This study aims to evaluate the experience and awareness of a hearing conservation program to explore its activation plan. Three focus group discussions were conducted with five health managers, five labor supervisors, and five workers. A single in-depth interview was conducted with a health manager. Since hearing loss has a significant influence on the quality of life of workers, all participants recognized the importance of management. Although the need for hearing conservation programs was acknowledged, the participants had negative views about their effectiveness. Most health managers have not been able to demonstrate tangible results from their efforts to solve hearing problems, and they have been unable to demand that their employers actively invest resources and personnel in solving or preventing hearing problems. The participants in this study did not entirely understand the hearing conservation program, negative comments suggested that it is impossible to eliminate noise sources from the workplace, and measures for noise reduction would reduce work efficiency. This study can be supplied not only as a basis for reidentifying the real problems of the hearing conservation program but also for the tailored implementation method of future hearing conservation programs at each worksite. Hearing loss causes communication problems, which can lead to problems such as accidents, loss of productivity, and social isolation ,2,3. TheWorkplace noise is one of the most common causes of hearing loss ,6. In KoA hearing conservation program is stipulated in rule 517 of the Occupational Safety and Health Standard to prevent hearing loss of workers in Korea . The heaDespite the regulations and related guidelines for workers exposed to noise, however, the number of diagnosed cases of occupational noise-induced hearing loss from special health examinations has increased every year in the last four years: 6684 cases in 2012, 7388 in 2013, 8428 in 2014, and 10,042 in 2015 [The implementation of a hearing conservation-related program in the workplace is an obligation of employers and can prevent and reduce the incidence of noise-induced hearing loss ,11,12. CThis study aims to evaluate the experience and awareness of the hearing conservation program to explore its activation plan. Specifically, we gathered opinions on experiences, problems, and facilitation methods of hearing conservation programs in the workplace through focus group discussions with workers, health managers, and labor managers to determine ways to improve hearing conservation programs.Qualitative research was executed using focus group discussions and in-depth interviews to evaluate the experiences and perceptions of hearing conservation programs. We used the consolidated criteria for reporting qualitative research (COREQ) using an in-depth interview or focus group discussion, as described below .This study was approved by the Institutional Review Board of Ulsan University Hospital (Project Number: 2018-07-004). All participants were informed about the purpose and process of the study and only those who agreed to participate joined this qualitative study.The research team consisted of nine persons. Two of the researchers have extensive experience in qualitative research, such as writing several theses and articles using the methodology, regularly attending qualitative research-related lectures and seminars, and teaching lectures. Seven of the researchers are either occupational and environmental specialists or have pervasive experience in occupational and environmental-related work and research, especially in noise problems. Four researchers are professors, three are residents of occupational and environmental medicine, and three are institution researchers.Purposive sampling was used to recruit research participants, no unique inclusion and exclusion criteria were set up, and participants were invited to provide detailed expert opinions and practical experiences on research topics. Five health managers, five labor supervisors, and five workers participated in the focus group discussion. A single in-depth interview was conducted with a health manager. The participant who was a health manager in a company with a relatively decent performance status of the hearing conservation program was selected for the in-depth interview. Separate interviews were conducted with participants who had successful experiences in the hearing conservation program. This interview design considered the possible influence of the successful experience of the program to the other participants in the focus group discussion.Researchers individually contacted and explained the purpose and content of the study to selected health managers and workers who agreed to participate in the study’s focus group discussions. The labor managers agreed to participate in the study with the cooperation of the Ministry of Employment and Labor and the Korea Occupational Safety and Health Agency. Consent was obtained from all research participants. No participant refused to participate in the study, nor did any drop out. The reflexivity, the possibility of responding to researchers’ preference, was evaluated to appear in the perspective of the research topic and purpose unlikely.Discussions and interviews were conducted using semi-structured guidelines developed through researcher discussions, reviewing primary precedent studies, and hearing conservation program descriptions . The guiAll of the focus group discussions and interviews were conducted in separately rented meeting rooms. Written informed consent was obtained from the participants after a verbal explanation of the study was given before the discussions and the interview proceeded. Two researchers executed discussions and interviews. One researcher has numerous experience in a focus group discussion facilitation, and the other has extensive research experience in hearing loss. The discussions and interviews took about two hours each. We attempted to elicit genuine opinions of the participants through sufficient ice-breaking time before the official focus group discussion and interviews. Additionally, the researchers tried to hide their opinions during data collection. They reviewed their prejudice or bias of the research before the execution of the focus group discussion and interviews. The discussions and interviews were recorded for transcription. A stenographer transcribed the content of focus group discussions and interviews, and the facilitator reviewed the content for any missing material. Additionally, the facilitator recorded a filed note during the process of the focus group discussions and interviews. The note was used to clarify the meaning of the participants’ statements.Content analysis of qualitative research was used for analysis . The anaUsing the accurate analysis method, one researcher repeatedly read the transcribed contents and memo and derived concepts, and then one of the other researchers reviewed the concepts. Afterward, the two researchers who participated in the primary analysis categorized similar concepts among the ones derived by agreement. All of the researchers then checked the results of the analysis, focusing on the framework of the whole category. The two researchers concluded the analysis after confirming the data saturation, which does not create any further concept. The research participants did not review the transcriptions and results of the data analysis, but experts in qualitative research, occupational and environmental medicine, and preventive medicine reviewed it.Five out of the six health managers participated in the focus group discussion, and one participated in the in-depth interview. The details of the socio-demographic characteristics of participants are shown in A total of 390 codes were derived from the analysis and categorized according to the awareness of the hearing loss problem, the overall perception of hearing conservation programs, the opinions of each component of the hearing conservation program, and the plan to vitalize the hearing conservation program. 1) Lack of voluntary interest in hearing loss problemsOverall, the participants acknowledged that they lacked interest in hearing loss. The health managers felt that workers were not interested in hearing problems, and the labor supervisors claimed that they focused on death and injuries rather than hearing problems. However, workers were more concerned about hearing problems than before.I know there is a problem because we tend to focus more on death, accident, and injury, but it is quite demanding for us just to invest all our capacity to solve the noise-induced deafness issue. To be honest, the noise-induced hearing loss is not death by post-industrial accident. (Labor Supervisor 5)2) Importance of hearing loss problemAlmost all the participants were aware that hearing loss was a significant health management issue. In particular, most health managers, labor supervisors, and workers have acknowledged that hearing loss is a crucial problem as it significantly deteriorates the quality of life of workers.I guess everything else too, but hearing is really related to the quality of life. There is a risk to any other disaster, but besides that, let us assume that I have been working in the heavy industry for 30 years (with hearing loss). And after retirement, my wife and I sit on the couch, but we can’t watch TV together. How low is the quality of life you have? Your family doesn’t have a conversation with you, with dad because he can’t hear you and understand you. When children watch a TV with dad, they tell him to watch it somewhere else because they can’t turn up the volume. So this guy is always lonely. He becomes a loner. It is not only just hearing loss, but also the quality of life itself gets totally worse. It does not compensate for any disability rating and rewards.3) Difficulty in solving hearing loss problemsThe health managers were, directly and indirectly, experiencing the problem that hearing loss was not easily exposed and difficult to improve with engineering solutions. Of this reason, the labor supervisors were not able to actively manage and supervise the delicacy of solving the hearing loss problem, and it was complicated for the workers to clarify the issues of hearing loss as they were aware of the trouble of enhancing the working environment in reality.It’s too expensive to upgrade it. I could only educate them (workers), give them some earplugs, and do some hearing tests.No one really cares about it, either they are big or small companies because it’s not on the surface level.(Worker 2)1) Priority issues of hearing managementFrom the health managers’ perspectives, hearing management problems were not a priority as the high volume of other tasks besides noise-related ones. On the other hand, the workers thought that hearing management was not at the top of the list as there are no immediate symptoms for hearing loss, and they have hearing aids for hearing deterioration alternatives.If you hurt your eyes, then you go blind and can’t see right away, so it becomes a problem. But with ears, wearing hearing aids solves the problem on the spot, so it’s not on the top of the list. Nobody talks about it, so nobody makes a problem of it.(Worker 2)2) Importance of workers’ hearing problems to health managersIt was substantial to the health mangers to prevent the occurrence of D1 workers with difficulty in hearing. If any incidence of D1 is verified, the level of supervision and supervision of the Ministry of Labor can be strengthened. Therefore, the employer and the health managers were concerned with preventing the D1 emergence.If the D1 comes out, the company is interested in it, but not with C1 because they think that it’s not that big of the deal or they think it could happen.3) Hearing conservation program not yet feasibleThe health managers felt that hearing conservation programs were inefficient as they had not witnessed evident cost-effectiveness from the previous investment. This experience discouraged them from demanding further resources from their employers actively. The labor supervisors, however, were worried that hearing loss problems were not well expressed in workplaces where hearing loss problems were serious, and hearing conservation programs were not applied well in paradoxically serious workplaces.Noise is our top priority because it is one of the themes of the work environment improvement. The noise is too loud, so there is a section for noise in the task objectives, and we also have a separate theme for it. There is no direct cost-effectiveness for the noise part, so it’s not so easy to touch upon that. And when you actually work on it, just simply saying "improve it!" won’t do much, so the noise section is the trickiest one.Hearing conservation programs were broadly divided into noise measurement, engineering control of noise, wearing the protective device, measuring of hearing threshold, health education, and documentation and effect evaluation.1) Noise measurementThe health managers were receptive to the importance of noise measurement. They were attempting to measure noise by themselves or outsourcing, and endeavoring to demonstrate the results in the form of noise signs visually. The noise was not measured; however, every time the process was changed, the noise mapping was hardly achieved.I put a noise sign up at a noisy facility, and I wrote down all the figures so that everyone is aware that ’Noise in this area is 90.1 decibels.’ I put it all over the noisy place. When I first put it up, some workers told me nothing good would come if the Ministry of Labor sees the over 90-decibel numbers visibly. Now, when the workers see it from a distance, they think ‘That field is over 100 dB. I should wear earplugs because it would be loud there.’ I did it anyway so that at least they could be aware of it and wear a protection device.2) Engineering control of noiseThe health managers recognized that engineering control is significant and pertained experience of solving noise problems at a low cost. Of cost problems, however, it was acknowledged that the engineering control could not solve all noise problems. Although the labor supervisors believed that engineering control is more economical from a broad perspective, they suggested that it would be difficult to share the engineering control between workplaces regarding intellectual property rights. Workers, nonetheless, speculated that engineering control of noise is impossible and had not expected the engineering control of noise via the experience of work efficacy diminution due to the noise reduction measure.As you said, it becomes an intellectual property for the establishment when they invest lots of money and get consulted to take measures. I think it’s a bit too much to force them to share that... (Labor Supervisor 3)We use a urethane hammer, and it cost far more than a sledgehammer because when you pound the urethane one a few times, it cracks. Besides the cost part, the urethane hammer does not work for us realistically. You have to give it a big hit. When you hit a sledgehammer, you hit it once, but with the urethane hammer... It means you have to pound 10, 20 times.(Worker 3)3) Wearing a protective deviceThe health managers expressed their frustrations that regardless of their strong recommendation to wear a protective device, such as earplugs, to prevent hearing loss problems, workers do not adequately wear even the protective device. There were some incidents where appropriate protective device wearing occurred via fitting tests. The workers wanted somewhat competent and individually suitable earplugs without inconvenience for wearing.Earplugs, I mean, people all have different shapes of ears. You put the earplugs deep inside of your ears. You put it in, hold it for 1 or 2 seconds, and let it go when they inflate. Some people can’t wear it for long if they put it in like that. So some people can’t put it all the way in, just around the hole. Cause it’s painful.(Worker 2)4) Measuring of hearing thresholdThe health managers did not perceive repetitive hearing screening as a fundamental measure to solve the hearing problem, and it was challenging to deal with workers who thought severely of hearing screenings that did not offer any countermeasures. The workers also had the unfortunate experience of receiving proper guidance and measures after hearing tests.The workers didn’t like it. They said they already know their ears are wrong, so why should they continue to do the same test. They complained that they would rather have a practical solution. No, I have not.(Worker 1)5) Health educationThe health managers stated that the training through the fitting test was effective, and the managers thought that training for the employer as well as the workers was necessary. The workers said, however, that the actual training was a rough reference to the importance of wearing earplugs and they did not receive any training in how to wear the earplugs. Therefore, they either read the manual or learned from their colleagues.The most motivating part of workers during the fitting tests was that they got to experience the effect of adequately wearing the device. We taught them that when they wear earplugs the way they are used to, the insulation of sound was only 5 to 10 dB. But they saw that the proper way of wearing the earplugs could create about 33 dB insulation of sound. We showed them that…There was no education, and nothing comes out when you actually get it from the company. They just say wear earplugs properly. That’s all.(Worker 4)6) Documentation and effects evaluationMost participants were not engaged in documentation and evaluating effects. Although some health managers supervised the hearing levels of workers individually, most of them relied on documentation from screening institutions, and workers relied on memories without recording test scores. Likewise, the effectiveness of hearing conservation programs has not been appropriately evaluated.(Do you know how much of your hearing level changed in the past?) I kind of do. I get the figures twice a year. Whenever I receive it, I think to myself ‘last year I was 45 dB, and this year it is 50 dB. It got a little worse.’ That’s how you think. I do not have separate documentation for the figures.(Worker 2)1) Willingness and attitude toward health manager’s hearing problem solvingNonetheless, it was suggested that health managers should have the willingness to solve the noise problem and that they should demonstrate proactive self-studying and endeavoring attitudes. There were also expectations that the health managers would be able to resolve the problem of hearing management more efficiently if they depend on the authority of law.They have to study; they need to study. … At least for the short-term thing, go to an educational center. No falling asleep, get all the questions you had, and just chat with professors. Say “I don’t know nothing, what do I do?” just go and ask and ask again to the experts who measure… "What do I do? I got no idea…"2) The necessity of management for subcontractors and small scale enterprisesThe labor supervisors acknowledged that the problems of subcontractors and small scale enterprises were more critical and noted that financial support and management for small scale enterprises are essential. The workers also thought that large companies should pay attention to the environment of subcontractors and small scale enterprises.The way you can enforce the domineering measure on small scale enterprises is that you first have to either assist them with the clean-business program or give them a monetary support measure. You can’t really cover all the workers working with noise in every establishment with prevention to follow up care. It’s not going to be like categorizing businesses by the noise level and give a different tailored solution. That is the biggest problem for me.3) Willingness to solve hearing problems of employersThe health managers and the labor supervisors considered the awareness and willingness of the employer were the most significant to solve the hearing problem.I think all business owners must have a willingness to change and to move everything forward. The hearing conservation program also requires the willingness of the top executive to actualize it.4) The necessity of strengthening the administrative and legal systemThere were several comments from the work managers and workers that it was necessary to legally enforce and regulate further hearing conservation programs for its poor performance. Additionally, it was suggested that a health manager should be a full-time employee for them to have enthusiasm and willingness, in genera, l to work on things such as noise problems.The reason the program doesn’t work is related to the hiring condition of the health manager. Managers who need to quit their job every two years can never make it work. Health manager? There are numerous temporary workers. It doesn’t let you do any work. I could never have a devotion to my company, and it’s not even about the work environment. It’s impossible to go to the field when you can’t even do the simple screening and cover all the incoming patients. You don’t get to visit the field until you quit your job.It means that if engineering control is not taken, it will be repeated, and even if the program is operated, it will be a program with the same information even after several years. So in that part, if the actual employers do not open their wallet, the countermeasures cannot be made, and I think that those are the parts where you need to regulate the law a little harder.(Labor Supervisor 4)5) Improving the hearing conservation program for a smooth applicationThe health managers claimed that easy to understand and use of the hearing conservation program is needed. The labor supervisors, however, believed that in order to revitalize the hearing conservation program, it is imminent to focus on advancing the practicality of the hearing conservation program rather than improving the contents itself. Moreover, the workers suggested the need for the program to consider the difficulties in the field.I wish there are realistic ways to easily access the programs or simplify or replace the procedures for health managers or labor supervisors in the field.Basically, no matter how well the hearing conservation program is made, it’s meaningless if the worker or employer in the field has a hard time to apply it or do a quick operation for it.(Labor Supervisor 4)This research is significant because the perception and experience of hearing conservation programs were examined from various points of view, including health managers, labor supervisors, and workers. In addition, national studies on hearing conservation programs are scarce in quantity, and we know of no studies confirming the views of the stakeholders on hearing conservation programs. A qualitative research methodology was utilized for the first time in Korea to hear not only the overall awareness of hearing loss problems and hearing conservation programs but also the specific components of hearing conservation programs. As the qualitative research methodologies are known for identifying problems that have not yet been elucidated and understanding experiences or perceptions that are not well represented by numbers , this stThe principal finding of this study was a lack of interest in hearing loss problems, and that the problem of hearing loss is not a top priority for health managers at the workplace. However, since hearing loss has a significant influence on the quality of life of workers, the health managers, labor supervisors, and workers all recognized the importance of management implementing a hearing conservation program. Therefore, for the invigoration of hearing conservation programs, it is necessary to convey that hearing loss problems are a priority in workplace health management and inform the industry of the immense problem . It is iAlthough the need for hearing conservation programs was generally acknowledged, there was a prominent negative perspective about their effectiveness. Most health managers have not been able to demonstrate tangible results from their efforts to solve hearing problems, and they have been unable to demand that their employers actively invest resources and personnel in solving or preventing hearing problems. However, one of the participants in this study who is performing well in the hearing conservation program showed that hearing loss problems could be minimized if the hearing conservation program is adequately performed with constant attention expressed. It is essential to actively share and promote the experience of a workplace that has successfully implemented a hearing conservation program to other workplaces ,18,19. AThe participants in this study did not understand the whole contents of the hearing conservation program. They were, however, aware of partial elements of the hearing conservation program, such as engineering control of the noise source, wearing hearing protection devices, fitness tests, and more. The result of the programs, the measurement of hearing thresholds, and their use in the audiometric database seem to be lacking. In particular, health managers need to re-measure noise when the process changes, but such mandatory procedures achieved insufficient performance. Moreover, the negative comments suggested that it is impossible to eliminate the noise source even in the case of workers, and measures for noise reduction would reduce work efficiency. Furthermore, most research participants were not involved in documentation and effect evaluation. It is necessary to perform proper training on each component of the hearing conservation program to benefit from the effects of the program .For practical application of the hearing conservation program, however, it is imminent to propose “application of a customized program at the workplace” by creating a program suitable for the size and the specific reality of the workplace rather than a theoretically complicated process. As many health managers have indicated, it will be necessary to develop and distribute a hearing conservation program that is easy to understand and activate. Therefore, it is necessary to develop and present examples of hearing conservation programs that are easy to apply and specific to the workplace.In addition to the improvement of the hearing conservation program itself, there was an emphasis on strengthening the willingness of the health manager and the administrative and legal system of the workplace. Specifically, it was suggested that employing a health manager as a full-time employee would enable him or her to manage the overall tasks of health care, including noise issues, with enthusiasm and passion. Moreover, it is necessary to consider offering incentives to the workplaces that grant authority to health managers. Some labor supervisors and workers mentioned that if the hearing conservation program is not appropriately performed despite these measures, the government will have to enforce and regulate the implementation of hearing conservation programs. Furthermore, as in previous studies highlighting the health inequalities in hearing loss , financiOne of the limitations of this study is that it only includes one health manager who has been successful in implementing a hearing conservation program. In future studies, it is necessary to include more people with successful experiences. The sharing and dissemination of successful hearing conservation programs will increase the awareness of effectiveness as well as the need for hearing conservation programs. Another limitation is that the entire transcriptions and the analysis content were not reviewed by the participants. Instead, qualitative research experts, occupational and environmental medicine experts, and preventative medicine experts reviewed the content to increase its validity.In this study, focus group discussions and an in-depth interview were conducted to review the experiences and perceptions of health managers, labor supervisors, and workers on hearing conservation programs. We found that the overall level of awareness of stakeholders on hearing conservation programs is not complete. In addition, this research shows that improvement of health managers’ attitudes, management of subcontractors and small business sites, employers’ willingness, and administrative and legal systems are important for the improvement of hearing conservation programs. This study can be supplied not only as a basis for reidentifying the real problems of the hearing conservation program but also for the tailored implementation method of future hearing conservation programs at each worksite.


