Introduction: To investigate the independent and joint effects of leisure activities on disability in activities of daily living (ADL) among the oldest-old Chinese population (aged ≥ 80 years).P < 0.001). Furthermore, participants engaging in multiple leisure activities showed a reduced risk of ADL disability (P for trend < 0.001).Results: A total of 3696 participants with ADL disability were identified during the median follow-up period of 3.1 years. Compared to the participants who “never” watched TV or listened to the radio and who “never” kept domestic animals or pets, those who engaged in these activities “almost every day” had a significantly lower ADL disability risk  (mean [SD] age: 89.5 [7.0] years) who managed to perform ADL independently at baseline in the Chinese Longitudinal Healthy Longevity Survey 1998-2014 waves. Cox proportional hazards models were used to examine whether leisure activities were associated with ADL disability. Disability in activities of daily living (ADL), a leading indicator of health status and a major determinant of quality of life, is an increasing major public health concern globally –3. Due tThe oldest-old population (aged 80 or older) has a high incidence of ADL disability  and is tWe therefore conducted a large community-based longitudinal study on oldest-old individuals (aged ≥ 80 years) in China with the aim of investigating the associations between leisure activities and the risk of ADL disability, examining each activity separately and in combination.P < 0.001). Moreover, participants with ADL disability tended to have a greater prevalence of stroke, heart disease, depression symptoms and cognitive impairment .P < 0.001) was more strongly associated with a reduced risk of ADL disability than engaging in them “sometimes” . Additionally, caring for animals “almost every day”  was more strongly associated with a lower risk of ADL disability than caring for them “sometimes” . However, there were no significant associations between the risk of ADL disability and the frequency of reading books or newspapers, playing cards or mahjong, gardening, or attending religious activities, with the exception of reading books or newspapers “almost every day” , playing cards or mahjong “sometimes” , and participating in gardening “almost every day” . An examination of the effects of participating in a variety of leisure activities on ADL disability showed that engaging in multiple leisure activities was associated with a decreased risk of ADL disability (P for trend < 0.001).During a median follow-up period of 3.1 years , 3696 participants with ADL disability were identified. P < 0.05) but not among women  (P for interaction = 0.014), and there were no significant effects on the interactions of associations between other leisure activities and ADL disability stratified by gender . Moreover, we conducted a stratified analysis by age group (< 90 and ≥ 90 years) using fully adjusted models (P = 0.003) but not among participants aged 90 years or older (P = 0.239) (P for interaction = 0.013), and there were no significant effects on the interactions of associations between other leisure activities and ADL disability stratified by age .We performed a subgroup analysis stratified by gender using the fully adjusted model . Attendid models . AttendiOur sensitivity analyses did not find substantial changes in the results after we adjusted for the time of recruitment , excludeIn the large population-based prospective longitudinal cohort study of 12,331 Chinese oldest-old individuals, we investigated the associations between leisure activities and ADL disability. Our analyses revealed that frequently watching TV or listening to the radio and keeping domestic animals or pets was associated with a lower risk of ADL disability, and the associations were independent of the covariates . Moreover, participation in an increasing number of leisure activities was associated with a significantly decreased risk of ADL disability. Previous studies have reported that frequently prolonged TV watching could lead to unhealthy outcomes such as obesity , diabeteFurthermore, our study found that keeping domestic animals or pets was associated with a decreased risk of ADL disability. In line with this finding, previous studies have reported that keeping pets can not only improve quality of life  but alsoInterestingly, our study also revealed that compared to older women, the oldest-old men were associated with a lower predicted probability of having ADL disability in the context of attending religious activities. Idler and colleagues  found thMeanwhile, the present study found that the risk of ADL disability progressively decreased with participation in an increasing number of leisure activities. Similarly, a previous cohort study indicated that older adults who participated in more leisure activities were less likely to develop ADL disability than those who engaged in fewer activities , 39. TheThe main strengths of this study included the large sample size of the oldest-old Chinese population, the ability to control for various known and potential confounding factors, and the use of community-based prospective data. Nevertheless, our study had several limitations. First, this study was limited by its observational design; therefore, a causal relationship cannot be concluded. Second, although we controlled for many potential and previously described confounders to optimize the outcome of this study, including health problems  and physical resources , other potential confounding factors  were not measured or controlled in this study, which might be one of the driving factors underlying the associations of leisure activities with ADL disability. Third, because participants lost-to-follow-up at the first follow-up survey were excluded, this might have caused potential selection bias that affected our findings. Moreover, our study investigated a finite number of leisure activities; hence, the number of activities evaluated was not consistent across different activity types . In addition, the time to ADL disability was defined as the period from baseline to the first time a disability was developed; however, the participants might have developed ADL disability at any time during a 2- to 3-year interval. Therefore, it was impossible to determine the exact date of the event, which may have biased the findings.In conclusion, later-life frequently participation in leisure activities, including watching TV or listening to the radio and keeping domestic animals or pets, was associated with a lower risk of ADL disability among the oldest-old Chinese population. Our results suggest that encouraging the incorporation of various leisure activities at advanced ages may enhance quality of life, probably by improving the ability to perform ADL independently. This finding has important public health implications, as encouraging elderly adults to participate regularly in multiple  leisure activities may help prevent the onset of ADL disability. Future studies are needed to examine the associations between leisure activity, especially watching TV and keeping pets, and different levels of disability or the number of items individuals are incapable of performing.The study was derived from the Chinese Longitudinal Healthy Longevity Survey (CLHLS), which is a national longitudinal survey on determinants of healthy aging. Details of the survey design and participants have been described previously , 40. BriData on self-reported leisure activities were collected through in-home interviews. At baseline, the participants were interviewed about their participation in leisure activities, including watching TV or listening to the radio, reading books or newspapers, keeping domestic animals or pets, playing cards or mahjong, gardening, and attending religious activities. The frequency of participation in each activity was described as “almost every day”, “sometimes”, or “never”. “Almost every day” was defined as participating in leisure activities at least 5 times per week, whereas “sometimes” was defined as participation at least once a week, once a month or once per quarter rather than almost every day. The binary variable of participation in leisure activities was coded as “1” if the answer was “almost every day” or “sometimes” and as “0” if the answer was “never” for each leisure activity. We then summed the scores for the six leisure activities, and the results were classified as 0, 1, 2, 3, and 4+ .ADL was measured based on participants’ self-reported results. ADL disability was defined as participants who could not perform or needed help at least one of six basic self-care tasks — feeding, dressing, transferring, bathing, toileting and continence — according to the Katz index scale , 44, 45.2); lifestyle behaviors, including smoking status , alcohol status , frequent fresh fruit consumption (yes or no), frequent fresh vegetable consumption (yes or no), and physical exercise (yes or no); and prevalence of hypertension (yes or no), diabetes mellitus (yes or no), respiratory disease (yes or no), stroke (yes or no), heart disease (yes or no), depressive symptoms (yes or no) and cognitive impairment (yes or no). Depressive symptoms were measured with two self-assessment questions: i) Have you ever been sad, blue or depressed for 2 weeks or more? ii) Have you lost interest in things, such as hobbies, work, or activities that usually give you pleasure? Participants who had at least one positive answer were defined as having depressive symptoms [Data on the independent variables were collected and classified as follows: sociodemographic information, including age (years), gender (men or women), residence , co-residence status , marital status (married or not married), educational level , and body mass index  and 95% confidence intervals (95% CIs) for ADL disability associated with baseline specific leisure activities over the follow-up period. Two sets of models were adopted. The basic model (model 1) was adjusted for baseline age and gender. The fully adjusted model (model 2) was adjusted for additional variables, including educational level, marital status, residence status, co-residence status, BMI, smoking status, alcohol status, frequent fresh vegetable consumption, frequent fresh fruit consumption, physical exercise, hypertension, diabetes mellitus, respiratory disease, stroke, heart disease, depression symptoms, cognitive impairment, and participation in other leisure activities. The Cox proportional hazards assumption was performed with Schoenfeld residual plots ; we founP < 0.05 (two-tailed) for all analyses. Since multiple interactions were tested, the Bonferroni correction was used to correct multiple testing conservatively, and a significance level of 0.05/6 = 0.008 was set.Subgroup analyses were performed according to gender (men and women) and age (< 90 and ≥ 90 years) using the fully adjusted model. A likelihood ratio test was conducted to test for interaction. Furthermore, we conducted several sensitivity analyses to determine the robustness of our primary results by i) adjusting for the year of recruitment, ii) restricting analyses to participants without missing covariate data, and iii) excluding all participants who developed ADL disability during the first two years of follow-up. The analyses were performed using R software, version 3.6.0 . The results were deemed statistically significant at Supplementary Tables


