Obtaining reliable and objective data on certain working conditions is necessary to analyse the causes and variables that can influence the development of hearing loss amongst the working population. Objective occupational data have been collected from a heterogeneous sample of 1418 workers in Spain, see “How activity type, time on the job and noise level on the job affect the hearing of the working population. Using Bayesian networks to predict the development of hipoacusia”  [1]. Among the main factors analysed are the noise levels to which these workers are exposed, measured at their respective workstations, and the assessment of their hearing status, evaluated by audiometric medical tests. These factors provide information to predict the development of hypoacusia. Specifications TableValue of data•The dataset shows the average noise levels to which workers from different sectors of activity are exposed and can be used to match data from other countries or sectors of activity.•The dataset can be used to show different aspects of occupational exposure to noise, such as daily noise exposure (hours), number of years in the workplace, noise exposure in previous employment, noise protection system based on hearing protection or time limitation.•The dataset can be useful for researchers to see the results of the audiometric studies carried out on workers. The workers hearing health has been compared to international indices of auditory assessment.•The dataset provides information for future health and safety at work studies, with special interest for Health and Safety Technical Experts and medical professionals.1Medical and occupational environment data were collected over a period of approximately two years from a sample of 1418 workers from different activity sectors, ages and nationalities, who were working in the provinces of Burgos and Valladolid, Spain. Ingemédica S.L., an occupational health and safety consultancy, has collaborated with the University of Burgos to collect the data.The dataset was designed to answer the basic questions of how and why some workers develop hypoacusia. The variables are classified as demographic and personal factors (meaning those that characterise a specific population) occupational factors (those related to the working conditions in different companies) and non-occupational factors (those that are manifested outside the work environment) Data from 1418 workers have been obtained including demographic/personal data , data on occupational factors  and data on non occupational factors .All the data were anonymised and collected with the consent of the companies and individuals involved.See 2The necessary data has been achieved through two main lines of work. The first, focused on obtaining the data referring to the noise levels at the workstations, has been carried out using sound level meters and noise dosimeters. These measurements have been made by qualified occupational hygienists. The second line of work was consisted of carrying out medical tests which included audiometries and questionnaires. The questionnaire, based on Occupational Health Surveillance Protocols, was developed by the Department of Health and Welfare of the Junta de Castilla y León and authorised by the Ministry of Health and Consumer Affairs of Spain This section considers the frequencies and categories associated with the main occupational factors selected as influential in the development of hearing loss:2.12.1.1The results of the noise levels were divided into four groups, in keeping with Spanish Royal Decree 286/2006. The groups are: Low (LAeq.d < 80 dB and LPeak < 135 dB), Moderate (LAeq.d ≥ 80 dB <85 dB and LPeak ≥ 135 dB < 137 dB), High (LAeq.d ≥ 85 dB < 87 dB and LPeak ≥ 137 dB < 140 dB) and Very High (LAeq.d ≥ 87 dB and LPeak ≥ 140 dB). The percentage frequency of each would be 30.68%, 46.54%, 7,69% and 15.09%, respectively.2.1.2•Sector: Construction.The sample has been divided into the traditional economic sectors which are: Construction, Agriculture/Livestock, Industry and Services. The percentage frequency of each would be 54.16%, 0.35%, 22.85% and 22.64%, respectively.•Sector: Agriculture/LivestockThe noise level distribution for the sample related to the construction sector can be seen in •Sector: Industry•Sector: ServicesNoise level distribution for the industry related sample can be seen in Noise level distribution for the sample related to the Services sector can be seen in 2.1.3•Job title: Administration•Job title: Warehouse operative•Job title: CarpenterThe noise level distribution for warehouse operatives is presented in •Job title: Sales representative•Job title: DriverThe noise level distribution for the sales representative position can be seen in •Job title: Shop assistant/receptionist•Job title: Nurse/Assistant nurseThe noise level distribution for the shop assistant/receptionist is shown in •Job title: Electrician/Technician/Installer•Job title: Section Manager/Site managerThe noise level distribution for the electrician, technician and installer workstations is shown in •Job title: Plumber•Job title: General Manager/DirectorThe noise level distribution for the plumber׳s workstation can be seen in •Job title: Engineer/ArchitectThe noise level distribution for the General Manager/Director is shown in •Job title: Gardener•Job title: CleanerThe noise level distribution for the gardener position is shown in •Job title: Production operator•Job title: Delivery driverThe job title “production operator” includes several job titles, e.g. construction worker, industry worker, food production worker, concrete production worker, manufacturing industry worker, paper production worker and chemical production worker. •Job title: Welder●Job title: Security guard2.22.2.12.2.2This variable has been discretized as shown in 2.2.32.2.4The sample is divided into two unique groups, depending on whether or not the worker uses hearing protection as a noise protection system. The results of the distribution can be seen in 2.2.52.2.6The sample has been divided into two groups, depending on whether the worker has been exposed to ototoxic agents or not, such as: carbon monoxide, lead, benzene and mercury. The results of their distribution in the two groups can be seen in 2.3Below are the overall results of the hearing tests performed. Sal, ELI and Global Hearing Loss Percentages have been used to analyse these results.2.3.1The SAL index (Speech Average Loss), evaluates the conversation frequencies in 500 Hz, 1000 Hz and 2000 Hz to then perform the arithmetic mean of the hearing loss in decibels of those frequencies. The SAL index classifies the results from A to G depending on the worsening of hearing; SAL-A meaning both ears are within normal limits and SAL-G total deafness 2.3.2The ELI index (Early Loss Index) is calculated by subtracting a correction value for presbycusis from the loss in the frequency of 4000 Hz (weighting the loss by age and by gender). The frequency of 4000 Hz is evaluated and the acoustic traumas are classified according to an increasing scale A-B-C-D-E, from higher to lower auditory capacity, assessing the two ears individually 2.3.3This variable has been classified by establishing groups in Percentage of Hearing Loss intervals. This index considers each ear individually  and both ears collectively  With respect to the Hearing Loss Percentage Index for the Right Ear, the average is a hearing loss of 1.45%, with a minimum value of 0% and a maximum value of 88.13%. In reference to the Hearing Loss Percentage Index for the Left Ear, the average is 1.66%, with a minimum value of 0% and a maximum value of 91.12%. Once it has been discretized and divided into groups. Finally, with respect to the Binaural Percentage Index, the average is 1%, with a minimum value of 0% and a maximum of 67%.


Background and Objective: Methadone maintenance treatment (MMT) as the most effective treatment for opioid addictions could induce both reversible and permanent hearing loss. Therefore, early detection of methadone-induced hearing loss is necessary to prevent irreversible cochlear damage. The present study aims to identify the early onset of hearing loss in patients who underwent MMT and to compare them with the age and gender matched normal hearing peers.Methods: This was an analytic cross-sectional study conducted on patients  who received 3 months MMT course (MMT group) and a control group consisting of age and gender matched healthy individuals . Before MMT, all patients underwent conventional audiometry  and those with normal hearing threshold participated into the study. One month after MMT termination, the patients were assessed for possible hearing loss using conventional pure tone audiometry (PTA), extended high frequency (EHF) audiometry, and distortion product otoacoustic emissions (DPOAEs).Results: Our results demonstrated that the mean EHF thresholds in the MMT patients were significantly greater than the age- and gender-matched healthy controls across all frequencies (p < 0.001). However, there was no statistically significant difference in conventional PTA thresholds between both groups (p > 0.05). DPOAE amplitudes significantly reduced at higher frequencies  in the MMT group, compared to the healthy control group. In contrast to the conventional PTA audiometry, the EHF and DPOAE assessments identified hearing impairments in 11 (40.74%), and 14 (51.85%) of the MMT patients, respectively. The main mechanisms proposed for methadone induced hearing loss are cochlear ischemia following vasospasm or vasculitis, direct effect of opioids on opioid receptors present in cochlear stria vascularis of inner ear, blood-labyrinth selective transport of opioidproteins and receptors, and genetic polymorphism and mutations.Conclusion: The EHF and DPOAE tests have the potential to detect earlier changes in auditory function than conventional frequency audiometry in the MMT patients. Methadone has been used for many years in the clinical setting for detoxification treatment of opioid addiction, maintenance treatment of opioid addiction, and as a treatment option for moderate to severe pain . MethadoSome studies have reported ototoxicity as a known but rare consequence of opioid medications –6. MoreoPure-tone audiometry (PTA) is the most common procedure used to evaluate hearing sensitivity of an individual, which can determine the degree and type of hearing loss. During “conventional” auditory testing, PTA is used to identify hearing threshold in frequencies from 250 to 8,000 Hz. In addition to conventional PTA, extra high frequency (EHF) audiometry technique identifies hearing thresholds within the range of 9,000–18,000 Hz .f1 and f2 (where f1 < f2). The response is initiated in the overlapping region of the basilar membrane's response to the stimuli, somewhat nearer to the f2 tonotopic place. A second component arises near the basilar membrane place that codes the distortion-product (DP) frequency (2f1 – f2). These two sources are combined within the ear canal and the resulting energy is measured as the clinical DPOAEs and may include generator sources basal to the primary tones. The presence of DPOAEs are generally associated with normal hearing and are reduced in individuals with mild to moderate hearing losses up to ~50–60 dB HL. In subjects with hearing thresholds greater than about 60 dB HL, DPOAEs are not generated (Otoacoustic emissions (OAEs) are sounds measured in the external ear canal and a reflection of active processes in the cochlea. Initiation and physical characteristics of OAE depend on the physiological status of the outer hair cells (OHCs); thus, OAE testing could serve as an objective measure of ototoxic damage. OAEs can provide valuable information on the integrity of the OHCs within the cochlea and can be utilized for early identification of hearing impairments –13. Chanenerated , 15.Furthermore, studies conducted on the patients who had been treated with ototoxic medications have shown that EHF audiometry and DPOAE measurements can detect evidence of ototoxicity in the inner ear earlier than conventional audiometry, potentially serving as a predictor to ototoxic effects prior to damage occurs in frequencies that are critical for speech and language comprehension , 16, 17.Several studies have reported the impacts of methadone as an