To (i) assess the delivery, accessibility, usability, acceptability, and adherence, and (ii) identify suitable outcome measures, for a mobile-enhanced multimedia educational programme (m2Hear) in first-time hearing aid users. A prospective, single-centre feasibility study. First-time hearing aid users (n = 59), recruited at their initial hearing assessment. Evaluations were made at 1-week and at 10–12 weeks post-hearing aid fitting.d > 1.6). m2Hear was most commonly accessed via tablets (42.3%). Usability was high for the System Usability Scale (88.5%), and the uMARS, particularly for the Information (M = 4.7), Functionality (M = 4.5) and Aesthetics (M = 4.2) subscales (maximum score = 5). Participant feedback was positive, with a high percent agreeing that m2Hear aided understanding of hearing aids (98%), held their interest (86%), improved confidence to use hearing aids and communicate (84%), and provided additional information to audiologist’s advice (82%). Learnings about practical hearing aid handling/maintenance skills and how to communicate with others were reportedly used equally in participant’s everyday lives. m2Hear was convenient to use, clear, concise and comprehensive. Outcome measures of social participation resulted in large effect sizes (Cohen’s  A theoretically-driven, personalised and co-designed educational m-health intervention is feasible and beneficial for use in the self-management of hearing loss and hearing aids. Hearing aids are the main clinical intervention for hearing loss, however take-up and adherence of hearing aids are often poor; 1 in 3 people who would benefit from hearing aids fail to access them, and non-use can be high, up to 24% . This was based on the concept of reusable learning objects (RLOs) that aimed to enhance patient benefit. RLOs include: (i) visual illustration of concepts, (ii) activity and engagement with content, and (iii) self-assessment. We have developed RLOs for first-time hearing aid users to address a range of practical (e.g. how to insert hearing aids) and psychosocial issues (e.g. communication tactics) relating to hearing aids and communication. Importantly, a participatory design was used that involved 32 hearing aid users and 44 hearing healthcare professionals to ensure the end-users’ “voice” was embedded in the development  of 203 first-time hearing aid users who received the RLOs at the hearing aid fitting appointment. The results were positive. There was significantly better knowledge of practical and psychosocial issues relating to hearing aids and communication, and significantly better practical hearing aid skills in the group receiving the RLOs (RLO+), with large clinical effect sizes (ES = 0.82–0.94). There was also significantly increased hearing aid use (15%) in the RLO + group compared to controls for patients who wore their hearing aids sub-optimally (ES = 0.83). In addition, the RLOs were rated as highly useful (9/10), and the majority (>80%) of participants agreed the RLOs were enjoyable, improved confidence and were preferable to written information. Take-up and use of the RLOs was also very high (78% and 94% respectively). In a second clinically registered RCT (NCT03912779), whereby the RLOs were offered at the hearing assessment appointment, self-efficacy for hearing aids improved significantly compared to a written booklet that covered similar information to the C2Hear RLOs, with a large clinical effect size (ES = 1.1)  approach because of the DVD platform that was used in the original development in 2012. This was because at that time, evidence from 1,235 people in Nottingham, UK showed that internet use was only 17% in the first-time hearing aid age group (70–74 years) and we wanted to maximise accessibility. The RCT showed that 32.9% accessed the RLOs through the internet , improve awareness of the consequences of hearing loss, and promote appropriate patient-directed self-management strategies to reduce participation restrictions associated with hearing loss. The development of m2Hear has been described elsewhere  , informing any content or usability modifications using a user-centered design with a panel of hearing aid users from the Think Aloud evaluation (n = 5). In addition, members of the project-specific patient and public involvement (PPI) panel formatively reviewed the intervention both in the lab and independently from home. These sessions were designed to assess user perceptions and interactions with the platform, as well as identify any potential problems.The subsequent development of the m-health platform was iterative .On completion of the development process described, m2Hear was evaluated in a mixed-methods study. The main research question was: is it feasible for first-time hearing aid users to use a personalised educational intervention delivered through mobile technologies in their everyday life? The specific objectives of the research reported here were to:Adult first-time hearing aid users were recruited following their hearing assessment appointment at the Nottingham Adult Audiology Service, Nottingham University Hospitals National Health Service (NHS) Trust. The inclusion criteria were (i) adults aged ≥18 years; (ii) never worn hearing aids; (iii) were familiar with smartphone technologies , and (iv) had a good understanding of the English language in order to understand the mRLO content. The exclusion criterion was those who were unable to complete questionnaires without assistance due to age-related problems (e.g. cognitive decline or dementia).The design was a single centre, prospective, registered feasibility study (NCT03136718). Interested patients who met the eligibility criteria and who had just been fitted with hearing aids were then invited to attend an initial study session at the National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre (BRC). The time duration between hearing aid fitting and attending the first study session was, on average, 5.25 days (SD= 4.81). Informed written consent was obtained prior to the start of this session. Outcome measures were obtained and then participants were shown m2Hear and given some instruction on how to use it. The participants were asked to use m2Hear on their own devices in their everyday lives as and when they needed, and were encouraged to use as much of the content that they thought was relevant to them. Following a period of independent use , participants attended a second study session where outcome measures were obtained. As per Terwee et al. , 50 partAll participants were each paid a nominal inconvenience allowance and travel expenses. The study was approved by the NHS Health Research Authority, East of England – Cambridgeshire and Hertfordshire Research Ethics Committee and Nottingham University Hospitals NHS Trust Research and Innovation department.https://www.nottingham.ac.uk/helm/dev-test/m2hear/) was based on the original C2Hear multimedia educational programme and is described elsewhere . The mRLOs were divided into categories relating to the likely need along the patient journey post-fitting .Series of 42 interactive mRLOs. Each has a specific user-centred question (e.g. How do I know which hearing aid is for my left/right ear?), which were between 20s and 1min 56s duration (average = 60s).Activities (n = 6). These were associated with specific mRLOs (e.g. drag and drop activities: (i) to label the different components of a hearing aid, and (ii) how to work with others to help take part in conversations). Additional feedback was provided, including whether the chosen selection was correct or not, and why. These activities can be used as many times as necessary.Interactive quiz (n = 34 questions). These incorporated feedback to inform whether the questions were answered correctly or incorrectly, with additional supporting information relevant to the specific situation.The m2Hear intervention  were fitted using the NAL-NL2 algorithm and verified by real-ear measurements according to local protocols and national guidelines. Hearing aids were fitted with either open-fit slim tubes (78%) or custom earmoulds (22%), and 73% were bilateral fits.The outcomes were selected based on the World Health Organisation’s International Classification of Functioning, Disability and Health (ICF) WHO  that proGlasgow Hearing Aid Benefit Profile (GHABP) (Gatehouse The Hearing Handicap Inventory for the Elderly (HHIE) (Ventry and Weinstein n = 13), and social/situational (n = 12) domains of older adults. It is scored on a three-point scale . The HHIE is not a unidimensional scale in its current form   and social perceptions (n = 10). It is scored on an 11-point scale . The SPaRQ is not a unidimensional scale, although both subscales are unidimensional.The Measure of Audiologic Rehabilitation Self-efficacy for Hearing Aids (MARS-HA) . Each item is scored on an 11-point percentage scale , with a mean score to give a global self-efficacy score.The Hearing Aid and Communication Knowledge (HACK)  and psychosocial factors (n = 8) relating to hearing aid use and communication. A pre-defined marking scheme was used to allocate one point for every correct response, with a maximum capped score. The scores were totalled for each subscale, and the total of the subscales was converted to a percentage score to give a overall knowledge score.The Clinical Global Impression Scale is a one-item question that asks, “All things considered, how is your overall hearing difficulty now, compared to before you started using the intervention?”. This was used to identify the minimally important change (MIC) for m2Hear when used with hearing aids. Responses were rated on a seven-point scale (much improved to much worse).The IT literacy was assessed using a validated three point scale for PC use   using data logging information from the hearing aids was obtained for the period between the fitting and evaluation sessions.Montreal Cognitive Assessment (MOCA)  of your experience with m2Hear? (ii) What was the most useful aspect of m2Hear? (iii) What did you learn from m2Hear that you used in your everyday life? and (iv) What would you change to make m2Hear more interesting, enjoyable or engaging?A System Usability Scale (SUS)  Sauro  is a 10-Mobile Application Rating Scale: user version (uMARS)  were held following the evaluation session with DWM, duration approximately one-hour. The transcripts were analysed using an established deductive thematic analysis procedure underpinned by the COM-B model  was categorised as small (0.2), moderate (0.5) and large (0.8). Significance was set to p ≤ .05.Descriptive statistics  were used to describe the characteristics of the sample, as well as the SUS and uMARS and outcome measures obtained at baseline (V1) and follow-up (V2). Planned statistical analysis to assess any change in the outcome measures between V1 and V2 was the paired n = 3, no reason offered n = 3, family bereavement n = 1). Participant demographics for both sessions are shown in Of the 59 first-time hearing aid users who consented and attended the first baseline post-fitting session (V1), 52 (88.2%) participants attended the second follow-up session . Attrition was lower than expected, with seven participants dropping out (11.8% attrition), compared to our estimate of 18%. Reasons offered were not intervention-specific  considering themselves IT literate. This is also reflected in the high use of devices, with 80% using smartphones, consistent with other reports Deloitte , and 86%All device delivery options were used to deliver and access m2Hear on the participants’ own devices. Mobile devices  were used by 50%, with the most common being tablets (42.3%) . SimilarIn terms of accessibility, all participants visited the m2Hear site at least once, with total of 178 recorded sessions. Two-thirds (65%) of devices that accessed m2Hear visited on 2+ occasions, and half (51%) on 3+ occasions. These return visits were higher than reported for C2Hear, although session duration was shorter (mean = 11mins 42 s), and individuals accessed m2Hear on more occasions. Unfortunately, due