Cochlear implants have provided hearing to hundreds of thousands of profoundly deaf people around the world. Recently, the eligibility criteria for cochlear implantation have been relaxed to include individuals who have some useful residual hearing. These recipients receive inputs from both electric and acoustic stimulation (EAS). Implant recipients who can combine these hearing modalities demonstrate pronounced benefit in speech perception, listening in background noise, and music appreciation over implant recipients that rely on electrical stimulation alone. The mechanisms bestowing this benefit are unknown, but it is likely that interaction of the electric and acoustic signals in the auditory pathway plays a role. Protection of residual hearing both during and following cochlear implantation is critical for EAS. A number of surgical refinements have been implemented to protect residual hearing, and the development of hearing-protective drug and gene therapies is promising for EAS recipients. This review outlines the current field of EAS, with a focus on interactions that are observed between these modalities in animal models. It also outlines current trends in EAS surgery and gives an overview of the drug and gene therapies that are clinically translatable and may one day provide protection of residual hearing for cochlear implant recipients. Cochlear implants have successfully provided hearing to over three hundred thousand hearing impaired people worldwide . TraditiThe typical EAS recipient is an adult who has lost high frequency hearing postlingually, whilst maintaining usable hearing in the low frequencies, creating a so-called ‘ski-slope' hearing loss  after partial hearing loss, with particular emphasis on the use of viral vectors for cell specific gene expression and discussion of clinical safety.One of the main areas of research into EAS focuses on the interactions between the responses to the electric and acoustic stimuli. While the clinical evidence indicates improved performance with EAS, it is possible that the stimuli can also effectively mask one another, reducing the quality of the incoming signal. If this were the case, additional clinical benefit may be achieved by segregating the signals either temporally or spatially (with regard to the intracochlear regions that each stimulus type activates) so that masking is minimised. This section presents an overview of the known interactions between electric and acoustic hearing, as well as discussing plastic changes that occur in the brain due to combined stimulation.It is important to note that the majority of studies investigating EAS interactions to date have been carried out in normal-hearing animals fitted with intra- or extracochlear stimulating electrodes –26. Althβ-component of the auditory nerve response). Higher current levels produced a short latency α-component which results from direct stimulation of the auditory neurons  under different stimulation combinations have made up the majority of the electrophysiological studies investigating EAS. This work has notably used masking paradigms, including forward masking of an acoustic signal by electric stimulation, forward masking of an electric signal by an acoustic signal and simultaneous EAS.Experiments in normal hearing animals show that acoustically-evoked CAPs are suppressed by a preceding electric pulse train presented at the base of the cochlea, with the strongest suppression occurring for responses to low intensity, high frequency acoustic stimuli that were masked by high current levels . SuppresFurther studies have investigated the effects of an acoustic masker on the electrically-evoked CAP (ECAP) and have shown that broadband noise can decrease both the ECAP amplitude and firing synchrony –30, resuThe role of background activity in EAS interactions was demonstrated by Miller et al. , who shoThe tuning of auditory nerve fibres under EAS stimulation has only been investigated in one study , which fThe dependence of the electric and acoustic masking upon the relative temporal position of the stimuli is of clinical relevance because the latter depends upon a number of factors: (a) the frequency of the stimulus, (b) the relative delay introduced by the speech processor, and (c) the power spectrum of the stimulus.Stimulus frequency will affect relative timing between the two stimulus modalities due to the travelling wave , where aThe electrically-induced basilar membrane motion that gives rise to electrophonic responses was thought to be generated by the electromotile properties of the outer hair cells OHCs; , 34, 35), 3534, 3Although most studies investigating EAS in animal models to date have used normal-hearing animals, there has been a recent increase in the number of published studies that aim to emulate a clinically relevant partial hearing loss , 37, andA further confound between clinical populations and animal models of partial hearing loss comes in the form of the fitted device. For recipients with residual hearing, it is common for combination devices that couple acoustic amplification with electrical stimulation to be used in the implanted ear . HearingEAS interactions at the level of the inferior colliculus (IC) in normal hearing animals have been investigated by Vollmer et al. . As descThere is evidence that the speech recognition benefits that recipients experience with EAS develop over time , suggestWe have previously reported that chronic intracochlear electrical stimulation in cats with a high frequency hearing loss caused a decrease in the extent of primary auditory cortex that could be activated by acoustic stimulation . AlthougThis section has outlined the physiological interactions between electric and acoustic stimulation, which are typically inhibitive for forward and simultaneous masking paradigms. However, there is currently little evidence of these interactions in clinically-relevant partial-hearing animals, although the plastic changes seen in chronically stimulated EAS animal models  could coCritical to the success of EAS is the health of the cochlea and, in particular, the residual hearing available to the listener. It is well reported in the literature that the insertion and use of a cochlear implant can cause a loss of residual hearing in the stimulated ear. This section outlines potential causes for this loss, which can be surgical or histopathological.Surgical factors are controlled by the implanting surgeon and include electrode selection, insertion route (cochleostomy or through the round window), insertion depth, and the use of atraumatic surgical techniques. Early traumas such as damage to the osseous spiral lamina, basilar membrane rupture, and lateral wall disruption have all been shown to have occurred during human cochlear implantation –45 and aThe cochlea's histopathological response to electrode insertion may also contribute to delayed or progressive hearing loss following cochlear implantation. Delayed effects include fibrotic changes around the electrode, new bone formation and foreign body reaction. There are a number of cochlear structures that can be affected by these changes after implantation, including the organ of Corti, the SGNs and their dendrites, and the stria vascularis along the lateral wall –45. AlteSuccessful preservation of residual hearing and prevention of delayed hearing loss have generally been advocated by either surgical technique alone or use of a particular electrode design , 48–51. Concerns over the potential loss of residual hearing are an important consideration for prospective recipients with significant residual hearing prior to implantation with a “hybrid” or shortened electrode. Given the potential for loss of residual hearing that is either due to the surgery, the biological response to the presence of the electrode array, or to progression of the underlying pathology, there is a potential benefit in having a longer electrode array with more electrodes within the cochlea that would allow for programming flexibility and pitch-matching similar to that used with current electrode arrays . Were re“Soft surgery,” a collection of techniques that would aid in the preservation of hearing following cochlear implantation, was first proposed as a concept by Lehnhardt in 1993 . This prSafe hypothermic induction can be noninvasive by using cooling blankets and ice packs, or a more invasive route can involve safe infusion of large volumes of cold fluids . HypotheFollowing implantation, the cochlea shows several pathological responses resulting from foreign body response to the electrode array. Apoptosis of auditory hair cells and SGNs , 74, infFibrosis within the cochlea and around the electrode array is an almost ubiquitous finding following implantation. This is not unique to cochlear implantation as fibrosis can occur as a reaction to other inflammatory processes to disrupt inner ear anatomy without electrode placement , 81. It New bone formation within the cochlea is another commonly observed consequence of cochlear implantation. Osteogenesis typically occurs in similar locations to fibrosis: at the cochleostomy site, along the path of implantation, and even in the nonimplanted apex of the cochlea , 82.Nonspecific inflammatory reactions within the cochlea have been known also to cause loss of residual hearing post-implantation . Most reHistological evidence suggests that there are many pathological processes associated with electrode insertion. It is unclear whether these pathological processes are associated with any observed hearing loss or cause the observed hearing loss. Direct electrode insertion trauma, apoptosis, acute inflammation, chronic inflammation and hypersensitivity/foreign body reaction can all potentially occur in the cochlea after implantation. With the common finding of inflammatory cells, fibrosis and giant cells, it could be postulated that potent anti-inflammatory drugs like corticosteroids have a role to play in hearing preservation. What remains unclear is what effect these pathological processes have on the hearing mechanisms of the cochlea, although it seems certain that the preservation of residual hearing through maintenance of neuronal survival and cochlear health can only be beneficial to the implant recipient.As discussed above, hearing preservation and the survival of both residual hair cells and SGNs in cochlear implant surgery have become an increasingly important goal in order to facilitate EAS outcomes. Along with surgical refinement, the delivery of therapeutic agents to the cochlea has the potential to provide protective effects within the cochlea and is likely to have significant clinical benefits.Various techniques, treatment regimes, and therapeutic agents are currently being used or are under investigatation for future use in this regard. Localised delivery of therapeutic agents into the cochlea is likely to be the most effective means to promote neuronal health, as it places the therapeutic agents in direct proximity to the target cells they are intended to protect. In addition, this approach minimises the high dose rates and other complications that can arise from systemic delivery.Direct infusion into the fluid spaces of the cochlea can be achieved via a cochleostomy to insert, for example, a cannula attached to a reservoir containing the drugs of interest, a drug-coated electrode, or to implant cells expressing therapeutic agents. Each