ototoxic medication on auditory system but most of these studies were case reports –4, 8, 18The current study aims to investigate the diagnostic value of EHF audiometry and DPOAE methods in detecting early onset of hearing loss in the patients addicted to opioid who had underwent MMT. In this regard, the hearing thresholds of the patients were measured using PTA, EHF, and DPOAE techniques and compared against the age and gender matched normal peers.This analytical cross-sectional study was conducted on 27 males  with opioid dependence who had been underwent an MMT course in a private clinic. The experiments of the study had lasted from March 2015 to July 2017. To reduce the bias and inter-individual variation we applied a robust inclusion and exclusion criteria. The inclusion criteria were patients who: (i) were at least 18 years of age; (ii) met the DSM-IV-TR or SM-5 criteria for opioid use disorder as assessed by an experienced psychiatrist; (iii) had positive test of opioid dependence in a urine examination before therapy; and (iv) continued to receive MMT for at least three months; (v) were not under any opioid or opioid treatment drugs. During MMT course, all patients were regularly monitored in a private addiction center and prescribed specific dose of methadone. The patients did not use any medication other than methadone for opioid treatment. The control group consisted of 27 healthy males with a similar age distribution  of the MMT group. All control participants showed normal hearing thresholds .All subjects had bilaterally normal middle ear functions before the start of the MMT course. Individuals with a history of chronic exposure to intense noise, acoustic trauma, ototoxic drug consumption, traumatic brain injuries and middle ear disorders were excluded from the study. Furthermore, we excluded those patients with a history of schizophrenia, neurocognitive disorders, neurodevelopmental disorders, major depressive disorders, bipolar disorders, and mental disorders due to medical conditions according to the definitions of DSM-IV-TR or DSM-5.All the procedures of this study were in complete accordance with the Declaration of Helsinki on ethical principles for medical research involving human subjects (2014) . After tThe MMT course that consisted of daily 30 mg methadone 7 days per week and for 3 consecutive months.The MMT course was continuous so that patients with interruption in methadone consumption (more than 2 days) were excluded from the study. During the MMT, patients just received methadone and consumption of any other medications was terminated at least 2 months before start of MMT course.Before starting MMT all patients underwent conventional audiometry  and those patients with normal hearing threshold were entered into the study. The audiological assessments (EHF and DPOAE) were conducted 1 month after termination of MMT course.A clinical two-channel audiometer  coupled with a standard  and extra high-frequency  headphones was used to record hearing thresholds. Conventional audiometry was determined for octave frequencies of 250–8,000 Hz, and EHF audiometry was determined for frequencies of 10,000, 12,000, 14,000, and 16,000 Hz. For EHF assessment, if the participants failed to respond to the maximum intensity produced by the audiometer, the instrument's highest output level was considered as their hearing threshold. All procedures for hearing assessment were carried out in an anechoic chamber according to ISO 8253-1.50 standards.The DPOAE measurements were performed using a Madsen Capella system  in an acoustically isolated chamber. Two primary pure tones at frequencies f1 and f2 were utilized, where f1 was set to 65 dB SPL and f2 to 55 dB SPL (f2/f1 ratio = 1.22). DPOAE amplitudes were recorded as a function of f2 frequency at 1,000–6,000 Hz. The acceptance criterion for DOPAE response was set to minimum level of 0 dB SPL and signal to noise ratio of ≥6 dB SPL at each f2 frequency .t-tests if K-S test indicated that the data were normally distributed. The Wilcoxon signed-rank test for related samples was used if the normality assumption was violated. For all statistical tests, the statistical significance level was set at p = 0.05.Statistical analysis was performed using SPSS version 18 software. Categorical variables were expressed as number and percentage and continuous variables were reported as mean ± standard deviation. Normality of the numerical data was verified using the Kolmogorov–Smirnov (K–S) test. Tests comparing paired data sets were conducted using paired-sample t-test, p > 0.05). In contrary, the mean thresholds for the EHF frequencies in the MMT group significantly increased from 10,000 to 16,000 Hz, compared to the healthy controls   . The meaEHF and DPOAE test, respectively, identified hearing loss in 11 (40.74%), and 14 (51.85%) of the patients who had previously received MMT. Ten (37.04%) patients exhibited abnormal hearing sensitivity in both EHF audiometry and DPOAE ranges in the MMT subjects.The present study was aimed to identify the early onset of hearing loss in patients who underwent MMT and to compare them with the age matched normal hearing peers. Our findings showed a high prevalence of hearing impairment in patients who received MMT for at least 3 months. The standard method for ototoxicity monitoring is sequential measurement of pure-tone hearing thresholds within the conventional frequency range, 250–8,000 Hz. However, it seems that EHF audiometry and DPOAE technique are more sensitive procedures to detect early damage to auditory system.All of the 27 enrolled patients who underwent MMT showed normal hearing at frequencies ≤ 8,000 Hz, whereas 11 (40.74%) subjects showed decreased hearing sensitivity at more than one of the four  EHFs. These findings show that methadone firstly damage the basal regions of the cochlea, leading to high frequency bilateral symmetrical sensorineural hearing loss (SNHL). In addition, hearing thresholds analysis in methadone group indicated a significant mild or moderate sloping hearing loss with high variability in EHF thresholds.DPOAE test is non-invasive, fast and pre-neural procedure that provides frequency- and ear-specific information regarding the integrity of OHCs function of the cochlea. DPOAE assessments are commonly used for newborn hearing screening programs and differential diagnosis of auditory system disorders –16. DuriMethadone is a synthetic opioid that is used as an analgesic and as a maintenance anti-addictive medication for patients with opioid dependency. There is a growing body of evidence that abuse of the synthetic opioid can lead to temporary or permanent SNHL . So far,In all cases with speedy recovery the methadone was withheld but in the cases with persistent hearing loss, one case did not stop methadone and used it at prescribed dose  and on tOpioid receptors function in neuronal systems and local networks involved in the initiation of drug action and the subsequent development of adaptations under repeated drug consumption. It has been shown that opioid neuropeptides participate in synaptic processing in inner hair cells of the cochlea . The expLong term consumption of opioids could induce damage in the basal section of the cochlear that could subsequently lead to hearing loss. This damage could increase the hearing threshold especially in higher frequencies and reduce the DPOAE amplitude. This adverse effect of opioid on hearing threshold should be considered in interpretation of our findings. It is possible that the observed higher EHF thresholds and reduced DPOAE amplitudes in the patients with opioid dependency could be due to the basal turn cochlear damage induced by opioid consumptions rather than the effects of MMT.The pathophysiology of methadone induced hearing loss is not fully understood yet. Different theories have been proposed to explain the effects of opioid drugs on hearing systems , 16, 22.Cochlear ischemia is mainly occurred following vasospasm or vasculitis of the branch of the spiral modiolar artery. The cochlear structure is very susceptible to hypoxia. Different studies have shown that opioid drugs trigger the production and release of endothelin-1 as an endogenous vasoconstrictor . This faGenetic polymorphism has been reportedly a possible predisposing factor for opioid-induced hearing impairments particularly aminoglycosides induced hearing impairments. Different mutations and polymorphisms such as allelic variants in the liver metabolic enzymes and mutations induced by mu-opioid receptor (MOR), which are occurred in response to opioid drugs may contribute to different levels of hearing impairments .Blood-labyrinth barrier plays pivotal role in regulating and establishing homeostasis of inner ear fluid mainly through selectively active transport of molecules based on the molecular weight. One hypothesis is based on the inter-person variation in the blood-labyrinth transport channels and differences in the molecular weight of opioid drugs so that in some opioid users opioid drugs are more likely to cross the barrier and induce hearing loss , 8.Other hypothesis on the mechanism of action of opioids in inducing hearing loss is the effect of opioids on specific opioid receptors present in the inner ear. The main opioid receptors present in the central and peripheral nervous systems are mu (MOR), delta (DOR), and kappa (KOR) opioid receptor. The majority of opioids are MOR-agonist. Opioid receptors are present in different structures of the inner ear including inner and OHCs, spiral ganglion, supporting cells of the organ of Corti, and nerve fibers. The activation of MOR can inhibit calcium which in turn inhibits the basal adenylate cyclase activity. Endogenous opioid peptides such as endorphin and enkephalin have likely important role in auditory neuromodulation. These inhibitory effects are more pronounced in cochlear stria vascularis of inner ear, a structure which is rich in blood vessels, and could negatively affect mechanoelectrical transduction of the signal within the cochlea , 24, 25.n = 86,186) of adults in the US. They reported that hearing loss was independently associated with an increased likelihood of substance abuse disorder. Moreover, hearing loss was independently associated with substance use disorders among age group of ≤ 49 years. Interestingly, these associations are particularly pronounced for prescription opioid use disorders in the group aged 18–34 years (Investigating the risk factors of methadone induced hearing loss, we should consider the mutual relationship between the substance abuse and prevalence of hearing loss. Several studies have suggested that individuals with hearing loss have higher susceptibility to substance abuse. McKee et al. compared the prevalence of substance use disorders among adults with and without self-reported hearing loss among a nationally representative sample (34 years . HoweverIn conclusion, our findings showed that EHF audiometry and DPOAE techniques have greater diagnostic values than the conventional PTA to detect early changes in auditory functions in patients undergoing MMT. However, opioid addictions could induce damage in the basal section of the cochlear which should be considered in interpretation of our findings. In this regard, it is possible that the observed higher EHF thresholds and reduced DPOAE amplitudes in the patients with opioid dependency may be due to the basal turn cochlear damage induced by opioid consumptions rather than the effects of MMT. Therefore, the effect of methadone treatment cannot be conclusively determined and further case control studies with large sample size with pre- and post-MMT assessments are necessary to shed more light on the effects of methadone on hearing functions.The datasets generated for this study are available on request to the corresponding author.All procedures of this study were approved by Ethics committee of Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.AB, NS, GM, and AY contributed conception and design of the study. AB and NS collected the data and organized the database. GM and AY performed the statistical analysis. AB wrote the first draft of the manuscript. NS, GM, and AY wrote sections of the manuscript. All authors contributed to manuscript revision, read 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.