to a technical problem, it was not possible to identify the number of times each mRLO was accessed. However, participants reported that they revisited the m2Hear mRLOs multiple times because they were shorter. In terms of patterns of use, participants reported revisiting the mRLOs across sessions for reminders of information. Activities were accessed multiple times within a session, but less so across sessions because once completed there was little need to revisit for reminders. The activities that were used the most were those that addressed practical knowledge and insertion, which were accessed at least once for one-third of sessions (39.3% and 33.1%). The communication activities were accessed at least once in 22.4% of cases.Usability, as measured by the SUS was high at 88.5% (SD= 6.6), where a score ≥68 is considered as average. Usability was also high when measured by the uMARS, shown in In terms of adherence, the participants were instructed to use the mRLOs however they wanted. The majority reported they watched all mRLOs (55.7%), and a third (36.5%) watched when they required specific information. A further 32.6% reported they watched the mRLOs regularly (e.g. 2–3 times a week), and a small proportion (7.7%) watched only those that seemed most relevant within the first 1–2 weeks. Participants’ use of mRLOs was varied, as expected, depending on their personal needs/preferences.the videos were pitched at the right level (92%), I liked that the videos were short in duration (98%)). This is consistent with the usability results. Interestingly, 5 of the 12 statements that were rated as >80% agreement, indicated that m2Hear had resulted in positive consequences for the participants (e.g. If I had a problem with my hearing or hearing aid I would refer back to m2Hear (92%)).Participant views on m2Hear were sought by asking 18 closed statements. n = 19), followed by being accessible and convenient to use (n = 8), and being clear, concise and comprehensive (n = 8). Some of this was reflected in terms of what individuals had learned, which they could use in their everyday life. There were equal responses to practical hearing aid handling and maintenance skills (n = 14), and how to communicate successfully with others (n = 14), with learnings also for persevering and acclimatising to hearing aids (n = 5). The highest number of reports for the worst aspects of using m2Hear were for “nothing” (n = 13) and initial navigation and/or orientation issues when first using m2Hear (n = 13), such as being unsure how to go back to previous content or where to click to access an mRLO. Some participants also reported that the worst aspect was that the hearing aid featured in some of the mRLOs was dissimilar to the model that had been fitted with (n = 8). In terms of what the participants reported they would like to change to make m2Hear more interesting, enjoyable or engaging, the highest number of comments was for “nothing” (n = 18). Nevertheless, some participants requested that they would have liked less content focussed primarily at older adults (n = 5), and would like additional content on the technical aspects of hearing loss and how hearing aids work (n = 4).A summary of the responses to the open-ended questions is shown in The mean and 95% confidence intervals for V1 and V2 outcomes and subscales are shown in One of the objectives of this study was to identify which outcome measures would be suitable for use as a primary outcome measure in a future clinical effectiveness trial. As part of the decision making, we intended to assess meaningful change from the patient’s perspective, classifying patients according to their responses on the CGI scale. In accordance with Terwee et al. , this isThere is an increasing use of e- and m-health technologies in healthcare generally, and the same is true in hearing healthcare. Since the systematic review of Swanepoel and Hall , there hIn this feasibility study, our focus was to assess these benefits, alongside aspects of delivery and usability, of the m-health educational m2Hear programme. In addition, we aimed to identify appropriate outcome measures for use in the evaluation of m2Hear in any future randomised controlled trials, in accordance with the MRC Guidance on developing and evaluating complex interventions , with tablets being the primary mobile device used. This was because it was easier to read and engage with a tablet, although some participants did report that they also used their smartphones to access m2Hear “on-the-go”. Laptop use was, however, a close second to tablets. The range of devices used as the primary device, and multiple use of secondary devices, indicates that in this sample recruited from a typical UK NHS audiology clinic, all options are relevant. A subtheme of the qualitative study was digital literacy skills associated with an individual’s capability to use m2Hear , as we left it to the individual to use m2Hear as and when they wanted to, in terms of seeking the information they needed, as and when required. This aligned well with the qualitative study where participants reported that m2Hear was convenient to use and provided useful reminders to help understand how hearing aids can be used and communication improved. The ease of use and conciseness of m2Hear, and the ability of the participants to choose which information they needed by homing in on the questions that were linked to each mRLO, provided a more personalised approach to meet their individual informational needs. Although we were unable to identify which mRLOs were watched and when, due to a technical problem, we saw that the practical activities  were the most commonly completed (between 33 and 39%), whereas the communication activities (e.g. where to sit in a restaurant) were completed in about a fifth of cases. This was similar to how C2Hear was used in the original RCT, where there was a greater focus on practical rather than psychosocial aspects. However, we saw that in the open-ended questions, which asked about what people had learned in their everyday life, both practical hearing aid handling skills and communication were rated most highly, and equally so. This suggests that when people did watch the communication mRLOs, what they learned was both useful and used.The usability of m2Hear was generally rated as being very good. In particular, the items relating to the Information subscale from the uMARS were all rated very highly (M = 4.65). As providing high-quality and relevant information was the main purpose of C2Hear when it was first developed, these usability scores indicate that the information embedded in m2Hear is doing what we originally set out to do. This aligns well with the analysis of the determinants of behaviour based on the COM-B and TDF, where capability in terms of knowledge and skills were the domains that were most evident in the materials , which all tap into activity limitations or participation restrictions. As improving participation, rather than improving listening to a talker (i.e. activity), is the main goal of auditory rehabilitation  and the 10-week follow-up , with generally large effect sizes. As the intervention was the hearing aids plus m2Hear, with no control group who used hearing aids only, we were not able to evaluate m2Hear separately. However, due to the nature of this feasibility study the aim was not to evaluate the effectiveness of m2Hear Outcomes for self-efficacy for hearing aids, and knowledge about hearing aids and communication, improved significantly with large effect sizes, which we have also demonstrated previously for C2hear  there was a sharp rise in views around the time that COVID-19 infections were at 100 and starting to rise in the UK. Interestingly, the drop in the YouTube version in March 2020 coincided with an increase in the standalone version. In part, this may be because both c2Hearonline.com and m2Hear were included in the UK’s COVID-19 guidelines from the professional audiology groups , first published in March 2020. It is unlikely that the global increase in the use of connected hearing healthcare during the COVID-19 pandemic will return to previous levels as both audiologists and patients become aware and recognise the benefits of connected hearing healthcare. This also coincides in the same year as the United States Food and Drug Administration (FDA) specifications for regulations for the over-the counter (OTC) hearing aids come into force. A recently published Delphi review of UK hearing healthcare professionals (HCPs) reached a consensus that online information is essential for OTC devices that are fitted without HCP support (92%), such as C2Hear/m2Hear (88%)  services to minimise face-to-face clinic appointments as a result of the COVID-19 pandemic. We have seen this for C2hear views also. Given the rapid growth of connected hearing healthcare in a relatively short period of several months, far exceeding what would have been expected prior to the pandemic, it is likely that the need for personalised information to improve the knowledge of hearing aids and communication will only increase. It can easily be envisioned that delivery of m-health interventions, such as m2Hear or m2Hear-like tools, could be delivered through a variety of routes. These may include apps, either standalone or as part of a hearing device system, or by integration with other technologies such as a virtual voice assistant . It is clear that m-health technologies offer new ways of providing and delivering (connected) hearing healthcare, and in this ever-changing landscape, the role of m2Hear and other m-health technologies are only likely to continue to rise.There were some study limitations. We were unable to identify which mRLOs were used and when due to a technical problem. This would have provided useful information to audiologists to help guide patients as to which mRLOs are likely to be the most helpful, and when. A second limitation was lack of outcome measures data to parse out the effectiveness of the incremental benefit of m2Hear over and above that of hearing aids. One way to address this would have been to ask the participants to complete the outcome questionnaires at V1. However, most participants would have only received their hearing aids a few days previously, so it was likely they would not have fully adjusted to their hearing aids. The inclusion of a control group would also have addressed this, although the purpose of this study design (i.e. to assess the feasibility of the intervention) did not support this.The feasibility study of 59 first-time hearing aid users showed that m2Hear was used most consistently with tablets, and around half of the sample used m2Hear with mobile technologies; the remainder used laptops/PCs. Usability was high, likely reflecting the user-centred co-production approach to develop m2Hear. Feedback on the use of m2Hear was very positive, with the vast majority reporting that the intervention was well-designed, enabling them to easily refer to relevant sections when they needed advice or answers to specific questions. m2Hear provides additional information and advice to that offered by the audiologist, suggesting that m2Hear would be an easy-to-use intervention to supplement clinical audiology practice. Outcome measures showed a range of benefits of using hearing aids alongside m2Hear, indicated by large clinical effect sizes. These included knowledge of hearing aids and communication, hearing aid self-efficacy, hearing difficulties, social engagement, and hearing hearing-related quality of life. We would recommend using the SPaRQ as the primary outcome measure in future trials of m2Hear. In conclusion, a theoretically-driven, personalised and co-designed educational m-health intervention (m2Hear) is feasible and beneficial for use in the self-management of hearing loss and hearing aids. With the rapid growth of connected hearing healthcare as a result of COVID-19, the relevance and use of m2Hear or m2Hear-like interventions is only like to increase in future.


