Dear colleague,In recent years we have seen a special attention being given to disabled individuals in all areas of society and public health care. Early diagnosis, treatment, rehabilitation and prevention policies have involved legislators, managers and multidisciplinary health care professionals with the aim of reducing as much as possible the, often times, devastative effects disabilities can cause.Hearing development follows gradual stages of complexity, already starting in the uterus. Thus, for a child to acquire language and develop speech, this child must be able to detect sounds, locate them, discriminate them, memorize them, recognize them and, finally, understand them. Any of these stages, especially the early ones, are very important for the process to complete. Its interruption can cause important functional loss to the child's development. Thus, action must be taken as soon as possible in order to minimize the difficulties brought about by sensorial disorders.In developed countries, sensorineural hearing loss affects 1 in every 1,000 newborns, and 40% of the cases may be due to hereditary factors, 30% to the many acquired etiologies and 20% still have unknown etiology. The Central Nervous System has great plasticity, when stimulated earlier on, especially before 12 months of age, enabling an increase in nervous connections and providing better results in the auditory rehabilitation and language development of children affected by hearing impairment. The first six months of life are decisive for the child's future development, and for these reasons otorhinolaryngologists, speech and hearing therapists and pediatricians have been concerned with campaigns to bring awareness to the population and health care professionals about the importance of an early identification and diagnosis of hearing loss, immediately following the medical and speech and hearing intervention measures.Because of the increase in the number of hospitals implementing Universal Neonatal Hearing Screening Programs (UNHS), and also because of the approval of municipal and state laws, we decided to give a professional opinion on UNHS, aiming at guiding the actions of the health care professionals involved.The multiprofessional Committee on Hearing Health (COMUSA), created in 2007, is a committee that involves Speech and Hearing Therapists, Otologists, Otorhinolaryngologists and Pediatricians. Its goals are to discuss and recommend actions regarding the hearing health of newborns, infants, pre-school aged children, school-aged children, teenagers, adults and the elderly. During two years we discussed, studied and created a text initially considering the UNHS. COMUSA is made up of representatives from the Brazilian Academy of Audiology (ABA), Brazilian Association of Otorhinolaryngology and Neck and Facial Surgery (ABORL), Brazilian Society of Speech and Hearing Therapy (SBFa), Brazilian Society of Otology (SBO) and Brazilian Society of Pediatrics (SBP), all signing this document we present in this issue of our Journal.I hope reading this text can help minimize and prevent the effects of hearing impairment in children and involve the largest possible number of otorhinolaryngologists in these programs.Enjoy!Prof. Dr. Silvio Antonio Monteiro Marone Full Professor of Otorhinolaryngology – Medical School – Catholic University of Campinas (S. P.)PhD in Otorhinolaryngology – University of São Paulo Medical School.


Hearing impairment, the most prevalent sensory deficit, affects more than 466 million people worldwide (WHO). We presently lack causative treatment for the most common form, sensorineural hearing impairment; hearing aids and cochlear implants (CI) remain the only means of hearing restoration. We engaged with CI users to learn about their expectations and their willingness to collaborate with health care professionals on establishing novel therapies. We summarize upcoming CI innovations, gene therapies, and regenerative approaches and evaluate the chances for clinical translation of these novel strategies. We conclude that there remains an unmet medical need for improving hearing restoration and that we are likely to witness the clinical translation of gene therapy and major CI innovations within this decade. This review summarizes the clinical translation of gene therapy and cochlear implant innovations and discusses if there is an unmet medical need for improving hearing restoration.  Adeno‐associated virus (AAV)Single‐strand DNA virus, considered to be non‐disease‐causing, is often used as the vector of choice for expressing transgenes of interest for gene therapeutic approaches. AAVs are engineered to not integrate their DNA into the host genome.Auditory brainstem response (ABR)Evoked population response reflecting summed synchronized action potentials in the auditory nerve, various auditory brainstem nuclei, and the auditory midbrain.ChannelrhodopsinsLight‐gated ion channels originally found in green algae. When introduced into excitable cells (such as neurons), channelrhodopsins enable precisely controlled light‐induced action potential generation.Cochlear implant (CI)Neuroprosthetic device, which directly stimulates the auditory nerve and thereby partially restores hearing in patients suffering from profound sensorineural hearing loss.Cochlear optogenetics (in this review)Optogenetic stimulation of spiral ganglion neurons.Electrical cochlear implant (eCI)CI that stimulates the auditory nerve by electrical impulses.Gene correction (=Gene editing)A gene therapeutic approach correcting the DNA sequence of a dysfunctional allele with detrimental effects to gain expression of a gene product with normal function.Gene replacementA gene therapeutic approach adding a functional gene copy to replace the present nonfunctional allele.Gene supplementationA gene therapeutic approach to augment the expression of a functional allele.Hereditary hearing lossHearing loss caused by mutations in genes involved in the normal function of the ear and is hereditable. Discrimination of syndromic (affecting more organs than the ear) or nonsyndromic forms (affecting only hearing) that are further specified by hereditability and gene affected as autosomal dominant , autosomal recessive , X‐linked  or mitochondrial.Infrared lightElectromagnetic irradiation with a wavelength longer than visible light (700 nm to 1 mm wavelength).Intraneural inserted eCIAn array with slanted needle electrodes penetrates the auditory nerve at the internal auditory canal.Light‐emitting diode (LED)Semiconductor light source, which emits photons when the electric current is applied.MechanotransductionConversion of mechanical stimulation such as pressure waves into electric signals by mechanosensory hair cells.ModiolusCentral axis of the cochlea housing the spiral ganglion.OptogeneticsGenetic modification of biological tissue enabling control of cells by light.Optical Cochlear Implant oCIActive vs. passive implementation, while “active” oCIs integrate optoelectronics such as micro‐LEDs generating light directly inside the cochlea, “passive” oCIs employ light‐guiding waveguide arrays to pipe the light from emitters placed in the extracochlear titanium‐housed stimulator into the cochlea.Organ of CortiSensory organ of the inner ear, housing inner and outer hair cells, and various supporting cells.OssiclesThree bones  in the middle ear, which amplify and relay pressure waves from the outer ear arriving at the eardrum to the inner ear via the oval window.OTOF (gene)Otoferlin (protein), OTOF gene coding for otoferlin cause autosomal‐recessive hearing loss DFNB9.A transmembrane protein expressed in inner hair cells essential for hair cell synaptic transmission, mutations in the PhotocurrentsIonic currents mediated by light‐gated ion channels upon illumination.PhototoxicityDamage of cells or tissue evoked by intense exposure to light.Ribbon synapsesSpecialized synapses in the inner ear and retina, which are characterized by electron‐dense structures (ribbons) that tether synaptic vesicles to presynaptic active zones.Rosenthal's canalCavity in the modiolus housing the cell bodies of spiral ganglion neurons.Scala tympaniPerilymph‐filled intracochlear cavity extending from the round window to the helicotrema.Sensorineural hearing lossHearing loss resulting from dysfunction of the cochlea and/or spiral ganglion.Spectral selectivityPrecision by which the cochlea can encode sound frequency upon acoustic, electrical, or optogenetic stimulation.Spiral ganglion neurons (SGNs)Bipolar neurons housed in Rosenthal's canal in the modiolus who innervate hair cells and whose axons form the auditory nerve, projecting to the cochlear nucleus in the auditory brainstem.Transmembrane channel‐like 1 protein (TMC1)A protein expressed in inner hair cells essential for mechanotransduction. Mutations in TMC1 are causative for autosomal‐dominant (DFNA36) or autosomal‐recessive (DFNB11) hearing loss.TonotopyPlace‐frequency code in the auditory system.TransductionGene transfer by viral vectors.Waveguide arrayArray of physical structures which guide electromagnetic waves in the optical spectrum to their target structures.et al, et al, et al, et al, Acoustic signals or sound, including human speech and music, are air pressure waves of different frequencies and amplitudes that fluctuate in time. Once picked up by the outer ear, pressure waves vibrate the ear drum, which along with the attached chain of ossicles aligns the low impedance of the air and the high impedance of fluids in the cochlea where sound is transformed into nerve signals , 466 million people (432 million adults and 34 million children) suffer from disabling hearing loss (HL), and more than 700 million people are estimated to be affected by disabling hearing loss in 2050 WHO, . Disabliet al, The pathophysiology of hearing impairment can be classified according to the site of the lesion Fig . ConductMore than half of the cases of congenital sensorineural hearing impairment are attributed to single‐gene defects  is arguably the most successful neuroprosthesis, and it is currently used by more than a million people. The eCI consists of an external component—a microphone(s), an audioprocessor, and a battery pack—and an internal part with an electrical pulse generator and a linear electrode array that is placed into the fluid‐filled cochlear compartment  along the tonotopic axis Fig . Externaet al, et al, Since the introduction of the multichannel eCI, its performance has been enhanced in several ways, including advances in coding strategies ; increasing the stimulation rates of the implant (~ 1 kHz per electrode); and employing wireless connectivity Lenarz, . Howeveret al, We conducted a survey among adult patients from the Department of Otolaryngology of University Medical Center Göttingen who were actively using a cochlear implant for 6 months or more during the