MicroRNAs (miRNAs) have been confirmed to be inextricably linked to the emergence of human complex diseases. The identification of the disease-related miRNAs has gradually become a routine way to unveil the genetic mechanisms of examined disorders.In this study, a method BLNIMDA based on a weighted bi-level network was proposed for predicting hidden associations between miRNAs and diseases. For this purpose, the known associations between miRNAs and diseases as well as integrated similarities between miRNAs and diseases are mapped into a bi-level network. Based on the developed bi-level network, the miRNA-disease associations (MDAs) are defined as strong associations, potential associations and no associations. Then, each miRNA-disease pair (MDP) is assigned two information properties according to the bidirectional information distribution strategy, i.e., associations of miRNA towards disease and vice-versa. Finally, two affinity weights for each MDP obtained from the information properties and the association type are then averaged as the final association score of the MDP. Highlights of the BLNIMDA lie in the definition of MDA types, and the introduction of affinity weights evaluation from the bidirectional information distribution strategy and defined association types, which ensure the comprehensiveness and accuracy of the final prediction score of MDAs.Five-fold cross-validation and leave-one-out cross-validation are used to evaluate the performance of the BLNIMDA. The results of the Area Under Curve show that the BLNIMDA has many advantages over the other seven selected computational methods. Furthermore, the case studies based on four common diseases and miRNAs prove that the BLNIMDA has good predictive performance.Therefore, the BLNIMDA is an effective method for predicting hidden MDAs.The online version contains supplementary material available at 10.1186/s12864-022-08908-8. MicroRNAs (MiRNAs) are a type of non-protein-coding ribonucleic acids with a length of approximately 22 nucleotides . It moduThe first category of computational methods is represented by models constructed on the basis of score functions. The assumption that functionally similar miRNAs are more likely to be linked with similar diseases was implemented in the computational method for inference of MDAs devised by Jiang et al. . This moThe second category of computational methods for predicting MDAs is represented by models constructed on the basis of complex networks. These models mapped matrices related to miRNA and disease into the networks to predict the score of MDAs. Among those models, Chen et al.  proposedThe third category of computational methods used for MDAs prediction is represented by models based on the machine learning algorithms. In this case, Chen et al.  proposedIn this study, we developed an MDAs prediction method based on a weighted bi-level network, named BLNIMDA. Specifically, a bi-level network is constructed based on the known MDAs as well as integrated similarities between miRNAs and diseases. In this constructed network, MDAs are defined into three categories, including strong associations, potential associations, and no associations. Then, each miRNA-disease pair (MDP) is assigned two information properties according to the bidirectional information distribution strategy. Finally, the association score of every MDP is obtained by averaging two affinity weights, which are derived from their information properties and association type. The Area Under Curve (AUC) values of five-fold cross-validation (FFCV) and leave-one-out cross-validation (LOOCV) are 0.9145 and 0.9176, respectively, which show that the BLNIMDA outperforms the other seven selected computational methods. Furthermore, the case studies based on four common diseases and miRNAs prove that the BLNIMDA has a good predictive performance. Thus, BLNIMDA can be used as a powerful tool to predict potential MDAs.g and miRNA h are confirmed to have an association, then The data of MDAs are obtained from the HMDD v2.0 , which chttp://www.cuilab.cn/files/images/cuilab/misim.zip. In this study, a g and miRNA h can be expressed as Wang et al.  developehttp://www.nlm.nih.gov/) contains the DAG information of all diseases. The semantic similarity scores between different diseases can be calculated by the relationship between their DAGs [Disease semantic similarity is calculated from the hierarchical directed acyclic graph (DAG) of each disease . The MeSeir DAGs , 20. Figwhere terature  The semaentclass1pt{minimaIt can be found that the more shared MeSH descriptor nodes in the DAG of the two diseases, the more similar the two diseases are. Therefore, the formula for calculating the semantic similarity score of disease I for brain neoplasms and liver neoplasms is shown in Fig. According to Eq. , \documementclass2pt{minimTo differentiate the semantic contribution values of different diseases, which appear in the same layer of the same disease DAG, another calculation frame  was propII, the formula for calculating the semantic similarity score of disease where whereFinally, the similarity of different diseases at the semantic level is obtained by averaging the above two frames, which is shown as follows:The GIP kernel  similariwhereThe original bandwidth t to 1.0 , 25.Whether miRNA functional similarity, disease semantic similarity or GIP kernel similarity, they only provide a single aspect of similarity. Therefore, it is essential to integrate the above similarity information to obtain a more accurate and comprehensive disease or miRNA similarity. For example, if miRNA An example of data processing, including the calculation of GIP kernel similarity and the process of integrating similarity, is shown in Figure SOn the basis of the hypothesis that functionally similar miRNAs are more likely to be linked with similar diseases, we proposed a method named BLNIMDA that combines the above-processed data, including integrated miRNA similarity, integrated disease similarity and MDAs and these data are mapped into a bi-level weighted network. The BLNIMDA predicts the MDAs based on this network and Fig. whereConsidering that the weak similarity nodes of  formula .16\documwhere  formula :17\documFrom disease to miRNA direction, the information property of each MDP is the same as the above steps, and the details are as follows:whereThe three types of miRNA-disease association are as follows:In the same way, from disease to miRNA, the affinity weight of each MDP are determined through information property and the MDA type. The specific definition is as follows:According to formulas - 21), t, t21), tA BLNIMDA calculation example, including the generation of two side information properties, the calculation of two affinity weights for each MDP and the MDA score, is shown in Figure STo validate the prediction performance of the BLNIMDA, we employed cross-validation, which is considered as a reasonably comprehensive measure. In this study, FFCV and LOOCV were used to verify the performance of the BLNIMDA. For the FFCV, all MDAs were randomly divided into five groups, and each group was chosen as the test sample set in turns. The remaining groups were used as the training sample sets. For LOOCV, each experimentally verified MDP was regarded in turn as the test samples where the rest of them were used as the training sample sets. The AUC and ROC were used to visualize the accuracy of the BLNIMDA in MDAs prediction. Specifically, the values closer to 1 indicated better performance of the BLNIMDA, on the contrary, the lower values of AUC revealed the worse prediction performance. By setting different thresholds, the ratio of samples above the threshold to other samples in all positive samples was taken as sensitivity (TPR), and the ratio of samples below the threshold to other samples in all negative samples was taken as 1-specificity (FPR). ROC curves were plotted by TPR and FPR under different thresholds.In the bidirectional information construction strategy, there are some noise nodes in the miRNA or disease similarity network, which may affect the performance of the BLNIMDA. In view of this situation, we set the parameter In order to show the superiority of the BLNIMDA, we compared seven models , 26, 27 In addition, an independent dataset was used as the test set to better verify the prediction performance of BLNIMDA. Considering that BLNIMDA uses HMDD v2.0 as its training set, the MDAs in the new version of the HMDD database (HMDD v3.2) not included in the training dataset were used as a test sample. The AUCs of BLNIMDA and the other seven methods are shown in Table To verify the accuracy of the BLNIMDA, we employ it to predict the association between miRNAs and four important diseases, including lung neoplasms, breast neoplasms, gastric neoplasms, and colon neoplasms.Colon neoplasms is one of the most common malignant neoplasms that seriously threaten human health, and its mortality rate ranks third in the world . AccordiAt the same time, we randomly selected four miRNAs and screened the top five diseases with their association scores. The predicted MDAs were verified in HMDDv3.2 and miRCancer databases, and almost all of them were confirmed by available evidence data and shown in Table Many miRNAs have been confirmed to have links with the occurrence of human diseases. Discovering the potential MDAs is of great significance for understanding the pathogenesis of diseases. Traditional methods for finding MDAs have some disadvantages such as low efficiency and difficult operation. Therefore, many computational models have been proposed, which are mainly divided into three categories, namely score function-based, complex network-based and machine learning-based. In this study, firstly, we proposed a computational method BLNIMDA based on a weighted bi-level network to predict the hidden MDAs. Specifically, the bi-level network is constructed based on the known MDAs as well as integrated similarities between miRNAs and diseases, in which nodes denote miRNAs and diseases. In this developed bi-level network, the MDAs are defined as strong associations, potential associations and no association according to the relationship between the miRNAs and diseases. Then, each MDP is assigned two information properties based on the bidirectional information distribution strategy. Finally, two affinity weights for each MDP are obtained from the information properties and the association type and then averaged as the final association score of every MDP. In experiments, FFCV and LOOCV are used to evaluate the performance of the BLNIMDA, and the AUC values of them are 0.9145 and 0.9176, respectively, which show that the BLNIMDA have advantages over the other seven computational methods. Furthermore, the case studies based on four common diseases and miRNAs prove that the BLNIMDA has good predictive performance. Therefore, BLNIMDA is an effective method for predicting hidden MDAs.The main contributions of the BLNIMDA are the ability for determining MDA type, and the introduction of two affinity weights in accordance to the bidirectional information distribution strategy and defined association types, which ensures the comprehensiveness and accuracy of the final prediction score for each MDP. However, BLNIMDA still has certain defects. First of all, the dependence on known information has not been completely eliminated. In addition, for the information between miRNAs and diseases, multiple dimensions similarity could be considered to improve prediction performance. Furthermore, BLNIMDA is essentially a traditional network method, which still needs to be improved through algorithms based on deep learning.In the future, we will consider in-depth researches for MDAs, such as the regulatory role of miRNAs in specific diseases and the multiple type MDAs instead of taking them as binary, which have important implications for the treatment of complex human diseases.In this study, a method BLNIMDA based on a weighted bi-level network was proposed for predicting the hidden associations between miRNAs and diseases. Highlights of the BLNIMDA lie in the definition of MDA types, and the introduction of two affinity weights by the bidirectional information distribution strategy. FFCV, LOOCV and case studies based on four common diseases and miRNAs are used to evaluate the performance of the BLNIMDA. The experimental results show that BLNIMDA has achieved excellent prediction performance. However, the BLNIMDA still has room for improvement, such as integrating more comprehensive data on the miRNA and disease similarities.Additional file 1: Figure S1. An example of data processing, including the calculation of GIP kernel similarity and the process of integrating similarity. Figure S2. A BLNIMDA calculation example, including the generation of two side information properties, the calculation of two affinity weights for each MDP and the MDA score.