In 2019, the Manchester Centre for Audiology and Deafness celebrates its 100thanniversary. To mark the centenary, this special issue is a collection of papersthat showcases current research in Manchester Centre for Audiology and Deafness.The Editorial provides a brief history and description of the Centre and anoverview of the special issue. The Department of Education for the Deaf was founded at The University of Manchesterin 1919. It was the first university department of deaf education in the world. Thedepartment was funded by a donation from the estate of Ellis Llwyd Jones, who wasborn deaf, by his father, businessman Sir James Jones. Irene Goldsack (later Ewing)was the first Ellis Llwyd Jones lecturer. Irene Ewing and her husband Alexander wereresponsible for the fundamental concepts of pediatric audiology. They alsoinfluenced professionals throughout the world on issues pertaining to theidentification and management of childhood deafness. In 1947, Irene Ewing wasawarded the Order of the British Empire for her services to audiology and deafeducation. In 1958, Alexander Ewing was knighted for his services to audiology anddeaf education.Medresco brand) that were issued free of charge by the U.K.National Health Service (NHS) in its foundation year, 1948. In 1944, the Ewingsdeveloped the Distraction Test , which reduced the age of diagnosis of hearing loss from 2 to3 years to 6 months. The Distraction Test was used around the world until the 1990s.The Ewings practiced and advocated for a child-centered focus when teaching deafchildren. This was seen to be unusual, but innovative, as their methods were farremoved from the standard practice of speech drills and rote learning. In 1944,Irene Ewing demonstrated the linguistic and developmental advantages displayed bychildren whose parents had engaged in their early support clinics. The foundationsof early, meaningful interaction are held central to all approaches in the field tothis day.The department has made a number of seminal contributions for patient benefit,particularly with respect to pediatric diagnostics, auditory devices, and deafeducation. In 1928, the department imported an electronic audiometer from the UnitedStates and conducted groundbreaking audiometry research, showing in particular thatdeaf children usually have residual low-frequency hearing that can be enhanced byhearing aids. Physicist Tom Littler from the department was a pioneer in the designof electronic hearing aids. In 1933, he developed a group hearing aid for use inclassrooms and then helped to develop individual aids  publishedChildren, whichwToday, the department, now known as the Manchester Centre for Audiology and Deafness(ManCAD), is stronger than ever, with 14 members of permanent academic staff. Ouraudiology research covers a wide range from the basic physiology of hearing andhearing impairment, noise-induced hearing loss, and hearing and cognition, toauditory devices, advanced diagnostics, and pediatric audiology. The translationalwork in deaf education continues to shape practice in the field and in recent yearshas focused on deaf children with complex needs, effective radio aid use, and thedevelopment of Theory of Mind skills for deaf children and young people. The impactof our research is underpinned by a close relationship with health and educationservice providers and with leading international manufacturers of hearing aids andcochlear implants. ManCAD is also a major provider of training for students ofaudiology and for teachers of the deaf.Manchester has made a world-leading, and life-changing, contribution to audiology anddeaf education in terms of education and training, research across the life span,service development and practice. To mark the ManCAD centenary, Laura Dawes, medicalhistorian, author, and broadcaster, has updated and revised her history of audiologyand deaf education at The University of Manchester .The special issue showcases a range of current audiology research in ManCAD. Advanceddiagnostics has long been a core component of our work at Manchester, and the issueincludes several papers on this theme. The paper by Similarly, our historical research strength in auditory devices continues to thepresent day. Two papers examine the use of electrophysiological responses in theevaluation of hearing aids. The study by The city of Manchester has a somewhat notorious reputation as a source of bothoccupational (cotton mills) and recreational  noise exposure.Perhaps appropriately, the effect of noise exposure on hearing health is a strongcurrent interest in the group. The paper by The papers illustrate the wide range of different approaches used in our research,including genetic testing, audiometry, electrophysiology, psychophysics, speechtesting, subjective quality assessments, questionnaire-based techniques, and the useof big data. With emerging cross-disciplinary projects in cancer treatments,biomarkers, genomics, health informatics and data science, artificial intelligence,health psychology, engineering, and advanced materials, we continue to exploreexciting new directions in audiology research. The expectation is that our next100 years will be even more transformative than the first.


This study is for reporting the outcomes of internal limiting membrane (ILM) peeling on persistent submacular fluid (PSF) after otherwise successful pars plana vitrectomy (PPV) for diabetic tractional retinal detachment (TRD). In this retrospective case series, five consecutive patients (5 eyes) who exhibited PSF following successful repair of diabetic TRD were included. The second operation was performed to remove ILM. The area of ILM peeling was expanded up to the major vascular arcade. Only air tamponade was used. The median interval between the first PPV and the second PPV with ILM peeling was 4.8 months (range: 4–6 months). PSF resolved completely within one (2 eyes) or 2 months after ILM peeling. The median logMAR best-corrected visual acuity (BCVA) was improved from 1.00  to 0.70 . In conclusion, wide ILM peeling is an effective treatment option for PSF subsequent to successful repair of diabetic TRD. ILM peeling might increase the elasticity of retina, thereby allowing the retina to flatten. This procedure can induce faster retinal reattachment in diabetic TRD involving the macula. Tractional retinal detachment (TRD) that involves the macula is the main cause of permanent vision loss in patients with diabetic retinopathy and requires prompt surgical intervention , 2. WithIn eyes with myopic traction maculopathy, the outer retina is stretched along with the posterior staphyloma, but the inner retina is not well-elongated, causing schisis-like deformation. Tractional force imparted by the rigid internal limiting membrane (ILM) and/or residual premacular vitreous cortex has been suggested to be responsible for the inability of the inner retina to conform to the posterior staphyloma –12. VitrWe speculate that stiffness of the contracted retina induced by the tractional membrane would not fully recover after removal of the fibrovascular membrane. The detached retina in the macular area might permit residual fluid to ingress and persist in the subretinal space. We hypothesized that removal of the rigid and contracted ILM over the detached retina would restore the elasticity of the retina and facilitate reattachment of the detached retina. In five consecutive patients who exhibited PSF after successful repair of diabetic TRD, ILM peeling was performed as a secondary procedure. In this report, we describe the efficacy of this surgical approach.This study was a retrospective case series and was approved by the Institutional Review Board of Seoul St. Mary's Hospital, Seoul, South Korea, and followed all relevant tenets of the Declaration of Helsinki.We reviewed the charts and imaging records of consecutive patients who exhibited prolonged PSF after successful PPV to treat diabetic TRD and underwent secondary operation of ILM peeling. Patients who had fibrovascular membranes not completely removed in the first operation, or who developed a new epiretinal membrane on SD-OCT, or who exhibited rhegmatogenous retinal detachment (RRD) were excluded. All the surgeries in this study were performed by a single vitreoretinal surgeon (WKL) at Seoul St. Mary's Hospital, the Catholic University of Korea, between January 2015 and October 2017.All patients underwent ophthalmologic examinations, including assessment of best-corrected visual acuity (BCVA) and refraction; slit-lamp biomicroscopy; fundoscopy with dilated pupils; fundus photography  or ultra-widefield fundus photography ; and SD-OCT . In the first operation, PPV using a Constellation 23- gauge (G) vitrectomy instrument  was performed for the repair of diabetic TRD involving the macula. Intravitreal antivascular endothelial growth factor (anti-VEGF) was preoperatively injected in all patients. The surgeon removed all visible tractional fibrovascular membranes using vitreous cutter, horizontal scissors, and forceps. When necessary, one 20-G sclerotomy port was created, and 20-G curved microscissors were used for the delamination procedure. Perfluorocarbon liquid was used to drain internal subretinal fluid when retinal breaks were detected. Endolaser photocoagulation was applied to retinal breaks and peripheral retina. The surgeon determined the necessity of tamponade at the end of surgery and chose an appropriate tamponade, such as octafluoropropane (C3F8) gas or silicone oil. Face-down positioning was recommended for at least 2 weeks in cases with gas or silicone tamponade.Secondary PPV for ILM peeling was scheduled when no improvement in the amount of PSF on OCT was apparent during more than 3 months of follow-up after gas absorption. To remove the ILM, 0.5% indocyanine green (ICG) dye  was injected slowly onto the posterior pole with the fluid-filled state and ILM was stained for 60 seconds. After flushing the ICG dye, ILM was pinched and peeled using forceps . ILM peeling included the area over the entire posterior pole and expanded up to the major vascular arcade and near to the optic disc. Fluid-air exchange was performed for all eyes, and face-down positioning was recommended for 1–3 days.n = 1), 14% C3F8 gas (n = 3), and silicone oil (n = 1). One or two months later, overall, the retina was well attached without any remaining membranes; however, PSF was evident on OCT. The median interval between primary PPV and secondary PPV with ILM peeling was 4 months (range: 4–6 months). The median logMAR BCVA before ILM peeling was 1.00 .Five patients (5 eyes) were eligible for inclusion. Their median age was 58 years (range: 41–59 years). Two patients were male and three were female. The tamponades in the first operation were air . Clinical and demographic characteristics of all subjects are shown in A 58-year-old male with newly diagnosed diabetes presented with a decreased visual acuity of both eyes for 3 months. He did not receive any ocular examination or treatment before. Initial logMAR BCVA was 1.70  in the right eye and 0.60 (Snellen 20/80) in the left eye. Fundus examination revealed severe fibrovascular proliferation around the optic disc and superior temporal vascular arcade of right eye . The fovOn both fundus examination and fundus photography, there was no obviously visible tractional or epiretinal membrane. Focal and thin epiretinal membrane was shown at the edge of the optic disc on OCT . It was A 41-year-old female presented with decreased visual acuity of left eye. She was newly diagnosed with diabetes and has no history of ophthalmologic treatment. Initial BCVA was hand motion in the left eye and logMAR 0.1 (Snellen 0.8) in the right eye. Fundus examination revealed proliferative diabetic retinopathy with retinal neovascularization of right eye and TRD involving the fovea with a subhyaloid hemorrhage in the left eye. Diffuse tractional membranes extended along the major vascular arcades , and extPersistent submacular fluid has also been reported after uneventful scleral buckling or PPV to treat RRD , 13. An It is commonly seen that a detached retina associated with severe fibrovascular proliferation cannot be completely attached on the operation table even though all fibrovascular tissues are successfully removed. Endolaser cannot be effectively delivered to such areas. In instances of iatrogenic or preexisting retinal break, the retina cannot be completely approximated to the retinal pigment epithelium despite repeated subretinal fluid drainage. And laser burns around the retinal tears are not made enough without scleral indentation. The thin peripheral retina seems to restore its elasticity rapidly and to become attached, and laser burns are readily made using a table laser within 1-2 weeks after operation under gas or a silicone tamponade. However, a longer interval might be required for restoration of the configuration and elasticity of the thick macular retina.μm. Under physiological conditions, the hyaloid membrane adheres to the ILM. Under pathologic conditions such as diabetic retinopathy, migrated fibroblasts and fibrinous materials attach to the surface of the ILM, increasing the ILM thickness. Contraction of these materials within the ILM may impart tangential traction to the underlying retina, although no fibrovascular membrane may be observed above the ILM [Based upon the promising results in the current study, ILM peeling can be considered as a primary procedure to induce faster macula reattachment in diabetic TRD involving the macula. The ILM is a fine multilaminar membrane composed of the expanded footplates of Müller glial cells. The thickness of ILMs ranges from 1 to 2  the ILM . Moreove the ILM , 17. Som the ILM , 19. ILM the ILM , 21. ILMObviously, this study has a limitation stemming from its small sample size and lack of a control group. PSF might be resolved spontaneously, and it is very hard to recommend the second operation in real clinical practice. Although the number is small, our cases revealed dramatic resolution of PSF with visual improvement. It is worthwhile to perform further comparative studies with more patients to confirm our observations.Wide ILM peeling was an effective treatment option for persistent macular detachment subsequent to otherwise successful repair of diabetic TRD. This procedure may increase the elasticity of a retina that has been detached and shortened by traction over a long period of time, facilitating retinal reattachment. It may be worthwhile to perform ILM peeling as a primary procedure in eyes with severe diabetic TRD although no obvious epiretinal traction is apparent.


