GJB2 gene mutation is the most genetic etiology. Gap junction protein 26  encoded by the GJB2 gene, which is responsible for intercellular substance transfer and signal communication, plays a critical role in hearing acquisition and maintenance. The auditory character of different Connexin26 transgenic mice models can be classified into two types: profound congenital deafness and late-onset progressive hearing loss. Recent studies demonstrated that there are pathological changes including endocochlear potential reduction, active cochlear amplification impairment, cochlear developmental disorders, and so on, in connexin26 deficiency mice. Here, this review summarizes three main hypotheses to explain pathological mechanisms of connexin26-related hearing loss: potassium recycling disruption, adenosine-triphosphate-calcium signaling propagation disruption, and energy supply dysfunction. Elucidating pathological mechanisms underlying connexin26-related hearing loss can help develop new protective and therapeutic strategies for this common deafness. It is worthy of further study on the detailed cellular and molecular upstream mechanisms to modify connexin (channel) function.Hereditary deafness is one of the most common human birth defects.  All Cxstrations , (2) memtrations , and (3)trations .stria vascularis (SVs), fibroblasts of the suprastrial region, mesenchymal cells of the vestibular scala, and dark cells  and the connective tissue gap junction system (C-sys) . In mammrk cells .The maintenance of normal function of the inner ear depends on the homeostasis of three fluid environments—the perilymph fluid , the endolymphatic fluid, and the intracellular fluid. Furthermore, the maintenance of the fluid environment homeostasis depends on the cellular network system of substance exchange and signaling transmission which is formed by intercellular GJ channels and extracellular hemichannels.GJB2 gene. GJB2 mutations cause about 50% of non-syndromic hearing loss. There are more than 340 mutations of GJB2 . GJB2 mutations affect the following: (1) the protein expression level  encodes by the  of GJB2 , includion level ; (2) theon level .Cx26 is the most common and harmful deafness gene. Cx26 is responsible for intercellular substance transfer and signal communication and plays a critical role in hearing acquisition and maintenance. Cx26 mutations can not only cause congenital deafness but also cause delayed deafness. The deafness mechanism caused by Cx26 mutation is not clear. Mouse models are widely used in hearing and deafness mechanism research . BenefitloxP/loxP; Otog-Cre, Gjb2loxP/loxP; Sox10-Cre, Gjb2loxP/loxP; Pax2-Cre, Gjb2loxP/loxP; Foxg1-Cre, Gjb2loxP/loxP; Rosa26-Cre, Gjb2loxP/loxP; Prox1-CreERT2, and Gjb2loxP/loxP; Rosa26cre-ER injected with tamoxifen at E19 or P1 , and cochlear amplifier function fail to form , finally returning to the perilymph . Potassi+ concentration in the perilymph is 10 times higher than that in the endolymph. This leads to the potential difference between different parts of the cochlea in the resting state. EP is the positive voltage (+80 mV) of cochlear endolymph in scale media at the resting state. Once acoustic stimulation, the positively charged EP becomes the driving force to promote potassium ions of endolymph in the scala media to pass through the mechano-transduction channel in the top of hair cells and generates auditory receptor current and potential. Thus, the positive EP is necessary for hearing maintenance  electromotility. OHC electromotility serves as a major source of active cochlear amplification in mammals . Active GJB2 mutations produce functionally defective or non-functional Cx26 proteins that affect the permeability of the cochlear GJ, impairing GJ coupling and disrupting potassium recycling, and also (1) leading to potassium excessive accumulation in extracellular space near hair cell, generating cell toxicity and eventually damaging the hair cells  leair cells .The potassium recycling dysfunction hypothesis can explain the pathogenesis of most of the GJ-related hearing loss including profound congenital hearing loss and late-onset progressive hearing loss. However, there has been no direct evidence found to support this hypothesis so far. Moreover, more and more model mice have been studied, and the theory of potassium recycling has been challenged and questioned in many ways . For exa2+ signaling transduction . During cochlear development, supporting cells of the Kölliker’s organ can spontaneously and rhythmically release ATP to the endolymphatic surface via hemichannels, as well as to adjacent supporting cells via GJ channels  and then passes rapidly through gap junction channels, synchronizing the entire Kölliker’so rgan syncytium, causing cumulative ATP release, and eventually activating the P2Rs on adjacent inner hair cells (IHC), which again leads to causing depolarization of IHCs and the release of calcium-dependent glutamate from ribbon synapses, activating spiral ganglion neurons (SGNs) to generate action potentials, causing osmotic cell contraction and wrinkle movement of tall columnar cells of Kölliker’s organ  of IHC at the prehearing stage, thus triggering synaptic vesicle exocytosis and promoting the development and maturation of IHC and SGN at prehearing stage  and Panx1–/– (MGI:3606250) mice, showed that normal Ca2+ waves spread in Kölliker’s organ and normal hearing phenotype (in vivo with BAAV (bovine adeno-associated virus) vectors encoding Cx30 via canalostomy at P4 not only restored calcium wave transmission in Gjb6–/– mice but also partially and significantly improved hearing threshold around P30  that promote glucose diffusion along concentration gradient and sodium-dependent glucose transporters (SGLTs) that transport glucose against a concentration gradient . Blood gDuring cochlear development, both hair cells and supporting cells require a large amount of energy for differentiation and maturation. The insufficient energy supply will disturb normal development. Autophagy provides important energy for early development, and the deletion of autophagy-related molecules can be lethal to mouse embryos . SimilarMutations in Cx26 reduce the coupling of CJs, which limits the transport of nutrients, especially glucose from distal vessels to avascular sensory epithelium. The glucose transport pathway mediated by GJs is critical for the differentiation and maturation of supporting cells, especially the inner and outer column cells of the tunnel of Corti during early development . LimitedCx26 plays a critical role for hearing acquisition and maintenance. Cx26 mutations can induce congenital deafness and late-onset hearing loss. Cx26 is responsible for intercellular substance transfer and signal communication. GJ channels and hemichannels generally allow the passage of potassium, ATP-calcium signaling, and glucose. Potassium recycling is critical for maintaining EP and OHC electromotility. Therefore, Cx26 mutation can disrupt potassium recycling in cochlea lymph, leading to EP reduction and active cochlear amplification impairment. ATP-triggered intercellular Ca2+ signaling is critical for cochlear development. Cx26 mutation can lead to cochlear IHC development disorder. Cochlear development for hearing acquisition and OHC electromotility for hearing maintenance require sufficient energy supply, which depends on the cochlear supporting cell by GJ-mediated glucose transport pathway. Thus, energy deprivation at different periods due to Cx26 deficiency can cause cochlear non-sensory and sensory epithelial cell development arrest or OHC electromotility impairment with aging or noise.GJB2 mutation-related deafness. Cx26 function has been studied for decades, most of which focus on downstream function changes. Nowadays, there are some advances in the treatment of PC: study conception and write the manuscript. WW and JZ: study conception and draft the manuscript and figures. JC, YL, and LS: study conception and screening. SH: quality control and write the manuscript. JY: study conception, quality control, and write the manuscript. All authors contributed to the article and approved the submitted version.


One in every 1,000 newborn suffers from congenital hearing impairment. More than 60% of the congenital cases are caused by genetic factors. In most cases, hearing loss is a multifactorial disorder caused by both genetic and environmental factors. Molecular genetics of deafness has experienced remarkable progress in the last decade. Genes responsible for hereditary hearing impairment are being mapped and cloned progressively. This review focuses on non-syndromic hearing loss, since the gene involved in this type of hearing loss have only recently begun to be identified. In developed countries, approximately 1/1,000 children have severe or profound hearing loss at birth or during childhood, at pre-lingual stage. About 60% of the cases have hereditary etiology, 30% of the cases are acquired, and 10% are idiopathic. Non-syndromic forms are responsible for 70% of the cases of hereditary etiology and syndromic cases represent 30% of them. Among the forms of heritage, autonomic recessive is the most frequent one (75%-85%), followed by dominant heritage 12-13%) and X-linked or mitochondrial, with 2-3% of the cases of non-syndromic hearing loss.-13% and Syndromic or autosomal dominant hearing losses may cause conductive, sensorineural or both losses. Conversely, pre-lingual non-syndromic cases of autosomal recessive losses are almost always sensorineuralSome of the identified genes that cause syndromic forms are also responsible for isolated forms of hearing loss. There does not seem to be a direct correlation between this type of mutations and the association with syndromic or non-syndromic hearing loss. Moreover, analyses of phenotypes together with mutations in some affected families by Pendred or Usher syndrome, for example, revealed that mutating gene of these syndromes may also cause non-syndromic hearing loss. In such cases, it is highly likely that modifying genes are contributing factors“deafness” and “non-syndromic”. Selected articles were those that provided the more recent information on genes involved and their respective proteins, sites of expression in the cochlea and audiological clinical picture.The purpose of the present study was to review some genes described to present that, if mutating, cause the most varied forms of non-syndromic hearing loss: autosomal recessive, dominant, X-linked and mitochondrial. We selected articles that were part of OMIM database using MedLine, and the search mechanism used key words such as deafness) followed by letters A or B, meaning autosomal dominant transmission (DFNA) and recessive transmission (DFNB), respectively. When using DFN isolated, it is X-linked deafness. After the letters, there is a whole number, indicating the order of gene discovery.Different chromosome sites of non-syndromic forms of genetic deafness are named under the acronym DFN Non-conventional myosin proteins:a)Myosin VIIA: it is expressed in inner ear outer hair cells and in a great variety of epithelial cells that present apical microvilosities, in addition to retina photoreceptor cells. In the cochlea, the protein is present along the stereocilia, close to the junction between hair cells and supporting cells and present in the synaptic region, Gene MYO7A, located in chromosome 11 (11q13.5), has 49 exons that codify non-conventional myosin protein VIIA (2215 amino acids).When the mutations cause also retina