This indicates that education and knowledge have a strong influence on student attitudes. It is obvious that the awareness of noise-induced hearing loss among adults in Jordan is very low. The authorities, policymakers, media, and educational institutes should recognize their responsibility in raising the awareness of the danger of loud music among young adults.Action to prevent noise-induced hearing loss is necessary, especially because many causes of permanent hearing loss are preventable. The aim of this study is to identify and raise awareness of the effect of loud sounds on hearing and effective ways to protect ears among young adults in Jordan. Using non-probability and convenience sampling, 245 students  from three universities participated in the study and filled the questionnaire completely. The questionnaire consisted of 19 questions targeting hearing health. The answers were analyzed statistically, and comparisons were made using the t-test. Hearing loss was regarded as an important issue by 64.1% of the participants. Among the participants, 58% already suffered from at least one hearing symptom, even though only 9.8% used earplugs to protect their hearing. After receiving information on noise-induced hearing loss, 56.3% were likely or somewhat likely to use earplugs in the future ( Hearing impairment is a major challenge for public health organizations. According to the World Health Organization (WHO), there are approximately 466 million people living with disabling hearing loss, including approximately 34 million children. Furthermore, of these, nearly 90% live in middle- and low-income countries. Previous reports have also highlighted the significance of noise-induced hearing loss (NIHL), both work- and recreational activity-related NIHL ,2. In thNoise and loud sounds are reported to be an important factor leading to hearing loss. NIHL is reported to be the second main cause of sensorineural hearing loss, after age-related hearing loss, even though it is virtually entirely preventable . OlusanyIn a study on strongly amplified music, Meyer-Bisch found that young adults using personal cassette players for prolonged periods (>7 h/week) had a significantly shifted hearing threshold in comparison to subjects using the players for 2–7 h/week . Dalton Tinnitus was observed by many researchers as the most common disturbance after hearing loud noises and loud music. In a study by Bogoch et al., 84.7% of music concert attendees experienced tinnitus, which is an important hearing loss symptom . In the Worldwide, some studies have been conducted on the public’s awareness of hearing health and hearing loss. The results of these studies varied from one country to another. Joubert et al. conducted a study in Limpopo province, South Africa, showing that 89% of their sample (n = 297) acknowledged the relation between loud noise and hearing damage . Chung eIn a study by Balanay et al.  conducteMore frequently, young adults are hearing loud music for long hours and exposing themselves to loud music in concerts and clubs. Sound levels of 120 to 140 dB have been reported in rock concerts , and aveTo our knowledge, there is no study on the awareness of NIHL among young people in Jordan and nearby countries. In this study, the authors use the results of a survey to evaluate the knowledge of young adults of hearing health and the issues related to NIHL. It includes an evaluation of hearing symptoms related to noise exposure, the acceptance of students to use ear protection, and the duration of exposure to loud music. The study tries to build a baseline of knowledge that may be used in any awareness-raising campaign and tries to better understand young adult’s acceptance to using hearing protection devices.The research was conducted in three universities (two public universities and one private university) in Jordan in the fall semester of 2018. The population of Jordan is 9.5 million citizens (2015). Jordan has 10 public and 16 private universities. A non-probability, convenience sampling strategy was used in selecting the participants.A total of 287 individuals were invited to participate in the questionnaire. Out of them, 250 participants accepted the invitation. A total of 245 participants (age = 21.52 ± 2.18 years) filled the questionnaire out completely. Only 5 participants did not fill it completely, and their forms are excluded from the study; 46.1% (n = 113) were females and 53.9% (n = 132) were males . Their aThe questionnaire used in this study was based on the 28-question survey from the Massachusetts Eye and Ear Infirmary, the Harvard School of Public Health, and Cogent Research, Inc. . The oriThe final questionnaire consisted of five demographic items about age, gender, educational level, place of residence, and family income. A total of 18 open- and close-ended questions on attitude toward hearing loss, hearing problem symptoms, NIHL, noise and loud sound exposure duration, the use of hearing protection, mainly earplugs, and the perception of the adults toward using them, were included. The full questionnaire can be found in A pilot study was done prior to the data collection to ensure clarity of the questions, content, and face validity. The pilot study was done on 10 participants and their comments on the questions were collected and considered in rewriting the questionnaire. Their questionnaires were later excluded from the final data analysis. After the pilot study, the questions were reviewed and reformatted.Students from the three universities were selected by asking every fifth student passing by a student’s gathering area to fill the questionnaire. Participants were fully informed about the study verbally and assured of their rights not to complete the questionnaire anytime with no consequences. The questionnaire was self-administrated while one of the researchers was present during the administration. All filled surveys were verified for completeness during data cleaning and incomplete questionnaires (n = 5) were discarded.The research was conducted in accordance with the principles of the Declaration of Helsinki. The participants received no rewards for their participation. Permissions were gathered from all participating universities before conducting the research on the campus. Forms were approved by the Deanship of Academic Research at the German-Jordanian University.p < 0.05 was used for a statistically significant difference.Data were stored on an Excel spreadsheet, and then transferred to the commercial program MATLAB  and analyzed using the statistical toolbox. The frequencies of occurrence and percentages are given for categorical questions. The mean values and ranges are given for continues measures. Statistical comparisons between values are provided where applicable using the two-tailed N-1 Chi-Square test for different groups and McNemar’s test for paired data. 2 = 10.01, p < 0.01, p = 0.0016)), and only 23.7% felt that it is either not a big problem or not a problem at all.The results are presented in the same flow of the questions in the survey. The first part aimed to identify the attitude toward hearing loss. Within the selected sample, 64.1% (n = 157) believed that hearing loss is a big or very big problem for people suffering from it. On the other hand, 35.9% (n = 88) viewed it as either no problem at all or not that big of a problem. In comparison with depression as another important health issue for young adults, 76.3% (n = 187) felt that depression is a big or very big problem .When asked about imagining themselves suffering from hearing loss, there was a slight insignificant change in their opinion, such that 63.3% assumed that hearing loss would be a challenging problem if they were suffering from it. However, the percentage of those believing depression is a big or very big problem if they were suffering from it dropped significantly to 63.7% from 76.3%  already have some idea or have heard something about hearing loss. For those 161 participants, the primary source of their knowledge varied from media, TV shows, and the internet for 46.0% (n = 74), followed by 31.7% who experienced one or more forms of temporary hearing loss themselves after participating in an activity that included loud sounds, hearing loud music, ear infection, or fireworks. The remaining 22.4% experienced hearing loss through relatives (mainly grandparents) or friends suffering from hearing loss problems. Around one-third of participants  have never faced or heard anything related to hearing loss before reading the questionnaire.2 = 2.38, p = 0.123). The overall percentage for both genders was 57.6%. 