In this paper we evaluate the economic gains of a joint deployment of femtocells                    and macrocells for the provision of Long Term Evolution (LTE) mobile broadband                    services in urban environments. Frequency bands of 2.6 GHz and 900 MHz are                    analyzed and different parameters related to the business model are considered                    for a 30% market share operator. Results show important benefits for the base                    case where the service is offered to fixed-broadband clients, up to 75%, for                    small bandwidths. It results feasible to attribute subscriber loop costs to the                    radio access network (RAN) costs, so that the service could be offered to non                    fixed-broadband clients, in both cases of closed access and open access                    femtocells. However, initial savings result notably reduced, up to 50% less than                    in the base case if closed access is adopted and up to 13% less for open access.                    Site reuse reduces the initial savings only in 3%.


The as-prepared samples and their precursors were characterized by X-ray diffraction (XRD), Scanning electron microscopy (SEM), Transmission electron microscopy (TEM), UV-Vis diffuse reflectance spectroscopy (DRS), and Photoluminescence spectra (PL). It was observed that the morphology of ZnnAl-MMO nanocomposites could be tuned from cubic aggregates, hierarchically flower-like spheres to porous microspheres by simply changing the molar ratio of metal cations of the starting reaction mixtures. The photocatalytic performance of ZnO/ZnAl2O4 nanocomposites in the photoreduction of aqueous Cr(VI) indicated that the as-prepared 3D hierarchical sphere-like ZnnAl-MMO nanocomposite showed excellent photocatalytic activity of Cr(VI) reduction under UV light irradiation. The results indicated that the maximum removal percentage of aqueous Cr(VI) was 98% within four hours at 10 mg/L initial concentration of Cr(VI), owing to the effective charge separation and diversion of photogenerated carriers across the heterojunction interface of the composite. Our study put forward a facile method to fabricate hierarchical ZnO/ZnAl2O4 composites with potential applications for wastewater treatment.Three dimensional (3D) ZnO/ZnAl Chromium is common environmental pollutant and it is listed as a priority pollutant by the U.S. Environmental Protection Agency (EPA) , which mg) semiconductor (3.37 eV) sustains an inherent limitation to only utilize UV light about 4% of solar energy for photoexcitation in the photocatalytic process. Adjusting the ZnO band structure to the lower band gap to accommodate light absorption is one of the main strategies. Therefore, the ZnO-based semiconductor composites have attracted tremendous research interests. The nanocomposites composed of N-doped ZnO/g-C3N4 core-shell nanosheets were prepared for the photocatalytic degradation of rhodamine B with visible-light and the results demonstrated that the photocatalytic removal rate of N-doped ZnO/g-C3N4 was more than six times higher than that of pure ZnO and g-C3N4 [2 nanocomposites and discussed their photocatalytic degradation of organic dye methylene blue in UV light with very high efficiency.ZnO as a semiconductor photocatalyst has been widely studied for its advantages, such as high efficiency, non-toxicity, and low cost. Nevertheless, ZnO as a wide band gap  is also extensively-studied semiconductor and its photocatalytic property has attracted the attention of researchers [2O4 composite photocatalyst not only has excellent stability, but it also has a much higher photocatalytic activity than a single oxide. Zhang et al. [2O4 composite with hollow microspheres by hydrothermal process and the maximum photocatalytic decoloration rate of methyl orange was 98.7% within 60 min under the photocatalyst concentration of 0.5 g/L. Zhao et al. [2O4 nanocomposites as plate-like by heated treatment of ZnAl-layered double hydroxide (ZnAl-LDH) precursors with different Zn/Al molar ratios at 800 °C in order to evaluate the photodegradation performance of methyl orange dye under artificial ultraviolet light. According to the survey, there are few studies involving the photocatalytic reduction of aqueous Cr(VI) while using hierarchical-structured ZnO-based photocatalysts are reported.Zinc aluminate  under UV light irradiation and it was found that only ZnO/ZnAl2O4 nanocomposites with 3D hierarchical sphere-like structure exhibited perfect photocatalytic activity for Cr(VI) reduction, owing to the effective charge separation and the diversion of photogenerated carriers across the interface of the composite.Herein, we reported a pacific preparation of ZnO/ZnAlAll the chemicals used in this study were of analytical grade and they could be used without further purification. Deionized (DI) water was used in all experiments.nAl precursors were synthesized while using urea hydrothermal method and n value referred to the Zn to Al molar ratio of the starting mixture, which were 5.0, 7.0, and 9.0. A mixture of Zn(NO3)2·6H2O and Al(NO3)3·9H2O in different Zn/Al molar ratios were dissolved in DI water to obtain a solution with a total cationic concentration of 0.04 M, that is, Zn2+ + Al3+ = 0.04 M. While maintaining the molar ratio of (Zn2+ + Al3+)/urea = 1:5, urea was added to the nitrates solution. Then, the clear aqueous solutions were transferred to a 100 mL Teflon-lined reactor and maintained at 150 °C for 24 h. The white precipitates were collected and rinsed three times with DI water until pH = 7 after cooling to room temperature. Finally, the white precipitates were dried in an oven at 80 °C for 12 h. The ZnO/ZnAl2O4 nanocomposites were obtained by calcining the synthesized ZnnAl precursors in air at 900 °C for 4 h and the prepared nanocomposites were denoted as Zn5Al-MMO, Zn7Al-MMO, and Zn9Al-MMO, respectively.The Zn4 as the reference sample. Room temperature PL measurements were done using a Hitachi F-7000 fluorescence spectrophotometer .XRD patterns were collected in a PANalytical X’pert Pro powder diffractometer  through Cu-Ka radiation (λ = 1.5418 Å) with a scan step of 0.013°. SEM  was used to study the morphology of some selected samples through a Hitachi SU8020 scanning electron microscope with acceleration voltage of 20 kV. HRTEM images were obtained by a FEI Tecnai G2 F20 field-emission transmission electron microscopy  at an accelerating voltage of 200 kV. Diffuse reflectance spectroscopy (DRS) was performed on a Hitachi U-4100 UV-vis spectrophotometer  while using BaSOnAl-MMO on the photocatalytic reduction performance of aqueous Cr(VI) was implemented using a 500 W high-pressure Hg lamp , with a maximum wavelength emission of 365 nm. Stock solution (150 mg/L) of Cr(VI) was prepared by dissolving K2Cr2O7 in distilled water and was diluted to the desired concentration prior to use. In each runs, 200 mg photocatalyst was dispersed in 50 mL of different concentrations of aqueous Cr(VI) solutions. Before irradiation, the mixture solution was magnetically stirred in the dark for 60 min to allow for the adsorption-desorption equilibrium to be established. While keeping magnetic stirring, 4 mL of the reaction product was extracted at regular intervals during the irradiation and the photocatalyst were separated by centrifugation from the solution. Determination of Cr(VI) concentration in the supernatant by UV-1000 spectrophotometer  at 540 nm from 1,5-diphenylcarbazide method [nAl-MMO photocatalyst under the same conditions.The effect of Zne method . As a conAl precursors and ZnnAl-MMO nanocomposites. For ZnnAl precursor, the characteristic reflections at 2θ = 13.4, 24.2, 28.3, 32.7, 54.2, 58.6, and 64.5° were observed, which were attributed to (200), (310), (020), (021), (800), (−622), and (−532) planes of the typical well-crystalized Zn5(CO3)2(OH)6 materials (JCPDS: 19-1458). The remain diffraction peaks donated with “▼” came from Al(OH)3 (JCPDS: 33-0018). The result showed that the precursors mainly consisted of Zn5(CO3)2(OH)6 and Al(OH)3 phases. As shown in 2O4 (JCPDS: 82-1043) at reflections 31.4°(220), 36.9°(311), 44.8°(400), 49.1°(331), 55.6°(422), and 65.2°(440). Meanwhile, the diffraction reflections of ZnO phase were much sharper and stronger than those of ZnAl2O4, indicating that ZnO phase had high crystallinity and dominance in MMO, which was beneficial to its photocatalytic activity in Cr(VI) photoreduction.nAl-MMO nanocomposite were investigated by SEM. As shown in 5Al-MMO displayed irregular flake-morphology and many cubic aggregates made up of irregular crystallites were visible on their surfaces. 2 during the calcination of Zn5(CO3)2(OH)6 at high temperature. From SEM images of 7Al-MMO was found to be consisted of many 3D flower-like spheres with a diameter of around 3–23 μm. These uneven assemblies were composed of dozens of closely impacted irregular nanoplatelets with thickness below 250 nm  photoredution activity , while 400–800 nm (visible area) has almost no absorption for these three samples. As Zn2+ to Al3+ molar ratio increased, MMO appeared slightly blue-shifted adsorption edge and the absorption intensity was observed to increased and then decreased. Zn7Al-MMO nanocomposite has the highest adsorption intensity among all the three samples, which could be ascribed to the 3D sphere-like hierarchical and loose structure.g) by the DRS spectra. The Eg were determined by plotting graphs of (Khν)1/2 versus (hv), with the help of reflectance spectra. The extrapolation of linear region of this plot to (Khν)1/2 = 0 is the direct band gap value. The results showed that the Eg value for the Zn5Al-MMO, Zn7Al-MMO, and Zn9Al-MMO were, respectively, found to be 2.85, 2.89, and 2.87 eV, which was lower than that for pure ZnO (3.37 eV) [nAl-MMO photocatalyst.3.37 eV) . The narnAl-MMO nanocomposites synthesized with different Zn to Al molar ratios are shown in 5Al-MMO > Zn9Al-MMO > Zn7Al-MMO. The PL intensity represents the recombination rate of photogenerated electrons-hole pairs. It has been established that the recombination rate of photogenerated electrons-hole pairs is lower and the photogenerated charge carriers have a prolonged lifetime as the PL intensity decreases, which is beneficial to photocatalytic performance [7Al-MMO > Zn9Al-MMO > Zn5Al-MMO.The PL spectra of Znformance . So, it nAl-MMO nanocomposites were evaluated by the photocatalytic reduction of aqueous Cr(VI) under UV light irradiation. From 5Al-MMO, Zn7Al-MMO, and Zn9Al-MMO, respectively, and the removal ratio value was almost unchanged for these three samples, indicating that the adsorption performance was independent on Zn2+ to Al3+ molar ratio of the original starting composition. Upon UV light irradiation, the Cr(VI) removal percentage was greatly enhanced within the same time intervals using ZnnAl-MMO samples as the photocatalyst. Zn5Al-MMO, Zn7Al-MMO and Zn9Al-MMO photocatalysts exhibited 90.3%, 98%, and 97.6% removal activity for aqueous Cr(VI), indicating that the Cr(VI) removal was predominated by the photocatalytic reduction process and the removal activity of the photocatalysts followed the order: Zn7Al-MMO > Zn9Al-MMO > Zn5Al-MMO. A