Topical corticosteroids misuse has become one of the burning issues in many countries across the globe. They are known to cause a myriad of adverse effects which include local effects commonly and systemic effects rarely. In dermatology practice, one of the common problems we see these days are steroid-induced and steroid aggravated dermatoses. So, this study was done to find the prevalence of misuse of topical corticosteroid among dermatology outpatients.A descriptive cross-sectional study was done in the outpatient department of dermatology at a tertiary care hospital for 18 months. Ethical clearance was obtained from the Institutional Review Committee of NMCTH (Reference no. 029-076/077). Convenient sampling was done. Statistical Package for the Social Sciences (SPSS) version 16 was used to tabulate the data and analyze the results. Point estimate at 95% Confidence Interval was calculated along with frequency and proportion for binary data.Out of 19464 patients, 614 (3.15%)  gave a history of applying steroid containing creams. Among them, 220 (35.8%) belonged to the age group 21-30 years. Dermatophytoses were the skin disease where TCS was most commonly misused followed by melasma in 425 (69.2%) and 115 (18.7%) respectively. Beclomethasone was the steroid preparation that was misused in the maximum number of patients in 271 (44.1%). Some form of adverse effects was seen in 554 (88.6%) patients.Non-prescription sale of topical corticosteroids is the major cause of topical corticosteroids abuse in Nepal. Creating awareness among the prescribers as well as the patients is the current need. Depending upon their potency, TCS has been divided into different groups/classes.2 In almost all inflammatory dermatoses they provide rapid symptomatic relief. But their indiscriminate use can cause significant local adverse effects.3TCS  is among the most commonly prescribed medication in dermatology in a wide variety of dermatoses including inflammatory, hyperproliferative and pruritic conditions.14 Some of the contributing factors are non-prescription sales, lack of awareness, and non-availability of a qualified dermatologist.8 Similar to the global scenario, steroid-induced and steroid aggravated dermatoses are common in dermatology outpatient departments throughout Nepal.16 These conditions are more difficult to treat and cause much more distress to the patients than the primary conditions for which TCS were misused.TCS misuse has become one of the burning issues in many countries across the globe.This study was therefore done to find the prevalence of patients misusing TCS among those visiting the dermatology outpatient department of a tertiary care hospital.st April 2018 to 30th September 2019. Informed consent was taken from the patients. Ethical clearance was obtained from the Institutional Review Committee of NMCTH (Reference no. 029-076/077). Patients of any age and sex who consented to participate in the study were enrolled. Convenience sampling was done and the sample size was calculated using the formula,A descriptive cross-sectional study was conducted in the dermatology outpatient department of Nepal Medical College and Teaching Hospital, Kathmandu over 18 months from 1Z = 1.96 for 95% Confidence Intervalp = population proportion, 50%e = margin of error, 1%Where,Since convenience sampling was used sample size was doubled to 19208. However, a total of 19464 patients were included in the study.Statistical Package for the Social Sciences (SPSS) version 16 was used to tabulate the data and analyze the results.The total number of patients attending the dermatology OPD during this period was 19464. Of these, 614 (3.15%) of patients gave a history of applying steroid containing or other creams  suspected to be containing steroid without indication. Out of these, 306 (49.8%) were male and 308 (50.2%) were female as shown in .The youngest patient was 6 months old and the oldest was 76 years old with a mean age of 29.09 years (SD: 12.512). The maximum number of patients (35.8%) belonged to the age group 21-30 years.The two most common indications where TCS misuse occurred were dermatophytoses 425 (69.2%) and melasma 115 (18.7%) .Regarding the prescriber of TCS, pharmacists were the ones who prescribed the most (66%) followed by relatives/friends/neighbors (19%) .TCS is available in the market as a single component or in combination with other drugs. Steroid in combination with antifungal and antibiotic cream was the most common form used in 247 (58.1 %) patients with dermatophytoses whereas in melasma modified Kligman's formula containing steroid, hydroquinone, and tretinoin was misused by maximum patients 52 (45.2%) .Beclomethasone dipropionate was the most commonly used TCS in 271 (44.1%) patients, followed by mometasone furoate in 107 (17.4%), clobetasol propionate in 86 (14%), and betamethasone valerate in 63 (10.3%) .In dermatophytoses, beclomethasone was the steroid that was used by maximum patients, 230 (54.1%) whereas, in melasma, mometasone was the most commonly used steroid in 67 (58.3%) . Out of 14 TCS provide dramatic relief from symptoms in many dermatology disorders which could be one of the reasons for rampant misuse. Besides in our country, it is easily available at a low cost over the counter and though there are regulatory laws in place preventing the sale of these drugs over the counter, the enforcement of these laws and monitoring of sales of TCS is almost nonexistent. Lack of awareness and non-availability of qualified dermatologists  are also contributing factors.TCS has a valuable role in the management of a plethora of dermatoses and is amongst the most commonly prescribed medications from dermatologists. But the major issue globally at present is the issue of TCS misuse which has been shown in several studies done across the world.12 In our study, males, and female were almost equal in number similar to a few past studies.13 Studies which include TCS use in facial skin show that the prevalence of misuse in the female is significantly high which may be because women are more conscious about the looks and melasma is commoner in females than males.22The prevalence of TCS misuse was 3.15% which was similar to an Indian study.8 In our study the most common age group affected was 21-30 years which was in accordance with other studies.12 The second most common indication for misusing TCS was melasma. The use of TCS on facial skin as a lightening agent has shown an alarming increase which has been depicted in many studies.22TCS is misused in an ample number of dermatological diseases, but we have seen that dermatophytoses are the dermatoses where TCS is significantly misused which is similar to several other studies.21 TCS is available in the Nepalese market either alone or as a fixed drug combination (FDC) with antibiotic and antifungal. Steroid in combination with hydroquinone and tretinoin is also available as Kligman's or modified Kligman's formula (depending on the formulation of steroid used in the cream). Almost half (46.3%) of the total patients were using the FDC cream containing a steroid, antibiotic, and antifungal in our study. In patients with dermatophytoses, 58.1% were using this FDC which was similar to few studies.12 But in patients with melasma maximum (45.2%) were using modified Kligman's formula like in few Indian studies.21 When we considered the steroid formulation, beclomethasone was the most commonly used followed by mometasone and clobetasol. In many Indian studies, clobetasol propionate is the commonest steroid misused.13 In our study in dermatophytoses, beclomethasone was the most common steroid whereas, in melasma, mometasone topped the list of steroids. This is justified by the fact that in the Nepalese market most of the FDC creams available over the counter contain beclomethasone as a triple-drug combination and another two-drug combination (beclomethasone and clotrimazole) is also used very commonly as a drug for dermatophytoses over the counter. However, in melasma, the triple combination cream (modified Kligman's formula) which is available as a lightening agent contains mometasone as the steroid component in many brands. Besides, certain brands containing mometasone alone is also given by beauticians as a treatment for skin hyperpigmentation and to achieve general fairness and glow. In a Nepalese study done by Kumar et al, it was reported that beclomethasone dipropionate was the most commonly misused steroid over the face followed by mometasone furoate.16Sixty-six percent of patients were using steroids on the advice of pharmacists. In 19% TCS use was suggested by relatives/friends/neighbors. In countries like Nepal and India, the easy availability of TCS over the counter at the chemist shops across the country without any valid prescription is compounding the problem of abuse which has been shown in multiple studies.12 TCS causes suppression of cutaneous inflammatory response which leads to ineffective elimination of the dermatophyte culminating in chronic and widespread infection.23Regarding the adverse effects of TCS misuse, different side effects were seen in patients with dermatophytoses and melasma. The most common adverse effect in patients with dermatophytosis was tinea incognito/ recurrence/extensive dermatophytoses. Tinea incognito also known as steroid modified tinea is a very common adverse effect of using TCS in dermatophytoses shown in many studies.24 In our study among people using TCS on the face for melasma, a significant percentage (99.17%) of patients had TDSF. TSDF includes various clinical features like erythema, papules, pustules , acneiform eruptions, hirsutism, telangiectasia, tinea incognito, hypo/hyperpigmentation, perioral dermatitis, rosacea like features, allergic contact dermatitis, photosensitivity, and atrophy/striae.24 Many studies have reported widespread abuse of TCS on the face and the common adverse effects mentioned are all part of TSDF.22A new entity “TSDF” has been coined which is defined as “the semi-permanent or permanent damage to the skin of the face precipitated by the irrational, indiscriminate, unsupervised, or prolonged use of TCS resulting in a plethora of cutaneous signs and symptoms and psychological dependence on the drug”.25 Bhusal M et al reported a 32-year-old female who developed iatrogenic Cushing's syndrome following the application of clobetasol propionate for disseminated tinea infection.26 However in our study we did not find any systemic adverse effects.Prolonged use of TCS (mostly high and ultra-high potency) can cause systemic adverse effects though lesser than systemic corticosteroids mostly in infants and early.4Our study is consistent with the observation that factors leading to misuse of TCS is at various stages from manufacturer to prescriber to salesperson to layperson.Our study is limited as the sample is restricted to one outpatient department in one location. A multicentre study across the country is recommended to find out the true magnitude of this multifaceted problem of TCS misuse. The adverse effects of TCS could be elaborated further by specifying the different types of lesions seen in tinea incognito and in TSDF which could help us determine the commoner manifestations in our skin type.The misuse of TCS has been increasing rampantly in recent years. TCS has been used as “steroid cocktails” mostly in dermatophytoses which have to lead to the emergence of the issue of resistant dermatophytoses. Besides the use of TCS as fairness cream and as a treatment for hyperpigmentation is also pretty common which has lead to the increasing occurrence of TSDF. Factors contributing to this epidemic are pharmaceutical industry manufacturing and promoting inappropriate FDC containing TCS, unregulated over the counter supply and unrestricted sale of TCS, professional ignorance , and public ignorance (layperson using it themselves or advising friends/family to use it). So it is high time we raise public awareness and educate the prescribers . Another major step would be to make the government aware of this issue and regulate the manufacture and over the counter sale of these steroid combinations. Topical steroids and their combinations need to be sold as “prescription-only” drugs.