time of the survey period, about their long‐term experience with the implant. This custom questionnaire specifically addressed eCI users about their perspectives on future means of hearing restoration in conjunction with the commonly used questionnaires SSQ‐12 . In terms of improving the transmission of time and frequency information, there have been recent advancements in temporal fine structure coding for electrodes that carry low‐frequency information , and advanced sound preprocessing that will eventually involve AI‐powered analysis of acoustic scenes. Another major development has been the totally implantable cochlear implant .https://youtu.be/eZJPqRmAzSA). They plan to use a Utah array with slanted needle electrodes for penetrating the auditory nerve. Challenges of the approach include: a more complicated mapping of frequencies to electrodes than for intrascalar eCI, the risk of scar formation increasing the electrode resistance, and surgical access to the implantation site.Pioneered by Middlebrooks and Snyder (2007), intraneurally inserted electrode arrays have been shown to improve the spectral selectivity in preclinical studies using silicon shaft multielectrode arrays. Moreover, the required current is lower than for intrascalar eCIs. Currently, the approach is being prepared for a clinical trial by the Lenarz and Lim teams in collaboration with Blackrock and MED‐EL companies . The method has remained somewhat controversial; however, the feasibility of direct infrared stimulation of SGNs has been challenged by studies in other laboratories , were demonstrated to mediate light‐driven action potentials in mammalian neurons  to the cochlea. Current preclinical work tries to identify the most suitable combination of ChR, AAV, and promoter with good tropism for SGNs and includes AAV2/6, AAV2/9, AAV‐PHP.B, and AAV‐PHP.eB  which generate light inside the cochlea, “passive” oCIs employ light‐conducting waveguide arrays to pipe the light from emitters in the extracochlear titanium‐housed stimulator into the cochlea Fig . Passiveet al, et al, et al, et al, et al, in vivo and in silico ; or an injection into the modiolar axis via the apical turn of the cochlea  energy , and the first FDA‐approved gene therapy—to treat one eye was initially priced at US$800,000.Monogenic hearing impairment is an attractive target for gene therapy if cochlear development proceeds normally and if its structure is preserved in the neonatal cochlea despite disrupted function. Genetic diagnostics and preclinical work in animal models promise that hearing restoration by gene therapy could become available within the coming decade , is not straightforward owing to the limited packaging capacity of standard AAV , DFNB8 (defects of TMRPSS3 coding for Transmembrane protease serine 3), and DFNB16 (defects of STRC coding for stereocilin).Most preclinical gene therapies and ongoing or planned clinical studies employ nonpathogenic AAVs that are less immunogenic than adenoviruses. Sendai virus, Vaccinia virus, and Herpes simplex virus have been evaluated preclinically for use in the inner ear but were not chosen for clinical trials possibly due to modest transduction rates . According to allied market research, the market for regenerative medicine would be worth US$67.5 billion by 2020 (doi: 10.1002/cpt.549). Notwithstanding this optimistic projection, to our knowlegde, only one regenerative medicine therapy has achieved regulatory approval (hematopoietic stem cell transplant for blood disorders and other immunodeficiencies [doi: 10.5966/sctm.2015‐0275]). Although the number of clinical trials for regenerative medicine therapies continues to increase, the field remains largely experimental—evidence on safety and efficacy is still lacking, and we have yet to see a “gold standard” regenerative medicine therapy for clinical application (https://doi.org/10.2217/rme.13.80).Although regenerative medicine has been seen as an attractive form of therapy for several decades, its overall success in clinical translation is poor . Questionnaires were distributed during routine check‐ups or by post, and were returned by post. Participation was voluntary and patients were informed that returned questionnaires implied consent.iProofing feasibility, safety, and level of hearing improvement by bridging the species gap from rodents to non‐human primates and humans.iiDemonstrating superior efficacy of the oCI over the eCI in non‐human primates and humans.iiiEnsuring efficiency and biosafety of gene therapies, improvement of high‐cell specificity, vector delivery to the target site, and controlled duration and extent of gene expression.ivDemonstrating long‐term biosafety and functional integration of transdifferentiated or transplanted hair cells or spiral ganglion neurons in patients.vCan the health insurance system cover personalized medicine and how can we find an ethical balance of society‐financed and individual‐health aspects?viSupport for academic research to accelerate translation and possibilities to involve patients at an early stage of therapy development to adapt to human needs.viiIdentify reliable ways of performing clinical trials on sophisticated novel therapies in efficient and reliable ways, even in small patient cohorts.Bettina Julia Wolf: Visualization. Kathrin Kusch: Visualization. Victoria Hunniford: Investigation; visualization. Barbara Vona: Validation. Robert Kühler: Investigation. Daniel Keppeler: Conceptualization; visualization; methodology. Nicola Strenzke: Conceptualization; resources. Tobias Moser: Conceptualization; resources; supervision; validation; visualization.D.K. and T.M. are co‐founders of the OptoGenTech company that works towards clinical translation of the optical cochlear implant. T.M and N.S. hold grants to develop and improve diagnostics and discussed in this review and currently prepare an original manuscript on the questionnaire study with their collaborators.ihttps://www.omim.org/iihttps://www.orpha.net/iiihttps://www.hearingloss.org/ivhttp://www.auditory‐neuroscience.uni‐goettingen.de/hearing_the_light_EN.htmlvhttps://www.innerearlab.uni‐goettingen.de/vihttps://www.cdc.gov/niosh/topics/noise/default.htmlviihttps://www.osha.gov/noise


Beauveria bassiana PfBb on the important agricultural pest Spodoptera frugiperda (Lepidoptera: Noctuidae) by determining the relative activities of protective enzymes and detoxifying enzymes in different larval instars. Our results show that the B. bassiana PfBb strain could infect all six larval instars of S. frugiperda, and its virulence to S. frugiperda larvae gradually increased with an increase in spore concentration. Furthermore, the activities of protective enzymes  and detoxifying enzymes  in S. frugiperda larvae of the first three instars infected with B. bassiana PfBb changed significantly with infection time, but such variations were not obvious in the fifth and sixth instars. These findings laid the foundation for further research on the mechanism by which B. bassiana controls S. frugiperda.In this study, we tested the pathogenicity of Beauveria bassiana PfBb on the important agricultural pest Spodoptera frugiperda (Lepidoptera: Noctuidae) by determining the relative activities of protective enzymes and detoxifying enzymes in different larval instars. Our results show that the B. bassiana PfBb strain could infect all six larval instars of S. frugiperda, and its virulence to S. frugiperda larvae gradually increased with an increase in spore concentration. Seven days after inoculation, the LC50 of B. bassiana PfBb was 7.7 × 105, 5.5 × 106, 2.2 × 107, 3.1 × 108, 9.6 × 108, and 2.5 × 1011 spores/mL for first to sixth instars of S. frugiperda, respectively, and the LC50 and LC90 of B. bassiana PfBb for each S. frugiperda instar decreased with infection time, indicating a significant dose effect. Furthermore, the virulence of B. bassiana PfBb to S. frugiperda larvae gradually decreased with an increase in larval instar. The activities of protective enzymes  and detoxifying enzymes  in S. frugiperda larvae of the first three instars infected with B. bassiana PfBb changed significantly with infection time, but such variations were not obvious in the fifth and sixth instars. Additionally, after being infected with B. bassiana PfBb, the activities of protective enzymes and detoxification enzymes in S. frugiperda larvae usually lasted from 12 to 48 h, which was significantly longer than the control. These results indicate that the pathogenicity of B. bassiana PfBb on the non-target host S. frugiperda was significant but depended on the instar stage. Therefore, the findings of this study suggest that B. bassiana PfBb can be used as a bio-insecticide to control young larvae of S. frugiperda in an integrated pest management program.Exploring the pathogenicity of a new fungus strain to non-target host pests can provide essential information on a large scale for potential application in pest control. In this study, we tested the pathogenicity of  Beauveria, Isaria, Lecanicillium, and Metarhizium genera, have been widely studied . The median lethal concentration (LC50) of S. frugiperda larvae was calculated based on the cumulative mortality of each treatment during the first seven days. The dead larvae were removed into a culture dish sterilized with 75% alcohol to moisten the culture. If mycelia were observed on the larval integument, they were considered cadavers. The number of insect cadavers was recorded to calculate the cadaver rate  ) caused by any dose id  at any time jt , where β is the slope of dose effect and jτ is the cumulative time effect parameter from t1 to jt. Note that ijp is a time-dependent variable. However, the above equation cannot directly fit the bioassay data because the binomial variable, ijp, for modeling does not satisfy the requirement for independence of time. To guarantee that the observed mortality probability was independent of time, the true mortality that occurred at jd at the interval  was considered. That is, the conditional death probability ijq, which can be expressed as ijq = 1-exp[-exp(jγ + βlog10(jd))], where, jγ is the time effect parameter to be estimated in the time interval   . S. frugiperda larvae of different instars were treated by the immersion method with 1 × 108 spores/mL of B. bassiana PfBb and Tween-80 (0.05%) as the treatment group and control group, respectively. The treated S. frugiperda larvae were reared the same way as above. During culturing, the treated larvae were sampled randomly at 12, 24, 36, 48, 60, and 72 h after treatment with B. bassiana PfBb or Tween-80 (0.05%). The number of samples for each test group at every time point was 50 (1st and 2nd instars), 10 (3rd and 4th instars), and 5 larvae (5th and 6th instars), respectively. The insect samples were homogenized with 0.1 mol/L PBS (sample weight: PBS = 1 g:9 mL) using an electric homogenizer . Next, the tissue homogenate was centrifuged  at 12,000 rpm and 4 °C for 15 min. The supernatant, as the enzyme source, was transferred to new tubes and stored at −20 °C  is an important factor for the difference in pathogenicity of B. bassiana to different hosts [B. bassiana PfBb strain needs further study. CYP450 is also a key enzyme involved in detoxification metabolism in insects. In this study, the CYP450 enzyme activity of the first instar larvae in the treatment was significantly lower than that of the control larvae (B. bassiana PfBb is not activate in the fatty acid degradation pathway, because the differences in cytochrome P450 gene expression are caused by differential degradation of thrips fatty acids of strains with similar virulence [Culex quinquefasciatus increased with increases in B. bassiana concentrations [B. bassiana PfBb is related to the activity of detoxification enzymes.To inhibit further damage by pathogenic fungi, detoxification enzymes, such as CarE, GST, and CYP450, in insects can efficiently metabolize exogenous toxic compounds . Theoret control . Similar. tabaci ,59. Our e damage . Our rescreasing . CarE iscreasing , which iflammans . The oppnt hosts . The difl larvae . Cytochrl larvae , probablirulence . In additrations . TherefoB. bassiana PfBb strain can infect all larval instars of S. frugiperda and result in a higher cadaver rate, especially for younger larvae. Furthermore, the virulence of B. bassiana PfBb to S. frugiperda larvae gradually increased with the increase in spore concentration, and the LC50 and LC90 of B. bassiana PfBb for each S. frugiperda instar decreased with infection time, indicating a significant dose effect. Although protective enzymes and detoxification enzymes in S. frugiperda larvae are usually activated between 12 and 48 h after treatment, the activity of these enzymes in the first three larval instars changed significantly over infection time, while such change in the fifth and sixth larval instars is not obvious. Our results indicate that the pathogenicity of B. bassiana PfBb on a non-target host, S. frugiperda, is significant but instar-stage dependent. In summary, our results suggest that B. bassiana PfBb can be used as a bio-insecticide to control young larvae of S. frugiperda in the integrated pest management program.Our findings confirm that the


The technological advances in cochlear implants and processing strategies have enabled subjects affected by severe to profound hearing loss to hear sounds and recognize speech in various different degrees. The variability of hearing outcomes in subjects with post-lingual deafness has been significant and cochlear implant indications have been extended to include an ever larger population.This paper aims to look into the groups of post-lingual deafness patients to find where cochlear implants have yielded better outcomes than conventional hearing aids.Review the literature available on databases SciELO, Cochrane, MEDLINE, and LILACS-BIREME. The publications selected for review were rated as A or B on evidence strength on the day of the review. Their authors analyzed and compared hearing aids and cochlear implants in populations of post-lingually deaf patients. Study Design: Systematic review.Eleven out of the 2,169 papers searched were found to be pertinent to the topic and were rated B for evidence strength. Six studies were prospective cohort trials, four were cross-sectional studies and one was a clinical trial.The assessment done on the benefits yielded by post-lingually deaf subjects from cochlear implants showed that they are effective and provide for better results than conventional hearing aids. The technological advances in cochlear implants and processing strategies have enabled subjects affected by severe to profound hearing loss to hear sounds and recognize speech in various different degreesSeveral studies have been published within the last few years comparing the hearing outcomes obtained by severe and profound hearing loss patients using conventional hearing aids or cochlear implantscochlear implants/cochlear implantation; hearing aid; therapy; prognosis; comparative study and the corresponding translated terms in various combinations.This is a systematic review carried out upon the medical literature after a search conducted on June of 2010, including papers written in Portuguese, English and Spanish. The search for relevant references was done on databases SciELO, Cochrane, MEDLINE, and LILACS–BIREME. The publications selected for review were rated as A or B on evidence strength on the day of the review. Their authors analyzed and compared hearing aids and cochlear implants in populations of post-lingually deaf patients. The following search terms (keywords and delimiters) were used: Some of the included studies might be biased, as they were written by cochlear implant manufacturersEleven out of the 2,169 papers searched were found to be pertinent to the topic and were rated B for evidence strength  to groups of conventional hearing aid users and users of single-channel and multichannel cochlear implants. Based on outcome comparison, the authors intended to predict which patients should not be deemed good candidates for cochlear implants. The MAC test, albeit not a standardized procedure, was considered as a useful tool in advising and selecting patients for cochlear implant use.Spillmann & DillierSnik et al.vs. 53% respectively). In noisy environments, post-lingually deaf patients with 25 years or less of hearing loss also performed better.In 2001, a study by MED-EL Ltda.Bamford-Kowal-Bench (BKB) Sentence Test in noisy situations to measure speech perception and showed a significant benefit for cochlear implant users .Ching et al.Performance Inventory for Profound and Severe Loss. The CI group scored better (p < 0.01) on Visual Cues (USV), Intensity (INT), Response to Auditory Failure (RAF). No significant difference was found on Environmental Sounds (ES), Visual Cues (USNV) and Personal (PER). Note that CI patients had mean preoperative hearing in their best ears of 113 dB. On the other hand, conventional hearing aid users had mean hearing of 82 dB. Nevertheless, at the end of the study the cochlear implant group had better social hearing capabilities.Mo et al.Patient Quality of Life Form (PQLF), Index Relative Questionnaire Form (IRQF), Short Form 36 (SF-36), Hopkins Symptom Check List (HSCL-25) and Performance Inventory for Profound and Severe Loss (PIPSL). The most significant differences were observed on quality-of-life and degree of depression and anxiety (HSCL-25) between the groups of cochlear implant patients and subgroup non-CI-A. Cochlear implant patients had significantly less depression and anxiety than their non-implanted counterparts. The only significant difference between cochlear implant and conventional hearing aid users was elicited on questionnaire SF-36, in which the CI group scored better.Mo et al.Hamzavi et al.United Kingdom Cochlear Implant Study GroupMark III Health Utilities Index. The study showed acceptable cost-effectiveness for cochlear implantation in all assessed patients. It further indicated median cost-effectiveness for cochlear implants in patients affected by hearing loss for over 30 years and who were then using conventional hearing aids. Additionally, age was a factor that worsened CI cost-effectiveness, once it is estimated that older individuals have fewer years of life ahead of them.In 2004, the Bamford-Kowal-Bench (BKB) Sentence Test and the City University New York (CUNY) Sentence Test before implantation and nine months since in patients with profound hearing loss. Results have shown improved scores on both measurements nine months after surgery .On that same UKCISGp<0.05). The author observed fewer cases of depression among older cochlear implant users and of loneliness in both older and younger subjects. Older cochlear implant users were not more depressed or lonely than their counterparts with mild to moderate hearing loss who used conventional hearing aids.According to Poissant et al.Assuming that conventional hearing aid users would have better musical perception skills than cochlear implant individuals, Looi et al.Hearing loss is a problem of significant prevalence in the population that affects one's personality and socialization, possibly leading to isolation and reclusion. Hearing test results of cochlear implant patients vary. Some can communicate without the aid of orofacial reading and even talk on the phone, while others can only hear sounds from the environment, alarm buzzers or beepers, and improve their lip reading skills.Several changes are taking place as to how cochlear implant candidates are chosen, often driven the increasingly global and dynamic pace of knowledge acquisition. Patients with low frequency residual hearing in the implanted ear can undergo less traumatic procedures, avoid endocochlear trauma, and use shorter or perimodiolar electrode bundles, thus allowing them to preserve their hearing at lower frequencies and even use conventional hearing aids and cochlear implants in a combined fashion on one ear.Uma questão importante é a comprovação científica de que o IC pode trazer benefícios superiores aos das próteses auditivas convencionais, que justifiquem o procedimento cirúrgico, em termos de riscos operatórios e encargos psicossociais e financeiros ao paciente, sua família e ao sistema de saúde. Thus, cochlear implant candidates must be chosen as a function of observed outcomes and their predictive factors.According to the Brazilian Association of Otorhinolaryngology, adolescents aged 12 and over and adults with post-lingual deafness are candidates for unilateral or bilateral cochlear implants if they meet the following criteria: severe or profound bilateral sensorineural hearing loss; open form sentence recognition of 50% or less; hearing aids on both ears and patient adequately motivated to use cochlear implants and undergo speech and hearing rehabilitation.After a broad systematic review, we have been able to find methodologically distinct studies, mainly when outcomes are analyzed. However, they make it clear that cochlear implants are superior when compared to conventional hearing aids in several aspects. Some studies, such as the UKCISGIt has been found that cochlear implants allow for improvements in speech understanding and on quality-of-life, aside from significantly easing one's insertion into the social and professional worlds and reducing the onset of depression and feelings of lonelinessThe analysis of the studies included in this systematic review has enabled us to conclude that cochlear implants allow for better performance in post-lingually deaf patients when compared to conventional hearing aids as verified by audiological tests, improved quality-of-life, and overall procedure cost-effectiveness.