Introduction: “Continuum” approaches to psychosis have generated reports of similarities and differences in voice-hearing in clinical and non-clinical populations at the cohort level, but not typically examined overlap or degrees of difference between groups.Methods: We used a computer-aided linguistic approach to explore reports of voice-hearing by a clinical group  and a non-clinical group . We identify semantic categories of terms statistically overused by one group compared with the other, and by each group compared to a control sample of non-voice-hearing interview data (log likelihood (LL) value 6.63+=p < .01; effect size measure: log ratio 1.0+). We consider whether individual values support a continuum model.Results: Notwithstanding significant cohort-level differences, there was considerable continuity in language use. Reports of negative affect were prominent in both groups . Challenges of cognitive control were also evident in both cohorts, with references to “disengagement” accentuated in service-users .Conclusion: A corpus linguistic approach to voice-hearing provides new evidence of differences between clinical and non-clinical groups. Variability at the individual level provides substantial evidence of continuity with implications for cognitive mechanisms underlying voice-hearing. In clinical settings, hearing voices  is typically associated with a diagnosis of schizophrenia , and explored the degree of overlap between groups in terms of the language used. We applied well-established analytical techniques from Corpus Linguistics , and to compare the groups both to each other and to a “reference corpus” of more general interview talk. We further investigated the dispersion of references to each aspect at the individual level across and within groups, to explore the degree of overlap between the two groups.N = 67) discussed their voice-hearing experiences with one of two interviewers trained in clinical and phenomenological interviewing. The samples – which had been collected previously as part of Durham University’s Hearing the Voice project  and 27 NCVHs : “spiritualist” participants reporting regular “clairaudient” voice hearing experiences, who had been recruited via the Spiritualist National Union. Developed from Woods et al. . Interviews typically lasted one hour (range: 24–124 min) and were transcribed verbatim according to a standard protocol. Users of Early Intervention in Psychosis (EIP) services were invited to take part if they (i) were aged 16–65We examined semi-structured interview data in which participants . The general categories are indicated by a letter and the sub-domains are numbered. Further subdomains indicate contrasting valence  and degree, as with the category “X3.2+”, which would contain the word “loud”, compared with “X3.2++”, which would contain “louder” . When applied to conversational data, the tool has a reported level of accuracy of approximately 91%  to determine the language features that occur with unusually high frequency (“key” or “overused”) in one dataset compared to another. “Key” features are taken to be characteristic of that dataset. We employed the UCREL Semantic Analysis System (USAS) tagger in the online corpus software Wmatrix Rayson,  to seman Rayson,  and refep < .01.Log Likelihood (LL) – a measure of statistical significance sensitive to the size of the evidence that a difference exists Dunning, . Our finhttp://cass.lancs.ac.uk/log-ratio-an-informal-introduction/). This indicates the degree of difference between relative frequency values. To focus on the semantic domains that demonstrated the most difference, we set a minimum threshold of 1.0, which indicates that the relative frequency for a dataset is at least twice that of the comparison data.Log ratio – a measure of effect size, i.e., the binary log of the ratio of relative frequencies in the two datasets :E2- Dislike E4.1- Sad E5- Fear/shock E6- Worry .Semantic domains that emerged as key in these comparisons were grouped according to the aspects of the voice-hearing experience that they were used to describe see . These gAffect, Control, Meaning-Making and Sensory Input. In our data, the groupings that are subsumed under each of the four themes relate to the following aspects of the experience of voice-hearing  indicating under which keyness comparison each semantic domain was found to be overused, and for which participant group. Our groupings were derived from this list.Our keyness analyses generated a total of 148 overused semantic domains. The table provided in the Affect, Control, Meaning-Making, and Sensory Input, and will be the focus of our analysis : “Sad”  and “Fear/shock”  , “Foolish”  and “Inability/Unintelligence” . Correspondingly, two semantic domains that make up the Positive affect grouping were found to be overused by NCVHs compared to service-users: “Content”  and “Confident” .The ic”) see . In bothAffect groupings is displayed in Negative affect, individual values for 44 of the 67 participants (65.7%) overlap (between 0.00 and 0.44). Similarly, 49 (73.1%) participant values for terms relating to Negative evaluations of self overlap. There is also overlap in the relative frequency values for Positive affect terms, although 16 CVHs (40%) do not use any terms in this grouping. In summary, while CVHs are more marked in their use of negative evaluative terms (for affect and the self), there is a notable overlap between the two cohorts.The distribution of relative frequencies across individuals for each of the three distract myself”) was overused by both CVHs and NCVHs compared to the reference corpus. Effect size values indicate a larger overuse in CVHs: 4.82 compared with 2.35 for NCVHs. The direct comparison showed that this semantic domain was also overused by CVHs when compared to NCVHs, along with two other domains relating to Disengagement: “Avoiding”  and “Speech: Not communicating”  (see Command over (the voices) were overused by NCVHs compared to CVHs: “Using” , “Open Finding; Showing” , and “Giving” . This was also the case for Developing understanding, which includes “Education”, “Learning” , and “Ability and intelligence” .The semantic domain “Inattentive”  see . In contDisengagement grouping as a whole (Command over (the voices) and Developing understanding , “Concrete/Abstract” , “Important”, “Evaluation: True” , and “Linguistic Actions, States and Processes; Communication” . However, an examination of these terms in context shows that both groups reflected on the “relevance” of their voice-hearing experiences to other aspects of their lives, evaluated the content of their voice-hearing experiences in terms of “prominence”, and described what the voices say as “messages”.The Meaning-making terms are particularly characteristic of the spiritualist interviews.The dispersion of values for this theme showed an overlap in the relative frequency values for NCVHs and CVHs up to a value of 0.35 , suggestStrength were overused by NCVHs compared to CVHs, i.e.: “S1.2.5++ Tough/strong”  and “S1.2.5+++ Tough/strong” . These terms tended to be used in reference to the intensity of the voices, as in “So at the times of real severe emotional upset that external voice seems to come in stronger”.Four semantic domains relating to sound were overused by both groups when compared with the reference corpus, reflecting the focus of some of the interview questions: “Sensory: Sound” , “Sound: Quiet (X3.2-)” , “Sound: Quiet (X3.2–)”  and “Sound: Loud” . Effect size values show a similar degree of overuse for “Sound: Quiet (X3.2-)” and a greater overuse by CVHs for the other domains. The direct keyness comparison showed that “Sound: Loud” was overused by CVHs compared to NCVHs. In contrast, the semantic domains included under Loudness , and “Sensory: Smell”. The latter was also overused in both cohorts when compared with the reference corpus, with a higher effect size value for CVHs.Participants were also asked about the phenomenological aspects of their voice-hearing beyond the perception of sound. Three semantic domains grouped under Debates around the “psychosis continuum” have highlighted areas of similarity and difference between clinical and non-clinical populations , but also used much more frequently by CVHs when directly compared with NCVHs, along with terms related to Negative evaluations of the self. In contrast, NCVHs used more Positive affect terms, consistent with previous research reporting the differences in emotional valence in the responses of clinical and non-clinical groups  cognitive models of voice-hearing where meta-cognitive appraisals – rather than underlying sensory atypicalities – mark out the main differences between help-seeking and healthy individuals  and “But they are relevant to the person” (NCVH). However, they occur much more frequently in the interviews with NCVHs. Similarly, we have shown that there is a qualitative difference in how participants discuss the intensity of their voice-hearing  but that overall cohort differences may actually only reflect a few key individuals. In these instances, we should be wary of overstating the relationship between such a feature and clinical status, and consider whether this indicates something of the phenomenology of the individuals’ experience, or – as researchers have observed . Similarly, the mean ages of the NCVHs (58.0) and CVHs (28.7) could have implications for how voice-hearing is experienced and reported by participants. The participant groups – on average – belong to the same “life stage” Labov,  and so wSupplementary Materials) might be relevant to exploring other aspects pertinent to the potential need for care. For example, terms relating to alcohol and recreational drugs were overused by CVHs, while terms related to the sense of professional identity that is associated with voice-hearing were overused by NCVHs.In addition to investigating differences in clinical and non-clinical spiritualist voice-hearers, further research should also consider the extent to which self-reports are shaped by such interpretive frameworks. While our analysis focused on semantic domains that we could relate to four key themes in the discussion of a psychosis “continuum”, some of the remaining key semantic domains similarities and (dis)continuities within and across clinical boundaries. In combining keyness analysis with an exploration of dispersion at the individual level, we have been able to report differences and some similarities between voice-hearing groups, as well as presenting measures that identify and document aspects of the voice-hearing experience that are variously “continuous” across our clinical and non-clinical groups.Click here for additional data file.