Cold snare polypectomy is a well-established method for the resection of colorectal polyps measuring less than 10 mm in size. It may be performed in patients with early colorectal cancers because of the difficulty of endoscopic diagnosis. However, the therapeutic effect of cold snare polypectomy on cancers is unknown, and the need for appropriate surveillance and additional treatment for these patients remains to be fulfilled. Endoscopic submucosal dissection has been reported as a safe and effective method for treating recurrent or residual colorectal neoplasia following hot endoscopic mucosal resection.This report is of a case of a colorectal tumor measuring 8 mm that was treated using cold snare polypectomy and resulted in residual cancer. Endoscopic submucosal dissection was selected as salvage treatment for the residual lesion, and histopathological examination revealed free horizontal and vertical margins.We believe that performing endoscopic submucosal dissection at the site of the cancer resected with cold snare polypectomy ensured that there was no residual cancer left. It may be hypothesized that endoscopic submucosal dissection could evolve as the treatment of choice for patients with colorectal cancer after cold snare polypectomy. Colonoscopic removal of a neoplastic polyp is the most effective therapeutic measure for colorectal cancer prevention ,2. Cold Regardless of the high diagnostic accuracy of magnifying colonoscopy in colorectal neoplasia, there are early cancers that are difficult to diagnose endoscopically ,7. As a With respect to treating residual lesions, endoscopic submucosal dissection (ESD) has been reported as a safe and effective method for treating recurrent or residual colorectal neoplasia following hot endoscopic resection . ColorecWe report a case of colorectal cancer after CSP that was successfully managed using ESD.A 76-year-old woman underwent colonoscopy at a medical facility, and an 8 mm pedunculated lesion was found in her sigmoid colon Figure . The lesMagnifying colonoscopy was then performed eight months after the initial colonoscopy. It showed disappearance of the SMT and a flat 1-mm lesion with an irregular pit at the same site Figure . The patTo our knowledge, this is the first report of a successful salvage using ESD for residual colorectal cancer after CSP. Colonoscopy and the removal of neoplastic polyps are very effective for colorectal cancer prevention ,2, and CWe report a case of residual colorectal cancer after CSP that was successfully managed using ESD. It may be hypothesized that ESD could evolve as a treatment for such cases. However, the therapeutic efficacy of ESD as an additional treatment for these cases is currently unknown in the given clinical context and further studies are required to validate the same.


Mucormycosis is a life-threatening infection, occurring mainly in immunocompromised patients, but also in immunocompetent patients after traumatic injuries . The infIn this Special Issue, we aimed to highlight and summarize novel aspects for Mucorales and mucormycosis, covering the fields of phylogeny, ecology, epidemiology, diagnosis, disease entities and animal models, thus enabling us to study pathogenesis and novel drugs.Apophysomyces variabilis has its highest prevalence in Asia and Lichtheimia spp. in Europe. A very detailed estimation of mucormycosis burden in different countries is provided.Prakash et al.  provide Clinical presentation of mucormycosis may be very diverse. Serris et al.  reviewedThe importance of cutaneous mucormycosis is highlighted in the paper of Devauchelle et al.  who perfBeside burns, necrotizing wound mucormycosis may also be seen in the context of natural disasters, civilian trauma and military injuries. Walsh et al.  reviewedGalleria mellonella or Drosophila melanogaster are also increasingly employed for virulence and therapeutic studies.Animal models are important both to understand the pathogenicity and virulence of fungal agents, as well as to test new therapeutic strategies. This is particularly true for rare diseases such as mucormycosis for which clinical trials are very difficult to set-up. In a comprehensive review about animal models in mucormycosis, Jacobsen  showed tThe portals of entry for mucormycetes are (a) the respiratory tract, (b) the skin and (c) the gut, corresponding to the three exposure pathways: inhalation, direct contact or ingestion, respectively. According to these exposure pathways, different niches and reservoirs are discussed by Richardson et al. . A detaiThe order Mucorales comprises 260 accepted species in 55 genera. Out of these, 38 were reported from human infections. The molecular revision of the order resulted in numerous taxonomical changes  conducteIn clinics, diagnosis of mucormycosis is based on culture and direct detection of the causative agent in patient material , blood, serum, plasma, urine) by molecular methods. In critically ill patients, non-invasive samples, such as blood, plasma or serum, have been successfully evaluated for diagnosing mucormycosis . For tisIdentification of Mucorales to the species level is notoriously difficult by standard morphological techniques. Although the molecular identification of these fungi is now well standardized, less time-consuming and faster techniques are needed. In that respect, Matrix-Assisted Laser Desorption Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF MS) has been a valuable technical advance for the precise identification of yeasts in routine clinical laboratories. Identification of filamentous fungi by this technique is still in progress. Schwarz et al.  construcRhizopus microsporus in a G. mellonella model. Further studies are needed to confirm these results. From a therapeutic point, mucormycosis represents a challenge and alternative therapeutic agents and treatment strategies are desperately needed to improve patients’ outcome. Currently, three agents are available for systemic treatment of deep-seeded infection: amphotericin B, posaconazole and isavuconazole. Among the new strategies, combination therapy is an interesting approach. Macedo et al.  have evaThe taxonomic position of Mucorales has been solved and a greater understanding of the high phylogenetic levels, such as orders and families, achieved, but still a lot of uncertainties and discussions exist on the genus level and below. Understanding the biology of mucormycetes is key to understand human infections and infectious sources. In the past years, novel niches and reservoirs have been identified for a better understanding of potential exposure sources. However, comprehensive data on indoor and outdoor spore concentrations are missing. Even though several vertebrate and invertebrate models were developed for invasive mucormycosis, the minimum infectious doses via a natural pathway of entry are not understood. Further studies are needed to understand how infections can be acquired from the environment. However, early diagnosis and issues around accurate pathogen identification has been solved. Novel molecular methods have been established for all sorts of clinical specimens; the next step is standardizing and comprehensively evaluating the methods at hand. Improved early diagnostics is a major advance towards efficient management of mucormycosis by the better identification of cultured isolates, but also by direct identification on clinical tissue samples.


MYH14 gene mutations have been suggested to be associated with nonsyndromic/syndromic sensorineural hearing loss. It has been reported that mutations in MYH14 can result in autosomal dominant nonsyndromic deafness-4A (DFNA4).In this study, we examined a four-generation Han Chinese family with nonsyndromic hearing loss. Targeted next-generation sequencing of deafness genes was employed to identify the pathogenic variant. Sanger sequencing and PCR-RFLP analysis were performed in affected members of this family and 200 normal controls to further confirm the mutation.MYH14 in the tail domain of NMH II C was successfully identified as the pathogenic cause in three affected individuals. The family member II-5 was suggested to have noise-induced deafness.Four members of this family were diagnosed as nonsyndromic bilateral sensorineural hearing loss with postlingual onset and progressive impairment. A novel missense variant, c.5417C > A (p.A1806D), in MYH14 that led to postlingual nonsyndromic autosomal dominant SNHL were identified. The findings broadened the phenotype spectrum of MYH14 and highlighted the combined application of gene capture and Sanger sequencing is an efficient approach to screen pathogenic variants associated with genetic diseases.In this study, a novel missense mutation, c.5417C > A (p.A1806D), in  MYH14 gene, also known as nonmuscle heavy chain II C (NMHCII-C), encodes one of the myosin members. In motility processes, such as cytoskeleton rearrangement, organelle translocation and ion channel gating, MYH14 is indicated to play a major role in the directed movement of cell components along actin filaments by ATP hydrolysis to generate force [MYH14 (NMHCII-C) has been characterized recently, but there is limited information on its biological functions. The MYH14 gene is located on the chromosome 19q13.33, contains 41 exons and encodes a protein with 1995 amino acids, which contains a myosin head region, two IQ domains, an N-terminal myosin domain, and a C-terminal myosin tail [MYH14 gene was reported to be related to peripheral neuropathy, myopathy, hoarseness and hearing loss (PNMHH) [MYH14 protein is expressed widely within cochlear tissues, such as the organ of Corti, spiral prominence epithelium, stria vascularis, and cochlear duct. Low expression was detectable in the Reissner’s membrane and spiral ligament, but no expression was detected in vestibular epithelia in mice [MYH14 plays a part in neurogenesis and maintenance of apical cell junctions in epithelial cells within the cochlea [MYH14 in mice and humans is generally higher in adults than in adolescents [The te force . MYH14 ( (PNMHH) , and the in mice . MYH14 p cochlea , 9. The lescents , 11.MYH14 gene can cause either syndromic or nonsyndromic SNHL and can be identified as the pathogenic factor DFNA4A [MYH14 gene have been reported in families with mild to severe degrees of AD SNHL, which usually manifests with milder hearing loss and later onset than AR inherited hearing loss. A recent study showed the MYH14 gene may be an essential gene related to nonsyndromic AD