Patients with congenital aural atresia (CAA) can present with concomitant temporomandibular joint (TMJ) retroposition, implying that even with a high Jahrsdoerfer score, canaloplasty and tympanoplasty cannot be performed. Therefore, this study aimed to summarize the clinical manifestations and share our diagnostic and treatment experience of this rare entity, which has not been described previously.Thirty patients (30 ears) with CAA and TMJ retroposition without maxillofacial dysplasia were included. Diagnosis was based on patient history, physical examination, pure-tone average test results, and temporal bone high-resolution computed tomography (HRCT) findings. Their Jahrsdoerfer scores and interventions were also recorded.Twenty-four and six patients among the 30 patients  had CAA and TMJ retroposition on the right and left sides, respectively. Seventeen ears had a normal auricle; most had an enlarged cavum conchae and a large tragus. Twelve ears had an accessory auricle, and two had a preauricular fistula. All external auditory canals had complete atresia, including four with a shallow concavity and four with a small orifice in the cavum conchae. Temporal bone HRCT revealed poor or undeveloped tympanic temporal bone in the diseased ears, atresia in the external auditory canals, and partial/complete occupation of the mandibular condyle with or without soft tissue. The average Jahrsdoerfer score was 8.17. Thirteen patients opted for different surgeries, three wore a bone-conduction hearing aid, and fourteen chose no intervention.CAA with TMJ retroposition was often unilateral, typically on the right side. Most patients had normal auricles, with an enlarged cavum conchae and a large tragus (“mirror ear”). Even with a high Jahrsdoerfer score, traditional hearing reconstruction surgery could not be performed. Patients can undergo Vibrant Soundbridge or Bonebridge implantation or wear bone-conduction hearing aids to improve hearing levels, or refuse intervention because of mild hearing loss. The TMJ location can be used as a Jahrsdoerfer Grading System supplement for preoperative evaluation. Congenital aural atresia (CAA) is an ear malformation evident at birth, with an incidence rate of 1:10,000–20,000 and a higher prevalence in men , 4. TherThis study aimed to summarize the clinical manifestations of patients with CAA and TMJ retroposition without maxillofacial dysplasia or any syndromes to provide a reference for diagnosis. Furthermore, we aimed to share our clinical experiences regarding interventions for these patients.We retrospectively analyzed the clinical data of 30 patients (30 ears) diagnosed with CAA with TMJ retroposition at our hospital between April 2012 and August 2021. Patients with maxillofacial dysplasia were excluded from the study.All auricles were classified based on the severity of auricular deformity as Grades I, II, III, IV, and normal , 5. In GPure-tone audiometry (PTA) parameters were measured using a US GSI-61  audiometer and analyzed. Bone conduction thresholds and air conduction thresholds were obtained at 0.25, 0.5, 1, 2, and 4 kHz. The air-bone gaps and average pure-tone threshold were calculated.All patients underwent high-resolution computed tomography (HRCT) of the temporal bone in our hospital using a Philips Brilliance 64 CT scanner  in a closed resting position. The imaging parameters were as follows: voltage, 120 kV; current, 200 mA; matrix, 512 × 512; and source image section thickness, 0.625 mm. Using a bone algorithm, the images were reconstructed in 1 mm slices in the axial, coronal, and sagittal planes. The window width was 4000 Hounsfield units (HU), and the window center was 700 HU. Two radiologists evaluated the external auditory canal (EAC), TMJ, and important middle and inner ear structures on HRCT images. An experienced otologist reviewed the cases, made a final diagnosis, and calculated the Jahrsdoerfer scores.Interventions for individual patients were recorded based on the Jahrsdoerfer scores, our clinical experience, and the requirements of patients and their families.Of the enrolled participants, 15 were men and 15 were women. Twenty-four participants presented with right-sided CAA, six with left-sided CAA, and none with bilateral CAA. The maximum, minimum, and average ages were 30, 4, and 9.53 years, respectively  implantation; one had auricular reconstruction and Bonebridge (BB) implantation on the contralateral side; four had unilateral/bilateral excision of accessory auricles; one had bilateral excision of accessory auricles and deformity side preauricular fistula excision; three wore a bone-conduction hearing aid; and 14 chose no intervention  and mandibular hypoplasia , 24. TheUsually, CAA with TMJ retroposition can be diagnosed based on careful physical examination and HRCT findings. However, those with a shallow depression or a small orifice in the cavum conchae could be misdiagnosed as EACS with cholesteatoma, which should be distinguished .The treatment objective includes improvement of esthetics and hearing. Auricular reconstruction and excision of accessory auricles and preauricular fistula could help to improve appearance. Hearing reconstruction methods are varied. In the early stage, due to our lack of experience with such diseases, we performed an EAC canaloplasty and tympanoplasty in patient No. 20 and an EAC canaloplasty in patient No. 27. We found that the operation was extremely difficult and the long-term hearing effect was not stable, despite short-term improvement following surgery. Therefore, we recommended VSB or BB implantation or the use of a bone-conduction hearing aid to improve hearing levels for future patients, even with a high Jahrsdoerfer score. However, some patients still chose observation and refused any treatment due to mild auricular deformity and hearing loss or the high price of hearing aids. Consequently, the final treatment strategy should be chosen based on both the wishes and economic conditions of patients and their families. Furthermore, some surgeries in the intervention were completed in stages, and the choice of hearing reconstruction method should consider the binaural condition.There are some limitations to our study. We conducted a retrospective study of our clinical findings; therefore, data were limited. Moreover, the sample size was small because it focused on a rare entity. Future prospective cohort studies involving these patients should consider increasing the sample size and obtaining more reliable data.CAA with TMJ retroposition was often unilateral, typically on the right side. Most patients had a normal auricle with an enlarged cavum conchae and a large tragus (“mirror ear”). Although the Jahrsdoerfer score was high, traditional hearing reconstruction surgery  could not be performed. Patients could choose auricular reconstruction or repair to improve esthetics, receive VSB or BB implantation or wear bone-conduction hearing aids to improve hearing levels, or refuse intervention entirely because of the mild hearing loss. Given that the location of the TMJ affects the choice of hearing reconstruction method, we suggest this as an adjunct to the Jahrsdoerfer Grading System for preoperative evaluation.