cell abnormalities, phenotypic picture is characterized as Usher syndrome. The chromosomic site for one of the genetic types of Usher syndrome – USH1B was also mapped in the same region of chromosome 11, responsible for 75% of the cases of USH type 1b)Myosin XV: non-conventional protein  codified by gene MYO15 with at least 50 exons and located on chromosome 17 (17p11.2). In the inner ear, the expression of this gene seems to be restricted to hair cells, on the cuticular plaque. Mutations of this gene determine DFNB3.c)Myosin VI: gene MYO6 (32 exons), located at chromosome 6 (6q13), codifies non-conventional protein myosin VI (1262 amino acids), concentrated on cuticular plaque of hair cellsd)Myosin III: non-conventional protein recently described in a Jewish family of Mosul, in Iraq, codified by gene MYO3A (10p11.1).Non-conventional myosin proteins form a family that is divided into 16 classes, found in most non-muscular cells2)Harmonin: gene site, if mutant, causes DFNB18, and was mapped at chromosome 11 (11p15.1), at the same gene location as USH1C (Usher Syndrome Type IC – 11p15.1).3)Villin: protein that belongs to the molecule that contains PDZ domain; it acts as an organizer of submembranous molecular complexes that control and coordinate polymerization of actin for the growth of membrane in stereocilia of inner and outer hair cells. Gene villin (9q32-q34), with 12 exons, codifies protein of the same name, with 465 amino acids and if mutant they are responsible for pre-lingual profound DFNB31. Protein villin is similar to protein harmonin because it shares 95% of its three PDZ domains.4)2+ ions, with over 20 different members, making part of a molecular structure of intercellular adhesion junctions or zones of adhesion (zonnula adherens). Chromosome sites for DFNB12 (10q21-q22)Cadherin-23: it belongs to the family of transmembrane proteins, dependent on Ca5)Drosophila. At the cochlea, the protein is found in hair cells and external supporting cells, but in small concentrations. Gene mutations affect the cytoskeleton of actin in outer hair cells and cause DFNA1, described in a family in Costa Rica, in which they located the first affected ancestral named Monge.Diaphanus-1: it belongs to family of proteins related to formins, involved in cell polarization and cytokinesis. Gene DIAPH1 or HDIA1 (26 exons), located at chromosome 5 (5q31), codifies protein diaphanous-1 (1252 amino acids),6)KCNQ4: gene KCNQ4, with 14 exons, mapped in chromosome 1 (1p34), codifies a protein subunit of family KCNQ of potassium channels, protein KCNQ4 (695 amino acids). In the cochlea, channels KCNQ4 are expressed not only in outer hair cells, but also in inner hair cells, whose main function is to promote the outflow of potassium from the cells to supporting cells.7)Otoferlin: gene OTOF, with 48 exons, codified protein otoferlin (1977 amino acids) located at chromosome 2 (2p22-p23), whose mutation determines DFNB9, characterized by pre-lingual profound hearing loss involving all frequencies.8)POU4F3: A deletion of only 8 base pairs was the mutation found in gene POU4F3 (2 exons), located in chromosome 5 (5q31), determining DFNA15, starting between 18 and 30 years, progressive, and which reaches moderate to severe level at the age of 50, approximetaly.Proteins genetically codified with expression on cochlear non-sensorial cells:1)Protein connexin:a)Connexin 26: in 1997, gene connexin 26 (13q11-12) was discovered, whose mutations caused DFNA3 and DFNB1.b)Connexin 31: it has not been determined yet if protein connexin 31 (270 amino acids) is present in all gap junctions of the inner ear. The site of Cx31 or GJB3, in chromosome 1 (1p34) is the same for gene KCNQ4, expressed in both hair cells, and if mutant, it causes DFNA2.c)Connexin 30: the gene that codifies connexin 30 (261 amino acids) is located in chromosome 13 (13q12)Protein connexin is the structural component of intercellular gap junctions, which are responsible for flow of potassium of supporting cells for fibrocytes of spiral ligament and spiral limbus back to endorphin, after it has been out from the hair cells.2)Pendrin: Protein pendrin (780 amino acids) is codified by gene PDS (21 exons), located at chromosome 7. Mutations in this gene are responsible both by Pendred Syndrome (7q21-34) and DFNB4 (gene SLC26A4 – 7q31).3)Claudin-14: gene CLDN14, located in chromosome 21 (21q22), codified protein claudin (239 amino acids), one of the components of gap junctions or tight junctions.4)Cocline: protein cocline (550 amino acids) is codified by COCH (11 exons), located in chromosome 14 (14q12-q13). In the cochlea, the gene is expressed in spiral ganglion and extracellular matrix especially spiral limbus, spiral ligament and bone spiral lamina.5)Drosophila), was mapped in chromosome 6 (6q22.3-23.3) that codifies protein EYA4 (639 amino acids).EYA4: gene EYA4 (21 exons), a member of family EYA homologous to Drosophila eyes absent (regulator of ocular development of 6)POU3F4: Gene POU3F4 (1 exon), mapped in chromosome X (Xq21.1) is responsible for transcription regulating elements.Genetically codified proteins with expression on tectorial membrane:1)Collagen XI : Collagen XI protein, codified by gene COL11A2 (62 exons) located in chromosome 6, is one of the components of tectorial membrane.2)Alpha-tectorine: many different types of cells synthesize alpha-tectorine protein during development of the inner ear. Due to sequence of DNA in TECTA gene, it is assumed that tectorine protein is synthesized from a precursor adjacent to plasma membrane, via glycosil-phosphatidyninositol, released from the membrane by proteolytic cleavage of precursor. Gene TECTA (23 exons), located in chromosome 11, codifies alpha-tectorine protein (2155 amino acids) and it is one of the components of tectorial membrane.Forms of hearing loss caused by mitochondrial DNA affections:Diseases related to mitochondrial DNA are transmitted to both genders, only by the mother, and they may be syndromic or non-syndromic. Mitochondral DNA codifies 13 RNA messenger (RNA-m), 2 RNA ribosomic (RNA-r) and 22 RNA-transporters (RNA-t).Mutation 1555A->G was detected in mitochondrial gene 12S rRNA in patients with family hearing loss and also in isolated cases of hearing loss induced by the use of aminoglycoside antibiotics.To present, other described non-syndromic mitochondrial mutations that cause hearing loss followed or not by other affections are located in gene RNA-transporter – gene tRNA Ser (UCN): 7445A->G = keratoderm palmoplantar; 7472insC = neurological dysfunction – ataxia, dysarthria and myoclonus; 7510T->C and 7511T->C = only hearing loss. Syndromic mitochondrial mutations can also be located in RNA-t, causing hearing loss associated with neuromuscular syndrome or diabetes mellitus. Recent studies suggested that mitochondrial mutations, such as deletions del4977 pb, del4834 pb and del3867 pb may be responsible for family cases of presbyacusis.3Hearing loss caused by clinical otosclerosis has prevalence of 0.2 to 1% among Caucasian adults. The mean age of onset is 3rd decade and 90% of affected patients are below the age of 50 years at the time of diagnosis. Conductive hearing loss is developed when the focus invades stapedial-vestibular articulation, on the oval window, interfering with free movement of stapes. Profound sensorineural hearing loss, reaching all frequencies, may also be present, characterizing cochlear otosclerosis, in about 10% of affected subejcts.The fact that one same mutation leads to different clinical presentations may be the indication that the knowledge of molecular genetics has not reached the details of auditory dynamics yet, as well as the myriad of neurological abnormalities involved. However, it seems to move towards that. New mutations are described, new genes are cloned and mapped, and there are about 34 genes already identified to form recessive autosomal non-syndromic forms, 40 genes for dominant autosomal forms, 8 for X-linked forms, and 2 genes for mitochondrial heritage.2Despite the significant advances in understanding molecular basis of hearing loss, precise identification of genetic cause still presents some difficulties, owing to phenotypical variation. First we have to rule out non-genetic causes, then syndromic causes, and then look for non-syndromic causes.Most non-syndromic recessive autosomal forms cause pre-lingual loss that is severe to profound and not associated with radiological findings. Exception to this rule are DFNB2 (MYO7A)Otorhinolaryngologists, pediatricians and geneticists should be aware of this phenotypical variety and especially that DFNB1 is the most frequent form of non-syndromic recessive autosomal hearing loss; molecular investigation should be made in such cases, reducing the costs of complementary tests normally requested for the investigation of patients with hearing loss.Facility and benefits of genetic tracking, especially for mutations that cause DFNB1, should make it an important public health issue so that determinations of early diagnosis of hearing loss can be properly established. Molecular tests can not help all children with hearing loss and it is not reasonable to wait for these tests to replace already existing screening programs. Whether or not screening programs with acoustic otoemissions and brainstem evoked audiometry should include molecular tests for DFNB1 is another different issue.Genetic counseling of families whose parents have normal hearing and one single hearing child has been very difficult owing to nonexistence of genetic tests to identify specific mutations, especially in developing countries. In most cases, considering the important role of environmental causes of pre-lingual hearing loss, it is difficult to recognize whether hearing loss is of genetic origin. It is essential to inform healthcare professionals, the general population, and the hearing impaired population about genetic advances, and to train professionals on genetic counseling.Genetic tests for hearing loss are a reality because they have changed the assessment pattern of patients with hearing impairment and should be used by physicians for diagnostic purposes. In the next years, there will certainly be an expansion in the role of these tests and counseling will not be limited to reproductive results. Even though tests may be confusing for medical professionals that are not used to them, in daily practice, they are an important part of medical care. New findings and technologies will expand and enhance complexity of these tests and it will be on Otorhinolaryngologists and Pediatricians to get familiar with recent discoveries and include them in their investigation protocols - the genetic tests.Reaction to sounds is the first sign that a child has his auditory capacity preserved. Owing to delay in speech acquisition, absence of reaction to sounds or other disorders, parents are the first ones to suspect of hearing loss. The delay between suspicion and diagnosis reduces significantly the possibilities of rehabilitation, because if intervention does not take place early, it will cause communication deficits that have significant morbidity, which can be manifested by paucity of social activities and professional opportunity losses. Conversely, it is surprising that some parents and even some professionals hesitate to accept hearing loss, considering it as unimportant, translating lack of knowledge about the importance of auditory function for the development of conceptual processes that support human's reasoning and speech.