The frequency and causes of underdiagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP) are uncertain. We aimed to assess the frequency and electroclinical features of pre-referral CIDP underdiagnosis and the duration of delay prior to diagnosis and treatment initiation in a tertiary specialist clinic.We retrospectively investigated 60 consecutive patients attending our Inflammatory Neuropathy Service, between 2015 and 2019, with a final diagnosis of treatment-responsive definite/probable CIDP. We reviewed the clinical and electrophysiological data in light of European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) guidelines and determined the frequency, causes and delay in diagnosis of CIDP.An initial alternative diagnosis to that of CIDP had been made in 68.3% (41/60) of patients. The commonest alternative diagnosis was of Guillain–Barré syndrome (GBS) in 23.3% (14/60) patients. Non-GBS underdiagnoses  mainly consisted of genetic neuropathy , diabetic neuropathy  and chronic idiopathic axonal polyneuropathy . Non-GBS underdiagnoses were predominantly due to non-recognition of proximal weakness (70.4%), multifocal deficits (18.5%) or proprioceptive loss (7.4%). Electrophysiological misinterpretation was contributory to pre-referral non-GBS underdiagnoses of CIDP in 85% of patients. Mean diagnostic delay in patients with non-GBS underdiagnoses of CIDP was of 21.3 months (range 2–132 months).Underdiagnosis of CIDP is frequent and may lead to significant diagnostic and treatment delay. We suggest that lack of comprehensive and precise attention to typical electroclinical features of CIDP and its diagnostic criteria at the time of initial evaluation are equally contributory to underdiagnoses. Chronic inflammatory demyelinating polyneuropathy (CIDP) is a progressive motor and/or sensory neurological condition affecting peripheral nerves. The prevalence of CIDP ranges between 1.6 and 7/100,000 population and may vary based on the diagnostic criteria used . CIDP caThe issue of overdiagnosis of CIDP i.e., patients receiving an erroneous diagnosis of CIDP and treated as such, has been the focus of attention in recent years. Potential causes of overdiagnosis with a wide range of alternative diagnoses have been studied by a North-American group . The delWe aim to ascertain, the frequency and electroclinical features leading to underdiagnoses of CIDP prior to attending a tertiary specialist neuropathy clinic i.e., pre-referral underdiagnoses, and the duration of resulting diagnostic and treatment delay in patients with treatment-responsive CIDP.We retrospectively reviewed our electronic institutional records of all patients with a diagnosis of CIDP attending our Specialist Inflammatory Neuropathy Service, Queen Elizabeth Hospital, Birmingham, UK. Sixty patients fulfilling the electroclinical diagnostic criteria of CIDP as per European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) Guidelines, for “definite” or “probable” CIDP , and havTreatment response was defined by a 1-point improvement of the Overall Neuropathy Limitation Score (ONLS) , 8, exceDetailed clinical records for each patient were reviewed for demographics, presenting complaints, examination findings, initial pre-referral diagnoses, and electrophysiological reports. Cerebrospinal fluid (CSF) examination and nerve imaging were performed at different times in the disease course and at different centres and were excluded from the current analysis.We calculated the frequency of pre-referral diagnosis and alternative diagnoses other than that of CIDP. To calculate the frequency of pre-referral underdiagnoses, delay to final diagnosis of CIDP and delay to receive first treatment, we excluded cases of acute or subacute onset, initially diagnosed with Guillain–Barré syndrome (GBS) or subacute inflammatory demyelinating polyradiculoneuropathy (SAIDP), as we considered these were due to unexpected clinical progression rather than diagnostic error.For each patient, we performed a detailed review of clinical records to ascertain the predominant clinical feature supporting the diagnosis of CIDP. We focussed on four common clinical features of CIDP based on EFNS/PNS criteria  which coFor each patient, we reviewed pre-referral electrophysiological studies for the actual data and waveforms, as well as the available interpretation and conclusion. We requested repeat of the electrophysiology studies at our institution . We then, independent of all reports, established fulfilment of EFNS/PNS criteria. Hence, we concurrently also identified the omissions and inaccuracies in the clinical neurophysiologist’s reports which had contributed to underdiagnoses. We focussed on 4 points derived from EFNS/PNS criteria  as previThere were 19 females and 41 males. Mean age was 61.7 years (range 24–86). Fifty patients were referred by neurologists, one by a neurophysiologist, three by general physicians and six by other specialists, after initial assessment. Fifty six (93.3%) had “definite” CIDP and four (6.7%) had probable” CIDP. Forty nine out of sixty (82%) patients had typical CIDP sub-type, 8/60 (13.3%) had atypical LSS variant, 2/60 (3%) had atypical pure motor variant, and one had sensory ataxic variant  received a pre-referral diagnosis of CIDP. Forty one of the 60 patients (68.3%) had received an alternative pre-referral diagnosis other than that of CIDP see Fig. . The mosTwenty seven out of 60 (45%) patients, at the time of pre-referral assessment, had non-GBS underdiagnoses. The most frequent non-GBS underdiagnoses was that of genetic neuropathy in 8/27 patients (29.6%). All patients with a pre-referral diagnosis of genetic neuropathy had genetic testing for CMT, HNPP and, if negative, our institutional CMT gene panel which includes MPZ and GJB1, as part of diagnostic work up. Two patients had genetically confirmed CMT1A, one had a genetically confirmed MPZ mutation, and the remaining five had negative genetics. However, the three patients with genetically confirmed CMT were diagnosed with “definite” co-existent CIDP in view of rapid recent deterioration, proximal weakness and proprioceptive sensory loss, electrophysiological features of acquired inflammatory neuropathy , and objective response to immunotherapy. The remaining five patients, for their part, all had CIDP clinically and electrophysiologically.Five out of 27 (18.5%) patients had a pre-referral diagnosis of non-CIDP neuropathies of diabetes. This included diabetic polyneuropathy in 4 (14.8%) and diabetic lumbosacral radiculo-plexus neuropathy in 1 (3.7%). In 4/27 (14.8%), the pre-referral diagnosis was one of chronic idiopathic axonal polyneuropathy (CIAP). Vasculitic neuropathy was the initial diagnosis in 1/27 (3.7%), compressive focal entrapment in 3/27 (11.1%), toxic neuropathy in 1/27 (3.7%), paraprotein associated neuropathy, considered unrelated to CIDP, in 1/27 (3.7%), and Lyme’s disease with polyradiculopathy in 1/27 (3.7%). Non-neuropathic conditions were initially diagnosed in three patients (11.1%): stroke in one and CNS inflammatory disease in two.We found that 16/19 (84.2%) patients with pre-referral CIDP diagnoses had typical clinical features of CIDP as per EFNS/PNS criteria. Two patients (10.5%) had atypical pure motor weakness, and one (5.2%) patient had atypical LSS with multifocal sensori-motor symptoms. In comparison, 19/27 (70.3%) patients with a pre-referral non-GBS underdiagnoses had typical clinical features of CIDP including proximal weakness or loss of proprioception. Seven patients (25.9%) had atypical LSS with multifocal sensori-motor symptoms and one (3.7%) had atypical sensory ataxic CIDP. Hence, although LSS was more frequent in the underdiagnosed than the correctly diagnosed group, this did not reach statistical significance, possibly due to small numbers included .In 27 patients with pre-referral non-GBS underdiagnoses, the main clinical features in favour of CIDP, which might have been discounted at the time of pre-referral assessment, were: proximal weakness in 19/27 (70.4%), multifocal motor and sensory deficit in 5/27 (18.5%), proprioceptive sensory loss in 2/27 (7.4%) and tetraparesis in 1/27 3.7%)  patients with pre-referral non-GBS underdiagnoses, electrophysiology reports were contributory to underdiagnosis, as 3 of the 4 electrophysiology points, derived from EFNS/PNS criteria as detailed in “The mean delay in final diagnosis of CIDP, in the 27 patients with a pre-referral non-GBS underdiagnoses, was of 21.3 months (range 2–132 months); and mean delay to initiation of first attempted treatment for CIDP was 22.4 months (range 0–134 months). In comparison, for 19 patients with a pre-referral diagnosis of CIDP, there was no delay in diagnosis and initiation of first attempted treatment.We investigated the frequency and causes of pre-referral underdiagnoses of CIDP in consecutive patients attending our specialist inflammatory neuropathy service, and also determined the diagnostic and treatment delay. This aspect of underdiagnoses in treatment responsive CIDP has been explored rarely , 5. To tIn our cohort, 23.3% cases had a pre-referral diagnosis of GBS which was corrected to acute-onset CIDP. In comparison others have reported acute-onset CIDP cases to be around 16% . As thisForty-five percent of patients had a pre-referral erroneous non-GBS underdiagnoses of non-inflammatory neuropathy, comparable to previous studies , 15, 16.Our findings of CIDP co-existent with genetic neuropathy is in line with previous studies –19. ThesIn 85% of pre-referral non-GBS underdiagnoses, electrophysiology technical reports and their interpretations were contributing to the underdiagnoses. This may be, in part, due to non-inclusion of specific EFNS/PNS criteria derived parameters  as in thAnother reason for CIDP underdiagnoses can be potential lack of coordination between Neurologists and Neurophysiologists prior to the referral to the specialist centres. Albeit, in particular to the United Kingdom, electrophysiology is performed and reported in the overwhelming majority of cases by clinical neurophysiologists following referral from general physicians, Neurologists and other specialists. Hence, there could be a difference of opinion in interpretation of clinical and electrophysiological findings between different specialists. In this setting, the electrophysiology reports become essential for decision-making.Our findings also point to the suggestion of lack of interest in existing EFNS/PNS Guidelines for inflammatory neuropathy, as demonstrated by a European Study Group on Guidelines for Neuropathy . This hiCIDP underdiagnoses, may lead to quite wide-ranging delay in appropriate diagnosis and offering immunotherapeutic treatment as shown in our study, in line with previous studies , 5. MoreOur study has some limitations, including its single centre and retrospective design as well as limited number of patients included. We did not consider the diagnostic consequences of CSF protein levels, of MR imaging or somatosensory evoked potentials (SSEPs) in this study as we aimed primarily to look at the clinical and electrophysiological features which contributed to the underdiagnoses of CIDP prior to the referral to a specialist neuropathy clinic. Future studies, focussing on these additional parameters can further delineate the understanding of underdiagnoses in patients with CIDP. However, we believe that despite above-mentioned limitations, this study offers a perspective on the important clinical and electrophysiological features leading to CIDP underdiagnoses which can be addressed.In conclusion, CIDP remains a rare disorder causing significant disability and impairment of quality of life. It is, however, most importantly treatable, which makes underdiagnoses and diagnostic delay highly undesirable. In view of our results, a focus of future disease guidelines and training on the frequently overlooked important clinical and electrophysiological aspects of the disease, appears essential for optimal care for patients with CIDP.