Age-related hearing impairment (ARHI) affects 20-40% of older adults. However, many people with hearing impairment fail to seek professional evaluation and treatment, delay seeking treatment, or abandon treatment. The purpose of this study was to identify barriers and facilitators of access to hearing healthcare resources in a rural setting and to characterize these barriers within the COM-B  framework. Survey packets were handed out following services at a rural community church; 72 completed surveys were returned. The mean age of participants was 54.4 years. Thirty-one percent of respondents reported moderate to severe hearing impairment; of these individuals, 7 (31%) were currently using a hearing aid. Rates of hearing protection use fell below the Healthy People 2020 target of 53% across occupational and leisure noise exposure. Forty-eight percent (N=34) of participants had never had their hearing tested as an adult. Overall perceived barriers were significantly correlated with age  and perceived hearing loss . Barriers were identified across all domains and subdomains of the COM-B framework. Barriers clustered in the reflective motivation domain, in which participants undervalue the significance of hearing loss. Barriers also clustered within the social and physical opportunity domains, suggesting a lack of access to providers and an undervaluation of hearing loss by others . These findings provide evidence regarding the accessibility of hearing healthcare services in rural settings and will serve as a foundation for the design of a community-tailored hearing health intervention.


Intralabyrinthine schwannoma is a rare, benign tumor that affects the most terminal portions of the vestibular and cochlear nerves. This tumor can be classified into 10 subtypes, according to its inner ear location.To carry out a comprehensive review of the most frequent auditory manifestations secondary to the intralabyrinthine schwannoma, describing the possible underlying pathophysiological mechanisms.Systematic review of the literature until October 2017 using the PubMed, Web of Science and Scopus databases. The inclusion criteria were clinical manifestations of the intralabyrinthine schwannoma. Three researchers independently assessed the articles and extracted relevant information. The description of a case of an intravestibular subtype intralabyrinthine schwannoma with multiple forms of clinical presentations was used as an example.Twenty-seven studies met our inclusion criteria. The most common intralabyrinthine schwannoma subtype was the intracochlear, followed by the intravestibular type. All the cases demonstrated hearing loss, usually progressive hearing loss.The diagnosis of intralabyrinthine schwannomas is based on high-resolution magnetic resonance imaging and should be included in the differential diagnosis of patients with vestibulocochlear complaints. Although there are approximately 600 cases in the literature, we still lack a detailed description of the clinical evolution of the patients, correlating it with MRI findings of temporal bones and tumor subtype. Intralabyrinthine schwannoma is a rare, benign tumor that affects the most terminal portions of the vestibular and cochlear nerves. It can be located in the vestibule, cochlea or semicircular canals.4In 1972, Karlan et al.6The intralabyrinthine schwannoma can be classified according to its location in the inner ear. Initially, seven subtypes were identified by Kennedy et al., and subsequently, in 2013, Van Abel et al., aiming at using a more specific nomenclature regarding tumor location, added another three subtypes .7, 8 TheTo the best of our knowledge, no previous study has stringently assessed the characteristics of hearing loss secondary to intralabyrinthine schwannoma and its association with the lesion subtype. Thus, the aim of this study is to carry out a comprehensive review of the most frequent hearing manifestations secondary to the intralabyrinthine schwannoma, describing the possible underlying pathophysiological mechanisms. At the same time, we report the case of a patient with hearing loss secondary to the intralabyrinthine schwannoma of the intravestibular subtype.A systematic review was carried out in the Pubmed, Web of Science and Scopus databases until October 2017. The following descriptors were used, indicated in the Portuguese language Health Sciences Descriptors (DeCS) terminology , as well as in the English language . The search strategies for the different databases are shown in The inclusion criteria consisted of studies describing clinical manifestations of intralabyrinthine schwannoma, irrespective of its subtype. Initially, the title and abstract in English were read, and then the full-text of studies that met the inclusion criteria were read in their entirety.Three investigators independently assessed the articles and extracted relevant information, and discrepancies were resolved by mutual agreement. In a complementary manner, we exemplified the literature review findings by describing a clinical case of an intralabyrinthine schwannoma (intravestibular subtype) with multiple forms of clinical presentation.The search for articles in the databases identified 330 articles, of which 27 were included in this review .Figure 1According to the Oxford Center for Evidence-Based Medicine classification about the levels of scientific evidence of the 27 articles read as full-text articles, 5 were Systematic Reviews (with homogeneity) of Cohort Studies (level 2A), 1 was an Article on Observation of Therapeutic Results, Ecological Study (level 2C) and 21 were Case Reports (level 4).Regarding the main tumor location, there was a consensus among the studies that the intracochlear subtype in all studies was the most frequent, followed by the intravestibular type, except the one by Salzman et al., who found the transmodiolar subtype as the second most frequent type .Table 3MRegarding the patients’ clinical picture, the main clinical manifestations are shown in Patient management reporting was carried out for 486 patients. In 276 patients (56%), clinical follow-up with serial MRI was chosen. In 210 (44%) patients, the patient chose the surgical management since most of them were patients with profound hearing loss and tumor growth evidenced by imaging examination and/or incapacitating vertigo without improvement with clinical treatment. Of the 210 patients submitted to surgical treatment, there are reports of cochlear implant surgery simultaneously or immediately after tumor excision in 11 patients.A 38-year-old female patient came to the outpatient clinic to have a consultation with an otorhinolaryngologist due to dizziness and imbalance for 3 years. She reported that each episode lasted only a few seconds, with no triggering factors or symptom improvement or worsening. The events were of minimal intensity and did not hinder the activities of daily living. After a few weeks of the condition onset, the dizziness became rotational and was triggered by head movements to the left. This dizziness symptom with a new characteristic lasted for minutes and also ceased spontaneously. When questioned, she denied headaches, visual or auditory symptoms associated with dizziness. She also denied comorbidities or continuous intake of medications for any disease.The general physical examination, otorhinolaryngological evaluation and neurological tests did not show any alterations, nor did the auditory assessment (audiometry and immittance audiometry). The patient was also submitted to video-electronystagmography, which showed left hypofunction on the caloric test. Considering the results of the physical, audiometric and vestibular function tests, β-histamine therapy was started, of which dose was gradually increased in the first 60 days until reaching the maximum recommended dose (216 mg/day) in addition to meclizine. However, the patient did not show improvement with the use of the medications.Four months after the initial consultation, the patient noticed a worsening in the frequency and intensity of rotational dizziness when exposed to specific sounds, such as alarms and sirens; the dizziness ceased as soon as the sound triggering it was interrupted. Six months after the condition onset, she also noticed ear fullness in the left ear associated with a hissing-type tinnitus, in addition to difficulty in understanding sounds in that ear.These symptoms  showed fluctuation, with moments of worsening and spontaneous improvement; in the moments of hearing worsening, she also noticed rotational dizziness worsening. Considering the worsening of the symptoms, the patient was evaluated by new serial audiometries, which showed fluctuation of auditory thresholds compatible with clinical worsening. She then underwent an MRI of the temporal bones, which disclosed a left vestibular lesion .Figure 3When she underwent vestibular function examination by vestibulo-ocular reflex detection through the had impulse test, she showed a normal vestibular-ocular reflex in all right semicircular canals assessed. On the other hand, regarding the left canals, there was a decreased vestibulo-ocular reflex gain in the lateral and anterior canals, with covered and uncovered corrective saccades; however, the vestibulo-ocular reflex gain of the left posterior canal was normal . Based oBecause it was a millimetric lesion, with little impact from the auditory point of view, it was decided to follow the patient by repeating the MRI and the audiometry annually .Figure 5In the third year of follow-up, the patient showed sudden hearing loss in the left ear, without worsening of the vestibular complaints. A new audiometry showed profound hearing loss in the left ear, compatible with the diagnosis of sudden sensorineural hearing loss, or sudden deafness .At this time, treatment with oral prednisolone (1 mg/kg/day) was started, lasting for 21 days at regressive doses, and an MRI of the temporal bones was carried out . The MRIRepeating the vestibular function examination by detecting the vestibulo-ocular reflex through the head impulse test at that moment showed that the previously investigated right semicircular canals remained normal. There was a significant decrease in gain at the left in all assessed semicircular canals with compensatory saccades .Figure 7After 21 days of treatment, the patient did not show any improvement from the point of view of hearing function or body balance. Therefore, translabyrinthine surgery was chosen, as the patient had no hearing to be preserved as she had before.It is still difficult to estimate the real prevalence of intralabyrinthine schwannomas, due to the small number of reported cases and the lack of specificity of their clinical manifestations, which makes them difficult to diagnose. Moreover, the clinical picture may suggest other more frequent diagnoses, which include Meniere's disease, vestibular neuritis or sudden idiopathic hearing loss.Another topic still debated in several studies is the tumor origin. Although some studies suggest that it is not possible to clearly identify the tumor origin,As for the clinical picture of the patients with intralabyrinthine schwannoma, there have been no studies that correlated tumor location with patient complaint. Moreover, studies describing long-term follow-up, changes in the clinical picture during tumor evolution and tumor radiological evolution are scarce and document limited samples. Therefore, our study seems to be the first one in the literature to correlate, based on a case report, the tumor subtype with the clinical manifestations, in addition to describing the clinical evolution and results of auditory and imaging tests in a long-term follow-up.In our review, the main clinical manifestation observed in patients with intralabyrinthine schwannoma, regardless of the subtype, is hearing loss, being usually sensorineural, progressive, with low speech discrimination.Although there is still no consensus regarding the pathophysiology of hearing loss in these cases, it is believed that in the intracochlear schwannoma, the loss is a consequence of direct compression or destruction of the cochlear nerve. In tumors located inside the vestibule, the hearing loss can be explained by the hydrolymphatic hydrops, which would cause compression of the adjacent structures.Although not limited to it, the complaint of vertigo occurs more frequently in the intravestibular schwannoma.The main clinical manifestation of patients with intralabyrinthine schwannoma is hearing loss, present in approximately 100% of the reported cases.The authors declare no conflicts of interest.