pseudo first-order linear relationship was further analyzed by the plots of −ln(C/C0) = kt for ZnnAl-MMO, where k was the rate constant (h−1) and t was the irradiation time (h). The determined reaction-rate constants k were 0.69166, 1.26331, and 1.14101 h−1 for Zn5Al-MMO, Zn7Al-MMO, and Zn9Al-MMO, respectively. There was a slight difference of the reaction rates in this photocatalytic system but they were much higher than previous report [nAl-MMO nanocomposites were composed of ZnO and ZnAl2O4 phases, where there was a heterojunction between the interface of the composite. Higher content of Zn element of the starting materials meant more content of ZnO phase in the composites, leading to excessive amount of ZnO, which could not form heterojunction with the ZnAl2O4 counterparts. This phenomenon implied the significance of the heterojunction between ZnO and ZnAl2O4 phases of ZnnAl-MMO nanocomposites toward photoreduction of aqueous Cr(VI). Moreover, our hierarchically flower-like ZnO/ZnAl2O4 composite is a three-dimensional micro- and nanometer assembly with highly porous structure and high specific surface area. Usually, hierarchical architecture contributes to the generation and migration of photo-carrier and provides more sites for pollutant and incident light adsorption. In combination with the structure analysis, it is easy to understand that Zn7Al-MMO with loosely 3D flower-like hierarchical structure exhibited higher photocatalytical activity toward the reduction of aqueous Cr(VI).The photocatalytic activities of Zn7Al-MMO photocatalysts. When initial Cr(VI) concentrations were 10 and 30 mg/L, the photocatalytic removal percentage of aqueous Cr(VI) was almost 98% and 63% in three hours of irradiation time, respectively. Increasing the initial Cr(VI) concentration enhanced the amount of Cr(VI) adsorbed on the surface of the catalyst while the photoelectron-hole pairs generated by the photo-excited catalyst didn’t increase due to the unchanged amount of catalyst, so the effective Cr(VI) concentration reduced was relatively decreased. Moreover, increased absorption of UV by the solution occurred since higher Cr(VI) solution could absorb more light in the UV-Vis range, leading to low light absorption of the photocatalyst. Additionally, with the increasing concentration of aqueous Cr(VI), the color of the solution became darker, which was not conducive to the absorption of UV light photons by the catalyst, thus reducing the efficiency of photoreduction of aqueous Cr(VI) [2-based photoreduction experiments tended to be low [7Al-MMO photocatalyst was actually quite fast.s Cr(VI) . While co be low ,45,46, t7Al-MMO photocatalyst was evaluated with the Cr(VI) concentration of 30 mg/L. The pH of solution is one of the most important influence factors in the photocatalytic process. From 4− or Cr2O72−, in a low pH solution [6+/Cr3+ becomes more positive. Additionally, Cr(OH)3 is deposited on the surface of the photocatalyst at high pH to inhibit the reduction of Cr(VI) [7Al-MMO exhibits different zeta potentials in different pH solutions  reduction. Conversely, in high pH solution, the surface of photocatalyst was much negatively charged, repelling chromium ions in the form of CrO42−, thus depressing the reduction rate of Cr(VI).The effect of differently initial pH on the photoreduction of Cr(VI) while using Znsolution . At low f Cr(VI) . Meanwhiolutions c. The pH2O4 for Cr(VI) photoreduction [7Al-MMO nanocomposite under UV light irradiation was conducted to study their long-term stability and the results are shown in 2O4 nanocomposite exhibited long-standing high photoreduction activity in recycles, and thus it could have potential application prospects in the water environmental restoration. The re-use of catalysts is very important for practical application. However, according to investigations, there is no research on the long term stability of ZnO/ZnAleduction . Repetit2O4 phases in high temperature calcined product ZnnAl-MMO for photoreduction of Cr(VI). The ZnO phase and the ZnAl2O4 phase absorb photon energy under UV light irradiation. The valence band (VB) electron is excited to transition to the conduction band (CB) while leaving holes in VB to form photogenerated electron-hole pairs. The VB and CB potential of ZnO are +2.89 eV and −0.31 eV and those of ZnAl2O4 are +2.66 eV and −1.14 eV, respectively. Due to the CB potential of ZnAl2O4 being lower than that of ZnO, the electron at the bottom of CB of ZnAl2O4 is transferred to the surface of ZnO. While the VB potential of ZnO is higher than that of ZnAl2O4, the hole at the top of VB of ZnO is migrated to ZnAl2O4. The well-formed band structure between ZnO and ZnAl2O4 phases facilitates the migration of photogenerated carriers, thereby effectively suppressing the recombination of photogenerated electrons and holes. Since the CB potential of ZnO is more negative than the Cr(VI) standard potential of Eθ(Cr2O72−/Cr3+) = +1.33 V, photogenerated electrons reduce Cr6+ to Cr3+ (Equation (1)). Meanwhile, due to the more positive VB position of ZnAl2O4 than the oxidation potential of Eθ(H2O/O2) = +1.23 V, the holes oxidize H2O to form O2 (Equation (2)). The consumption of the holes greatly reduces the rate of recombination of photogenerated carriers, enhancing the photocatalytic activity of ZnAl-MMO nanocomposite towards Cr(VI) reduction.2O4 composites with 3D sphere-like nanostructures synthesized through a simple hydrothermal process and subsequent high-temperature calcination. The molar ratio of the Zn/Al metallic cations in the starting mixture played a key role in the morphological transformation of the resulting products from cubic aggregates, hierarchically flower-like spheres to porous microspheres and all the building blocks of the composites exhibited a heterojunction nanostructure between ZnO and ZnAl2O4 phases. ZnO/ZnAl2O4 composite showed outstanding photocatalytic activity towards aqueous Cr(VI) reduction under UV light irradiation. The excellent photoreduction performance of the ZnO/ZnAl2O4 nanocomposite was attributed to 3D sphere-like hierarchical structure and well-formed heterojunctions within the nanocomposite.In conclusion, hierarchical ZnO/ZnAl


The capacity of the auditory system to extract spatial information relies principally on the detection and interpretation of binaural cues, i.e., differences in the time of arrival or level of the sound between the two ears. In this review, we consider the effects of unilateral or asymmetric hearing loss on spatial hearing, with a focus on the adaptive changes in the brain that may help to compensate for an imbalance in input between the ears. Unilateral hearing loss during development weakens the brain's representation of the deprived ear, and this may outlast the restoration of function in that ear and therefore impair performance on tasks such as sound localization and spatial release from masking that rely on binaural processing. However, loss of hearing in one ear also triggers a reweighting of the cues used for sound localization, resulting in increased dependence on the spectral cues provided by the other ear for localization in azimuth, as well as adjustments in binaural sensitivity that help to offset the imbalance in inputs between the two ears. These adaptive strategies enable the developing auditory system to compensate to a large degree for asymmetric hearing loss, thereby maintaining accurate sound localization. They can also be leveraged by training following hearing loss in adulthood. Although further research is needed to determine whether this plasticity can generalize to more realistic listening conditions and to other tasks, such as spatial unmasking, the capacity of the auditory system to undergo these adaptive changes has important implications for rehabilitation strategies in the hearing impaired. •Unilateral hearing loss in infancy can disrupt spatial hearing, even after binaural inputs are restored.•Plasticity in the developing brain enables substantial recovery in sound localization accuracy.•Adaptation to unilateral hearing loss is based on reweighting of monaural spectral cues and binaural plasticity.•Training on auditory tasks can partially compensate for unilateral hearing loss, highlighting potential therapies. This is particularly the case if the source lies beyond the detection range of the other senses, either because it is located outside the visual field or is too far away to be registered by other sensory receptors. The basis for directional hearing relies principally on the fact that animals have two ears that are physically separated on either side of the head, or in the case of some insects, on other parts of the body. This means that, depending on the location of the sound source, the signals reaching each ear may differ in their time of arrival or intensity, giving rise to binaural spatial cues  may be generated by a combination of the spectral filtering effects produced by the external ears and the attenuation at the far ear due to the acoustic shadow cast by the head A. In addBecause of the tonotopic organization of the auditory system, these binaural comparisons mostly take place within frequency-specific channels. For simple periodic sounds, such as pure tones, the temporal fine structure is represented by the phase-locked discharges of auditory neurons at relatively low frequencies only e.g., . MoreoveBecause of their unusual ear asymmetry, barn owls are able to use the two binaural cues for localizing sounds at any angle relative to the head, relying on ILDs in the vertical plane while ITDs provide the principal basis for localization in the horizontal plane . In mostIn addition to providing a basis for localizing sounds, the ability to extract interaural information facilitates target detection in noisy environments , a phenoAlthough spatial release from masking can occur in the absence of subjective sound localization, two key processes that support this phenomenon, better-ear listening and binaural unmasking, are explicitly dependent upon the interaural disparities that arise when a sound source is located to one side of the head. Better-ear listening can improve the signal-to-noise-ratio (SNR) at one ear for a target sound if the masker is attenuated due to the shadowing effect of the head. In realistic speech-in-noise scenarios, such as when multiple spatially-separated maskers are present, the better ear may fluctuate over time and frequency. Consequently, better-ear effects are thought to result from the auditory system's ability to “glimpse” these short-term changes in SNR e.g., . In contMuch less attention has been given to the role of spectral cues in spatial release from masking. Because the spectral filtering provided by the head, and particularly the external ears, is direction dependent, this will contribute to the better-ear effect at high sound frequencies. Indeed, there is some evidence that speech intelligibility in the presence of spatially-separated masking noise improves if natural spectral cues are available than when they are not . Neverth3Estimates of the prevalence of unilateral hearing loss, in which the impairment is restricted to one ear, vary with numerous factors, including the age of