GJB2 mutations could be predicted by distinguishing between truncating and non-truncating mutations and whether the genotype could predict the hearing loss level. Additionally, we examined the progression of hearing loss in individuals monitored for over 2 years for an average of 6.9 years. The proportion of truncating mutations was higher in patients with profound and severe hearing loss, but it was not accurate enough to predict the degree of hearing loss. Via genotype analysis, mutations of the p.Arg143Trp variants were associated with profound hearing loss, while mutations of the p.Leu79Cysfs*3 allele exhibited a wide range of hearing loss, suggesting that specific genotypes can predict the hearing loss level. Notably, there were only three cases of progression in four ears, all of which involved the p.Leu79Cysfs*3 mutation. Over the long-term follow-up, 4000 Hz was significant, and there was a trend of progression at 250 Hz, suggesting that close monitoring at these frequencies during follow-up may be crucial to confirm progression. The progression of hearing loss was observed in moderate or severe hearing loss cases at the time of the initial diagnosis, emphasizing that children with this level of hearing loss need regular follow-ups.We aimed to investigate whether the degree of hearing loss with  Congenital hearing loss is estimated to occur in 1 in 500–1000 births, with genetic factors contributing to over 50% of cases [Approximately 70% of all hereditary hearing loss cases are of an autosomal recessive type . AutosomThe age at which the indication for cochlear implantation is recommended has decreased in recent years, and earlier interventions have been shown to be more effective ,4. BecauA change in genetic information occurs when a mutation occurs in the translation region, which is replaced with an amino acid sequence read by the RNA. This change is highly dependent on the site within the translational region, leading to two categories of mutations: truncating mutations for nonsense mutations, such as deletions, insertions, duplications, and changes in the termination codon, and non-truncating mutations for missense mutations, such as amino acid substitutions.Non-truncating mutations may produce a protein product with partial functional activity. For example, a missense mutation alters different amino acids and changes the structure of the protein, though this impact is insignificant. Since a codon encodes one amino acid in units of three bases, inserting or deleting one or more amino acids in multiples of three may result in a minimal amino acid change in protein structure but not in a significant change in function.Conversely, regarding truncating mutations, a nonsense mutation results in the termination of protein synthesis. In cases of non-3 multiple base insertions or deletions, the reading frame of the codon is shifted, and a frameshift occurs, leading to significant changes in the amino acid sequence. Most turn into stop codons after several amino acid arrangements and protein synthesis stops. In this case, major changes occur in the protein structure, resulting in a complete loss of activity or the absence of the protein itself. The degree of hearing loss depends on the degree of protein degeneration caused by the mutation and varies from mild to severe . In geneGJB2 accounts for approximately half of all autosomal recessive forms of hearing loss and is the most common form of hereditary hearing loss. The carrier frequency is notably high, ranging from 2.53% to 3.73% in East Asia [GJB2 mutations per 10,000 people. The severity of hearing loss due to GJB2 mutations varies from mild to profound [Hearing loss caused by mutations in ast Asia ,16. Consprofound .GJB2 encodes connexin 26 [GJB2 gene result in impaired ion cycling, leading to loss due to difficulty in maintaining inner ear homeostasis.Gap junctions are cell–cell communication pathways formed by a ring of membrane protein hexamers called connexins, which surround channels in the membrane and are found in all tissue cells, except skeletal muscle. nexin 26 , which inexin 26 . In the nexin 26  and servnexin 26  and homeGJB2 mutations have been reported globally (https://research.cchmc.org/LOVD2/home.php (accessed on 1 August 2023)). There are racial differences in the mutation spectrum: the p.Gly12fs mutation is common in Europeans and Americans [GJB2 mutations also have variations from mild to profound hearing loss. It has been speculated that the genotype of the various genetic mutations, which vary in frequency between races, determines the degree of hearing loss [Over 150 mericans , p.Leu56mericans . In the mericans ,25. Peoping loss ; howevering loss , and colGJB2 mutations are associated with bilateral sensorineural non-syndromic hearing loss from birth, presumed to be non-progressive [GJB2 mutations. Scattered reports suggest late onset [Traditionally, gressive . Recent gressive , revealite onset ,29, and te onset . HoweverGJB2 by distinguishing between truncating and non-truncating mutations. Additionally, we sought to establish whether the relationship between genotype and hearing loss could be predicted based on comprehensive data. Furthermore, we aimed to report the long-term hearing course with GJB2 mutations with residual hearing and investigated the detailed background of the population with progressive hearing loss among patients with GJB2 mutations.We, therefore, aimed to investigate whether the degree of hearing loss could be predicted by The mean age of the 75 patients at their first visit was 2.8 years old. The clinical follow-up ranged from 2 to 24 years, with an average of 6.9 years. Forty-four patients (fifty-two ears) underwent cochlear implant surgery during the follow-up period. After cochlear implantation, the follow-up hearing assessment of the implanted ear ended.GJB2 mutations are shown in A total of 150 allele types and the hearing level of the better ear for each allele type obtained from 75 patients diagnosed with hearing loss due to p < 0.05) in the proportion of truncating and non-truncating mutations between the profound and the mild hearing loss groups. Genotype combinations also showed a higher proportion of biallelic truncating (T/T) in profound and severe hearing loss  and a higher proportion of biallelic non-truncating (NT/NT) in mild hearing loss (1/3 = 33%) and moderate hearing loss (2/12 = 17%) than in profound hearing loss (2/49 = 4%) (49 = 4%) .The degree of hearing loss in the better-hearing ear at the first visit was predominantly profound: 102 alleles (68.0%) in 51 patients with profound hearing loss, 14 alleles (9.3%) in 7 cases with severe hearing loss, 26 alleles (17.3%) in 13 patients with moderate hearing loss, and 8 alleles (5.3%) in 4 patients with mild hearing loss. When looking at the levels of hearing with a focus on each type of allele, the subjects with the p.Leu79Cysfs*3 allele had a wide range of hearing loss from profound to moderate; the subjects with the p.Arg143Trp allele had profound hearing loss, while those with the p.Val37Ile allele had moderate or mild hearing loss.The final mean age of the 46 patients enrolled in the long-term hearing follow-up was 10.5 years old, and the mean follow-up was 6.5 years, ranging from 2 to 18 years. The average age at the initial audiometry was 5.0 years old. Among the cases, three had mild hearing loss, nine had moderate, seven had severe, and twenty-nine had profound. Hearing loss progression ranged from a maximum of 7.1 dB/year for those with worsening hearing loss to −8.2 dB/year for those with conversely improving hearing loss, resulting in a wide range of results. The overall average showed a minor worsening of −0.3 dB/year. The initial mean threshold was 86.4 dB, and the last mean threshold was 86.1dB, with no significant difference.Individually, three cases exhibited thresholds that progressed by more than 10 dB from the initial hearing evaluation to the final follow-up in four ears . The changes in hearing thresholds for these four ears are shown in p < 0.01). GJB2 mutations based on genotype. Truncating mutations showed a strong tendency to result in profound or severe hearing loss, whereas non-truncating mutations were more likely to result in mild hearing loss. Notably, the truncating mutation p.Leu79Cysfs*3 displayed a wide range in the degree of hearing loss, while the presence of the non-truncating mutation p.Arg143Trp allele was associated with profound or severe hearing loss. These findings highlight that the degree of hearing loss cannot be solely explained by the classification of mutations into truncating or non-truncating mutations. Progression of hearing loss was observed in 4 ears in 3 cases out of 46, and when examined by frequency, the overall average did not change; however, at 4000 Hz, hearing loss was significantly worsened compared with during the follow-up period. Individually, 25% of the cases showed deterioration at 250 Hz.We investigated the degree of hearing loss and the long-term progression of hearing loss in patients with GJB2 mutations. Nonsense mutations, including frameshifts, deletions, insertions, duplications, and mutations of the splicing site, are classified as truncating mutations, while mutations such as amino acid substitutions and in-frame deletions are classified as non-truncating mutations. The degree of hearing loss decreases in the order of homozygotes for truncating mutations (T/T), compound heterozygotes for truncation/non-truncating mutations (T/N), and homozygotes for non-truncating mutations (N/N) [Protein conformational changes associated with genetic mutations are considered influential factors that determine the degree of hearing loss with ns (N/N) ,14. In tns (N/N) ,14. In tns (N/N) . Howeverns (N/N)  have shoOne of the reasons for the higher percentage of non-truncating mutations in profound hearing loss is attributed to the impact of non-truncating mutations, specifically the p.Arg143Trp variants, which cause profound hearing loss. Functional studies have shown that p.Arg143Trp variants exert dominant-negative inhibition of connexin hemichannel activity . The mutGJB2 gene mutation in Asia [Hearing loss associated with p.Val37Ile is generally characterized as mild–moderate ,26,33. O in Asia ,24,25, h in Asia ,35. Simi in Asia . Notably in Asia , and gen in Asia .GJB2 mutations was 68%. To date, this is one of the highest reported incidence rates. The percentage of patients with profound hearing loss among those with GJB2 mutations varies across reporting centers, with rates of 60.8% in those undergoing cochlear implant surgery [In our study, the percentage of patients with profound hearing loss and  surgery  and 28.8 surgery , showingGJB2 mutations is considered non-progressive [GJB2-mutation-related hearing loss pass newborn hearing screening tests [GJB2 has been