However, not everyone who needs them has them, and of those who do, a significant proportion of people do not use them at all, or use them infrequently. Despite literature reviews listing key barriers and enablers to the uptake and use of hearing aids, there is little evidence to describe how this varies by population and context. This review will describe The aims of this review are as follows: (1) To iteratively review and synthesise evidence surrounding the provision of hearing aids for hearing loss in adults. (2) To generate a theory-driven understanding of factors that are important, for whom, and in what context. (3) To develop a programme theory describing contexts that can support the provision of hearing aids to result in improved outcomes for adults with hearing loss. A scoping literature search will aid the development of programme theories, to explain how the intervention is expect to work, for whom, in what circumstances and in which contexts. We will locate evidence in the following databases: CINAHL, Cochrane Library, EMBASE, MEDLINE, PsycINFO, PubMED, Web of Science with no date restrictions. A realist analytic approach will be used to refute and refine these initial programme theories. Throughout the review, relevant key stakeholders  will be consulted to test and refine the programme theories.This study was approved by the University of Nottingham Faculty of Medicine and Health Sciences Research Ethics Committee: (FMHS 95-0820) and the London Brent NHS Research Ethics Committee (Ref: 21/PR/0259). The review will be reported according to the RAMESES guidelines and published in a peer-reviewed journal.CRD42021282049. The review team is interdisciplinary including expertise in adult aural rehabilitation, clinical audiology service provision and health behaviour change, which will support the development of robust programme theories across different disciplines.Using a realist approach to identify context, mechanism and outcome configurations will further our understanding of why the provision of hearing aids results in different outcomes across adults with hearing loss.The review may be limited by the richness and relevance of evidence relating to mechanisms of change and contextual elements available in the literature.Hearing loss represents a major public health concern and a growing disease burden in an ageing global population, with the vast majority of losses attributed to age-related sensorineural degeneration.2 3More than 40% of people aged over 50 years old live with hearing loss, increasing to more than 70% of those aged 70 years or older.7In the absence of medical or surgical treatments for sensorineural hearing loss,The impacts of untreated hearing loss in adults are far-reaching and include problems with listening and communication,29Due to its typically gradual onset, recognition of acquired hearing loss can be poor among those affected, which can result in a delay in help seeking of up to 10 years.32Once referred for hearing assessment, a clinical decision will be made regarding eligibility for hearing aid provision. For those who are eligible, a diverse range of barriers to hearing aid use, benefit and satisfaction have been reported in the literature, including discomfort, sound quality, perceived benefit, background noise, sound of own voice, ear infections, wax, manual dexterity problems, perceptions of the clinician or service, patient–clinician rapport, peer support, perceived stigma and self-stigma.In 2015, the UK Action Plan on Hearing Loss set out five key objectives to tackle the rising prevalence and personal, social and economic costs of uncorrected hearing loss. It provides a national plan to spread good practice and address variation in access and quality of services experienced by people with hearing loss. The key objectives are as follows: early diagnosis, integrated patient-centred management, ensuring those diagnosed do not need unscheduled care or become isolated and ability to partake in everyday activities including work.Realist review is a theory-driven approach to reviewing and synthesising evidence to understand complex interventions.What factors are important to whom in what context, when adults are prescribed hearing aids for hearing loss?To iteratively review and synthesise evidence surrounding the provision of hearing aids for hearing loss in adults.To generate a theory-driven understanding of factors that are important, for whom, and in what context.To develop programme theories describing contexts that can support the provision of hearing aids to result in improved outcomes for adults with hearing loss.What are the reasons for low hearing aid uptake, use and adherence?People with hearing loss, their family and clinicians helped define the topic of this review via a James Lind Alliance priority setting partnership,This protocol has been reviewed by a Patient Research Partner who has lived experience of managing hearing loss with hearing aids, for content, clarity and relevance.This realist review will formulate, test and refine programme theories to generate new insights into factors important for the provision of hearing aids for hearing loss in adults.how an intervention is expected to work,whom, in what circumstances and in which contexts.A programme theory is an overarching theory which explains If an audiologist discusses, describes and explains the extent and implications of a patients hearing loss during the hearing assessment appointment and offers the patient an opportunity to ask questions, then the patient has an increased understanding of their hearing loss and how it affects them personally which results in greater acceptance of their hearing loss and an increased readiness to address their hearing loss through the use of hearing aids.The review started in September 2021 and the anticipated end-date is no later than end May 2023. It will follow Pawson’s five stages in conducting realist reviewsA scoping search will be conducted to locate and generate initial programme theories which relate to the provision of hearing aids for adults with hearing loss. This process will be two-fold:An exploratory informal literature search of explanatory theories which may be relevant to explaining how the intervention works.Reviewing primary data exploring views and experiences of barriers and facilitators to using hearing aids from focus groups and semistructured interviews with relevant stakeholders  previously conducted by the research team.The scope will include the provision of hearing aids in adult auditory rehabilitation and will include wider relevant literature on personal factors  and social factors  which may influence which elements works well within hearing aid provision.Documents sourced within the scoping search will be examined for evidence which will be used to develop initial programme theories of the provision of hearing aids to adults with hearing loss and thus explain how hearing aid provision is supposed to result in its intended outcome . The initial programme theories developed from the scoping search will be revised by members of the research team who have knowledge of the field of adult auditory rehabilitation including academics, audiologists and public involvement representatives. The initial programme theories will be then tested, developed and refined against data from documents included in the review.To identify suitable evidence to test and refine the initial programme theories developed in step 1.Following the convention of a realist review, the search strategy will be purposive and will include the following elements:Search terms will be entered into the following electronic databases: CINAHL, Cochrane Library, EMBASE, MEDLINE, PsycINFO, PubMed and Web of Science, Google Scholar and NICE Evidence search or equivalent. The list of search terms will be piloted and modified with an information specialist. An example of the search terms for PubMed is given in Interrogation of reference lists of relevant reviews and primary studies, with forward and backward citation tracking.Searching grey literature including policy documents, charities, user groups and patient associations.10.1136/bmjopen-2021-059836.supp1Supplementary dataBox 1Search terms in Medline (OVID)exp Hearing Loss/exp Deafness/exp Persons With Hearing Impairments/exp Presbycusis/(hearing loss* or deaf* or hearing impair* or hearing disabilit* or hearing disorder* or hearing handicap* or hearing problem* or presbycus* or presbyacus* or auditory rehabilit*).af.exp HearingAids/(hearing aid* or listening device* or sound amplif* or acoustic amplif* or hearing device*).af.