the subjects and, of course, the type and extent of the hearing loss e.g. . For exa4Experimental studies of the effects of unilateral hearing loss on spatial hearing have focussed primarily on the consequences of conductive loss Fig. 6). It is unclear whether providing these animals with intermittent episodes of normal hearing while they were being raised with one ear occluded is required for the observed adaptation in their spatial hearing abilities. However, it has been shown that providing cats with brief periods of binocular vision during development can reduce the amblyopia, or loss of visual acuity, that would otherwise result from monocular deprivation . It is t5Reversible manipulation of acoustic localization cues has been widely used to probe the adaptive capabilities of the auditory system in adulthood. Plasticity during development is clearly important for calibrating neural circuits during the period when these cues are naturally changing in value as the head and ears grow . It alsoSeveral studies have shown that horizontal localization by adult humans can adapt to varying degrees to asymmetric hearing loss induced by occluding one ear, resulting in a partial recovery in their ability to localize sound . An impoExperiments in monaurally-plugged adult ferrets have shown that the extent of the recovery in localization accuracy is determined by the frequency of training . These aAs with monaural deprivation during development, when broadband sounds are used as stimuli, adaptation of auditory localization behavior to asymmetric hearing loss in adulthood is based on subjects learning to rely more than before on the unchanged spectral localization cues provided by the normal ear  Fig. 7A or by prNevertheless, reweighting of different spatial cues is not the only means of learning to localize sounds accurately when one ear is occluded. Perceptual learning studies carried out in listeners with normal hearing have shown that sensitivity to binaural spatial cues can improve with training  and, as The behavioral plasticity observed in ferrets raised with a unilateral conductive hearing loss is mirrored by changes in the processing of sound localization cues in A1 . However6Compared with the large body of work that has examined the effects of sound localization training in normal-hearing listeners with unperturbed or perturbed hearing, attempts to translate such training to clinical populations have only recently gathered pace. This is perhaps because of a prior emphasis on providing speech recognition training , and alsGiven the considerable evidence from earplugging studies that a key step in compensating for an imbalance in inputs between the two ears is to change the weighting of different spatial cues, with the auditory brain becoming more dependent on the unchanged spectral cues available at the non-affected ear, it is important to ask how clinically relevant this might be. It is clear that at least some people who are deaf in one ear do indeed utilize monaural spectral cues for localization in the horizontal plane e.g. . FurtherHowever, whether listeners provided with hearing devices can benefit in the affected ear in a similar fashion is more questionable. For one thing, the progressive loss of high-frequency hearing in age-related sensorineural hearing loss will restrict the availability of spectral cues. Although modern hearing aids can have bandwidths of up to 10 kHz or more , which cThe finding that listeners with one ear plugged can be trained to partially recover their sound localization accuracy by learning to remap the distorted ILDs and ITDs onto appropriate spatial locations  potentia7The studies discussed in this review have demonstrated that the auditory system can adjust to changes in the available sound localization cues in ways that can help to preserve spatial hearing abilities. This can be achieved either by reweighting different cues, as demonstrated by the evidence for greater reliance on spectral cues when ITDs and ILDs are compromised by unilateral hearing loss, or by learning a new relationship between altered binaural cues and sound source location. Utilizing the remarkable plasticity of auditory localization mechanisms in the treatment of clinical populations will require the development of training protocols that are practical to use outside the laboratory and which confer maximum generalization to regions of space and stimulus types other than those used for training. This includes identifying the type of feedback most likely to promote learning, with recent studies suggesting that sensorimotor feedback can improve the rate and extent of adaptation to altered spatial cues . Most im


With the extensively spread of industrialization in the world, noise exposure is becoming more prevalent in the industrial settings. The most important and definite harmful effects of sound include hearing loss, both permanent and temporary.This study was designed aimed to use the C5 algorithm to determine the weight of factors affecting the workers’ hearing loss based on the audiometric data.This cross-sectional, descriptive, analytical study was conducted in 2018 in a mining industry in southeastern Iran. In this study, workers were divided into three exposed groups with different sound pressure levels (one control group and two case groups). Audiometry was conducted for each group of 50 persons; hence, the total number of subjects was 150. The stages of this study include: 1) selecting factors (predictive) to check and weigh them; 2) conducting the audiometry for both ears; 3) calculating the permanent hearing loss in each ear and permanent hearing loss of both ears; 4) classifying the types of hearing loss; and 5) investigating and determining the weight of factors affecting the hearing loss and their classification based on the C5 algorithm and determining the error and accuracy rate of each model. To assess and determine the factors affecting the hearing loss of workers, the C5 algorithm and IBM SPSS Modeler 18.0 were used. SPSS V.18 was used to analyze the linear regression and paired t-test tests, too.The results showed that in the first model (SPL <70 dBA), the 8KHz frequency with the weight of 31% had the highest effect, the factors of work experience and the frequency of 250Hz each with the weight of 3%, had the least effect, and the accuracy of the model was 100%. In the second model (SPL 70–80 dBA) the frequency of 8KHz with the weight of 21% had the highest effect, the frequency of 250Hz and the working experience each had the lowest effect with the weight of 7% and the accuracy of the model was calculated as 100%. In the third model (SPL >85 dBA), the 4KHz frequency with the weight of 31% had the highest effect, and the work experience with a weight of 1% had the lowest effect, and the accuracy of the model was 94%. In the fourth model, the 4KHz frequency with the weight of 22% had the highest effect and 250Hz and age each with the weight of 8% had the lowest effects; the accuracy of this model was calculated to be 99.05%.During investigating and determining the weight of the factors affecting hearing loss by the C5 algorithm, the high weight and effect of the 4KHz frequency were predicted in hearing loss changes. Considering the high accuracy obtained in this modeling, this algorithm is a suitable and powerful tool for predicting and modeling the hearing loss. Significant evidence exists indicating that noise is among the most prevalent kinds of occupation-related dangers in today’s world. Research shows that, each day in Europe, about 450 million people experience noise levels of minimum 55 dB (A), 113 million individuals are exposed to a noise level of at least 64 dB (A), and 9.7 million persons experience the noise levels of 75 dB (A) or higher . AccordiExcessive noise causes physiological complications such as hypertension, adrenaline production, an increased risk of heart attack, high blood pressure, changes in respiratory rate, and the amount of consumed oxygen, affecting the auditory system, and increased stomach and intestinal activities, and other social and economic effects, and influences the efficiency and effectiveness of the exposed people. It also leads to interferences with verbal communication and perceptions of warning signs and affects the safety and performance of individuals 5. Althou6The extreme sound may lead to temporary or permanent hearing threshold change with the macroscopic  and microscopic  effects in the ear . HearingNoise-induced hearing loss (NIHL) is a public health problem happening during daily life, which is primarily disregarded, but may lead to the intense morbidity as it is developed. Noise-induced hearing loss (NIHL) is a complex disorder that may possibly be affected by environmental and genetic factors . NIHL isThe National Institute of Occupational Safety and Health (NIOSH), USA, still classifies the noise-induced hearing loss among the top ten work-related problems, which involves at least 11 million workers in the US. It was reported in the recent studies that despite the hearing conservation programs, employees continue to develop NIHL . OccupatData mining (DM) is an interdisciplinary subfield of computer science. It is the computational procedure of discovering patterns in large data sets, which include the methods at the intersection of artificial intelligence, statistics, machine learning, and database systems. To extract information from a data set and convert it into an understandable structure for further use are the general objectives of the DM process. Such information may involve data classification and prediction of outcomes after an intervention, or it may investigate the association, group, or detection of variable deviation . Our choRule sets are preferred in many applications, because of simplicity and easiness for understanding compared to the decision trees. C5 can create classifiers demonstrated either as decision trees or as rule sets. C5 algorithm follows the rules of the algorithm of C4.5, as well as the rules of the ID3 algorithm. C5 algorithm involves many features, as the large decision tree can be considered as a set of rules easy to understand, providing the knowledge on noise and missing data. In classification technique, problem of over fitting and error pruning are solved and the C5 classifier can determine the relevant and irrelevant attributes in classification. The algorithm C5 indicates that how the rule sets are created with improved features while generating fewer rules, therefore, compare to other classifiers, memory usage is low .Because hearing loss is one of the most common noise exposure impairments, it results in high costs for workers in the industry and exposed individuals. Considering that, fewer studies exist in the world conducted on weighting and prioritizing factors affecting the workers hearing loss based on the audiometry data using the C5 algorithm, this study was designed to examine the following objectives:Determining the workers’ equivalent sound level.Determining the hearing loss of both ears.Determining the weight of the factors affecting hearing loss based on the C5 algorithm.Determining the error & accuracy rate of the C5 algorithm.This