Noise Induced Hearing Loss (NIHL) is an insidious and cumulative disease that worsens over the years with work-related noise exposure.To evaluate the noise spectrum influence on NIHL prevalence in workers.This a cross-sectional historical cohort carried out in steel mills, lumber mills and marble shops, with noise levels above 85dB, in which we evaluated the auditory thresholds for frequencies from 250Hz to 8,000Hz. To evaluate the work environment, we observed the entire setting, aiming at checking sound intensities in an eighth frequency filter.We carried out 192 hearing threshold evaluations after an occupational anamnesis. Concerning NIHL, we noticed that 49% of the audiometry results presented hearing deterioration in the acute frequencies. We studied the mean values and standard deviations for frequencies over 3,000Hz, in all workers, and we observed that the highest average values were in the frequency of 6,000Hz. We did not notice any association among frequency bands carrying intense noise levels and the hearing damage frequency.Noise intensity seems to be the main risk factor for loss hearing, regardless of frequency range. Noise Induced Hearing Loss (NIHL) has many names, such as “Hearing Loss by Noise Exposure”, “Occupational Hearing Loss”, “Professional Hearing Loss”, “Professional Deafness”, “Occupational Dysacousia”, “Occupational Noise Induced Hearing Loss” and “Sensorineural Hearing Loss by Continuous Exposure to High Levels of Occupational Hearing Loss”; however, they are all part of a profession-related disease, characterized by a gradual reduction in hearing acuity because of continuous exposure to intense levels of sound pressure, causing damage to outer and inner hair cells of the Organ of CortiAccording to the National Institute of Occupational Safety and HealthIt is estimated that there are approximately nine million American workers with hearing loss caused by occupational exposure to noise. In developing countries, the situation is usually more severe, since it is common for workers to be exposed to intense noise levels in their work places, besides low compliance with the measures used for collective and individual protection.There is a consensus in the literature that the duration of noise exposure is associated with NIHL onset. In the study carried out with bus drivers in Campinas, they found a positive association between NIHL and accumulated duration of noise exposure.According to the World Health Organization, the excessive exposure to noise can cause other health problems, such as auditory stress under exposures of 55 dB; physical reaction such as blood pressure raise, heart rhythm and muscle contractions; the increase in adrenaline production and other hormones; irritability; stress; insomnia and anxiety.Epidemiologic studies reveal that occupational hearing problems affect more frequently workers of the following occupations: steel workers, mechanics, graph, textile, chemist/petrochemist, transportation and those in the food and beverage industry, industries with high noise levels.In the metropolitan region of Salvador, Bahia, a prevalence study was carried out based on the audiometric data of workers from 44 plants in nine different industries. Such study revealed that 45.9% of the population studied had hearing loss. As far as NIHL is concerned, the prevalence seen was of 35.7%. The highest prevalence rates were found in the editorial/graph (58.7%), mechanic (51.7%), beverages (45.9%), chemist/petrochemist (42.3%), metallurgic (35.8%), steelworker (33.5%), transportation (29.3%), food (28.0%) and textile (23.4%) industries, corroborating with the literature.A study carried out with workers exposed to noise in marble mills at the Federal District found a high prevalence of hearing damage as well (48.0%) and association between exposure duration and NIHL.Considering the problem relevance, this study intends to carefully assess the work environment where the worker is exposed, the noise spectrum and the influence it has on the workers' hearing.This is a cross-sectional epidemiological study of historical cohort, carried out in different industries with noise levels above 85 dB, in which we assessed their hearing thresholds and through an occupational anamnesis we identified occupational data, life styles and issues associated with morbidity.The population under study was selected by means of a convenience sample, made up only by those companies which agreed to participate in the study. The companies are geographically restricted to the Federal District area, and the industries assessed were: marble mills, timber mills and metallurgic mills.We assessed workers between the ages of 18 and 65 years, males and with a minimum of 1 (one) year on the job. Workers from these industries with occupational noise below 85 dB, workers with a past history of hearing alterations of air conduction or mixed type, and workers with a history of acoustic trauma.The audiologic assessment was preceded by an ear canal inspection and acoustic rest of 14 hours. Such assessment was carried out in order to check for the minimum response level for frequencies 250 Hz, 500 Hz, 1,000 Hz, 2,000 Hz, 3,000 Hz, 4,000 Hz, 6,000 Hz and 8,000 Hz. The bone pathway was tested only when the hearing thresholds exceeded 25 dB HL, in the frequencies of 500 Hz, 1,000 Hz, 2,000 Hz, 3,000 Hz and 4,000 Hz.In order to classify hearing thresholds, we used the audiometric alteration criteria that classifies in accordance with the mean values of the 500, 1,000 and 2,000 Hz frequencies. The audiometries with scores suggesting Noise Induced Hearing Loss were the ones with normal reports and a notch in the frequencies of 3,000 Hz, 4,000 Hz, 6,000 Hz and or 8,000 Hz or characterizing a sensorineural curve with drops in the high frequencies and descending curve with a notch shape.Each worker underwent an audiometric exam. The equipment used in the audiologic evaluation were: a Welch Allyn otoscope with WA accessories; Interacoustics clinical audiometer, AC 40 model with two channels and frequency range of 125 Hz to 16,000 HZ; Redusom sound-treated booth, model RO-80 Std. All the equipment was calibrated according with Standards ISO 389/64 and ANSI S3.6/69 duly registered. The audiometric booth has internal noise patterns within levels accepted by law, about 30 dB HL, as per ANSI S3.1 from 1991.The environmental evaluation was carried out at two moments. In the first one, we noticed the sound intensity distribution in an octave frequency filter, using an equipment that measures sound pressure levels (SPL). This assessment was carried out in central points of the plant environment. To do that, we used one sound pressure level measurement device, of the SIP 95 brand from the 01dB manufacturer, with a built-in frequency analyzer, duly calibrated. Data collection time in each plant was of approximately 30 minutes.The equipment equalizing circuits has the option of choice for curves A, B, C and D; two time constants, which were: slow and fast.The A-Weighed curve damps the low sounds, providing greater gain for the 2 to 5 kHz frequency band, and then it goes back to damping the high-pitched sounds. This is exactly the hearing aid sensitivity curve. The C-weighed curve is linear and is incorporated to the measuring devices when there is the need to measure the entire room sound level, or to assess the presence of low frequency sounds. For this study we used the linear-weighed curve, since the objective of this analysis is to measure the sound of the entire room with precision.In a second moment, we analyzed the individuals' exposure to noise during their work hours. The device used for this analysis is the dosimeter, capable of measuring the worker's true exposure, because the latter continuously follow up on all the noises that reach the individual during their work hours, providing the mean value. For such a measurement, we used the 01dB dosimeter, made in Brazil, which the worker during 4 (four) hours of work. For such analyses, we selected 2(two) workers from each plant. Both equipment pieces were placed in such a way that the microphones were at approximately 20 cm for the worker's ear.The daily exposure level was calculated according to the following expression:For these calculations, we used the mean time of daily exposure (Texp) of 9 hours (according to information obtained from the workers) for 8 hours of work (T0), Leq represents the equivalent level of sound pressure, according to NBR 10.151 standard.In order to calculate the percentage dose of noise absorbed daily, the following expression was used:For the exchange factor q, the value of 5 was used and Lcrit of 85 dB(A), according with the NR 15 standard.The estimate of the maximum time of Tt tolerated exposure by the workers of the metallurgical, timber and marble mill plants, resulted from expression 3.The audiologic evaluation information data was stored in Microsoft Excel, thus performing the statistical analysis . In order to analyze the results obtained, we used the t Student statistical test  and the Fisher Exact Test , both with a 95% level of significance.This paper was submitted to the Ethics in Research Committee - Faculdade de Ciências da Saúde da UnB, protocol # 048/2004.We carried out 192 evaluations of hearing thresholds (audiometry), preceded by an occupational patient interview. Of these, 91 tests in 2 metallurgical plants, 54 in 3 timber mills and 47 in 5 marble mills.The workers evaluated had mean age of 34.6 years (SD± 8.8); and 38.5% were 30 years old or younger. As far as gender is concerned, we only assessed male workers.Data regarding individual protection equipment, collected prior to the audiometric test, can be observed on In relation to the industries, this variable pointed out that the timber mills which are the ones that least used this equipment, 48.1% of the employees stated they did not use it and 29.6% said they rarely use it. Nonetheless, the metallurgical plants and the marble mills were the ones that most used IPE. According to audiometric results, we have observed that 49.0% of the workers evaluated had a notch in the high frequencies, shown in the audiogram . Among others, 13.8% in the right ear, 23.4% in the left ear and 62.8% in both ears.As far as the industry is concerned, the results point out that 53.8% of the workers from the metallurgical plants had an audiometric notch, followed by those from the timber mills, with 48.1%, and marble mills with 40.4%.As we assess auditory damage laterality, associating it with the person's occupation, we noticed that in all the industries there was an audiogram notch in both ears, and the metallurgical plant individuals had equal prevalence in the right and left ears. As to the timber and marble mills, we observed a tendency towards laterality, since in these industries the left ear had high prevalence when compared to the right ear. We did not see statistically significant differences among the industries (p>0.05-Fisher Exact Test). Table 2PrAs we analyzed the workers in relation to the average of audiometric thresholds according to the frequencies starting at 3,000 Hz, we observed that the highest averages were found in the frequency of 6,000 Hz, characterizing the presence of a notch configuration. In the analysis of variation among the frequencies in each ear alone, we noticed that it was highly significant (p<0.0001-t Student test) in all the frequencies for both the right and the left ears.As we studied the mean and standard deviation values of the audiogram thresholds of workers according with age range and the frequencies starting at 3,000 Hz it was possible to see that as age progresses, there is an increase in the degree of loss, and we can state that at an older age (> 50 years) the workers presented mild to moderate losses involving frequencies starting at 3,000 Hz. When we compared the auditory thresholds between the left and right ears, we noticed no statistically significant differences (p>0.05-t Student test), although the left ear had worse auditory thresholds in some frequencies.In analyzing the mean values of audiometric thresholds according to frequencies starting at 3,000 Hz and the time of exposure, we observed that the longer the time of exposure, the greater the degree of hearing loss, with significance (p< 0.05-t Student test) in all the frequencies, when compared among themselves.According to the environmental evaluation, it was possible to see that in each one of the industries studied, there was a result which was different among the environmental noise spectrums. We notice that for each frequency band, there is an equivalent level of sound pressure represented in decibel.In the metallurgical plants, the 8,000 Hz frequency band is