(treatment adherence and compliance).mp. exp Patient Compliance/(prescri* or provi* or complian* or cooperat* or co operat* or non complian* or noncomplian* or non adheren* or nonadheren* or accept* or nonaccept* or satisfaction or benefit* or adapt* or perception* or use* or usage or adopt* or uptake* or reject* or return* or success* or orientat* or take-up or utilis* or non-use).af.1 or 2 or 3 or 4 or 56 or 78 or 9 or 1011 and 1213 and 1415 and ‘Adult’.sa_suba.There will be no date restrictions for the formal searchThe search terms were developed in collaboration with information specialists at the University of Nottingham Libraries.Initial searches were conducted March 2022. As the review progresses additional searches will be undertaken, as required, throughout the synthesis. Additional data will be used to test the programme theories until theoretical saturation has been achieved.39Document selection will be based on the extent to which identified evidence can contribute towards testing and development of the initial programme theories developed in step 1.Inclusion criteria:Adults provided with hearing aids for the primary complain of hearing loss.Any healthcare practitioners, for example audiologists, supporting adults provided with hearing aids for hearing loss.Communication partners, for example family members, supporting adults provided with hearing aids for hearing loss.Adult audiology patient pathway including assessment and auditory rehabilitation.Any study design. Documents such as editorials, opinion pieces, commentaries, process evaluations, qualitative research, programme manuals and systematic reviews may be included, if holding information relevant to developing a programme theory.Any outcomes related to the use of hearing aids by adults with hearing loss.Exclusion criteria:Participants <18 years old.Documents which do not summarise an empirical study.Non-English papers.Documents identified during the search strategy will be downloaded into Endnote reference management software where duplicate returns will be removed, then returns will be imported into Covidence review management software for document screening, and data extraction.Selection of relevant evidence will be systematic and will follow a two-step procedure. The titles and abstracts will first be independently screened by two reviewers to assess eligibility for inclusion. Subsequently, the full text of potentially relevant documents will also be independently screened by two reviewers to assess against eligibility criteria for inclusion in the review. The full text will be obtained for documents where the title and/or abstract is too vague to clarify whether they meet the inclusion criteria. The following identification tool, comprised of three questions, will be used to assist with the screening of evidence:49Does the document summarise an empirical study of hearing aids for adults with hearing loss?Does the document indicate the specific context of adult auditory rehabilitation?Does the document provide data on patient outcomes?A list of reasons for exclusions will be recorded by the reviewers. Disagreements will be discussed by both reviewers until a consensus is reached. The wider research team will adjudicate any contested evidence if required.The selection criteria listed below will be applied by the reviewers to the full text of all potentially relevant documents. There will be no restrictions to types of study design eligible for inclusion in keeping with realist review guidelines.Selection tool adapted from the following:49Does the full-text document still indicate adult audiology patient pathway?Does the full-text document describe the setting ?Does the full-text document indicate empirical research ?Does the full-text document describe a population who are provided hearing aids for hearing loss as the primary complaint ?Does the full-text document describe any outcomes related to the use of hearing aids by adults with hearing loss ?Does the full-text document describe the processes or context related to the provision of hearing aids for adults with hearing loss (or is there a reference to the process/context in a companion document)?Document screening and selection will be recorded using an adapted Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram.50During the data extraction phase, the full text of the documents will be screened for their relevance to the initial programme theories, and their rigour, using the definitions below:51Relevance: whether the study contributes to the development of the programme theories under examination.Rigour: whether the methods used to draw inferences are credible and trustworthy to test a particular theory in terms of sample size, data collection and analysis and inferences drawn by the authors.51The realist approach does not adhere to the hierarchy of study designs used in other types of review for example, systematic reviews. In realist review, diverse data sources will be used to further our understanding of how and why programmes function.relevance and rigour. The following process will be employed:The quality appraisal process involves assessing each document on a case-by-case basis for the concepts of Reading the full-text document in its entirety.Documenting what contribution the document makes to the synthesis (relevance) for example, does the document contain content which can be examined against the initial programme theories? Does the document contain information on how the programme works?Documenting any methodological or conceptual difficulties with the document (rigour) for example, appraising the quantitative or qualitative methods used.Relevance and rigour characteristics of included studies will be recorded in a bespoke data extraction form.A 10% random sample of included study documents will be selected, assessed and discussed regarding quality appraisal, with a second reviewer for consistency. Any disagreements or ambiguity in relevance or rigour will be resolved by discussion with the wider review team to enhance validity and consistency.Data extraction for selected documents will follow a hybrid approach and will be undertaken by the lead reviewer, and a second reviewer. This approach to data extraction includes manually theory-tracking by highlighting, annotating and note-taking as well as the use of a bespoke data extraction form to provide a descriptive overview of the evidence.39 54The bespoke data extraction form will be developed, piloted with a small sample of included documents , and used to record pertinent characteristics of each included document. As the review progresses and the initial programme theories are iteratively refined, the data extraction form will be modified to ensure all new insights which are relevant to the programme theories are captured. As the data extraction form is modified, included documents will be revisited to ensure that all appropriate and relevant data is extracted. The data extraction form will record the following information:Document information: authors, publication date, document type, where and how the document was sourced.Context: geographical location, healthcare system context.Design: research aim, design, methods, setting, intervention details , method of assessment, and summary of reported outcomes.Relevance to the review question.It is anticipated that not all of these aspects will be available for each document.The theory-tracking phase of data extraction will be guided by the initial programme theories developed in step 1. Selected texts will be imported into a data management software and relevant sections of the document text will be reviewed, highlighted and annotated in relation to contexts, mechanisms and outcomes and/or their relationships. In this phase, any information which relates to theories on how or why the intervention works or does not work will be examined and recorded.Codes will cover concepts which are considered important and relevant to the initial programme theories. Coding of the data will be both inductive  and deductive ; both approaches will be used to identify contexts, mechanisms and outcomes and the associations between them. The data will be used to refine the initial programme theories, into configurations of contexts and main mechanisms which influence specific outcomes for different populations. As the theories are refined, the included studies will be revisited to search for data relevant to the revised programme theories.Step 4 will use a realist analytic approach to build on the evidence, refute or provide alternative explanations for key factors associated with hearing aid provision for adults with hearing loss. The analysis will focus on refining the programme theories to explore what works well in hearing aid provision, how different elements are thought to have made this happen and what needs to be in place for this to occur. Again, this process will be iterative, interrogating and refining the initial programme theoriesThe following realist synthesis strategies will be employed:Organising extracted data from the included documents.Identifying similarities and juxtapositions across each data source aligned to the realist concepts of context, mechanism, and outcome.Examining and exploring disparities between the data.Moving within and across each data set, linking demiregularities (patterns) in the data to test and refine each programme theory.As the synthesis progresses, it may be necessary to conduct additional iterative literature searches, in order to examine or explore particular aspects of the refined programme theory. Any additional documents identified will provide evidence to support, refute or refine the programme theory.55The data synthesis process will involve reflection and discussion with the research team. Stakeholders, identified through professional contacts of the research team, including healthcare professionals, people with hearing loss and those who they communicate regularly with will be consulted and will assist in the refinement of the final programme theory through workshop discussions.Ethical approval for the primary data component of our review was granted by both the University of Nottingham Faculty of Medicine (Ref: FMHS 95-0820) and the London Brent NHS Research Ethics Committee (Ref: 21/PR/0259).Findings will be presented in narrative form and will include tables and figures, with a diagram used to present the final programme theories. The review will be reported in line with the RAMESES standards.This realist review will provide a theory-driven understanding of what works in terms of the provision of hearing aids for hearing loss in adults. Data generated in this review will provide new insights into causal mechanisms which influence hearing aid provision and outcomes for adults with hearing loss, to further our understanding about how adult hearing healthcare and hearing services may be improved in future.