SNHL [MYH14 mutations and sensorineural hearing loss is still unclear.Hereditary sensorineural hearing loss (SNHL) can be classified into nonsyndromic and syndromic hearing loss. 75% of hereditary SNHL cases are nonsyndromic. Eighty percent of nonsyndromic SNHL is in an autosomal recessive (AR) inheritance pattern and tends to result in severe SNHL with prelingual onset, whereas autosomal dominant (AD) inherited deafness usually leads to mild and flat downsloping hearing loss with postlingual onset , 13. Patr DFNA4A . To date AD SNHL . HoweverMYH14 on the tail domain of NMH II C. By reporting novel pathogenic variants, the phenotypic spectrum of the MYH14 gene could be broadened in the field of hereditary hearing loss.In the current study, we investigated pathogenic variants in a four-generation Han Chinese family suffering from nonsyndromic sensorineural hearing loss with postlingual onset. We screened 127 genes known to be related to deafness by gene capture and next-generation sequencing and identified the novel variant c.5417C > A (p.A1806D) in Fifteen members from a four-generation Han Chinese family were enrolled in this study, and four of them were diagnosed as sensorineural hearing loss with postlingual onset and progressive impairment. All participants agreed to undergo clinical examinations as well as audiometric and vestibular function evaluations, including otoscopy, tympanometry, pure-tone audiometry (PTA), speech recognition score (above the hearing threshold of 30 dB HL) evaluation, auditory brainstem response (ABR) evaluation, distortion product otoacoustic emission (DPOAE) recording, a vestibular bithermal caloric test, and ocular/cervical vestibular evoked myogenic potential (o/c VEMP) evaluation. High-resolution computed tomography (HRCT) to image the temporal bone and brain MRI were used to define cochleovestibular malformation. The hearing loss onset of members IV-1 and IV-2 at the ages of 3 and 1 was evaluated by behavior observation audiometry. The degree of SNHL was classified into five grades, namely, normal hearing (PTA ≤ 25 dB HL) and mild (26 ~ 40 dB HL), moderate (41 ~ 60 dB HL), severe (61 ~ 80 dB HL), and profound hearing loss (PTA ≥81 dB HL), based on the average PTA threshold applied at 250, 500, 1000, 2000, 4000, and 8000 Hz. The study protocol was permitted by the Ethics Committee of Shandong Provincial ENT Hospital (XYK20140101), and adhered to the Declaration of Helsinki principles. Informed written consent was obtained from each subject or, in the case of minors, from their parents.http://www.1000genomes.org) and the HapMap database (combined Phases II and III). The American Medical Genetics and Genomics Guide were referred to interpret and filtered the data based on a simple AD inheritance pattern by keeping only the heterozygous variants. Remaining variants were then filtered using a low likelihood of adverse functionality on the basis of the mutation type, as assessed with pathogenicity prediction tools, including Mutation Taster, SIFT and PolyPhen 2. The American College of Medical Genetics and Genomics (ACMG) guidelines were used to define the DNA variants.To investigate the pathogenic mutations in this family, a genomic DNA (gDNA) purification kit  was applied to extract gDNA from peripheral blood by the manufacturer’s instructions. Targeted deafness gene capture and next-generation sequencing were performed in the probands to screen 127 genes   mutation in the MYH14 gene. Primers flanking the candidate mutation were designed to amplify a 512-bp PCR product, which was then digested into 308-bp and 204-bp fragments by the restriction enzyme Eco130I . The digested products were analyzed through electrophoresis by using a 2% agarose gel. MYH14 mRNA (RefSeq NM_001077186.2) was used to align the sequences as a reference by Lasergene SeqMan software. Multiple-sequence alignment was conducted to perform phylogenetic analysis by ClustalW2 software. The Multiple sequences aligned included NP_001070654.1 (Homo sapiens), NP_001094160.1 (Rattus norvegicus), NP_001258467.1 (Mus musculus), XP_014980128.1 (Macaca mulatta), XP_003316592.1 (Pan troglodytes), XP_023988172.1 (Physeter catodon), and XP_010813541.1 (Bos taurus).PCR amplification and Sanger sequencing were carried out to verify candidate variants. As previously described , PCR wasA four-generation Chinese family with 15 members from Shandong Province, China, was enrolled in the study. The family members of II-5 and III-1 were probands, and the pedigree is shown in Fig. One of the probands (patient III-1) in this family was a 30-year-old male suffering from bilateral nonsyndromic hearing impairment that started in his teens and developed progressively. The PTA performed in our hospital at the age of 29 years showed moderate and flat downsloping SNHL in both ears. The maximum speech recognition scores (SRSs) were 36% in the left and 32% in the right ear. The vestibular function tests showed coordination, and III-1 never complained of vertigo or dizziness. Another proband (II-5) had bilateral nonsyndromic hearing loss with onset in his thirties. However, he has worked in a glassware factory since his twenties and was exposed to noise more than 8 h every day over 10 years.Constant binaural tinnitus was a common symptom among these patients. The tinnitus volume was at 5 ~ 10 dB HL, which was higher than the auditory threshold of 3 ~ 6 kHz. Family member II-1 had bilateral nonsyndromic hearing loss with onset in his thirties, and member I-2 was affected by progressive hearing impairment since her twenties. The two affected members failed to pass the DPOAE test bilaterally at most or all frequencies, and their ABR results were consistent with the PTA results, which revealed moderate sensorineural hearing loss  are listed in Table To identify the pathogenic variants in this Chinese family, targeted gene capture sequencing was performed in the two probands (II-5 and III-1). All variants were filtered through NCBI dbSNP, the HapMap database, the 1000 Genomes database and the in-house databases. The c.5417C > A mutation in MYH14 alignments from different species, including Homo sapiens, Rattus norvegicus, Mus musculus, Macaca mulatta, Pan troglodytes, Physeter catodon and Bos taurus. The high conservation of alanine at position 1806 in MYH14 demonstrates that it might play a key role in the biological function, and a variant at this amino acid position could be pathogenic.Sanger sequencing was employed to verify this candidate mutation in all the family members. We found that three affected adults I-2, II-1, III-1) and the three-year-old daughter (IV-1) of patient III-1 harbored this heterozygous variant c.5417C > A (p.A1806D). None of the other subjects carried this variant  and grandmother (I-2) suffered from bilaterally symmetric SNHL with postlingual onset at ages ranging from teens to thirties, and their hearing loss gradually accelerated with aging. All three affected members were identified as carrying this novel variant c.5417C > A (p.A1806D) in the MYH14 gene, but this variant was absent in 200 normal controls and all the other unaffected family members except for patient III-1’s three-year-old daughter (IV-1). Considering the late onset of SNHL in her family, we will closely follow-up with the three-year-old girl. Interestingly, the SRS of III-1 was much worse than that of II-1. This finding might be related to the age of onset of hearing loss, which exhibited a slow progression. We should follow-up with these individuals from the family.In our study, we examined a four-generation Han Chinese family presenting with autosomal dominant nonsyndromic deafness and identified a novel missense mutation, c.5417C > A (p.A1806D), in the Patient II-5 worked in a glassware factory and was exposed to noise for more than 8 h every day over 10 years since his twenties. His PTA hearing test showed an increase in medium-high frequencies but normal levels in low frequencies bilaterally, and the SRS values were 92% for the left side and 88% for the right side, which also suggested noise-induced hearing loss. The syndromic features associated with the brain, heart and kidney in this family were excluded.MYH14 in vestibular epithelia in mice [MYH14, patient III-1 did not show any clinical vestibular symptoms, which could be due to functional compensation of the vestibular system during the long course of disease.Although there were no clinical symptoms of vestibular dysfunction in any of the members of this Chinese family, the functional evaluation in proband III-1 showed vestibular impairment. Previous studies reported that there was no detectable expression of  in mice . TherefoMYH14 gene that cause mild to severe degrees of nonsyndromic and progressive SNHL with postlingual onset, as well as the novel variant identified in the current study. Interestingly, among these missense mutations, only one mutation has been reported to lead to syndromic hearing loss, but the others cause nonsyndromic hearing loss [MYH14 that could have led to moderate nonsyndromic SNHL with postlingual onset in a Han Chinese family. There are some East Asian alleles reported in gnomAD, indicating that this mutation may be an allele in Asians that causes hearing loss. The evolutionary conservation of the alanine residue at codon 1806 (A1806D) in MYH14 indicates to us that the variant could be pathogenic and cosegregated with the disease in this family. PCR-RFLP was performed to further confirm the results in all the family members and 200 individuals with normal hearing. However, the mechanism by which the c.5417C > A (p.A1806D) variant is associated with hearing loss is not clear. Further functional researches are required to analyze the pathophysiologic mechanism underlying the auditory defects caused by the variant in MYH14 by constructing a transgenic mouse model.Table ing loss . In thisMYH14 gene; this variant is responsible for postlingual nonsyndromic SNHL in a four-generation Han Chinese family. The findings also highlighted the combined application of gene capture and Sanger sequencing is an efficient approach to screen pathogenic variants associated with genetic diseases such as autosomal dominant nonsyndromic deafness.This study identified the novel and potentially pathogenic heterozygous missense variant c.5417C > A (p.A1806D) in the Additional file 1: Table 1. Summary of the 127 targeted deafness genes.Additional file 2: Table 2. Candidate variants were verified in the family using Sanger sequencing.