2 = 4.80, p = 0.0285) than for males (15.9%). However, the differences in ear pain between males (28.0%) and females (38.9%) was not statistically significant .In the second part, the participants were asked if they experienced any noise-related hearing symptoms based on their own judgment. Within the male participants, 53% reported that they had at least one symptom. For female participants, the percentage was 62.8%, and this percentage was not significantly different from that of males (xThe students aged 21 years old had the highest percentage of at least one hearing symptom (64.6%). However, within the relatively small sample size, there was no clear statistically significant difference between the different ages and frequency of hearing symptoms.2 = 5.96, p = 0.0146) than those belonging to families with average income (33.3%), and significantly higher  than those belonging to families with a below-average income (22.2%). There was no significant difference between middle- and low-income students .The next part of the questionnaire examined the relation between family income and the existence of hearing symptoms. The percentage of students who experienced at least one hearing symptom among families with an above-average income (57.6%) was significantly higher (xp < 0.01). However, males’ attendance at clubs, raves, and discos (49.2%) was significantly higher than females (15.0%) with a p < 0.01. The overall percentage of students exposed to loud music in at least one of these activities is 90.6%, and the rest (9.4%) do not participate in any of these loud activities. Regarding these activities, it is important to highlight that 60.6% listen to loud music using media devices on a daily basis.In the third part of the questionnaire, the participants were asked if they participated in a list of activities that included loud sounds, and how often they do that. Visiting parties with loud music and listening to loud music with headsets and other devices were reported as the most common activities, with 79.2% and 81.2%, respectively. The different percentages are shown for both males and females in The percentage of students who experienced at least one hearing symptom often or very often after participating in activities involving loud sounds is 72.3% after participating in concerts, 65.9% after attending discos and raves, 53.6% after weddings and parties with loud music, and the smallest percentage was for personal music players and media devices with 43.2%.2 = 0.065, p = 0.7992) when considering the opinion “it is weird and ugly” . Similarly, there was no significant difference between genders of who saw the use of earplugs as normal . However, a significantly higher percentage of females (53.1%) saw it as funny and cool in comparison with males .To evaluate attitudes toward the use of hearing protection, the students were asked about their opinions regarding the use of hearing protection by others and how they accept it. The opinions were grouped into four categories: 44.1% viewed it as funny and cool; 30.2% viewed earplugs negatively; as ugly and weird; 23.67% thought it was normal and a part of personal freedom; and only 2% saw it positively, and as part of having a good attitude toward protecting their hearing. A comparison based on gender gave no statistically significant difference . As the number of hearing protection users was very small, comparison based on gender or hearing problems is not indicative. Out of the 90.2% that have never used ear protection, 43.0% believe there is no need to use them and prefer loud sounds, 14.9% never heard about hearing protection before, and 9.0% do not want to use it due to its shape. Within this question, 73 participants did not write the reason for not using ear protection (33.0%).The reported use of protection for hearing was just 9.8% (n = 24) of the whole sample size, which was divided into 11 participants wearing it to protect their hearing, 6 because they already had hearing problems, 5 to avoid sleeping problems after loud music, and 2 because they got nervous hearing loud music. From the participants who experienced at least one hearing symptom, 12.8% already used hearing protection, and only 5.8% of those with no hearing symptoms used hearing protection. This difference was not statistically significant  of the participants had heard about the use of earplugs. The source of knowledge was mainly friends followed by media . 2 = 0.159, p = 0.69).When asked about their knowledge of induced hearing loss, 81.2% (n = 199) admitted having known that loud sounds can be damaging to the hearing, and just 18.8% had no idea before reading this survey. There was no significant difference between males and females . There was 134 (54.7%) participants who did not know where to get earplugs. After reading this survey and the information paragraph, 56.3% expressed that they will very likely or somewhat likely use earplugs in the future. In comparison with the 9.8% of participants who used earplugs. This change is statistically significant and strongly indicates a change in attitudes . However, the presence of tinnitus showed a statistically significant correlation with the time spent listening to music weekly . No significant correlation was found between ear pain and music listening time . For listening to music, 26.9% use a headset, 20% use loudspeakers, and 49.8 use both, while 3.3% do not listen to music.The students were asked about the time they spend hearing music weekly. The current survey provided insight into the awareness and knowledge of hearing loss among young adults. Almost two-thirds of the sample believed that hearing loss is a big problem or a very big problem, but they believed it is less important than depression. Similarly, in the survey conducted by Chung et al., the participants viewed depression as a more important problem. In this study, 27.8%, as compared to 8% in the Chung sample, considered it to be a very big problem. The same attitude was noticed in the Quintanilla-Dieck et al. study, where the percentage was around 31%. Furthermore, the differences between males and females were not statistically significant, which was reported in the other studies ,17.p < 0.01). However, this study was performed on graduate and undergraduate students, while the other studies included younger high school students.The percentage of participants who already experienced something related to hearing loss was 65.7%, which is relatively high in comparison with other studies ,17,  was the most common, followed by visiting parties and wedding celebrations (79.2%), with a small difference between them. Lass et al.  reportedIn this study, it was also clear that the number of male students attending discos and clubs was higher than female students in Jordan, in contrast to a study in the USA  that shoThe overall use of ear protection was very low in this study (9.8%), even though 57.6% had at least one hearing symptom, and furthermore, 35.5% already knew about earplugs and their uses. This was similar to what was found in previous studies ,17,23,24A majority of the participants admitted to knowing about the relation between loud sounds and hearing loss. Similarly, Joubert reported that 89% (n = 265) of their sample admitted to knowing about the relation between loud noise and hearing problems, and Quintanilla-Dieck et al. reported more than two-thirds of their sample (n = 2500) knew about noise-induced hearing loss .The results on attitudes toward the use of hearing protection and the specific result that most respondents knew about the relation between loud noise and hearing loss needs, in our opinion, more studies and analysis in the future on larger samples and with consideration of psychosocial factors. According to this survey, only 2% (n = 5) viewed using earplugs positively and for the right reason of protecting the ears, and 30.2% responded negatively, viewing earplugs as either ugly or weird. Other researchers, like , also reThe results of the survey reveal a very strong opportunity for education to improve the attitude towards using earplugs and hearing protection. After education, 56.3% of participants were either very likely (20.0%) or somewhat likely (36.3%) to use protection in the future, which is a significant jump from the 9.8% that already use earplugs. Similarly, the MTV survey of 2002 and 2007 showed an opportunity to educate, where the percentage of participants increased from 14% using earplugs to 22% willing to use earplugs for the 2002 study, and 15% using earplugs to 28% willing to use them for the 2007 survey ,17.This study reveals a strong correlation between tinnitus and time spent listening to music. This dependency was not significant for other ear diseases within this study. The 2007 MTV survey also found that music listening activities were related to temporary tinnitus. A significant percentage (18%) spend more than 20 h weekly listening to music, and 37% spent more than 16 h a week. These measures are very indicative and need to be considered in any educational campaign in the future. Furthermore, in our opinion, action from the local authorities to legally force electronic device manufacturers and suppliers to have safety-warning labels on their devices, including information about NIHL, is needed.The authors made every effort to avoid any bias in the study results. It is important to mention that bias may be present due to the size of the sample and that doing a study on a larger sample size and possibly in neighboring countries is recommended. Future studies may utilize audiometric tests to avoid any bias due to the self-reporting nature of this study.The results indicate a clear need to raise the awareness of NIHL among young adults. This can be achieved primarily by focusing on advertising campaigns, utilizing the online media and university webpages. The authors believe that such campaigns, even if they are costly, can help improve society’s health and reduce the future cost of NIHL. For example, the estimated reduction in income for people with hearing loss in the UK is around 2000 pounds annually, which adds up to four billion annually over the whole UK . The awaThe available data on NIHL and the attitudes toward hearing loss and hearing protection among university students is limited. Some studies have been performed in developed high-income countries. However, less has been done in middle- and low-income countries. We believe this study adds to the already existing studies worldwide and highlights the issue in one of the Middle Eastern countries. Even though the sample size, taken from three different universities, is relatively small (n = 245), it can be seen as guidance for more studies and for policymakers. The results of this study show the need for action by the relevant authorities and institutes to enhance public knowledge on NIHL. NIHL can be controlled and prevented by taking proper actions as suggested by Olusanya et al. . More TVEven though knowledge of hearing loss and the existence of ear protection is comparable with other studies conducted in other countries. There is a clear lack of knowledge about the importance of using earplugs and hearing protection. This study indicated potential for education within the young adult segment of the population.