reported to cause progression at a rate of 1.409 dB/year [GJB2 mutations suggests that progression can be estimated using the formula: 3.78 + 0.96 × initial hearing level + 0.55 × years of follow-up [Hearing loss caused by gressive . Howeverng tests , suggestng tests . A trunc dB/year . In addiGJB2 gene mutations. A more detailed evaluation of the progression of hearing loss by frequency revealed that there was a significant threshold shift at 4000 Hz during the follow-up period. When we examined each case across all frequencies, there was a constant improvement in the thresholds in some of the cases, alongside instances of unchanged and worsening hearing loss. The observed improvement in thresholds was attributed to improvement in test accuracy with age, indicating challenges in hearing assessments for young children [GJB2 mutations exhibit an increase in the threshold, especially at 250 Hz. Therefore, close monitoring at these frequencies during follow-up may be crucial for confirming progression. A report examining eight cases also demonstrated a gradual progression of hearing loss at middle–high and low frequencies, which is consistent with the present study findings and previous reports [In this study, there was no discernible overall trend in the progression of hearing loss, indicated by an annualized rate of −0.3 dB/year. However, individual case analyses revealed that in three cases with four ears, hearing loss progressed by 10 dB or more until the last observation, suggesting the presence of progressive sensorineural hearing loss caused by children . Several reports .In our study, deterioration was observed in cases with the p.Leu79Cysfs*3 mutation, and no progression was observed in patients with the p.Val37Ile mutation. In contrast, Lee et al.  suggesteOne notable limitation of this study is the insufficient total number of cases for robust statistical analysis. Although the frequency-by-frequency evaluation showed that there were a few cases with threshold elevation at 250 Hz, the number was too small to be meaningful. Although we have highlighted that the p.Arg143Trp mutation is indicative of severe hearing loss, the relationships between other genotypes and hearing levels cannot be adequately described from this study alone because of the limited sample size for each genotype. Similarly, the observed trend toward progressive hearing loss due to p.Leu79Cysfs*3 cannot be fully supported by this study alone. However, we anticipate that the emerging results of analogous studies in the future will contribute to a clearer understanding of the relationship between genotype and the degree of hearing loss, as well as the risk of hearing loss progression. In this context, we believe it is worthwhile to report the results of this study. Another limitation lies in the relatively short observation period for some cases. Although the average follow-up period of 6.9 years is considered relatively long compared with other reports, a subset of cases was tracked for only approximately 2 years. We believe that the progression of hearing loss needs to be evaluated over a longer period, and it is imperative to continue monitoring these cases over an extended timeframe to thoroughly analyze their long-term prognosis. Additionally, we decided to exclude the data of ABR and ASSR in favor of relying solely on behavioral audiometry data because the evaluation of accurate hearing levels with ABR and ASSR remains controversial. This decision introduces another limitation to our study. Consequently, this approach may have led to a potential oversight of cases with progression occurring within the first year after birth. Future studies with more extensive datasets and prolonged observation periods should consider integrating multiple assessment methods for a comprehensive understanding of hearing progression.GJB2 mutations. Seventy-five patients  with homozygous or compound heterozygous GJB2 mutations were identified. The subjects included 7 adults, 9 pediatric cases, and 59 infants. The genotype, degree of hearing loss, and progression of hearing loss were retrospectively examined. All procedures were performed in accordance with the Declaration of Helsinki and approved by the University of Tokyo Human Ethics Committee (no. 3543-3). All the patients provided informed consent for the use of their clinical data. If patients were less than 20 years old, informed consent was obtained from their parents.Patients with hearing loss who visited the Department of Otolaryngology and Head and Neck Surgery at the University of Tokyo Hospital between 2009 and 2022 were tested for The level of the better-hearing ear at each frequency was assessed with behavioral audiometry at the time of the first visit. In cases where the first visit was before the age of 1 year, hearing was assessed after the age of 1 year when behavioral audiometry shows relatively consistent results. Hearing was assessed separately for the left and right ears using standard pure-tone audiometry or play audiometry (for subjects using headphones). The degree of hearing loss was calculated as the mean hearing levels . Profound hearing loss was defined as 90 dB or more, 70 dB to 90 dB as severe, 40 dB to 70 dB as moderate, and 25 dB to 40 dB as mild hearing loss. The proportion of truncating mutations and non-truncating mutations between profound and mild hearing loss was compared using Fisher’s exact test. Tympanic findings were evaluated by an otolaryngologist, but tympanometry was not routinely performed except in cases where hearing loss had progressed. In cases of progressive hearing loss, a close examination of the tympanic membrane with a microscope and tympanometry was necessary to rule out conductive hearing loss.The progression of hearing loss was examined in 46 patients (92 ears) monitored for more than 2 years since infancy, using play audiometry or standard pure-tone audiometry. If the mean hearing loss increased by 10 dB or more from the first examination to the last examination, the case was recorded as progressed hearing loss. In addition, the differences between initial and last hearing evaluations were compared using paired t-tests, and the hearing loss progression rate was calculated as the change in hearing loss from the last observation to the first examination in each ear divided by the number of years observed.For 36 ears of 22 patients with complete hearing data from 250 to 4000 Hz at the time of the initial examination, the presence or absence of hearing changes at each frequency were individually evaluated. Hearing and mean hearing levels for each frequency in each ear were categorized according to the follow-up period and age, and their trends were examined. In addition, differences between the initial hearing evaluations and last evaluations were compared using a one-way analysis of variance, and cases with an increase in the threshold by 10 dB or more from the initial hearing threshold to the last examination were categorized as worsening cases, and cases with a decrease in the threshold of 10 dB or more were categorized as improving cases, as reported previously . The remGJB2 mutations were classified as truncating or non-truncating mutations, respectively. The genotypes representing the combinations of mutant alleles were classified and evaluated for each.The Sanger sequencing method was performed for patients who underwent genetic testing between 2009 and 2011. The invader method  has beenGJB2 mutations. Most patients with hearing loss due to GJB2 mutations displayed profound hearing loss at the initial diagnosis (68%). The accurate prediction of hearing levels proved challenging using classifications based on truncating and non-truncating mutations. Genotype analysis revealed that mutations of the p.Arg143Trp variants were associated with profound hearing loss, while mutations of the p.Leu79Cysfs*3 allele exhibited a wide range of hearing loss, suggesting that specific genotypes may serve as predictors for hearing levels. Progressive cases were identified in 6.5% of patients via long-term observation, with the mutation of p.Leu79Cysfs*3 appearing to be linked to progression. On a frequency-by-frequency assessment, there was a significant difference at 4000 Hz and some tendency for progression at 250 Hz, suggesting that close monitoring at this frequency during follow-up may be important to confirm progression. Progression of hearing loss was observed in moderate or severe hearing loss cases at initial diagnosis, emphasizing the need for regular follow-ups in children with these levels of hearing loss.This study investigated the genotypes, degree of hearing loss, and the long-term progression of hearing loss in cases of


Noise (noise-induced hearing loss), and ototoxic drugs (drug-induced ototoxicity), and aging (age-related hearing loss) are the major environmental factors that lead to acquired sensorineural hearing loss. So far, there have been numerous efforts to develop protective or therapeutic agents for acquired hearing loss by investigating the pathological mechanisms of each types of hearing loss, especially in cochlear hair cells and auditory nerves. Although there is still a lack of information on the underlying mechanisms of redox homeostasis and molecular redox networks in hair cells, an imbalance in mitochondrial reactive oxygen species (ROS) levels that enhance oxidative stress has been suggested as a key pathological factor eventually causing acquired sensorineural hearing loss. Thus, various types of antioxidants have been investigated for their abilities to support auditory cells in maintenance of the hearing function against ototoxic stimuli. In this review, we will discuss the scientific possibility of developing drugs that target particular key elements of the mitochondrial redox network in prevention or treatment of noise- and ototoxic drug-induced hearing loss. Sensorineural hearing loss (SNHL), the most common type of permanent hearing impairment, is caused by physical and/or functional damage of cochlear hair cells in inner ear or auditory nerves including spiral ganglion neurons. Acquired SNHL, resulting from continuous accumulation of cellular damage due to various environmental stimuli, increases in prevalence with aging: Being identified in approximately 5–8 of 1,000 children, 33% of adults 65–74 years of age, and over 80% of adults 85 years of age . This prThe main pathological factors of acquired SNHL, aging, noise exposure, and ototoxic drugs, induce multiple, simultaneous responses in cochlear hair cells, that directly damage macromolecules , change ion homeostasis, and activate/inhibit intrinsic and extrinsic signaling pathways . These r2+ from Ca2+ stores, such as endoplasmic reticulum (ER) to cytosol and into mitochondria  and NADPH that are essential factors for antioxidant enzyme function . CisplatVarious types of antioxidants were also tested in drug-induced ototoxicity to examine their ability to prevent hearing loss. The widely-used antioxidants, NAC, sodium thiosulfate, and D-methionine, effectively protected or rescued cisplatin-induced ototoxicity, due to their high affinity for platinum molecules, as well as their antioxidative activity . In our Mitochondria, referred to as the center of cellular energy metabolism, are organelles that synthesize ATP through the TCA cycle and oxidative phosphorylation processes. Because this aerobic respiration unavoidably produces ROS, mitochondria are the primary cellular source of ROS . Mitocho2+ ions are the most likely to trigger ROS elevation. Particularly after intense noise stimulation, Ca2+ is released from the ER and translocated into mitochondria through an ion transporter such as VDAC or MCU. Abnormal Ca2+ influx can dysregulate Ca2+-regulated enzymes that are involved in ROS metabolism, leading to increased mitochondrial ROS levels, free-radical damage, and ultimately to mitochondrial dysfunction , a kind of lipophilic cation, has been conjugated to various potent antioxidants , and num2O2 treatment increased mitochondrial ROS leading to loss of mitochondrial membrane potential, which was attributed to decreased expression of the mitochondrial respiratory chain complex I, III, and V. When MitoQ was administered 1 h prior to H2O2 treatment, the mitochondrial oxidative stress responses were almost completely neutralized, thus protecting hair cells from apoptotic cell death (We previously used a mitochondria-targeted antioxidant, MitoQ, to evaluate the therapeutic potential of mitochondria-specific antioxidants in oxidative stress-induced hair cell damage. In mouse cochlear explants, Hll death . Other sll death .α-lipoic acid can inhibit the death of cancer cells as well as normal cells, thereby inhibiting the anticancer effect. Thus, α-lipoic acid cannot be administered in combination with the anticancer drugs such as cisplatin.Extensive scientific evidence strongly suggests mitochondria as a key target to protect auditory cells and maintain hearing function. Although a number of previous studies have shown that general antioxidants can provide protection against drug-induced ototoxicity, there are two significant limitations. First, since the general antioxidants are not highly selective for specific target molecules and can affect multiple signaling pathways simultaneously with low specificity, it is difficult to determine drug efficacy and safety at low concentrations. Second, general antioxidants have the potential to cause unintended side effects when co-administered with other medicines. For instance, antioxidants such as To overcome these limitations, it will be important to discover and develop novel therapeutic agents that interact with specific mitochondrial factors that contribute to mitochondrial redox homeostasis, such as antioxidant enzymes or mitochondrial pore proteins. This will be essential information for developing common drugs that are widely effective in different types of acquired hearing loss.


The aim is to recommend a minimum standard set of clinician-reported outcome measures (CROMs) and patient-reported outcome measures (PROMs) on hearing for people with osteogenesis imperfecta (OI). This project is part of the larger “Key4OI” project initiated by the “Care4BrittleBones foundation” of which the goal is to improve quality of life of people with OI. Key4OI provides a standard set of outcome measures and covers a large set of domains affecting the well-being of people with OI.An international team of experts in OI, comprising specialists in audiological science, medical specialists, and an expert patient representative, used a modified Delphi consensus process to select CROMs and PROMs to evaluate hearing problems in people with OI. In addition, focus groups of people with OI identified key consequences of their hearing loss. These criteria were matched to categories of preselected questionnaires to select a PROM that matched their specific hearing-related concerns best.Consensus on PROMs for adults and CROMs for adults and children was reached. The focus of the CROMs was on specific audiological outcome measures and standardized follow-up.This project resulted in a clear consensus statement for standardization of hearing-related PROMs and CROMs and follow-up management of patients with OI. This standardization of outcome measurements will facilitate comparability of research and easier international cooperation in OI and hearing loss. Furthermore, it can improve standard of care in people with OI and hearing loss by incorporating the recommendations into care pathways. Osteogenesis imperfecta (OI) is a rare genetic disorder also known as “brittle bone disease.” The estimated incidence is around 1:10.000 to 1:20.000 newborns, but incidence data vary worldwide . Other cHearing loss can be present from childhood, but prevalence increases with age and differs per Sillence type of OI . The repwww.key4OI.org)  may be much larger. Given that OI is a rare disease, most studies include small patient populations with heterogeneity of outcome measures being used. This makes it hard to compare outcomes from different clinics and different countries. A standard set of outcome measures can allow for pooling of data to facilitate 1) decision-making between providers and patients, 2) quality improvement, 3) allow for learning together, including benchmarking across organizations, and 4) accelerate and focus research and clinical trials. In 2018, the Care4BrittleBones foundation initiated a project named Key4OI (4OI.org)  to devel4OI.org) ,23. At a4OI.org) ,23.The present article reports the results of the Key4OI hearing initiative. The objective is to propose a standard set of hearing-related outcome measures, including follow-up measurements using the input from people with OI and an international group of healthcare professionals (audiologists and otologists) with expertise in OI.three-step modified Delphi technique was used to develop consensus on a minimal standard outcome set of CROMs and PROMs . In the preparation sessions of the expert team, key themes were compared with items in the preselected PROMs and discussed.During the focus group sessions, 28 themes were considered. Of these 28 themes, 14 themes were discussed in depth within the focus groups and clustered into 10 key themes (Table http://links.lww.com/MAO/B665). The entire process resulted in the following recommendations for the assessment of hearing in people with OI.Results of the consensus statements are reported in Table Seven PROMs were selected for evaluation -34. The We do not recommend any specific PROM for use with children with OI. The reasons are as follows: 1) there was no input from focus groups specific to children, 2) none of the experts in the group had experience using PROMs for children with OI related to hearing, and 3) no publications exist on hearing-related PROMs used in children with OI yet. However, considering that hearing loss deeply affects communicative abilities and language development in children, outcomes need to be established in an open dialogue with the family with the support of a multidisciplinary team (audiologists and speech language pathologist trained for children with hearing loss).A key theme not included in the selected PROM but mentioned by 16 of 22 participants of the focus groups was “difficulty in accessing good medical care.” They reported difficulties in finding otolaryngologists and audiologists with both knowledge and experience in treating people with OI, which can lead to delays in getting optimal treatment.In all age groups , tympanometry and acoustic reflex testing are recommended. Wideband absorbance and wideband reflectance are promising techniques but currently not recommended for the minimal standard set, as they are not widely available. In adults and children ≥4 years, pure tone audiometry is recommended, including air and bone conduction measurements up to 8 kHz. As a minimum standard, we recommend reporting bone and air conduction thresholds averaged across 0.5, 1, 2, and 4 kHz. In children <4 years, conditioned play audiometry or visual reinforcement audiometry is recommended, depending on cognitive abilities. If behavioral audiometry cannot be performed, otoacoustic emission measurements and auditory brainstem response (ABR) testing are recommended to estimate hearing thresholds. It is important to perform ABR at a young age to increase the chance of successful testing in natural sleep.Speech recognition in quiet is recommended for adults and children ≥4 years. For hearing aid users, additionally aided speech recognition in quiet should be tested at a 50-dB hearing level or a speech level equivalent to approximately 65-dB sound pressure level. Aided speech-in-noise testing is recommended for adults and children ≥4 years; unaided testing is optional. As a large variety of speech-in-noise tests is available, we do not recommend a specific speech-in-noise test.Rules and schedules regarding neonatal hearing screening might be different depending on the country. If children pass the neonatal hearing screening, follow-up hearing assessment around the age of 3.5 and 5.5 years is recommended. It is recommended to perform the hearing assessment before starting preschool or primary school. Starting at the age of 3.5 years, ear-specific pure-tone audiometry can be performed reliably. If testers are unable to assess the child with pure-tone (play) audiometry, visual reinforcement audiometry should be performed. In case of a suspected hearing loss or delayed speech and language development, assessment at an age under 3.5 years is required. For children with a confirmed hearing loss, at least annual assessments in a pediatric audiological center are recommended. The audiological assessment can be set more frequently considering the progression of hearing loss in first-degree relatives.Adults without a hearing loss or with nonprogressive hearing loss are recommended to have an audiological assessment every 5 years. In cases with a progressive hearing loss, testing should be done at least annually.The expert team recommends genetic testing for everyone with OI, as genetic factors may influence the occurrence or progression of hearing loss. This will also provide more data required for such research. The outcome of the genetic testing may support better hearing loss management through early recognition of “at risk” individuals.Audiological assessment is recommended before and within 12 months after surgery.In this study, a Delphi consensus panel sought to provide a standardized set of PROMs and CROMs on hearing for people with OI. The current project on hearing is part of a larger project named Key4OI, which uses