Electrical cochlear implants (eCIs) partially restore hearing and enable speech comprehension to more than half a million users, thereby re‐connecting deaf patients to the auditory scene surrounding them. Yet, eCIs suffer from limited spectral selectivity, resulting from current spread around each electrode contact and causing poor speech recognition in the presence of background noise. Optogenetic stimulation of the auditory nerve might overcome this limitation as light can be conveniently confined in space. Here, we combined virus‐mediated optogenetic manipulation of cochlear spiral ganglion neurons (SGNs) and microsystems engineering to establish acute multi‐channel optical cochlear implant (oCI) stimulation in adult Mongolian gerbils. oCIs based on 16 microscale thin‐film light‐emitting diodes (μLEDs) evoked tonotopic activation of the auditory pathway with high spectral selectivity and modest power requirements in hearing and deaf gerbils. These results prove the feasibility of μLED‐based oCIs for spectrally selective activation of the auditory nerve. Electrical cochlear implants effectiveness in individuals remains limited by the spread of the electric current in the cochlea. This study explores the potential of optogenetics for hearing restoration through combining optogenetic manipulation of the auditory nerve with microsystems engineering. Electrical cochlear implants restore hearing by electrically stimulating the auditory nerve. As the electric current spreads far from each electrode, precision of electrical hearing restoration is limited, resulting in poor frequency resolution of cochlear implants.Here, we optogenetically rendered the auditory nerve of the gerbil light sensitive and evoked neural responses with μLED‐based, 16‐channel optical cochlear implants. We demonstrated that the combination of gene therapy and microsystems engineering enables optical activation of the auditory nerve with higher spectral precision.These results suggest that optogenetic stimulation of the auditory nerve with μLEDs might enable hearing restoration with improved frequency resolution to patients suffering from sensorineural hearing loss.et al, 2019), 6.1% of the human population suffers from disabling hearing loss, with an economic impact of 750 billion dollars spent on treatment development. Approximately 90% of the cases suffer from sensorineural hearing loss resulting from dysfunction of the cochlea and/or the auditory nerve. As of today, causal therapies for sensorineural hearing loss do not exist. Hence, the methods of choice for hearing restoration are hearing aids and the electrical cochlear implant (eCI). When hearing loss is profound or complete, eCIs are used to bypass dysfunctional or lost sensory hair cells and electrically stimulate SGNs. eCIs utilize the intrinsic place‐frequency map (known as tonotopy) of SGNs to provide the patient with spectral information of acoustic stimuli  could increase the frequency resolution of artificial sound encoding  by the implementation of conical concentrators and spherical micro‐lenses on the emitter surface  and with gallium nitride‐based, custom‐developed thin‐film LEDs in the micrometer range (μLEDs)  into SGNs of adult Mongolian gerbils with optical stimulation by 16‐channel, μLED‐based oCIs. We demonstrate μLED‐mediated activation of the spiral ganglion by 32‐channel recordings of multi‐neuronal clusters in the auditory midbrain in hearing and deaf gerbils in a tonotopic manner. Modest SGN activation was achieved even with some of the individual μLEDs, and the strength of responses substantially increased when recruiting additional emitters. Finally, μLED‐based optogenetic stimulation, even with four neighboring μLEDs, achieved increased spectral selectivity as compared to electrical stimulation via clinical‐style eCIs. This proof of increased frequency resolution by μLED‐based, multi‐channel oCIs raises hope that optogenetic hearing restoration might indeed overcome the major limitations of eCIs and increase the quality of artificial hearing for deaf patients in the future.In this study, we combined viral gene transfer of the ChR‐variant et al, CatCh, fused to the reporter protein eYFP, under control of the human synapsin promoter, into the cochlea of adult gerbils , which is consistent with previous studies where tonotopic slopes were reported between 4.08 and 4.58 octaves/mm , and no responses were observed with clicks up to 100 dB SPL 5–10 days after kanamycin application  were constructed based on iso‐contour lines at integer d′ values Fig A–D. A sution Fig E. Optogetion Fig F and G. tion Fig H.P = 0.26/0.80/0.43/1 for individual/block/all μLEDs and optical fiber stimulation, respectively).When stimulating SGNs with individual μLEDs of the oCI at maximum intensity, only approximately one‐third of the μLEDs 206/528) evoked neural responses in the ICC . An average maximal d′ value of 1.97 (± 0.71 SD) was obtained from responsive multi‐units  or in sacrificed animals . In wild‐type animals, fewer multi‐units  were responsive to light in hearing control gerbils. Responses had longer latencies (5.0 vs. 3.25 ms) and shorter duration (5.5 vs. 14 ms) as compared to neural responses in CatCh‐injected animals  were also observed upon driving all 16 μLEDs of 3 out of 7 oCIs in two non‐injected, hearing control animals  recording sites per animal, indicating that almost all units could potentially be driven by light. Thus, the selective activation of SGNs by oCI indeed originates from limited spread of light rather than from inhomogeneous SGN transduction . However, a difference was found for stimulation with individual μLEDs of oCIs , which most likely results from the relatively low number of deafened animals used in this study. Nonetheless, as the average number of activated electrodes was higher in deafened animals  we can rule out that neural activation due to an opto‐acoustic effect majorly contributed to the evoked responses recorded in hearing animals. Thresholds for optical stimulation of IC activity were lower for SGN illumination with oCIs  as compared to optical fibers  electrodes per animal, blockwise stimulation evoked activity on 18.0 ± 8.6 electrodes, and oCI stimulation with all μLEDs recruited 24.12 ± 5.5 units  amounts to approximately 11 mm in gerbils  and 1.67 electrodes  when stimulating with blocks of four neighboring μLEDs , different insertion depths (due to varying implant lengths), and different μLED pitch, μLED locations in the cochlea were normalized to the apical‐most μLED on each implant which elicited neuronal responses in the ICC. Hence, the BE of each STC has been normalized to the BE of the STC elicited by the apical‐most μLED in the cochlea. In other words, for each implant and animal, μLED‐dependent shifts in neural activation have been normalized to the apical‐most μLED in the cochlea and the focus of neural activation evoked by this μLED. Upon SGN illumination with different μLEDs, a stimulus location‐dependent shift of ICC activation was observed which amounted to 1.75 electrodes  in the ICC per millimeter stimulus location in the cochlea when stimulating with individual μLEDs  and post hoc pairwise comparison; Fig Intracochlear spread of excitation (SoE) was estimated at different levels of response strength in the ICC. Since the average strength of neural responses to optical stimulation with individual μLEDs did not exceed a d′ of 2 Fig C. The spin vivo functionality in a tonotopic manner and with near‐physiological spectral selectivity of optogenetic SGN stimulation by μLED‐based oCIs in a rodent model of cochlear optogenetics.In this study, we have applied multi‐channel, μLED‐based optical cochlear implants to activate the optogenetically modified auditory nerve, successfully combining the biomedical and optoelectronic work toward optogenetic hearing restoration. We demonstrated For two of the implants, X‐ray tomograms have been reconstructed Fig . Intereset al, The average threshold of neural activation in the ICC upon oCI stimulation with all 16 μLEDs of SGNs was found to be 0.35 mW . The maximum strength of neural responses in the ICC amounted to a d′ of 1.97, 2.86, and 3.35 for oCI stimulation via 1 (activation‐efficient), 4, and 16 active μLEDs, respectively. This compares to a d′ of 4.27 upon fiber‐based stimulation in the same animals and a maximum d′ of 4.4 reported in a previous study, when driving SGNs with an optical power of up to 30 mW , we have rather over‐than underestimated the spread of excitation in this study, since such combined SGN excitation was most likely broader than for sole optogenetic stimulation as the optically evoked responses in wild‐type gerbils where found more dorsally (lower frequency) in the ICC.Upon oCI stimulation in non‐injected wild‐type gerbils, weak neural responses were observed in 3 out of 8 implants. These responses differed from the optogenetically evoked neural responses in ency Fig A and tonency Fig B. We suget al, CatCh has been observed gene therapy and the oCI as a medical device. Toward the gene therapeutic aspect, specific and efficient expression of opsins within the tonotopic range of the spiral ganglion in adult animals remains a challenging task. In this study, robust oABRs could only be evoked in 43% of injected animals, which agrees with the success rate of 46% reported in an earlier study  of either sex between 6 and 14 months of age. Animals originated from our own breeding colony and were housed in a 12/12 h light–dark cycle with access to food and water ad libitum. Out of these 39 animals, 4 were non‐injected control animals (2 hearing and 2 deafened) and 35 were CatCh‐injected animals. Of these 35 animals, 20 were oABR negative and 15 oABR positive. Of the 15 oABR‐positive animals, IC data could be recorded from 12 animals (9 hearing and 3 deafened). For each surgical procedure, gerbils were placed on a heating pad and anesthetized with isoflurane . Anesthetic depth was monitored by the absence of hind limb withdrawal reflexes and adjusted if necessary. Analgesia