of these techniques has been demonstrated to successfully deliver the drug in question to the cochlea and be very efficacious for SGN protection , 85–89; Several classes of compounds are available as therapeutic agents to protect the sensory hair cells and SGNs from trauma and degeneration, including neurotrophic factors, antioxidants, antiapoptotic agents, and anti-inflammatory steroids, and a number of companies are currently involved in the commercial development of novel otoprotective drugs. Treatment with these agents, in combination with surgical refinement such as hypothermia, may enhance the outcomes from EAS.Brain derived neurotrophic factor (BDNF) and neurotrophin-3 (NT3) are neurotrophins that are produced by the hair cells , 94 and While the specific effects of neurotrophins have not been investigated in studies using EAS, enhanced SGN survival, and decreased electrically-evoked auditory brainstem response EABR thresholds were observed when neurotrophins such as BDNF were delivered in conjunction with chronic electrical stimulation from a cochlear implant , 108. InCorticosteroid treatments are now a common therapy for many forms of hearing loss, such as autoimmune inner ear disease, sudden hearing loss, and Menière's Disease . More reNumerous aetiologies of hearing loss occur as a result of the generation of reactive oxygen species and subsequent oxidative stress. For example, cisplatin, a potent antineoplastic agent used for the treatment of a variety of tumours and aminoglycoside antibiotics, which are commonly used to treat aerobic, gram-negative bacterial infections, has ototoxic side effects due to the generation of reactive oxygen species and oxidative stress , 120. InHearing loss has also been associated with the initiation of apoptotic pathways such as those mediated by c-Jun N-terminal kinase (JNK) and the caspases. The inhibition of each of these apoptotic proteins inhibits aminoglycoside-induced hair cell death , 131. FuAn effective treatment strategy to promote residual hearing via preservation of hair cells and SGNs may require a combined application of a number of these therapeutic agents, or agents with multiaction properties which can elicit neuroprotective, antiapoptotic, and antioxidant effects. Indeed, the combined application of neurotrophic factors and antioxidants has previously been shown to protect both SGNs and hair cells against ototoxin-induced damage , 134, wiAn alternative promising combined treatment option in the cochlea is the use of cell-based therapies, in particular, NTCELL, which are alginate encapsulated porcine choroid plexus cells (Living Cell Technologies Pty Ltd.) has potential application in the cochlea. Clinical trials for the treatment of Parkinson's Disease by NTCELL have recently begun. NTCELL secretes many neurotrophic and growth factors which can increase neuronal survival in response to traumatic injury, hypoxia or chemical challenges . SpecifiFuture therapies may also incorporate the initial application of a steroid such as dexamethasone to protect against implant-related trauma, as well as an ongoing delivery method for neurotrophic factors and/or free radical scavengers for more long-term protective effects. Alternatively, gene therapy may facilitate long-term neurotrophic support to promote preservation of hearing.The introduction of neurotrophins into the cochlea has proven to play a key role in the survival of SGNs after SNHL , 21, 101Previous studies of neurotrophin gene expression, in supporting cells in particular, have demonstrated beneficial effects on SGNs such as survival and neuronal resprouting , 138 butSimilar to studies using other neurotrophin delivery systems, expression of BDNF by adenoviral vectors in combination with electrical stimulation from a cochlear implant promoted SGN survival and improved thresholds for SGN stimulation . It is pViral vectors are currently the most efficient way to introduce transgenes into cochlear cells. There are a number of viral vectors that have been tested in the cochlea including adenovirus, adeno-associated virus (AAV) and herpes simplex virus –148. EacCell-specific gene expression can have a big impact on the protective effects observed after hearing loss. Gene expression that was localised mainly to supporting cells of the organ of Corti not only had greater SGN survival compared to expression in cells of the scala tympani , but alsExpression of reporter genes in SGNs has been demonstrated after injection into the scala tympani using vectors such as AAV , 154 andThe anatomy of the cochlea makes it suitable for localised gene delivery in many ways: It is surgically accessible; the fluid chambers are partitioned allowing certain cells to be targeted; and the blood-cochlear barrier ensures there is minimal spread of the virus beyond the injection site. The scala tympani is easily accessible via the round window membrane or a cochleostomy, similarly to the insertion route used during cochlear implantation. Injection of viral vectors into the scala tympani results in gene expression predominantly in cells lining the perilymphatic space, but also in hair cells and supporting cells , 156. ThIn most cases, injection of viral vectors into the cochlea results in gene expression that is localised to the cochlea. However, there have been reports of viral vector spread to the contralateral ear as well as the cerebellum , 159. FuIt is important to demonstrate the clinical safety of gene therapy in the cochlea. Gene therapy is finding increased clinical acceptance with multiple clinical trials demonstrating that viral gene therapy in the human nervous system is both beneficial and safe. AAV in particular has been used in numerous clinical trials. For example, AAV2-GAD (glutamic acid decarboxylase) is being trialled for advanced Parkinson's disease and AAV2-RPE65  is under investigation for severe retinal dystrophy. No serious adverse effects attributed to the vector were observed and each showed apparent biological effects of the transgene –166. Of Although more controlled trials will be needed to prove the overall safety and effectiveness of gene therapy, it is encouraging that gene therapy has been conducted in the human nervous system. There is increasing evidence that gene therapy is providing clinical benefits to a range of diseases with ever improving vector design eliminating the adverse events that used to be associated with gene therapy . A recenDespite being an emerging field, EAS promises to improve the lives of partially deaf people to whom a hearing aid does not provide a satisfactory listening experience.There are two clear areas of research required to improve EAS outcomes: improving our understanding of how EAS is processed by the brain, and prevention of the hearing loss that occurs in a significant proportion of EAS listeners. This paper has focused on these two key areas and has shown that the interactions between acoustic and electrical stimulation at the level of the cochlea and along the auditory pathway require further exploration in order to understand their perceptual effects. This research, in turn, will lead to the refinement of processing strategies that will enable the benefits of combined EAS to be optimised to full effect, and minimise any interactions that may hinder ideal results.The protection of residual hearing, both at the time of implantation and postimplantation, is of critical importance to successful EAS. A number of innovations have recently been made in terms of electrode array design and surgical technique that aim to promote residual hearing, but there are still reports of implantation-related hearing loss. As such, administration of protective agents prior to, during or after cochlear implantation could provide the required promotion of cochlear health to maintain residual hearing. There are a variety of therapeutic agents that have the potential to protect residual hearing and support SGN survival to enhance the benefits of EAS. Future studies in this field need to elucidate (i) the most suitable therapeutic agents, or combination thereof, (ii) the most effective treatment regime, which may be made up of various regimes and different drugs, and (iii) appropriate delivery methods, including acute administration and longer-lasting gene therapy treatments, in order to preserve residual hearing and SGN survival in cochlear implantation and maximise the benefits and outcomes of EAS.We have shown that the combination of these agents with electrical stimulation can further promote neuronal growth  and it s


Congenital sensorineural hearing loss is the most common sensory disorder, with approximately 1 in every 1000 newborns in developed countries suffering from severe-to-profound hearing loss. At least half of those cases are attributable to genetic causes with more than 90 causative genes identified to date reflecting the complex clinical and genetic landscapes of hereditary hearing loss .Recent advances in molecular genetics technologies, notably next-generation sequencing (NGS), have drastically accelerated the identification of novel genes involved in hearing mechanism and expanded the mutational spectrum of known deafness-causing genes –9. In adThis special issue is to exhibit the advances and recent progress in the fields of molecular genetics and molecular biology of hearing and deafness.The review paper by S. Kitajiri and T. Katsuno (Kyoto University) summarized the importance of the tricellular tight junction proteins  in the inner ear by acting as a barrier separating the endolymphatic and perilymphatic spaces, which is essential for the generation and maintenance of the endocochlear potential.Callithrix jacchus). KIAA1199 has been reported as a cause of progressive hearing loss, but its spatial expression showed different and distinct patterns in mouse and rat cochlea. In this report, M. Hosoya at al. showed a more widespread KIAA1199 protein expression in the marmoset. These results are of importance for further investigation and elucidation of the functional role of KIAA1199 in primate cochlea.M. Hosoya et al. described the cochlea distribution patterns of KIAA1199 proteins in a nonhuman primate, the common marmoset  is the most important and effective treatment for patients with profound sensorineural hearing loss. However, outcomes vary among patients due to several reasons, one being the heterogeneous nature of the clinical as well as genetic etiology of hearing loss. H. Koyama et al. reported the CI outcomes in five patients with Waardenburg syndrome. They showed that CI is a good and suitable treatment option for Waardenburg syndrome cases.Statins are inhibitors of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase and widely used as cholesterol-lowering drugs. However, in the last decade, conflicting data about the effect of statins on neuronal cells and the auditory system has been published. K. Leitmeyer et al. studied the effect of simvastatin on spiral ganglion neurons explants in vitro and showed its neurotoxic effect that seems to be at least partially mediated by the mevalonate pathway.In this special issue, we collected both basic and clinical original research articles stimulating the continuing efforts to understand the mechanisms of deafness and hearing systems. It is our wish to increase interest in this field and further accelerate future treatment options based on solid basic research.