ICHOM methodology to create a standardized set of outcome measures on all domains of health, psychological, and daily functioning in people affected by OI . The goaAs a sensory disability, hearing loss is often referred to as an “invisible disability.” Especially in people with OI who often have multiple health issues, hearing loss can be easily overlooked. In the focus group sessions, participants mentioned low awareness of the high prevalence of hearing loss in the OI community and among caregivers involved in supporting patients with OI. The reduced mobility of some people with OI can make speech understanding more challenging, as head orientation can affect speech intelligibility in noise . Focus gCurrently, a pilot is running for the original standard outcome set of Key4OI (hearing not included) in six different clinical care teams from different countries. The feasibility of implementing Key4OI in a clinical setting as well as a research setting is analyzed. One of the features of the Key4OI project is a standardized “checklist” with topics relevant to people with OI, such as pain, fatigue, anxiety, and much more. All this information flows into a treatment plan for the coming year(s). Hearing is part of this checklist, and follow-up and treatment are part of this plan. By measuring hearing in all patients with OI, clinics involved in research on OI will develop a much better idea of the prevalence of hearing loss in OI and subtypes of OI. We aim to create an increased awareness of minimal hearing healthcare among people involved in the care for people with OI. Furthermore, this might be a start to develop an international guideline for hearing healthcare for people with OI.The strength of this study is that the consensus statements were developed based on input by a variety of hearing health care professionals, including audiologists and otologists. In addition, by using the input from focus groups, a PROM could be selected based on items that are important for people in the OI community with a hearing loss.The limitation of the study is the geographic spread of the expert team, which only involves professionals from Europe and North America. Specific expert experience in other regions was thus not considered in the development of the consensus statements. The number of participants in the expert team was eight. This relatively low number of participants was due to limited research available on hearing and OI, which limited the number of people we could approach with apparent clinical and research experience in hearing and OI. However, “the Delphi group size does not depend on statistical power, but rather on group dynamics for arriving at consensus among experts” . No pareThe scope of this study was to develop consensus statements for standardization of PROMs and CROMs and follow-up management of people with hearing loss and OI. The consensus statements establish a standardized approach and should improve the quality of care for both children and adults with OI. It can also facilitate research and international cooperation in OI and hearing loss by allowing pooling of data from multiple centers to give a more accurate picture of outcomes. Further research is required to identify risk factors associated with hearing loss, to predict the progression of hearing loss, and to optimize treatment for people with OI.


The abuse of tetracycline antibiotics (TCs) has caused serious environmental pollution and risks to public health. Degradation of TCs by cold atmospheric plasmas (CAPs) is a high efficiency, low energy consumption and environmentally friendly method. In this study, a reactive molecular dynamics (MD) simulation is applied to study the interactions of reactive oxygen species (ROS) produced in CAPs and TCs (including tetracycline (TC), oxytetracycline (OTC), chlortetracycline (CTC) and demeclocycline (DMC)). As revealed by the simulation data at the atomic level, the main reaction sites on TCs are the  With the development of the modern synthetic chemical industry, a variety of synthetic organic pollutants (SOPs), including antibiotics, pesticides and detergents, have been detected in aquatic environments . AntibioSo far, the commonly used degradation techniques for SOPs include physical degradation, chemical degradation and biodegradation methods. Physical degradation methods remove SOPs by transferring them from a liquid to a solid surface. These methods mainly include adsorption ,17, filtCold atmospheric plasmas (CAPs), as an advanced oxidation process, can effectively remove SOPs from water with high toxicity and low biological activity ,32. CAPsde (NO3) ,34. Thesttention .In recent years, many experiments on the CAP treatment for SOPs in water have been carried out, and good results have been obtained. In a study by Aggelopoulos et al. , gas–liqAlthough a large number of experiments on the plasma degradation of SOPs have yielded good results, there is still a paucity of research on the fundamental mechanisms. Limited by the experimental conditions and equipment, researchers are speculating the reaction pathways between CAPs and SOPs by experimentally measured macroscopic products. It is difficult to observe their interaction processes at the atomic level and to distinguish the actual contribution of each oxygen species. This has caused difficulties in further studying how to apply CAP technologies to industry. The development of computer simulations has made it possible to solve this problem, where reactive molecular dynamics (MD) simulations can simulate the breaking and formation of chemical bonds during interactions, thus allowing visualization of the mechanisms of molecular interactions. Using reaction MD simulations, Tian et al. investigated the interaction processes between ROS generated in atmospheric plasma and fatty acids in vegetable oils, revealing the mechanisms of plasma interaction with vegetable oils and providing support for further in-depth studies of plasma medicine . Zang etBased on reactive MD simulations, the reaction processes of ROS produced in CAPs and TCs are investigated in this study. The interaction mechanisms of plasma degradation of TCs at the atomic level are deeply explored based on computational data, and the final products obtained from the computation agree well with the experimental observations, which partly supports the reliability and validation of the reactive MD simulation. In The interaction processes of ROS and TCs have common and individual mechanisms. In this study, TC is selected as representative to display the common mechanisms, followed by the analysis of interactions between ROS and other TCs, respectively. Finally, dose effects are discussed.Upon the impact of OH radicals, a H atom in the eriments ,42. The Two reaction processes of OH radicals and the eriments . As the The reaction process of OH radicals with the As one of the most common active functional groups, benzene rings have always been a focus of researchers. Upon the impact of OH radicals, the H atom at the In The difference between the structure of OTC and that of TC is the Compared with TC, the unique reactive functional group of CTC is the The structure of DMC is similar to that of CTC, with the exception that DMC lacks the Through calculation and analysis, it is found that ROS produced in CAPs can have a variety of common and individual interactions with TCs. In the simulation, ROS first abstract H atoms from TCs; then, a series of reactions such as hydroxylation, dehydroxylation, carbonylation, carboxylation and aldehyde occur subsequently. ROS produced in CAPs can effectively destroy crucial active functional groups in TCs, indicating that CAPs can effectively degrade TCs. It is worth mentioning that the reaction processes between ROS and active functional groups of TCs occur synchronously rather than sequentially; thus, the reaction products observed in the experiment contain all the reaction results that have occurred. In experiment , detachmperiment , formatiperiment , carbonyIn the experiments of plasma degradation of TCs, the concentration of ROS can be changed by varying various chemical doses and discharge parameters, such as the concentration of catalyst, voltage amplitude, discharge frequency, etc. ,42,43. IAs can be seen from these simulation data, m/z = 274) [m/z = 477b), similar to the formation of the m/z = 364) [Subsequently, the simulation results are compared with the degradation pathways postulated in the experiments. As shown by the simulation results in and O16) ,43. The z = 274) ,44. An Oble bond . Breakagz = 364) ,44. The In recent years, CAPs have attracted more and more attention due to their excellent degradation effects. According to different discharge methods, they can be mainly divided into DBD plasma and atmospheric-pressure plasma jets (APPJs) . In plasmination ,42,43. Smination ,48. In fmination . As showd by ROS . Indeed,d by ROS . Since tIn order to investigate the interaction processes between TCs and ROS more accurately and to summarize the interaction mechanisms, four different natural tetracyclines  are selected in the present computational study. Before starting the simulation, the simulation model is established according to the structure in All the simulation processes in this study are carried out in the NVT ensemble (constant number of particles (N) under constant volume (V) and constant temperature (T)); T = 300 K. The optimized structural model of TCs and different numbers  of ROS  has attracted more attention, and degradation of TCs by cold atmospheric plasmas (CAPs) is widely accepted to be an efficient and low energy consumption way. In this study, the interaction mechanisms of CAPs and TCs are deeply investigated by a reactive MD simulation based on the ReaxFF field at the atomic level. The computational data indicate that different kinds of ROS (OH radicals, O atoms,