The electrophysiological responses obtained with the complex auditory brainstem response (cABR) provide objective measures of subcortical processing of speech and other complex stimuli. The cABR has also been used to verify the plasticity in the auditory pathway in the subcortical regions.To compare the results of cABR obtained in children using hearing aids before and after 9 months of adaptation, as well as to compare the results of these children with those obtained in children with normal hearing.Fourteen children with normal hearing (Control Group – CG) and 18 children with mild to moderate bilateral sensorineural hearing loss (Study Group – SG), aged 7–12 years, were evaluated. The children were submitted to pure tone and vocal audiometry, acoustic immittance measurements and ABR with speech stimulus, being submitted to the evaluations at three different moments: initial evaluation (M0), 3 months after the initial evaluation (M3) and 9 months after the evaluation (M9); at M0, the children assessed in the study group did not use hearing aids yet.When comparing the CG and the SG, it was observed that the SG had a lower median for the V–A amplitude at M0 and M3, lower median for the latency of the component V at M9 and a higher median for the latency of component O at M3 and M9. A reduction in the latency of component A at M9 was observed in the SG.Children with mild to moderate hearing loss showed speech stimulus processing deficits and the main impairment is related to the decoding of the transient portion of this stimulus spectrum. It was demonstrated that the use of hearing aids promoted neuronal plasticity of the Central Auditory Nervous System after an extended time of sensory stimulation. The auditory brainstem response (ABR) is widely used in clinical practice to assess the auditory pathway integrity in the brainstem, as well as the electrophysiological threshold in children and infants. Although of great importance in clinical practice, the ABR with click and tone burst stimuli provides a few information on auditory processing for environmental sounds.The terminology used in the literature to refer to the electrophysiological responses, captured in the brainstem and elicited by complex sound stimuli, is varied, and thus, there is complex-ABR (cABR), speech-evoked ABR and music-evoked ABR.The electrophysiological responses obtained with the cABR provide objective measurements of subcortical processing of speech and other complex stimuli.Therefore, cABR corresponds to the neural decoding (or coding) of complex sound stimuli, such as music, speech, environmental sounds, among others. One of the characteristics of the cABR is that the captured electrophysiological responses are similar to the spectrum of the complex acoustic stimulus used, thus reproducing its spectral and temporal characteristics.Several stimuli can be used to investigate how temporal and spectral characteristics are preserved in ABR; one of the most often studied is the speech stimulus, especially the syllable-evoked (vowel–consonant) responses.Considering that the acoustic characteristics of the speech stimulus are directly involved in the responses that will arise in the ABR (or speech-evoked ABR), some studies have used syllables in the consonant–vowel format (ex: /da/) with duration of 40 ms, and identified the emergence of seven components , which would represent the transient (brief) and sustained characteristics of the acoustic stimulus.For some authors, speech is represented in the brainstem as follows: components V, A, C, and O are generated by neural mechanisms that reflect the transient characteristics associated with aspects of the speech filter , while components D, E and F are generated by neural mechanisms that encode the source of the stimulus production, such as the fundamental frequency (F0)The components V, A, C represent the beginning of voicing and component O, its end. The V–A complex arises from the consonant/d/onset response,According to the literature, cABR is used in research with several populations: Musicians,Speech processing begin in the peripheral auditory pathway and occurs in several structures of the central auditory pathway, finishing in the auditory cortex.The use of cABR in individuals using hearing aids has been suggested in the literature, as this procedure reflects both the sensory and cognitive processes, being able to help in the assessment of the central auditory function, hearing aids adaptation, in addition to monitoring the maturation/plasticity of the auditory pathway after the hearing aids adaptation.9Considering that the deprivation of sensory stimuli, such as in hearing impairment, affects the normal development and the connectivity required to form a functional auditory system,Therefore, the objective of the present study was to compare the results of ABR with speech stimulus obtained in children users of hearing aids before and after 9 months of its adaptation. We also compared the results of these children with those obtained from children with normal hearing.This is a prospective and longitudinal study, approved by the Research Ethics Committee (no 266512/2013). The study was conducted after the parents or guardians were informed about the research and after the signing of the Free and Informed Consent form. It was also necessary for the child to accept participation in the study, with all the procedures being explained to the child through the Term of Assent.Thirty-two children participated in the study, aged 7–12 years (mean age: 9 years and 8 months (Control Group) and 9 years and 2 months (Study Group), of both genders, without neurological damage or any impairment that could interfere with the cABR measurements, of which 14 had normal hearing  (control group – CG) and 18 with bilateral mild to moderate sensorineural hearing loss,The children were submitted to pure tone and vocal audiometry using the Grason Stadler audiometer, model GSI 61 and supra-aural headphones, model TDH 50; Measures of Acoustic Immittance using the Madsen Zodiac 901 Immittanciometer; cABR with a two-channel device, universal Smart Box Jr™ Smart EP, of the Intelligent Hearing System, calibrated at the hearing level (dBnHL), using in-ear ER3A headphones. The cABR was performed only in the right ear.To obtain the cABR, the child remained seated in a comfortable position in an acoustically and electrically treated room. The skin was cleaned with abrasive paste and the electrodes were fixed to the skin using electrolytic paste and surgical tape (micropore). The active (Fz) and the ground (Fpz) electrodes were positioned on the forehead, and the reference electrode was positioned on the right mastoid (M2). The positioning of the electrodes was in accordance with the International Electrode System IES 10–20 norms.The children were evaluated at three different moments: CG: initial evaluation (M0) and three (M3) and nine (M9) months after the initial evaluation; SG: before the hearing aids adaptation (M0) and three (M3) and nine (M9) months after hearing aids using It should be noted that two children from the SG and one from the CG did not attend all three evaluations.All assessments were carried out by the same evaluator at the three different times and the analysis of the ABR components was performed by the evaluator and by two referees, considering the consensus analysis. In cases where there was no consensus among the three referees regarding the assessments, the tracings were disregarded and excluded from the sample.In addition to the tabulation of the latency and amplitude values of the ABR components at each moment of evaluation, the results for each individual were classified as: present  and partial (absence of one or more components). There were no individuals with absence of all components in this sample .Table 1CThe statistical analysis showed that data was not normally distributed for all variables and thus, for the descriptive analysis, the median and interquartile range were used. Non-parametric tests were used for inferential analysis. Friedman's ANOVA was used to compare the performance of the individuals at the three moments of assessment . The Mann–Whitney test compared performance between the groups. The significance level was set at 5% and the significant results were identified with an asterisk (*).When comparing the CG and SG regarding the V–A amplitude, a statistically significant difference was observed in the initial evaluation (M0) and in the second evaluation (M3), with the CG showing a higher median .Figure 1Regarding the CG, no statistically significant differences were observed when comparing the latencies of the ABR components with speech stimulus between the assessed moments . HoweverWhen comparing the latencies of ABR components with speech stimulus, between the CG and SG, there was a statistically significant difference for component V at M9 (higher median in CG), and for component O at both M3 and M9, with the SG showing the higher median .Figure 2The cABR has been used in studies with different populations, as it provides objective data regarding the processing of relevant stimuli in the subcortical region of the CANS,10In the present study, when comparing the V–A amplitude between the different assessed moments, we observed that the medians remained similar in both groups, and there was no statistically significant difference between the assessed moments . It is wHowever, when comparing the CG and the SG, we found differences between the M0 and M3 moments, with the SG showing lower amplitude values . These rAlthough the SG showed a lower V–A amplitude value at M9, we observed there was no statistically significant difference between the groups, thus demonstrating that there was a change in the central auditory pathway of the SG children after 9 months of hearing aids use, showing that the response to the onset burst  was closRegarding the study of the latencies of the cABR components in each group separately , Table 4These findings indicate that the maturational process of the central auditory pathway of children aged 7–12 years during the 9-month period did not have an effect on the cABR results in the group of children with normal hearing (CG). However, the auditory pathway stimulation using hearing aids (SG) for nine months seems to have resulted in a structural/functional change in the neurons responsible for the transmission and decoding of the speech stimulus. This neuroplasticity was demonstrated mainly by the decrease in transmission/decoding time in the structures responsible for wave A generation.Although they did not use cABR, studies with cortical auditory evoked potential in children with sensorineural hearing loss showed an improvement in the latency values of component P1When comparing the groups, it was observed that the children of the SG had a lower latency of component V, at M9, when compared to the children of the control group . The modThe use of hearing aids possibly promoted greater auditory stimulation and an increase in responsive neuronal fibers, and consequently, new neuronal connections of the subcortical CANS regions. The electrophysiological responses showed significant changes after the ninth month of hearing aids use, showing that the neuronal plasticity process depended on a longer period of auditory stimulation. The findings of the present study demonstrated a lack of agreement with the studies that showed electrophysiological changes after the first month of use of hearing aids.3The results of the present study also showed that the SG had higher latency values of component O at M0, M3 and M9, being statistically significant at M3 and M9. These results suggest that, even with auditory stimulation through hearing aids the children of the SG demonstrated a delay in the central auditory pathway maturation, responsible for the generation of the O component (offset), that is, the structures that decode the end of the syllable (/da/). According to the literature, children with auditory deprivation (profound hearing loss) for more than 7 years do not reach the expected normality for the P1 component even after years of stimulation (cochlear implant), demonstrating a delay in the central auditory pathway maturation.It should be noted that the results of the present study showed similar results between the groups for some cABR components . One of the hypotheses for these findings may be the degree of hearing loss (mild to moderate) of the individuals assessed in this study and, thus, the sensory deprivation was not complete, which led to a lower degree of speech stimulus decoding impairment. Additionally, hearing loss is known to interfere with electrophysiological responses, generally reducing the amplitude and increasing the latency of the componentsIt was observed that the components with the worst results in the SG (V–A amplitude and O latency) are generated by neural mechanisms that reflect the transient characteristics of the speech stimulus spectrum and are associated with aspects of the speech filter .The results of the present study were similar to those found by Johnsons et al.Temporal resolution is the ability of the auditory system to detect small changes  in the sound stimulus over time,In a study with individuals with mild to moderate sensorineural hearing loss, it was observed that this population had a significantly poor performance in temporal resolution.In the present study, cABR was shown to be an important tool for the monitoring of auditory processing and auditory system plasticity after stimulation with hearing aids. Studies using this potential can bring important contributions to clinical practice, especially regarding the use of these biological markers in the evaluation of the effectiveness and benefits of hearing aids during the auditory rehabilitation process.Children with mild to moderate hearing loss showed impairment in speech stimulus processing, as measured by cABR, when compared to children with normal hearing. The main impairment is related to the decoding of the transient portion of the speech stimulus spectrum (components V–A and O), which may originate from altered temporal resolution.Additionally, it was verified that the use of hearing aids promoted neuronal plasticity of the CANS, leading to structural and temporal changes in the responses obtained in individuals with hearing loss, after a prolonged sensory stimulation time.The authors declare no conflicts of interest.


Since the 1990s, the study of inherited hearing disorders, mostly those detected at birth, in the prelingual period or in young adults, has led to the identification of their causal genes. The genes responsible for more than 140 isolated (non-syndromic) and about 400 syndromic forms of deafness have already been discovered. Studies of mouse models of these monogenic forms of deafness have provided considerable insight into the molecular mechanisms of hearing, particularly those involved in the development and/or physiology of the auditory sensory organ, the cochlea. In parallel, studies of these models have also made it possible to decipher the pathophysiological mechanisms underlying hearing impairment. This has led a number of laboratories to investigate the potential of gene therapy for curing these forms of deafness. Proof-of-concept has now been obtained for the treatment of several forms of deafness in mouse models, paving the way for clinical trials of cochlear gene therapy in patients in the near future. Nevertheless, peripheral deafness may also be associated with central auditory dysfunctions and may extend well beyond the auditory system itself, as a consequence of alterations to the encoded sensory inputs or involvement of the causal deafness genes in the development and/or functioning of central auditory circuits. Investigating the diversity, causes and underlying mechanisms of these central dysfunctions, the ways in which they could impede the expected benefits of hearing restoration by peripheral gene therapy, and determining how these problems could be remedied is becoming a research field in its own right. Here, we provide an overview of the current knowledge about the central deficits associated with genetic forms of deafness. Hearing impairment is the most frequent sensory defect. It affects 466 million people, more than 6% of the world population. It has been estimated that, by 2050, over 700 million people will be affected by disabling hearing disorders [defined as a hearing impairment of more than 35 decibels (dB) in the ear with the best hearing] WHO . The incIt has been estimated that 60–80% of congenital or prelingual forms of deafness in high-income countries are of genetic origin , revealing crucial roles for structures that were originally underappreciated, such as the top connectors of hair cell stereocilia  has indirect deleterious effects on the development and morphofunctional organisation of the central auditory system. Hearing impairment in children delays the acquisition of speech and language, and may, thus, affect cognitive development and may lead to social isolation —a protein acting as the calcium sensor of synaptic exocytosis in the inner hair cells (IHCs), the auditory sensory cells that make synaptic contacts with the dendrite of primary auditory neurons  leads to a strong decrease in vascular density in all the major relays in the auditory brainstem, midbrain and cortex  mediating an outwardly rectifying current, was the first gene shown to play a crucial role in both the peripheral and central auditory systems   specialists, SLPs (speech-language pathologists), paediatricians, and gerontologists to improve their management of hearing impairment in patients. An awareness of central deficits will be essential for the development of genuine cochlear gene therapies and to ensure scientifically-driven sensory rehabilitation before and/or after peripheral intervention.