study was conducted in mining industry in southeastern Iran, for which according to the individual’s equivalent sound level and previous studies, as well as the type of algorithm used in hearing loss modeling, totally three groups (one control group and two case group) was considered. For each group, 50 people were assigned . Thus, the total number of subjects under study was 150 .This is a cross-sectional, descriptive-analytic prospective study. The general stages in orders are as the following: 1) choosing the predictive factors; 2) performing the audiometry and calculating the permanent hearing loss of each ear and then overall hearing loss; 3) classifying the types of hearing loss ; 4) determining the weight of factors effective on the hearing loss based on the C5 algorithm; and 5) determining the error and accuracy rate . Four va21Using Clinical Audiometer CA 120 made in Denmark, pure-tone hearing thresholds at 250, 500, 1000, 2000, 4000, 6000 and 8000 Hz were recorded [At first, the permanent hearing loss of the left and right ear was calculated separately, for this aim, the hearing loss in each 4 important frequencies of 500, 1000, 2000, and 4000 was entered in the related equation after the fraction of age, and the rate of permanent hearing loss caused by sound was calculated (Equation 1). Subsequently, Equation 2 was used to calculate the total permanent hearing loss .Equation 1:TL: Hearing loss at the considered frequency per ear (dB)NIHL: Permanent hearing loss caused by sound (dB)Equation 2:t:NIHL Total permanent loss in both ears (dB)b:NIHL permanent loss of the stronger ear (dB)p:NIHL permanent loss of the poor ear (dB)Hearing loss classification based on the WHO categorization is such that hearing in the range of 0–25 dBA was classified as normal hearing, 26–40 dBA as a mild loss, 41–60 dB as average loss, 61–80 dBA as severe loss and over 80 dBA was classified as deep loss [In this method tree, structure was used to create the classification models. A dataset is divided in this method into smaller subsets. Leaf node provides a decision. The decision trees classify the cases based on feature values of instances. Each node indicates a feature in an instance in a decision tree, which is to be classified, and each branch provides a value. Based on the feature values Classification of Instances starts from the root node and it is sorted. Decision trees can control categorical and numerical data  Figure .The objective is to discover classification rules determining the class label of any object (Y) from the values of its attributes (X). Each internal node (non-leaf node) provides a test condition on an attribute, an outcome of the test is obtained from each branch, and a class label is represented by each leaf node . Let a node N provides the tuples of partition D. The attribute with the highest information gain is selected as the splitting attribute for the node N. Through this attribute the information needed to classify the tuples in resulting partitions is minimized and the least randomness in these partitions is reflected. The expected information needed to classify a tuple in D is given as the following :Equation 3:iP represents the probability that an arbitrary tuple in D is associated with class iC and is estimated by |i, DC|/|D|. Info D is the average amount of information required to determine the class label of a tuple in D. Info (D) is also recognized as the entropy of D. Suppose that we to attempt to partition the tuples in D on an attribute A having υ distinct values {1, a2,…,aυa}. The obtained partitions are associated to the branches of the node N. InfoA (D) is the expected information needed to categorize a tuple from D based on the partitioning by A.Where Equation 4:j th partition. The information gain is explained as the difference between the original information necessity (i.e. based on just the proportion of classes) and the new necessity (i.e. obtained after partitioning on A).The term Equation 5:The attribute A with the highest information gain, Gain (A), is selected as the splitting attribute at node N .In classification algorithms that are used to categorize discrete-type output factors, the evaluation criteria such as accuracy, confusion matrix, sensitivity, and attribute are used. In this study, two criteria of accuracy and confusion matrix were used. The confusion matrix is a square matrix with the dimensions equal to the number of output factors classes. In this matrix, the main diameter represents the percentages that were correctly predicted. According to Equation 6, the accuracy of the model is actually the ratio of the correct predicted cases to the total cases .Equation 6:The Ethics Committee of Kerman University of Medical Sciences approved the present work ethically (ID: IR.KMU.REC.1396.2458). All participants signed a consent form.Using Statistical Package for Social Sciences V.18 (SPSS) , the collected data were analyzed. Mean, standard deviation and correlation coefficient were analyzed using linear regression statistical and paired t-test tests. Moreover, modeling the hearing loss changes was performed using IBM SPSS Modeler 18.0.The demographic data of participants are showed in Table The first group was exposed to an equivalent sound level of less than 70 dB. The second group was exposed to the equivalent sound level of 70 to 80 dB, and the third group was exposed to the equivalent sound level over 85 dB. The mean and standard deviation of the equivalent sound level for the first, second and third groups were 70 ± 3 dBA, 77.62 ± 4.43 dBA, and 89.7 ± 3.03 dBA, respectively.The results of the workers’ hearing loss in both ears based on the severity of hearing loss are provided in Table In this study, four different models of hearing loss were calculated. In the first model, the Audiometric data of the first group workers (SPL <70 dBA), in the second model the Audiometric data of the second group workers (SPL 70–80 dBA), in the third model, the audiometric data of the third group workers (SPL >85 dBA), and ultimately, in the fourth model the total audiometric data of workers in the three groups were modeled.Inserting the results of the above factors for the first model (n = 10) in IBM SPSS Modeler 18.0, the results are obtained as shown in Figure The model predicted correctly the severity of hearing loss for all people with the normal and mild hearing loss, and the accuracy of the C5 algorithm of 100% in this modeling.The results of modeling the hearing loss changes in the second model (n = 10) are shown in Figure The model predicted correctly the severity of hearing loss of all people with normal, mild and moderate hearing loss, and the accuracy of the C5 algorithm was obtained 100% in modeling hearing loss changes.The results of modeling the hearing loss changes in the third model (n = 10) are provided in Figure The model predicted accurately the severity of hearing loss of all people with moderate & severe hearing loss; 6.67% of the people with mild hearing loss were mistakenly predicted as the normal and 6.9% of those with normal hearing loss, were incorrectly predicted with mild hearing loss. The accuracy of the C5 algorithm was 94%.Inserting the results of the effective factors for the fourth model (n = 30) in the software, the results are obtained as shown in Figure The model precisely predicted the severity of hearing loss for all people with mild, moderate, and severe. 0.95 percent of those with normal hearing loss, were incorrectly predicted as mild. The accuracy of model was 99.33% with an error rate of 0.67%.This study aimed to use the C5 algorithm to determine the weight of factors affecting workers’ hearing loss based on the audiometric data. The mean exposure to equivalent sound level for the first, second and third groups was 70 ± 3 dBA, 77.62 ± 4.43 dBA, and 89.7 ± 3.03 dBA, respectively. There was a significant statistical difference between age and work experience with hearing loss in the first and second groups, so that in the first group between age and hearing loss, P = 0.008, R = 0.385 and in the second group, P = 0.008, R = 0.394. There was a statistically significant difference between work experience and hearing loss in the first group  and second group , too. However, in the third group, there was no significant statistical difference between age and working experience with hearing loss, as between the age and hearing loss, R = 0.189, P = 0.277, and between work experience and hearing loss, R = 0.28, P-value = 0.076. Based on the correlation and linear regression, there is a statistically significant difference between hearing loss and sound in all the subjects (n = 150), .In a study conducted by Aghilienejdad et al. to investigate the effect of work environment noise on workers’ hearing at small workshops in Tehran, in 2007, 109 people among the employees in the workshops with less than 50 workers were selected as a case group and the same number were selected as the control group considering all the aspects. In the case group, according to regression model coefficients and regression analysis results, the equivalent sound level was as the first factor, age, and work experience was considered as the next predictor of hearing loss. For the working people in the case group, the progression of hearing loss was associated with the increased work experience . The resAccording to C5 modeling, in the first model (SPL <70 dBA), the 8KHz frequency had the highest weight 31%), and the work experience and 250Hz each with a weight of 3% had the least effect , age and work experience. This is despite the fact that most studies for modeling the hearing loss changes in the world report only the error & accuracy rate and did not mention the weight and effect of each of these factors. Among the constraints of this study are the problems with the industry and not cooperating of some people in conducting audiometric tests.This article aimed to investigate the hearing loss and weight the factors affecting it by using C5 algorithm. According to the results in the first model, with the predictive factors , the frequency of 8KHz with the weigh of 31%, had the highest effect and the factors of work experience & frequency of 250Hz each with a weight of 3% had the lowest effect. The accuracy of the predicted hearing loss model was also 100%. In the second model, considering the predictive factors, the frequency of 8KHz with a weight of 21% had the highest and the work experience & frequency of 250Hz each with a weight of 7% had the lowest effect; the accuracy of the predicted model was 100%. In the third model, the frequency of 4KHz with the weigh of 31% had the highest effect and the work experience with a weight of 1% had the lowest effect and the accuracy of the predicted model was 94%. Ultimately, in the fourth model, the frequency of 4kHz with the weight of 22% had the highest effect and the frequency of 250Hz and the age each with a weight of 8% had the lowest effect and the accuracy of the predicted model was 99.33%. Therefore, considering the high accuracy of the predicted models in the groups, the C5 algorithm is recommended as an appropriate and powerful tool for predicting and modeling the hearing loss.