Preference for noise reduction (NR) strength differs between individuals. The purpose of this study was (1) to investigate whether hearing loss influences this preference, (2) to find the number of distinct settings required to classify participants in similar groups based on their preference for NR strength, and (3) to estimate the number of paired comparisons needed to predict to which preference group a participant belongs. A paired comparison paradigm was used in which participants listened to pairs of speech-in-noise stimuli processed by NR with 10 different strength settings. Participants indicated their preferred sound sample. The 30 participants were divided into three groups according to hearing status . The results showed that (1) participants with moderate hearing loss preferred stronger NR than participants with normal hearing; (2) cluster analysis based solely on the preference for NR strength showed that the data could be described well by dividing the participants into three preference clusters; (3) the appropriate cluster membership could be found with 15 paired comparisons. We conclude that on average, a higher hearing loss is related to a preference for stronger NR, at least for our NR algorithm and our participants. The results show that it might be possible to use a limited set of pre-set NR strengths that can be chosen clinically. For our NR one might use three settings: no NR, intermediate NR, and strong NR. Paired comparisons might be used to find the optimal one of the three settings. Nowadays nearly all commercially available hearing aids contain a single-channel noise reduction (NR) algorithm. The goal of such an algorithm is to improve patient satisfaction when listening in a noisy background. NR algorithms in hearing aids have been shown to increase listening comfort at equal speech intelligibility . CommercPreference for NR settings varies between individuals . It is nThe studies described above all investigated differences in preference for NR turned on or off between NH and HI listeners. They did not investigate if NH and HI listeners differ in which setting of the NR algorithm was preferred. In a previous paper, different settings of a single parameter (the maximum gain reduction) were compared to investigate the preferences of NH listeners for NR strength in a laboratory experiment . That woHere we focus on NR strength, defined as the maximum gain reduction of an NR algorithm. Based on the literature we hypothesized that both NH and HI participants would have a large spread in preferences for NR strength. We further hypothesized that groups of NH and HI participants would differ in their preferred strength of NR. The direction of the preference difference is unknown. On the one hand, HI listeners might be less sensitive to signal distortions , and migUsing hearing aid-based NR, we investigated if preferences for NR strength differ between NH and HI listeners for speech in babble noise. To achieve good sensitivity we used a paired comparison design and analyzed the data with a statistical model that was specifically developed for this task by The following research questions were formulated:Research Question 1: Do preferences for NR strength differ between NH and HI listeners?Research Question 2: How many distinct settings are required to classify participants into similar groups based on their preferences for NR strength?Research Question 3: How many paired comparisons are required to find the preferred NR strength for an individual?Approval by the Medical Ethical Committee of AMC was obtained on 24 April 2008 (MEC 08/082). Participants were recruited from the patients of the Audiological Centre of the AMC and had to sign an informed consent prior to participation.There were three groups of 10 participants in the study. The audiometric data are given in Appendix A. Two additional participants quit the experiment early stating that they did not hear any difference between the stimuli. Although their incomplete data sets were not used for analysis, their audiometric data are included in Appendix A for completeness.The included number of participants was based on a power calculation with data from NH listeners from a previous study . In that- NH: all hearing thresholds (octave frequencies ranging from 0.25 to 8 kHz) equal to or better than 20 dB hearing loss (HL) for both ears.1, 2, 4 kHz) of at least one ear was equal to or better than 40 dB HL.- Mild to moderate HI (HI-mild): hearing loss exceeding that of NH while the PTA hearing loss at 1, 2, 4 kHz : hearing loss exceeding HI-mild  was 16 dB with a standard deviation of 10 dB. The mean PTA1, 2, 4 Hz difference between the ears was 6 dB HL with a standard deviation of 6 dB HL. Hearing loss of the participants was sensorineural, there were no significant conductive losses.The audiometric inclusion criteria for the three hearing loss categories were as follows:The speech reception threshold (SRT) for consonant–vowel–consonant (CVC) words in quiet was also measured. The SRT is the sound pressure level at which the participant correctly repeated 50% of the phonemes. For the first five NH participants, no SRT measurement is available due to a measurement mistake. The mean age (with standard deviation) of the three groups was 47 ± 12 years, 61 ± 15 years, and 67 ± 7.5 years, for NH, HI-mild, and HI-moderate, respectively.not comfortable to very comfortable. The four sentences were selected to have equal scores and average listening comfort.The unprocessed stimuli were recordings of four sentences spoken by a female, taken from the VU-98 sentence materials . During NR processing was done using a low-latency single-microphone NR algorithm (SNRA), implemented in Matlab. This algorithm has been used before to measure individual preferences for the strength of NR , 2013. TThe incoming speech signal is first split into a signal and an analysis path. For the signal path, all filtering and processing is done in the time domain, and for the analysis path, this is done in the frequency domain . The twomin). This threshold was used to limit the strength of the NR. The calculated gain was subsequently applied to the signal in the signal path. The variable under investigation, the threshold for gain depth (Gmin), limits the maximum gain reduction that is applied by the SNRA to Gmin. Higher values of Gmin led to more gain reduction. The variable Gmin can be applied independently from the NR algorithm since it does not alter the gain function but only applies a threshold of maximum gain reduction. In the literature on spectral subtraction, this limit is also known as “spectral floor”  of the output signal to that of the input. The correction is thus done on the overall speech-in-noise signal.At the start of the visit, hearing status was checked for each participant by means of pure-tone audiometry. Following audiometry, they participated in a paired comparison listening test which is explained in the next two paragraphs.min, which is explained in the previous section. Ten values of Gmin were used , each of which was compared to all the others, leading to 10 × 9 unique comparisons . Each comparison was done twice  leading to 180 paired comparisons per participant. This value was a trade-off between measurement accuracy (more runs are better) and total time required to do the experiment (less is better). On average, a session took about 1.5 h.A between-participants design was used, the three hearing loss groups each containing 10 participants. The main experimental parameter was GIn each trial, participants had to listen to two successive processed speech-in-noise stimuli and choose which they preferred. The participants were asked the following question “Imagine that you will have to listen to these signals all day. Which sound would you prefer for prolonged listening?” The question was intentionally stated in a broad context. The reason is that we were primarily interested in general preference and not in perceived specific signal qualities such as “speech quality” or “amount of background noise.” Before commencing with the paired comparisons listening test, a training session was performed with 20 paired comparisons with similar stimuli. The data obtained during the training session were discarded.The experimental set-up consisted of a Focusrite Saffire Pro 10 audio interface and a Presonus HP40 headphone buffer with Sennheiser HDA200 headphones. All stimuli were presented bilaterally with an input SNR of +5 dB. This value was chosen because it is representative of real-life situations, which is shown in a field study by min that corresponds to the participant's highest preference . Hierarchical cluster analysis was done with R function “hclust” using the Ward criterion (method = “ward.D”). The distances between win counts were calculated using R function “dist” using the Manhattan (L1) distance metric (method = “manhattan”). We chose hierarchical clustering over alternatives like k-means clustering, as this hierarchical clustering gives insights into clustering quality for different numbers of clusters. We chose Ward's minimum within-cluster variance as method, as this method “tends to find same-size, spherical clusters” , we analyzed the data with a non-parametric Kruskal–Wallis test with hearing loss category as the main effect. Prior to this analysis, we checked for homoscedasticity with Bartlet's test for equal variances. The effect was not significant , indicating that the variances were not different for the three hearing loss categories, and that a Kruskal–Wallis test could be used.Because the analysis of variance (ANOVA) assumption of normality of the residuals was not met . Post hoc testing (Bonferroni corrected with α = 0.05 and n = 3) showed that the mean ranks of the NH and HI-moderate groups differed significantly (p < .05).The Kruskal–Wallis test gave a significant effect of hearing loss  = 13.31; p < .001. The PTA1, 2, 4 kHz was significantly correlated with age: ρ = 0.65, p < .001 (Spearman correlation), but p = .12 (Spearman correlation).We investigated the relation between age and hearing loss, and between age and The second research question was to define the required number of distinct NR settings to be able to classify our participants into similar groups based on their NR preference. To answer this question a cluster analysis was performed. From left to right, the dendrogram shows the possible different levels with different numbers of clusters starting with two clusters in the first level and finishing with 30 separate clusters, one for each participant see , one gromin gives us information on the differences in preferences between the different clusters throughout the range of Gmin. The average win-count data for each of the identified relevant clusters with respect to Gmin (with mean min (mean min (mean The preference in Cluster 1 (shown in orange) is for low Gmin levels of 0, 7, 8, 9, 10, and 18 dB were used in a simulation study. These Gmin levels coincide approximately with the min = 0 dB and each of Gmin = 7, 8, 9, or 10 dB , between Gmin = 18 dB and each of Gmin = 7, 8, 9, or 10 dB (eight pairs) and Gmin = 0 dB and Gmin = 18 dB (two pairs). To increase the weight of these last pairs, the data were used twice for a total of 8 + 8 + 2 × 2 = 20 pairs. The data contained only two pairs of comparisons between Gmin = 0 dB and Gmin = 18 dB and hence only two out of 18 pairs compare preference for Cluster 1 versus 3 (cluster numbering as in The last question addressed is how many paired comparisons are needed to place a participant in one of the three preference clusters. As 180 paired comparisons (the number we used in this study) is too many for clinical practice, only Gmin = 0 dB over Gmin = 18 dB one is unlikely to get new information by asking the participant