Triclosan (TCS) and bisphenol analogues are used in a variety of consumer goods. Few data exist on the temporal exposures of adults to these phenolic compounds in their everyday diets. The objectives were to determine the levels of TCS and five bisphenol analogues  in duplicate-diet solid food (DDSF) samples of adults and to estimate maximum dietary exposures and intake doses per phenol. Fifty adults collected 776 DDSF samples over a six-week monitoring period in North Carolina in 2009–2011. The levels of the target phenols were concurrently quantified in the DDSF samples using gas chromatography/mass spectrometry. TCS (59%), BPS (32%), and BPZ (28%) were most often detected in the samples. BPB, BPF, and BPP were all detected in <16% of the samples. In addition, 82% of the total samples contained at least one target phenol. The highest measured concentration of 394 ng/g occurred for TCS in the food samples. The adults’ maximum 24-h dietary intake doses per phenol ranged from 17.5 ng/kg/day (BPB) to 1600 ng/kg/day (TCS). An oral reference dose  is currently available for only TCS, and the adult’s maximum dietary intake dose was well below a level of concern. Bisphenol A (BPA) is a high-production volume chemical that has been used in a variety of consumer goods, including food packaging  ,2. The uTriclosan (TCS) is a chlorinated, phenolic compound that is lipophilic and is used as an antimicrobial agent in a wide variety of consumer goods, including household, personal care, and in clothing ,15,16. IIn previous dietary exposure studies, researchers have collected food items from grocery stores or supermarkets and then analyzed these food items for specific phenols in a laboratory setting ,18,19,20Our “Pilot Study to Estimate Human Exposure to Pyrethroids Using an Exposure Reconstruction Approach” (Ex-R study) is the only study in the literature that has assessed the dietary exposure of adults to any phenol (BPA) in actual foods prepared and/or eaten in their real-life environments . In the Ex-R study, BPA residue levels were found in 38% of the 776 duplicate-diet solid food (DDSF) samples (maximum = 138 ng/g) collected by 50 adults over a six-week monitoring period in North Carolina (NC) 2009–2011 . We are n = 776) were removed from US EPA laboratory freezers (−20 °C) and quantified for the concentrations of BPB, BPF, BPP, BPS, BPZ, and TCS.The Ex-R study was originally designed to assess the temporal and cumulative exposures of adults to pyrethroid insecticides over a six-week monitoring period in their everyday settings . BrieflyThe University of North Carolina’s Institutional Review Board approved the Ex-R study design and sampling procedures (study number 09-0741) in August of 2008. All adult volunteers read and signed an informed consent form prior to participating. In addition, the 50 adults signed a second inform consent form permitting the archived DDSF samples to be analyzed for additional chemicals commonly found in residential settings.The collection of the food diaries was discussed in-depth in Morgan et al. . The adu®, Pleasant Prairie, WI, USA). Then, this food sampling bag was placed into another resealable polyethylene bag (31 cm × 31 cm) for double containment. The food sampling bags were temporarily stored by the participants in provided portable thermoelectric coolers .The collection of the DDSF samples was described earlier in Morgan et al. . DDFS san = 776) were homogenized individually using a vertical cutter mixer (R10-Ultra® or Robot Coupe R4N-D®) or a high-speed blender (WaringMBB518®) for high-liquid content foods like soups or fruit smoothies . Ma. Ma24]. n = 47), therefore, no background correction made. Extraction efficiency was calculated by dividing the found concentration by the expected concentration in the spiked samples. The result was multiplied by 100 to express the value in percent recovery. The mean percent recoveries for the 49 matrix spikes ranged from 92.3–133% for all analytes. For the 49 recovery spikes, the mean percent recoveries were between 93.9% and 113% for all analytes.In this study, the QC samples consisted of reagent blanks, matrix spikes (25 ng/g), and recovery spikes (25 ng/g). Among the six target phenols, there was only slight contamination of TCS (mean/standard deviation = 0.3 ± 0.6 ng/g) in the reagent blanks  for the six phenolic compounds in each food sample are provided in For the three most frequently detected phenols, At the subject level, the results showed that 10% of the participants had a minimum of three different phenols occurring in five or more of their DDFS samples over the six-week monitoring period. For these five participants, BPS, BPZ, and TCS were found together the most often in these samples, and residues ranged from <0.3–14.0 ng/g (BPS), <0.5–57.9 ng/g (BPZ), and <0.3–10.9 ng/g (TCS). In addition, two of these participants had at least eight DDFS samples that contained a minimum of three different phenols, and BPS, BPZ, and TCS co-occurred the most frequently in these samples. For these two male participants, the phenolic residue levels in the samples ranged from <0.3–14.0 ng/g (BPS), <0.5–57.9 ng/g (BPZ), and <0.3–6.7 ng/g (TCS).In the last several years, BPA replacement analogues  have been increasingly used in food packaging and in other types of consumer goods , worldwide ,4,5,6,16n = 9) by this participant contained TCS residue levels of less than 6.5 ng/g. We suspect that this participant’s unknown personal behavior  likely attributed to the much higher TCS residue levels (>151 ng/g) in these two DDSF samples. This is plausible as research has shown that measurable levels of TCS residues (>40 ng/g) can migrate from kitchenware (cutting board) into foods within five minutes of contact [TCS is not known to be incorporated into any food packaging materials , but thi contact . In addi contact . Further contact . It is i contact . It is cA few published studies conducted before 2002 have quantified the co-occurrence of several different phenolic compounds in DDSF samples of children, but none of adults ,37,38. OIn this current work, we estimated the Ex-R adult’s maximum dietary intake doses to BPB, BPF, BPP, BPS, BPZ and TCS via consumed solid foods over a 24-h sampling period . Only feFew data are currently available on the aggregate exposures of adults  to these newer BPA replacement analogues, and none for TCS . In a reIn conclusion, the Ex-R adults were exposed to levels of BPB, BPF, BPP, BPS, BPZ and TCS residues in a variety of solid foods they consumed over a six-week monitoring period. Among the target phenols, only TCS was detected frequently (>55%) in the 776 DDSF samples. As there are no known uses of TCS in food packaging in the US , these T


Even 250 years after Beethoven’s birth, the irrevocable cause of his hearing impairment remains unclear despite multiple publications by different professional groups. This study aimed to analyse the development of the most likely aetiologies during the last 100 years by a systematic review of the relevant medical literature.®, PubMed Central®, and Web of Science® for the period 1920–2020 was conducted. Medical publications between 1920 and 1935 were additionally searched manually by review of reference lists. Studies were eligible when a statement regarding the most likely aetiology of the hearing loss of Beethoven was the aimed objective of the publication.A systematic review of medical literature in PubMedn = 10), syphilis (n = 9), Paget’s disease (n = 6), neural deafness (n = 5), immunopathy with inflammatory bowel disease, neural deafness with otosclerosis, sarcoidosis or lead intoxication (n = 2), and systemic lupus erythematosus, trauma, labyrinthitis or inner ear disease (n = 1). There is an ongoing effort with a mean publication frequency in this topic of 0.48/year. From 1920 to 1970, otolaryngologists were the group with the highest interest in this field (67%), whereas since 1971 most authors have belonged to non-otolaryngologic subspecialities (81%).48 publications were included. The following aetiologies were supposed: otosclerosis (Over the past 100 years, otosclerosis and syphilis were predominantly supposed to be the underlying causes. The hypothesis of syphilis—although rejected for a long time—has had a remarkable revival during the past 20 years. Regarding the outcome following therapeutic intervention by cochlear implantation, the differential diagnosis of neural deafness would be relevant today. The hearing impairment of the composer Ludwig van Beethoven is one of the best-known cases of hearing loss among historical artists. It has attracted great interest over centuries as one might speculate that perfect hearing is essential to be able to create musical masterpieces like Beethoven did. Ludwig van Beethoven represents one of the best examples that the creation of ingenious musical masterpieces does not necessarily require an intact auditory feedback loop . HoweverFrom the medical point of view, the scientific interest mainly focuses on the aetiology of his hearing impairment which is still the source of ongoing controversial scientific discussions on whether Beethoven might have benefitted from modern concepts of hearing rehabilitation such as cochlear implantation, which is today’s treatment of choice in subjects with severe to profound hearing loss.Therefore, the aim of this study was (1) to create a systematic review of the medical literature listed in medical databases over the past 100 years on the aetiology of Beethoven’s hearing loss and (2) to critically discuss the pros and cons of the most frequently stated diagnoses.To evaluate the aetiology of Beethoven’s hearing loss, one mainly has to rely on contemporary primary sources. The medical history can be reconstructed by letters of the composer, his conversational books and documents from his physicians, biographers and other contemporaries. Results of medical examinations are documented in the protocol of the post-mortem examination in 1827 and additionally by a more recent analysis of the bone fragments of his skull in 1985 and 2005 and of his hair in 2000 .I am deaf! In any other profession this might be more tolerable, but in mine such a condition is truly frightful […].My ears are buzzing and ringing perpetually, day and night. I can with truth say that my life is very wretched; for nearly 2 years past I have avoided all society, because I find it impossible to say to people, I hear none of the high notes of instruments or singers.[…] I often can scarcely hear a person if speaking low; I can distinguish the tones, but not the words, and yet I feel it intolerable if anyone shouts to me […]”“The ringing and buzzing in my ears have certainly rather decreased, particularly in the left ear, in which the malady first commenced, but my hearing is not at all improved; in fact I fear that it is become rather worse […]” Herein, Beethoven gave a detailed description of his hearing impairment which started in the high frequencies with a progressive hearing loss initially affecting the left ear more than the right ear. Besides, he complained about a loss of sound discrimination and permanent tinnitus and showed signs of a positive recruitment.Also in 1802, Beethoven mentioned his hearing impairment in the “Heiligenstädter Testament”, a letter to his brothers Kaspar Karl und Johann from 1802:“[…] But you must remember that six years ago I was attacked by an incurable malady […] I was yet obliged early in life to isolate myself, and to pass my existence in solitude. If I at any time resolved to surmount all this, oh! how cruelly was I again repelled by the experience, sadder than ever, of my defective hearing!