The standard therapy for patients suffering from sensorineural hearing loss is cochlear implantation. The insertion of the electrode array into the cochlea, with potential mechanical trauma and the presence of this foreign body inside the cochlea, may lead to free radical formation and reduced blood perfusion of the cochlea which can result in a loss of residual hearing. Studies have suggested that a particular combination of the antioxidants vitamins A, C and E as well as the vasodilator magnesium (together: ACEMg) may protect the residual hearing.The potential protective effect of ACEMg on residual hearing preservation in cochlear implant (CI) patients was investigated in a single-centre, randomized, placebo-controlled, double-blind phase II clinical trial. CI candidates with some residual hearing in low frequencies receiving MED-EL implants of different FLEX electrode array lengths were treated with ACEMg tablets or placebo respectively 2 days preoperatively and up to 3 months postoperatively. The study objective was to demonstrate that ACEMg is more efficacious than placebo in preserving residual hearing during cochlear implantation by comparing the hearing loss (change in hearing thresholds at 500 Hz from baseline) 3 months after the first fitting between the two treatment groups and to investigate the treatments’ safety.Fifty-one patients were included in the study, which had to be terminated before the recruitment goal was reached because of IMP-resupply mismanagement of one partner. In the intention-to-treat population, 25 patients were treated with ACEMg and 24 patients with placebo. The mean hearing loss at 500 Hz was (± 15.84) 30.21 dB (placebo) or (± 17.56) 26.00 dB (ACEMg) 3 months after the initial fitting. Adjusting the postoperative hearing loss for the baseline residual hearing, planned electrode length and surgeon results in 8.01 dB reduced hearing loss in ACEMg-treated patients compared to placebo-treated ones. The safety analysis revealed that ACEMg was generally well-tolerated with adverse event frequencies below the placebo level.This is the first clinical trial investigating a drug effect on residual hearing in CI patients. These first-in-man data may suggest that a perioperative oral administration of ACEMg is safe and may provide protection of residual hearing in CI patients.2012-005002-22. Registered on 6 December 2013. Funding: European Commission FP7-HEALTH-2012-INNOVATION-2.EU Clinical Trial Register No.  The cochlear implant (CI) is the standard treatment for uni- and bilateral severe and profound sensorineural hearing loss, both in adults and children. Around 600,000 deaf individuals have already received cochlear implantations worldwide . AudibleThe whole frequency range of the acoustic signal is split into different frequency bands and allocated to the different electrode contacts, mimicking the physiological tonotopic organization of the cochlea . As speen = 22) [Even though the preservation of the residual hearing is possible, however, the preservation rates achieved are not satisfactory. Substantial acoustic hearing loss (mean threshold increase of > 30 dB) is reported in 13% of cochlear implant patients receiving electric-acoustic stimulation (EAS) . A modern = 22) , and minn = 22)  and for n = 22) . Suhlingn = 22) .The insertion of the electrode array into the cochlea has been shown to cause trauma to inner ear structures such as the basilar membrane, osseous spiral lamina and modiolus, and cascading molecular effects such as inflammation and oxidative stress , 10.The loss of residual hearing after cochlear implantation is, as age-related hearing loss and noise-induced hearing loss, closely linked to the oxidative stress which is based on the formation of reactive oxygen species (ROS) . The freA meta-analysis aimed to evaluate randomized clinical trials to determine the effect of antioxidant supplementation on the auditory threshold in sensorineural hearing loss in patients of different age groups shows that there are no antioxidative therapies to preserve residual hearing after cochlear implantation .The PROHEARING clinical trial  is the first trial in humans to assess the efficacy of the antioxidative vitamins A, C and E and the vasodilator magnesium to reduce hearing loss caused by cochlear implantation in CI patients with residual hearing.This was a randomized, placebo-controlled, double-blind phase II clinical trial. The primary objective was to demonstrate that ACEMg is more efficacious than placebo in preserving residual hearing during cochlear implantation by comparing the hearing loss (air conduction hearing threshold postoperatively minus baseline threshold) at 500 Hz 3 months after the first fitting. For this purpose, cochlear implantation candidates with low-frequency residual hearing were recruited. Treatments (ACEMg or placebo) were administered orally for 106 days. Patients were followed up 12 months post first fitting which is approximately 13 months postoperatively. The study was registered (EudraCT-No.: 2012-005002-22), and as demanded by the National Institute for Health and Clinical Excellence for clinical research publications to allow greater transparency of the study methods and measures used , the detStudy candidates were aged 18 years and older and suffered from pure/isolated cochlear-related hearing loss. This was proven with an objective audiological test battery before implantation. They had no or only little benefit from conventional hearing aids, defined as preoperative auditory speech understanding of less or equal to 60% in Freiburger monosyllables at 65 dB sound pressure level (SPL), best aided in the ear to be implanted. Their air conduction thresholds had to be better or equal than 85 dB hearing loss (HL) at 125 Hz, 90 dB HL at 250 Hz and better or equal than 95 dB HL at 500 Hz in the ear to be implanted. All patients received within routine CI surgery a Concerto or Synchrony implant from MED-EL  see the “” sectiont test with a two-sided type I error rate of 5%. Under these assumptions, 150 patients per treatment group were calculated to be necessary to achieve a power of 80%.The initial sample size calculation of this trial was based on historical data form the Hannover Medical School Department of Otolaryngology. In patients receiving different electrode lengths, a change in hearing thresholds at 500 Hz from baseline to 3 months after the first fitting (FF) of 15.6 dB with a standard deviation of 15.5 dB has been observed. Assuming equal standard deviations for ACEMg- and placebo-treated patients and a difference in change of hearing threshold between the treatment groups, the sample size calculation was conducted using a two-group Due to recruitment difficulties caused by the inclusion and exclusion criteria, which may have been too stringent, the sample size target was reduced to 70 patients per group in a subsequent amendment resulting in a power of approximately 50% under the initial assumptions. However, for this phase II trial, the reduced sample size was judged acceptable to at least generate a signal whether ACEMg offers a promising treatment concept for the protection of residual hearing in CI patients .Patients were randomized 1:1 to ACEMg or placebo. The randomization was stratified by the length of the electrodes (short (= 16 and 20 mm) vs. medium (24 mm) vs. long (28 mm) as planned preoperatively . Randomization was performed centrally using a web-based randomization tool. For details, please see .dl-α-tocopherol acetate; 267 mg) and magnesium  , vitamin C , vitamin E  starting 2 days before CI surgery. The study medication was also taken preoperatively at the day of surgery and after surgery for 103 further days.To quantify compliance with the study medication, serum vitamin E levels were measured in all randomized patients before, during (at surgery and 4 weeks postoperatively) and after the treatment period (month 3). Moreover, patients returned their treatment kits to the study site and provided information on their compliance via a short, self-administered questionnaire.Patients under ACEMg treatment are only classified as compliant , if their vitamin E level 4 weeks postoperatively was ≥ 20 μg/ml.Patients in the placebo group with postoperative vitamin E levels ≥ 20 μg/ml were judged as non-compliant to the study procedures, since they agreed with their informed consent not to use daily multi-vitamins or other supplements during the course of the study, but show vitamin E levels that are unrealistic without vitamin supplements.Additionally, patients were classified as non-compliant if they state in a questionnaire a non-compliance > 50%, and/or if the returned treatment kits contain > 50% of study medication, whereas missing bottles were considered as full bottles.Surgery was performed by nine experienced otosurgeons at Hannover Medical School. The technique was described previously . Based oThe primary objective was to compare the change in hearing thresholds at 500 Hz from baseline to 3 months after FF between the ACEMg- and placebo-treated groups.To detect the frequency-specific acoustic hearing thresholds, air conduction thresholds were measured using a calibrated audiometer according to DIN EN 60318. The test method follows DIN ISO 8253 with headphones for air conduction and headset for bone conduction. Tested frequencies were 125, 250, 500 and 750 Hz, and 1, 2, 4 and 8 kHz. Pure-tone audiometer limits were 95 dB at 125 Hz, 100 dB at 250 Hz, and 110 dB at 500 to 1500 Hz. All subjects underwent pure-tone air conduction audiometry preoperatively, at the first activation and 3, 6 and 12 months after the first fitting.To determine the frequency-specific hearing loss, the difference between the preoperative threshold level and the respective threshold measured at each postoperative time point was calculated.Four to 5 weeks after cochlear implantation, the audio processor OPUS 2 or DUET2, SONNET or SONNET EAS  was first fitted in all patients.The intention-to-treat (ITT) population consists of all randomized patients who took the study medication at least once. Patients were analysed as randomized independently of their real treatment (ACEMg or placebo).The per-protocol (PP) population comprises all patients complying with the protocol, i.e. patients who were eligible, received the treatment they were randomized to, were compliant to the study medication (see above) and procedures and had an outcome assessment at the respective time points.In the safety population, all patients were analysed who received at least one dose of the study medication (verum or placebo). Patients were analysed as treated.The primary analysis was performed