Understanding the risk factors for hearing loss is essential for designing the Belgian newborn hearing screening programme. Accordingly, they needed to be updated in accordance with current scientific knowledge. This study aimed to update the recommendations for the clinical management and follow-up of newborns with neonatal risk factors of hearing loss for the newborn screening programme in Belgium.A literature review was performed, and the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system assessment method was used to determine the level of evidence quality and strength of the recommendation for each risk factor. The state of scientific knowledge, levels of evidence quality, and graded recommendations were subsequently assessed using a three-round Delphi consensus process (two online questionnaires and one face-to-face meeting).Congenital infections , a family history of hearing loss, consanguinity in (grand)parents, malformation syndromes, and foetal alcohol syndrome presented a ‘high’ level of evidence quality as neonatal risk factors for hearing loss. Because of the sensitivity of auditory function to bilirubin toxicity, hyperbilirubinaemia was assessed at a ‘moderate’ level of evidence quality. In contrast, a very low birth weight, low Apgar score, and hospitalisation in the neonatal intensive care unit ranged from ‘very low’ to ‘low’ levels, and ototoxic drugs were evidenced as ‘very low’. Possible explanations for these ‘very low’ and ‘low’ levels include the improved management of these health conditions or treatments, and methodological weaknesses such as confounding effects, which make it difficult to conclude on individual risk factors. In the recommendation statements, the experts emphasised avoiding unidentified neonatal hearing loss and opted to include risk factors for hearing loss even in cases with weak evidence. The panel also highlighted the cumulative effect of risk factors for hearing loss.We revised the recommendations for the clinical management and follow-up of newborns exhibiting neonatal risk factors for hearing loss on the basis of the aforementioned evidence-based approach and clinical experience from experts. The next step is the implementation of these findings in the Belgian screening programme.The online version of this article (doi:10.1186/s12887-015-0479-4) contains supplementary material, which is available to authorized users. The prevalence of bilateral hearing loss is substantial, particularly in neonates admitted to the neonatal intensive care unit (NICU) who frequently present with risk factors for hearing loss. The prevalence of significant bilateral hearing loss in this group is 1–3 %, which is 10 times higher than that in the well-baby nursery population –4. ThereFollow-up on toddlers’ hearing to diagnose potential delayed-onset or progressive hearing loss in childhood is a major issue. In 2007, the Joint Committee on Infant Hearing (JCIH) released a unique list of risk indicators associated with congenital/neonatal hearing loss and delayed-onset/acquired or progressive hearing loss . The JCIAs in other regions, in Belgium, knowing the risk factors for hearing loss is essential for designing a newborn hearing screening programme with different organisations and tests. According to the programme of the Fédération Wallonie-Bruxelles  launched in 2006, different protocols and neonatal hearing tests are performed depending on the presence or absence of particular risk factors; in their absence, an automated screening test of the cochlea is performed, whereas an audiological assessment is recommended in the presence of risk factor(s). This audiological assessment comprises diagnostic tests that evaluate the entire auditory function, including that of the central auditory system. The identification of risk factors directs neonates to the appropriate clinical pathway and thus is essential.Since the beginning of the newborn hearing screening programme in the FWB, the risk factors were based on the JCIH 2000 Position Statement  and the The present study aimed to update the recommendation for the clinical management of newborns with neonatal risk factors for hearing loss on the basis of current scientific knowledge. The recommendations were obtained by performing a literature review and then grading the evidence. Finally, the recommendations were validated by the consensus of a panel of experts in the context of the newborn hearing screening programme in the FWB. We also present the recommended follow-up regime for newborns with neonatal risk factors for hearing loss.A consensus research procedure was used to update the clinical management of newborns exhibiting neonatal risk factors for hearing loss in the newborn hearing screening programme in the FWB Fig. .Fig. 1Flpopulation, intervention, comparison, and outcomes (PICO) tool. This framework was applied to each risk factor for hearing loss used in the newborn hearing screening programme in the FWB  is it scientifically pertinent to consider it as a risk factor for hearing loss in the newborn hearing screening programme? and (2) how is the risk factor defined?We reviewed the PubMed database, the academic library of our institution, and the Cochrane Library for articles in English and French. The following search terms were used: [‘hearing loss’ OR ‘hearing impairment’ OR ‘deafness’] AND [‘newborn’ OR ‘neonatal’]. In addition, each risk factor was searched  terms or not). To the extent possible, the literature review was limited to the last 15 years to avoid the effects of changes in healthcare. Nonetheless, if the literature review results were insufficient, the search period was prolonged and the literature research was extended to ‘neurodevelopmental outcomes’ on the condition that the articles in question investigated hearing loss. In cases in which few relevant papers were found, bibliographies were used to find other references. Review articles were included, but animal model studies were excluded. The literature review revealed three potential risk factors not included in the original list that were included in the analysis: congenital diaphragmatic hernia, extracorporeal membrane oxygenation, and inhaled nitric oxide.When available in the selected papers, scientific information about follow-up and postnatal hearing loss was also reviewed for the risk factors from the original list . To ensure all risk factors were included in the list of the FWB, a global literature review was performed using the search terms ‘neonatal hearing loss’ and ‘postnatal hearing loss’. We also searched the web to identify specific documents from other newborn hearing screening programmes .The main findings from each paper were summarised in a table using the same framework for all risk factors. The state of the scientific knowledge was subsequently rated according to the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system . The quaRecommendations were formulated on the basis of the literature review, quality of evidence, confidence in the ‘balance between desirable and undesirable effects’ of the management strategies, required resources, and patients’ values and preferences (based on experts’ experience) . Each reThe Delphi consensus method was used. Experts in paediatrics, otorhinolaryngology, or newborn hearing screening were recruited to participate in the panel of experts. The final panel was comprised of six otorhinolaryngologists , three paediatricians , and one neurophysiologist. These experts were not mandated by a government organisation and had no competing interests related to this project; their sole motivation was to improve the newborn hearing screening programme in accordance with clinical realities and current medical knowledge.The consensus process was conducted between January 2015 and April 2015 in three rounds: two rounds of online questionnaires and one face-to-face meeting. The first online questionnaire aimed to validate the state of scientific knowledge, the rated evidence for each neonatal risk factor, and the proposed graded recommendations. All pertinent scientific literature and the aforementioned summary of the scientific papers were available for the panel of experts. The online surveys were conducted using SurveyMonkey®, and responses were coded on a Likert scale from 1 to 5 . A consensus was reached when at least two-thirds of the panel agreed or disagreed, and when the mean Likert score was ≤2 or ≥4 [The ethical approval and informed consent are not necessary according to Belgian regulations .The rated levels of evidence and graded recommendations for each risk factor are summarised in Table The prevalence of sensorineural hearing loss was higher in neonates with congenital cytomegalovirus (CMV) than those without risk factors for hearing impairment. Observational studies  reported a strong association in neonates between hearing impairment and congenital CMV infection regardless of whether the infection is symptomatic or asymptomatic at birth , 17. MorSimilarly, congenital toxoplasmosis, syphilis, and rubella are reportedly associated with neonatal hearing impairment –27. NowaA systematic literature review evaluated the association between congenital herpes infections and sensorineural hearing loss in neonates: only three studies were identified, and limited evidence supports the assumption that herpes simplex virus infection is a cause of sensorineural hearing loss . MethodoThe panel of experts recommends performing audiological assessment during the neonatal period for newborns with congenital CMV, toxoplasmosis, rubella , or syphilis infection.The panel of experts recommends performing a hearing screening test on newborns with congenital herpes simplex virus.The panel of experts clarifies that congenital infection means that the newborn is infected, not merely maternal seroconversion during pregnancy. Neonatal infection should be identified by blood test  or urine test  according to the infection.This recommendation places high value on the level of evidence of the risk factor for hearing loss and low value on the treatment status of the neonate.In the literature, a family history of hearing loss is often analysed with consanguinity –36. HoweThe panel of experts recommends performing audiological assessment during the neonatal period in cases with (a) a family history of congenital or early-onset hereditary hearing loss ; (b) consanguinity of first or second degree ; and (c) malformations and syndromes associated with hearing loss.The panel of experts suggests audiological assessment during the neonatal period in the presence of isolated malformations of the pinnae.Maternal alcohol consumption in pregnancy, without foetal alcohol syndrome, is not a risk factor for hearing loss. Nevertheless, the prevalence of sensorineural and conductive hearing loss is higher among children who suffered from foetal alcohol syndrome than in the general paediatric population –54; the The panel of experts recommends performing audiological assessment during the neonatal period in the presence of foetal alcohol syndrome.The panel of experts recommends performing a hearing screening test in neonates born to mothers who abused drugs during pregnancy.Studies analysing low birth weight used different classifications of birth weight, such as low, very low, or extremely low birth weight. Most studies do not provide evidence of a direct association between the neonatal hearing loss and low birth weight, although the prevalence of sensorineural hearing loss is higher in low-birth-weight neonates –66. ThisAnother specific indicator of neonates is the Apgar score, which is used as an indicator of birth asphyxia. Studies analysing the association between Apgar score with hearing loss were difficult to compare: the timing of the Apgar score  and cut-off for birth asphyxia  varied considerably. In some studies, the Apgar score was not associated with hearing loss, whereas in others, a low Apgar score was associated with sensorineural hearing loss or abnormal hearing results, particularly when measured 5 min after birth  –73. TherHyperbilirubinaemia is frequently encountered in neonates; severe and very severe cases must be treated by phototherapy or exchange transfusion, respectively. Hearing disabilities among infants with a history of hyperbilirubinaemia are more prevalent than in the general paediatric population , 76. IndVery low birth weight/prematurity, a low Apgar score/birth asphyxia, and hyperbilirubinaemia have a cumulative effect, increasing the vulnerability of the brain and auditory function , 78, 84.The panel of experts recommends performing audiological assessment during the neonatal period in cases of (a) a