–and yet I found it impossible to say to others: Speak louder; shout! for I am deaf! […].Completely isolated, I only enter society when compelled to do so. I must live like an exile.My intelligent physician recommended me to spare my hearing as much as possible, which was quite in accordance with my present disposition, though sometimes, tempted by my natural inclination for society, I allowed myself to be beguiled into it. But what humiliation when any one beside me heard a flute in the far distance, while I heard nothing, or when others heard a shepherd singing, and I still heard nothing! […].Ah! how could I possibly quit the world before bringing forth all that I felt it was my vocation to produce? And thus I spared this miserable life–so utterly miserable that any sudden change may reduce me at any moment from my best condition into the worst […].My brothers Karl and Johann, as soon as I am no more, if Professor Schmidt be still alive, beg him in my name to describe my malady, and to add these pages to the analysis of my disease, that at least, so far as possible, the world may be reconciled to me after my death.[…].I joyfully hasten to meet death. If he comes before I have had the opportunity of developing all my artistic powers, then, notwithstanding my cruel fate, he will come too early for me, and I should wish for him at a more distant period; but even then I shall be content, for his advent will release me from a state of endless suffering. Come when he may, I shall meet him with courage. Farewell! […] In 1802, the substantial impact of the progressive hearing loss on his mental state was already described. Social isolation, obvious signs of depression and suicidal tendencies were found. Moreover, Beethoven explicitly asked the medical posterity to figure out the aetiology of his hearing loss in this document.According to these most cited documents, Beethoven’s hearing loss started in 1796 at the age of 26. In the subsequent years, his hearing thresholds deteriorated so that Beethoven began to use ear trumpets in 1813 which were constructed for him by J. N. Mälzel. Another tool to alleviate the hearing impairment—however also with limited benefits—was a resonating plate which was placed on the piano and reflected the soundwaves . The vault of the skull showed great tightness throughout and a thickness of about half an inch.” Fig.  10]10]However, there is no description of the middle ear structures available. According to G. Breuning, physician and son of a long-time friend of Beethoven, the temporal bones of the composer were stored in a jar for further examination after autopsy at the Institute of Anatomy at the University of Vienna because the anatomist J. Hyrtl (1810–1894) stated that he had still seen them on the desk of the dissection attendant A. Datter . HoweverBeethoven himself and his physicians associated his hearing loss with his lifelong abdominal problems resulting in diarrhea, impaired digestion, and abdominal colics first mentioned at the age of 25:“The chief cause of this infirmity proceeds from the state of my digestive organs, which, as you know, were formerly bad enough, but have latterly become much worse, and being constantly afflicted with diarrhea, has brought on extreme weakness. my hearing became worse, and my digestion continued in its former plight.[…] I suffered from most dreadful spasms, and sank back into my former condition. digestive pills four days ago, and a tea for my ears. I certainly do feel better and stronger” .Other diseases temporally associated with the beginning of the hearing loss were an unspecified “dangerous illness [in 1796] which shock hits his hearing tools, from which time his deafness gradually increased”  and the In addition to the life-long abdominal problems, Beethoven also suffered from other diseases. According to several authors who try to place all of Beethoven’s symptoms under one single umbrella, the other diseases might be partially related to his hearing loss. In young adult life, Beethoven suffered from an arthropathy and in 1821 from jaundice. A painful eye condition in 1823 lasting for about 6 months was by some classified as an inflammatory ocular disease. Hematemesis and epistaxis which he suffered from in 1824 and 1825 might have been a prelude to the terminal illness of liver cirrhosis with a chronic pancreatitis. In this context, at the end of 1826/beginning of 1827, Beethoven was affected by extensive ascites and tapped four times before his death in March 1827.®, PubMed Central®, and Web of Science® were used. The search was carried out from January 1, 1920, to June 30, 2020. The applied search terms in PubMed® and PubMed Central® were “Beethoven” in conjunction with “1920:2020[dp]“ AND “deafness” or “hearing loss”. Search terms in Web of Science were “Beethoven* deafness” or “Beethoven* hearing loss”. After deduplication, two independent reviewers separately screened for eligibility and in case of incongruency a third reviewer provided consent. Titles and, if available, abstracts were screened for inclusion or exclusion.For a systematic review of the medical literature of the last 100 years on the aetiology of Beethoven’s hearing impairment, a computer-based search of medical publications was performed following the PRISMA guidelines . Due to As a first step, publications which did not deal with the medical history of the composer Beethoven  were excluded; as a second step, publications written in other languages than English, German, Spanish, Italian and French were discarded; and as a third step, publications which did not deal with the aetiology of Beethoven’s hearing loss were excluded. Then, the full-text versions of all publications that passed the screening were thoroughly evaluated. As a fourth step, further publications which do not deal with the aetiology of Beethoven’s hearing loss were discarded. As a fifth step, publications which did not give a statement regarding the underlying cause of the hearing loss were excluded. Studies were considered eligible if they comprised the description of a single favoured aetiology or if a clear exclusion of a cause was at least one of the study aims.® covers only medical literature at the earliest from 1936 to the present day. Therefore, to get complete access to all publications published in medical journals over the past 100 years, medical publications published between 1920 and 1935 were additionally searched manually by review of all reference lists of the above-mentioned eligible papers.Currently PubmedThe results of the literature retrieval process regarding the medical literature from 1920 up to now is illustrated in the flow diagram depicted in Fig. n = 10), syphilis (n = 9), Paget’s disease (n = 6) and neural deafness not otherwise specified (n = 5).The number of the most likely supposed cause of Beethoven’s hearing loss is shown in Fig. Even 250 years after Ludwig van Beethoven’s birth, medics still deal with the cause of his deafness which is still obscure. We are presenting the first systematic review of medical publications on the most likely cause of Ludwig van Beethoven’s deafness. Over the past 100 years, there was a mean release frequency of about one new publication supposing an underlying aetiology of his hearing loss in the medical literature in every 2.1 years with a quite continuous publication activity except for the period during and after the Second World War.Regarding the subspecialities of the authors, there is an obvious change in the publications on this topic over the past 100 years. Whereas from 1920 to 1970, otolaryngologists represented the dominating discipline with 14 of 21 publications, in the past 50 years only 4 of 21 author groups originate from otolaryngology. So, experts from different disciplines like pharmacologists, pathologists, infectiologists, gastroenterologists, rheumatologists, neurologists, psychiatrics and even paediatricians might be increasingly interested in this topic.In the literature, several differential diagnoses regarding the aetiology of Beethoven’s hearing loss have been controversially discussed. According to the number of publications, the leading cause supposed to explain Beethoven’s hearing loss is otosclerosis which was already favoured in the medical literature between 1921 and 1935 by otolaryngologists , 15 and Syphilis is the aetiology second most accused of being the cause of Beethoven’s hearing loss. In the nineteenth century, syphilis was a very common venereal infectious disease which was considered the cause of Beethoven’s deafness by several non-medical authors and the composer’s biographers. The non-physician G. Grove was the first who mentioned this in the first edition of his musicology dictionary “Grove’s dictionary of Music and Musicians” in 1879 by the entry “the whole of these [postmortem] appearances are most probably the result of syphilitic affections at an early period of his life”. This statement had been initiated by third-hand information of the biographer A. W. Thayer who assumed Beethoven had syphilis based on two prescriptions for Beethoven by his physician Dr. Bertolini in 1820 for medication containing mercury . Even inBesides otosclerosis, another bone-remodelling disease with fixation of the stapes, the Paget´s disease, was accused of being the cause of Beethoven’s deafness in perennial publications from 1965 up to these days , 33. AboFrom 1920 up to the turn of the millennium, neural deafness was periodically accused of being the underlying cause of Beethoven’s hearing impairment , 36. ThiBeethoven himself assumed a relationship between his lifelong gastrointestinal problems and his hearing impairment. This is also reflected throughout the medical literature during the last 100 years. While assumptions about a toxic labyrinthitis or an unspecified cochlear nerve disorder caused by intestinal problems which were popular in the 1920s and 1930s , 38 are In the 1990s, Drake and Palverman favoured independently of each other sarcoidosis as a diagnosis, as sarcoidosis encompasses most of the different diseases that Beethoven had. The multisystemic involvement of sarcoidosis can cause chronic active hepatitis followed by cirrhosis, inflammatory bowel disease, post-dysenteric seronegative arthropathy, hypercalcemia, and nephrolithiasis . In 5% oIt lasted up to 2013, that lead intoxication was mentioned in the medical literature as a potential cause of Beethoven’s hearing loss. Evaluations of Beethoven’s hair and parietal skull bones in the first decade of this century revealed substantially elevated lead levels indicating chronic lead exposure which might have caused