in the ITT population and was conducted as an ANCOVA model  including the treatment (ACEMg or placebo), the baseline residual hearing at 500 Hz, the surgeon and the anticipated electrode length as covariates. The dependent variable was hearing loss at the implanted ear at 500 Hz 3 months post first fitting (hearing loss = 3 months post first fitting threshold minus 1–2 days preoperatively measured threshold) measured by air-conducted pure-tone audiometry. The frequency 500 Hz was chosen because it is the most important frequency for use of residual hearing, e.g. for voice recognition and speech in noise enhancement. If the patient reached at 500 Hz, the upper air-conducted detection limit of the audiometer (110 dB) without hearing, the measurement was set to 120 dB. Missing values were replaced by worst possible value per frequency (i.e. upper detection limit + 10 dB).n = 70 verum and n = 70 Placebo) should have been enrolled [Based on the power calculation 140 patients . Based on compliance measurements N = 11 (ACEMg) and N = 12 (placebo), patients were included in the per-protocol population (PP set)  measured by air-conducted pure-tone audiometry in the ear with a cochlear implant.p = 0.3468, Table In the placebo group, the mean hearing loss (mean ± SD) was increased by 30.21 (± 15.84) dB whereas in the ACEMg group, the mean hearing loss increase was 26.00 (± 17.56) dB. The superiority of ACEMg over placebo in preserving residual hearing during cochlear implantation could not be concluded because the 95% confidence interval for the difference in hearing loss between the ACEMg and placebo groups derived from the ANCOVA model used for primary analysis  includes zero  is tremendously lower than in patients receiving a Flex 24  or a Flex 28 . Statistical analyses revealed a significantly lower loss of residual hearing in Flex 20-implanted patients compared to those receiving a Flex 24 or 28 . The shorter the used electrode, the smaller is the hearing loss in this study. However, as secondary findings, these results are merely exploratory and do not allow causal inference because electrode length was not randomly assigned, but chosen preoperative by the surgeon. Out of the 49 patients receiving a CI, 29 were implanted by one surgeon (surgeon 2) and 20 patients were implanted by 8 other surgeons  even though patients being implanted by surgeon 2 exhibited a 2.03-dB lower mean hearing loss than patients being implanted by the other surgeons  of 11.25 ± 12.50 dB in individuals implanted with a Flex 20 or Flex 16  less or equal to 65 dB or (ii) larger than 65 dB.Subgroup results regarding sex are in line with the primary analysis results (data not shown). The treatment effect estimates in both subgroups did not differ significantly from 0. Thus, the primary analysis results interpretation did not change, and no inferential conclusions could be made.The treatment effect estimates for ACEMg vs. placebo in the young and old subgroup were contrary. While in the subgroup of patients of less or equal to 55 years, ACEMg is estimated to be superior to placebo (8.24 dB lower hearing loss in ACEMg than in placebo), in the subgroup of patients older than 55 years, placebo is estimated to be superior over ACEMg (4.56 dB lower hearing loss in placebo than in ACEMg). However, both estimates did not differ significantly from 0 Table .Table 7Adjusting the primary analysis model for age (either as a continuous variable or a binary variable) did not change the analysis results regarding the treatment effect, and the estimated interaction term does not differ significantly from 0 , which indicates no perseverance of the observed difference 3 months post first fitting . The outcome of two AEs was recovered with a sequel (hypertension and upper limb fracture) while the status of one AE remained unknown at database closure.In total, 29 adverse events (AE) were registered, 14 of which were serious (supplement 7). Most adverse events were of grade 1 (68.9%). 10.3% and 17.2% were of grades 2 and 3, respectively. One event (3.4%) was of grade 4. No grade 5 adverse events were documented. Patients recovered completely from most AEs  than in the ACEMg group .The number of both non-serious and serious adverse events (SAE) was numerically higher in the placebo group (n = 15) than in the ACEMg group (n = 8). Finally, the number of AEs that were assessed as possibly causally related to the study medication  by the reporter was also higher in the placebo group (n = 10) than in the verum group (n = 4).Also, the number of AEs that resulted in the withdrawal of the study medication was numerically higher in the placebo group  of the planned sample size of 140.Nevertheless, the analysis of the primary objective in the recruited ITT population showed that the mean hearing loss measured at 500 Hz 3 months post first fitting compared to baseline in the placebo group was 30.21 (± 15.84) dB whereas in the ACEMg group, the hearing loss was 26.00 (± 17.56) dB. There was no statistically significant difference, but a 4.15-dB smaller mean hearing loss was observed in the ACEMg-treated patients compared to the placebo group. Clinically, in general, a difference of 4.15 dB in hearing ability is a relevant improvement. This tendency of residual hearing preservation 3 months after the first fitting was still detectable 1 year after the implantation with 36.25 dB mean hearing loss in patients receiving placebo and 29.80 dB mean hearing loss in ACEMg-treated patients, even though the main amount of radicals is released immediately after implantation. This suggests that the initial intake of ACEMg within the first 3 months after the first fitting may have a prolonged protective effect on residual hearing. As in the placebo group, the hearing loss was ongoing in the ACEMg group within the first 12 months after the first fitting. For the ACEMg group, some analysis suggested a lower extent of hearing loss over time than the loss over time detected in the placebo group. However, it needs to be noted that for 18% of the patients in the ITT set, the measurement of residual hearing 12 months after the first fitting was missing, and the prolonged protective effect could not be replicated in sensitivity analyses applying different missing data assumptions. Consequently, further studies have to be conducted to proof this potential benefit of ACEMg.Since the likelihood of residual hearing preservation in cochlear implantation is related to medical history and surgical factors such as duration of hearing loss, aetiology, route of implantation (round window approach vs. cochleostomy), and device-related factors such as shape, length and flexibility of the array, it has to be concluded that there are multiple factors which affect the residual hearing. Zanetti et al. correlated age, side of implant, implant model and type of cochleostomy to hearing loss after cochlear implantation and reported that the mean threshold variations did not reach statistical significance for any of these variables. A slight trend in favour of better residual hearing preservation in children vs. adults was seen, especially at lower frequencies . ConformIn the placebo group, the hearing loss at 500 Hz determined 3 months (30.21 ± 15.84 dB) or 12 months (36.25 ± 19.63 dB) after the first fitting was in the range of hearing preservation rates reported previously –26.p = 0.3413). Clinically, 3.7 years are judged as irrelevant, but since the residual hearing may correlate with age due to age-related hearing loss, the hearing performance of the patients may decline with age. Therefore age is a relevant factor and it has to be avoided to have a mismatch in age between the treatment groups. The potential influence of this imbalance was investigated by subgroup analyses with age added as either continuous or dichotomized (by median age) factor to the primary analysis model. Without showing statistically significant differences, the subgroup analyses estimate ACEMg to be superior to placebo in patients aged 55 years or younger with an effect size of 8.24 dB lesser hearing loss in ACEMg-treated patients. This effect is turned to the opposite in patient older than 55 years, where placebo shows a not significantly reduced hearing loss with an estimated effect of 4.56 dB. It is well known that, in general, the free radical formation is higher in older people [In our study, the subjects enrolled did not substantially differ regarding their demographical data between the treatment groups. The mean age in the ACEMg group was 3.74 years lower than in the placebo group  the placebo level. No actions for safety had to be taken during the PROHEARING trial.The data of this prematurely discontinued trial show a tendency that ACEMg therapy in patients aged 55 years and younger starting directly before cochlear implantation and lasting for about 100 days may lead to a better hearing preservation 3 months after the first fitting and lasting for at least 13 months after surgery. We hypothesize that a food supplement of the metabolic imbalances during and after surgery by antioxidative and vasodilatative supplementation may improve the benefit some patients will have by receiving a CI. Further studies need to be conducted addressing this topic to verify the promising preliminary data of this trial.Additional file 1. Includes the general medical history for all patients in the ITT-set as Supplement 1. Ear specific medical history for the implanted ear is stated in Supplement 2 of the additional file 1. Supplement 3 shows the aetiology of the implanted ear. Concomitant medication for the ITT-set summarized by events is stated in Supplement 4. Supplement 5 gives the hearing loss over time at 500 Hz with imputation of 110 dB if the upper detection limit is reached or 120 dB if the measurement is missing. Supplement 6 reports the hearing preservation measured by air conducted audiometry at 500 Hz including all timepoints analyzed in the modified ITT population using a mixed model with change from baseline as dependent variable and treatment, baseline hearing threshold, surgeon, electrode length, electrode length - visit interaction and visit-treatment interaction as fixed effects. The mixed model for repeated measures was conducted adjusting for either the planned electrode length (Supplement Table 6.1) as was done in the primary analysis model, or by adjusting for the used electrode length (Supplement Table 6.2). The estimated mean hearing loss at all time points with 95%-confidence intervals based on the mixed model for repeated measures adjusted for the planned electrode length is illustrated in supplementary figure 6. AEs are listed in supplement 7.