a seventh or eighth time  from the 40 paired comparisons selected previously and the Euclidian distance was calculated between the win counts of the sample and the mean win counts of each cluster as shown in min to adequately estimate the actual preference. This results in more comparisons than the Gmin range in our simulation. We have no explanation for why the probability of choosing the correct cluster of HI-mild7, which belongs to the third cluster, was significantly lower in comparison to the other participants in this cluster.The results of this simulation are shown in 1, 2, 4 kHz and In line with our hypothesis, there was a significant difference in mean preference between NH participants and HI participants with moderate hearing loss. On average, the participants with moderate hearing loss preferred stronger NR than the NH participants did. Also, there was a moderate positive correlation between PTA1, 2, 4 kHz. Age and PTA1, 2, 4 kHz were significantly correlated. This was expected because age was not a selection criterion for participant inclusion and hearing loss generally increases with age  is in line with the hypothesis that HI listeners are less sensitive to signal distortions . Neher aWe found a significant effect of hearing loss on preferred NR strength, although the effect size was only moderate (ρ = 0.46). This could be explained by the large individual differences in preferences see . Thus, tN = 32) could be divided into two equal groups: those who are sensitive to distortions and those who are sensitive to noise. N = 30) who were classified either as “noise-haters” or “distortion-haters” in complex listening situations with different maskers. In the results shown in A possible and promising explanation for the spread of preference is the individual trade-off between noise tolerance and distortion tolerance. Several researchers have used this trade-off theory to explain individual differences in preferences for NR settings . Sugiyammin, we might have concluded that four settings were required to be able to accommodate all preferences for NR strength. The results also imply that we can assume that simply offering an NR-on or NR-off option in a hearing aid is too limited, as there are listeners who do not prefer the maximum, nor do they prefer the minimal amount of gain reduction. The actual amount of three clusters is only a starting point based on a limited data set.The results of the cluster analysis showed that for our NR algorithm, the participants could be divided into three groups with similar preferences. The In the results of the cluster analysis, we can see that there was a trend for those with more severe hearing loss to belong to a cluster with a higher preferred NR strength, which is in line with our results for Q1. Most NH participants fell in Cluster 1 (low NR strength) or 2 (intermediate NR strength). HI-mild and HI-moderate participants fell more in Clusters 2 or 3 (high strength) than in Cluster 1. This suggests that most HI participants should be fitted with a device with NR active. However, the categorization of a participant in a cluster was not clear-cut because all three clusters contained one or more participants for the HI-moderate group. So there are, at least some, moderately HI participants who prefer no NR. These results reinforce earlier findings that the amount of hearing loss cannot reliably predict the preference for NR strength for an individual . TherefoIf one could a priori categorize a participant into one of the three clusters in a reliable way, one could optimize the NR for that individual. Paired comparisons have been used for many decades to evaluate preferences for hearing aid features , and areAlthough the NR algorithm used in this study is comparable to NR systems used in modern hearing aids, the optimal NR strength levels from this experiment apply only to the limited conditions tested in this study. Moreover, this study did not account for the effects of other non-linear processing, such as amplitude compression. We do not know if preferences for NR strengths differ at other input SNRs. However, since the chosen input SNR of +5 dB is representative of real-life scenario this limitation does not influence the conclusions of this work.It is important to discuss other possible effects of our signal processing that might contribute to the differences in preference for NR strength. It is currently not known if or how the chosen hearing aid fitting rule  influences the preference for NR. To achieve results that are relevant to H users, one needs to use fitting rules. Fitting rules are used in hearing aids to prescribe individual, frequency-dependent amplification to compensate for the personal hearing loss. Research on preference with HI participants is thus complicated by the individual frequency-dependent hearing loss. The combination of the hearing loss with the chosen frequency-dependent fitting rule will determine the amount of spectral coloring relative to participants without hearing loss. Note that even without the use of frequency-dependent amplification there is some spectral coloring relative to NH . We chose to apply the linear NAL-RP filter because it resembles the commonly used NAL fitting rule and it avoids the known complicated interactions with non-linear amplification . To whatThe results showed that preferred NR strength in hearing aids was moderately correlated with the degree of hearing loss. An individual with more severe hearing loss is likely to prefer stronger NR. However, there was large variation in preference for NR strength. Therefore, choosing NR strength based on the audiogram alone can result in suboptimal hearing aid fitting. For the conditions tested in this study, three distinct settings of NR strength sufficed to adequately accommodate individual preference. Thus it might be possible to use a limited set of pre-set NR strengths that can be chosen clinically. For most participants, the appropriate setting could be found with about 15 paired comparisons. For clinical practice, we advise using hearing status as a (first) guess to select the NR strength and then measuring individual preferences by using a limited number of paired comparisons.


Mucormycosis is a rare but fatal disease caused by a filamentous fungus involving the nose, paranasal sinuses, and brain. These organisms usually cause severe infections in immunocompromised individuals. Granulomatous polyangiitis (GPA), also known as Wegner's granulomatosis, is a rare, aseptic necrotizing granulomatous vasculitis involving small and medium-sized vessels commonly affecting the nose, ears, lungs, and kidneys. The simultaneous occurrence of mucormycosis and GPA, two rare diseases, in the same patient is exceedingly rare. In this case study, we describe a 40-year-old woman who presented with manifestations of both GPA and mucormycosis. She was started with steroids and antifungal agents and achieved significant improvement. Mucormycosis is a necrotizing, destructive disease. Immunocompromised individuals are frequently affected by it, including those with acquired immunodeficiency syndrome (AIDS), hemochromatosis, severe burns, prolonged steroid therapy, cancer, and diabetic ketoacidosis. However, some studies show the presence of mucormycosis without any predisposing factor . GranuloBoth GPA and mucormycosis are rapidly progressive and potentially fatal diseases, so early diagnosis and prompt appropriate treatment are required for a better prognosis , 2. In tA 40-year-old Asian female with no known comorbidity presented to the outpatient department with complaints of progressive bilateral loss of hearing and a runny nose for four weeks. A high-grade fever was documented up to 103°F with a productive cough and dull frontal headache for one week. Previously, she had been treated for sinusitis and otitis media in a local hospital with various antibiotic regimens and antihistamines, with no notable improvement. Therefore, the patient was referred to us at the tertiary care hospital. On physical examination, she had right-sided facial swelling, right eye proptosis with conjunctival redness, saddle-shaped nose deformity, bilateral polypoid growth, right-sided lower motor type of facial nerve palsy Figures , and senThe complete laboratory workup is shown in A diagnosis of GPA with coexisting mucormycosis was made. Treatment started with intravenous (IV) methylprednisolone 1000 mg for three days (pulse therapy), followed by an oral steroid of 50 mg/day, and slow infusion of liposomal amphotericin B (LAm-B) 3 mg/kg/day in two divided doses for two weeks. There were marked improvements in proptosis and hearing. Thus, she was started on injectable cyclophosphamide (CYC) 1 gm undercover of mesna. The patient showed progressive improvement and was discharged after 20 days. The patient received a monthly IV CYC 1 Gram daily under cover of mesna for three months, LAm-B 3 mg/kg/day in 2 divided doses for a month, and oral steroids, which were tapered off gradually. Mucormycosis can mimic relapse or progression of GPA. It is crucial to timely diagnose and treat mucormycosis infection in order to prevent a disseminated disease with a poor prognosis . There aMucormycosis is a rare, necrotizing, rapidly progressive disease due to its angioinvasive pathogenesis , 7. OrgaMucormycosis is generally diagnosed through tissue biopsy, which reveals broad, nonseptate hyphae with right-angle branching , 7. AlteSurgical debridement of necrotic tissue and amphotericin B (AMB) is the treatment of choice for mucormycosis , 9. In cGPA is a rare aseptic necrotizing granulomatous vasculitis of small and medium-sized blood vessels belonging to a group of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) , 3. CytoPatient with mucormycosis and GPA can present with varying severity. In our case, patient was successfully managed with debridement and conservative management. However, there have been cases of GPA with mucormycosis requiring otorhinolaryngological surgical procedures . Because