the one that represents the highest noise level (85.4 dB); therefore, we see that it prevails in the environment, and it is the one most noxious to workers. Nonetheless, we see that the differences among levels of sound intensity are similar among the other frequency bands. We notice that among the octaves that go from 250 all the way to 8,000 Hz, the intensity difference is low, showing that the sound energy in this industry is almost uniformly distributed among these frequency bands. Table 3EnAs far as timber mills are concerned, this analysis reveals that the 2,000 Hz frequency band is the one which prevails in the environment, and this may very well be the one that causes the worst damage, since among the others, this is the one that has the highest sound pressure level (80.5 dB). We also see that, contrary to what is seen in the metallurgical plant, the distribution of sound energy does not remain equivalent among the many frequency bands, it is possible to see that the octaves 1,000 Hz and 2,000 Hz have the highest intensity levels .We see that marble mills have less noxious levels to the health of workers, the spectral analysis reveals that the highest noise level was of 79.3 dB in the 4,000 Hz frequency band, which prevails in the environment. Global intensity levels in the environment in each one of the industries we studied can be seen on Based on the noise dose assessment (dosimeter), we see that the results presented different sound pressure levels when compared to those on Comparing audiometric thresholds with results from spectral analyses and the different industries, we did not observe any association among the frequency octave bands with the higher levels of noise and the auditory damage frequency. We notice that frequencies with the highest thresholds do not coincide with the frequency bands which intensity levels reach higher values. We also observe that, despite the difference between noise spectrum in these three industries, the mean values of audiometric thresholds are similar. Table 5CoWorkers' hearing health has received growing attention in the recent decades, since the problems found are not limited only to hearing loss. Many studies stress the extra-auditory effects of noise, occlusion effects caused by protective phones, temporary threshold alteration, tinnitus and others.We see that among the three industries analyzed, timber mills were the ones showing the lowest compliance with ear protection (IPE), suggesting less attention paid to issues of prevention, corroborating with the high prevalence in those who state they do not wear protection. Nonetheless, the metallurgical and marble mill plants, which were found to be more zealous as far as the use of protection equipment is concerned, also pointed to an alarming number of hearing damage, reinforcing the results of many studies which prove that the choice of equipment must be equivalent to its real need, since for each type of noise exposure, a specific type of ear protection is recommended, which can vary among the types: cup, plugs, and others.13We stress that the ear IPE used by the workers hereby discussed, suggest little effectiveness, since in all the industries evaluated, there is a relevant prevalence of workers who developed some kind of hearing damage in at least one of the ears, and in at least one frequency.The issue of hearing loss laterality has been discussed by many authors who state that NIHL is usually bilateral.1 Such event was observed in this study, since the highest prevalence of NIHL notch happened in both ears. However, the left ear proved to be slightly more prone to it than the right ear. As far as a possible asymmetry, some authors report that the left year is more vulnerable to noise-induced damage, however, there was no evidence for such statement.The high prevalence of notches in NIHL in the left ears that we noticed in timber and marble workers may, at least partially, be explained by the fact that, contrary to what was observed in metallurgical plants, most marble and timber plants are located in buildings which are closed on one side and open on the other, probably because of the excess dust in these environments, and with this, the physical organization of the production areas can influence and cause a greater involvement of one ear in relation to the other; nonetheless, further and more specific studies should be carried out in order to confirm this causality relationship.As we analyze the mean obtained in the frequencies of 3,000 to 8,000Hz of the entire sample, we observed that in 6,000Hz we find the mean values above 25 dB, in other words, the auditory damage seems to affect mostly these frequencies. Recent studies which used only conventional audiometry, point out that 6,000Hz was the first frequency to be affected because of exposure to occupational noise.One of the points that most calls our attention in this study is the result involving the two stages of the environmental analysis. We see that the data regarding sound pressure intensity in the environment is different, and based on the dose assessment, noise is more intense in all the industries. Such event may be justified by the way through which the data was collected, since the sound pressure level monitor, at the time of the assessment, was placed in a central point within the plant, capturing the entire environment sound. Now, regarding the evaluation carried out with the dosimeter, this time the equipment had been placed next to the worker's ear, whom remained in direct contact with the production machine, thus capturing higher levels of sound intensity. Scholars have revealed that there is a reduction in sound propagation by air, stressing that low frequency sounds are easier to convey by air when compared to high frequency sounds. Thus, the high pitch noise lose their power in a short distance, thus justifying the findings from this study.It is known that the Organ of Corti injury mechanism is based on the cochlear basal turn - the area responsible for the high frequency soundsThe lack of association between the frequency bands with intense noise levels and the hearing damage frequency found in the present investigation also justify the findings from a research paper which discussed the prevalence of NIHL in bus drivers.We also stress that the lack of association among the frequency bands of the noise spectrum and the hearing loss frequency does not rule out the importance of this type of environmental analysis, since in order to obtain a thorough and efficient program for occupational noise control it is extremely important to know the frequency bands that bear the most intense noise levels, in order to establish safety measures, thus facilitating the creation of projects to reduce sound levels.The environmental analysis did not show association between the frequency bands and the intense noise levels and hearing loss frequency. Given that, despite the three industries having presented different noise spectrum results, the hearing loss pattern is similar among them. Thus, in this case it is possible to state that the noise intensity seems to be the major risk factor associated with the hearing loss. As to noise induced hearing losses (49.0%), we noticed that the frequency bearing the biggest notches is 6,000 Hz.


GJB2, SLC26A4, and mitochondrial 12S rRNA. The probands of each family were performed whole-exome sequencing (WES) or targeted next-generation sequencing (NGS) for known deafness genes to study for pathogenic causes. We found four novel mutations of CDH23, one novel mutation of MYO15A, one novel mutation of TMC1, one novel mutation of PAX3, and one novel mutation of ADGRV1, one novel CNV of ADGRV1, and one novel CNV of STRC. Hearing loss is a highly hereditary and heterogeneous disease. The results in the limited samples of this study show that Usher and Waardenburg syndrome-related genes account for a major proportion are strongly associated with Chinese Han hearing loss patients negative for GJB2, SLC26A4, and mitochondrial 12S rRNA, followed by STRC resulting in mild to moderate deafness.Hearing loss affecting about 2/1000 newborns is the most common congenital disease. Genetic defects caused approximately 70% of patients who have non-syndromic hearing loss. We recruited 13 Chinese Han deafness families who tested negative for  MitochoGJB2, SLC26A4 and mitochondrial 12S rRNA. The probands of each family were performed targeted NGS for known hearing loss genes or whole-exome sequencing (WES) to study for pathogenic causes.Currently, next-generation sequencing (NGS) is increasingly applied in clinics to enable accurate diagnosis. In this study, we recruited 13 Chinese Han deafness families negative for Thirteen patients (HL1~13) were recruited from the Department of Otorhinolaryngology-Head and Neck Surgery of Xinhua Hospital affiliated with Shanghai Jiaotong University School of Medicine. Informed consent was approved from all subjects to participate in this study from October 1, 2018 to December 31, 2020. For child participants, written consent will be sought from their parents or guardians. All patients had a detailed medical history and a thorough examination to rule out noise, trauma, pregnancy infection, and other non-genetic factors. All affected subjects were evaluated by audiological examinations, including otoscopy, pure-tone audiometry (PTA), distortion product otoacoustic emissions (DPOAEs), and auditory brainstem response (ABR). Magnetic resonance imaging (MRI) was performed on the HL13 proband. The research was approved by the Ethics Committee of Xinhua Hospital affiliated to Shanghai Jiaotong University School of Medicine (No. XHEC-D-2021-060).GJB2, SLC26A4, and the mitochondrial 12S rRNA exon were directly sequenced first in 13 probands. A panel of 415 hearing loss–related genes was performed by targeted NGS in 12 probands excluding HL6  amplification, ding HL6 . Data prThe whole exome sequence of the HL6 proband was sequenced in the Illumina platform by the NextSeq500 sequencer, and the obtained reads by whole exome sequence were mapped to the human genome reference sequence hg19.We used SNP arrays to detect the chromosomal regions of CNV identified by targeted NGS in the HL5. SNP arrays were performed as previously reported in detail  was used to identify deletion/duplication of STRC-CATSPER2 in HL6 and HL7 family members, according to the manufacturer's instructions. The PCR amplification products were analyzed on ABI 3500 Genetic Analyzer  using Gene Marker 1.91 software .The SALSAThere are eight female and five male probands. Those affected individuals ranged in age from 14 months to 49 years. Patients from 13 Chinese families all had congenital, bilateral, and sensorineural hearing loss. They all come to the doctor because they have failed newborn hearing screening or were diagnosed with hearing abnormalities in infancy. Their hearing loss was relatively stable, with the exception of a mild progression of HL5 proband. Hearing loss was defined as varying degrees, including moderate, severe, and profound hearing loss. Click on the auditory brainstem response thresholds was 60–70 dBs for HL5, 40 dBs for HL6, 60–70 dBs for HL7, 40 dBs for the left ear, and 90 dBs for the right ear of HL11 proband. The other probands had profound hearing loss. The HL5 proband was diagnosed with retinitis pigmentosa by an ophthalmologist as a teenager including symptoms of small vision, night blindness, and amblyopia. The HL10 proband had a heterochromia iridis, and her father had a heterochromia iridis but no hearing loss. The HL11 proband had excessive freckles, and his father had excessive freckles but no hearing loss. The HL12 proband had hydronephrosis. Ear malformation was observed in the HL13 proband by MRI, including abnormal enlargement of inner ear canal, bone defect of cochlear apex and skull base, and cerebrospinal fluid.USH2A (OMIM 608400), p.Q2137X and p.W778X in CDH23 (OMIM 605516), c.3795 + 5 G>A and c.7051_7054 + 1dup in CDH23 (OMIM 605516), p.R1898Q and c.10258_10260 del in MYO15A (OMIM 602666), c.12177_12181delGGTTG and a duplication in ADGRV1 (OMIM 602851), partial or whole gene deletion in STRC (OMIM 606440), c.16 + 1C>T and c.535 + 5G>A in TMC1 (OMIM 606706) (PAX3 (OMIM 606597), c.1174-2A > T in PAX3 (OMIM 606597), p.T303T in MITF (OMIM 156845), and p.Y113H in PROKR2 (OMIM 607123), as well as partial co-segregating with the phenotype  . In 4 dohenotype . In the quencing , 2. Of tquencing .STRC, CKMT1A, CKMT1B, and CATSPER2 genes. Using MLPA, we found that the sibling in the HL6 family with the same symptoms also had the same CNV  X3] . Whole esame CNV . In the  proband .CDH23, homozygous nonsense, frameshift, some missense and splice site mutations, or compound heterozygotes combined of these above USH1D alleles are considered hypomorphic alleles with no sufficient retinal, vestibular, and auditory cochlear function leading to USH1D. Conversely, missense mutations in CDH23 are associated with non-syndromic DFNB12 deafness. The DFNB12 allele maintains normal retinal and vestibular function and is dominant to the USH1D allele phenotypically, even in the presence of the USH1D allele , with clinical features, typically include progressive mixed hearing loss, stapes fixation, and temporal bone anomalies, is the most common type of X-linked deafness in humans , 14. Theof DFNX2 . Affecteof DFNX2 . In our Our research resulted in a limited number of sporadic family samples, and the genetic results of some families are lack of validation by other affected family members, which needs a further evaluation from other relevant studies, especially those novel mutations. Our results also further verified the pathogenicity of the reported mutation sites in the hearing loss population.GJB2, SLC26A4, and mitochondrial 12S rRNA, Usher and Waardenburg syndrome-related genes account for a major proportion in Chinese Han families, followed by STRC causing mild to moderate hearing loss.The results of the limited samples of this study show that hearing loss is a highly genetic heterogeneous disease. In hearing loss patients negative of https://www.ncbi.nlm.nih.gov/, PRJNA876030.The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found at: The studies involving human participants were reviewed and approved by the Ethics Committee of Xinhua Hospital affiliated to Shanghai Jiaotong University School of Medicine. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.LS and ZL wrote the paper. XW, JS, YL, and YH collected and analyzed the data. JY and LS designed the research. All authors contributed to the article and approved the submitted version.This research was supported by grants from the National Natural Science Foundation of China, Grant/Award Numbers: 81873698.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


One of the most important applications of the Brainstem evoked response audiometry (ABR) is in the evaluation of hearing loss in children. Today the ABR is also indicated in the screening of cochleo-vestibular syndromes to detect retrocochlear lesions, to monitor patients in a coma (brain death), in monitoring the brainstem during skull base surgery, etc. Among the many BERA qualities, is its capacity to evaluate the neurophysiologic integrity of the auditory brainstem pathway. In doing so, sometimes while evaluating hearing function in children we are faced with ABR waves that suggest the presence of retrocochlear lesions , many times confirmed through image studies. These cases are seen as occasional findings of neurologic disorders during children hearing loss evaluation. In this study we report 2 cases of neurologic disorders diagnosed with the use of the ABR to evaluate hearing loss in children. The auditory system neurophysiology and its means of assessment were restrict to audiology research labs until thirty years ago. With the progress in electronic equipment it became possible to develop systems for stimulation, capture, amplification, computation e recording the neurophysiologic activities of our hearing system that made it possible its clinical application. As a consequence, such equipment started to be produced in large scale, making auditory neurophysiology and its methods of assessment shift from highly sophisticated laboratories to the clinical settings. Thus, a new and fascinating chapter started in audiology: electrophysiology of hearing .Electrical response audiometry is the generic denomination of the methods that allow us to study the bioelectrical phenomenon that occurs in the auditory system as a response to sound stimulus , from the inner ear all the way to the cerebral cortex. All these electrophysiological tests aim at detecting a bioelectrical activity related to an event . This bioelectrical activity is produced when the sound stimulus is transformed into electricity within the inner ear and in all the synapses that occur successively in the auditory pathway.The development of computers able to individualize and mediate different responses made feasible the exclusive recording of neural potentials emitted by the auditory pathways. It is likely that the ultimate step towards the clinical use of evoked response audiometry was the work of Jewett, who in 1970, based on experimental studies in cats, described the presence of 4 waves that were related to specific sites or origins located in the brainstem, which follow a first potential, the action potential (wave I)1. Since then, evoked response audiometry has been increasingly used in the clinical setting, broadening the potentials of its application. Currently, hearing electrophysiological tests are indispensable tools for the assessment, diagnosis and monitoring of numerous neurotologic diseases. Among evoked potentials, it is possible that the brainstem evoked response audiometry (BERA) be the one most used in the clinical practice. It allows us to acquire the hearing system electrophysiological activity in the brainstem, mapping auditory synapses of auditory pathways from the cochlear nerve, cochlear nuclei, superior olivary complex (pons) all the way to the inferior colliculus .A series of seven waves  may be recorded from the forehead-lobule or mastoid leads during the first 12ms after a moderate sound stimulus. These waves, sequentially labeled with Roman numerals seem to represent successive tracts and/or auditory path synapses. Of these seven waves, the first five of them are the ones that interest us, and among them, waves I, III and V are the ones that offer us the most important parameters for BERA interpretation. Waves I and II are generated in the auditory nerve, wave III in the neurons that leave the cochlear nuclei complex2-4, waves IV and V in the lateral superior lemniscus and the major negative potential that follows wave V in the inferior colliculus depolarization.At present, ABR applications are increasingly more used, in investigating childhood hearing loss, the screening of cochleo-vestibular syndromes, the search for retro-cochlear lesions, in monitoring coma status (brain death), in monitoring the brainstem in skull base surgeries etc.One of ABR’s quality is its very capacity of assessing the neurophysiologic integrity of brainstem hearing paths. We are able to compare stimulus progression speed (latencies) in both ears. Thus, sometimes, during the study of children’s hearing thresholds, we see ABRs that suggest the presence of retro-cochlear lesions in the auditory pathways , often times proved by an image exam. It is an occasional finding of some neurologic disease when in search of children’s hearing thresholds.In this present investigation we report 2 cases of neurologic diseases as occasional findings during the investigation of childhood hearing loss through the ABR.B.N.C.C., 1 year and 11 months old, female, with suspicious auditory behavior. An electrocochleography showed objective bilateral thresholds of 30dBNA. Following with the investigation, the ABR revealed a wave V delay in the left ear, and also an increase in inter-peak intervals I-III, I-V, III-V, when compared to the right ear. The exam suggested conduction impairment at the left side brainstem. The suggestion of a retrocochlear lesion by the ABR motivated us to order an image study that revealed an arachnoid cyst pushing the cerebral mid-line and the brainstem to the left. It is an occasional finding of a neurologic disease when a child’s auditory threshold was investigated by using the ABR  and 2.FiY.S.F.A., 3 months, female. Was referred to hearing objective assessment. She had risk factors for hearing impairment. In her personal history, her mother reported seizures. The ABR revealed increase in inter-peak intervals I-V 5.4ms) and low amplitudes in waves III and V in both ears. Hearing thresholds were found to be moderately high in both ears. Her personal history coupled with the ABR’s finding led us to order an image study that revealed hydrocephaly  and 4.Fims and loRecording brainstem auditory evoked potentials (ABR) allows us a glimpse of the physiology of this noble central nervous system segment (brainstem) that goes from the cochlear nucleus, going through the pons, all the way to the inferior colliculi .The ascending hearing pathways form numerous connections with central nervous system nuclei as part of a complex system of auditory reflexes. Intersections and internuclei communications make the auditory pathways occupy all the levels of the brainstem Any disorders, degenerative, inflammatory, vascular, expansive or traumatic, that affect the brainstem would have to be extremely unique not to compromise the ABR’s wave synchronicity Understand the ABR’s physiologic principles broadens and enhances its clinical applications, for it is a test that detects and records brainstem and auditory nerve evoked potentials, the ABR indirectly provides us with information regarding the auditory pathway-related structures, for its proximity and through neural interaction mechanisms. Besides hearing investigation, numerous other applications have been described for the hearing pathways evoked potential test recently.The investigation of retrocochlear pathologies, especially vestibular nerve schwannomas, illustrates such fact. For the anatomical proximity of structures within the inner ear and because these structures are encased in a bone tunnel, tumors and other inflammatory and expansive disorders of the vestibular and facial nerves may alter the electrical stimulus conduction through the auditory nerve, even if it is not a hearing alteration detected by some other method. Despite the fact that some authors question the ABR’s capacity to detect small retrocochlear tumors In our experience with hearing electrophysiology, ABR has been able to differentiate cochlear alterations from those of the VIII nerve. We have used the ABR as a screening procedure to detect retrocochlear lesions such as vestibular schwannomas, other tumors in the posterior fossa (e.g. meningiomas), neuro-degenerative diseases (multiple sclerosis), vascular anomalies, etc.In a patient with hearing loss consequent to a cochlear disorder, stimuli of the same intensity presented to both, the diseased and the normal ear, will evoke waves V with latencies very close to one another. A cochlear lesion causes the phenomenon of electrophysiologic recruitment, in other words, we do not see, despite the hearing loss, any important delay in wave V latency in the affected ear, when compared to the contralateral ear. Actually, it is quite the contrary, sometimes we see wave V with lower latency in the affected ear, when compared to the normal ear.In retrocochlear lesions we see major delays in wave V. Moderate hearing losses caused by such lesions may bring about delays of up to de 1.0ms, considered an eternity in short latency potentials electrophysiology (ECOG and ABR). Besides these delays in wave V, the ABR trace may present itself in other ways, as shown in •Wave V latency delay in the affected ear above 0,1ms for each dB of hearing loss (arithmetic average of psychoacoustic thresholds in the frequencies from 2 to 4 KHz), when compared to the wave V latency of the contralateral ear;•Any wave V latency delays above 0,3ms  regardless of the hearing loss level in the affected ear;•Presence of wave I only and absence of the others;•Lack of all the waves in an ear with hearing loss below 70 dB (arithmetic average of psychoacoustic thresholds in the frequencies from 2 to 4 KHz).In our retrocochlear lesions screening protocol, the ABR traces in the affected ear, evoked by 90 dBHL stimuli, are considered as suggestive of retrocochlear lesions when the following characteristics are present:The rigorous observation of ABR traces in the 2 aforementioned cases allowed us to suspect the presence of retrocochlear lesions in the auditory pathways, and through an image study we could prove the occasional finding of neurologic diseases when we were investigating children’s hearing thresholds.ABR has proved to be an excellent exam for the investigation of hearing loss and hearing pathway disorders. However, proper knowledge about hearing electrophysiology and, consequently, the correct interpretation of the data obtained in the brainstem evoked potential survey will bring about accurate diagnosis, given by a broader view of the patient at hand. We presented two cases in which we encountered undiagnosed neurological disorders, through the investigation of hearing in children by means of the brainstem evoked response audiometry.