What is the association between hearing, hearing aid use, psychological distress, and utilization of mental health services?In this cross-sectional study using data from 25 665 participants in the 2017 National Health Interview Survey, hearing loss was associated with increased odds of psychological distress and increased utilization of mental health services. Hearing aid use was associated with decreased odds of psychological distress.The results of this study suggest that hearing loss may be a modifiable risk factor for psychological distress. This cross-sectional study investigates the association between hearing loss, psychological distress, and mental health care utilization among adults in the United States. Psychological distress affects health and health care utilization. Hearing loss (HL) is highly prevalent and undertreated, and it may be a potentially modifiable risk factor for psychological distress.To investigate the association between HL, psychological distress, and mental health care utilization among adults in the United States.This cross-sectional study included 25 665 individuals aged 18 years and older who participated in the 2017 National Health Interview Survey, a home-based nationally representative cross-sectional survey of noninstitutionalized US adults conducted by trained interviewers.Self-reported hearing and hearing aid use.Kessler psychological distress scale (scores ≥5 indicating moderate distress), self-reported use of medication to treat depression or anxiety symptoms, and use of mental health services in the past year.A total of 25 665 adults  were included in the analysis. Compared with 11 558 participants  with no HL, the 9390  with mild HL and 4717  with moderate or worse HL had increased odds of moderate psychological distress  and were more likely to report antidepressant medication use , and antianxiety medication use . Moderate HL was associated with increased odds of use of mental health services . Among individuals with moderate HL, those with hearing aids (1066 [22.6%]) were less likely to experience psychological distress than those without hearing aids .In a large nationally representative sample of US adults, self-reported HL was associated with both greater psychological distress and increased rates of antidepressant and antianxiety medication use and utilization of mental health services. Further research is needed to investigate whether HL may be a modifiable risk factor for these outcomes. In the present study, we analyze data from the 2017 National Health Interview Survey (NHIS) to describe the association between HL, psychological distress, and mental health care utilization and to conduct exploratory analyses to assess the association of hearing aid use with observed outcomes.The existing literature suggests potential associations between HL and psychological distress, but studies have been limited by small sample sizes or nongeneralizable cohorts.15 Our primary analytic cohort comprised 25 665 individuals with complete data on hearing, covariates, and other outcomes of interest. The NHIS was evaluated and approved by the Research Ethics Review Board of the National Center for Health Statistics. Informed consent was obtained from the respondent to participate in the household interview. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.The NHIS is an annual cross-sectional household interview survey conducted by the National Center for Health Statistics to evaluate the health of the civilian, noninstitutionalized US population. The survey uses a stratified multistage sample design with oversampling of individuals from minority groups. We used data from the 2017 sample, which consisted of a total of 26 734 adults aged 18 years and older.16 Participants were also asked if they currently used a hearing aid.Sample participants were asked by interviewers to rate the quality of their hearing without a hearing aid. Responses were analytically collapsed into 3 hearing categories, as follows: no HL (response of excellent hearing), mild HL (response of good hearing), and moderate or worse HL . Prior published research has also collapsed these latter variables into a single variable.17 Participants were asked how much of their time in the past 30 days they felt hopeless, nervous, restless, sad, worthless, or that everything was an effort. Responses are on a graded scale ranging from none (0), a little (1), some (2), most (3), or all of the time (4). Scores are summed to give a total Kessler 6 psychological distress score . The original proposed cutoff to define severe psychological distress, with probable diagnosable Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) condition(s), was a Kessler 6 score of at least 13, but recent research has recommended a cutoff of 5, which was defined as moderate psychological distress that warrants evaluation and treatment.18 Kessler scores were used in 3 analyses, as follows: a binary cutoff of at least 13, a binary cutoff of at least 5, and as a continuous variable. Interviewers also asked participants if they saw or talked to a mental health professional in the past 12 months. A total of 974 participants (3.6%) did not have complete data on the Kessler psychological distress scale.The Kessler 6 scale was used to evaluate psychological distress.A random sample of respondents were also asked a series of questions as part of the Adult Functioning and Disability Supplement to the NHIS. Those selected were asked if they used medications for feelings of depression or feelings of worry, nervousness, or anxiety, which were classified as antidepressant or antianxiety medication use, respectively. Approximately half of adults were randomly selected for these questions, yielding an unweighted group of 12 723 participants (49.6%) for antidepressant medication and 12 733 participants (49.6%) for antianxiety medication, respectively. Those with missing medication data were similar to those with medication data, but were less likely to report hypertension , and less likely to be African American participants than white participants .19 Age was not included in the modified Charlson Comorbidity Index because it was included separately in the regression analyses. A total of 163 adults (0.6%) had missing data on comorbidities.Self-reported demographic variables include age, race , sex, marital status , family income , highest education achieved , and self-reported health status . Participants were asked if they had smoked 100 or more cigarettes in their life. A modified Charlson Comorbidity Index was also created using self-reported health conditions, which included 1 point each for asthma, emphysema, cardiac arrest, heart disease, stroke, diabetes, ulcer, liver disease, and renal disease and 2 points for cancer.P < .05, and all tests were 2-tailed.Analyses were conducted with sample weights provided by the NHIS to be representative of the civilian noninstitutionalized US population. Multiple logistic regression models and Poisson regression models with incident rate ratios were used to evaluate the association between levels of HL and outcomes of interest. Analyses of hearing aid use and outcomes of interest were limited to individuals with moderate or worse HL. Multivariate models included age, sex, race, family income, education, marital status, self-reported health, and cardiovascular comorbidities . A separate analysis was performed using the modified Charlson Comorbidity Index instead of individual cardiovascular comorbidities. Subgroup analyses were performed using a cutoff of 5 for the Kessler 6 score to assess effect modification by age  and sex. All analyses were completed using Stata version 13 (StataCorp). Statistical significance was set at A total of 25 665 adults  were included in the analysis. Baseline weighted population characteristics stratified by self-reported HL are presented in Compared with adults without no HL , individWe next investigated whether self-reported hearing loss was also associated with indicators of mental health care utilization . In fully adjusted models , there wTo compare the magnitude of the association of hearing loss and psychological distress with other factors associated with psychological distress, the We next examined whether self-reported hearing aid use was associated with reduced odds of psychological distress and mental health care utilization . Among iWe performed a sensitivity analysis evaluating the raw hearing data (not collapsed in 3 groups) in an adjusted logistic regression model in all ages using the cutoff of 5 for Kessler 6 scores. Compared with those with self-reported excellent hearing, those reporting good hearing (presented elsewhere as having mild HL) had increased odds of psychological distress . The other groups also had increased odds of psychological distress , while those who reported being deaf  did not have significantly increased odds of psychological distress .We performed additional sensitivity analyses to test the robustness of our observed results. The association between mild HL and a score of at least 5 on the Kessler 6 was significantly lower among those aged 65 years and older compared with those younger than 65 years , and there was not a significant difference between age groups for moderate or worse HL . Sex-stratified analyses yielded qualitatively similar results for both mild HL  and moderate or worse HL . Finally, we performed analyses adjusting for a modified Charlson Comorbidity Index rather than adjusting for individual cardiovascular risk factors, and the results did not differ substantively from the presented results (data not shown).In a large nationally representative sample of US adults, we observed an association between greater self-reported HL and increased odds of psychological distress. Compared with those with no HL, individuals with moderate or greater HL had approximately 2-fold greater odds of reporting psychological distress and using antidepressant or antianxiety medications and approximately 1.5-fold greater odds of seeking mental health care in the past 12 months.26 The evidence for an association between hearing impairment and depression is mixed. Many larger studies identified increased odds of depressive symptoms with hearing impairment28; however several smaller studies did not.30 Several reviews provide a comprehensive analysis and discussion of the existing literature on hearing loss and depression.31 The present study adds to the literature demonstrating the potential association of HL with psychological distress in the largest study, to our knowledge, of a population-representative cohort of noninstitutionalized US adults.Prior studies have linked HL with a number of adverse health and quality-of-life outcomes. Individuals with impaired hearing have been found to have greater rates of cognitive decline and incident dementia.14 found increased rates of depression with HL and a slight increase in the use of antidepressant medications, but we are unaware of other studies demonstrating increased rates of antidepressant or antianxiety medication use or increased utilization of mental health services in adults with HL. Psychological distress and depression are common1 and costly to the health care system and economy.4 Annual US health care expenditures for depression were estimated at $71 billion, the sixth most costly condition, behind diabetes, heart disease, back and neck pain, hypertension, and falls.32 Often easily treated with hearing aids or other interventions, HL may be a modifiable risk factor for psychological distress.Importantly, findings from the present study demonstrate higher utilization of mental health medications and services in adults with HL. One prior study of 5328 Hispanic adults33 found lower rates of depression in individuals with hearing loss who use hearing aids. Pronk et al35 found a similar result in their cross-sectional analyses of 996 individuals from the Longitudinal Aging Study Amsterdam. In a prospective observational study of 113 individuals with hearing loss receiving hearing aids (n = 63) or cochlear implants (n = 50), loneliness and depression scores improved among those who received cochlear implants at 6 and 12 months and depression scores improved at 6 months among those who received hearing aids.36 Another study of 94 older adults with profound postlingual deafness37 found significantly decreased depression scores at 12 months after cochlear implant.The present study found that among those with moderate or worse HL, individuals who reported using hearing aids had lower rates of psychological distress than those who did not. Additionally, adults younger than 65 years with HL who used hearing aids were less likely to use antianxiety medications than those aged 65 years or older. Several prior studies have examined the treatment of hearing impairment and psychiatric outcomes. Analysis of data from 1328 older adults from the Blue Mountain Eye and Hearing Study5 nicely summarized potential mechanisms linking hearing loss and depression in a 2018 review. Effects of HL on social engagement and loneliness as well as on changes in brain structure and function may both contribute to psychological distress and depression. Individuals with HL are more likely to avoid social environments because of difficulty communicating.39 Several neuroimaging studies have also found decreased activation and decreased volumes in several areas of the brain, including the primary auditory cortex; superior, middle, and inferior temporal gyri; thalamus; brainstem; and parahippocampus,41 and adults with HL have decreased activation of the parahippocampus, right middle temporal gyrus, and left superior temporal gyrus in response to affective auditory stimuli compared with individuals with no HL.42Rutherford et alOur results suggest that hearing impairment may be a strong risk factor for psychological distress, which is reflected in increased rates of utilization of mental health medications and services. Further longitudinal studies and clinical trials are needed to assess the basis of this association and whether treatments for HL could potentially lower rates of psychological distress and utilization of mental health care.44 and the prevalence of HL in our study was comparable with prior studies of US adults that used audiometric data,46 other factors associated with self-assessment of hearing could potentially confound observed associations of HL with psychological distress. We accounted for these potential confounders by adjusting for both self-reported health and cardiovascular risk factors as well as by performing additional analysis with the modified Charlson Comorbidity Index, but residual confounding is still a possibility. Furthermore, our exploratory analyses suggesting that hearing aid use among those with moderate HL may be associated with reduced odds of psychological distress must be interpreted with caution. Individuals with HL using hearing aids vs those who do not use hearing aids are likely to differ across multiple measured  and unmeasured  factors that cannot be fully accounted for in our analyses and may lead to a bias toward seeing beneficial associations with hearing aid use. In contrast, hearing aid use could also be indicative of individuals who are the most severely affected by HL, which could plausibly lead to a potential bias toward seeing hearing aid use as associated with greater psychological distress. We did observe an isolated finding of hearing aid use being associated with greater odds of reporting mental health care utilization by older adults, which is of unclear significance.This study has limitations. Our results are from a cross-sectional analysis that limits robust causal inference. While self-reported hearing has been validated as a reliable indicator of hearing measured with criterion-standard audiometryIn this study, self-reported HL was associated with psychological distress, antidepressant and antianxiety medication use, and utilization of mental health services in a nationally representative sample of US adults. Further research is warranted to determine whether hearing loss may be a modifiable risk factor for psychological distress.