NPHS2 gene, encoding the slit diaphragm protein podocin, accounts for genetic and sporadic forms of nephrotic syndrome (NS). Patients with NS often present symptoms of volume retention, such as oedema formation or hypertension. The primary dysregulation in sodium handling involves an inappropriate activation of the epithelial sodium channel, ENaC. Plasma proteases in a proteinuria‐dependent fashion have been made responsible; however, referring to the timeline of symptoms occurring and underlying mechanisms, contradictory results have been published. Characterizing the mouse model of podocyte inactivation of NPHS2 (Nphs2∆pod) with respect to volume handling and proteinuria revealed that sodium retention, hypertension and gross proteinuria appeared sequentially in a chronological order. Detailed analysis of Nphs2∆pod during early sodium retention, revealed increased expression of full‐length ENaC subunits and αENaC cleavage product with concomitant increase in ENaC activity as tested by amiloride application, and augmented collecting duct Na+/K+‐ATPase expression. Urinary proteolytic activity was increased and several proteases were identified by mass spectrometry including cathepsin B, which was found to process αENaC. Renal expression levels of precursor and active cathepsin B were increased and could be localized to glomeruli and intercalated cells. Inhibition of cathepsin B prevented hypertension. With the appearance of gross proteinuria, plasmin occurs in the urine and additional cleavage of γENaC is encountered. In conclusion, characterizing the volume handling of Nphs2∆pod revealed early sodium retention occurring independent to aberrantly filtered plasma proteases. As an underlying mechanism cathepsin B induced αENaC processing leading to augmented channel activity and hypertension was identified.The  In the rat model of PAN‐induced nephrosis, sodium retention was shown to start before or at the same time as the onset of proteinuria.fl/flNphs2(control) and Nphs2fl/flcrossbred with inducible podocyte‐specific Cre recombinase transgenic mice, termed Nphs2∆pod hereafter and found that sodium retention and hypertension established before the onset of an unselective gross proteinuria. Increased ENaC channel activity, proteolytic processing of αENaC together with the appearance of proteases in the urine were encountered. Among several lysosomal enzymes identified by proteomic analysis, only cathepsin B was able to cleave αENaC and augment channel activity. Inhibition of cathepsin B influenced the development of hypertension demonstrating its important role in this disease model.We used 2Detailed methods are presented in the supplement files.2.1fl/flNphs2(control) and Nphs2fl/flcrossbred with inducible podocyte‐specific Cre recombinase transgenic mice, termed Nphs2∆pod,∆pod and control mice received tamoxifen  by daily ip injection for 4 days in the evening after spot urine sampling and blood pressure measurements. A second set of animal experiments was performed (V242‐20597/2018) using amiloride (Sigma‐Aldrich) 10 µg/g body weight administered i.p. once daily starting on the first day of the experiment, simultaneously with the tamoxifen injection, till the end of the experiment at 14 days. A third set of animal experiments  was conducted using the cathepsin B inhibitor CA‐074Me . Six weeks old Nphs2∆pod and control received Me‐074 or vehicle by osmotic mini pump  for 14 days. Implantation of pumps was performed 1 day after the first tamoxifen injection. CA‐074Me was administered by mini‐pump infusion at a rate of 2.5 mL/h . Vehicle control infusion was conducted with 1.5% DMSO in saline. All mice entered also completed the experiment.All animal experiments were conducted according to the NIH Guide for the care and use of Laboratory animals, as well as the Swiss and German law for the welfare of animals and were approved by local authorities . Mice were housed in a SPF facility with free access to chow and tap water and a 12‐hour day/night cycle. Breeding and genotyping was performed as described.2.2U test, the parametric two‐tailed Student's t test and, where appropriate one‐way ANOVA followed by Tukey, Dunnett or Newman‐Keuls post hoc test was employed. P values of less than 0.05 were considered statistically significant.Quantitative data are presented as means ± SEM. Statistical comparisons were performed with the GraphPad Prism Software Package 6 . For statistical comparison, the non‐parametric Mann–Whitney 33.1∆pod at 3 weeks of the experiment. These results show in detail renal volume handling and proteinuria during the development of NS in Nphs2∆pod and confirm previous published data.Inactivation of podocin resulted in transiently reduced urinary sodium/creatinine ratio, which was significantly reduced between day 4 to 7 after tamoxifen administration Figure A. Systol3.2∆pod compared to control  expression level by measuring fluorescence intensity levels of cortical collecting ducts identified by aquaporin‐2 expression . All six protease‐positive HPLC fractions were analysed by liquid chromatography (LC)‐tandem mass spectrometry (MS/MS) and identified proteases are summarized in Table Because of the early αENaC processing already at 5 days after FSGS induction, we analysed the urine of Nphs23.6cl14 cell monolayers with cathepsin B resulted in a significant augmentation of equivalent transepithelial currents within 30 minutes .Next, the proteases furin, cathepsin B and D were analysed on their expression level. Western blot analysis of cathepsin B revealed significantly augmented expression in Nphs2n Figure C and 6’.n Figure . At 5 dat Figure . Albumin3.8∆pod, an additional animal experiment was performed with control and Nphs2∆pod receiving either CA‐074Me (a membrane‐permeable cathepsin B inhibitor) or vehicle for 14 days starting on the day after the first tamoxifen injection. As expected at day 9, Nphs2∆pod receiving vehicle developed significantly higher blood pressure, which remained high until the end of the experiment at 14 days (Figure ∆pod receiving CA‐074Me, however, remained at control levels.To analyse whether cathepsin B may impact the disease progression in Nphs2s Figure . Blood p4∆pod, the augmented ENaC expression levels and or αENaC cleavage at 5 and 9 days is of functional relevance because NKA expression levels from the cortical collecting duct are consistently increased compared to control and other nephron segments in the same section. Supporting evidence for early increased ENaC activity was gained from daily administration of amiloride to control and Nphs2∆pod. Highest plasma values for amiloride occur 3‐4 hours after amiloride administration, the time‐point where sodium was determined from spot urine. From our experiment, we observed that between day 5 and 9 before sodium/creatinine ratio increased in control/amiloride and augmented strongly in Nphs2∆pod/amiloride suggesting that using this application procedure sodium/creatinine ratio mirrors ENaC channel activity. These results support the overfill hypothesis where sodium retention is related to an intrinsic renal defect in sodium handling.Proteinuria, volume retention and subsequent hypertension and/or oedema are hallmarks of the NS and possible mechanisms have been identified previously. The murine model of targeted podocin gene inactivation was shown to develop the entire characteristics of FSGS with NS until the fourth week after inductionWith disease progression, proteinuria establishes, plasma albumin values decrease and oedema can be regularly encountered at 17 days of analysis. Those later changes support rather the under fill hypothesis where decreased plasma oncotic pressure by hypoalbuminemia and fluid shifts from intravascular to the interstitial compartment can be found.∆pod which constantly increase with the time. From HPLC‐purified urine of Nphs2∆pod, we identified known γENaC cleaving proteases, such as prostasincl14 cells. Among other lysosomal proteases only cathepsin D cleaved αENaC; however, at a yet unknown site leading to 50 and 40 kDa fragments. Whether cathepsin D cleavage is of functional relevance needs to be identified in future. Additionally, we tested whether the identified lysosomal proteases cleave αENaC. Using trypsin as positive control, we observed a very mild processing by cathepsin D and legumain by in vitro protease assays. Although Tan et alcl14 cells at 2 hours. A more detailed analysis for further exploration needs to be performed in future.The appearance of αENaC fragments at 5 days suggests the existence of local proteases; therefore, the urine was tested for proteolytic activity. Already at the second day of animal experiment, elevated levels of proteases can be found in the urine of Nphs2∆pod during the time of early sodium retention between day 5 and 9, overall glomerular morphology remains largely intact, the glomerular filter however is altered and shows albuminuria/selective proteinuria. Therefore, plasma proteases as shown for plasminogen are still unable to pass and do not account for the sodium retention during this period assuming that urinary proteases identified might stem from the kidney itself. Lysosomal cathepsin B activation and proximal tubular spill over into the primary ultrafiltrate was postulated to account for increased urinary cathepsin B activity in proteinuric diseases.∆pod at 5 and 9 days, increased cathepsin B expression was found in glomeruli and more strongly in intercalated cells; therefore, we assume that either glomerulus‐derived cathepsin B via ultrafiltrate or intercalated cell‐derived cathepsin B paracrine reach the principal cells for αENaC cleavage and therefore ENaC channel activation. The important role of cathepsin B in renal disease progression was demonstrated recently showing that cathepsin B knockout mice were more resistant and recovered faster after glomerular damage upon podocyte injury induced by nephrotoxic serum.In Nphs2∆pod mice, we were able to identify the chronology of the development of hallmarks of the NS. Early after genetic Nphs2 deletion, sodium retention occurred, followed by hypertension and gross proteinuria. This early sodium retention is based on augmented ENaC activity through proteolytical processing of αENaC. Cathepsin B was identified as αENaC cleaving enzyme where its blockade prevented hypertension.In summary, using the Nphs2There is no conflict of interest. Click here for additional data file. Click here for additional data file. Click here for additional data file. Click here for additional data file. Click here for additional data file. Click here for additional data file.