lead poisoning , 7. WherBeethoven’s explicit wish to clarify the cause of his deafness after his death has been fulfilled in numerous medical publications. Based on primary historical sources including the autopsy report and more recent investigations of probes of his skull and hair, several different hypotheses on the aetiology of the hearing impairment of Beethoven have been postulated.Otosclerosis and syphilis have been the predominant supposed causes in the medical literature of the past 100 years, whereby the long-rejected hypothesis of syphilis has shown a surprising and probably questionable revival during the last 20 years. In addition to numerous other causes, the hypothesis of a chronic lead intoxication has recently been developed in the medical literature over the past decade.To date, no single aetiology exists which might on its own completely explain Ludwig van Beethoven’s hearing impairment without a pertinent argument against this hypothesis. So, it is most likely that the question regarding the irrevocable cause of his deafness will probably remain unanswered forever.Whereas during his lifetime only insufficient hearing rehabilitation via hearing aids in the form of ear trumpets and a resonating plate was available, it is supposed that Beethoven would now probably benefit from an electrical stimulation by a cochlear implant. In this context, it has to be mentioned that the composer anticipated the physical fundamentals of this therapeutic option already at the beginning of his hearing loss when he wrote in 1801: “I hear wonders of galvanism; what do you say to it? A physician told me that he knew a deaf and dumb child whose hearing was restored by it, and likewise a man who had been deaf for seven years, and recovered his hearing” [


The majority of children with sensory impairments live in low- and middle-income countries. More studies of hearing and vision impairment prevalence are needed, in order to generate more accurate estimates of trends in sensory impairments. This study aimed to estimate the prevalence and describe the characteristics of hearing and vision loss among preschool children (4–7 years) in an underserved South African community following community-based mobile health  supported hearing and vision services.A screening program of sensory impairments was undertaken of children attending preschools in the communities of Khayelitsha and Mitchell’s Plain, Cape Town, from September 2017 until June 2019. Hearing and vision screening were done by trained community health workers using mHealth technology. Children who failed hearing and vision screening were seen for follow-up assessments at their preschools. Follow-up assessments were conducted using smartphones that host point-of-care validated and calibrated hearing and vision testing applications . Descriptive statistical analysis and logistic regression analysis were conducted after extracting data from a secure cloud-based server  to Microsoft Excel (2016).p < 0.05), but not for hearing loss (p = 0.06). Gender was not a significant predictor of hearing (p = 0.22) or vision loss (p = 0.20).A total of 10,390 children were screened at 298 preschools over 22 months. Of the children screened, 5.6 and 4.4% of children failed hearing and vision screening respectively. Community-based follow-up hearing tests were done at the preschools on 88.5% (514) of children of whom 240 children  presented with hearing loss. A preschool-based follow-up vision test was done on 400 children (88.1%). A total of 232 children  had a vision impairment, and a further 32 children passed the test but had obvious signs of ocular morbidity. Logistic regression analysis found that age was a significant predictor of vision loss (. Timely identification of sensory losses can be facilitated through community-based hearing and vision services supported by mHealth technology.Hearing loss is prevalent in at least 22 per 1000 and vision loss in at least 23 per 1000 preschool children in an underserved South African community Childhood hearing and vision loss are significant contributors to the global burden of disease , 2 affecUnfortunately, the majority of children 80 to 90%) with sensory impairments live in low- and middle-income countries (LMICs) , 10, 12 0 to 90% . In this study, trained community health workers (CHWs) used validated smartphone-based applications (apps) for hearing screening  [Estimating the prevalence of sensory loss in this population is an important step to ensure adequate planning and successful implementation of community-based hearing and vision care in preschools in this context. There is a lack of contemporary population-based information about childhood hearing loss and visual impairment, from which the scope and priorities for prevention and treatment can be identified , 21, 22. Africa) –28, 30 a Africa) , 25. In  Africa) , 24, 31, Africa) .The aim of this study was to estimate the prevalence and describe the characteristics of hearing and vision loss among preschool children (4–7 years) in an underserved South African community following the mHealth supported community-based hearing and vision services described by Eksteen et al., (2019).Institutional Review Board clearance for the study was obtained from the University of Pretoria (HUM020/1019).A community-based hearing and vision screening program for preschool children by community health workers (CHWs) was implemented using validated mHealth technologies , 32. FouHearing and vision screening were done by trained CHWs at the preschools in the community using smartphones that host point-of-care validated hearing and vision screening applications  . The heaAll children who failed the screening were scheduled to undergo a follow-up assessment at their preschool.Children who failed the hearing test received a follow-up assessment by an Audiologist at their preschool a week or two later . The folChildren who failed the initial vision screening were retested on the same day at their preschool by the trained CHWs, using the validated Peek Acuity application on the same smartphone  . This teChildren presenting with hearing or vision loss at the follow-up assessment were referred to public health care clinics (audiology or optometry clinics) in their area for further assessments and intervention , 32. ChiData collected by the smartphone were uploaded to a cloud storage facility through mobile telephone networks at the end of each test , 37, usip-value cut off was set at 0.05 and indicated the level of significance throughout this study.Data of the follow-up test were extracted from the secure cloud-based server  to Microsoft Excel (2016) and coded according to test outcomes (sensory loss or not), characteristics  and severity of loss for descriptive statistical analysis. Logistic regression was used to estimate the association between the presence of sensory loss and gender and age using IBM SPSS Statistics for Windows . A A total of 10,390 children 50.2% female) with a mean age of 5.7 years (SD 0.61) were screened at 298 preschools over 22 months  resulting from hearing screening  of children of whom 240 children  presented with hearing loss (Table 4 of chilA follow-up vision test was done on 400 children (88.1%) on the same day that they failed the initial screening at the preschool Fig. . A totalTable p < 0.001), with each year older a participant was 51.4% less likely of having vision loss . Age was not a significant predictor of hearing loss (p > 0.05). Gender was not a significant predictor of hearing (p > 0.05) or vision loss (p > 0.05).Table This study aimed to estimate and describe hearing and vision loss among preschool children (4–7 years) in an underserved South African community. A critical issue in health services research related to infants and children is that of timely, necessary, and appropriate referrals for early childhood intervention services , 2, 16. A high proportion of the children who failed the screens completed the follow-up assessments (88.5% for hearing and 88.3% for vision). These figures are high compared to rates of 32.5 and 25.1% reported by Manus et al. (2020) and 45.3% reported by Hussein et al. (2018), when follow-up assessments were done at the health care facilities , 24. LosOut of the children who failed hearing and vision screening, 41.3% presented with hearing loss and 51.2% presented with vision loss at the follow-up assessment and were referred for treatment in the health care system. The community-based follow-up assessments assure selective referrals, thereby reducing the burden upon the health care systems and scarce specialized healthcare professionals , 21, 26.Due to the risk of loss to follow-up at health care centres, it is more accurate to report the prevalence of sensory losses according to the follow-up assessments at the preschools at that point in time , 24. TheAbout half of the children with hearing loss (53.5%) had obvious signs of external and/or middle ear abnormalities. The prevalence of ear disease might have been even higher, as tympanometry was not conducted and therefore not all middle ear pathology was identified , 45. TheThe prevalence of bilateral hearing loss was found to be more common than that of unilateral hearing loss, in agreement with reports of others , 47. Als. In comparison to previous studies, mild vision loss was least prevalent [Prevalence of vision loss in the current study ranged between 2.2 and 2.8%. The global prevalence, as well as the prevalence in SSA, for 5–9 year olds are estimated at 3.1% for vision loss [More than half (137) of children with vision loss had bilateral loss and 95 had unilateral loss. Thirty-two children passed the visual acuity assessment, but had obvious ocular abnormality. Nirmalan (2003) found that CHWs can be trained effectively to identify children with ocular abnormalities and they should not be limited to screening for vision impairment alone . TherefoIt is reported that sensory impairments commonly co-occur, with an estimated 40 to 60% of children with hearing loss also having some degree of vision loss , 39. In In agreement with previous studies, gender did not have a significant effect on sensory losses , 23, 36.Strengths of this study include a large study population, assessment of both hearing and vision, as well as the use of validated tools for community-based screening and assessments. Limitations of the current study included that sensitivity and specificity for these assessments could not be determined. The hearing assessment protocol did not include tympanometry or bone conduction audiometry and therefore, the nature  and cause of hearing loss could not be determined. The visual assessment protocol did not include a basic ocular examination using torchlight and may have resulted in an underestimation of ocular morbidity. The cause of vision loss was also not determined.. Community-based follow-up assessments ensured a high follow-up return rate (88.5% for hearing and 88.3% for vision) and assured selective referrals, thereby reducing the burden upon the health care systems and scarce specialized healthcare professionals. Children who were identified with sensory losses were referred to health care clinics where they received interventions . Future studies aim to report on causes of visual or hearing loss, as well as outcomes and the impact of interventions on the children diagnosed with sensory impairments. Timely identification of sensory losses is essential to ensure optimal outcomes and can be facilitated through community-based hearing and vision services supported by mHealth technology.According to this study, hearing loss is prevalent in at least 22 per 1000 and vision loss is prevalent in at least 23 per 1000 preschool children in an underserved South African community