In the present study, we investigated the possibility that NO and CO can regulate the endogenous levels of H2S in bovine isolated neural retina.Nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide  elicited a concentration-related increase in H2S levels from 18.3 nM/mg of protein to 65.7 nM/mg of protein. ZnPP-IX (300 nM–10 µM) caused a concentration-dependent increase in the endogenous production of H2S whereas hemin (300 nM–20 µM) attenuated the basal levels of H2S.L-NAME (300 nM–500 µM) caused a concentration-dependent decrease in basal endogenous levels of H2S in the retina. The demonstrated ability of NO, CO and H2S to interact in the mammalian retina affirms a physiological/pharmacological role for these gaseous mediators in the eye.We conclude that changes in the biosynthesis and availability of both NO and CO can interfere with the pathway/s involved in the production of H H2S has been reported to play a regulatory role in CO/heme oxygenase pathways in cardiac and pulmonary diseases 2S/CSE pathways have been demonstrated to inhibit each other in aortic smooth muscle cells 2S biosynthesis in the retina. The aim of the present study was, therefore, to investigate whether inhibitors and/or activators of both NO and CO pathways can alter H2S concentrations in the bovine isolated neural retina. Parts of the work described in this paper have been communicated in an abstract form The presence of enzymes responsible for the biosynthesis of hydrogen sulfide , L-nitroarginine methyl ester (L-NAME), sodium nitroprusside (SNP), aminooxyacetic acid (AOAA), ethylenediamine tetra-acetic acid solution (EDTA), zinc acetate, ferric chloride, borate buffer (pH 11.0) and 2.2.Bovine eyes were obtained from Vision Tech, Dallas, TX within 24 hours following enucleation and transported to the laboratory on ice. An incision was made along the equator of each eye and the vitreous humor and lens were delicately removed. The neural retinae were isolated by gentle removal from the posterior segment of the eye and immediately immersed in ice-cold 50 mM potassium phosphate buffer (pH 7.4). Time elapsed between animal sacrifice and tissue preparation was less than 24 hours.2.3.2S production was measured using the Methylene Blue method, a widely used assay that has been shown to produce quantifiable measurements of H2S production in mammalian tissues comparable to data obtained using H2S probes 2S measurement in retinal tissues was essentially the same as previously reported by Xia et al. 2S as reported by 2S concentration was calculated against the calibration curve of standard H2S solutions (10–750 µM). The protein content of the residual pellet after centrifugation was measured using the Bradford method.H2.4.2S produced per milligram soluble protein. Values given are arithmetic means ± SEM. The means were determined from three separate experiments performed in triplicates. Significance of differences between control and treatment groups were evaluated using one-way analysis of variance (ANOVA) followed by Newman-Keul comparison test. . The level of significance was chosen as p < 0.05.Results were expressed as nanomolar of H3.3.1.2S in isolated bovine retinae were enhanced by the substrate, L-cysteine and attenuated by inhibitors of enzymes responsible for the biosynthesis of this gas 2S levels reaching a maximum at 100 µM (65.7 nm/mg of protein)  . On othe protein .3.2.2S in the bovine isolated retina. As shown in 2S from 18.9 to 3.6 nm/mg of protein. Conversely, the heme oxygenase inhibitor, ZnPP-IX (300 nM–10 µM) significantly increased the concentration of H2S from 19.2 to 26.5 nm/mg of protein in a concentration-dependent manner, reaching a maximal effect at 10 µM  on basal concentrations of Hat 10 µM .4.2S can serve as a gaseous neurotransmitter/neuromodulator in several mammalian tissues and organs. Indeed, there is abundant evidence that H2S is involved in several physiological and pathophysiological processes as diverse as learning and memory, inflammation, and the regulation of blood pressure 2S has been shown to play an important role in maintenance of vascular smooth muscle tone whereas in the central nervous system, this gas has been found to act as a neurotransmitter/neuromodulator at synapses 2S has also been reported to exert a neuroprotective action on neurons 2S in the vasculature and brain have been reported to resemble those of other established gaseous transmitters like CO and NO 2S in cardiovascular, central nervous and immune systems, there is limited evidence of an interaction between NO, CO and H2S in regulating some of the observed responses in the above-named systems 2S in the bovine isolated retina.It is well-established that H2S producing enzymes 2S in regulating vascular function 2S in the presence of NO donor, SNP. The incubation time period for optimal production of endogenous basal levels of H2S was previously established in our laboratory 2S suggesting that increased NO availability can regulate the production of this gas in the retina. We also observed that at a high concentration of SNP (300 µM) the basal endogenous levels of H2S was decreased, suggesting that NO may also have the ability to inhibit H2S production. The precise mechanism for this effect is not clear. However, it may be due to the fact that at high concentrations of SNP, the NO generated binds to CBS and thus has the potential to inhibit its activity and therefore the generation of H2S. Despite this, our observations correlate well with studies in the vasculature depicting the ability of SNP to increase the biosynthesis of H2S 2S are significantly enhanced 2S production may be due to an augmented activity of enzymes responsible for the biosynthesis of H2S by the NO-induced S-nitrosylation of their cysteine residues or indirect stimulation of CSE by NO through an increase in the activity of cyclic GMP-dependent kinases 2S production. To confirm the nature of this interaction, we investigated the effect of an inhibitor of NO synthase, L-NAME on endogenous H2S production. Our results demonstrate that L-NAME reduced basal H2S levels suggesting that endogenously generated NO can modulate the basal levels of H2S presumably through an interaction with pathways involved in H2S production. Other studies in the vasculature have also reported a similar inhibitory effect of L-NAME on H2S production and activity 2S and NO interactions in the neural retinae are unknown and merits further investigation.There is evidence that in the cardiovascular and central nervous systems, nitric oxide synthase (NOS) substrates or NO donors can up-regulate the expression or activity of H2S, we designed experiments to determine whether changes in CO production can regulate the endogenous levels of H2S in neural retinae. In these studies, hemin and ZnPP-IX were employed as an inducer and an inhibitor of heme oxygenase, respectively 2S. In contrast, ZnPP-IX elicited a concentration-dependent increase in endogenous H2S levels. Our results reveal that increasing CO production led to a decrease in basal concentrations of H2S whereas, inhibiting CO biosynthesis can cause an elevation of H2S levels. These results correlate well with studies reported by Jin et al. 2S production in aortic smooth muscle cells. A similar interaction between these two gaseous transmitters has also been observed in the carotid body, the liver, and the microvasculature of the brain 2S production. It is, however, unclear how CO acts to regulate the biosynthesis of H2S in the retina.In addition to studying the possible interaction between NO and H2S was found to enhance phenylephrine induced tone in the rabbit ophthalmic artery, while CO and NO both caused concentration dependent relaxations 2S was found to reduce cGMP levels and prevent a NO induced increase in cGMP Previous evidence from our laboratory and others suggests that crosstalk between the three gasotransmitters exists in ocular tissues 2S in the bovine isolated retina. The present observation that basal levels of H2S can be altered by manipulation of pathways involved in NO/CO production is of great interest and merits further investigation.In conclusion, changes in the biosynthesis and availability of both NO and CO can interfere with the pathway/s involved in the production of H2S is based on the assumption that tissue concentration of sulfide are high, and hence it does not distinguish between acid labile sulfur stores or bound sulfane stores. In addition the enzyme inhibitors being used in the studies are pyridoxal-5′ phosphate (PLP) enzyme inhibitors that are not specific for H2S biosynthesizing enzymes, CBS and CSE as these enzymes are known to be involved in other cellular processes in mammals. Thus, it would be worthwhile to investigate whether H2S synthesis alters the expression of these biosynthesizing enzymatic proteins. Despite the limitations of the study protocol, the results provide a basis for future studies on the role of H2S in the posterior segment of the eye.Despite these novel findings, the results should be interpreted with prudence due to limitation of our study protocol. For instance the colorimetric methodology used for determination of endogenous production of H