Mild hearing and visual difficulties are common in childhood, and both may have implications for educational achievement. However, the impact of co-occurring common hearing and visual difficulties in childhood is not known.To determine the prevalence and impact of co-occurring common hearing and visual difficulties of childhood on educational outcomes in primary and secondary school.The sample was drawn from the Avon Longitudinal Study of Parents and Children, a longitudinal birth cohort study in England. The exposures were hearing and visual difficulties at age 7 . The outcomes measured were achievement of level 4 or above at Key Stage 2 (KS2) in English, Maths and Science, respectively, at age 11, and attainment of five or more General Certificate of Secondary Education (GCSEs) at grades A*–C at age 16. Multiple logistic regression models assessed the relationship between hearing and visual difficulties and educational outcomes, adjusting for potential confounding factors.2909 children were included in the study; 261 had hearing difficulties, 189 had visual difficulties and 14 children had co-occurring hearing and visual difficulties. Children with co-occurring hearing and visual difficulties were less likely to achieve the national target at KS2 compared with children with normal hearing and vision, even after adjustment for confounding factors . Differences in IQ, behaviour, attention and social cognition did not account for this relationship. The impact of co-occurring hearing and visual difficulties on GCSE results was explained largely by poor performance at KS2.Co-occurring hearing and visual difficulties in childhood have an enduring negative impact on educational outcomes. Identification of affected children and early intervention in primary school is essential. Mild hearing and visual difficulties are common in childhood.The most common cause of hearing difficulties in childhood is chronic otitis media with effusion, which may be associated with lower academic performance.The impact of common co-occurring hearing and visual difficulties on educational outcomes is not known.Children with co-occurring mild hearing and visual difficulties have poorer educational outcomes than children with isolated hearing or visual difficulties.Mild visual difficulties alone do not negatively impact on academic performance at school.Hearing and visual difficulties are prevalent among children in the UK. The majority of affected children have mild, temporary difficulties, which may not be formally diagnosed and for which they do not receive additional educational support. However, there is evidence that even mild deficits in hearing or vision can have implications for learning and development throughout childhood.The most common cause of chronic hearing loss in childhood is persistent otitis media with effusion . There is ongoing controversy regarding the impact of OME on language development and cognition. While several large studies have found no association between OME and language or academic attainment,The impact of common visual difficulties on academic attainment in childhood is not well characterised.The impact of co-occurring common hearing and visual difficulties on educational outcomes in childhood has not previously been studied. However, it is well established that integration of auditory and visual information is essential for many cognitive processes, in particular speech perception, and key for the development of language and communication skills.The aim of this study is to investigate the prevalence and impact of co-occurring common hearing and visual difficulties in childhood on educational outcomes at primary school and secondary school using a large population cohort. We hypothesise that children with co-occurring mild hearing and visual difficulties are more likely to have poorer language and communication skills, and thus lower levels of academic attainment, relative to those with a single sensory deficit or children with normal hearing and vision.The Avon Longitudinal Study of Parents and Children (ALSPAC) is a longitudinal, population-based birth cohort study. All pregnant women residents in Avon, UK, with expected dates of delivery between 1 April 1991 and 31 December 1992 were eligible for participation, resulting in an enrolment of over 14 000 live births.http://www.bristol.ac.uk/alspac/researchers/our-data/.Please note that the study website contains details of all the data that are available through a fully searchable data dictionary and variable search tool: ALSPAC participants advise on ALSPAC studies through the original cohort advisory panel and contribute to the ALSPAC ethics and law committee. ALSPAC participants were not directly involved in the design of this study.All participating children in ALSPAC were invited to attend a research clinic at 7 years of age. Of the children, 59.3% (8299 children) attended during the period September 1998–September 2000, of whom 98.9% (8205 children) were eligible for inclusion see . The cli10.1136/bmjpo-2018-000389.supp1Supplementary file 1Hearing difficulties were defined as the presence of mild-moderate conductive hearing loss and/or OME in either ear, characterised by air conduction greater than 20 dB and less than 70 dB averaged across 500 Hz, 1 kHz, 2 kHz and 4 kHz  were excluded. Triplets, quadruplets and children with Down’s syndrome or cerebral palsy were also excluded from this analysis.Educational outcomes at primary school were assessed using Standardised Assessment Test results, obtained from the National Pupil Database (NPD).Educational outcomes in secondary school were assessed using General Certificate of Secondary Education (GCSE) results at Key Stage 4 (KS4). GCSEs are taken at the end of compulsory schooling (year 11) at age 16 and are graded A*–G. Achievement of 5 or more GCSEs (including Maths and English) at grades A*–C is the national benchmark measure of achievement, and we used this as our single outcome at secondary school. We adjusted outcomes for KS2 attainment, as performance at KS2 is well known to predict performance at GCSEs.Information on children receiving Special Educational Needs (SEN) support was provided by the Pupil Level Annual School Census (PLASC). SEN status was obtained for each child at KS2 and KS4, with information on the level of individual educational support being provided. We dichotomised these data into children receiving no special provision and those receiving some level of support.NPD and PLASC data were not available for children attending independent schools, or schools outside of England, and these children were excluded from this analysis.Gender, prematurity, low birth weight, admission to a special care baby unit (SCBU), maternal age, parity, smoking during pregnancy, duration of breast feeding and socioeconomic status were selected as potential confounding factors, based on their previously identified associations with hearing or visual difficulties in childhood and well-established links with academic performance.The ALSPAC Family Adversity Index, derived from a questionnaire about socioeconomic status completed by mothers at 2–4 years, was used as a measure of family adversity. The Indices of Multiple Deprivations at age 7, a census-derived score of relative deprivation of a neighbourhood, was used as a measure of social deprivation.IQ, attention, social cognition and behaviour were selected as potential mediating factors, as they may be influenced by visual and hearing difficulties and can impact on educational achievement.Binary univariate logistic regressions were used to calculate ORs and 95% CI to assess the relationship between hearing and visual difficulties and educational outcomes. The analyses were repeated, controlling for all potential confounding factors significant at the 5% level in the univariate analyses and all potential mediating factors which fulfilled the Baron and Kenny mediation model steps 1–3.Multiple imputation using chained equations was used to impute missing data for all variables included in the final logistic regression models, including the outcome, and variables that predicted missingness. This technique helps to minimise attrition bias and improve precision of estimates.Of the 8205 children who attended the research clinic at 7 years and were eligible for inclusion, 2909 (33.5%) had complete data for hearing and vision, educational outcomes and potential confounding variables see .Children attending the research clinic were more likely to come from families of higher socioeconomic class and achieve higher levels of academic attainment at both KS2 and KS4 than children who did not attend the clinic  had hearing difficulties, 189 (6.5%) had visual difficulties and 14 (0.5%) had both hearing and visual difficulties. Types of hearing and visual difficulties are demonstrated in Conductive hearing loss was identified in 159 children; 145 of these children (91%) had mild hearing loss , and 14 children had moderate hearing loss . The majority of children with conductive hearing loss had evidence of concurrent OME.The overall prevalence of OME in either or both ears was 6.7%. A higher proportion of children undergoing assessment in winter months had OME compared with those attending clinic in the summer months (8.0% vs 5.6%), but this association was weak (p=0.09).Amblyopia was the most common cause of visual difficulties, affecting 4.4% of all children. There was considerable overlap between amblyopia and strabismus; of the 128 children with amblyopia, 47 (36.7%) also had strabismus.Only seven children had reduced habitual acuity in the best-seeing eye; four children had mildly reduced visual acuity (0.3–0.44 logMAR), and three children had moderately reduced acuity (0.50–0.7 logMAR), with a mean acuity of 0.45 logMAR. These reduced acuities most likely represent uncorrected refractive errors, given that acuity was not assessed with full refractive correction and the exclusion of children with ocular pathology.Children with hearing and visual difficulties had similar characteristics to those with normal hearing and vision  of the study sample achieved five or more GCSEs (including English and Maths) at A*–C grade, which is significantly higher than the national average of 47.6% children achieving this standard the same year.The association between hearing difficulties and poorer performance at GCSEs is attenuated after adjustment for performance at KS2 and IQ, suggesting that the association between hearing and education is mediated through these factors . This relationship is attenuated after adjustment for performance at KS2, suggesting that poorer outcomes at KS4 in these children can be partly explained by poorer educational outcomes at primary school.At KS4, the overall proportion of children receiving SEN support was similar to that at KS2 . Children with visual difficulties were almost twice as likely to receive SEN support than those with normal hearing and vision (see online In this longitudinal study we have demonstrated that co-occurring mild hearing and visual difficulties in childhood have a negative impact on educational outcomes, greater than the effect of hearing or visual difficulties alone. We have shown a weak association between mild hearing difficulties at age 7 and academic achievement at KS2 and KS4, which may be mediated by IQ. We found no negative association between mild visual difficulties and academic outcomes. In contrast, children with co-occurring hearing and visual difficulties were less likely to attain the expected academic standards at the end of primary school, an effect which is not wholly mediated through IQ, behaviour, attention or social cognition, suggesting a substantial, unexplained educational disadvantage. They were also less likely to achieve five or more GCSEs at KS4, which may be attributable to poor performance at KS2. However, this relationship is weak, likely due to the relatively low prevalence of co-occurring mild sensory difficulties and potential small effect size.A higher proportion of children with visual difficulties had SEN status at both primary school and secondary school relative to those with normal hearing and vision. Common visual difficulties, as defined by this study, are of themselves not sufficient to merit SEN support, suggesting a higher prevalence of additional disabilities among children with visual difficulties. This is consistent with previously reported findings.The major strength of this study is that it uses a large population-based birth cohort, with an accurate assessment of hearing and vision. Furthermore, it uses standardised national tests as objective outcome measures, and longitudinally collected data on a wide range of confounders.The most important limitation of this study relates to missing data and the under-representation of children from ethnic minorities and those from lower socioeconomic backgrounds. A multiple imputation technique was used to minimise potential bias and improve precision. An additional limitation is the single time-point used to assess hearing, and possible inclusion of children with transient OME as a result, which may have led to underestimation of the effect of persistent OME-related hearing loss on academic attainment. Furthermore, we did not have information regarding which children were treated for their hearing and visual difficulties either prior or following the assessment at age 7. Finally, while we excluded children with known diagnoses of Down’s syndrome or cerebral palsy, we did not have full data regarding developmental disorders or medical comorbidities. However, such conditions affect only a small minority of children with hearing or visual difficulties, and this was a population-based study designed to evaluate the impact of common, mild difficulties.Previous studies investigating the impact of co-occurring hearing and visual difficulties in childhood have focused on children with severe deficits. Developmental disorders commonly co-occur with severe hearing and visual difficulties, or ‘deaf-blindness’,The impact of childhood OME on cognition and educational performance has been studied previously by prospective cohort studies, although there is no clear consensus. Data from the longitudinal Dunedin Study demonstrated an association between childhood OME and lower IQ in early teenage years,Previous research investigating the impact of common visual difficulties in childhood on educational outcomes has focused largely on refractive errors, which were not included in this study.Furthermore, we demonstrated higher rates of SEN among children with visual difficulties; this is consistent with previous research demonstrating that visual difficulties commonly co-occur with developmental disorders.This study has important clinical implications. Children with known visual or hearing difficulties should be routinely tested for additional sensory difficulties, as even mild co-occurring visual or hearing deficits are associated with poorer educational outcomes. The impact of co-occurring hearing and visual difficulties on performance at secondary school is largely explained by poor performance at primary school; hence, early identification and intervention is essential.Future research involving larger numbers of participants are required to replicate these findings and elucidate further the factors mediating this association. We recommend that future investigators focus next on the role of reading and language skills as potential mediators which could explain these findings.