very low birth weight ; (b) an Apgar score of 0–6 at 5 min; and (c) early hyperbilirubinaemia (before day 2) requiring treatment or hyperbilirubinaemia at any day of life requiring either intensive phototherapy or exchange transfusion (based on reference curves).By placing a high value on avoiding unidentified neonatal hearing loss and because it is painless to perform an audiological assessment, the panel of experts considers very low birth weight a risk factor for hearing loss, even with a ‘very low’ level of evidence. Moreover, in addition to exchange transfusion, the panel considers early hyperbilirubinaemia and intensive phototherapy a stronger risk factor than that in the JCIH Position Statement (2007) . The panThe JCIH Position Statement (2007)  considerNewborns admitted to the NICU can receive ventilation support with endotracheal ventilation or nasal continuous positive airway pressure (CPAP). The prevalence of hearing loss does not differ significantly between mechanical ventilation and CPAP , 91. MulOtotoxic drugs, specifically aminoglycosides and loop diuretics, can be administered to newborns. However, the association between aminoglycoside administration and hearing loss is inconsistent among studies; most studies reported no significant association with treatment duration, total dose, or peak or trough serum concentrations –98, wherExtracorporeal membrane oxygenation (ECMO) is an extreme medical therapy used in critically ill newborns. The incidence of sensorineural hearing loss reported among infants who have received ECMO varies widely among studies, but is higher than that in the general paediatric population , 104. HoThe panel of experts recommends performing audiological assessment during the neonatal period after ECMO treatment.The panel of experts suggests performing audiological assessment during the neonatal period in cases of (a) a NICU stay exceeding 5 days; (b) assisted ventilation lasting at least 24 h; and (c) ototoxic drug  administration regardless of treatment length.The panel of experts’ recommendations regarding NICU stay and ototoxic drugs are concordant with those of the JCIH Position Statement (2007) . They coNeurologic diseases in neonates include meningitis and intraventricular haemorrhage. The risk of hearing loss due to meningitis varies widely in the literature, although the reported rates are higher than those in the general population; the long-term consequences such as improvement/worsening of impairment also vary –114. NeoCongenital hypothyroidism is strongly associated with a higher prevalence of hearing loss than that in the general population; reported cases of hearing loss are mostly bilateral and of mild to moderate severity –120. PheThe panel of experts recommends performing audiological assessment during the neonatal period in neonates (a) who have suffered from meningitis or require a neurologic consultation  and (b) with congenital hypothyroidism.Meningitis is confirmed by positive culture. The panel of experts highlights some specific neurologic conditions for paediatricians and otorhinolaryngologists, even without rigorous evidence of an association with hearing loss. This recommendation is based on the experts’ clinical experience.The panel of experts suggests performing audiological assessment during the neonatal period in neonates with white matter lesions or intraventricular haemorrhage.The panel of experts explicitly highlights situations in which newborns exhibit more than one risk factor for hearing loss; the prevalence and severity of hearing loss increase with an increasing number of risk factors . TherefoThe panel insists these neonatal risk factors for hearing loss are applicable during the first month of life and should be reassessed in cases showing changes in health condition during that period .When an audiological assessment is suggested or recommended, the panel of experts highlights the necessity to perform (to the extent possible) hearing tests before hospital discharge. In cases involving admission to the NICU in particular, neonate hospitalisation is stressful for the parents; therefore, they should not be required to return to the hospital after discharge, if possible. The goal is to avoid losses to follow-up and thus undiagnosed cases. If audiological assessment is not performed before discharge because of a short hospital stay, an outpatient appointment should be made during the following month at the latest. The appointment should be scheduled before discharge.The panel of experts states that the audiological assessment should at least include an auditory brainstem response to assess the entire auditory brainstem pathway. The tests should be chosen within the competency of the otorhinolaryngologist in charge of the patient and in accordance with the context and situation.The panel of experts recommends audiological follow-up for all children who have undergone audiological assessment at birth; this follow-up should be performed once between the ninth and twelfth months of life. The panel of experts identifies two exceptions. First, children with congenital CMV infection, a family history of congenital or early-onset hereditary hearing loss, a family history of consanguinity of the first or second degree, malformations and syndromes associated with hearing loss, or those treated with ECMO should undergo audiological follow-up every 4–6 months during their first two years of life. Their hearing should be reassessed annually between 2 and 6 years of age. Second, neonates treated with ototoxic drugs should undergo audiological follow-up once during the first 3 months of life. The otorhinolaryngologist will judge the appropriate hearing tests to perform during follow-up, depending on the child’s risk factors and age.This study aimed to update the recommendations for the clinical management and follow-up of children with neonatal risk factors for hearing loss in the newborn hearing screening programme in the FWB in Belgium. To this end, we used methodological tools, including the formulation of PICO questions, a literature review to establish the state of scientific knowledge on risk factors for hearing loss, the GRADE system assessment, and a consensus process with a panel of experts. The findings of this study will ultimately improve clinical practice through the earlier identification of newborns suffering from hearing loss and adequate follow-up of children at risk of delayed or late-onset hearing loss. Indeed, the newborn hearing screening programme in Belgium is based on the presence or absence of risk factor(s) for hearing loss. Therefore, an accurate, sensitive, and well-formulated list of neonatal risk factors for hearing loss and recommendations for their management is essential. However, the misidentification of risk factors for hearing loss may lead to unnecessary assessment and stress for parents; alternatively, newborns with neonatal hearing loss may be overlooked because of having been subjected to an insufficiently accurate audiological test. Modification of the protocol design of the hearing screening programme was unfeasible because it would have required the analysis of complex technical questions such as available automated hearing tests and their classification algorithms of normal versus unsatisfactory results, organisational matters, cost-effectiveness, and the global system of newborn hearing screening in Belgium.The state of knowledge about the neonatal risk factors for hearing loss highlights the effects of treatment; in the cases of some infectious risk factors such as congenital CMV, toxoplasmosis, and syphilis infections, treatments have modified the risk of developing hearing loss or prevented hearing deterioration. When such diseases are treated early after birth, congenitally infected children have a lower risk of developing hearing loss than those without treatment , 25, 29.Drawing conclusions from published studies was sometimes made difficult by the studies themselves. In particular, multivariable analyses were not performed systematically, and the numbers of children with hearing impairment identified in the studies were limited. Firstly, ill newborns frequently exhibit multiple risk factors such as prematurity, NICU stay, ototoxic drug administration, ventilation, etc. Hence, it is essential to consider the actual impact of individual risk factors on hearing function. Therefore, univariate analyses were insufficient, and multivariable models were not performed systematically. Second, the few cases of children with hearing impairment also complicated the drawing of conclusions; the low prevalence  of hearing loss applied to small samples  led to the identification of only a few hearing-impaired newborns. Random sampling may have dramatically affected the numbers of identified children with hearing impairment results and thus statistical power. Furthermore, there were multiple definitions of hearing loss and a wide range of hearing tests and clinical criteria as well as failure to consider other risk factors and inconsistent results among studies in some cases.To avoid bias in the literature review and determine the states of scientific knowledge, we developed a thorough and exhaustive approach. Although we investigated the risk factors for hearing loss individually, when pertinent, we presented their cumulative effects on hearing function by using a transversal approach. By making specific inquiries during the literature review, we detected risk factors for hearing loss that would not have been included in the original list. Because of this exhaustive approach, we decided to add three risk factors to our investigation: ECMO, congenital diaphragmatic hernia, and inhaled nitric oxide. We strictly limited our research to medical conditions and factors, although sociodemographic factors have been reported as other potential risk factors for neonatal hearing loss . AlthougIt is important to note that the studies retrieved through the literature review were mostly observational and thus started at a ‘low’ level of evidence quality. Nonetheless, the GRADE system is flexible, as the quality of evidence can be rated on the basis of methodological criteria . Indeed,The GRADE system is usually used in the clinical management of therapies but can also be used in all healthcare management decision making , 126. OuBeyond the quality of evidence, the recommendation formulation considers other parameters such as benefit/harm balance, resource use, and patients’ values and preferences . The panTo foster rapid and complete acceptance, the recommendations were written to be helpful and clear. The next step after the publication of these updated recommendations is to implement the updated list of risk factors for hearing loss in the programme. The challenge is to convince paediatricians and otorhinolaryngologists to implement this updated list and follow the recommendations by adapting their clinical practice. Having pertinent and adequate recommendations but not using them would negatively impact the newborn hearing screening programme. Therefore, the dissemination of the updated list, recommendations, and underlying scientific arguments is strongly advised. They can be presented at national paediatric or otorhinolaryngology congresses and directly to local hospital staff.We updated the risk factors for hearing loss for the newborn hearing screening programme in Belgium (FWB) by combining an evidence-based approach and the clinical experience of a panel of experts. Hence, we developed recommendations for the clinical management and follow-up of newborns with neonatal risk factors for hearing loss. As the recommended hearing tests and follow-up regime differ depending on the presence or absence of these risk factors in newborns, it is essential to correctly identify newborns with neonatal risk factor(s) for hearing loss. The quality of evidence for the risk factors for hearing loss ranged from ‘very low’, due to the absence of scientific evidence or methodological weaknesses in studies, to ‘high’, mostly when the physiopathology of the risk factor on the auditory function is understood. The recommendations were also graded as ‘weak’ or ‘strong’. Moreover, the panel of experts emphasises avoiding unidentified neonatal hearing loss and recommends considering unclear factors as risk factors for hearing loss. The next step is to implement these recommendations, which will improve the ability of the hearing screening programme to identify hearing loss in children and perform adequate follow-up of children at risk of later onset; regular monitoring of the screening programme should integrate this updated list of risk factors.