was achieved by injections of buprenorphine (0.1 mg/kg BW s.c.). All experiments were performed in compliance with the German national animal care guidelines and approved by the animal welfare office  of the state of Lower Saxony, Germany, and the local animal welfare committee of the University Medical Center Göttingen.Data were obtained from 39 Mongolian gerbils  via micropipettes, muscles and connective tissue were repositioned to close the surgical site, and the skin was sutured. Animals recovered for at least 4 weeks after surgery before electrophysiological measurements were performed.Virus suspensions of the recently engineered AAV‐variant PHP.B  3–10 days before experiments were performed as described before  was recorded with linear 32‐channel silicon probes  from the ICC and was described in detail before (Dieter th order Butterworth filter). After each time stamp, an artificial refractory period of 1 ms was implemented to avoid overestimating the spike rates. Frequency tuning of multi‐units was assessed by presenting 100 ms pure tones (5 ms sine ramps) of frequencies between 0.5 and 32 kHz (quarter octave steps) and varying sound pressure level in a pseudo‐random order at a repetition rate of 4 Hz. Frequency response areas were constructed from 20 to 30 repetitions of each frequency–intensity combination, and the frequency that evoked neural activity at the lowest intensity was defined as the characteristic frequency , the distance between the dorsal‐ and ventral‐most electrodes with a d′ greater or equal to 1 was used to calculate the spread of excitation in order to avoid underestimation. Data from oCIs in which STCs evoked by at least two different optical emitters reached threshold at a minimum of 3 electrodes and a d′ of 1.5 or more were taken to analyze tonotopic activation of the auditory nerve.All data analysis was performed with custom‐written MATLAB scripts R2019b). Time stamps of multi‐units were extracted as peaks exceeding a threshold (median plus three median absolute deviations) from filtered data traces  were incubated at 4°C overnight. Goat anti‐guinea‐pig‐568  and goat anti‐chicken‐488  were used as secondary antibodies and incubated at room temperature for 1 h. Images were acquired using an Abberior Instruments Expert Line microscope in confocal mode using a 20× oil immersion objective or on a Zeiss LSM 510 using a 40× air objective. Images were processed for display in ImageJ.Sample preparation and immunohistochemical staining were performed as described previously . As this study was limited by the number of available implants, we have decided to perform most experiments in CatCh‐injected, hearing animals, in order to quantify the response properties. In deafened animals, we mainly intended to demonstrate the feasibility of optogenetic SGN stimulation by μLEDs in an animal model of sensorineural hearing loss, rather than quantifying these measures and comparing them against hearing animals. Analysis of variance has been used to compare more than two groups of data.http://www.innerearlab.uni-goettingen.de/materials.html.The MATLAB code used to analyze the data published in this study is provided as source data. Source data and analysis code can also be downloaded from AD, EK, MJ, PR, and TM designed the study. EK and PR designed optical cochlear implants with input of AD, DK, MJ, and TM. EK manufactured optical cochlear implants under the supervision of PR and OP. LJ and TH designed software for driving optical cochlear implants. GH designed hardware for driving optical cochlear implants. MJ designed hardware and software for multi‐channel electrophysiological recordings. VR produced the virus used in this study and performed immunohistochemistry of SGNs. AD performed virus injections and electrophysiological recordings. AD performed data analysis under the supervision of MJ and TM. DK performed post‐mortem X‐ray reconstructions and initial insertion studies in explanted cochleae to optimize oCI design. AD and TM prepared the initial draft of the manuscript. All authors edited and finalized the manuscript.TM and DK are co‐founders of the company OptoGenTech.(i)https://www.who.int/news-room/fact-sheets/detail/deafness-and-hearing-loss(ii)http://eurociu.eu/(iii)https://www.asha.org/public/hearing/Cochlear-Implant/(iv)http://www.auditory-neuroscience.uni-goettingen.de/hearing_the_light_EN.htmlAppendixClick here for additional data file.Expanded View Figures PDFClick here for additional data file.Code EV1Click here for additional data file.Review Process FileClick here for additional data file.


Noise induced hearing loss (NIHL) is a major contributor to disabling hearing loss. Engineering controls are superior to hearing protection devices (HPDs) in prevention of occupational noise induced hearing loss (ONIHL), although the latter are more commonly used. Effective use of audiometry requires quick categorization of audiograms. The UK Health and Safety Executive (UKHSE) scheme for the categorization of audiograms is a tool that accomplishes this.The objective of this paper is to provide an overview of the classification of audiograms and build a case for the preferential use of the UKHSE’s scheme to achieve this.The author provides a literature review of methods of classification for audiograms and uses a case study in a Tanzanian mining company to demonstrate how the UKHSE scheme was successfully used to enhance the existing hearing protection program.The literature review identified several methods of classification based on a variation of threshold shifts from baseline. The difference was in the frequency and level of threshold shift used to determine hearing loss, and the recommended course of action once hearing loss is detected. The UKHSE scheme is simple and provides guidance on steps to be taken thereafter. This was demonstrated in a case study among miners in a mining company in Tanzania.The UKHSE audiogram classification scheme has the advantage of providing a straightforward, easy to determine classification that allows for intervention appropriate to the findings. Occupational noise-induced hearing loss (ONIHL) contributes significantly to the burden of disabling hearing loss  is prevalent in many industries on the African continent and the world at large. Historically, there have been very few studies conducted on ONIHL in African countries, as priority was given to primary healthcare issues. Over the years, data have been collected on this subject as occupational health practice begins to take root in areas where it did not previously exist  has previously been used for the purposes of hearing conservation and compensation [the OSTS method that is less onerous and is a statutory requirement. In addition, its indiscriminate use of any test frequency reduces its specificity towards identifying ONIHL. In the same vein, an alternative method uses the temporary threshold shift (TTS) that occurs immediately after exposure to predict the likelihood of a significant threshold shift  which also uses a standard threshold shift (OSTS). The major difference lies in the option for age adjustment of hearing levels using standard tables to account for age-related hearing loss (OSTS-A). In addition, the US method provides specific instructions on steps to be taken when OSTS is detected. The National Institute for Occupational Health and Safety (NIOSH) advocates what it calls a significant threshold shift (NSTS), defined as a 15-dB change from baseline at any test frequency. The method discounts correction for age and requires a third audiogram to confirm the STS. In terms of steps to take when an STS is detected, the NIOSH method provides clear guidance including retraining of employees on noise hazards, the use of HPDs and relocation to a quieter work environment. A study comparing the NSTS, OSTS and OSTS-A methods in terms of hearing impairment detection showed a higher prevalence for the NSTS than the other two methods. The prevalence using the OSTS and OSTS-A methods yielded 36% and 74% less detections, respectively, than the NSTS method (Masterson, Sweeney, James, Themann, & Wall, McBride, .The UKHSE developed a simple and practical method for categorising audiograms (Codling & Fox, The UKHSE categorisation scheme has come under great criticism for not utilising the characteristic notch at 4 kHz, which is regarded as an early sign pathognomonic of ONIHL. In addition, the criticism has arisen because of the use of a predominantly urban Caucasian reference population to formulate the classification; therefore, this scheme has limited generalisability (Cheesman & Steinburg, Although there is no doubting the fact that the most effective controls for ONIHL are higher up in the hierarchy of controls, and include substitution for quieter equipment, elimination of processes that generate excessive noise and automation, there are few studies evaluating the effectiveness of these controls (Morata & Meinke, Health surveillance through audiometry plays a key role in hearing conservation. The practice is beneficial only if it prompts the correct actions towards preventing NIHL. In order for audiometry to be effective, assuming that the technicians are competent and the equipment adequately calibrated, the audiograms need to be classified. The classification utilised ought to also be able to prompt occupational health practitioners to take the next vital step in preventing NIHL. Unfortunately, the majority of classification methods seem to be more suitable for compensation than for prevention purposes. The UKHSE audiogram categorisation scheme is simple and straightforward and requires basic addition skills. Furthermore, it prompts specific actions for every level of hearing threshold determined. Coupled with adequate training in the identification of noise hazards and the correct use of HPDs, the scheme can be a valuable tool in the prevention of NIHL. The method was used successfully in a Tanzanian mining company and continues to assist the early diagnosis and intervention of ONIHL.


