obtained by each research center from every participant or their parents.From March 2010 to May 2019, 541 individuals with unilateral or bilateral hearing loss of unknown etiology were examined for cCMV infection. The inclusion criteria are those patients who (1) have unilateral or bilateral deafness with the degree of mild, moderate, severe, or profound; (2) have preserved umbilical cords and consented to the use of a part of them for CMV examination; and (3) developed hearing loss before the age of 20. The exclusion criteria are those patients who (1) are diagnosed with hearing loss due to environmental factors  other than cCMV infection, (2) have been clinically diagnosed as a syndromic hearing loss, or (3) are diagnosed with sudden deafness. cCMV infection was defined by the presence of CMV DNA in the dried umbilical cord detected using real-time quantitative PCR . Hearing levels of the patients were measured by pure-tone audiometry. NHS results were obtained from medical records or by interviewing the patients’ parents. NHS was performed using automated otoacoustic emission (AOAE) or automated auditory brainstem response audiometry (AABR) in Japan.In total, 541 patients with unilateral or bilateral hearing loss with no apparent causes underwent umbilical cord CMV testing, and 44 (8.1%) were positive for cCMV infection. Of these 44 cases, 27 (61%) were female and 17 (39%) were male. Although the median age of SNHL diagnosis was 2 years (0–7 years), the median age of cCMV infection diagnosis was 3.5 years (0–30 years) . About 7We were able to determine whether 38 of the 44 cases underwent NHS. Thirty-three of them underwent NHS and five did not. Among these 33 cases, NHS was performed by AOAE in six cases, by AABR in 18 cases, and by unknown methods in nine cases. Thirteen cases (39.4%) passed bilaterally, eleven cases (33.3%) did not pass bilaterally, and nine cases (27.3%) passed unilaterally A. For NHThis study indicates that cCMV-related hearing loss is highly heterogeneous and there is a high risk of missing this condition through NHS. cCMV-related hearing loss is characterized by a high frequency of asymmetric hearing and the frequent occurrence of late-onset or progressive hearing loss.Although the median age of SNHL diagnosis was 2 years (0–7 years) in this study, about 70% of all cases of CMV infection were diagnosed after 2 years of age. In contrast with hereditary SNHL, hearing loss due to cCMV infection is often asymmetric, which is a clue for diagnosis. Detection of CMV DNA using urine within 21 days after birth is the gold standard for diagnosis of cCMV infection and has been covered by insurance policies since January 2018 in Japan. cCMV infection is treated with valganciclovir  or ganciIn this study, 67% of cases had bilateral SNHL and 33% of cases had unilateral SNHL, which is consistent with previous cohort studies. According to eight cohort studies .About 8% of individuals with unilateral or bilateral hearing loss of unknown etiology were positive for cCMV infection. cCMV-related hearing loss is highly heterogeneous and there is a high risk of missing this condition through NHS. Although immediate CMV screening is recommended for infants who do not pass NHS, such targeted cCMV screening will not capture infections that result in late-onset hearing loss. Universal cCMV screening offers larger net savings and the greatest opportunity to provide directed care.