Immune-mediated neuropathies, such as chronic inflammatory demyelinating polyneuropathy (CIDP) are treatable neuropathies. Among individuals with diabetic neuropathy, it remains a challenge to identify those individuals who develop CIDP. Corneal confocal microscopy (CCM) has been shown to detect corneal nerve fiber loss and cellular infiltrates in the sub-basal layer of the cornea. The objective of the study was to determine whether CCM can distinguish diabetic neuropathy from CIDP and whether CCM can detect CIDP in persons with coexisting diabetes.n = 55) with (n = 10) and without (n = 45) diabetes; participants with diabetes (n = 58) with (n = 28) and without (n = 30) diabetic neuropathy, and healthy controls (n = 58) underwent CCM. Corneal nerve fiber density (CNFD), corneal nerve fiber length (CNFL), corneal nerve branch density (CNBD), and dendritic and non-dendritic cell density, with or without nerve fiber contact were quantified.In this multicenter, case-control study, participants with CIDP (Dendritic cell density in proximity to corneal nerve fibers was significantly higher in participants with CIDP with and without diabetes compared to participants with diabetic neuropathy and controls. CNFD, CNFL, and CNBD were equally reduced in participants with CIDP, diabetic neuropathy, and CIDP with diabetes.An increase in dendritic cell density identifies persons with CIDP. CCM may, therefore, be useful to differentiate inflammatory from non-inflammatory diabetic neuropathy.The online version contains supplementary material available at 10.1186/s12974-021-02130-1. Immune-mediated neuropathies are a heterogeneous group of conditions mediated by inflammatory processes resulting in impaired sensation and muscle weakness which impose a significant burden of disease . The mosCorneal confocal microscopy (CCM) is a relatively rapid non-invasive ophthalmic imaging technique that is reproducible , 9 and w2 at baseline identified clinical progression with a sensitivity and specificity of 100% . Dendritic and non-dendritic cells were counted per mm2. F/mm2 comprises all cells/mm2 with fiber contact (DCF and NCF), whereas P/mm2 combines all cells per mm2 without fiber contact .Corneal images were captured using a Heidelberg Retina Tomograph . Corneal integrity was confirmed by slit-lamp examination. Local anesthetic (0.4% benoxinate hydrochloride) was used to anesthetize the eye, and a drop of Viscotears Liquid Gel was used between the lens and the disposable lens cover. CCM is a corneal contact technique which has a very low risk for corneal injury or keratitis; however, none of our patients developed any of these complications. Four scan cycles were conducted across the entire depth of the central cornea, especially the sub-basal nerve layer. At least 15 images per patient, meeting established quality criteria were analyzed . AutomatP values, which were calculated using GraphPad Prism software version 9.0 . Differences between groups were assessed using Kruskal-Wallis one-way analysis of variance with Dunn’s multiple comparison post hoc tests, after analyzing for parametrical distribution with Shapiro-Wilk test. A P value < 0.05 was considered to be significant . Specificity, sensitivity, and positive predictive value were calculated for distinguishing CIDP from DN and healthy controls with the parameter DCP and DCF by using the lower z value of two times the SEM from the median as the cut-off value.All data are presented as mean, standard error of the mean, and The mean age of patients with CIDP was 58 ± 12.7 years and 60% were males, compared to the group of patients with diabetes who had a mean age of 52 ± 16.7 years and 47% were males. The groups and subgroups  were matched with regard to demographic characteristics and did not differ significantly. The mean age of healthy controls was 49 ± 15.3 years and 58% were males , the ratio of DCF + NCF to CNFL was identified as the most selective (F/mm2/CNFL d = 0.857), followed by F/mm2/CNFD (d = 0.664), F/mm2/CNBD (d = 0.408), P/mm2/CNFL (d = 0.225), P/mm2/CNFD (d = 0.083), and P/mm2/CNBD (d = 0.079). However, these derived parameters did not improve the ability to distinguish CIDP from DN beyond the number of infiltrating dendritic cells, which showed the highest effect size . DCP distinguished CIDP from DN with a sensitivity of 0.701, specificity of 0.879, and a PPV of 0.784. DCF distinguished CIDP from DN with a sensitivity of 0.596, specificity of 0.775, and a PPV of 0.723. For distinguishing CIDP from healthy control, DCP showed a sensitivity of 0.701, specificity of 0.767, and a PPV of 0.754, while DCF showed a sensitivity of 0.596, specificity of 0.722, and a PPV of 0.693.By comparing effect sizes (Patients with diabetes were further subdivided into patients with (+to) and without (−to) neuropathy according to the Toronto criteria. Both +to and −to had significantly lower numbers of DCP and DCF compared to patients with CIDP Fig. a, b. The1c > 7.0% vs. ≤ 7.0%, Supplementary Figure There was no significant difference in corneal cellular infiltrates in a comparison of participants with poor versus good glycemic control  and without (n = 44) MGUS  or Diabetes and Effect of Glycemia on Corneal Infiltrating Cells. In participants with CIDP or diabetes and controls, ratios were calculated for (a-c) total corneal cell counts to corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), and corneal nerve fiber length (CNFL); (d-f) DCF + NCF  to CNFD, CNBD, and CNFL; and (g-i) DCP + NCP  to CNFD, CNBD, and CNFL. All participants were stratified into two groups based on glycated hemoglobin (HbA1c) levels: >7.0% and ≤7.0% and corneal infiltrating cells were quantified (j-l). Mean ± SEM, *P<0.05, **P<0.01, ***P<0.001, ns indicates not significant.


The results are consistent with the hypothesis that noise exposure during military service accelerates the progression of hearing loss for frequencies where the hearing loss is absent or mild at the end of military service, by about 1.7 dB/year on average for frequencies from 3 to 8 kHz, but has no effect on or slows the progression of hearing loss for frequencies where the hearing loss exceeds about 50 dB. Acceleration appears to occur over a wide frequency range, including 1 kHz. There remains a need for further longitudinal studies using larger sample sizes. Longitudinal studies are also needed to establish whether exposure to other types of sounds, for example at rock concerts or from work in heavy industries, affects the subsequent progression of hearing loss.It is traditionally believed that the effects of exposure to noise cease once the exposure itself has ceased. If this is the case, exposure to noise relatively early in life, for example during military service, should not affect the subsequent progression of hearing loss. However, recent data from studies using animals suggest that noise exposure can accelerate the subsequent progression of hearing loss. This paper presents new longitudinal data obtained from 29 former male military personnel. Audiograms obtained at the end of military service were compared with those obtained at least five years later. Rates of change of hearing threshold level (HTL) in dB/year were compared with those expected from ISO7029 (2017) for men at the 50 It is traditionally believed that the effects of exposure to noise cease once the exposure itself has ceased . If thisThe noise occuring in many noisy work places is relatively steady, and it is typically broadband with levels of 90–110 dB SPL. Prolonged exposure to such noise typically produces a “notch” or “bulge” in the audiogram for a frequency close to 4 kHz . In contThe possibility that noise exposure can accelerate the progression of hearing loss following the exposure is supported by studies using mice. In a similar study using mice , the effThere are three published studies that are directly relevant to this issue.  The other two studies that are relevant to the hypothesis  were botth percentile.The present paper presents new longitudinal data from former military personnel. Audiograms obtained at the end of military service were compared with those obtained at least five years later. Rates of change of HTL in dB/year were compared with those expected from Data were available for 29 UK male military veterans, most of whom had served in the army. Their age at entry to military service ranged from 16 to 24 years. Their age at the end of military service ranged from 23 to 44 years; 5 were aged 23–25, 6 were aged 26–30, 5 were aged 31–35, 4 were aged 36–40, and 9 were aged 41–44 years. All had HTLs better than or equal to 20 dB HL from 0.5 to 6 kHz at the start of military service . All were claiming compensation for NIHL. The claims were initiated from 5 to 20 years after the end of military service, with a mean of 10 years, a median of 10 years and a standard deviation of 6 years. They were selected from larger databases on the basis of reliable audiograms, obtained according to the standards of the f,  and each ear separately, the end-of-service HTL, HTLEOS(f), was subtracted from the HTL obtained at least 5 years later, denoted HTLfinal(f).For each audiometric frequency, actual (f).The difference obtained in step (1) was converted to the rate of change of HTL in dB/year by dividing the difference by the elapsed time in years between the the end-of-service audiogram and the later audiogram. This rate of change is denoted Rth percentile based on The expected audiogram for a man at the 50expected(f).The difference obtained in step (3) was converted to the expected rate of change of HTL in dB/year by dividing the difference by the elapsed time in years between the the end-of-service audiogram and the later audiogram. This rate of change is denoted RIf Ractual (f) is greater than Rexpected(f), this indicates an accelerated progression of hearing loss following the end of military service. If Ractual (f) is less than Rexpected(f), this indicates a slowing of the progression of hearing loss following the end of military service. If Ractual (f) is equal to Rexpected(f), this indicates that the noise exposure during military service had no effect on the subsequent progression of hearing loss.The steps in the analysis of the data were:actual (f) − Rexpected(f) are shown separately for each ear in actual (f) − Rexpected(f) (bold line in each panel) was above 0 for every audiometric frequency for both ears, indicating, on average, accelerated progression of hearing loss following the end of military service. The