During routine diagnostic BAER testing of dogs of various breeds for private owners at the Western College of Veterinary Medicine in Saskatoon, it became evident that some individual dogs developed hearing loss as adults. Although inherited congenital deafness has been widely reported in dogs, this type of deafness had not.Special clinics were set up to screen working Border Collies at herding competitions. To determine the typical age that geriatric deafness might be expected, retired dogs were also recruited. Five of the 10 Border Collies 12 years of age or older had hearing loss . The adult onset deafness which exhibited in three families, did not usually occur until 5 years of age, too young to be geriatric deafness. This adult onset deafness fits an autosomal dominant pattern of inheritance. Several of these dogs had been BAER tested at younger ages with no sign of deafness. The deaf dogs were not associated with either gender. A survey was developed which was completed by the dog owners, that indicated that the hearing loss was gradual, not sudden. In addition, some family studies were conducted.Dogs at 5 years of age were often in the prime of their herding careers and then did not respond appropriately to distant commands. This type of deafness is important to dog owners but is also a potential medical model for some forms of hearing loss in humans. This report also suggests that geriatric hearing loss is common in dogs older than 12 years.The online version of this article (doi:10.1186/2052-6687-1-6) contains supplementary material, which is available to authorized users. Although congenital (from birth) deafness has been widely recognised and reported in dogs, little has been done to characterise or study adult and geriatric onset deafness. The latter form of deafness is likely to represent a good model for human adult deafness (known as prebycusis). This study examines adult hearing loss in herding strains of Border Collies, a breed where owners have previously anecdotally reported adult onset deafness in their dogs. Border collies were examined using a standard established method to measure deafness in dogs (Brainstem Auditory Evoked Response (BAER)). Within a group of 216 dogs, five dogs over the age of 12 years had hearing loss, suggesting that a geriatric onset may be common in this cohort of dogs. A genetic component contributing to this form of deafness in dogs is suggested and discussed in the context of previous studies.Loss of hearing was reported by owners in herding strains of Border Collies. The loss of hearing appeared to be gradual, with distant hearing lost first. This was noticed in winning dogs that began to fail to respond to verbal commands when they were given from 200 m or more, but progressed to loss at 50 m. Luckily this form of deafness seems to be relatively rare, but occurred in some families.An otoscopic examination was performed by a veterinarian to rule out any disease of the external ear and/or eardrum that may interfere with hearing. Border Collies with any sign of such disease were excluded from further study. All procedures were conducted according to the Canadian Council of Animal Care guidelines. A DNA cheek brush sample was taken from each dog for possible future study.Two hundred and sixteen Border Collies were tested with the Brainstem auditory evoked response (BAER) hearing test at two herding trial events, one in Virginia and one in Pennsylvania. The stimulus intensity used was between 70 and 80 dB which is within the range recommended by the Orthopedic Foundation for Animals for their certification program. The BAER testing was performed at 21 Hz, which is within the effective range reported by Wilson et al. [One hundred and twenty-eight of these 216 Border Collies were female and 88 were male. However, 4 of the dogs with hearing loss were female (3%) and 7 were male (8%).Four additional dogs in this portion of the study were reported as having some hearing loss by their owners at 100 to 200 m. None of these four dogs were deaf with BAER testing at 70 dB, which is considered the estimated loudness of an alarm clock These dogs are likely in the early stages of hearing loss. However, all but one of the dogs found to have bilateral hearing loss by BAER testing at 70 dB, were also reported as having difficulty hearing at 50 m by their owners.It was subsequently suggested that the four additional dogs suspected as deaf by their owners might have also tested as deaf with BAER testing at higher dB. In order to comply with Canadian Animal Care guidelines for studies of privately owned dogs, the veterinarian had to use dB below 85 dB since it has been reported that prolonged exposure to a stimulus of that intensity could lead to hearing damage.None of the dogs with hearing loss were reported to have other health issues. Thus this type of deafness appears to be nonsyndromic.In another portion of this study, three families of Border Collies showed a pattern of adult onset deafness. Some dogs were BAER tested at more than one age, but most were tested only at the age indicated in Figure Although BAER hearing tests can be used to diagnose dogs with reduced hearing to an advanced stage and complete deafness, no diagnostic test is currently available for early identification of those Border Collies likely to become deaf. A recent study using some of the dogs reported here, but assuming an autosomal mode of inheritance and an earlier age of onset, and a GWAS approach, reported a region on CFA6 that appeared to be implicated . An earlCongenital Deafness has also been reported in Border Collies , assesseGeriatric hearing loss, also known as presbycusis, is typically bilateral in humans . The curIn 2000, in humans, approximately equal numbers of non-syndromic deafness were reported as inherited as autosomal dominant 31 DFNA) as autosomal recessive (28 DFNB) conditions, with few (6 DFN) X-linked conditions . The Her DFNA as TJP2) [CCDC50 gene [Most forms of progressive late onset adult deafness in humans have been reported to be inherited as dominant conditions . One sucTJP2) . Another50 gene . However50 gene  reports Congenital deafness appears rare in Border Collies (1/216), although deafness from multiple possible causes was present in 11 of 216 dogs (5%) of various ages BAER tested at two herding field trials.At 12 years of age, 4 of 6 Border Collies BAER tested were deaf in one or both ears and this may suggest that geriatric hearing loss is common by this age in this breed.Adult onset bilateral deafness was not found in dogs under 3 years of age in the family studies and may begin as late as 7 years, based on BAER testing at the herding trials. Therfore many dogs will have been bred prior to the onset of this adult onset form of deafness.Adult onset deafness was perceived to have a gradual progression over years by the dog owners in both the family studies and field trial tested dogs. There is currently no diagnostic test to identify affected individuals until deafness becomes advanced, although higher dB levels of BAER testing than used in this study may have detected dogs at earlier ages.This adult onset deafness fits an autosomal dominant pattern of inheritance better than a recessive pattern.“The data set supporting the results of this article is included within the article Additional file 1:


The abundance of TCS along with its antimicrobial properties have given rise to concern regarding its impact on antibiotic resistance in the environment. The objective of this review is to assess the state of knowledge regarding the impact of TCS on multidrug resistance in environmental settings, including engineered environments such as anaerobic digesters. Pure culture studies are reviewed in this paper to gain insight into the substantially smaller body of research surrounding the impacts of TCS on environmental microbial communities. Pure culture studies, mainly on pathogenic strains of bacteria, demonstrate that TCS is often associated with multidrug resistance. Research is lacking to quantify the current impacts of TCS discharge to the environment, but it is known that resistance to TCS and multidrug resistance can increase in environmental microbial communities exposed to TCS. Research plans are proposed to quantitatively define the conditions under which TCS selects for multidrug resistance in the environment.Triclosan (TCS) is a commonly used antimicrobial agent that enters wastewater treatment plants (WWTPs) and the environment. An estimated 1.1 × 10 The World Health Organization warns that we may enter a post-antibiotic era in the twenty-first century due to the spread of antibiotic resistance . Antibioin vivo to treat bacterial infections in eukaryotes  will be referred to as antibiotics .In addition to antibiotics, synthetic antimicrobial agents are also pervasive in households and hospitals, mainly for disinfection and sanitation purposes. The term “antimicrobial” has been used to describe a broad range of compounds, including antibiotics that destroy or inhibit microorganisms . For thiTriclosan is widely used for personal hygiene and disinfection purposes; in fact, 350 tons were produced for commercial use in the European Union in 2002. Based on 1998 records from the Environmental Protection Agency, approximately 500–5000 tons were produced in the U.S., and the industry has reported growth . With thBecause of its wide use, TCS is found in many natural and engineered environments, including surface water, wastewater, soil, drinking water, wastewater treatment plants (WWTPs), biosolids, landfills, and sediments . As TCS At application concentrations , TCS induces cell damage that causes cell contents to physically leak out of the membrane . At conc5 to 4.2 × 105 kg of TCS are distributed to the environment annually through WWTPs in the U.S. . The FabI protein catalyzes the elongation cycle in the synthesis of fatty acids, an essential process for cell viability  confer resistance to TCS as well as other antibiotics in P. aeruginosa and Rhodospirillum rubrum  overexpress SmeDEF. These mutants had an increased tolerance to tetracycline, chloramphenicol, and ciprofloxacin. Even though SmeDEF is intrinsically contained in the genome of Stenotrophomonas maltophilia, TCS exposure selected for up-regulation of this efflux pump which increased antibiotic resistance.Efflux is a common method of resistance, but the specific efflux system used and the resulting cross-resistance profile can vary between species. In sistance . Exposur, SmeDEF . ExpressE. coli O157:H7 exhibited increased resistance to chloramphenicol, tetracycline, amoxicillin, amoxicillin/clavulanic acid, trimethoprim, benzalkonium chloride, and chlorhexidine, while TCS-adapted E. coli O55 exhibited resistance to only trimethoprim  susceptible to antibiotics  of the influent TCS load to WWTPs is captured by solids following sorption . The conThe range of TCS concentrations found in the environment is depicted in Figure –4, 5 × 10–4, 1 × 10–3, 5 × 10–3, and 1 × 10–2 mg/L, and resistance to TCS significantly increased in bacterial populations exposed to TCS concentrations over 5 × 10–4 mg/L  solution of soap containing TCS was pumped over the biofilm . OverallThese studies show that TCS in the environment could select for resistance genes. It seems likely that TCS resistance coincides with TCS-derived cross-resistance to antibiotics in the environment, but further studies are required to validate this point.S. epidermidis, are less susceptible to TCS today than they were in the past  were found on plasmids , by viral infection (transduction), or by transfer of plasmids and other mobile genetic elements (conjugation); the resulting pathways for genetic transport are complicated to constrain for modeling . GeneticThe rate of transfer of antibiotic resistance genes in the environment to humans is also under investigation . Better 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.