This study examined the extent to which cognitive ability at 5 years of age predicted language development from 5 to 9 years of age in a population-based sample of children with hearing loss who participated in the Longitudinal Outcomes of Children with Hearing Impairment (LOCHI) study. The developmental outcomes of 81 children with hearing loss were evaluated at 5 and 9 years of age. Hearing loss ranged from mild to severe degrees, and all participants used hearing aids. They all used spoken language as the primary mode of communication and education. Nine-year-old language was assessed using the Clinical Evaluation of Language Fundamentals – 4th edition (CELF-4), the Peabody Picture Vocabulary Test – 4th edition (PPVT-4), and the Expressive Vocabulary Test – 2nd edition (EVT-2). Multiple regression analyses were conducted to examine the extent to which children’s scores on these standardized assessments were predicted by their cognitive ability  measured at 5 years of age. The influence of early language scores at 5 years and a range of demographic characteristics on language scores at 9 years of age was evaluated. We found that 5-year-old digit span score was a significant predictor of receptive and expressive language, but not receptive or expressive vocabulary, at 9 years of age. Also, 5-year-old non-word repetition test score was a significant predictor of only expressive language and vocabulary, but not receptive language or vocabulary at 9 years of age. After allowing for the effects of non-verbal IQ and 5-year-old receptive vocabulary, early digit span score (but not non-word repetition score) was a significant predictor of expressive and receptive language scores at 9 years of age. The findings shed light on the unique role of early verbal working memory in predicting the development of receptive and expressive language skills and vocabulary skills in children who use hearing aids. Children with hearing loss achieve lower language outcomes, on average, than children with normal hearing. Findings from a recent, population-based study, the Longitudinal Outcomes of Children with Hearing Impairment or “LOCHI” study, show that 5-year-old children with hearing loss are about 0.5–1 SD on average behind their normally hearing peers on standardized tests of receptive and expressive language and receptive vocabulary . AverageMuch of the past research on this topic has focused on the association between executive function and language outcomes achieved by cochlear implant users. This focus has often been underpinned by a theoretical perspective in which early exposure to sound is seen as vital for the typical development of cognitive abilities that relate to the representation and processing of sequential information, which in turn is associated with language development . AlthougIn a study of 64 cochlear implant users and 74 normally hearing peers, ages 7–27 years, In accordance with the need for longitudinal studies to address questions of development, Several recent studies of cochlear implant users have provided evidence that early language abilities are a good predictor of later language and cognitive outcomes. Further supporting evidence comes from In a similar vein, as noted earlier, both expressive vocabulary and executive function using a battery of explicitly non-verbal measures. By contrast, assessments of cochlear implant users often targeted receptive vocabulary and verbal measures of cognitive ability. It is unknown the extent to which these differences in participant samples and methodology might have influenced the findings, but what is apparent is the need for further systematic investigation into whether early measures of cognitive ability predict later language outcomes in children with mild to severe hearing loss who use hearing aids.In comparing the results of the studies by The current study addressed this gap in the literature. The participant sample was drawn from the cohort taking part in the population-based LOCHI study in which children with hearing aids outnumber those with cochlear implants approximately 2:1. Although the advent of universal newborn hearing screening has made it possible for early detection and fitting of hearing devices to children with permanent childhood hearing loss, it remains uncertain as to whether those at risk for suboptimal long-term outcomes for speech and language may be identified through early measures of speech, language, and working memory. We took advantage of the prospective nature of the LOCHI study to examine the influence of early cognitive and language abilities on later language abilities for children with permanent hearing loss using hearing aids. The study measured outcomes of a population-based cohort of about 450 children in Australia who were born with hearing loss and received hearing intervention before 3 years of age. Details of the study have been reported in From a theoretical perspective, we drew on the multi-component model of working memory described by In the current study, the capacity of the phonological loop was measured using both memory span for digits and non-word repetition (the ability to repeat an unfamiliar spoken form). These measures were selected in light of positive results from previous research with normally hearing children e.g., . LanguagThe research questions addressed in the study were as follows:1.Does the capacity of the phonological loop, assessed at 5 years of age, predict 9-year-old outcomes in receptive and expressive language and vocabulary in a population-based sample of hearing aid users after controlling for variation in non-verbal cognitive ability and relevant demographic variables? If so, which measure of 5-year-old phonological short-term memory, digit span, or non-word repetition, is more strongly associated with 9-year-old outcomes?2.Does the capacity of the phonological loop, assessed at 5 years of age, predict 9-year-old outcomes in receptive and expressive language and vocabulary in a population-based sample of hearing aid users after controlling for 5-year-old receptive vocabulary, non-verbal cognitive ability, and relevant demographic variables? If so, which measure of 5-year-old short-term memory, digit span, or non-word repetition, is more strongly associated with 9-year-old outcomes?In accordance with the working memory theoretical framework and empirical findings from previous literature with cochlear implant users e.g., , we hypoThe Australian Hearing Human Research Ethics Committee approved the protocols used in the current study. Participants in the LOCHI study were included if they continued to use hearing aids by 9 years of age, and completed direct assessments of cognitive and spoken language abilities at 5 and 9 years. Data on measures of 81 participants in the LOCHI study were included in this report. Parents of participants provided written informed consent to the protocol approved by the local institutional human research review board. As part of the LOCHI study, each child was assessed directly by research speech pathologists on norm-referenced tests using standard protocols when they turned 5 and 9 years of age. All data were audited and checked for reliability by double scoring 10% of the evaluations.The 5-year-old assessment battery included the PPVT-4 , the MemThe PPVT-4 is a standardized test of receptive vocabulary, using a four-alternative-forced choice, picture-pointing format in administration. It gives an overall score on receptive vocabulary.The EVT is a standardized test of expressive vocabulary. It gives an overall score on expressive vocabulary.The MD subtest of the CTOPP is a standardized test of capacity of the phonological loop. Recorded digits are presented at a rate of two per second, and forward-only recall is measured. It gives an overall score on phonological short-term memory.The NRT is another measure of the phonological loop  in shortThe WNV is a standardized test of non-verbal cognitive ability. It gives a full-scale IQ score.The CELF is a standardized test of spoken English. The test includes verbal tasks which enable children to demonstrate understanding of and ability to produce English language structures. It gives an overall core language score, and two subtest scores – receptive language and expressive language. It also gives a language memory score.Parents were requested to complete a custom-designed questionnaire to provide demographic information. Audiological information was retrieved from individual clinical files, with permission from parents. All hearing level information and hearing device information were current within 6 months of the evaluation, and at a time closest to the actual evaluation date for each child.Descriptive statistics were used to report quantitative outcomes for each measure. To examine the relations between early measures of language and working memory at 5 years of age and later language outcomes, correlational analyses were carried out. To determine whether any relations found between early working memory remained after accounting for the effects of early language abilities and other demographic variables and non-verbal intelligence, multiple linear regression analyses were conducted. Two models were fitted with the 9-year CELF Receptive Language and Expressive Language standard scores as dependent variables with repeated measures. In the first model, age at hearing aid fitting, maternal educational level (three categories: university vs. certificate or diploma vs. schooling