Apophysomyces variabilis was involved. This is the first published case of CAM and the third case of mucormycosis due to this mold.A fatal case of COVID-19-associated mucormycosis (CAM) affected a 40-year-old woman who was initially admitted to our hospital due to a SARS-CoV-2 infection. Her clinical condition worsened, and she finally died because of respiratory failure, hemodynamic instability, and mucormycosis with invasion into the orbit and probably the brain. According to DNA sequence analysis of the fungus isolated from the patient,  Mucormycosis (zygomycosis) is a disease caused by an opportunistic infection in humans and animals by members of the order Mucorales . MucormyMost severe cases of COVID-19 suffer from low oxygen levels, high iron levels, a hyperglycemic state, acidosis, and lowered phagocytic activity. These conditions facilitate opportunistic fungal infections, such as mucormycosis . RecentlRhizopus. Other etiological agents include Mucor, Rhizomucor, Lichtheimia (previously known as Absidia), Apophysomyces, Saksenaea, Cunninghamella, Syncephalastrum, and Cokeromyces  due to On 11 September 2021, a 40-year-old Afghan woman was hospitalized in Shahid Beheshti Hospital, Kashan, Iran, due to COVID-19. She had a fever, dry cough, dyspnea, hemoptysis, myalgia, and severe weakness, which had been ongoing for 5 days. Physical examination revealed a body temperature of 38.7°C, a blood pressure of 100/80 mm Hg, a respiratory rate of 26 breaths per minute, and an oxygen saturation of 90% on ambient air. Laboratory examination revealed leukopenia, lymphopenia, and a significant increase in C-reactive protein (CRP), and the patient underwent oxygen supplementation therapy. Nasopharyngeal and oropharyngeal swabs were obtained and subject to a real-time reverse transcriptase polymerase chain reaction test using the Light Cycler 96-well system  for SARS-CoV-2 targeting N and RdRp genes  . The samhttps://blast.ncbi.nlm.nih.gov/Blast.cgi) queries. The isolate was identified as A. variabilis, with a 99.86% sequence identity to the reference sequence. The sequence has been submitted to GenBank under the accession number OL804547.The clinical samples obtained using sterile swabs and cultured on Sabouraud dextrose agar plates containing chloramphenicol (50 mg/L)  yielded colonies of fluffy, cottony growth that filled the plate within 4 days. The colony surface was white when young, becoming cream-to-yellow or brownish-gray later on . The intCandida parapsilosis ATCC 22019 was used as quality control. AFST of the isolate against amphotericin B, fluconazole, itraconazole, voriconazole, posaconazole, and isavuconazole revealed minimum inhibitory concentration (MIC) values of 2, >64, 1, >16, 0.5, and 2 μg/ml, respectively, and minimum effective concentration (MEC) for caspofungin was >8 μg/ml. Written informed consent was obtained from the next of kin of the patient for the publication of any potentially identifiable images or data.Antifungal susceptibility testing (AFST) was performed based on the Clinical and Laboratory Standards Institute (CLSI) M38-A2 broth Dilution AFST , and theA. variabilis occurring in an apparently immunocompetent patient with severe COVID-19, with fungal identification obtained using sequencing of the ITS region of ribosomal DNA.We report the first case of CAM caused by Mucormycosis is the third most common opportunistic invasive fungal infection and is characterized by high morbidity and mortality in immunocompromised and immunocompetent hosts . It maniRhizopus is the genus most commonly involved in human mucormycosis, followed in frequency by Mucor and Lichtheimia, together representing 70%–80% of all cases of mucormycosis, whereas Apophysomyces spp. account for less than 3% of the infections , a high temperature in comparison to other human pathogens (37°C–42°C), and prolonged incubation (7–10 days)  . In spitbidities .Recent studies have shown that CAM may occur especially in immunocompromised hosts . A numbeA. variabilis has most often been isolated in cases of cutaneous mucormycosis . Written informed consent was obtained from the next of kin of the patient for the publication of any potentially identifiable images or data.ME and SA performed all the experiments and participated in data collection. SA drafted the manuscript and assisted in data analysis and interpretation. ME, MH, JH, AA, and SS participated in collecting the clinical isolate and in data collection. HM was in charge of supervising the study and critical review of the manuscript. All authors contributed to the article and approved the submitted version.This work was supported by Isfahan University of Medical Sciences, Isfahan, Iran (grant number 1400180), which we gratefully acknowledge. Also, the authors thank the staff at Shahid Beheshti Hospital, Kashan, Iran.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.


To evaluate the association between hearing threshold and reduced physical performance in older people.Association between a higher hearing threshold and poorer physical performance was observed.It is important to assess balance and falls risk in older people with hearing loss. To evaluate the association between increased hearing loss and reduced physical performance in older people.N = 13,197). Analyses were performed on all participants who had completed audiometry and measured balance using the Short Physical Performance Battery (SPPB), which was scored from 0 (worst score) to 12. The hearing threshold was expressed as a pure tone average (PTA). Associations between the hearing threshold for the best and worst ear and physical performance were analyzed by linear regression models adjusted for age, sex, education, diabetes, and cardiovascular disease. Hearing threshold was indicated with steps of 10 dB.Cross-sectional population-based study using data from the fourth wave of the Trøndelag Health Survey (HUNT4) in Norway. Data were obtained from the subproject HUNT4 Hearing which collected audiometric data of people > 70 years  and the worst ear .Of 13,197 eligible participants, 4101 who completed audiometry and SPPB (52.3% women. mean age 76.3 years) were included. The analyses revealed an association between reduced SPPB and increased hearing threshold in the best ear (In this population study, we found that the increased hearing threshold was associated to reduced physical performance as measured by SPPB. The association seemed to be strongest for the best ear. The association between hearing threshold and physical performance illustrates the importance of assessing physical performance in people with hearing loss to prevent the risk of falls and disability. The underlying causes of the associations between hearing loss and poorer physical performance are not fully understood and should be further investigated.Level 3. Approximately 1.57 billion people live with hearing loss worldwide, and this is projected to increase to 2.45 billion by 2025. In 2019, hearing loss was the third leading cause of years lived with disability for all ages, and the leading cause among those who were 75 or older .Age-related hearing loss is associated with many factors such as long-term exposure to noise, genetic predisposition, chronic diseases , ototoxic medications, poorer socioeconomic status and unhealthy lifestyle (e.g. smoking) , 4. VeryThere is evidence to suggest that a higher hearing threshold is associated with poorer physical performance in older people , but furThe present study is a cross-sectional population-based study using data from HUNT4. While the proportion of people with higher educational levels and number of immigrants in this part of Trøndelag is slightly lower, the general health, unemployment rate, disability insurance, and mortality rate are close to the national average . 13,197 Inclusion criteria for the present study were the availability of audiometric and physical performance data based on the SPPB. The current study included 4110 people with such data participating in both HUNT70+ and HUNT4 Hearing. The data collection for HUNT4 70+ and HUNT4 Hearing took place from September 2017 until March 2019 . ParticiHearing was examined without hearing aids by air-conduction pure-tone audiometry at eight frequencies from 0.25 to 8 kHz. For this study, the pure tone-average (PTA) was calculated separately on each ear as the average hearing thresholds from the frequencies of 0.5, 1, 2 and 3 kHz, measured in dB hearing level (HL) as recommended by the Hearing Committee of the American Academy of Otolaryngology—Head and Neck Surgery . The assPhysical performance was measured using the SPPB. The SPPB was developed to measure physical capability and to assess the lower extremity physical performance status of an older individual . SPPB haThe participant can be awarded 0–4 points for each task, and so the total score can vary from 0 to 12. For interpretation, 0–6 is considered a low score, 7–9 a middle score, and 10–12 a high score. For a detailed description of how points are awarded, please see Guralnik et al. .http://www.dagitty.net/). The DAGitty was designed to create, edit and analyze causal diagrams for minimizing bias in empirical studies in epidemiology and other disciplines [To assess the independent role of hearing on physical performance, we accounted for other variables that may have an impact on both hearing and physical performance. To select variables for adjustment, we used direct acyclic graphs (DAG) and the online software DAGitty . To examine the relationship between hearing threshold (independent variable) and SPPB (dependent variable), we used linear regression models. Information on sex, age, education, diabetes, cardiovascular disease, PTA variable, total SPPB score, static balance, gait speed and chair rise were quantified using descriptive statistics. The complete SPPB score, static balance, gait speed, and chair rise were outcomes under study. The PTA hearing thresholds in the better and the worse ear were the main exposures. Analyses were performed crudelu and after adjustment for the following potential confounding factors: sex, age, education, diabetes and cardiovascular diseases as independent categorical variables in the regression models.Among 4110 participants with a total SBBP score who were included in the analyses, 9 did not have complete hearing data. To analyze the association of hearing threshold with SPPB total score, and the separate tests standing balance, gait speed and chair stand, we included 4101 participants with complete information about their age, 4067 with complete information on education, and 3846 with complete information on cardiovascular diseases and 4002 on diabetes. We had no information about how many of those included lived in their own homes and were tested at the test stations, and how many were nursing home residents. Demographic data on the study participants, and comorbidities, as well as summary statistics on hearing thresholds and SPPB scores are shown in Tables Table Table In this cross-sectional population-based study, we examined the association of hearing threshold with physical performance in 4101 older people in the HUNT4 study, making this one of the largest studies on the topic to date. We found that a higher hearing threshold measured by audiometric tests was associated with poorer physical performance as measured by SPPB.Our results suggested that the association between hearing threshold and physical performance was stronger for the best ear, compared with the worst ear. This is in line with the findings of Berge et al., who found a stronger association between body sway and best ear hearing in adults who attended a specialist clinic for vestibular complaints . In otheIn Tables Overall, the 70–75 years group had an average total score of 11 on the SPPB, and the group that was 80 years or older had an average of 9.1 , the researchers found that approximately 35 percent had mild cognitive impairment and 15 percent had dementia. We cannot say that these proportions apply to our sample, but we assume that a fair number of our participants also had dementia or mild cognitive impairment. Lack of knowledge about cognitive status limits the interpretation of our results, as associations between cognition, and disability, frailty and physical performance have been found previously [The link between dementia and hearing loss in older adults has been the focus of increasingly more research and cognitive function may therefore represent a confounder in our study. In memory clinic patients, individuals with severe hearing loss measured by audiometry had significantly more dementia than others . In a reeviously , 39. CogStrengths of our study include the large population-based sample, objective hearing assessments and a balance test that is widely used in clinical practice. The large number of participants included in this study provides the good statistical power to detect associations. However, 13,197 people were invited to participate in both the 70+ -cohort and hearing study of HUNT4. Of these, only 4101 had audiometry and underwent the SPPB test. As such, the generalizability of our study results can be questioned. Further, we do not have information about how many of the participants were ones that lived in their own homes, and how many that were in residential care. A selection towards healthier subjects in terms of both balance and hearing loss may have underestimated the associations. Since this was a population study, we have limited data on the diagnosis of both hearing loss and reduced physical performance in individual cases. Conductive hearing loss could not be analyzed, since bone conduction thresholds were not available to us. However, in the elderly, sensorineural hearing loss is predominant, and at least unilateral conductive hearing loss can be ruled out as a major factor since physical performance was most strongly related to hearing threshold on the best hearing ear. This applies to both hearing and physical performance. Therefore, we were provided solely with data on air conduction and not on bone conduction. Tests of vestibular function could have given relevant information on some of the causes of reduced physical performance. However, previous studies  indicated that poor balance even in dizzy patients may be more related to age and general physical weakness than to peripheral vestibular function as measured by the caloric test. Another limitation is that we have no information about the use of hearing aids during balance testing. Rumalla and co-authors found that physical performance was better when habitual hearing aid users wore them compared to when they did not , 41. It In conclusion, an increased hearing threshold is associated with poor physical performance in a population-based study of older people. For this reason, it is relevant to assess falls risk in older patients with increased hearing threshold due to hearing loss. Likewise, older people with reduced physical performance should be screened for symptoms of increased hearing threshold. It is not clear whether treatment of hearing loss leads to improved postural stability or physical performance. Further research is needed to investigate possible preventive measures that may improve both hearing threshold and physical performance in the aging population, and to investigate the possible causality between increased hearing threshold and physical performance. This could be researched through cohort studies or experimental studies.