Haptic devices transmit information to the user, using tactile stimuli to augment or replace sensory input. People with limited sensory abilities, such as vision or hearing can receive supplementary information by relying on them. This review analyses recent developments in haptic devices for deaf and hard-of-hearing individuals by extracting the most relevant information from each of the selected papers. The process of finding relevant literature is detailed using the PRISMA guidelines for literature reviews. In this review, the devices are categorized to better understand the review topic. The categorization results have highlighted several areas of future research into haptic devices for hearing-impaired users. We believe this review may be useful to researchers interested in haptic devices, assistive technologies, and human–computer interaction. Based on the number of people with a hearing loss greater than 35 decibels in their better ear , the WorThus, given the high number of hearing-impaired people, efforts aimed at supporting the said population can positively impact a large part of the population, including those close to them. For example, parents of children with disabilities who receive support and have an action plan experience lower stress levels .The World Health Organization has also estimated that the annual cost to the global economy due to the lack of proper care of the hearing impaired is 980 billion USD. These costs are transferred to the health sector (not including the cost of hearing devices such as cochlear implants), educational support costs, reduced productivity, and social costs . In otheAs Julia Taylor and Kellie Mote point out, accessibility refers to designing systems that allow everyone the same access and opportunities, regardless of their personal characteristics, ensuring that all can fully participate . TherefoCertain technology tools for assistance can help people with hearing disabilities, thereby improving their accessibility and inclusion. One such example is the haptic technology, which consists of devices that apply tactile stimulation to the user. This technology allows deaf and hard-of-hearing (DHH) individuals to receive information through one of their fully functioning senses.Aside from technology, policy implementation can also contribute to inclusion. In this regard, the United Nations has established a strategy titled “United Nations Disability Inclusion Strategy”. This strategy has four areas: leadership, strategic planning and management, inclusion, programming, and institutional culture .The strategy aims to collaborate with people with disabilities in order to create an inclusive environment where they can integrate with both internal work of the parent organization and the external work of other organizations.Haptic devices and technology play a key role in achieving the above strategy. In order to understand the relevance, it is important to first to know the difference between equality and equity. Paula Dressel states: “The path to equity will not be met by treating everyone equally. It will be achieved by treating everyone fairly according to their circumstances” .This means that if you treat everyone equally, then individuals in disadvantaged situations will still be disadvantaged. For example, if a company offers video calling tools to all its employees to promote online meetings, a deaf employee will still be unable to hear their colleagues during such meetings, unless they have the option to transcribe the audio. Thus, to promote fairness, a deaf employee should receive support through a transcription tool.Technology plays an important role in inclusion. It enables people with disabilities to fully participate in activities where they might otherwise be excluded from. People with partial or complete loss of one or more senses can better integrate into different activities by using devices that serve as sensory augmentations or substitutions, such as haptic devices.In a previous study  the authPeople with disabilities face a variety of challenges that differ from those faced by the rest of the population. Technologies, including those mentioned above, are not intended to solve the entirety of their barriers. However, these devices can still be of substantial help in reducing the problems experienced during certain activities.The Web Accessibility Initiative mentions three relevant aspects of accessibility . First, Hearing impairment generally refers to a diminished ability to hear sounds and can range from barely perceptible noise to total deafness. It can originate from different areas, such as the conduction of sound to the inner ear, the perception of sound by the sensory cells of the cochlea, the processing of sound by the cochlear nerves, the auditory pathway, or cortical auditory centres .Hearing impairment or hearing loss should be distinguished from other hearing disturbances such as hypersensitivity to sound (hyperacusis) or tinnitus, although these conditions can be caused by auditory loss itself .Hearing loss implies that an individual is unable to hear as well as the average person, which is at least 20 decibels in both ears. It can be classified as, depending on its severity, into mild, moderate, moderately severe, severe, or profound hearing impairment .Hearing impairment can be described through a variety of aspects. Depending on whether it affects one or both ears, hearing impairment can be unilateral or bilateral. Based on whether the person had already learned to speak before the hearing loss, hearing impairment can be pre-lingual or post-lingual.In addition, hearing impairment can be symmetric or asymmetric depending on whether the hearing loss is the same in each ear. Moreover, it can be classified as either progressive depending on whether the loss increases over time or not. If the hearing loss is present at birth, it is said to be congenital, and if it appears at a later age, it is considered to be acquired . From anHearing loss can be caused by a variety of factors. On the one hand, hearing loss can be caused by temporary problems, such as wax build-up in the outer ear. Hearing loss due to eardrum ruptures caused by objects inserted into the ear, pressure, or sudden loud noises can heal over time if the loss is not severe. Ototoxic medicines, which can damage the ear, can result in temporary or permanent damage to the ears. On the other hand, constant exposure to loud sounds that damage the inner ear, as well as certain congenital or postnatal infections can cause permanent hearing loss. In addition, hearing loss can be hereditary or caused by conditions such as diabetes, high blood pressure, heart attacks, brain damage, or tumours .Haptic devices allow for human–computer interaction through touch and external forces. Unlike traditional interfaces, such as visual screens and audio systems, haptic devices present mechanical signals that are perceived by human touch .Haptic devices focus on tactile communication to transmit information, and these forms of information communication include the use of pressure, vibrations, and temperature . In geneFleury et al.  present Vibration: applied normally or transversely to the skin’s surface and can vary in frequency, amplitude, duration, or timbre.Contact/Pressure: an object can make contact with the body and then break that contact, alternating between these two states or varying the level of pressure.Temperature: changes in temperature, such as going from cold to hot, or from hot to even hotter.Geometry: shape, such as the curves or reliefs of an object.Texture: the sensation generated by touching certain surfaces, which may be smooth or rough, for example.Softness/Hardness: a material’s resistance to pressure, such as when pressed by a finger.Electricity: electrical stimuli can be used to generate haptic sensations, known as electro-haptic stimuli.Friction: resistance to movement between two solid bodies whose surfaces are in contact.Haptic devices can be further classified based on the type of their tactile interaction. As described in a previous study , there aSensory augmentation, as part of “hybrid biology”, involves the addition of synthesized information to a person’s sensory channel . An examSensory substitution is a similar concept that is described as the use of one sense to provide environmental information that can normally be obtained from another sense . Haptic Compared to visual feedback, haptic feedback does not interfere with the user’s view, and can be applied anywhere on the body . As a reThese examples demonstrate how haptic devices are capable of augmenting and substituting sensory information, while this literature review focuses on hearing impairment, haptic devices can support the other senses, as compiled by . These fThere are six main previous literature reviews as shown in Shull and Damian  focused Sorgini et al.  focused In a recent paper by Fletcher , haptic Two other literature reviews cover the topic of haptic stimuli as a replacement for sound but, specifically, for the purpose of communicating musical information. The paper by Remache et al.  compiledThere are also survey articles on haptic stimulation such as . This reIn conclusion, other reviews focus on particular aspects of hearing impairment: music, localization, and cochlear implants. No reviews are dated after 2021, and one paper does not focus on accessibility issues.This study presents a review of haptic devices with applications for hearing impairment In addition, possible areas of opportunity and future work were discussed. The study followed an adaptation of the PRISMA guidelines .The following research question guided the literature review, including the search and selection process.What have been the recent developments in haptic devices aimed towards helping people with hearing impairments?Different electronic databases and digital libraries were searched to locate relevant published papers and reduce any bias that may arise from using a single source, as seen in Deaf;Hard-of-hearing;DHH.In order to construct the final search strings, terms related to hearing impairment were grouped into one category, while terms related to haptic devices were grouped into another category. The basic terms related to hearing impairment were:Hearing, auditory, audition;Impairment, loss, deficiency, disability, problem, impediment.As well as the combination of the following two lists of terms:Haptic;Vibrotactile;Electrotactile.The basic terms related to haptic devices were:Tactile, tactual, touch, vibration;Aid, device, technology, display, interface, feedback.As well as the combination of the following two lists of terms:Terms from each category were combined using an "AND" operator to search for potential papers relating to haptic devices for hearing-impaired individuals. Proximity operators were used for the last items in each category, which consist of a list of terms that should be combined with another list of terms. Thus, the following general search string was generated (with syntactic variations for different sources): PRE/5 (aid OR device OR technology OR display OR interface OR feedback)) OR vibrotactile OR electrotactile) AND (((hearing OR auditory OR audition) PRE/5 (impair* OR loss OR deficiency OR disability OR problem OR impediment)) OR deaf* OR DHH OR "hard-of-hearing")Some sources did not offer proximity operators. To obtain the different possible combinations for these cases, another search string was created by joining the previously mentioned pair of term lists with a script. This search string was: AND ("hearing impairment" OR "hearing loss" OR "hearing deficiency" OR "hearing