Li, Na and K ions were introduced into MnO2 nanotubes to tailor their magnetic properties. It was found that with a doping concentration lower than 12 at%, the nanotubes showed ferromagnetic-like ordering at low temperature (<50 K), while antiferromagnetic coupling dominated their physical behavior with doping concentrations beyond 12 at%. Such experimental phenomenon was in very good agreement with associated first principle calculations. The ferromagnetic-like ordering originates from the breaking of equivalence between two different Mn-O octahedrals in α-MnO2 due to the filling of alkaline ions in the tunnels. Both small charge transfer and lattice distortion play important roles in the ferromagnetic ordering.α-MnO The framework of these mesopore channels, called octahedral molecular sieve structures, can form infinite alternating 1 × 1 and 2 × 2 tunnels. β-MnO2 has 1 × 1 tunnels, whilst α-MnO2 has 2 × 2 tunnels by sharing the edges and corners of the MnO6 octahedrons7910Manganese dioxide, MnO2 can be tuned for practical applications through careful selection of doping elements. It is well known that the Li ion has a small atomic radius (0.076 nm), in comparison with the size of the tunnels (0.48 nm). As such, a cluster of Li ions can be housed in the tunnels and can migrate freely in these tunnels under electrochemical stimulus. Such physical behaviour is promising for many applications such as supercapacitors and batteries21213141516The properties of α-MnO2 is antiferromagnetic due to the symmetric nature of Mn-O-Mn bonds. However, α-MnO2 nanorods prepared through a hydrothermal method using KMnO4 as the precursor have been discovered to show ferromagnetic-like behaviour at very low temperatures (i.e. 5 K)18192021+ is greater than 15 at%, the ferromagnetic-like behaviour disappears due to the appearance of antiferromagnetism. The mechanism of this phenomenon still remains unclear. The geometrical frustration on the triangular lattices and the mixture of Mn3+ and Mn4+ ions have been considered to be attributed to the ferromagnetic-like properties2 have shown that Mn3+ is formed due to the electron transfer for the K+ doping, which results in the overlap of the Fermi level with the conduction band, leading to metallic behaviour3+ has never been observed and the magnetic properties of K-MnO2 by DFT calculation have never been reported. Since the tunnel is as large as 0.48 nm in diameter, the doping from K+ may not change the geometry significantly at low doping concentrations. Furthermore, antiferromagnetism appears in these samples when the doping concentration of K+ is higher than 15 at%. This suggests that the lattice distortion alone may not be the origin of ferromagnetic-like propertiesThe ground state of α-MnO2 nanotubes. X-ray absorption near edge spectroscopy (XANES) indicates that Mn is very close to 4+ valency rather than 3+, suggesting very weak charge transfer and this weak charge transfer alone may not be the origin of ferromagnetic-like behaviour. Detailed investigations reveal that neighbouring tunnels which may be filled and unfilled lead to differences in the magnetic moment of Mn atoms in the apex site and plane site, thus breaking the balance of Mn-O-Mn bonds. This results in the ferromagnetic-like ordering. Furthermore, we can also fill Li or Na ions into these tunnels by exchanging Li/Na ions with K+ and this leads to filling behaviour and induced ferromagnetic properties that are similar to that observed by K+ doping. α-MnO2 is one of the most promising anode materials for lithium batteries. However, the existence of K+ during fabrication has impeded charging/discharging of these batteries. This work has shown that Li or Na ions can totally replace K+ through a solution exchanging method. The understanding of Li or Na filling mechanism in MnO2 may be of importance for the development of high performance batteries.In this work, we studied the ferromagnetic behaviour in K-doped MnO2 nanotubes. This demonstrates that the phase of all the samples is α-MnO2 and no secondary phase is observed  peak, which has the strongest intensity (2 are similar to that of K-doped MnO2. No secondary phases were observed in either sample.We first examine the X-ray diffraction (XRD) patterns of K-doped MnOobserved . In addintensity , we can 2 nanotube under low magnification TEM imaging. All the tubes with doping concentrations lower than 12 at% show strong crystalline structures as seen from 2 exhibits some localised disordering  plane of α-MnO2 respectively (2 results in geometry change. Li and Na-doped MnO2 have a lattice spacing of 0.510 and 0.512 nm in the (200) plane, respectively, which are smaller than that of K-MnO2 with 6 at% K doping. This may be due to the relatively lower dopant concentration and relatively smaller radii of Li+ (0.9 nm) and Na+ (0.116 nm)  analysis was used to investigate the microstructure of the doped oxides as shown in ordering , which iectively . This in.116 nm) .3+ and Mn4+ valence state in α-MnO2 has been considered as one of the reasons for the ferromagnetic ordering/spin glass behaviour at low temperature2, X-ray absorption fine structure (XAFS) measurements were performed for all the samples, as shown in 4+. No trace of Mn3+ species can be observed in the spectra. 2 compared to other forms of manganese oxide, such as MnO, MnO2, Mn2O3 and Mn3O4. It is found that the XANES of the 6 at% K-MnO2 in the near edge overlaps with that of MnO2, indicating a Mn4+ valence state for this sample. These results indicate that charge transfer between K and Mn is very weak, which is not readily detected by XAFS analysis.As discussed, the mixture of Mn2 has very small distortion in its structure  and Na+ (0.116 nm) may also explain the smaller distortion in MnO6.Fourier transform of the XAFS data and the fitting to the first Mn-O shell indicate that 2% K-MnOtructure . 6 at% a-O shell , suggest2 is polymorphic with α, β, ε and γ phases. 2 and standard traces for the α, β, ε and γ phases. From the comparison of Mn-O and Mn-Mn shells, it confirms that all the nanotubes fabricated in this work are α-MnO2 and this is consistent with the XRD analysis.MnO2 has been observed in previous studies2 presents the highest saturation magnetization (5.2 emu/g at 30 kOe) and coercivity (7500 Oe). The mechanism for the high coercivity is not very clear. It may be associated with the exchange coupling between antiferromagnetic phase and ferromagnetic-like phase as that in NiO nanostructures2626282 with the lower doping concentrations. This suggests that the sample may become antiferromagnetic again. In order to study the M-H curves in detail, we enlarged the M-H curves for 12 at% and 16 at% K-MnO2 over a narrow scale as shown in 2, the curve is almost linear, suggesting the antiferromagnetic signal in dominant. However, a small coercivity (25 Oe) can still be detected in the sample, suggesting very weak ferromagnetic-like ordering. For the 16 at% K-doped MnO2, a coercivity of nearly 650 Oe was observed, indicating relatively strong ferromagnetic-like ordering in this sample in addition to the more dominant antiferromagnetic signal. This results suggest that ferromagnetic-like behavior may not only originate from the electron charge transfer by K doping and also the Mn3+ related to Jahn-teller distortion as the increase of K doping concentration should lead to more charge transfer, thus enhances the ferromagnetic-like ordering if the ferromagnetic-like behavior is arisen from charge transfer alone. However, it has been discovered that 12 at% K doped MnO2 has a very weak ferromagnetic-like ordering compared to that of 6 at% K doped MnO2. It should be noted that we did not measure pure α-MnO2 nanotubes without K, Li or Na doping since it is impossible to achieve totally alkaline element free MnO2 tubes with a chemical synthesis technique using KMnO4 as a precursor. 2, 6 at% Li-MnO2 and 6 at% Na-MnO2 taken at 40 K, respectively. K-MnO2 has the highest saturation magnetization among the samples at the same doping concentration. While Li and Na doped MnO2 nanotubes have similar saturation magnetization and coercivities. The M-H curves of 6 at% Li-MnO2 and 6 at% Na-MnO2 measured at 5 K are shown in 2.Ferromagnetic-like behavior of K-MnO3O4, is ferrimagnetic, which may contribute to the magnetic ordering in MnO2 nanorods. Our TEM, XRD and EXAFS have not detected any impurities phases other than α-MnO2 nanotubes. The resolution is better than 1%. From Ref. 3O4 is around 20 emu/g. Hence, the contribution from Mn3O4 is only 0.2 emu/g, which is negligible for the sample with a saturation magnetization of 5.2 emu/g. In addition, the Curie temperature of Mn3O4 nanoparticles is around 40 K, while in our work, the Curie temperature is around 50 K. Furthermore, by increasing or decreasing alkaline doping concentration, the magnetization and coercivity will vary accordingly, supporting that the magnetization in our samples are not from Mn3O4 impurities.Since Mn impurities, such as Mn2 has a Curie temperature of 50.4 K. The reverse susceptibility indicates that the nanotubes also have a negative susceptibility, which indicates the samples have a mixture of ferromagnetic-like and antiferromagnetic phase. It is known that pure MnO2 is antiferromagnetic. Hence, the antiferromagnetic signal should come from antiferromagnetic MnO2 itself. The ferromagnetic-like signal is from alkaline element doping. When the doping concentration is 6 at%, the Curie temperature increases to 55.8 K and the antiferromagnetic phase is undetectable. Continual increase of the doping concentration leads to a decrease of critical temperature. 