mean values of Rexpected(f), Ractual (f), and the differences Ractual (f) − Rexpected(f) are shown for each ear in The individual and mean values of Ractual (f) − Rexpected(f) should be negatively correlated with HTLEOS(f). actual (f) − Rexpected(f) against HTLEOS(f). Each panel shows results for one frequency. The correlations between Ractual (f) − Rexpected(f) and HTLEOS(f), shown in each panel, were small but were consistently negative, for all frequencies and both ears. Based on a directional hypothesis that the correlation should be negative, for a sample of 29 cases, a correlation should be more negative than −0.31 to be significant at p < 0.05. This condition was satisfied for both ears at 4, 6 and 8 kHz, but not at 3 kHz. Since the results were similar for the two ears (open and filled circles) for each frequency, a linear regression line was fitted to the data for both ears combined for each frequency (thick gray lines). The regression lines all had negative slopes, consistent with the hypothesis that the rate of decline in HTL decreases with increasing HTLEOS(f).If the rate of progression of hearing loss decreases with increasing hearing loss at the end of military service, then REOS(f) in the range −5 to 40 dB HL most values of Ractual (f) − Rexpected(f) were positive, i.e. for small values of HTLEOS(f) the actual rate of change was mostly greater than expected. In contrast, for values of HTLEOS(f) of 50 dB HL or more, the values of Ractual (f) − Rexpected(f) were roughly equally often positive and negative. This pattern of results is consistent with the hypothesis that for frequencies where HTLEOS(f) is small, exposure to noise during military service accelerates the subsequent progression of hearing loss, while for frequencies where HTLEOS(f) is above about 50 dB HL, the prior noise exposure has no effect on or slows the subsequent progression of hearing loss. The regression lines for f = 3, 4, 6 and 8 kHz had a mean value of 1.7 dB/year at HTLEOS(f) = 0 dB HL, indicating an acceleration of about 1.7 dB/year when there was no hearing loss at the end of military service.It is noteworthy that for values of HTLactual (f) − Rexpected(f) and HTLEOS(f) may partly occur because of random errors in HTLEOS(f). The value of HTLEOS(f) is used to calculate Ractual (f) (but with a − sign). Hence, if HTLEOS(f) is “too high” as a result of a random error, Ractual (f) will be “too low”, while if HTLEOS(f) is “too low”, Ractual (f) will be “too high”. This would tend to lead to negative correlations. There will also be random errors in the value of HTLfinal(f) but these will be unrelated to HTLEOS(f). To assess the magnitude of the correlations that would be expected from random errors of measurement in HTLEOS(f) and HTLfinal(f), the following analysis was performed.A problem with the analysis described above is that the relationship between Rth percentile using EOS(f) and the expected final HTL is denoted HTL(ISO)final(f). The expected change in HTL from end of service to final isactual(f) − Rexpected(f) and HTLEOS(f) that would be expected based on random errors of measurement in HTLEOS(f) and HTLfinal(f), the effects of such errors were simulated assuming that Ractual(f) is independent of HTLEOS(f) and that Rexpected(f) = Ractual(f). The analysis was done separately for each ear and each frequency of the 29 cases. The steps were as follows:expected(f) was set equal to the value of Ractual(f).The value of REOS(f) was “jittered” to simulate a random error, by adding a random number drawn from a Gaussian distribution with a mean of 0 and a standard deviation of 3.8 dB. The value of 3.8 dB represents the standard deviation of the difference in HTLs for manual audiometry conducted by two different testers .For each frequency and each ear, the value of HTL testers . The resfinal(f), giving HTLfinal.A similar but independent jitter was applied to HTLThe actual minus expected rate of change in HTL from EOS to final was calculated asEOS.For each frequency, the correlation was determined between Diff(f) and HTLEOS was determinedFor each frequency, the slope of the best-fitting line relating Diff(f) to HTLSteps 5 and 6 were repeated for 40 realizations of the random applied jitters and the resulting correlations and slopes were averaged. f) and HTLEOS with the measured correlations between Ractual(f) − Rexpected(f) and HTLEOS(f). For frequencies from 3 to 8 kHz, and for both ears, the measured correlations were more negative than the correlations resulting from random errors of measurement in HTLEOS(f) and HTLfinal(f).The actual change in HTL from end of service to final isf) as a function of HTLEOS with the measured slopes of the lines fitted to Ractual(f) − Rexpected(f) as a function of HTLEOS(f). For frequencies from 3 to 8 kHz, and for both ears, the measured slopes were markedly more negative than the slopes resulting from random errors of measurement. On average, the obtained slope was more negative than the simulated slope by a factor of 9.9 for the right ear and 14.8 for the left ear. EOS(f) and HTLfinal(f).To assess how the simulated correlations and slopes would be affected by the magnitude of the assumed jitter, the simulations were repeated with the jitter increased to an unrealistically high value of 7.6 dB. For frequencies from 3 to 8 kHz, and for both ears, the measured correlations remained more negative than the correlations resulting from random errors of measurement and the measured slopes remained markedly more negative than the slopes resulting from random errors of measurement. It can be concluded that the negative measured slopes are not solely a consequence of random errors of measurement in HTLth percentile for the CLB data and the 75th (best) percentile for the data of Flamme et al., as recommended by the authors (see below for more discussion of this point). The results are shown in EOS(f).A possible objection to the analysis used to derive the results shown in th percentile to represent longitudinal trends.Another potential problem is that the three databases discussed above were all based on cross-sectional data; longitudinal trends were inferred from those data, although the results of EOS(f). It should be noted that while There are only a few studies of longitudinal changes in HTLs for younger people with little noise exposure. One relevant study is that of A study with a similar design and the same exclusion criteria as EOS(f).Another relevant study is that of EOS(f).Finally, a longitudinal study of It can be concluded that, regardless of the reference database that is used, the data support the hypothesis that for frequencies where the NIHL at the end of military service is mild, exposure to noise during military service accelerates the subsequent progression of hearing loss.The results of the analyses support the hypothesis that for frequencies where the NIHL at the end of military service is mild or absent, exposure to noise during military service accelerates the subsequent progression of hearing loss. In contrast, for frequencies where the NIHL is moderate or severe at the end of military service, the prior noise exposure has no effect on or slows the subsequent progression of hearing loss. This is consistent with existing data, as reviewed in the introduction . These fSome limitations of the study should be noted. Firstly, the men studied were all claiming compensation for NIHL incurred during military service. This sample may not be fully representative of the general population of military veterans. Also, the sample studied was relatively small. It would be desirable to assess the hypothesis using a larger representative sample of military veterans.th percentile in Another limitation is that there was no control group of age-matched non-exposed men with similar demographics. Rather, the rate of change of HTL expected for each man in the sample was estimated using the 50The reason for the accelerated progression of hearing loss following the end of noise exposure when the hearing loss at the end of military service is mild or absent is not clear. A possible explanation comes from the concept of a “cochlear reserve”, as described in the introduction. Studies of animals have shown that a certain amount of damage to the OHCs can occur with little or no change in the threshold for detecting sounds . ConsistA common consequence of noise exposure is tinnitus . TinnituThe concept of the cochlear reserve probably applies also to the function of IHCs/synapses/neurons, but in a different way. Substantial damage to the IHCs, or to the synapses between the IHCs and the neurons that make up the auditory nerve, can occur with little effect on the detection threshold . ProbablOverall, these findings suggest that the cochlea has a certain “spare capacity” and can sustain some damage with only a small or no effect on the audiogram. However, once the reserve is sufficiently depleted, further minor damage associated with aging may produce a substantial worsening in the audiogram. It is also possible that depletion of the cochlear reserve is partly responsible for the frequent occurrence of problems in understanding speech in noise among former military personnel with normal or near-normal audiograms .Individual variability in the progression of hearing loss following the end of military service was substantial. This partly reflects errors of measurement of the HTLs. However, some individuals with little or no hearing loss at the end of military service showed a marked acceleration of the subsequent progression of hearing loss for most audiometric frequencies, while others showed little or no progression for any frequency. The origin of these large individual differences is unknown.The data and analyses presented in this paper were exclusively concerned with the effects of noise exposure during military service. Such noise exposure typically includes both intense impulsive sounds, such as rifle shots and the sound of artillery fire or mortars, and more steady sounds, such as vehicle and aircraft noise . It remath percentile and with those expected from several other databases. The results suggest that noise exposure during military service accelerates the progression of hearing loss for frequencies where the hearing loss is absent or mild at the end of military service, by about 1.7 dB/year on average for frequencies from 3 to 8 kHz, but has no effect on or slows the progression of hearing loss for frequencies where the HTL exceeds about 50 dB HL. Acceleration, when present, appears to occur over a wide frequency range, including 1 kHz, consistent with the data of This paper tested the hypothesis that for frequencies where NIHL at the end of military service is mild or absent, exposure to noise during military service accelerates the subsequent progression of hearing loss. In contrast, for frequencies where the NIHL is moderate or severe at the end of military service, the prior noise exposure has little or no effect on or slows the subsequent progression of hearing loss. The analysis was based on new longitudinal data obtained from 29 former military personnel, all men. Audiograms obtained at the end of military service were compared with those obtained at least five years later. Rates of change of HTL in dB/year were compared with those expected from