Evidence on the association between hearing loss and sick leave or disability pension is to a great extent based on few cross-sectional studies and remains unclear. We aim to assess the associations in a long-term follow-up population study.We used baseline data from a large population-based hearing study in Norway, the HUNT Hearing study (1996–1998). The sample included 21 754 adults . We used register data on sick leave and disability pension (1996–2011). Cox regression was used to assess the association between hearing loss at baseline (Pure tone average/PTA 0.5–4 kHz > 20 dB) and time to first physician-certified sick leave episode, as well as time to first disability pension payment.Hearing loss at baseline (yes/no) was weakly associated with time to first physician-certified sick leave episode: Hazard ratio (HR) 1.2  1.1–1.3). Restricting the exposed group to people with both hearing loss and tinnitus, the HR was slightly increased: 1.3 (95% CI 1.1–1.6). Hearing loss in 1996–1998 was also associated with time to first received disability pension: HR 1.5 (95% CI 1.3–1.8). Stronger associations were found for disabling hearing loss (PTA > 35). Restricting the exposure to hearing loss and tinnitus, the HR was increased: 2.0 (95% CI 1.4–2.8).This large population-based cohort study indicates that hearing loss is associated with increased risk of receiving disability pension, especially among younger adults and low educated workers. Hearing loss was weakly associated with sick leave. This paper evaluates the association between hearing loss and sick leave or disability pension. Our large population-based cohort study indicates that hearing loss is associated with increased risk of receiving disability pension and weakly associated with an increased risk of sick leave.Hearing loss is regarded as one of the most prevalent disabilities  and a grImportant risk factors for hearing loss include increasing age, genetic factors, ear disease and noise exposure . TinnituA systematic review conducted in Sweden assessed 18 different studies concerning hearing difficulties, ear-related diagnoses and sickness absence or disability. The authors specify that their most striking finding was the low number of published studies about sick leave or disability pension due to hearing difficulties/diagnoses, considering the high prevalence of such hearing difficulties. They conclude that remarkably few studies were identified and that the results presented in them could not provide evidence for direction or magnitude of potential associations [The present study aims to assess the association between hearing loss and sick leave or disability pension in a large long-term follow-up population study. We also aim to assess whether the associations are influenced by various factors, such as tinnitus, age, sex, or occupational class.The Trøndelag Health Study (The HUNT Study) is a longitudinal population health study that was conducted in the Norwegian county Trøndelag. Data from questionnaires, clinical measurements, and samples are included in the study, and lay a strong platform for population health studies. HUNT is regarded as one of the most comprehensive cohort studies that has been conducted, its data and samples were gathered from four separate waves  spanning the years 1984 to 2019.Audiometric investigations were performed in HUNT2 (1996–1998) and in HUNT4 (2017–2019). For the present study, the HUNT2 sample was used for follow-up analyses. Participants in the HUNT2 Hearing study came from 17 of the county’s 24 municipalities. The participation rate was 63%, and altogether 50 560 persons attended [N = 25 118), non-employed persons at baseline (N = 3293), persons with missing audiometric data (N = 98) and persons with missing questionnaires (N = 297). Non-employed persons at baseline were excluded to ensure that all participants were in work and at risk for sick leave or disability pension at the starting point of the follow-up period. The final sample included 21 754 subjects.From the total HUNT population of 50 560 persons, we excluded persons in the following order: persons not in the age-range 20–49 years  were measured in accordance with ISO 8253–1 , with fiWe constructed a dichotomous variable to compare participants with hearing loss and tinnitus (exposed) to normal hearing and no tinnitus as reference category. For the construction of this variable, we used the following question from the HUNT2 questionnaire: «Have you experienced ringing in your ears/tinnitus during the last 12 months?». Participants with missing values were excluded from this particular analysis.We obtained yearly data on physician-certified sick leave (episodes of more than 16 days) and disability pension from 1996 to 2016 from Statistics Norway. Based on the personal identification number given to all Norwegian citizens, data from Statistics Norway were linked on an individual level with the data from the HUNT survey. Identification numbers were removed before the researchers were given access to the matched data material. We linked the HUNT data with individual records covering sick leave episodes between 1998 and 2016.In all analyses, we adjusted for age and gender.Data from Statistics Norway on education was used to construct this variable. Educational level was divided into 4 groups: primary education, secondary education, university < 4 years, university ≥ 4 years.N = 13). We Adjusted for education in all analyses.A dichotomous variable was created by combining primary school and secondary school to give the group “lower education” and university < 4 years with university ≥ 4 years to give the group “higher education” . This diN = 6495).Occupational codes from Statistics Norway were available from 1990 and 1980. We used NYK codes , based on the International Standard Classification of Occupations, ISCO-58 . At the We used STATA version 17.0. Statistical tests were calculated at a 95% confidence interval.We assessed the association between hearing loss in 1996–1998 and time to first physician-certified sick leave episode (1996–2011) by using Cox Proportional Hazards Regression. We chose to end the follow-up period at the year 2011 because a Norwegian pension reform was introduced that year. It allowed people over 62 years of age to combine work and retirement, which would have made the time period before and after 2011 non-comparable in terms of the censoring at time of retirement. We analysed time in calendar days to incident sick leave during the follow-up period, starting at the date of the hearing test in 1996–1998 (baseline), ending at the end of 2011.We used data from Statistics Norway (SSB) on employment status to construct categories for censoring. The SSB data on employment status were categorized in 5 groups: wage earner, self-employed, unemployed, outside of workforce  or in labour market programs. Labour market programs are part of the Norwegian social welfare system aiming to improve chances of finding employment, offering job-finding measures, work experience and job training.Participants were censored at year of leaving employment , at date of death or at the end of the follow-up period with a mean follow-up time of 6.7 years and a maximum of 15.0 years. This summed up to a total follow-up time of 145 723 person-years.We assessed the association between hearing loss in 1996–1998 and time to first pay out of disability pension (1996–2011) using the same method as for sick leave. Participants were censored at year of retirement from work, at year of death or at the end of the follow-up period with a mean follow-up time of 14.1 years and a maximum of 15 years and a total follow-up time of 304 000 person-years.Finally, we performed subgroup analyses investigating the risk of physician-certified sick leave and the risk of receiving disability pension when the exposed group was defined as persons with both hearing loss and tinnitus.For the above analyses, we adjusted for age (using a continuous age variable), sex, and education. We chose not to adjust for cardiovascular risk factors or smoking, because although many cardiovascular risk factors are associated with hearing loss, the effects have been shown to be small . We alsoThe final sample included 21 754 persons . The participants with any hearing loss were older than those with normal hearing (mean age 41.6 years vs. 36.5 years), and the proportion of males was higher (62.9% vs. 48.2%)  had at least one episode of sick leave during the follow-up period (81–89%), whereas for men the proportion varied between 63–74% Table . The groThe group with the lowest proportion of people receiving disability pension during follow up was young adults with normal hearing (2.7%), followed by young adults with mild hearing loss (6.5%) and men with normal hearing (6.9%) Table . The groThere was a weak association between any hearing loss in 1996–1998 and time to first sick leave episode for the total sample Table . StratifHearing loss in 1996–1998 was associated with getting a disability pension during the follow-up period Table , statistp = 0.003) and hearing loss (continuously scored)*education (p = 0.001).In other words, the association between hearing loss and disability pension was modified by age group (stronger association among younger than older adults) and by education (stronger association among lower educated than higher educated persons).There were two statistically significant interaction terms: hearing loss (continuously scored)*age  and time to first physician-certified sick leave episode. A systematic review concluded that remarkably few studies on this topic were identified and pointed out a lack of follow-up studies . To our Our study showed that subgroup analysis including people who had both hearing loss and tinnitus, showed a somewhat increased risk of sick leave. A paper by Holgers et al. aimed to investigate risk factors for incapacitating tinnitus by measuring absence from work relating to tinnitus . The stuWe found a higher risk for receiving disability pension in the group with hearing loss, particularly for persons with disabling hearing loss. Helvik et al. investigated hearing loss and the risk of disability pension in Norway in 2013 . Helvik From our findings, we saw that there was a stronger association between hearing loss and receiving disability pension than there was between hearing loss and physician-certified sick leave during the follow-up period. Speculating on the causes of this disparity, it could be due to the relative commonness of sick leave compared to disability pension. Having an episode of sickness absence from work is relatively common, whereas receiving disability pension less so. Most people on sick leave do not receive a disability pension later in life. Gustafsson et al. assessed the risk of future disability pension among people with sick leave due to otoaudiologcal diagnoses (OAD) compared to other sickness absentees and found more than 40% higher risk among those on sick leave due to OAD . AlthougWe found that younger adults and people with low education were at increased risk of disability pension. The finding of a greater effect of hearing loss among young adults corresponds with the findings of another study evaluating hearing loss and mental health , which sWe can only speculate about the underlying cause of our findings. Impaired hearing affects communication and psychosocial functioning . A recenOur findings indicate that effort should be made to implement preventive measures for hearing impaired in the workplace. A greater emphasis has been placed on adapting workplaces to accommodate for hearing impairment. Moreover, there has been an increase in the education level of people with hearing impairment in recent times . AdditioStrengths of the present study includes the large number of participants, the long follow-up period, register-based dates of sick leave and disability, standardized audiometric measurements, and the representative population sample from Trøndelag County, which has been shown to be representative of Norway .It is well known that some subgroups, such as low socioeconomic groups and those in poor physical condition, have lower participation rates in health surveys . This maThis large population-based cohort study indicates that hearing loss is weakly associated with later physician-certified sick leave and with receiving disability pension. These associations were stronger for participants with both hearing loss and tinnitus. For disability pension, women, younger adults, and low educated workers seem to be more vulnerable.