disability" OR "hearing problem" OR "hearing impediment" OR "auditory impairment" OR "auditory loss" OR "auditory deficiency" OR "auditory disability" OR "auditory problem" OR "auditory impediment" OR "audition impairment" OR "audition loss" OR "audition deficiency" OR "audition disability" OR "audition problem" OR "audition impediment" OR deaf* OR DHH OR "hard-of-hearing")The full information about the search strings used for each source is shown in The paper should be published between 2017 and 2022 (inclusive);The paper should be published in English;The full text of the paper should be available online or be accessible by contacting the corresponding author;The document should be either a journal article or a conference paper.A set of inclusion and exclusion criteria were established to determine which papers should be selected. There were two types of criteria: general criteria (which could be applied to any paper) and content-specific criteria (specific to this review’s topic). The general inclusion criteria were as follows:The paper should explicitly indicate that the developed device is aimed at people with hearing impairments.The content-specific inclusion criteria were as follows:Papers published in non peer-reviewed sources  were not considered;Literature reviews were not considered.The general exclusion criteria were:Papers that described devices without developing their own were not considered;Papers about devices that only included a minimal haptic feature which was not its main focus, were not considered.The content-specific exclusion criteria were:The paper should present a developed prototype/device that goes beyond the design or conceptual stage;The device should have been tested by at least one user;The paper should include the results of the tests.In addition to the inclusion and exclusion criteria, three more aspects were considered as a proxy to assess the quality of the relevant papers for the review. The aspects were as follows:The search results from all the sources, excluding Google Scholar, provided 1745 papers. Google Scholar returned 18,700 results. Of these, only the first 53 pages were considered (the selection process ended 10 pages after the last relevant result). As Google Scholar displays 10 elements per page, 530 records were counted for this source to be added to the 1745 number. In total, 2275 results were found. The content-related inclusion and exclusion criteria were not considered when selecting papers from the search results. At this stage, the only content-related criterion was selecting papers related to haptic devices with applications for hearing impairments. This allowed to focus on narrow selection criteria when working with many papers. Consequently, we could perform the process more effectively and with less errors.In addition, it reduced the number of false negatives. Later, the content-related inclusion and exclusion criteria were applied to the reduced number of papers to further refine the initial selection.During the first stage of the selection process, which consisted of going through the search results, the only content-specific criterion considered was selecting papers related to the topic of haptic devices with applications for hearing impairments. At this stage, the number of papers is at its highest, and this simpler selection criterion allowed us to be more effective and less error-prone. In addition, the criterion reduced the number of false negatives. The initial selection was improved further using the entirety of the inclusion and exclusion criteria.Title inspection;Abstract inspection;If the paper was not discarded from the previous criteria, its contents are inspected.The following steps were taken to determine whether these papers passed the inclusion and exclusion criteria:A total of 25 papers were finally included in the literature review.The different body parts where haptic stimuli were applied by the devices from the 25 selected papers are shown in Fourteen of the 35 locations involved the wrist, hand , and fingers. The fingers and hands were the most commonly used body area for haptic stimuli application, as five papers included each of them. Six papers showed haptic stimulation applied to the arms, divided among the upper arms and forearms. Three papers involved the legs, including the upper and lower legs. Apart from the back and chest, which appeared in two papers, all of the other body parts appeared only once. As shown in a previous study , two adjIn two instances the haptic stimuli were not limited to a single location, but rather the entire body experienced the stimuli to varying degrees. In , the useAs shown in Regarding the reason for using a single stimuli location, the information conveyed through the haptic stimuli does not rely on specific patterns in cases such as ,53. InstSome devices, such as in ,36, use As shown in In six papers, the haptic devices used helped the users to experience music. These devices used vibrations to represent or complement music, whether to enhance the experience for hard-of-hearing users, or to allow deaf users to experience it in their own way. This category of devices may be of greater interest to researchers due to the prevalence of music in history and culture.As shown in As shown in Our results showed that fingers and hands were the most popular body parts for haptic stimulation because they are highly sensitive to touch, making them a convenient choice for haptic stimulation. In addition, people generally use hands and finger for touching and interacting with their physical environment. Another key factor to consider is how practical or common the devices are for those parts of the body. Bracelets allow for the application of haptic stimuli to the wrist, and people are accustomed to such designs because of other wearables such as wristwatches. Gloves can also be used to apply haptic stimuli to the wrist. Users may find it more familiar and comfortable wearing technology in these forms. In addition, haptic actuators can be easily incorporated into them. It is important to mention that despite the many advantages of haptic actuators on the hands, this reduces the user’s ability to employ them for other things.Note that neither the face nor the feet were targeted for haptic stimulation. The face is a crucial part of one’s identity and communication, and one may not want the haptic device to obstruct it. In addition, some may find haptic stimuli to the face to be more inconvenient than placed elsewhere. The feet, are usually covered by footwear, and it may not be practical to place a device on them. Similar to wristwatches and wristbands, haptic devices can be placed on the ankles. However, the sensitivity of ankles must be tested in order to determine their usefulness.The concept of using haptic devices to apply haptic stimuli to different body parts can be explored further. From among our selected studies, only a few devices used this concept. The device shown in  used theIn the selected papers haptic devices that allow for real-time interaction between multiple people were not directly represented. Some papers, however, indirectly incorporated the concept. The haptic device shown in  alerted Haptic devices that enable DHH people to create content rather than consume or experience is another aspect that can be explored. Such devices will allow users to actively participate in interactions. In a closely related paper , a devicHaptic devices tailored to a particular industry or profession could be developed. The majority of the reviewed devices are suitable for a wide range of users. DHH individuals from diverse backgrounds can benefit from using haptic devices intended for experiencing music, or devices that alert people to critical sounds in their homes. Although such devices are useful for a large percentage of the DHH population, developing devices that help in more niche areas may also be worthwhile. This could include devices for specific professions, as mentioned before. This will enable more industries to become more inclusive and accessible. A device using this concept was described in , which wThe bumping alert robot shown in  was the Due to the limited number of portable devices, there is scope for further exploration. Given that wearable haptic devices are easy to use, it is expected that the number of these devices will increase tremendously. However, none of the studied devices have combined mobile and stationary components. For example, considering a hypothetical device with portable components that can be used alone and be coupled with non-portable components for a different experience.Lastly, the selected papers did not explore the concept of configurable haptic devices where users could customize their behaviour. A device that uses vibrations might allow users to adjust their intensity. Devices that detect sounds in the environment and map them to haptic stimuli, such as the one in , might aThis study reviewed recent peer-reviewed literature on haptic devices for DHH people. The selected studies showed that haptic devices exhibit extraordinarily varied aspects, while some other aspects, mostly related to hardware and technical features, much less so. Researchers might find it interesting to explore these lesser-represented topics in future studies, even though this is not necessarily a key issue.The haptic devices showed the most variations with respect to the number of stimulation zones, the area where the stimulation was applied, and the purpose of the device. Nevertheless, there were prevailing categories within each of these criteria. Most devices used a single location for the stimuli. Hand and finger stimulations were the most common application zones. Most of the devices were wearable and focused on alerts. Minimal variety was observed in terms of portability, general actuator type, or haptic stimulation type. Moreover, the majority of actuators were vibration motors. Finally, vibration was the only haptic stimulation method used.Placement of devices at other areas, such as those previously described, may receive more attention as the haptic device research area matures. Future research should focus on actuators on different body parts. If actuators can be used on the arms, legs, or chests, it will be useful for people without arms, for example. Further research must be performed on electrical and heat stimuli. Currently, the under-represented haptic devices may not be as convenient or practical as other alternatives, but this may be improved with technological advancements. It is also possible to use artificial intelligence in order to send alerts when a user needs to pay extra attention to sound stimuli by combining cochlear implants with haptic devices. Given that the global hearing-impaired population is expected to reach 2.5 billion by 2050 , devices