of 12 years or less), degree of hearing loss , and 5-year-old standard scores for WNV, MD, and NRT were used as independent variables to predict 9-year-old language outcomes. The second model included all predictor variables together with 5-year-old PPVT scores to examine the effects of early cognitive measures after allowing for the effect of early language ability. To investigate the relationship between early measures and later vocabulary outcomes, two separate models were fitted in the same manner, but using 9-year-old PPVT scores and EVT scores as dependent variables. Statistical significance was set at the 0.05 level.Demographic characteristics of participants in this study are reported in Descriptive statistics for the scores of each of the outcome measures are shown in Correlations between language scores and non-verbal IQ at 9 years of age and characteristics at 5 years of age are shown in Regression models predicting language and vocabulary at 9 years of age are shown in This study reports findings that extend current knowledge, focusing on the early cognitive predictors of later language abilities in a prospective cohort of children who received early intervention for mild to severe hearing loss using HAs. On average, children’s receptive and expressive language scores were around 1 SD below the normative mean, whereas vocabulary scores were within −0.5 SD of the mean.p > 0.05; To address the first research question of whether the capacity of the phonological loop assessed at 5 years of age predicted 9-year-old language outcomes, we found that higher digit span and non-word repetition scores at 5 years of age were significantly associated with better language and vocabulary skills measured at 9 years of age. Of the early cognitive predictors, 5-year-old digit span score was a significant predictor of receptive and expressive language but not receptive or expressive vocabulary. Further, 5-year-old NRT score was a significant predictor of only expressive language and vocabulary, but not receptive language or vocabulary. We also found that higher maternal education and higher non-verbal ability were significantly associated with higher language and vocabulary scores at 9 years of age. However, the regression analyses revealed that only non-verbal ability accounted for unique variance. The failure to find a unique contribution of maternal education is probably not due to its association with non-verbal IQ because the correlation between them is not significant . In an earlier report , we showFuture investigations on predictors of language outcomes of children using hearing aids at 9 years will need to include a wider range of factors reported in the literature e.g.,  than wasWe conclude that early phonological short-term memory assessed using a digit span task significantly predicted later expressive and receptive language abilities, even after allowing for the effect of early receptive vocabulary. Future studies will examine the importance of phonological working memory in speech perception in children with hearing loss.The datasets for this study will not be made publicly available because the ethics approval for this study does not include the dissemination of the dataset.This study was carried out in accordance with the recommendations of the ethics guidelines of the Australian Hearing Human Research Ethics Committee with written informed consent from all subjects. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the Australian Hearing Human Research Ethics Committee.TC conceptualized and designed the study, took overall responsibility for all aspects of the study, and drafted the manuscript. LC consulted in the design of the study, and drafted and reviewed the manuscript. VM coordinated the acquisition of data and collation of data, and reviewed the manuscript. TC, LC, and VM approved the final manuscript as submitted.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Cathepsin Z mRNA level strongly correlated with low bone mineral density (BMD) (g/cm2), lumbar spine L2-L4 and femoral neck (T-scores) . Importantly, cathepsin Z mRNA was significantly associated with fragility fracture in osteoporosis patients (P = 0.0018). The levels of cathepsin Z mRNA were not significantly higher in patients with chronic inflammatory disorders in these two groups compared to those without . ROC analysis showed that cathepsin Z mRNA has strong diagnostic value for osteoporosis and osteoporotic fracture. The results show for the first time that cathepsin Z could be a future diagnostic biomarker for osteoporosis including female osteoporosis patients over the age of 50 years.Osteoporosis, one of the most prevalent chronic ageing-related bone diseases, often goes undetected until the first fragility fracture occurs, causing patient suffering and cost to health/social care services. Osteoporosis arises from imbalanced activity of osteoclasts and osteoblasts. Since these cell lineages produce the protease, cathepsin Z, the aim of this study was to investigate whether altered cathepsin Z mRNA levels are associated with osteoporosis in clinical samples. Cathepsin Z mRNA in human peripheral blood mononuclear cells was significantly differentially-expressed among non-osteoporotic controls, osteopenia and osteoporosis patients ( Osteoporosis often goes undetected until the first fragility fracture occurs, which causes unnecessary suffering to the patient and cost to the health service1. Thus, there is a need to identify biomarkers that could be exploited, in the future, for a clinical test that could indicate the presence of osteoporosis before fragility fracture occurs.Osteoporosis is one of most common chronic ageing-related bone diseases in the world3 and bone-synthesising osteoblasts derived from mesenchymal stem cells4. The lysosomal cysteine protease, cathepsin Z, believed to be encoded by the same mRNA sequence as cathepsin X (NCBI reference sequence NM_001336), is highly expressed in cells of the immune system. In particular, it is expressed in T-lymphocytes5 and monocytes6 the latter being precursors of osteoclasts7, which produce the related protease, cathepsin K that has been shown to be required for bone resorption8. Both T-lymphocytes and monocytes are components of the peripheral blood mononuclear cell (PBMC) fraction that can be isolated from whole blood9. In addition, cathepsin Z protein has been reported to be secreted by human osteoblasts10 and thus cathepsin Z appears to be produced in cells of both osteoclast and osteoblast lineages.Osteoporosis is thought to arise from an imbalance between the activity of bone degrading osteoclasts, derived from monocyte lineages of immune cells11. A genome wide association study into the genetic factors that may be associated with fragility fractures arising from the treatment of estrogen-receptor-positive breast cancer patients with aromatase inhibitor, identified a single-nucleotide polymorphism in or near a 3-gene cluster on chromosome 20 containing the cathepsin Z gene. This polymorphism was shown to be associated with the occurrence of fragility fractures11. Using an osteoblast cell culture model system, the estrogen-receptor dependence of cathepsin Z gene expression was demonstrated in these cells. The polymorphism not only affected the expression of the cathepsin Z gene, but experimental knockdown of cathepsin Z levels affected the expression of osteoporosis-associated genes11, suggesting an association between cathepsin Z expression, fragility fracture and the expression of osteoporosis-related genes in an estrogen-reduced, clinical situation. However, the direct effect of cathepsin Z on other cell activities was not studied.Alterations in the expression of the cathepsin Z gene have been linked, bioinformatically, to fragility fractures in cancer patients in association with reduced levels of circulating estrogenThat cathepsin Z is found in both osteoblast and osteoclast lineages of cells, the two cell types predominantly dysregulated in osteoporosis, raises the possibility that the occurrence of osteoporosis in human subjects might be associated with changes in cathepsin Z expression in these cells. In the present experiments, it is shown that levels of cathepsin Z mRNA in clinical samples of peripheral blood mononuclear cells are significantly associated with osteoporosis, low bone mineral density and occurrence of fragility fractures.T-Score were obtained following standard clinical procedures. Participants were categorised into three groups based on their T-Scores: a non-osteoporotic control group having T score ≥−1.0, an osteopenia group with T score <−1.0 and >−2.5 and an osteoporosis group with T score ≤−2.5  and seven female osteoporosis patients were being treated with bisphosphonate, such as Alendronate, Ibandronate, Risedronate and zoledronic acid. Two female osteoporosis patients were being treated with Denosumab.P < 0.0001; non-osteoporotic control group vs osteopenia, 95% CI = −0.32 to −0.053, P = 0.0067; non-osteoporotic control group vs osteoporosis, 95%CI = −0.543 to −0.24, P = < 0.0001; osteopenia vs osteoporosis, 95% CI = −0.325 to −0.084, P = 0.0011, post hoc Bonferroni correction).Cathepsin Z mRNA levels were measured by RT-qPCR in PBMCs from the non-osteoporotic control group, the osteopenia group and the osteoporosis group as shown in Fig. P < 0.0001; non-osteoporotic control group vs osteopenia, 95% CI = −0.39 to −0.051, P = 0.0113; non-osteoporotic control group vs osteoporosis, 95% CI = −0.604 to −0.234, P = < 0.0001; osteopenia vs osteoporosis, 95% CI = −0.324 to −0.072, P = 0.0025, post hoc Bonferroni correction).The significant increases in cathepsin Z mRNA levels in osteopenia/osteoporosis were also evident when 11 participants who were below the age of 50 were excluded from the analysis Fig.  ; nor when 19 patients (12 osteopenia and 7 osteoporosis) with non-osteoporotic disorders were excluded , suggesting that all the sample results were not subject to bias from age, osteoporosis treatment or the presence of other diseases in this cohort.The results were not affected when 17 participants (8 osteopenia and 9 osteoporosis) receiving treatment for osteoporosis were excluded from the analysis Fig.   and the results were not affected when 14 patients (5 osteopenia and 9 osteoporosis) receiving treatment for osteoporosis were excluded as shown in Fig. P = 0.0012; Fig. P = 0.038; non-osteoporotic control group vs osteoporosis, 95% CI = −0.716 to −0.231, P = 0.0003; osteopenia vs osteoporosis, 95% CI = −0.461 to −0.072, P = 0.0084, post-hoc Bonferroni correction). When 13 patients (8 osteopenia and 5 osteoporosis) with non-osteoporotic disorders were excluded, there was no change to the overall result , or to the relationship between the osteoporosis and the non-osteoporotic control group  or to the relationship between the osteoporosis and osteopenia groups . However, there was a slight loss of significance between the non-osteoporotic control group and osteopenia group .The strong, significant increase in cathepsin Z mRNA levels in osteopenia and osteoporosis patients compared to the non-osteoporotic control group was also found when the analyses were confined to the 63 female participants over the age of 50-years as shown in Fig. ult Fig.  . However, it is also possible that the elevated levels of cathepsin Z mRNA could be a consequence of underlying chronic viral infections. The levels of the mRNA for γ interferon inducible protein, IFI16, were determined in the PBMCs of osteopenia and osteoporosis patients. IFI16 is associated with myeloid differentiation and is expressed in CD14+ monocytes13. However, unlike for cathepsin Z mRNA, there was no significant difference in IFI16 mRNA levels between non-osteoporotic controls, osteopenia and osteoporosis patients, either when all participants were included  = 0.612), P = 0.546). Furthermore, there was no significant difference in IFI16 mRNA levels between osteopenia and osteoporosis patients who were also suffering from chronic inflammatory disorders and those that were not, either when all osteopenia/osteoporosis patients . The results suggest that neither chronic inflammatory disorders nor chronic viral infections account for the observed increase in cathepsin Z mRNA levels in the osteopenia/osteoporosis patients compared to non-osteoporotic controls.Patients with chronic inflammatory diseases often suffer osteoporosis-like conditionsT-score , significantly inversely with femoral neck T-score  and significantly inversely associated with bone mineral density (BMD) (g/cm2) , strengthening the observed relationship between cathepsin Z mRNA levels and osteoporosis.Overall, the levels of cathepsin Z mRNA in isolated PBMCs were significantly inversely-associated with bone mineral density Fig. : mean luore Fig.   Fig.   or for the osteopenia patients , suggesting that cathepsin Z mRNA levels were not, per se, a consequence of the occurrence of the fracture in these groups. However, for the osteoporosis group of patients, those patients with previous fractures exhibited levels of cathepsin Z mRNA that were highly significantly higher than for those without previous fractures . Thus, an increase in cathepsin Z mRNA in patients’ PBMCs was associated with reduced bone density using three clinical measures, lumbar and femoral T-score and BMD and with fracture in osteoporosis patients.When the non-osteoporotic, osteopenia and osteoporosis patient groups were divided into those with and without previous fractures, there was no significant difference in the level of cathepsin Z mRNA between those with or without fracture for the non-osteoporotic control subjects Fig.  , stronger than the moderate accuracy for osteopenia vs non-osteoporotic control group  curve analysis was performed. The diagnostic values of cathepsin Z mRNA in clinical samples for osteoporosis patients vs the non-osteoporotic control group was of high accuracy Fig. 14 . Thus, we cannot rule out entirely the possibility that cathepsin Z levels are, in part, a function of age for all participants. However, the increase in cathepsin Z mRNA level in osteopenia/osteoporosis was also observed when male and female participants over the age of 50, or female participants over the age of 50 were analysed. In these cases, the ages of the osteopenia and osteoporosis groups were not significantly different from the non-osteoporotic controls . These observations suggest that at least for participants over the age of 50, age is not an important factor in the increase of cathepsin Z mRNA in osteopenia/osteoporosis.Cathepsin Z mRNA has been shown for the first time to be significantly elevated in the PBMCs of patients with either osteopenia or osteoporosis compared to non-osteoporotic controls. For all participants, the mean ages of the non-osteoporotic control, osteopenia and osteoporosis groups were significantly different at 56, 65 and 69 years with the ages of the osteopenia and osteoporosis groups being significantly different from the non-osteoporotic control group . The results suggest that the increase in cathepsin Z mRNA in patients’ PBMCs was independent of chronic inflammation, at least in this group of patients. Similarly, no evidence was found for cathepsin Z mRNA levels being associated with virally-induced inflammation via the γ interferon pathway, although a more direct assessment of chronic inflammation, by directly assaying the blood levels of inflammatory cytokines, such as tumour necrosis factor 15 would help to confirm these findings.That the PBMC preparations consist predominantly of immune cells raises the possibility that the observed osteoporosis-related increase in cathepsin Z mRNA reflects a change in the immune state of the osteopenia/osteoporosis patients relative to the normal controls. For example, osteoporosis could be a co-morbidity with chronic inflammatory disorders9, dendritic cells6 and CD14+, CD16− monocytes7, some of the latter being precursors of osteoclasts7. Cathepsin Z mRNA/protein has been reported to be present at varying levels in all these cell types6. Thus, in the present study, the precise cell type that is the source of the elevated cathepsin Z mRNA is unknown. It has been reported, using PBMC preparations, that the mature form of cathepsin Z interacts with lymphocyte function-associated antigen-1 (LFA-1), a β-2-integrin on the surface of T lymphocytes16. Using specific cathepsin Z inhibitors, this interaction has been shown to alter T lymphocyte behaviour, for example, increasing activated proliferation rates in PBMCs16 and migration, invasion and aggregation using a cultured T cell line5. Cathepsin Z can also alter the behaviour of differentiated monocytes, by interacting with the Mac-1 β2-integrin17. Thus, the presence of elevated levels of cathepsin Z mRNA/protein in the PBMC cells of osteoporosis patients, might be associated with altered behaviour of monocytes and T lymphocytes. Whilst monocytes are the precursors of osteoclasts7, the role of T lymphocytes and the various subtypes in osteoporosis has been recognised, but is not yet fully understood18.Cathepsin Z mRNA was measured in PBMC preparations from human subjects. Such preparations contain many types of circulating cells of the immune system, including both B and T lymphocytes19. Furthermore, the observation that subjects with osteopenia also showed a significant increase in cathepsin Z mRNA compared to non-osteoporotic controls, strongly suggests that if replicated in a larger study, the cathepsin Z mRNA in patients’ PBMC preparations could form the basis of a test for osteoporosis, which could aid in the detection of osteoporosis before a critical and expensive fragility fracture occurs.Irrespective of the biological effects of cathepsin Z, it has now been shown for the first time here that the increase in cathepsin Z mRNA in isolated PBMC fractions is very strongly diagnostic for osteoporosis, at least in the patient group studied. Overall, using the optimal cut-offs shown in Fig. 20. Informed consent was obtained from all participants prior to sample collection. Participants were recruited from referrals to the Nuclear Medicine Department for a bone density scan at the Royal Liverpool University Hospital. In accordance with WHO guidelines on the diagnosis of osteopenia and osteoporosis, T scores of left femoral neck and lumbar spine (L2–4) were used.The study conformed to the principles of the Helsinki Declaration and was carried out under ethical approval from the England Health Research Authority National Research Ethics Service Committee, East of England-Essex [REC reference 15/EE/0051] Ethics Committee. The inclusion and exclusion criteria for this study were as described previouslyBlood samples from participants were drawn into 9 mL S-Monovette® K3E, Potassium EDTA tubes by phlebotomists following a standard Safety Protocol. After centrifuging at 2,500 g (Thermo Heraeus Multifuge 3SRT centrifuge) for 30 min at room temperature, the buffy coat was transferred to a  15 mL centrifuge tube and diluted with an equal volume of Dulbecco’s Phosphate Buffered Saline (DPBS). 