Results: In the Dex-Plu-AuNP group, the threshold shift was less than that in the free dexamethasone group, but no statistical significance was noted between the groups. When compared individually, only the 8 kHz frequency showed statistically significant, better results after one week, in favor of the Dex-Plu-AuNP group. The mean postoperative 8 kHz threshold in the Dex-Plu-AuNPs was significantly lower than that of the control group . For the other frequencies, statistical analysis showed no significant differences between the mean threshold shifts of the two cohorts. Conclusions: The local application of Plu-AuNPs containing dexamethasone following cochlear implantation may better protect the residual hearing than dexamethasone alone, but a larger sample size is needed to reach a possible statistical significance. Dex-Plu-AuNPs do not seem to cause ototoxicity and may be used as a carrier for other agents. In a clinical setting, Dex-Plu-AuNPs may have the effect of protecting lower frequencies in patients with partial deafness who are candidates for electric acoustic stimulation (EAS). If we consider this tendency, Dex-Plu-AuNPs may also be beneficial for patients with Ménière’s disease. Introduction: During cochlear implantation, electrode insertion can cause cochlear damage, inflammation, and apoptosis, which can affect the residual hearing. Nanoparticles are increasingly studied as a way to increase the availability of inner ear protective factors. We studied the effect on rats of Pluronic-coated gold nanoparticles (Plu-AuNPs) containing dexamethasone, which were applied locally in the rat’s middle ear following the implant procedure. Methods: Seven rats were used in the study. The right ear served as a model for the Dex-Plu-AuNP group. Following the intracochlear dummy electrode insertion through the round window, Dex-Plu-AuNPs were placed in the round window niche. In the right ear, following the same insertion procedure, free dexamethasone (Dex) was placed in the same manner. Auditory brainstem response thresholds  were measured before and one week after the procedure. A two-tailed T-test was used for the variables. Statistical significance was set as  Reducing cochlear damage and preserving the residual hearing capacity has long been a primary objective of inner ear procedures, particularly cochlear implantation (CI) . In receThe loss of hearing remnants following CI surgery, especially for low frequencies, generally presents two possible outcomes: an early and a late phase. The immediate loss of residual hearing can be due to insertion trauma  and the subsequent inflammatory response . Later rThe prospects of HPCI have greatly increased with the development of less traumatic electrodes, in conjunction with the application of soft surgery principles . As surgMetallic and metal oxide nanoparticles are among the most promising inorganic substances for the treatment of inner ear diseases . Gold naNP-based medication delivery can be employed to reduce inflammation and fibrosis after CI and to maintain residual hearing. In recent years, the number of FDA approvals for the use of NPs to treat various auditory diseases has increased . In a prSeven adult male Wistar rats, weighing 250–300 g, with good general health were included in a prospective randomized experimental pilot study. Otologic inclusion criteria were considered to be good general health and the absence of otitis media. All the included subjects were endoscopically screened to exclude external and middle ear pathology. All protocols were conducted according to European law regarding the welfare of experimental animals and followed the guidelines established by our institution’s ethical committee (AVZ 81/28.03.2022) and the National Veterinary Health and Food Safety Authority . Following the 3Rs approach , we mini6H5Na3O7∙2H2O, ≥99%), hydrogen tetrachloroaurate (III) hydrate , Pluronic F127, and dexamethasone were purchased from Sigma-Aldrich. Ethanol (96%) was obtained from Chemical Company, Iași, Romania. All chemicals were used without further purification. The aqueous solutions were prepared using ultrapure water.Trisodium citrate (C4∙3H2O (10−3 M) was boiled on a magnetic stirring hot plate. Then, 10 mL of an aqueous sodium citrate solution (38.8 × 10−3 M) was quickly added while maintaining magnetic stirring. The stirring process was continued for 10–15 min after the color of the colloidal suspension became a deep burgundy red. The color changes in the solution from yellow to intense burgundy red indicate the formation of colloidal nanoparticles. Pluronic-coated gold nanoparticles (Plu-AuNPs) were obtained by incubating AuNPs with an aqueous Pluronic F127 solution at a final concentration of 4 × 10−4 M. The obtained Plu-AuNP suspension was then purified by centrifugation at 12,000 rpm for 20 min. To prepare dexamethasone-loaded Plu-AuNPs (Dex-Plu-AuNPs), the colloidal solution was incubated with Dex at a final concentration of 0.18 mg/mL, and the resulting mixture was ultrasonicated for 50 min. The prepared Dex-AuNP nanoconjugate was then incubated with Pluronic F127 (4 × 10−4 M), followed by centrifugation to remove the unbound polymer and drug. The formation of Dex-Plu-AuNPs was monitored by UV–visible absorption spectroscopy, using a Jasco V-670 UV–vis-NIR spectrometer . The concentration of loaded Dex was estimated indirectly, according to the Beer–Lambert law, by calculating the amount of unloaded Dex molecules remaining in the supernatant. The final concentration of loaded Dex was 10 µg/mL. The concentration of gold nanoparticles expressed in µg/mL was determined by atomic absorption spectroscopy ).Citrate-capped gold nanoparticles (AuNPs) of spherical shape were prepared according to the Turkevich–Frens method . In brieAnesthesia was achieved using a mix of Ketamine (80 mg/kg) and Xylazine (8 mg/kg), administered intramuscularly . Additio® microscope . Insertion of the electrode analog was achieved via the round window (RW), using a retroauricular approach to the tympanic bulla. Access to the middle ear was achieved through a bony defect in the posteroinferior aspect of the bulla. A 1-millimeter diameter cutting drill was used to access the bony defect, with good exposure of the stapedial artery, RW niche, and RW membrane . The wound was covered with a topical spray containing oxytetracycline. All surgical procedures were performed under aseptic conditions.The surgical intervention was performed using a Leicamembrane . The bon®, Raritan, NJ, USA) with a length of 5 mm was employed for the insertion [A monofilament 5/0 polypropylene suture  with the contralateral ear representing the control group (group 2). In group 1, after inserting the analog electrode through the RW, 30 µL of Dex-Plu-AuNP solution was applied in the middle ear and above the RW. The concentration of Plu-AuNPs was 1005 µg/mL, while the dexamethasone concentration was 64 µg/mL. In group 2, after the same insertion procedure, 30 µL of free Dex solution with a dexamethasone concentration of 64 µg/mL was applied.All rats included in the study presented normal hearing before surgery. We determined the hearing thresholds bilaterally before surgery and seven days following the implantation procedure. We assessed the external and middle ear status before the audiological measurements, to exclude a conductive hearing loss component.We measured ABR thresholds in a soundproof room using the Opti-Amp bio amplifier  connected to the Smart EP system. Click stimulus, and pure tones of 8 kHz, 16 kHz, 24 kHz, and 32 kHz were presented through closed tubes placed into the external ear canal, with 1.3 ms duration at a 20/s repetition rate. ER insert earphones were used for the click stimulus and high-frequency transducers were used for the tone burst stimulus. Stainless steel needle electrodes were placed subcutaneously in the retroauricular area (recording negative electrode), on the vertex (positive reference), and rear leg (ground electrode). Ipsilateral evoked potentials were averaged over 1024 sweeps in decreasing intensity increments of 10 dB SPL; thresholds were defined as the minimum stimulating level with an ABR response that can be identifiable and repeatable.® SPSS®  was used for statistical analysis. Analyses were performed on the outcome measures between pre-implantation (T0) and post-implantation (T1). A two-tailed Student’s t-test was used for independent variables to assess group heterogeneity, as well as to compare pre- and post-implantation audiological data, represented as dB SPL for the selected frequencies. The significance level was set at p < 0.05.IBMThese spectral changes are related to the modification of the refractive index of the medium surrounding the particles due to the attachment of Dex onto the gold surface and encapsulation with Pluronic F127. p values > 0.05, t-test). Before cochlear implantation, all rats presented similar hearing thresholds in both ears . There wOne week after implantation, neither animal displayed otorrhea, signs of middle ear infection, or infection at the incision site. Therefore, the determinations of ABR thresholds followed the same protocol as the preoperative ones. At seven days after bilateral CI, both groups displayed a significant elevation in hearing threshold across all frequency ranges . When inp = 0.048, t-test)  . p = 0.21, t-test) (p = 0.32)   . At 24 k = 0.32) . In addi t-test) . p = 0.44, t-test)  .Since cochlear surgery can be considered a traumatic event, it is of the utmost importance to maintain the normal architecture and surface anatomy throughout the early periods of recuperation. The reduction of local trauma and preservation of long-term residual hearing are major focuses for patients undergoing cochlear implantation surgery. There have been many attempts to develop adjuvant therapy strategies to avoid or diminish the acute and late inflammatory phases seen after CI. Corticosteroid usage had a substantial influence on auditory brainstem response, impedance, and histopathological alterations in the animal models. However, the otoprotective effect was only long-lasting with continued administration ,20. ClinAuNPs belong to a promising nanocarrier-mediated drug delivery class; they have easy surface functionalization and the ability to modify their size, shape, and surface chemistry . They alThe results of this study confirm some of the previous observations regarding the significant and variable nature of hearing loss after cochlear implantation in experimental models . The limOur study’s hearing threshold shift was greater than other rodent-based CI experimental models . AlthougThe results that have emerged from our study show the tendency for a lower hearing threshold shift in the group where CI was associated with Dex-Plu-AuNPs, but no statistical difference was noted except at the 8 kHz frequency. Obtaining better protection of the lower frequencies is the desired effect when considering CI in patients with residual hearing. A larger study group could elicit further information about the sustainability of this finding.On the other hand, when considering the possible cell toxicity, if no statistical significance was noted between the two groups, it is plausible to add that Plu-AuNPs presented no ototoxicity in the short term. Therefore, this carrier can be considered a safe alternative delivery method for other possible otoprotective agents. In the future, we need to pursue more extended follow-up periods through audiological threshold measures and note histopathological alterations considering different Dex and Plu-AuNP concentrations.Translating the effect of Dex-Plu-AuNPs in a clinical setting may serve as a better alternative to utilizing free Dex, offering beneficial preventive short-term residual hearing protection from damage caused by the cochlear implantation process itself. The short-term effects do not suggest any cytotoxicity but rather imply a protective effect on hearing thresholds. The potential to better protect lower frequencies needs to be further studied; cochlear implant recommendations have expanded to include patients with partial deafness who are candidates for electric acoustic stimulation (EAS). Clinical implementation can be also beneficial for patients with Ménière’s disease, in which the low frequencies are initially those most affected.Pluronic-coated AuNPs carrying dexamethasone, applied to the round window, may be useful as an additional treatment for limiting the short-term inner-ear damage caused by cochlear implantation, along with the soft surgery principles. The long-term effects need to be evaluated, together with the capacity to sustain a delayed and prolonged anti-inflammatory effect. Since no statistical differences were found in the audiological parameters, more evidence is needed to support the use of Plu-AuNPs containing dexamethasone as a pharmacological compound for the protection of residual hearing. Dexamethasone may be beneficial in its free form without the need for a carrier.