To investigate the sensitivity and specificity of 5 questions of the SSQ in Brazilian Portuguese for its application as a hearing screening instrument in adults.A total of 135 adults with a mean age of 49.6 years and education of 9 years took part in the study. All subjects underwent hearing tests and were divided into 2 groups according to hearing acuity: G1 – 66 individuals with normal hearing on audiometric test: and G2 – 69 participants with impaired hearing on audiometric evaluation in one or both ears. The 5 items of the SSQ5, derived from the Brazilian Portuguese version of the SSQ49 were applied. The level of significance was set at a p-value ≤ 0.05, with a 95% confidence interval.G1 subjects were younger and higher educated (p<0.01). A weak positive correlation was found between education and SSQ5 score only in G1. In G2, there was no correlation of age or education with SSQ5 performance. The area under the ROC curve (AUC) for the relationship between SSQ5 and audiometric average was 0.854 and p-value was <0.001 with bounds of 0.79 and 0.91. SSQ5 scores were lower in G2 (p<0.001). The cut-off point with optimal balance between sensitivity and specificity was 7.3, yielding 80% accuracy, 81.8% sensitivity and 78.3% specificity.The Brazilian Portuguese version of the SSQ5 proved suitable for screening hearing loss in adults, offering good accuracy, sensitivity and specificity for detecting hearing loss. According to the World Health Organization (2018), handicapping hearing loss affects 432 million adults, one third of whom are over 65 years of age. These estimates are set to rise to 630 million by 2030 and 933 million by 2050. In addition, an estimated 1.1 billion young individuals aged 12-35 years run the risk of hearing loss due to exposure to noise levels in recreational environments., hearing loss stems from problems in function or structures of the auditory system, causing impaired performance of hearing functions, such as: detecting sounds, monitoring the environment, perceiving distance and direction of sounds, locating sound sources and recognizing speech. Any difficulty the individual has performing these tasks characterizes handicap in activities. Disabilities in hearing tasks can handicap the individual in everyday situations, given that these compromise social interaction, relationships, occupational activities, leisure, learning and creativity.According to the International Classification of Functioning, Disability and Health – ICF. Traditionally, hearing loss is measured by pure-tone threshold audiometry, considered the gold standard for audiologic diagnosis. However, such testing requires a service with the physical infrastructure, equipment and human resources needed for treatment in the case of risk of or suspected hearing impairment.Early detection of hearing loss by a hearing healthcare professional can promote effective interventions. The resources used for hearing rehabilitation reduce communication difficulties by improving hearing performance, thereby allowing greater inclusion and integration of hearing-impaired individuals into society-5. A variety of different self-assessment instruments have been developed for measuring hearing disabilities, handicap and for documenting self-reported difficulties caused by hearing loss-17.The ideal strategy for evaluating functional hearing of adults is using a combination of tools, such as questionnaires and audiometric tests which measures the capacity to listen to speech; localization of sound events for different directions, distances and movement, the listening experience in relation to segregating sounds, identification/recognition, the naturalness and clarity of sounds; musical perception and situations requiring listening effort.For this purpose, a promising scale is the Speech, Spatial and Qualities of Hearing Scale - SSQ. Consequently, abbreviated versions have been devised with improved clinical applicability and more rapid assessment.The scale is lengthy and time-consuming to administer, containing 49 items, some of which often go unanswered,17,20-23.A number of different studies have shown a strong correlation of the original 49-item scale with different versions in other languages, and also with other short forms. As a follow-up, the same authors carried out a pilot study of a shorter 12-item version (SSQ12) confirming similar mean scores for both the SSQ49 and SSQ12.The SSQ49 was translated and adapted to Brazilian Portuguese by Gonsalez and Almeida led to the development of a short SSQ5 version containing only 5 questions to predict the presence or absence of hearing loss in settings where behavioral measurements cannot be carried out. The authors stressed the importance of using measures of disability and handicap to complement measures quantifying hearing loss, such as pure-tone threshold audiometry.A study conducted in 2012The use of a 5-item scale measuring disability is deemed useful as an instrument for screening hearing loss in adults. However, any scale developed for hearing screening, besides being rapid to apply, should be an accurate method of detecting the presence of impairment, when this indeed exists (sensitivity), while excluding cases without impairment (specificity).Thus, the purpose of the present study was to investigate the sensitivity and specificity of 5 questions of the short version of the Speech, Spatial and Qualities of Hearing Scale (SSQ5) in Brazilian Portuguese as an instrument for screening hearing in adults.An exploratory prospective, clinical quantitative study, approved by the Research Ethics Committee of the institution under permit no. 1817374, was conducted. All individuals involved signed the Free and Informed Consent Form. The study involved individuals referred for audiometric testing at a Speech-Language Therapy Clinic.A total of 135 individuals took part in the present study, selected based on the following eligibility criteria: adults aged >18 years; literate in Portuguese; adequate hearing to understand during interview; and exhibit no apparent cognitive or intellectual deficit.. Thus, Group 1 (G1) comprised individuals with normal audiometric results (Average 500 1K 2K 4K Hz≤ 25dBNA) in both ears and Group 2 (G2) with impaired audiometric results (Average 500 1K 2K 4K Hz> 25dBNA) in one or both ears.Participants were divided into two different groups according to the WHO hearing acuity classificationG1 included 66 participants, comprising 30 females and 27 males, with mean age 43.27 (SD 13.22) years, mean education 11.38 (SD 3.61) years, and audiometric average of 8.9 dBNA in the right ear (SD 6.61) and 9.5dBNA in the left ear (SD 7.31). G2 included 69 participants, comprising 51 females and 18 males, with mean age 55.70 (SD 15.66) years, mean education 8.43 (SD 8.43) years, and audiometry average 42.3dBNA in the right ear (SD 26.16) and 45.3dBNA in the left ear (SD 23.90)., derived from the Portuguese version of the SSQ49 translated by Gonsalez and Almeida, were applied (Annex 1). The scale included items involving the 3 core domains: speech-hearing, spatial hearing, and qualities of hearing.All participants were submitted to pure-tone threshold audiometry in a sound-proofed booth using a TDH39 headset. Auditory levels (dBNA) were measured and recorded by air conduction in the 250-8000 Hz frequency range and by bone conduction in the 500-4000 Hz frequency range. The five questions comprising the SSQ5The questions derived from the SSQ49 making up the SSQ5, along with the domains and pragmatic subscales of each question, are shown in The questionnaire was administered orally in the form of an interview and each response option was rated on a visual analog scale from 0 to 10 points. All subjects marked the condition and situation addressed in each item with a rating, where “0” indicated the individual was unable to perform the hearing function in question , whereas “10” indicated ability to perform the activity perfectly (no limitation in activity). In addition, there was an option “not applicable” for cases where the questions did not represent an everyday situation for the interviewee.Analysis was carried out based on mean total score, which was calculated by summing each item score and dividing by the total number of questions (five). Questions with “not applicable” circled were not included in the calculation of mean total score on the SSQ5. and the mean total score on the SSQ5 (SSQ5T).The level of significance adopted was set at a p-value = 0.005 (5%). Confidence intervals were calculated with a 95% confidence interval. The ANOVA test was applied to determine the SSQ5 scores of G1 and G2. The Receiver Operating Characteristic (ROC) curve was employed to determine the optimal cut-off point on the SSQ and identify individuals from each group showing sensitivity (“patients” – positive on the screening test) and specificity (“non-patients” – negative on the screening test). Pearson's correlation was adopted to measure the degree of correlation between age, education and mean total score on the SSQ5 (SSQ5T) in each group. The Equality of Two Proportions test was adopted to calculate the measures for the relationship between the audiometric four-tone averageDescriptive statistics for age and education of the sample of GI and G2 , are given in Individuals in the normal hearing audiometry group (G1) were younger and higher-educated than subjects in the hearing-impaired audiometry group (G2). Given the groups differed for age and education , correlaThe results of this analysis revealed a weak positive correlation between education and mean score on the SSQ5 only in G1, i.e. among the normal-hearing individuals. This relationship indicated that the higher the educational level, the greater the score on the SSQ5. By contrast, there was no correlation of age or education with SSQ5 performance among the hearing-impaired individuals (G2).The mean score for each of the five questions and mean total score on the SSQ5 (SSQ5T) for G1 and G2 are given in 500 1K 2K 4K Hz) for all possible cut-off points between 0 and 1. The vertical axis of the ROC curve denotes sensitivity, whereas the horizontal axis represents specificity (The ROC curve was plotted for the relationship between mean score on the SSQ5 and audiometric four-tone classification (Average cificity .500 1K 2K 4K Hz) was 0.854 with p-value <0.001, lower bound of 0.791 and upper bound of 0.917.Note that the line obtained (blue) is located toward the top left of the graph and distal relative to the diagonal line (green), indicating a significant AUC value. The AUC for the relationship between mean total SSQ5 and audiometric four-tone classification  and Negative Predictive Value (NPV) .Comparing the two measurements of tone threshold audiometry and SSG5 score, a positive result on the SSQ5 screening test (< 7.3) was associated with a 78.8% likelihood of hearing loss on audiometry (PPV). Conversely, a negative result on the SSQ% screening assessment (>7.3) correlated with an 81.8% likelihood of normal hearing on audiometry (NPV).The need for performing hearing tests in the pediatric population is clear, given the impacts of hearing loss, particularly in the development of speech and oral language. However, the same does not seem to hold for the adult population.https://educa.ibge.gov.br/jovens/conheca-o-brasil/populacao/18318-piramide-etaria.html. Damage and loss of cilia cells of the inner ear due to aging, exposure to occupational or leisure-related noise, use of ototoxic drugs, chemical products present in the environment and genetic diseases are factors contributing to an increase in the prevalence of hearing loss among the adult population.In Brazil, 57.1% of the population is aged over 30, while the proportion of individuals aged 65 years or older represents 10.5% of the population  Listeners use there auditory system to carry