Supplemental Digital Content is available in the text. To conduct a systematic review to address two research questions: (Q1) Does hearing loss have an effect on fatigue? (Q2) Does hearing device fitting have an effect on fatigue? It was hypothesized that hearing loss would increase fatigue (H1), and hearing device fitting would reduce fatigue (H2).Systematic searches were undertaken of five bibliographic databases: Embase, MedLine, Web of Science, Psychinfo, and the Cochrane Library. English language peer-reviewed research articles were included from inception until present. Inclusion and exclusion criteria were formulated using the Population, Intervention, Comparison, Outcomes and Study design strategy.Initial searches for both research questions produced 1,227 unique articles, after removal of duplicates. After screening, the full text of 61 studies was checked, resulting in 12 articles with content relevant to the research questions. The reference lists of these studies were examined, and a final updated search was conducted on October 16, 2019. This resulted in a final total of 20 studies being selected for the review. For each study, the information relating to the Population, Intervention, Comparison, Outcomes and Study design criteria and the statistical outcomes relating to both questions (Q1 and Q2) were extracted. Evidence relating to Q1 was provided by 15 studies, reporting 24 findings. Evidence relating to Q2 was provided by six studies, reporting eight findings. One study provided evidence for both. Using the Grading of Recommendations Assessment, Development and Evaluation guidelines, the quality of evidence on both research questions was deemed to be “very low.” It was impossible to perform a meta-analysis of the results due to a lack of homogeneity.As the studies were too heterogeneous to support a meta-analysis, it was not possible to provide statistically significant evidence to support the hypotheses that hearing loss results in increased fatigue (H1) or that hearing device fitting results in decreased fatigue (H2). Despite this, the comparative volume of positive results and the lack of any negative findings are promising for future research (particularly in respect of Q1). There was a very small number of studies deemed eligible for the review, and there was large variability between studies in terms of population, and quantification of hearing loss and fatigue. The review highlights the need for consistency when measuring fatigue, particularly when using self-report questionnaires, where the majority of the current evidence was generated. The detrimental effects of hearing loss go beyond reduced audibility, problems with speech recognition and subsequent communication difficulties. Evidence has shown that hearing loss is also related to poorer psychosocial outcomes. People with a hearing loss can experience impaired social interactions, which may lead to reduced participation and benefit from social situations . The redWhile hearing loss-related fatigue can be a major problem for some people, this is not universally the case for all those with hearing loss. Previous research has identified additional factors, relevant to hearing loss, which could potentially modulate fatigue. These factors include motivation, negative emotions, the varied lifestyles of people, and differing utilization of coping strategies to alleviate difficulty in challenging listening situations . While tOne of the possible reasons that inconsistent results are found is that fatigue itself is not a simple construct. Fatigue can be viewed as transient (momentary and task related) or long term  the impact of hearing loss on levels of fatigue and (2) whether hearing device fitting influences levels of fatigue. The objective of the current systematic review was to address two research questions:Q1) Does hearing loss have an effect on fatigue?Q2) Does hearing device fitting have an effect on fatigue?It was hypothesized that hearing loss results in increased fatigue (H1) and that hearing device fitting results in reduced fatigue (H2).The “preferred reporting items for systematic reviews and meta-analyses” (PRISMA) were utilized in this review to ensure full and transparent conduct and reporting of the systematic review .http://links.lww.com/EANDH/A673.Systematic searches were undertaken of the bibliographic databases of Embase, MedLine, Web of Science, Psychinfo, and the Cochrane Library. The search variables used included control terms and free-text terms. Two focused questions were the basis of the searches, namely: (Q1) Does hearing loss have an effect on fatigue? (Q2) Does hearing device fitting have an effect on fatigue? All peer-reviewed research articles identified were included initially from inception until February 1, 2017, with later searches including all recent articles until October 16, 2019. The search terms can be found in Supplemental Digital Content 1, To determine the inclusion and exclusion criteria for the study, the Population, Intervention, Comparison, Outcomes and Study design (PICOS) strategy was utilized . The useAdults aged at least 18 years old with a hearing loss. This could be measured audiometrically or by other means such as self-reported hearing loss.The exposure variable of interest (“Intervention” in the PICOS framework) was hearing loss (Q1) or hearing device fitting (Q2). Hearing loss as an exposure variable was considered as either the presence of a hearing loss or the level of hearing loss. Measurement of hearing loss could be self-reported hearing difficulty, pure tone audiometric assessment, or indirect measures such as hearing handicap . A broad range of measures of the presence of a hearing loss was provided to include studies that did not primarily investigate hearing loss and fatigue. Hearing device fitting was considered either as aided versus unaided or as one versus two hearing devices. This included, but was not limited to, hearing aids and cochlear implants.The comparison of interest in studies was a lack of, or varied levels of, the exposure variable (intervention). The possible alternatives for comparison with the intervention were between-group comparisons (control group with no hearing loss or no hearing device), within-group comparison , or within-subjects repeated measures designs .The primary outcome was the level of fatigue (acute or long term). This could be either directly through self-report questionnaires (subjective), through the reduction in performance over time on tasks , or through changes in physical response . To avoid an unmanageably large and unproductive initial search result, these criteria were translated into practicable search terms by requiring that in order for a study to be included, it had to mention some form of fatigue terminology. Due to the use of widely differing fatigue terminology and lack of clear consensus on how to classify fatigue, indirect measures of subjective fatigue were included. Terms referring to a reduction in energy or vitality were included, for example, “lack of energy” or “need for recovery.” The full range of terms used by studies was not known prior to the searches.All studies were English language peer-reviewed research studies. Types of study to be included were randomized controlled trials (RCTs), non-RCTs, experimental studies with repeated measures design, and observational studies. Qualitative studies were not included.https://www.crd.york.ac.uk/PROSPERO, registration number: CRD42018090924).The selection of studies went through several stages: First, all articles identified via the database searches were screened for duplicates, which were then removed. The updated list of studies was then screened for potential relevance through inspection of titles and abstracts by one author (J.H.). To ensure that no studies were rejected accidentally, the author and one other researcher (G.N.) then independently used the full texts of all remaining articles for categorization. Studies were categorized as “yes” when they were definitely relevant, “maybe” where there was some doubt about at least one criterion, and “no” when it was deemed that the study did not meet the criteria for inclusion and there was no need for further discussion. This technique was utilized by For all relevant articles, the information related to PICOS was extracted: population details, population numbers, method and criteria for measuring hearing loss or hearing device fitting, comparison population details, method of measuring fatigue, study type, and study outcomes. The outcome measures relating to fatigue were categorized as either subjective, behavioral, or physiological measures. The results were then coded based on their addressing of the hypotheses of Q1 or Q2. The hypothesis of Q1 stated that “hearing loss is associated with higher levels of fatigue.” This included both the presence of a hearing loss, as well as the severity of hearing loss. The hypothesis of Q2 stated that “hearing device fitting is associated with lower levels of fatigue.” Results from the selected studies that supported the hypothesis were listed as “supported” (+). Results that showed no statistical support were listed as “no effect” (=). Where results showed the opposite effect to the hypothesis, they were listed as “negative effect” (-). Each study could provide more than one result relating to Q1 or Q2.It was not possible to conduct a meta-analysis across studies based on outcome measures, as the studies were too heterogeneous. This was true of most of the key PICOS criteria such as population demographics, measurement and classification of hearing loss, outcome measures used to measure fatigue, and study design. Despite this, it was possible to make comparisons between the studies based on the support or otherwise of the hypotheses, as well as the descriptive information extracted from studies in the form of PICOS information. The study findings and evidence quality were considered to give an informed interpretation of the studies.The rating of the quality of the evidence provided by the selected studies was derived from the Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines . The GRAThe criterion of “risk of bias” consists of several subcriteria, which are scored differently to the other GRADE criteria listed previously. As the GRADE guidelines for assessment of risk of bias in studies was created to compare studies with an ideal RCT, a different set of subcriteria is necessary for nonrandomized studies. The risk of bias in Non-Randomised Studies of Interventions , nine studies included both participants who had a hearing loss and participants who did not have a hearing loss . Three of these studies measured the level of hearing loss, rather than including those without a hearing loss as a separate group. Four studies included only participants with a hearing loss , and one study compared their data from participants with a hearing loss with normative data (n = 149). With regards to the effect of the hearing device fitting on fatigue, two studies measured participants with and without hearing devices . Four other studies measured the same group of participants twice, either before and after fitting, or as part of a crossover study . Three of these studies involved cochlear implants exclusively.The intervention of interest for Q1 was hearing loss. This was either the existence of hearing loss or the level of hearing loss. Varying thresholds were utilized to quantify hearing loss using either pure-tone audiometry or speech in noise tests. Self-reported hearing loss was used as the eligibility criterion by two studies. The intervention for Q2 was hearing device fitting. Six studies measured hearing device fitting against no hearing device fitting. One study compared the difference between using one and two hearing devices.The comparator for Q1 was either a group difference between participants with a hearing loss and those without, or within-group differences in the level of hearing loss. For Q2, the comparator was either the fitting of a hearing device versus no hearing device, or the difference between using one and two devices.For the purposes of this review, transient (acute) fatigue was defined as fatigue experienced in a given moment, or immediately following the moment in question. Long-term fatigue was defined as either fatigue experienced over a period of time  or as average feelings of fatigue . The duration of fatigue measured for each study outcome type is displayed in Table http://links.lww.com/EANDH/A678.All subjective outcomes were self-report questionnaires, some of which were not validated. For the purposes of this review, questionnaires were considered validated if there was any published material demonstrating adequate reliability and validity of the measure in a representative sample . Most of the questionnaires followed a Likert scale reporting system and consisted of between 1 and 10 responses. Six questionnaires consisted of dichotomous questions, offering a “yes” or “no” response. Three questionnaires measured fatigue using questions about energy, one questionnaire asked questions relating to anergia (a lack of energy), three questionnaires asked about vigor, and two questionnaires asked about “need for recovery.” The energy index of the “Nottingham Health Profile”  was usedOne study included behavioral outcomes. Transient fatigue was measured based on performance in a dual-task