KNSTRN) is mainly involved in mitosis. Somatic mutations in KNSTRN are known to lead to the occurrence and development of certain tumors. However, the role of KNSTRN in the tumor immune microenvironment (TIME) as a tumor prognostic biomarker and potential therapeutic target has not been clarified. Accordingly, in this study, we aimed to investigate the role of KNSTRN in the TIME. mRNA expression, cancer patient prognosis, and correlations between KNSTRN expression and immune component infiltration were analyzed using Genotype-Tissue Expression, The Cancer Genome Atlas, Cancer Cell Line Encyclopedia, Human Protein Atlas, ImmuCellAI, TIMER2.0, and KM-Plotter. The Genomics of Drug Sensitivity in Cancer database was used to evaluate the relationship between KNSTRN expression and the half maximal inhibitory concentration (IC50) of several anticancer drugs, and gene set variation analysis was performed. Data were visualized using R version 4.1.1. KNSTRN expression was upregulated in the majority of cancers and was associated with a worse prognosis. Additionally, KNSTRN expression was highly correlated with the infiltration of multiple immune components in the TIME and was related to a poor prognosis in tumor patients receiving immunotherapy. KNSTRN expression was also positively correlated with the IC50 of various anticancer drugs. In conclusion, KNSTRN may be a significant prognostic biomarker and promising target for oncotherapy in numerous cancers.Kinetochore-localized astrin- (SPAG5-) binding protein ( Malignant tumors, which pose a serious threat to human health, require more effective treatments. New targets must be identified, and novel drugs need to be developed. Because the tumor immune microenvironment (TIME) affects the occurrence and development of cancer in intricate ways, it has attracted increasing attention from the medical community. The TIME features a wide variety of immune cells and contains noncellular components such as cell-surface molecules, immune checkpoints, and soluble immune factors . During KNSTRN) encodes a centromere-associated protein involved in chromosome division [KNSTRN is mutated under ultraviolet irradiation and has attracted attention as an oncogene in cutaneous squamous cell carcinoma (SCC), the second most common skin cancer. KNSTRN has also been reported to play a role in melanoma. Together with TP53 and CDKN2A, KNSTRN is one of the three most commonly mutated genes [KNSTRN is also frequently somatically mutated in basal cell carcinoma in addition to cutaneous SCC and melanoma, although this mutation usually occurs in advanced stages of the tumor [KNSTRN not only cause the occurrence of malignant tumors but also promote tumor development. KNSTRN promotes the movement of AKT to PIP3 and stimulates AKT phosphorylation, resulting in metastasis and gemcitabine resistance in bladder cancer [KNSTRN have mainly focused on somatic mutations, and research on the involvement of KNSTRN in tumor immunity remains scarce, even though KNSTRN has been shown to have a significant influence on immune cells in the tumor microenvironment of lung adenocarcinoma (LUAD) [KNSTRN has been mainly researched in individual tumors; pan-cancer studies on KNSTRN are lacking.Kinetochore-localized astrin- SPAG5-) binding protein (division . KNSTRN ed genes . KNSTRN - bindingr cancer . Studiesa (LUAD) . AdditioKNSTRN, as well as the associations between KNSTRN expression and patient prognosis, immune score, tumor-associated immune cells, immune-related components, and the half maximal inhibitory concentration (IC50) of anticancer drugs, we conducted a series of bioinformatics analyses. We aimed to determine whether KNSTRN may serve as a potential pan-cancer prognostic biomarker and to explore the influence of KNSTRN on the TIME and anticancer therapy outcomes.Therefore, to better understand the expression of https://xenabrowser.net/datapages/). The expression of KNSTRN in tumor cell lines was evaluated using the Cancer Cell Line Encyclopedia (CCLE) (https://sites.broadinstitute.org/ccle). The tissue immunohistochemical (IHC) and immunofluorescence (IF) images of various tumor cells were obtained from the human Protein Atlas (HPA) database (https://www.proteinatlas.org/).RNA expression and clinical data from the Genotype-Tissue Expression (GTEx) database and The Cancer Genome Atlas (TCGA) were obtained from the UCSC Xena database , disease-specific survival (DSS), disease-free interval (DFI), and progression-free interval (PFI). Kaplan-Meier analysis was performed to evaluate the OS, DSS, PFI, and DFI of patients from TCGA cohort. OS and progression-free survival (PFS) data of cancer patients receiving immunotherapy were obtained from the Gene Expression Omnibus database.Univariate Cox regression analyses were performed to estimate the significance of http://bioinfo.life.hust.edu.cn/web/ImmuCellAI/), TIMER2 database (http://timer.cistrome.org/), and published studies [http://bioinfo.life.hust.edu.cn/ImmuCellAI#!/). All cancer patients were divided into two groups (high or low KNSTRN expression) based on the median KNSTRN expression level to determine the influence of KNSTRN expression on the extent of immune cell infiltration.We obtained and evaluated the immune cell infiltration score of TCGA cohort from the ImmuCellAI database  with the following parameters: nPerm = 1000, minGSSize = 10, maxGSSize = 1000, and p value cutoff = 0.05.Correlation analysis of the expression of https://www.cancerrxgene.org/). Correlation analysis was conducted to identify associations between KNSTRN expression and IC50 value.The IC50 values of 192 drugs and gene expression profiles of 809 cell lines were obtained from the Genomics of Drug Sensitivity in Cancer database (GDSC) .Data are presented as the mean ± standard error. Differences between groups were analyzed using Student's KNSTRN expression profiles from pan-cancer data, expression analysis of KNSTRN was conducted in 33 types of tumors and 31 types of paired normal tissues, using data from TCGA database and the GTEx database. KNSTRN expression in tumor tissues was higher than that in normal tissues in the majority of tumors, including the following 27 tumor types: adrenocortical carcinoma (ACC), bladder urothelial carcinoma (BLCA), breast invasive carcinoma (BRCA), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), cholangiocarcinoma (CHOL), colon adenocarcinoma (COAD), lymphoid neoplasm diffuse large B-cell lymphoma (DLBC), esophageal carcinoma (ESCA), glioblastoma multiforme (GBM), head and neck squamous cell carcinoma (HNSC), kidney chromophobe (KICH), kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP), brain lower grade glioma (LGG), liver hepatocellular carcinoma (LIHC), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), ovarian serous cystadenocarcinoma (OV), pancreatic adenocarcinoma (PAAD), prostate adenocarcinoma (PRAD), rectum adenocarcinoma (READ), sarcoma (SARC), skin cutaneous melanoma (SKCM), stomach adenocarcinoma (STAD), thymoma (THYM), uterine corpus endometrial carcinoma (UCEC), and uterine carcinosarcoma (UCS).To establish KNSTRN was downregulated in tumor tissues , testicular germ cell tumors (TGCT), and thyroid carcinoma (THCA) —in which  tissues . Expresspancreas . Among c in KIRP . FurtherLL cells .KNSTRN, we analyzed KNSTRN expression in tumors and paired adjacent tissues. In 27 types of tumors, KNSTRN expression in tumor tissues was upregulated compared to that in paired adjacent tissues : ACC, KIRC, KIRP, LIHC, and LUAD , osteosarcoma cell (U-2 OS), and astrocytoma cell (U-251 MG) , ERK_2440, OTX015, PRT062607, WZ4003, AZD5153, Oxaliplatin, SB216763, AZ6102, Doramapimod, and I-BET-762 (Figures KNSTRN overexpression has not been clarified. GSVA (KNSTRN expression, and ER stress has been reported by several studies to be an essential contributor to anti-tumor drug resistance. Therefore, ER stress may be one of the potential mechanisms through which KNSTRN contributes to anticancer drug resistance.In addition to assessing the effect of  Figures . The reaed. GSVA  revealedTo address uncontrolled tumor growth, metastasis , 11, andIn addition, despite the profound significance of immunotherapy, targeted therapy and chemotherapy remain important strategies for radical treatment, palliative care, and postoperative adjuvant therapy in several tumors, such as hematological malignancies, breast cancer, CRC, and lung cancer. In breast cancer, AKT-targeted therapy alleviates resistance to tumor immunotherapy and chemotherapy and controls tumor progression and immunosuppression . In CRC,KNSTRN has rarely been studied in relation to tumor immunity. Only an analysis of lung adenocarcinoma identified a positive correlation between KNSTRN expression and the levels of Th2 and CD56dim NK cells [KNSTRN in tumor immunity. To address the gap in the literature regarding the role of KNSTRN in tumor immunity, we conducted a series of bioinformatics analyses. We first analyzed the RNA expression of KNSTRN in various cancer tissues and tumor cell lines. We also evaluated KNSTRN expression in cancer tissues, paired normal tissues, and tissues classified according to TNM stage. To better understand the expression of KNSTRN in tissues, we used the IHC data to assess the differential expression of KNSTRN between cancer tissues and paired normal tissues. We also analyzed immunofluorescence data to evaluate KNSTRN expression of distinct tumor cells at the cellular level.As a molecule mainly involved in cell cycle checkpoints, DNA replication, damage repair, and other biological processes –21, KNSTNK cells , which hKNSTRN in most tumor tissues was higher than that in normal tissues. High expression of KNSTRN was also associated with the advanced stages of multiple tumors. This is consistent with previous reports that KNSTRN is highly expressed in bladder cancer [KNSTRN is usually associated with a worse prognosis. In esophageal cancer, KNSTRN expression is positively correlated with that of GSK-3β, which is associated with a poor prognosis [The expression analysis results showed that the expression of r cancer . In varirognosis .KNSTRN in the TIME, we analyzed the link between KNSTRN expression and levels of TIME-related components. The significant negative correlation between KNSTRN expression and immune score and infiltration score in multiple cancers indicated that KNSTRN has a negative effect on immune cell infiltration and immune activity in the TIME. Therefore, we further analyzed the correlation between KNSTRN expression and immune cell infiltration. KNSTRN expression was positively correlated with the infiltration of immunosuppressive cells, such as Tregs, neutrophils, and monocytes, and negatively correlated with the infiltration of immune-activating cells, such as NK cells and CD8 + effector T cells. Combined with data indicating a close association between KNSTRN and immune-related protein-encoding genes, these findings demonstrated the importance of KNSTRN in the TIME.To further explore the role of KNSTRN expression was associated with a poor prognosis in patients receiving immunotherapy for certain tumors. KNSTRN was positively correlated with the IC50 of various anticancer drugs, suggesting that the overexpression of KNSTRN may promote resistance to anticancer drugs. To determine the mechanism by which KNSTRN induces drug insensitivity, we performed GSVA. The unfolded protein response, as one of several prominent enriched pathways, contributes to drug resistance. When addressing the clinical challenges of multidrug resistance and metastasis in breast cancer, some researchers have found that continuous ER stress and chemotherapy synergistically induce immunogenic cell death, which results in tumor suppression [In addition, high pression . ER strepression .KNSTRN expression was identified in a variety of tumors. KNSTRN expression was closely associated with the TIME and with a poor prognosis in patients with tumors. KNSTRN may serve as a critical prognostic biomarker and potential therapeutic target that may affect sensitivity to immunotherapy and other anticancer treatments.In conclusion, high KNSTRN was highly expressed in various cancers. High KNSTRN expression was associated with a poor prognosis. KNSTRN affected the infiltration of multiple types of immune cells in the TIME and was closely associated with several immune-related genes in pan-cancer data. High expression of KNSTRN was associated with a poor prognosis in tumor patients receiving immunotherapy and was closely related to decreased sensitivity to other anticancer drugs. In summary, KNSTRN may serve as a prognostic biomarker and potential therapeutic target.