IR) or sham untreated control (C). Data collected included heterophil/lymphocyte (H/L) ratio, pecking force, feather cover, behavioral expression, and beak histology. Data were analyzed as a 2 × 2 factorial of beak treatment and gender, in a completely randomized design and analyzed using PROC MIXED (SAS 9.4). H/L ratio (indicative of a stress response) did not differ between treated and control poults during early life, except at 20 d of age when H/L ratio was higher for C poults than IR poults. Pecking force, measured as a method of monitoring pain, was different only at 1 wk of age, when IR poults pecked with more force than C poults. Feather cover was better in IR poults at 12 wk of age. Differences in behavior between treatments were minor over the 12-wk period. Overall, infrared beak treatment of commercial turkeys had minimal negative impacts on behavior and welfare. The results suggest that stress may be reduced in flocks that are beak treated and that the procedure itself does not cause a pain response.This study aimed to determine the effects of infrared beak treatment on the behavior and welfare of male and female turkeys reared to 12 wk of age. To do this, poults  were assigned to one of 2 beak treatments: infrared beak treated on day of hatch ( Beak treatment is a common management practice used to control cannibalism and injurious pecking behavior in commercial layers, broiler breeders, and turkeys . In the H/L) ratio is considered to be a reliable indicator of chronic stress  or sham untreated control (C). Poults were beak treated using the Poultry Service Processor  at a lamp power of 35 and no reflective mirror, resulting in only the top beak being treated. Poults in the C treatment were handled and loaded on the infrared beak treatment equipment to simulate conditions experienced by the treated poults; however, their beak tips were not exposed to the infrared light. Upon arrival at the research facility, poults were housed in floor pens  and a brooder ring (8 cm circumference) was used for the first 10 d. Stocking density for the pens was based on the predicted 12-wk body weight and was a maximum of 32 kg/m2   were hatched and sexed at a commercial hatchery. Poults were randomly assigned to one of 2 beak treatments: infrared beak treated (per pen) . The remSupplemental feeders and drinkers were provided for each pen for the first week. Each pen also had a heat lamp for the first two weeks. Wood shavings were used as bedding and wheat straw was provided equally to all pens after brooding if litter quality was poor. Poults were given ad libitum access to age-appropriate commercial diets in tube feeders . Ad libitum water access was provided using bell drinkers . For the initial brooding period, temperature was 30°C. Temperature was reduced by approximately 2°C per week to reach a final temperature of 13°C at 12 wk of age. Photoperiod and light intensity were 23L:1D (40 lux) for the first 5 d and then reduced by one hour of light and 6 lux per day to reach a final photoperiod of 18L:6D (5 lux) at 10 d of age.Blood samples were collected for H/L ratio determination from 10 turkeys per treatment from the jugular vein at 1, 5, and 10 d of age, and the brachial vein at 15 and 20 d of age. Blood smears were prepared on the same day blood was collected. The slides were allowed to dry and then stained with PROTOCOL Hema 3 . Slides were analyzed under 100× oil magnification and all heterophils and lymphocytes within a field of view were counted until a total of 100 cells was counted .N) by multiplying the mV value by the sensitivity reciprocal (see below).The force that poults used to peck at food objects was measured weekly for the first 4 wk of the experimental period. Six turkeys per treatment were randomly chosen and removed from their home pen. Birds were weighed to determine BW and then placed into an enclosure (40 cm × 40 cm) within the same room as their home pen, that contained a force plate connected to a load cell, which was connected to a P-3500 Portable Strain Indicator unit  and visualized on a TDS1002R oscilloscope  situated in the center. Three pecks were recorded and averaged per bird where a peck was considered any hit from the beak onto the force plate (load cell). Once a bird had pecked the force plate, the force (measured in millivolts [mV]) was recorded and converted to newtons . Five body areas were scored: neck, back, breast, wings, and tail. These areas were given a score of 1 (0–25% feather cover), 2 (26–50% feather cover), 3 (51–75% feather cover), or 4 (75%-full plumage) using a scale adapted from Behavior on d 1, 6, and 8 of age was recorded for 24 continuous hours from 2 replicates per treatment using HFR700 camcorders . These camcorders were unable to capture the entire pen, so any bird not present on the screen was recorded as unknown. At 3, 8, and 12 wk of age, behavior from 2 replicates per treatment was recorded for 24 continuous hours using ceiling mounted infrared video camera systems  that captured the whole pen. Videos were analyzed using scan sampling at 15-min intervals. Behavioral expression was classified using the ethogram described in On 1, 5, 10, 15, and 20 d of age, beak samples from 2 birds per treatment were collected. Birds were humanely euthanized by manual cervical dislocation and their beaks were removed by cutting where the beak attached to the skull. Beaks were then placed in 10% neutral buffered formalin and stored at room temperature. Beaks were trimmed into sagittal cross sections and placed in cassettes. Samples were submitted to an independent diagnostic laboratory for slide preparation . Beaks from d 15 and 20 were decalcified in 20% formic acid for 24 h prior to sectioning.P ≤ 0.05 and a