This study aimed to examine the relationship between Dietary Phytochemical Index (DPI) and resting metabolic rate (RMR), mediated by inflammatory factors, in overweight and obese women.Unhealthy dietary patterns are the most important modifiable risk factors for obesity and overweightA total of 404 women, aged 18–48 years, were included in the cross-sectional study. DPI was calculated using the 147-item food frequency questionnaire (FFQ). Anthropometric measurements, RMR, and blood biomarkers were assessed using standard protocols.P = 0.09). After adjusting for potential confounders, a significant association was seen between the DPI and increase RMR.per.kg . Our results indicated that plasminogen activator inhibitor-1 (PAI-1), transforming growth factor (TGF-β), and monocyte chemoattractant protein-1 (MCP-1) had a mediatory effect on the association between RMR and DPI (P > 0.05). Indeed, it was shown that, PAI-1, TGF-β, and MCP-1 destroyed the significance of this association and could be considered as mediating markers. However, no mediating effect was observed for high-sensitivity C reactive protein (hs-CRP).There was marginally significant association between adherence to DPI and RMR status in the crude model (OR = 1.41, 95% CI 0.94–2.11, Adherence to DPI can improve the RMR by reducing levels of inflammatory markers, and may be considered as a treatment for obesity. However, more long-term studies are recommended. Obesity is defined as an excessive increase in adipose tissue, that may increase the risk of other chronic diseases, such as diabetes mellitus, cardiovascular disease (CVD), inflammatory disorders, high blood pressure, cancers, etc. [Incidence of overweight and obesity , aged 18–48 years, an absence of any acute or chronic inflammatory disease, no history of hypertension, no alcohol or drug abuse, and not being pregnant. Accordingly, participants who had a history of diabetes mellitus, stroke, kidney disease, and cancer, cardiovascular and thyroid diseases were excluded from the study. Furthermore, we excluded those women with weight loss history in recent years, menopause, smokers, and those who reported total daily energy lower than 800 kcal/d (3347 kJ/d) or higher than 4200 kcal/d  [In this cross-sectional study, 404 overweight and obese women were recruited between 2017 to 2019, from health centers of all the regions of West and Central Tehran, using community-based comfort sampling. The protocol was accepted by Ethical Commission at Tehran University of Medical Science (IR.TUMS.VCR.REC.1395.1597). All methods were performed in accordance with the declaration of Helsinki. This study was supported by grants from the TUMS . All participants were invited to the nutritional laboratory of Tehran University of Medical Sciences and all signed a written informed consent prior to participation in the study. The study participants were selected based on pre-defined inclusion criteria, body mass index (BMI 25–40 kg/m73 kJ/d) .2 and obesity is grading Grade 1, 2 and 3 as 30 ≤ BMI ≤ 34.9 kg/m2, 35 ≤ BMI ≤ 39.9 kg/m2 and BMI ≥ 40 kg/m2.Body weight was measured with a calibrated digital scale to the nearest 0.1 kg with minimum of clothes and without shoes. Standing height was measured with an accuracy of 0.5 cm without shoes, using a tape measure. BMI was calculated by weight (kg)/ height (m) squared. A non-elastic tape was used to assess waist and hip circumferences to the nearest 1.0 cm. These measurements were performed in compliance with WHO recommendations . All meaFasting blood samples were collected after 12–14 h from all study participants. The serum was centrifuged and stored at a temperature of − 80 C. Fasting serum glucose, triglyceride levels, total cholesterol levels and direct high density lipoprotein-cholesterol were measured by the GOD/PAP method, GPO–PAP method, Enzymatic Endpoint method and enzymatic clearance assay, respectively. Serum hs-CRP was measured by the use of an immunoturbidimetric assay  and for other inflammatory factors  the ELISA kit was used .Dietary intake was assessed by a validated and reliable semi-quantitative 147-item food frequency questionnaire (FFQ) that has been validated in previous work . Items aPhysical activity (PA) levels were measured using the international physical activity questionnaire-short form (IPAQ), which also included normal activities of daily living, frequency, and time spent each week for that activity during the last 12 months. The level of physical activity was expressed as metabolic equivalent hours per week (METs-h/week) .®3B, made in Germany). The RMR was assessed in the morning after a requested overnight fast (10–12 h). The indirect calorimetry device was calibrated before each assessment. Before the test, participants had to rest in a supine position for 10–20 min to create relatively stable conditions. Further, the first 5 min were not considered for analysis to ensure a stable condition, and only the final 15 min were used to calculate the RMR [RMR was measured by indirect calorimetry using a metabolic cart . Quantitative variables were presented as mean and SD and qualitative variables were reported in percentages. The relationship between quantitative variables among high and low RMR.per.kg and DPI was assessed using independent-sample t-tests and re-analyzed using analysis of covariance (ANCOVA) to adjust the effects of confounders, including age, BMI, energy intake, and physical activity. Binary logistic regression was used to discern the mediating role of inflammatory factors on the relationship between RMR.per.kg and DPI. Low adherence to DPI and RMR.per.Kg < 20 kcal/24 h/kg represented our reference group. In model 1, the effect of age, waist to hip ratio (WHR), energy intake, and physical activity were adjusted, and in model 2, all components of food which were significant after adjustment for energy intake, marital status, housing status, job, weight loss history in past years, economic status, number of family members, housing situation, blood pressure, and education, were also added to model 1. To estimate the mediatory role of inflammatory factors, we added the final modified model to the complete model. If inflammatory factors attenuated significance, they were considered as mediators, but if a significant relationship remained, they were regarded as having no mediating effect. In the present study P < 0.05 was a priori considered statistically significant.The mean age, weight, BMI, RMR.per.kg, RMR, WC, and WHR of 404 women who were participating in our study were 36.72 (SD = 9.10) years, 81.29 (SD = 12.43) kg, 31.26 (SD = 4.29) kg/m2, 19.59 (SD = 3.09) kcal/24 h/kg, 1574.96 (SD = 259.71) kcal/day, 99.61 (SD = 10.07) cm, and 1.16 (SD = 4.54) cm, respectively. The percentage of participants that were illiterate, had a diploma, and > Diploma was 0.9%, 12.12%, and 86.88%, respectively.P < 0.0001), weight (P < 0.0001), LDL (P = 0.05), WC (P < 0.0001), RMR (P < 0.0001) and marital status (P = 0.01) between people with RMR/kg < 20 kcal/24 h/kg, and RMR/kg ≥ 20 kcal/24 h/kg. After adjusting for age, BMI, PA  and energy intake a significant difference was seen between weight (P < 0.0001), WC (P < 0.0001), WHR (P < 0.0001), TG (P = 0.04), RMR (P = 0.001), DBP (P = 0.009), SBP (P = 0.03) and job (P = 0.02) between two groups.To examine the association of biochemical variables, body composition and serum inflammatory marker levels with RMR.per.kg, the individuals were grouped based on RMR /kg; group 1 with low RMR/kg  and group 2 with high RMR/kg  (n = 171 and n = 233 respectively), (Table P = 0.005), glucose (P = 0.01), fructose (P = 0.005), sucrose (P = 0.007), and olive (P = 0.02) between the two groups.The dietary intake of the participants across two groups of RMR.per.kg is shown in Table P < 0.0001) and there was a significant difference between two groups for economic status (P < 0.05)  Table .Table 3CP = 0.09). However, in model 1 after adjusting for age, WHR, energy intake and PA, there was no significant association . But in model 2, after adjusting for model 1 plus all components of dietary intakes that were significant after adjustment, marital status, housing status, job, weight loss history in past years, number of family members, economic status, blood pressure and education the results showed that woman with higher adherence to DPI increased odds of RMR.per.kg  , on the other words had lower odds of hypometabolic status .The association between DPI and RMR/kg is displayed in the crude and two adjusted binary regression models in Table P = 0.95), TGF-β  and MCP-1  eliminated this significance so they can be considered as mediatory markers. Although, the results shown that hs-CRP cannot be considered as mediatory