Congenital toxoplasmosis may cause sensorineural deficit in up to 20% of the patients and proper treatment in the first year improves prognosis. In Brazil, this infection's impact on hearing impairment is unknown.To evaluate hearing of newborns with congenital toxoplasmosis identified by the newborn screening service.This prospective study analyzed children with congenital toxoplasmosis identified by newborn screening (IgM anti-T.gondii) in Belo Horizonte during 2003/2004. The presence of IgM and/or IgA in the first 6 months or IgG at 12 months-of age in serology was used as case definition. Hearing tests were carried out at the time of diagnosis and 12 months later, including behavioral audiometry, evoked otoacoustic emission and brainstem evoked responses audiometry.Among 30.808 screened children (97% of live births), 20 had congenital toxoplasmosis, 15 (75%) were asymptomatic at birth. Nineteen children were evaluated by hearing tests. Four had sensorineural impairment (21.1%). One child had other risk factors for hearing impairment; the other three had no other risk factors but toxoplasmosis. Two properly children treated still had hearing loss, in disagreement with current literature.Results suggest that congenital toxoplasmosis, common in Brazil, is a risk factor for hearing impairment and its impact on hearing loss deserves further studies. Hearing plays an important role in the development of human beings. The peripheral hearing system is fully formed at birth, while the central auditory system takes two years to mature. This period corresponds to that of the greatest neuronal plasticity of the auditory pathway, and this maturing process depends on the quantity and quality of the external stimuli captured. Early identification and rehabilitation in cases of hearing loss are paramount for speech development ,,,Hearing acuity loss (hypoacusis) evolves silently, especially in the first years of life, when the child still does not complain of hearing loss. During childhood, it has a world prevalence of 1/1000 live birthsHearing losses may be classified according to type , laterality, symmetry, clinical characteristic (syndromic or not), time of onset , hereditary (genetic or not), time of manifestation ,,It is well established the association between some congenital infections and hearing loss. The most frequent infectious agents associated with hearing loss are Cytomegalovirus (CMV),,,,,,Toxoplasma gondii has been associated with disorders of the auditory pathways since the 1950'sConsidering the little information available about significant hearing loss in children with congenital toxoplasmosis, especially those with subclinical infection, this study aims at characterizing the hearing loss pattern in children with congenital toxoplasmosis, identified at the neonatal screening process in Belo Horizonte, Minas Gerais.From September, 2003 to October, 2004, we carried out a pilot project in the city of Belo Horizonte, Minas Gerais, for neonatal screening, using the IgM anti-T. gondii immune assay in dry blood, in order to assess the incidence of congenital toxoplasmosis in live births in the city and neonatal screening as a strategy for early diagnosis and treatment of infected children. According to 2004 data from SINASC/SES, the Neonatal Screening Program tested about 97% of newborns. The criteria used to define congenital toxoplasmosis were those accepted by a consensus on the theme: positive IgM and/or IgA in the first six months, or persistently positive IgG at 12 months of lifeThe infected children were treated  during 12 monthsFor speech and hearing anamneses, we used the UFMG-HU Department of Audiology protocol, which investigates the variables most commonly associated with hearing loss4: family history of hearing loss; gestational problems ; delivery complications , post-natal complications . We used a careful history taking as criteria to establish the possible etiologic associations, because it is considered the most efficient methodWe used the following equipment in order to carry out the audiologic exams: (PA5) Interacoustics Pediatric Audiometer and Impedanciometer, ANSI S3.6/ISO 389 calibration pattern. In behavioral audiometry we used Brazilian musical percussion instruments  which were standardized for the evaluation. Otoacoustic emissions were captured using Biologic's AuDX Plus device  which has a stimuli generator inside. As they hit the cochlea, these stimuli produce an echo - the otoemissions - which trails the inverse sound pathway, that is, from the inner ear to the middle and then to the external acoustic meatus, and then captured by a microphone placed in the EAM. If present, otoemissions hint to middle and external ear integrity6. Transient evoked otoacoustic emissions were considered present when their reproducibility was above 70% and the response amplitude / noise ratio (R/N) was above that or equal to 6 dB. Distortion product evoked otoacoustic emissions were considered present whenever the R/N ratio was higher than or equal to 6 dB.The hearing loss variables investigated were: type , intensity , laterality and symmetry.In behavioral audiometry, the response patterns suggesting central auditory alterations were: exacerbated response, response latency increase, difficulty of localization with normal acuity, no habituation at repetitive stimuli, and no cochleo-eyelid reflex with normal hearingStimuli were psychoacoustically calibrated in dBHL . In order to classify hearing loss levels, we considered the guidelines from the Bureau International D'Audiophonologie (BIAP) which classifies the losses in mild (minimum response levels between 21–40 dBHL), moderate (minimum response levels between 41–70 dBHL), severe (minimum response levels between 71–90 dBHL) and profound (no response to the stimuli employed at a maximum output of 85 dBHL)Responses were considered symmetrical when the hearing losses were classified at the same level of impairment on both sides. Asymmetry was of level 1 when the one side hearing loss classification was immediately adjacent in severity level to that of the contralateral side. The asymmetry was deemed of 2 levels when the classification of sides was not adjacent in levels of severity.In order to build the database, we used the Epi Info version 6.0 statistical package. For analysis we also used the StatXact software to perform Fisher's Exact Test. We used the Student t test in order to compare the mean values and the Fisher's Exact Test to compare gender and risk factor distribution. This study was approved by the COEP-UFMG (ETIC 157/01) and we honored the standards established for research with human beings, according to resolution 196/96 from CONEP.From September 2003 to October 2004, 30,808 children (about 97% of live births) were screened in Belo Horizonte (BH) and 20 were identified with congenital toxoplasmosis, resulting in a rate of 1:1590 infected by live births. In relation to the time of diagnosis for these 20 children, six (30%) had already been identified during prenatal care , four (20%) were identified in the neonatal period because they had clinical manifestations suggesting the infection; and ten (50%) were identified by neonatal screening alone.Among these 20 children identified by neonatal screening in BH, one was taken off the analysis because for having died in the neonatal period. We carried out behavioral auditory evaluations and Otoacoustic Emission tests (EOAE) in 19 children and Brainstem Evoked Auditory Potential - BEAP in 17. We noticed that 13 children (68.4%) had normal evaluation for their ages, and six had hearing deficit - four (21.1%) were sensorineural and two (10.5%) had conductive hearing loss. There was no gender wise difference among the three groups (p=0.99). On In the population studied, we did not observe the following risk factors for hearing loss: family history, other TORCH intra-uterine infections, hyperbilirubinemia, use of ototoxic drugs, bacterial meningitis, parents who used drugs/alcohol, syndromes.As far as neonatal signs and symptoms are concerned the group without hearing alterations had three children with systemic manifestations (liver and spleen enlargement and/or petechias) and, of these, two also had hydrocephaly and microphthalmia. Among the children with hearing impairment we observed that one presented systemic manifestation and prematurity . After mAs to the age when the children were submitted to the first hearing evaluation, we observed a median value of 157 days, and 75% of the children were first assessed before 270 days. However, as we can see in Among the children with sensorineural deficit (n=4), the hearing loss was severe and profound in one, moderate in one and mild in two children; and was asymmetrical in only one of the children with bilateral involvement . Only onIn three children without hearing impairment, who underwent BEAP evaluation in the first three months of life, and repeated the test after 18 months, we noticed hearing deficit in the first exam and a normal results in the second, suggesting a slower neural maturation in these children.In four children deemed normal by the BEAP at two years of age, in the first hearing evaluation there were not TEOAE, and there were DPOAE, suggesting that these may be more sensitive to audiologic diagnosis.There is a consensus about the importance of early hearing deficit diagnosis for a better development of language, cognition and child socialization. Neonatal hearing screening, recently mandatory as public health policy, will slowly reach the universe of newborns, however, risk factors identification for hearing loss allows us to follow children up and to reassess them at the end of the first year of life, thus increasing the auditory screening sensitivity. Therefore, there is the need to implement effective strategies to identify risk factors associated with this deficiency. Among the risk factors, toxoplasmosis - a prevalent disease in Brazil, has not been often associated with hearing deficits. However, identifying children with sensorineural hearing loss (4/19), among those screened with congenital toxoplasmosis, brings up this discussion about the impact of this congenital infection in children hearing deficiencies.Among the 20 children identified by neonatal screening, 15 (75%) have subclinical infection and, of these, nine were identified by neonatal screening only.,Recent epidemiological studiesLongitudinal studies with newborns followed up during long periods pointed to a high index of abstention from the mothers at scheduled return visits,Long standing treatments (one year) for congenital toxoplasmosis have been associated to better children prognosis by some authors,The results observed in this study are similar to those found by Wilson et al.As to hearing loss intensity and its functional meaning, studies have assessed the importance of unilateral or bilateral mild hearing losses for the development of children and have suggested that these losses may affect many domains such as language skills, speech perception, auditory functional skills, academic performance, socio-emotional development, motor skills including early movements and coordinationA historical cohort study carried out at the Pediatric Infectology Service of the UFMG-UH, evaluating BEAP audiometry in 49 children with congenital toxoplasmosis, most of them with early manifestations of the infection, and followed for 10.3 years in average, showed alterations in five cases (10.2%) and no association between treatment type in the first year of life and hearing deficitThe results observed in the present study suggest that congenital toxoplasmosis, common in Brazil, is a risk factor for hearing loss; and studies assessing the impact of the subclinical infection on hearing loss are imperative. Facing the possibility of implementing a prenatal or neonatal screening program for congenital toxoplasmosis, its planning must include early auditory evaluation for identified cases. Toxoplasmosis, especially when asymptomatic at birth, may be included among the “Unknown causes” of hearing loss and all effort should be put up in order to identify the children at risk and allow for early diagnosis and treatment, which have been associated with a significantly better prognosis