In this work, methylamine and acetamide are used as representatives of amine and amide groups, respectively. This new selection leads to significant improvements in the calculation of noncovalent interactions in the validation set.Recently, we reported a new approach to develop pairwise analytical corrections to improve the description of noncovalent interactions, by approximate methods of electronic structures, such as semiempirical quantum mechanical (SQM) methods. In particular, and as a proof of concept, we used the PM6 Hamiltonian and we named the method PM6-FGC, where the FGC acronym, corresponding to Functional Group Corrections, emphasizes the idea that the corrections work for specific functional groups rather than for individual atom pairs. The analytical corrections were derived from fits to B3LYP-D3/def2-TZVP (reference). PM6 interaction energy differences, evaluated for a reduced set of small bimolecular complexes, were chosen as representatives of saturated hydrocarbons, carboxylic, amine and, tentatively, amide functional groups. For the validation, the method was applied to several complexes of well-known databases, as well as to complexes of diglycine and dialanine, assuming the transferability of amine group corrections to amide groups. The PM6-FGC method showed great potential but revealed significant inaccuracies for the description of some interactions involving the –NH The development of corrections for the description of noncovalent interactions by semiempirical quantum mechanical (SQM) methods has attracted much attention in the last two decades. It is worth mentioning the work carried out by Hobza et al. ,2,3,4, tTruhlar, Gao, and their co-workers, implemented the polarized molecular orbital (PMO) method ,9,10,11,Significant contributions were also made by Thiel et al., who improved the semiempirical Hamiltonian through the ortogonalization-corrected methods OMx ,15,16 anIn general, the corrections included in the above studies for dispersion and hydrogen bonding interactions are modelled on potential functions, based on physically sound formulas and parameterized using quite large training sets, which when properly selected, can ensure wider applicability range. The above studies considerably improved the evaluation of noncovalent interactions using SQM methodology, but they still show significant deficiencies in some cases . Often tVery recently, we developed the PM6 Functional Group Corrections (PM6-FGC) approach  to corre2 groups in amines and, tentatively, in amides. We evaluated IPECs for the six different pair combinations of these molecules, considering orientations of the interacting molecules that emphasize the atom–pair interactions in the complexes. In our previous work , the corThe reference data for the fittings were obtained by calculations using Density Functional Theory (DFT), with the B3LYP functional ,28,29, iOur analytical pairwise corrections are parameterized by fits to a series of curves obtained by the difference between the IPECs calculated at the B3LYP-D3/def2-TZVP level and those computed with the PM6 method, following a strategy similar to that employed in the derivation of intermolecular potentials for dynamics studies ,38,39,402 group in amines and amides , which is one of the most successfully applied SQM methods. For this system, 50 independent parameters were fitted simultaneously. The parameters of the best fit are collected in the The methylamine molecule has four different types of atoms; therefore, the dimer exhibits ten different types of pairwise interactions. For the fits, we considered ten orientations that emphasize the different types of two-body interactions, as well as a cyclic configuration that facilitates the simultaneous interaction between most of the atoms (orientation 11). Four of these orientations are depicted in In orientation 2, an amine hydrogen of one of the molecules interacts with the nitrogen of the other molecule in a way that favors the formation of a hydrogen bond. As expected, this orientation leads to the deepest well among those considered in the present study. The B3LYP-D3 interaction energy is −15.4 kJ/mol at 2.3 Å . Both corrected methods, that is, PM6-D3H4 and PM6-FGC, reproduce the DFT IPEC quite well. The PM6 method underestimates the strength of the hydrogen bond, which is one of the well-known deficiencies of this method. The PM6-D3H4 method clearly overestimates the strength of the interaction in the well region for orientations 3, 4, and 5. Hobza and co-workers used the S66 database ,20 for tThe case of orientation 5 is particularly interesting. This orientation stresses the interaction between amine hydrogens, which is repulsive at the B3LYP-D3 level. The PM6-D3H4 method predicts a significant well depth, similar to that found for the ammonia dimer . Our metIn general, for the 11 orientations considered here, the performance of our method is quite good and the improvement over the PM6 and PM6-D3H4 is clear. This may be quantified by the values of the mean absolute errors (MAEs), which are collected in For acetamide, we defined five different atom types, as shown in For some orientations , the PM6-D3H4 method overestimates the well depth of the minima. In addition, and resembling the results obtained for the methylamine dimer, the PM6-D3H4 method predicts a significant minimum for the orientation in which amide hydrogens face each other , 0.47 kJ/mol (PM6-D3H4), and 0.18 kJ/mol (PM6-FGC). If we increase the energy range for the calculation of MAEs, the values for the PM6 and PM6-D3H4 methods increase significantly see , thus, fFor this complex, we considered 20 different orientations, which is the number of different types of pairwise interactions exhibited in this system. In 3–HCOOH complex in our previous work [For several orientations, the PM6-D3H4 curves show remarkable discrepancies with the reference IPECs. This is the case for orientations 1 and 6, in which the carboxylic carbon faces the nitrogen atom and the amine hydrogen, respectively. Resembling the results found in previous complexes, wherein hydrogen bonding can take place, the most striking result appears for orientation 9, in which the carboxylic hydrogen faces one of the amine hydrogens. This orientation is repulsive at the B3LYP-D3/def2-TZVP level, but the PM6-D3H4 method predicts a clear minimum (4.8 kJ/mol at an H⋯H distance of 1.9 Å). We found the same behaviour for the NHous work . As for 3NH2–CH4 complex, both corrected methods afford results in good or reasonably good agreement with the reference IPECs. The improvement of PM6-FGC over the PM6-D3H4 method is reflected in the values of the calculated MAEs . The remaining orientation corresponds to the most stable configuration of the complex, which facilitates the formation of a double hydrogen bond (orientation 37). 3NH2–HCOOH complex, The PM6-D3H4 method significantly overestimates the well depth for several orientations. This is the case for orientation 11, in which the carboxyl hydrogen attacks the carbon atom of the amide group. For this orientation, the PM6-D3H4 predicts a well depth 18.5 kJ/mol, whereas the DFT value is 2.8 kJ/mol. The PM6-FGC curve, with a well depth of 6.5 kJ/mol, also deviates significantly from the reference IPEC, although not as much as the PM6-D3H4 curve. Another significant failure of our method occurs for orientation 29, in which the carboxyl hydrogen faces one of the amide hydrogens. Although the PM6-FGC curve is repulsive, it is less repulsive than that predicted by the B3LYP-D3/def2-TZVP calculations. For this orientation, the PM6-D3H4 method shows a clear minimum, thus, resembling the behaviour found for other complexes /CBS benchmark values reported in ref. [qu-methylacetamide, were “CAN” and “HCAN”, respectively . Therefore, to try to solve these limitations, in the present investigation, we decided to use methylamine and acetamide as representatives, instead of ammonia. In addition, and with the purpose of exploring parameter transferability, we also considered the acetic acid molecule.We followed the procedure described in our previous work , where wSince in ref. , we selei and j refer to atoms belonging to different interacting molecules, and ijr is the interatomic distance between atoms i and j. The parameters ijA, ijB, ijC and ijD depend on the nature of the considered pair of atoms. The parameters ijA and ijC may be either positive or negative. In our previous work [ijD parameters to be integers. In this study, to get additional, although small, flexibility, these parameters were considered real (positive) numbers instead. ijr distances: ijs is a parameter that controls the strength of the damping for the interaction between atoms i and j, and ijd is the distance at which the cutoff function takes the value ½. As in our previous study, we set ijs = 10. The functional form of our corrections, i.e., Equation (1), was justified in our proof-of-concept work [The general expression for the noncovalent potential energy correction to the PM6 Hamiltonian is given as a pairwise sum of the form:ous work , we consept work . As showχ2:ix, iy) represents one of the N data points, a is the collective variable formed by the total number of fitting parameters and f  is the value of the model function at ix . The square of the difference between iy  and the corresponding model value, calculated with Equations (1) and (2), may be multiplied by a weighting factor (iw), assigned to each data point. The use of a genetic algorithm has the advantage of efficiently exploring the search space and provides near optimal solutions when the number of fitting parameters is large. Since genetic algorithms may lead to many solutions that can be equally valid, our corrections should be viewed more as whole functional group corrections, rather than as individual pairwise corrections. As already mentioned, the parameters were evaluated by fits to differences between the interaction energies calculated at the B3LYP-D3/def2-TZVP level and those computed with the PM6 method. The SQM calculations were carried out with the MOPAC2016 program . We usedBearing in mind the key role noncovalent interactions play in chemistry and biology, we recently presented a new approach, i.e., the PM6-FGC method, to improve the performance of SQM methods in the description of noncovalent interactions . The cen2 groups. For this reason, in the present study, we performed new parameterizations, using methylamine and acetamide as representatives of the amine and amide functional groups. The results of this work show a clear improvement over our previous parameterization and reinforce the importance of considering sufficient orientations of the interacting molecules in the reference database. We plan to extend the method to other functional groups relevant to biological compounds and implement the corrections in the MOPAC program. A Python script to calculate PM6-FGC corrections is available upon request.In our previous study , we used