markers because remain this significance .We assessed the effect of inflammatory markers including; PAI-1, TGF-β, MCP-1 and hs-CRP as mediatory markers for the significant association between DPI and RMR.per.kg. Table . By inclIn this study, we assessed any potential association between DPI and RMR, mediated by inflammatory factors , in overweight and obese women. The findings of this study provide novel insight into the relationship between adherence to DPI and reducing the chance of developing hypo-metabolism and mediation of inflammatory factors  in obese and overweight women. By modulating the effect of other confounders, this association remained, and no mediating effect was observed for hs-CRP. Previous studies have shown that the quality of a diet is positively associated with obesity and overweight, which is consistent with the present study . Indeed,The strengths of this study are the adjustment of all known confounders, such as age and total energy intake, physical activity, and waist circumference, the high sample size, and, to our knowledge, it is the first study to evaluate the relationship between DPI and RMR mediated by inflammatory factors in overweight and obese women. The limitations of the present study include the evaluation method of measuring DPI, where, in this method, the amount of phytochemicals received was determined based on the intake of foods rich in phytochemicals and energy intake, and we were unable to measure the actual amount of phytochemicals received. Moreover, due to the cross-sectional nature of the study, causal inferences cannot be drawn. Finally, although we used a valid and reliable FFQ for assessing dietary intakes, the potential for recall and misclassification bias cannot be entirely ameliorated.The results of the present study showed that adherence to a high phytochemical diet may decrease the chance of developing hypometabolism, by reducing inflammatory factors  that have a mediating effect. Nevertheless, due to the paucity of supporting evidence, the authors advocate that further prospective and interventional studies on a larger scale would be advantageous in further explaining this relationship.


Cholinergic transmission is essential for survival and reproduction, as it is involved in several physiological responses. In the auditory system, both ascending and descending auditory pathways are modulated by cholinergic transmission, affecting the perception of sounds. The auditory efferent system is a neuronal network comprised of several feedback loops, including corticofugal and brainstem pathways to the cochlear receptor. The auditory efferent system’s -final and mandatory synapses that connect the brain with the cochlear receptor- involve medial olivocochlear neurons and outer hair cells. A unique cholinergic transmission mediates these synapses through α9/α10 nicotinic receptors. To study this receptor, it was generated a strain of mice carrying a null mutation of the Chrna9 gene (α9-KO mice), lacking cholinergic transmission between medial olivocochlear neurons and outer hair cells, providing a unique opportunity to study the role of medial olivocochlear cholinergic transmission in auditory and cognitive functions. In this article, we review behavioral and physiological studies carried out to research auditory efferent function in the context of audition, cognition, and hearing impairments. Auditory studies have shown that hearing thresholds in the α9-KO mice are normal, while more complex auditory functions, such as frequency selectivity and sound localization, are altered. The corticofugal pathways have been studied in α9-KO mice using behavioral tasks, evidencing a reduced capacity to suppress auditory distractors during visual selective attention. Finally, we discuss the evolutionary role of the auditory efferent system detecting vocalizations in noise and its role in auditory disorders, such as the prevention of age-related hearing loss. Acetylcholine is an important neurotransmitter for both the maintenance of internal homeostasis and the interaction of individuals with the external environment . Severalvia muscarinic and nicotinic receptors, which involve metabotropic and ionotropic signaling, respectively  collicular-thalamic-cortico-collicular- loop; (ii) cortico-(collicular)-MOC circuit; and (iii) cortico-(collicular)-cochlear nucleus loop . The mos2+ concentration, permitting the opening of K+ channels (SK2) at the basolateral domain, followed by an outward current that hyperpolarizes the OHCs , including the cochlear duct, hair cells, supporting cells, and spiral ganglion neurons , severalAs evaluated by behavioral detection of tones in quiet and background noise conditions, hearing thresholds are normal in the α9-KO mice . SimilarOther auditory alterations have been found using the prepulse inhibition of the Acoustic startle response, as it is decreased in the α9-KO mice and increased in mutant mice that have an enhanced MOC function (L9’T-KI) . FurtherOne of the proposed functions of the AES is the suppression of irrelevant auditory distractors during visual attention. This hypothesis emerges from studies performed in behaving cats and chinchillas during visual selective attention tasks, in which the animals showed a reduction of auditory nerve responses to distracting sounds . This idRecent works in humans and chinchillas have raised the hypothesis that visual working memory could also recruit MOC neurons. In this line, The MOC reflex involves brainstem circuits, and its activation reduces the cochlear gain, in a physiological effect that can be useful protecting against acoustic trauma and aging. In this line, the strength of the MOC reflex has been correlated with the susceptibility to noise-induced hearing loss (NIHL) . This fiAge-related hearing loss or presbycusis is a highly prevalent condition in elderly people, especially in individuals chronically exposed to acoustic noise. The disorder is characterized by reduced hearing sensitivity and speech understanding in noisy environments, altered central auditory processing, and a higher risk for developing cognitive impairment and dementia . On thisTherefore, enhancing MOC feedback arises as a promising approach to prevent age-related hearing loss. In this context, the α9/α10 nAChR offers varied opportunities to be a therapeutic target in the future. Two molecules known for being able to enhance the activity of this receptor are ascorbic acid and ryanodine , openingThe prevention or treatment of NIHL could also be intervened by pharmacological modulation of α9/α10 nAChR. Like by presbycusis, drugs that augment the effect of the MOC system on the OHCs could be used to prevent NIHL in workers performing in noisy conditions. Exposure to loud noise has short and long-term consequences since there may be a transient attenuation of hearing acuity or a permanent threshold shift . HoweverDespite the evidence supporting an important role for MOC cholinergic transmission in protecting against acoustic trauma and cochlear synaptopathy, it is unlikely that this was a critical factor in the evolutionary history of the AES. It is far more probable that its evolution is linked to its function with hearing in noise. The reason is that high-intensity noise that induces acoustic trauma is not common in natural conditions, making it more likely that this function arose as an exaptation or evolutionary spandrel . If we cIn this context, future research in the α9-KO mice could evaluate the differences in vocalization patterns between them and WT mice. Furthermore, in the case of animals with high-intensity vocalizations, such as bats that vocalize above 100 dB , protectIn conclusion, experimental models such as the Chrna9 KO mouse have allowed the development of multiple lines of auditory research, facilitating substantial advances in the knowledge about AES functioning, providing therapeutic possibilities for the treatment of auditory pathologies. Notwithstanding all the advances that the Chrna9 KO mouse has permitted in the study of auditory physiology, we believe that the development of a time-dependent conditional knock-out is key to the future understanding of AES role in audition and cognition. This type of tool would allow a better control of the possible compensatory effects on embryonic development or neurotransmitter plasticity due to the lack of cholinergic transmission , and to rule out the impact of non-neural tissues that are also affected in α9-KO mice.HA-M and GT: original idea. HA-M, GT, SV-J, PJ, and PHD: manuscript writing. PJ: figure editing. HA-M, GT, and PHD: manuscript editing. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.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.