Deafness is the most frequent sensory deficit in humans. Incidence is estimated at 4:1000 births in Brazil. Specific programs for clinical care of patients with hearing loss are still scarce in Brazil and the issue is an important public health problem.GJB2 and GJB6 genes respectively in patients with non-syndromic sensorineural hearing loss from Minas Gerais, Brazil.To determine the frequency of 35delG and D13S1830 mutations in GJB2 gene and D13S1830 in GJB6 gene by polymerase chain reaction and restriction enzyme digestion.This research involved 53 individuals, who were assessed by a questionnaire for predicting the possibility of non-syndromic deafness and for data collecting. Samples were tested for the presence of the 35delG mutation in Epidemiological research has shown that the majority of the subjects are unaware of the etiology and the pathogenesis of hearing loss. In 9 patients (16.98%), 35delG mutation was found in heterozygosis and the allele frequency was estimate to be around 8.5%. Although 9.61% of the patients reported having some degree of consanguinity between the parents and 12.08% reported other cases of deafness in their families, this mutation was not found in homozygosis. The D13S1830 mutation was not found in this study.This research describes for the first time the frequency of the 35delG and D13S1830 mutation in hearing-impaired individuals from Minas Gerais, Brazil, and the collected data reinforce the need for further studies in this population due to heterogeneity of hearing loss. Deafness is the most frequent sensory deficit in humans, with an incidence that ranges from 1:300 to 1:1000 children. According to the World Health Organization (WHO), hearing loss affects about 10% of the world population.3Non-syndromic hereditary forms, which are not associated with other clinical manifestations, account for about 70% of cases and can be autossomal recessive (DFNB), autossomal dominant (DFNA), X-linked or mitochondrial. The recessive forms are more prevalent (75%–80% of cases) and tend to be more severe and often associated with defects in the cochlea, leading to the neurosensorial disability. The dominant forms (15%–20% of cases) are milder and contribute in most cases to post-lingual deafness progressive. The X-linked forms are rarer, as well as the mitochondrial form.GJB2 (Cx 26), GJB6 (Cx 30), and GJB3 (Cx 31), were found to cause hearing impairment, and the occurrence in the first two are most frequently described.GJB2 gene account for up to 50% of all genetically caused non-syndromic hearing loss cases in Caucasians.GJB2 gene and D13S1830 in GJB6 gene in unrelated hearing-impaired patients from Minas Gerais, Brazil.More than 150 loci have been mapped and 93 genes have been identified for non-syndromic hearing loss,We conducted a cross-sectional study, in which 53 disabled, 32 males and 21 females, all unrelated, were studied. We included in the study patients without medical confirmation about disability's cause. Therefore, were included patients with hearing impairment classified as unknown case, with no diagnostic hypothesis about the cause of hearing loss, absence of confirmation through specific tests and/or medical confirmation described in the report. There was no age restriction for participation in this study. All individuals are residents of the Midwest region of Minas Gerais. Patients were recruited from school Audio-Visual Assistance for Hearing Impaired (AAVIDA) and the Deaf Association, both from Divinópolis, Minas Gerais, Brazil.This study was approved by the Ethics Committee on Human Research from Universidade Federal de São João Del Rei, Minas Gerais, with favourable opinion number 009/2011. All steps for clarification of the study were performed using the Brazilian Sign Language (Libras) and Portuguese language, so all participants have full autonomy in deciding their participation in research. Those individuals who have decided to participate signed an informed consent.We used a questionnaire to collect data related to age of onset of hearing loss, presence of other cases in the family, consanguineous relationships in the family, manifestation of syndromes associated to hearing loss to confirming non-syndromic deafness and exclusion of environmental causes with medical confirmation: prenatal infections such as rubella or toxoplasmosis, postnatal infections, and exposure to ototoxic drugs.GJB2 gene was performed with primers previously described and the annealing temperature used was 65 °C.Blood samples (5 mL) were collected from the patients and genomic DNA isolated according to standard procedures.The D13S1830 mutation in the GJB6 gene was detected by standard PCR technique using three primers, F: (TTT AGG GCA TGA TTG GGG TGA TTT), R1: (CAC CAT GCG TAG CCT TAA CCA TTTT) and R2: (TCA TCG GGG GTG TCA ACA AACA).The PCR products were visualized on 8% polyacrylamide gel stained with silver nitrate. The DNA extraction product was stored in the freezer (mean −6 °C) and in a similar manner as the PCR products. All analyzes were carried out in a specialized laboratory in molecular biology of the Federal University of São João del-Rei, Divinópolis, MG, Brazil.In this study, a total of 53 individuals with hearing impairment were evaluated. The age of patients ranged from 5 to 42 years old, with an average of 23.5 years.Regarding the stage of hearing loss, 32.07% of the individuals presented manifestation at birth, 26.41% perceived the disability before 2 years old, and 11.32% after 2 years old. This information was not assessed for 30.18% of the individuals.Among patients who answered questions about the etiology of deafness, nobody had medical report confirming the etiology of hearing loss. Patients with suspicions about the possible cause of disability but without medical confirmation corresponded to 60.37% of the sample; data were not available for 39.62%. The large number of missing data may be related to the lack of information of individuals on the probable cause of hearing disability.Brazilian Sign Language (Libras) is a form of communication used by most participants, 86.79%. Only 9.43% use oral communication and data were not accessed for 3.77% of the sample.In consanguinity analysis, 9.61% of people reported having some degree of consanguinity between the parents (confirmed only by simple genedogram) and 12.08% reported other cases of deafness in their families.GJB2 and GJB6 respectively. Of the 106 alleles present in the 53 individuals who underwent molecular analysis, nine were 35delG mutation. So, the allele frequency of 35delG mutation in the sample studied was 8.5%. All subjects with this mutation were heterozygous (16.98%). Even though patients reported the presence of consanguinity relationships in some families, homozygous individuals for this mutation were not found. The D13S1830 mutation was not found in any of the individuals tested.About molecular analysis, individuals with deafness of unknown etiology and who lived in the Midwest state of Minas Gerais, Brazil, were investigated for the presence of 35delG and D13S1830 mutations in Cases of pre-lingual deafness may be associated with environmental factors or genetic inheritance. Environmental factors in Brazil are among the major causes of hearing loss, and congenital rubella syndrome and neonatal anoxia are the most prevalent associated risk factors (33.5%), followed by those of unknown etiology (18.5%). In post lingual deafness cases the loss may be a consequence of the use ototoxic drugs, family history of hearing loss or in some cases can be considered idiopathic.GJB2 gene is the main cause of genetic deafness in caucasian populations and it has been described in all studies conducted in other Brazilian regions.GJB2 gene, to investigate a possible compound heterozygosis as a justification of the manifestation of deafness.The 35delG mutation in the The frequency of 35delG mutation in a sample of hearing impairment from Minas Gerais state has been described for the first time in this study. This frequency is similar to others already described in populations from Southeastern Brazil . Those tGJB2 gene almost exclusively cause prelingual autosomal recessive hearing loss, this disorder is very heterogeneous.GJB2 gene could be useful to identify the second mutant allele and in spite of sequencing of the GJB6 gene was not reported in Brazilian populations until now, it would be interest to identify other possible frequent mutation associated to the hearing disability.Although variations in This study describes for the first time the molecular investigation of two genes related to the hearing loss in Minas Gerais population. The allele frequency of 35delG mutation in the sample studied was 8.5% and the D13S1830 mutation in GJB6 gene was not found in the patients investigated. These results reinforce the need for further studies about the investigation of deafness in Brazil, in order to improve public health issues and genetic counseling. Genetic and epidemiological information make possible etiologic identification, genetic counseling for families and better assessment to the possibility of treatment.The authors declare no conflicts of interest.