out everyday activities such as listening, hearing, understanding and communicating. Whenever there is a hearing deficit that affects understanding and communications, this negatively impacts the functioning of the individual in dimensions of activities and involvement in activities of daily living.Therefore, early detection of hearing loss in adulthood is fundamental to avoid the communication and psychosocial losses caused by impaired hearing that impact quality of life. This scenario justifies hearing screening in adults.Traditionally, hearing tests are done using calibrated equipment which requires sound-proofed testing booths.,27. Other notable aspects inherent to the application of these tests include the fact that they dispense with the need for a room with an acoustically controlled environment or specialized equipment and personnel, since these tests do not require the conditions needed for performing audiometry.However, self-administered scales serve as a good marker of hearing loss in adults, besides providing a more accurate guide for the individual on the need for further diagnostic assessmentThe SSQ5 scale yields information on real-life hearing abilities and predicts the presence or absence of hearing loss based on disabilities and handicap in activities of daily living.In the present study, normal-hearing individuals on audiometry were younger and had higher educational level than hearing-impaired participants . HoweverLiterature findings for the SSQ consistent with the normative reference of the present study were compiled to categorize individuals as having clinically-normal or impaired hearing on audiometry.,22,24,28. The SSQ5 used in the present study yielded an average SSQ score of 8.3 points for the normal-hearing participants and 5.4 in the hearing-impaired group. A significant difference between the groups was found for total score on the SSQ5 and for each item  and for the generic question: “Do you have a hearing loss?” (AUC 0.56).The ROC curve was used to establish the sensitivity, specificity and cut-off point of the SSQ5  and the ,4.Self-reporting scales assessing disabilities and handicap for activities have been applied as hearing screening instruments in adults and shown higher sensitivity and specificity values than for informal interviews, as in the present study,8,9,11, whereas cut-offs established for the scale in the present study were 81.8% sensitivity and 78.3% specificity.In the literature, specificity and sensitivity percentages for audiological diagnosis for other self-administered scales are available. There is disagreement among some authors on choice of ideal cut-off point in terms of level of sensitivity and specificity. Some authors favor sensitivity for detecting possible hearing impairments, while others prefer specificity for selecting possible cases of normal hearing. Values reported in the literature for the HHIE-S, a scale widely used for screening hearing of older adults, range from 23.5% to 100% for sensitivity and 50% to 95% for specificity, whereas subjects scoring <7.3 points may have unilateral or bilateral hearing loss  and SSQ5 cut-off point, a positive result on SSQ5 screening (< 7.3) correlated with a 78.18% likelihood of hearing loss on audiometry testing (PPV). Conversely, testing negative on SSQ5 screening (>7.3) was associated with an 81.8% likelihood of normal hearing on audiometry evaluation (NPV).In the current study, application of the 5 questions from the SSQ took 3 minutes on average. As expected, the scale containing fewer items had a much shorter test completion time, favoring its application as a hearing screening instrument.The Brazilian Portuguese version of the reduced 5-item SSQ scale provided rapid assessment with straight forward questions and good specificity and sensitivity for detecting hearing loss. These results suggest its potential for use in hearing screening, both in primary care and epidemiological research settings. This Brazilian Portuguese questionnaire has utility for identifying hearing difficulties and providing more effective referral of adults for diagnostic evaluation.Further studies of the reduced SSQ5 version, involving larger samples and different settings, should be conducted to elucidate the influence of hearing and non-hearing related variables on scale responses.The Speech, Spatial and Qualities of Hearing Scale in Brazilian Portuguese, version of the reduced 5-item (SSQ5), proved a suitable instrument for screening hearing, providing good accuracy, sensitivity and specificity for detecting hearing loss in adults.


Diabetes and immunosuppressive diseases have been reported as increased risk factors for developing invasive pulmonary tuberculosis and mucormycosis.Mycobacterium tuberculosis was confirmed through molecular diagnosis using a real-time polymerase chain reaction assay. The nasal cavity biopsy revealed the fungal elements (aseptate hyphae) and confirmed mucormycosis infection. Amphotericin B liposomal, teicoplanin, and tazobactam were administered to treat the mucormycosis. The patient was successfully treated with a recommended four-drug regimen for TB without any adverse reaction. We presented here a case of a 55-year-old uncontrolled diabetic male with rhinosinus mucormycosis and pulmonary TB coinfection. Maxillary and ethmoid sinus involvement wasobserved in paranasal computed tomography. His chest computed tomography showed tree in the bud sign and cavitary lesions in the lungs.  The clinicians must consider tuberculosis and mucormycosis tests when confronted with an uncontrolled diabetic patient with clinical symptoms of hemoptysis, fever, and cavitary lesions Mucormycosis is an emerging opportunistic fungus causing the development of invasive infection, especially in immunocom-promised individuals and those with uncontrolled diabetes  , 2. MuAbout half of mucormycosis infections occur in patients with uncontrolled diabetes due to tooth removal, or ophthalmic surgeries  . InhalaIn April 2019, a 55- year-old man with uncontrolled diabetes was referred to Masih Daneshvari Hospital, Tehran, Iran, with complaints of fever, weakness, productive cough, and occasional hemoptysis for three months. He was addicted to cannabis for 20 years and had experienced localized one-side facial pain and swelling seven days after dental extraction.  In this recumbent patient, the Glasgow coma scale was determined as 15 without focal neurologic shortage or meningeal signs, dehydrated skin and mucosal membrane, and awareness of his environment. His medical history showed that he had uncontrolled diabetes for many years with fasting blood sugar level, weight, and height of 273 mg/dL, 70 kg, and 170 cm, respectively. His chest examination and chest x-ray were normal . Precordial auscultation showed normal heart sounds, and abdominal exploration was normal as well. The chest CT imaging showed ground‑glass opacities in the right lower lung in both lungs Vital signs and the laboratory results at the time of admission are presented in The early antibiotic regimen included liposomal amphotericin B, piperacillin, tazobactam, and teicoplanin. Due to the high likelihood of mucormycosis rhinosinusitis, nasal sinus endoscopy was performed with a positive result. Considering the high probability of pulmonary tuberculosis, a direct smear was prepared from sputum and induced sputum samples. bacillus was detected from three frequency sputum specimens . In brief, the specimen was cultured in a Lowenstein-Jensen medium, and DNA was extracted using the QIAamp DNA Mini Kit . A quantitative RT-PCR assay was conducted using a Rotor-Gene 6000 RT-PCR cycler  and PCR kit qPCR master mix . Acid-fast pecimens  and the In the second week of hospitalization, angioembolisation was performed and the histopathological report of functional endoscopic sinus surgery from the nasal cavity revealed respiratory-type mucosa with necroinflammation and the presence of fragmented and thick hyaline fungal hyphae, compatible with Mucorales Mucoral species .In addition, a biopsy of the nasal cavity ( prepared in KOH wet mount) confirmed mucormycosis by the presence of fungal elements (aseptate hyphae) . A final diagnosis of mucormycosis and tuberculosis coinfection was made. The treatment was initiated with the administration of rifampicin 600 mg PO q24 h, isoniazid 300 mg PO q24 h, pyrazinamide 1500 mg PO q24 h, and ethambutol 1200 mg PO q24 h, followed by liposomal administration of Amphotericin B (5 mg/kg/d for 3 weeks). His rhinosinus mucormycosis was treated with a total dose of 6.5 g tazobactam 4.5g q 8 h teicoplanin 400mg q1 2 h for three doses and then 400 mg daily. Paranasal sinus endoscopy was performed. Ophthalmology consultation was also performed several times. The patient was discharged 30 days after admission due to clinical improvement. Directly observed therapy was continued and oral posaconazole (400 mg bid) was administered as an antifungal. No histopathological findings of sinus mucormycosis were reported in the last surgical endoscopic piece biopsy report.Opportunistic infections are common forms of infections in patients with uncontrolled diabetes  . ConcomCoinfection of mucormycosis and TB was successfully treated in our non- ketoacidosis diabetic case. The patient responded well to the treatments for TB and rhinosinus mucormycosis. Other studies showed that the poor outcome of this coinfection may be the consequence of a late diagnosis. Diabetes leads to immune dysfunction and flare-up of mucormycosis coinfection with latent TB which may progress to active TB and fulminant outcome. Clinical manifestations include fever, consolidation, or nodules  , 11 . Previous studies reported only nine concomitant mucormycosis and TB in England, Japan, and India  , 13. TIn Asian people, poor glycemic control (as indicated by HbA1c level) represents a potentially important risk factor for active TB  . DiabetThe high mortality of TB coinfection and opportunistic fungal pathogens, such as mucormycosis, necessitates a high degree of clinical suspicion, definitive diagnosis, and early aggressive treatment  .M. tuberculosis mycobacterial ribosomal RNA was observed as well using RT-PCR. Moreover, fragmented thick hyaline fungal hyphae confirmed mucormycosis on culture. Therefore, mucormycosis and TB were successfully treated.The chest X-ray and the thorax CT of our case suggested TB, a smear of sputum that indicated the presence of acid-fast bacillus (AFB). It should be noted that the poor outcome of other similar studies may be the consequence of a late diagnosis due to the focus on treating diabetic ketoacidosis  . The reAlthough identification of the fungi to the species level is essential for further proper treatment, the lack of specific- species identification of the recovered isolate from the patient posed a limitation to this study.Mycobacterium tuberculosis and rhinosinus mucormycosis coinfection in a patient with uncontrolled diabetes. The clinicians must consider tuberculosis and mucormycosis tests when confronted with an uncontrolled diabetic patient with clinical symptoms of hemoptysis, fever, and cavitary lesions.This potentially fatal opportunistic fungal infection remains a poorly understood disease. The case presented here was associated with We would like to thank the staff of Masih Daneshvari Hospital for their special co-operation in this study.SH. SH. and T. P. contributed to the experimental studies, diagnosis, and treatment of the case, T. P., A.G, and SH. SH. contributed to discussion, implications, analysis of the data, and preparation of the manuscript. All authors read and approved the final manuscript. The authors declared that they have no competing interests.None.This case report was approved by the human research ethics committee of Shahid Beheshti University of Medical Sciences, Tehran, Iran (IR.SBMU.REC 1398.809).