3 mL of Ficoll-premium (1.077 g/mL) solution was added into the bottom of a Greiner Bio-One 10 mL Leucosep® tube and centrifuged for 1 min at 900 g, to descend the porous barrier. Around 6 mL of DPBS-diluted blood samples were carefully pipetted down the side of the Leucosep® tube held at 45 degrees and the tube was centrifuged at 900 g at room temperature for 30 min. The interface layer containing the PBMCs was then collected into a new sterile 15 mL tube, and washed with DPBS, followed by centrifuging at 1,000 g at room temperature for 5 min to discard the supernatant. Cell pellets were then suspended with 10 mL of cold ammonium-chloride-potassium lysing buffer, and incubated at 4 °C for 1 min, followed by centrifuging at 2,500 g for 5 min at 4 °C. The pellets were washed twice using 10 mL DPBS, centrifugation at 2,500 g at room temperature for 5 min. Finally, the cell pellets were suspended with 0.5 mL DPBS, and transferred into 1.5 ml tubes and centrifuged at 14,000 g at 4 °C for 2 min to form a tight cell pellet, which was stored at −80 °C until required for further analysis.Total RNA from human PBMC cells was extracted using a combination of TRIzol reagent and PureLinkRNA mini kit , according to the manufactures’ recommendations. The resulting purified RNAs were eluted in 30 μL of RNase-free water and stored frozen at −80 °C until used. RNA concentrations and purity were measured using a Thermo Scientific NanoDrop™ 2000 spectrophotometer.−ΔΔCT method21. All Ct values obtained from RT-qPCR greater than 35 were considered to be below the detection level of the reaction.Reverse transcription and RT-qPCR reactions were carried out using RT-First Strand kit, RT-qPCR Primer Assays and SYBR Green PCR kit , according to the manufacture’s recommendations. Briefly, 500 ng of purified RNA was reverse transcribed in 20 μL reactions using an RT-PCR kit (Qiagen). A separate reaction, in which RNase-free water replaced reverse transcriptase, provided a no-DNA control for subsequent RT-qPCR. Reverse transcription reactions were diluted 1:20 with RNase-free water prior to RT-qPCR amplification. RT-qPCR analyses were conducted in duplicate in 10 µL volume using RT-qPCR primer assays for human cathepsin Z or glyceraldehyde-3-phosphate dehydrogenase (GPDH) and SYBR Green PCR kit  using a Roche LightCycler 96 Real-Time PCR system . The no-reverse transcriptase control sample was included for each RT-qPCR amplification. All primers used for RT-qPCR in this study are listed in Supplemental Table 20. Other statistical analyses were carried out using Stats Direct 3 software . P values of < 0.05 were considered significant.RT-qPCR results were statistically analysed as described previouslySupplementary information


Plant growth-defense tradeoffs are fundamental for optimizing plant performance and fitness in a changing biotic/abiotic environment. This process is thought to involve readjusting resource allocation to different pathways. It has been frequently observed that among secondary cell wall components, alteration in lignin biosynthesis results in changes in both growth and defense. How this process is regulated, leading to growth or defense, remains largely elusive. In this article, we review the canonical lignin biosynthesis pathway, the recently discovered tyrosine shortcut pathway, and the biosynthesis of unconventional C-lignin. We summarize the current model of the hierarchical transcriptional regulation of lignin biosynthesis. Moreover, the interface between recently identified transcription factors and the hierarchical model are also discussed. We propose the existence of a transcriptional co-regulation mechanism coordinating energy allowance among growth, defense and lignin biosynthesis. Lignin is a heterogeneous polymer of monolignols and is polymerized at the surface of the cell walls. The three essential monolignols of plant lignin are p-hydroxyphenyl (H), guaiacyl (G), and syringyl (S) units . Lignin The biosynthesis process of lignin has attracted much attention as lignin is the major contributor to the recalcitrance of biomass feedstocks , dramatiGiven the extensive biological and industrial importance of lignin, the understanding of lignin biosynthesis in plants is beneficial for both agricultural and industrial purposes. In this review, we summarize the current understanding of the lignin biosynthesis process and its transcriptional regulation. We then offer a working hypothesis on the transcriptional coordination of energy flux among plant growth, defense, and lignin biosynthesis.Arabidopsis. Genetic modulation of these enzymes has been shown to dramatically alter the accumulation and/or composition of lignin.In plants, there are two major steps to produce lignin: monolignol biosynthesis and monolignol polymerization via free radical coupling. Enzymes catalyzing monolignol biosynthesis have been well defined in the model plant Arabidopsis, monolignols are synthesized from phenylalanine via the phenylpropanoid pathway. Therefore, most key phenylpropanoid biosynthetic enzymes are also critical for lignin biosynthesis. A recent study of 221 independent transgenic Populus lines has demonstrated the importance of phenylpropanoid biosynthetic enzymes for lignin biosynthesis in Populus , p-coumaroylshikimate 3′-hydroxylase (C3′H), caffeoyl shikimate esterase (CSE), caffeic acid O-methyltransferase (COMT), and caffeoyl-CoA O-methyltransferase (CCoAOMT), which work downstream of 4CL, are also indispensable for normal lignin biosynthesis . In Arabidopsis, the down-regulation of HCT and C3′H has been shown to induce the enrichment of H units in lignin polymers  also exhibits reduced lignin content, as well as reduced G units  did not change lignin content in switchgrass . The down-regulation of F5H can result in significant increase of G units in lignin .In addition to enzymes involved in the general phenylpropanoid pathway, enzymes specific for lignin biosynthesis have been identified and characterized, including cinnamoyl-CoA reductase (CCR), ferulate 5-hydroxylase (F5H), cinnamyl alcohol dehydrogenase (CAD) . These ln lignin . Arabido S units . BesidesArabidopsis have illustrated the close relationship between these enzymes and lignin accumulation in secondary cell walls. Arabidopsis peroxidases  have 11–25% reduction in lignin content (Arabidopsis (LAC4 and LAC17) in Arabidopsis  . With fewer steps, the tyrosine shortcut pathway is energetically more efficient than the canonical lignin biosynthesis pathway. The tyrosine shortcut pathway is capable of guiding carbon and electrons into the biosynthesis of lignin via skipping the production of cinnamate, which is the essential precursor of benzenoid volatiles and salicylic acid. Therefore, the discovery of the tyrosine shortcut pathway provides an alternative approach to optimize the energy investment of lignin production. Although PTAL activity has been detected in some non-grass species, such as tobacco callus and castor bean endosperm (A recent study of the model grass er steps . In thise (PTAL) . Consequndosperm , the invFigure 1; In addition to the H, G, and S units of lignin, a natural lignin  solely containing an unusual Catechyl (C) unit was found in seed coats of vanilla orchid and most Cactoidae genera , 2013. IFigure 2).A key finding of lignin biosynthesis studies is that AC elements widely exist in the promoters of major phenylpropanoid and lignin biosynthetic genes . AC elemArabidopsis, MYB46 and MYB83 have been found to activate the expression of PAL1, C4H, 4CL1, C3′H1, HCT, CCoAOMT, CCR1, F5H1, CAD6 genes via binding to AC elements in the promoters of these genes  were also found to be functional in the regulation of lignin biosynthesis  were capable of triggering ectopic lignin deposition in Arabidopsis and Populus plants  and its close homologs NST1, NST2, VASCULAR-RELATED NAC DOMAIN6 (VND6), and VND7 regulate lignin biosynthesis in bidopsis . Similar vessels . In cont vessels ], siliqu vessels ], and an vessels ]. Howevey growth . In monoy growth .Figure 2). Similarly, MYB46/MYB83 directly activates MYB58, MYB63, and MYB85, and they together directly activate lignin biosynthetic genes . These feed-forward loops are probably to ensure the robust regulation of lignin biosynthesis. Besides feed-forward loops, the NAC-MYB network also contains feed-back regulations to fine-tune lignin biosynthesis . For example, SND1 and VND7 were found to directly target and activate the expression of themselves in Arabidopsis, representing positive feed-back regulation  and ASL19/LBD30 genes are activated by VND6 and VND7  in Populus (Populus homolog of 5-enolpyruvylshikimate 3-phosphate (EPSP) synthase, an enzyme catalyzing the shikimate pathway. Aside from the well-established enzyme function of EPSP synthase, PtrEPSP-TF can act as a transcriptional repressor. Genetic and molecular studies further revealed that PtrEPSP-TF activates PtrMYB021 expression and lignin biosynthesis by inhibiting the expression of a transcriptional repressor of PtrMYB021, which is named PtrhAT (Arabidopsis), woody perennial plants  have extensive secondary cell wall thickening over multiple growing seasons. The discovery of the additional regulatory loop of MYB46 in Populus supports the existence of woody plant-specific regulatory mechanisms in lignin biosynthesis. Moreover, the discovery of an activator (PtrEPSP-TF) and