12 at% K-doped MnO2 has the lowest critical temperature (43.7 K). From the M-H measurements, a very weak ferromagnetic-like signal is detected  measurements, the critical temperature of ferromagnetic-like ordering was measured as shown in detected , thus ha2 nanotubes, we employ first principle calculations to investigate the origin of ferromagnetic-like behavior. For pure MnO2, the most stable spin configuration is the antiferromagnetic state as shown by the density of states (DOS) (23In order to understand the mechanism of ferromagnetic-like behavior in MnOes (DOS) , consistB, corresponding to 0.0625 µB/Mn. It is noted that K and O do not show any magnetic moment from our calculations. A saturation magnetization of 5.2 emu/g (at 30 kOe) was experimentally observed in K doped MnO2, corresponding to 0.085 µB/Mn, agrees well with theoretical calculations. Further increasing the doping concentration, K ions will be incorporated in neighboring tunnels. The K doping then affects the two different Mn-O octahedrals , which is similar to that 6 at% K-doped MnO2, as shown in 2. The results have shown that the ferromagnetic-like ordering can be achieved in all the three alkaline elements. The ferromagnetic-like ordering can be tailored by tuning the doping concentration.Similarly, first principle calculations were also employed to calculate Li and Na doped MnOK doping . Experim2. α-MnO2 is one of the hollandite-romanechite families with 2x2 tunnel structure, similar to β or rutile-MnO2. A Mn-O octahedral is expected in every side of tunnel  than that of the purple Mn (2.9 μB) around the Fermi level. Hence, the symmetry between the purple and blue Mn-O octahedrals is broken, resulting in ferromagnetic-like properties observed in the experiment2 sample there will be charge transfer of 6 electrons to MnO2 given that the cell size has 100 Mn atoms. Then, the transferred electrons will change the Mn valance from 4+ to +3.94, which is a very small change that may not be detected by XAFS examination.This doping effect on magnetic properties can be understood by the special crystal structure of α-MnOons I in  while thons I in , the int2 with different doping concentrations using a hydrothermal method with KMnO4 as the precursor. K-doped MnO2 nanotubes with doping concentration lower than 12 at% show ferromagnetic-like ordering. 6 at% alkaline ions doping in MnO2 leads to the maximum saturation magnetization. Doping concentration higher than 12 at% leads to disordered structure since some of K ions may enter the interstitial sites due to the higher doping concentration. Li and Na doping also lead to ferromagnetic-like behavior. The results of first principle calculations are consistent with the experimental data. The ferromagnetic-like ordering is due to incomplete filling of K ions in the tunnels, which affects the symmetry of Mn plane, forming ferromagnetic-like ordering.We have synthesized K-MnO2 nanotubes were prepared using a hydrothermal method, similar to that previously reported184 was used as the precursor and was dissolved in HCl solution for 12 hours at 413 K. All chemicals in this work were purchased from Sigma-Aldrich with a purity of 99.99%. The prepared α-MnO2 nanotubes contain approximately 8 at% K that was measured using inductively coupled plasma  analysis. In order to control the K doping concentration in the MnO2 nanotubes, the prepared MnO2 nanotubes were soaked into 1 M HCl or 1 M KOH solution for different durations from 1 hr to 6 hrs at 413 K. The nanotubes soaked in the KOH solution showed an increase in the K doping concentration. On the other hand, the nanotubes soaked in the diluted HCl solution resulted in a decrease in doping concentration. It was found that K doping concentration is proportional to soaking time. Through the control of the soaking time combined with the ICP analysis, the K doping concentration was estimated to be approximately 2 at%, 6 at%, 8 at%, 12 at% and 16 at% in atomic ratio respectively. Similarly, 1 M NaOH and 1 M LiOH solutions were also used for the doping process for Li or Na, respectively. MnO2 nanotubes were first heated in a diluted HCl solution for more than 24 hrs at 413 K. The amount of residual K in the MnO2 tubes was reduced and eventually could not be detected by energy disperse X-ray spectroscopy (EDX) attached to a scanning electron microscope. After soaking the nanotubes in either 1 M NaOH or 1 M LiOH, K ions could not be detected by ICP. The concentration of Li was subsequently measured with ICP. In this work, we prepared Li/Na doped samples with a concentration of approximately 6 at% by controlling the soaking time. X-ray diffraction , scanning electron microscopy  and transmission electron microscopy  were used for the characterization of phases and microstructures. A superconducting quantum interference device  was used for magnetic property measurements. X-ray absorption fine structure (XAFS) spectra were measured in transmission mode at the XDD beamline at Singapore Synchrotron Light Source (Singapore).α-MnO2 is a = b = 0.96 nm and c = 0.28 nm, which is in agreement with previous experimental measurements3536First-principles calculations were performed using density functional theory from Vienna ab initio simulation package with a plane wave basis33J.Y. and L.T. did the characterization of materials. H.F. prepared the samples. Y.L. performed the first principle calculations. X. L. did XRD analysis. T.L. did the XAS analysis. M. P. carried out TEM analysis. J. Y. drafted the manuscript. Y. L. drafted the part of calculations. Y.W. revised the part of manuscript on calculations. L.T., S. L. and M.P. gave revision of the manuscript.Magnetic properties in α-MnO2 doped with alkaline elements


Previously, we documented the presence of TCs in liver. However, the possible roles of TCs in liver regeneration remain unknown. In this study, a murine model of partial hepatectomy (PH) was used to induce liver regeneration. The number of TCs detected by double labelling immunofluorescence methods  was significantly increased when a high level of hepatic cell proliferation rate  as shown by 5-ethynyl-2′-deoxyuridine (EdU) immunostaining and Western Blot of Proliferating cell nuclear antigen (PCNA) was found at 48 and 72 hrs post-PH. Meanwhile, the number of CK-19 positive-hepatic stem cells peaked at 72 hrs post-PH, co-ordinating with the same time-point, when the number of TCs was most significantly increased. Taken together, the results indicate a close relationship between TCs and the cells essentially involved in liver regeneration: hepatocytes and stem cells. It remains to be determined how TCs affect hepatocytes proliferation and/or hepatic stem cell differentiation in liver regeneration. Besides intercellular junctions, we may speculate a paracrine effect via ectovesicles.Telocytes (TCs) are a novel type of interstitial cells which are potentially involved in tissue regeneration and repair ( As shown in Figure Our study shows that the number of TCs detected by double labelling immunofluorescence methods  was significantly increased at the proliferative peak period of liver regeneration. Meanwhile, the number of CK-19 positive-hepatic stem cells peaked at 72 hrs post-PH, co-ordinating with the time-point when the number of TCs was most significantly increased. These results indicate a close relationship between TCs and hepatocytes and/or stem cells essentially involved in liver regeneration.etc. However, the roles of TC in the proliferative capacity of hepatocytes remain to be further clarified in liver regeneration.Liver regeneration is a highly orchestrate response to the loss of effective liver mass after liver resection or toxic injury . The proIn the present study, the increased number of TCs 72 hrs after PH was accompanied by a corresponding increase in hepatic stem cells. Previous studies documented the presence of TCs in heart, lung, liver, skeletal muscle, skin and eye in tandem with stem cells ,11,24,25Several limitations of the present study should be highlighted. TCs, as a new type of interstitial cells, are characterized by extremely long and thin prolongations called Tps extending from the cell body . Althougvia ectovesicles. Three possibilities of the relationship between TCs and the proliferating cells in PH could be proposed: (i) the co-ordinating increase in TCs and proliferating cells in PH is just a coincidence; (ii) the increased TCs is just associated with the increase in proliferating cells in PH and (iii) the increased TCs is the cause for the increase in proliferating cells in PH. Considering that CD34/PDGFR-α, CD34/PDGFR-ß and CD34/Vimentin positive TCs after PH increase with an accompanying increase in hepatocytes and hepatic stem cells, we speculate that TCs participate in liver regeneration either via intercellular junctions or a paracrine effect via ectovesicles though the direct evidence of relationship between TCs and hepatocytes/hepatic stem cells is required in the further studies. Further understanding the molecular and cellular mechanisms by which TCs affect hepatocytes proliferation and/or hepatic stem cells differentiation in liver regeneration will help establish novel therapeutic strategies for liver failure.In conclusion, our study indicates a potential role of TCs in liver regeneration, probably through their close relationship with hepatocytes and hepatic stem cells or a paracrine effect


TCs) are novel interstitial cells that have been found in various organs, but the existence of TCs in the testes has not yet been reported. The present ultrastructural and immunohistochemical study revealed the existence of TCs and differentiate these cells from the peritubular cells (Pc) in contact with the surrounding structures in the testes. Firstly, our results confirmed the existence of two cell types surrounding seminiferous tubules; these were Pc (smooth muscle like characteristics) and TCs (as an outer layer around Pc). Telocytes and their long thin prolongations called telopodes (Tps) were detected as alternations of thin segments (podomers) and thick bead‐like portions (podoms), the latter of which accommodate the mitochondria and vesicles. The spindle and irregularly shaped cell bodies were observed with small amounts of cytoplasm around them. In contrast, the processes of Pc contained abundant actin filaments with focal densities, irregular spine‐like outgrowths and nuclei that exhibited irregularities similar to those of smooth muscle cells. The TCs connected with each other via homocellular and heterocellular junctions with Pc, Leydig cells and blood vessels. The Tps of the vascular TCs had bands and shed more vesicles than the other TCs. Immunohistochemistry (CD34) revealed strong positive expression within the TC cell bodies and Tps. Our data confirmed the existence and the contact of TCs with their surroundings in the testes of the Chinese soft‐shelled turtle Pelodiscus sinensis, which may offer new insights for understanding the function of the testes and preventing and treating testicular disorders.Telocytes ( In either case, the Pc are elongated, very thin, and spindle‐shaped and express the characteristics of smooth‐muscle‐like cells because they contain abundant actin filaments and other cytoskeletal proteins Testes are components of both the reproductive and endocrine systems. The main functions of the testis are the production of spermatozoa (spermatogenesis) and androgens, primarily testosterone via the paracrine secretion of signalling molecules and cell‐to‐cell contacts Telocytes are a special type of interstitial cells that was recently identified by Popescu's research group Pelodiscus sinensis were purchased from a wild breeding base in Jiangsu province of China. Turtles, weighing 0.8–1 kg each, were housed in a local facility for laboratory animal care and held, fed adlibitum, according to the local ethical guidelines. All animals were rendered