trend was noted when 0.05 < P ≤ 0.10.The experimental design for this study was a 2 × 2 factorial arrangement of beak treatment and gender, in a completely randomized design with 4 pen replicates per treatment. The experimental unit used for feather cover and behavior was pen. The experimental unit used for H/L ratio and pecking force was bird. Data were analyzed with ANOVA using PROC MIXED  with Tukey's range test to separate means. Percentage data was checked for normality using PROC UNIVARIATE (SAS 9.4) and log transformed (data log + 1) when necessary. Differences were considered significant when Leaving turkeys with intact beaks resulted in a higher H/L ratio at 20 d of age . No diffInfrared beak treatment had minimal impact on the force with which turkeys used to peck at food objects . At one At 8 wk of age, feather cover on the back was better in IR turkeys compared to C  while feather cover of the wings was better in C than IR turkeys . Female C turkeys spent more time (1.53%) performing these behaviors compared to all other treatments .At 1-d post-beak treatment, beaks showed coagulative necrosis of the epithelium and tissue below the treatment line. Hemorrhage and edema were also observed A and 1B.There is significant pressure to eliminate the practice of beak treatment in all commercial poultry species, with many European countries banning any form of treatment while others allow only infrared beak treatment until reliable alternatives are available . InfrareOne of the concerns regarding any form of beak treatment is that it may cause stress and pain to the bird . AlteratPrevious research has shown that infrared beak treated hens consistently have better feather cover compared to their untreated counterparts . This caBeak treatment had minimal and inconsistent effects on behavior during the first 3 wk of rearing. Previous studies have reported that birds with intact beaks spend more time exploring their environment compared to those that were beak treated (either by hot-blade trimming or infrared beak treatment)  and thisIn the present study, IR turkeys were observed spending a greater percent of time resting compared to C turkeys 1 d post-beak treatment. Inactivity  following beak treatment may be an indicator of pain or discomfort . MarchanIn conclusion, infrared beak treatment had a minimal impact on the welfare of male and female turkeys reared to 12 wk of age. Infrared beak treatment did not appear to cause acute or chronic pain in the turkeys as there was no evidence of neuroma formation or abnormal nerve growth. The results of the present study support the continued use of infrared beak treatment to help improve turkey welfare by reducing the damage that birds can inflict upon each other until reliable and effective alternatives to beak treatment are found.


Mucormycosis is an opportunistic fungal disease that commonly presents as cutaneous or rhinocerebral infections associated with immunocompromised states. It may exceptionally present as isolated involvement of the brain with a varied clinical presentation, which may be difficult to diagnose early, leading to increased mortality. Herein, we report the case of a 42-year-old immunocompetent female with left-sided limb weakness and a history of recurrent vomiting and headache for the last two years. Clinically, glioma was suspected, but histopathological examination revealed a few broad aseptate fungal hyphae. As no other organ was involved, the diagnosis of isolated cerebral mucormycosis was rendered. Reporting this case, we show an unusual presentation of a central nervous system mucormycosis masquerading a tumor in an immunocompetent patient. The case also highlights the importance of a careful histopathological examination to avoid missing the presence of occasional fungal hyphae. Ideally, recognition of fungal hyphae in the brain, during intraoperative consultation, can prompt brain tissue culture for definitive diagnosis and early empirical antifungal therapy, which may prove life-saving. All the biochemical findings, including liver and kidney function tests and serum electrolytes, were within the normal range. Chest X-Ray and abdominal ultrasonography were normal. The brain Magnetic resonance imaging (MRI) showed a space-occupying mass in the right frontal lobe, involving the caudate nucleus, genu, and body of corpus callosum , packed cell volume (hematocrit) 33.06%, total leucocyte count of 5,500/mmcallosum . Sinusescallosum A. The glcallosum 22D. Gomocallosum 3B, and tIsolated cerebral mucormycosis, a sporadic presentation, accounts for 8% of total cases of mucormycosis.Typical cerebral mucormycosis occurs due to the extension of the paranasal sinuses infection associated with immunosuppression, and 82% of the cases of isolated cerebral mucormycosis occurs due to intravenous drug abuse.,Another important feature of our case was the initial suspicion of cerebral tumors based on the clinical presentation and the imaging examination. Dussaule et al.,,The definite diagnosis of isolated cerebral mucormycosis may pose a problem as culture may be negative in 62% of cases.,,The mortality rate of the isolated cerebral mucormycosis cases is high and rapid and is reported to reach 65% and within 20 days of admission to the hospital.The case highlights the unusual presentation of a rare case of isolated cerebral mucormycosis mimicking a CNS tumor in an immunocompetent patient with the absence of any risk factors and chronic history. Careful histopathological examination for the identification of fungal hyphae and associated subtle features is helpful in its diagnosis. The definite early diagnosis followed by prompt treatment proves beneficial to prevent mortality in this otherwise fatal disease.