paradigm, whereby a word recall task and a reaction time task were completed simultaneously. Slowing reaction times was described as signaling fatigue. In behavioral studies of fatigue, it is possible that fatigue-induced decrements in performance over time could be masked by learning effects in shorter trial blocks. However, the duration of the trial blocks in the study in question are adequately long to avoid this.No studies included physiological outcomes directly indicating fatigue. For example, Table This review included RCTs, non-RCTs, experimental studies with repeated measures design and observational studies. Qualitative studies were excluded. No RCTs were found. Thirteen observational studies were included. Three studies were prospective non-RCTs, two were repeated measures experiments, one was a diagnostic test study  and one was a crossover study (a subset of repeated measures design). Between-group test parameters were employed by thirteen studies; this was either hearing loss versus normal hearing, un-fitted versus fitted, or one versus two hearing devices. Nine studies utilized a within-group test parameter, which was always level of hearing loss. Two studies used both types of parameter.http://links.lww.com/EANDH/A678. Evidence pertaining to Q1 was provided by 24 findings from 15 studies. Evidence pertaining to Q2 was provided by 8 findings from 6 studies. One study provided evidence for both research questions. All outcomes were rated as “important” as they have an effect on the lives of people with a hearing loss. They were not listed as “critical” as the outcomes did not involve threat to life or serious medical impact .For both of the research questions in this review, the evidence provided was from very different methodological approaches and inconsistent outcome measures. This lack of homogeneity meant that it was not possible to create reliable confidence intervals for each outcome. Therefore, following the approach adopted by All evidence relating to the effect of hearing loss on fatigue came from subjective measures. The findings are summarized in Table The GRADE evidence results for Q1 (the effect of hearing loss on fatigue) are given in Table The criterion “risk of bias” consisted of subcriteria which were different depending on the design of the study. The risk of bias for observational studies was rated on “bias due to confounding,” “selection bias,” “bias due to measurement of exposure and/or outcome,” and “incomplete follow-up.” The risk of bias for nonrandomized controlled studies was rated on “bias due to confounding,” “selection bias,” “bias in measurement classification of interventions,” “bias due to deviation from intended interventions,” “bias due to missing data,” “bias in measurement of outcomes,” and “bias in selection of the reported result.” Eleven studies were at “moderate risk” or greater of “bias due to confounding,” most commonly due to a lack of controlling for hearing device use in either the study design or statistical analysis Grimby & . Most stThe criterion “inconsistency” was rated as “very serious” due to large variations between studies on populations , measurement of hearing loss , measurements and terminology used for fatigue , and study design. “Indirectness” was rated as “serious” due to selective populations being used  and surrogate measures of fatigue being used . The criterion “imprecision” was rated as “serious” as power sufficiency was rarely documented and the sample size was very small (16) for one study , while “A majority of the findings relating to the effect of hearing device fitting on fatigue came from subjective measures Table . Of a toOnly one study produced a finding using behavioral measures, pertaining to Q2 . The stuThe GRADE evidence results for Q2 are given in Table As the studies used so many different variations of self-report questionnaire, these are addressed together. The quality criterion “risk of bias” was judged separately for non-RCTs and observational studies, as in Q1. Both non-RCTs and observational studies were rated as “not serious.” Each subcriterion was rated as “low risk” other than “bias due to confounding” and “measurement of exposure and/or outcomes” which were rated as “moderate” due to no control for age  and prioOnly one study was found to use behavioral measurement of fatigue to address Q2. The “risk of bias” was found to be “not serious” as only controlling for age and prior knowledge of the intervention were found to bias the respective subcriteria. The criteria of “inconsistency,” “indirectness,” and “publication bias” were rated as “undetected.” “Imprecision” was rated as “serious” due to a low sample size, and therefore low power. As the evidence comes from only one study, and “imprecision” is rated as “serious,” the quality of the evidence was downgraded to “very low” quality.This systematic review aimed to investigate the available evidence regarding two research questions: (Q1) Does hearing loss have an effect on fatigue? (Q2) Does hearing device fitting have an effect on fatigue? It was hypothesized that hearing loss results in increased fatigue (H1) and that hearing device fitting results in reduced fatigue (H2).Only studies utilizing subjective measures to investigate Q1 were found. As the search terms did not include the terms “performance” or “reduction in performance,” it is possible that relevant behavioral studies which did not use fatigue terminology could have been missed. All subjective measures assessed long-term fatigue, as opposed to transient fatigue. The evidence found from across these studies gives some support for H1; that hearing loss results in increased fatigue. Despite the small number of findings, the volume of positive results suggests that the research question is promising, particularly given the lack of any negative findings (hearing loss resulting in less fatigue). One of the possible reasons that more positive results were not found could be the large variation in the questionnaires used. Ten different questionnaires were used across the studies with the most commonly used questionnaire  being utilized by three studies. In addition, different forms of questionnaire were used , as well as varying ranges and varying terminologies. While superficially all the questionnaires might seem to be addressing the same topic, terminology such as loss of energy, need for recovery, and vitality each address slightly different aspects of fatigue. The “very low” GRADE rating for the quality of the evidence was mostly due to the lack of homogeneity among the studies and the fact that the systematic search found only non-RCTs . To reach a point where research outcomes can be reliably compared, more standardization is needed in terms of terminology and methodology. Equally, as more information is gathered regarding behavioral and physiological measurement of fatigue in normal-hearing populations, the use of these methodologies should be explored with regards to the impact of hearing loss on fatigue .The majority of studies investigating Q2 utilized subjective measures. Almost all subjective measures assessed long-term fatigue; only one nonvalidated questionnaire measured transient fatigue. The evidence from the subjective measures did not support H2 in full; that hearing device fitting results in reduced fatigue, although the evidence is more promising for cochlear implant fitting than hearing aids. It must be noted that hearing device fitting does not necessarily equate to hearing device use, and any reduction of fatigue from the use of a hearing devices could be masked by those who do not use their devices regularly. An issue with the evidence from subjective measures pertaining to Q2 was the dearth of relevant literature. As the studies have the same lack of consistency in measuring fatigue as highlighted for Q1, as well as measuring different populations (hearing aid users versus cochlear implant users), results are even harder to compare and synthesis. The “very low” GRADE rating for the quality of the evidence is again mostly due to the lack of homogeneity in the studies, the small number of studies found and the fact the systematic search found only non-RCTs .Only one study used behavioral measures to investigate Q2. This study assessed transient fatigue, as opposed to long-term fatigue and supported H2. However, given that there is only one result from one study, no overall summary conclusions can be made. Likewise, ratings of the quality of the evidence are far less meaningful, given the identification of only one study that is not an RCT.Overall the evidence on Q2 is sparse. The lack of evidence, and the low quality of this evidence, means that wider conclusions cannot be drawn. However, the positive result from the behavioral measure in particular means that further studies should be conducted to try and replicate the results using behavioral methodologies investigating transient fatigue. More consistency in measurement between studies is almost certainly required to obtain a clearer picture of the relationship between hearing device fitting and fatigue.This review highlights the lack of existing information related to the relationship between hearing loss, hearing device fitting, and fatigue. Given that fatigue was not the main research aim of some studies, the measurement of fatigue was not always sufficiently thorough to support confidence in the comparison of conclusions. A serious limitation which was known before the search took place, and which the review has highlighted, is the difficulty measuring a construct as complex as fatigue. Studies used many different questionnaires to measure fatigue as well as using varied terminology. This could mean that some variables measured were not directly comparable. Instead these variables could be merely related, or part of a larger concept. More consistent terminology needs to be used regarding fatigue to allow solid conclusions to be drawn.The majority of the studies in the review used self-report questionnaires to measure fatigue. All but one of the subjective findings measured long-term fatigue as opposed to transient fatigue. The search terms for the review included many different possible terms for fatigue as it was understood that studies used a wide variety. Given the lack of common understanding about fatigue as a concept and the potential semantic differences between terms, this almost certainly meant that several of the chosen studies did not measure the same thing. This was seen as unavoidable given the dearth of research available, but also as important to highlight the issue of defining fatigue in research. The inclusion criteria provided the possibility to include studies which measured performance decrement over time. However, only one such study was found, which was surprising given the recent increase in studies investigating listening effort using performance-based tasks. The search terms did not include the terms “performance” or “reduction in performance” as it was deemed that the large increase in search result size would not have significantly enhanced the search results. Thus, it is possible that some relevant studies involving a fatigue-related reduction in performance might have been missed due to not having used the included fatigue and performance reduction-related terms. Several other studies reported fatigue as a potential research outcome; however, only listening effort was measured. As there is no solid evidence of a direct link between listening effort and fatigue, these studies could not be included.According to the GRADE protocol, the ratings of evidence provided in this review are “very low”: the worst rating. This is not a reflection on the individual studies themselves however, but stems from the fact that the majority of the studies were observational or non-RCTs. The GRADE system starts outcomes from this type of research at a rating of “low” quality. As fatigue was often measured as one of many health-related outcomes, the studies tended to be very different from one another in terms of population, measurement of fatigue, and measurement of hearing loss. This meant that it was almost inevitable that the quality of evidence would be downgraded.The follow-up searches on March 1, 2019, and October 16, 2019, revealed eight new studies, which is a comparatively large proportion of the total number. This suggests that the volume of research in the area is growing, and thus this review is timely as a spur to the execution of more consistent studies in the future.One of the main conclusions of this systematic review is that the volume of evidence regarding the impact of hearing loss and hearing device fitting on fatigue is very small and the research area is in its early stages. This, combined with the diversity of studies and the “very low” quality of evidence generated, means that solid conclusions are not possible at this stage. There is some support given to H1 (hearing loss results in increased fatigue) and H2 (hearing device fitting results in reduced fatigue) however as a majority of results were positive and no results were negative, albeit nonsignificant. The majority of studies used subjective measures to investigate fatigue, with only one study using behavioral measures  and noneThis work was supported by the Medical Research Council ; and by the Chief Scientist Office of the Scottish Government. The funder had no role in study design.