comatose using sodium pentobarbital  administered intraperitoneally and were killed at one time by cervical dislocation. The study was performed according to accepted international standards and approved by the Ethic Committee for Animal Care and Use, by Science and Technology Agency of Jiangsu Province (SYXK (SU) 2010‐0009).Five male adult soft‐shelled turtles, Specimen were placed in 10% neutral buffered formalin for fixation, and then embedded in paraffin wax and wax blocks were prepared. Sectioning was done at 5 μm. These sections were stained with haematoxylin and eosin staining for light microscopic analysis using Olympus microscope , camera (Olympus DP73).The specimen were cut into small parts and then immersed in 2.5% glutaraldehyde in PBS  for overnight. Tissue were rinsed in the same PBS and then post‐fixed for 60 min. at room temperature by using buffered 1% osmium tetroxide  and washed in the buffer. The samples were then dehydrated in ascending concentrations of ethyl alcohol, infiltrated with a propylene oxide–Araldite mixture and then embedded in Araldite. The blocks were then sectioned by using an ultramicrotome  and the ultrathin sections (50 nm) were mounted on cooper coated grids. The pieces were stained with 1% uranyl acetate and Reynold's lead citrate for 20 min. Finally samples were examined and photographed by using a high resolution digital camera (16 mega pixel) connected to the TEM, Hitachi H‐7650 .l‐lysine‐treated glass slides and were stained according to immunohistochemical standard techniques. Briefly, after deparaffinization and washing in PBS, these sections were covered with 3% hydrogen peroxide in PBS for 15 min. at 37°C to block the further activity of endogenous peroxidase. The samples were blocked with 5% bovine serum albumin and incubated with rabbit anti CD34 (1:100) antibody  in a moisture chamber at 40°C for 24 hrs. After washing, the sections were incubated with biotinylated anti‐rabbit IgG  for 1 hour at room temperature. The sections were then rehydrated in PBS (pH 7.2), incubated with avidin‐biotinylated peroxidase complex for 45 min. at 37°C. After being washed with PBS, peroxidase activity was revealed using DAB  according to the instructions of company.Paraffin sections (6 μm) were placed on poly‐i.e., the interstitial cells of Leydig) were found adjacent to the seminiferous tubules within the interstitial tissue   Fig. A, abundaei) Fig. B. The Pcei) Fig. B.i.e., concertina nuclei)  Figs. A and 5A.i) Figs. .Furthermore, the TCs were frequently located around blood vessels. Complete TCs and their Tps near large blood vessels were examined Fig. . The vasIn our study, the endothelium and TCs were positively labelled for CD34, consistent with previous reports i.e., TCs, in different organs that had previously been termed ICLC. This study provides the first confirmation of the existence of TCs within the interstitial tissue  and the differentiation of these cells from the Pc of the testes of the soft‐shelled turtle based on the diagnostic criteria for TCs recommended by Popescu and Faussone‐Pellegrini i.e., concertina nucleus‐like features) In the past few years, numerous studies have demonstrated the existence of a novel type of cell, via the blood stream via the direct stimulation of target cells or receptor‐mediated interactions The present study revealed the presence of TCs that were directly connected to Leydig cells, which suggests that TCs are indirectly involved in the secretion of testosterone, rostenedione and dehydropiandrosterone The present study observed that TCs are found embedded in the collagen fibres that may be involved in the remodelling, regeneration and repair of the interstitial tissue of the testis. Our findings are in line with those of previous studies that have reported that skin TCs are found in close proximity to collagen and elastic fibres The identification of TCs in this study was also performed immunohistochemically using CD34 antibodies. However, the TCs and endothelial cells of the blood vessels exhibited immunoreactivity but were clearly distinguishable by their different morphologies. The TCs appeared as small pyriform or spindle‐shaped cells with two or more thin, long processes surrounded on both sides by a small amount of fibres The authors confirm that there are no conflicts of interest.


Hearing impairment is a serious disease with increasing prevalence. It is defined based on increased audiometric thresholds but increased thresholds are only partly responsible for the greater difficulty understanding speech in noisy environments experienced by some older listeners or by hearing-impaired listeners. Identifying the additional factors and mechanisms that impair intelligibility is fundamental to understanding hearing impairment but these factors remain uncertain. Traditionally, these additional factors have been sought in the way the speech spectrum is encoded in the pattern of impaired mechanical cochlear responses. Recent studies, however, are steering the focus toward impaired encoding of the speech waveform in the auditory nerve. In our recent work, we gave evidence that a significant factor might be the loss of afferent auditory nerve fibers, a pathology that comes with aging or noise overexposure. Our approach was based on a signal-processing analogy whereby the auditory nerve may be regarded as a stochastic sampler of the sound waveform and deafferentation may be described in terms of waveform undersampling. We showed that stochastic undersampling simultaneously degrades the encoding of soft and rapid waveform features, and that this degrades speech intelligibility in noise more than in quiet without significant increases in audiometric thresholds. Here, we review our recent work in a broader context and argue that the stochastic undersampling analogy may be extended to study the perceptual consequences of various different hearing pathologies and their treatment. Hearing impairment is a serious and growing disease: its prevalence worldwide is around 11% for adults; around 280 million people have hearing impairment; and adult-onset hearing impairment is the third leading cause of disability  higher than normal  or as a distribution of energy over time (a waveform). It is controversial whether intelligibility is based on the audible portions of the speech spectrum, on the audible features of speech waveform, or on a combination of both.The cochlea, a snail shaped structure in the inner ear, functions like an auditory prism separating the frequency components of the incoming sound so that they stimulate different populations of auditory neurons. Each region along the length of the cochlea may be described as acting as an acoustic filter tuned to a particular sound frequency and with a certain bandwidth. The cochlea as whole may be described as acting as a bank of such filters functioning in parallel.Cochlear amplifier contributes to our exquisite auditory sensitivity. Prolonged exposure to intense sounds or treatment with some ototoxic drugs can damage OHCs or even reduce their number. OHC loss or dysfunction reduces mechanical cochlear sensitivity to low-intensity sounds , a specialized type of cells in the inner ear. OHCs amplify mechanical cochlear responses to low-intensity sounds. This KEY CONCEPT 4. Cochlear amplifierA mechanism within the cochlea that provides acute sensitivity in the mammalian auditory system. Key to the normal functioning of this mechanism is the physiological status of outer hair cells, a specialized type of cells in the organ of Corti.A first side effect of OHC dysfunction is broadened cochlear filters  by simultaneous sounds with neighboring frequencies. Suppression might facilitate speech-in-noise intelligibility by enhancing the most salient frequency features of the target speech against those of the background noise  due to impaired cochlear mechanics or to a degraded representation of the speech spectrum in the pattern of mechanical cochlear responses. Instead, the evidence points to other physiological mechanisms that probably reduce the listeners' ability to encode and/or process the rapid temporal changes in speech. The idea that intelligibility relies on a waveform code is not new. It was favored by early studies that showed that the representation of the speech spectrum in terms of the discharge rate of populations of auditory nerve fibers degenerates at high intensities while a representation based on the temporal aspects of the discharge pattern is stable across sound intensities  cochlear- and spectral-centered theory of hearing impairment with the (more recent) evidence that hearing impaired listeners suffer from diminished access to speech temporal cues. However, it has been questioned that broader cochlear tuning Pichora-Fuller et al.  argued tIn the following sections, we review our proposed mechanism that could contribute to reduced speech-in-noise intelligibility both for audiometrically normal, aged listeners and for hearing-impaired listeners  from a continuous sound at random time intervals. This is in contrast to the standard form of sampling where pressure samples are extracted at regular time intervals.deafferentation, a reduction in the number of available nerve fibers. The latter is what we explored in the study at the focus of this review  would reduce auditory sensitivity to soft sounds and hence the probability of firing of individual nerve fibers to these sounds. Since the defects of stochastic undersampling may be described as noise, stochastic undersampling by OHC dysfunction would decrease the effective speech-to-noise ratio in the auditory nerve to soft speech features without greatly affecting the representation of intense speech features. Other hearing pathologies not reviewed here may also reduce the probability of firing of individual fibers (or subpopulations of fibers) to different waveform features. In the impaired ear, multiple pathologies can occur simultaneously. A long-standing goal of hearing research is to disentangle the relative importance of different pathologies for speech-in-noise intelligibility. To this end, the stochastic undersampling model offers an alternative conceptual framework in terms of how individual pathologies alter the normal probability of firing of individual nerve fibers and how the “abnormal” firing probabilities degrade the encoding of the stimulus waveform in the population nerve response.This framework may be applied to explore further perceptual effects of deafferentation. For example, because deafferentation comes with aging  to users suffering from deafferentation. In other words, deafferentation might be the reason why some listeners prefer lower stimulation rates than others.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.