repressor (PtrhAT) of MYB46 provides alternative approaches to fine tune lignin biosynthesis.Using genome-wide association studies (GWAS), a novel transcription factor was identified that regulates the expression of  Populus . This trd PtrhAT . Differed PtrhAT . Howeverd PtrhAT . As oppoArabidopsis have demonstrated crosstalk among lignin biosynthesis, growth, and defense. Meanwhile, the complexity of the crosstalk is demonstrated by these studies. To date, the relationship of lignin content with growth and defense remains unpredictable due to the limited understanding of the underlying mechanisms.Crosstalk among biological processes is widespread. Genetic studies in C4H and CCR1, was found to co-occur with the suppression of growth rate (C3′H mutant (ref8-1) illustrated that the growth suppression of ref8-1 might be due to the flavonoid hyperaccumulation, rather than the impaired lignin biosynthesis  displayed enhanced disease resistance, which was thought to be caused by cell wall integrity damage-triggered high immunity level  and the expression of PATHOGENESIS-RELATED (PR) genes  genes ,b.Arabidopsis HCT mutant further illustrated the crosstalk among lignin biosynthesis, growth, and defense. HCT mutant has reduced lignin content, stunt growth, and enhanced defense  has been shown to uncouple growth and defense, resulting in plants displaying more growth and more defense  of one subunit of the transcriptional co-regulatory complex Mediator (MED5b) was found to exhibit the dwarfism phenotype, as well as repressed phenylpropanoid and lignin production (MED5b is capable of rescuing both the growth and lignin biosynthesis deficiencies of the C3′H mutant (Medicago WRKY transcription factor gene WRKY W109669 in tobacco was shown to enhance the accumulation of lignin and the transcription of PATHOGENESIS-RELATED 2 (PR2) gene (Gossypium barbadense ethylene response-related factor gene (GbERF1-like) also demonstrated the transcriptional co-regulation of defense and lignin biosynthesis. Overexpression of GbERF1-like in Arabidopsis significantly enhanced the transcription of phenylpropanoid/lignin biosynthetic genes , as well as pathogenesis-related genes including PR3, PR4, and PLANT DEFENSIN1.2 (PDF1.2)  gene , which iR2) gene . A recen(PDF1.2) . Moreovenfection .Arabidopsis have demonstrated the possibility of the transcriptional co-regulation of growth, defense, and lignin biosynthesis. In mutants of C4H and CCR1, which display significantly reduced lignin accumulation, many defense-responsive genes and many growth-related genes  are down-regulated  and defense (to fight against pathogens). The competition for energy suggests that growth and defense of plants may have a negative relationship, which means the activation of defense processes negatively affect the growth and reproduction of plants. Such tradeoffs between growth and defense have been observed in many studies . AlthougLignin biosynthesis is traditionally thought as one indivisible part of plant growth and defense, to provide structural support, transport water, and act as physical barrier. However, discoveries of transcriptional mechanisms underlying the crosstalk of lignin biosynthesis, growth, and defense suggest the possibility to unlock lignin biosynthesis from growth and defense. On the other hand, lignin accounts for approximately 30% of the organic carbon in the biosphere . This laArabidopsis are well established. Although the lignin biosynthesis process has been well-studied and monolignol biosynthetic enzymes have been systematically analyzed in woody plants, such as Populus, the regulation of lignin biosynthesis remains poorly understood. The regulatory mechanism in a woody perennial plant is much more complex than that in Arabidopsis, due to the complex genome and long life-cycle. With the application of genome-wide approaches, such as GWAS, expression quantitative trait loci (eQTL), and expression quantitative trait nucleotide (eQTN) mapping, in plant studies, it is plausible to identify causal genes affecting complex traits including lignin biosynthesis. Together with efficient post-GWAS characterization and validation, species-specific mechanisms of lignin biosynthesis can be defined.To date, the lignin biosynthesis process and its regulatory mechanism in the model plant Arabidopsis. A comprehensive understanding of this transcriptional hub will have significant impacts on the field of bioengineering. Current studies of NAC-MYB network are restricted in secondary cell wall biosynthesis, although RNA-seq analyses have illustrated that NAC and MYB transcription factors can induce broader gene expression changes. By identifying genome-wide targets of secondary cell wall-related NAC and MYB transcription factors using ChIP-seq, molecular mechanisms linking lignin biosynthesis, growth, and defense are expected to be discovered. In the woody plant Populus, although data is relatively limited, our recent study demonstrated the transcriptional co-regulation of lignin biosynthesis and defense. A defense-responsive WRKY transcription factor was found to regulate the expression of a Populus HCT gene (PtHCT2)  . With thMX drafted the manuscript. JZ, TT, GT, J-GC, and WM revised the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Hearing loss is a marker of risk for cognitive decline and dementia. Controlled hearing intervention studies of long-term cognitive outcomes are challenging, and thus the evidence for the impact of hearing interventions is primarily from observational studies and will likely continue to be from studies other than randomised controlled trials. Seven studies of hearing interventions with cognitive outcomes assessed over longer than 3 years are reviewed. Most were of low-to-moderate quality. One cochlear implant study had indeterminate findings. Of six hearing aid studies, three reported a positive impact of hearing aid use while three reported no impact of hearing aid use on cognitive decline or incident cognitive impairment. Further studies are required to elucidate the benefit of hearing interventions on long-term cognitive outcomes. Research should include objectively ascertained hearing data, theoretically motivated cognitive outcomes including dementia subtypes, characterisation, and control for confounds and application of advanced statistical modelling to test causal hypotheses. Identifying treatments and management strategies to prevent or delay the onset of dementia is an international priority. A recent review of modifiable risk factors for dementia concluded that up to 35% of dementia cases may be preventable. The review also identified that around 9% of dementia cases may be attributable to hearing loss in midlife.The proportion of potentially preventable cases attributable to hearing loss at a population level was relatively high partly because hearing loss is highly prevalent among those aged over 50 years ; in the The conclusion that 9% of dementia cases are linked to hearing loss was based on a meta-analysis of three studies that linked baseline levels of hearing loss to risk of incident dementia –5. The lHearing loss may be a marker of neurological frailtyA key question, then, is whether hearing loss is causally linked to the risk of cognitive decline and dementia and whether treating hearing impairment (e. g. with hearing aids) may reduce cognitive decline and risk of dementia.Some hearing aid and cochlear implant intervention studies have measured cognitive outcomes; the results are mixed –18. But However, well-controlled hearing intervention studies with long-term cognitive outcomes are challenging. In addition to the long durations required to examine cognitive decline, studies interested in incident dementia would need to be large in size as well as long in duration . Such lControlled trials of hearing interventions are challengingAdherence to some hearing interventions may be problematic. Up to 30% of hearing aid owners do not use their hearing aids or use them infrequently , and thSome researchers have grappled with these issues, and prospective studies of hearing interventions for long-term cognitive outcomes are planned or under way –27. HoweThe following is an overview of studies of hearing interventions for adults with normal cognition that evaluated cognitive outcomes (including cognitive change and incident cognitive impairment) over durations longer than 3 years that were published up to December 2018 . A further limitation of this analysis was that the diagnosis of MCI/dementia was based partly on the study cognitive tests, which were repeatedly administered and were likely to be subject to practice effects. The lack of a control group makes it difficult to isolate the impact of cochlear implantation on the cognitive outcomes reported in this study.Mosnier and colleagues  tested 7Studies modelling the impact of hearing aid use on cognitive outcomes have mixed findings. Some studies reported a reduction in the rate of cognitive decline associated with hearing aid use –33, whilHearing measures have tended to be neglected in large epidemiological data resources, perhaps owing to the lack of recognition of hearing loss being an important public health issue and/or the difficulty in assessing hearing using gold standard audiometric methods in large-scale studies. However, most of the aforementioned studies utilised large data sets that contained gold standard audiometric measures of hearing.Studies used a variety of cognitive outcome measures, which may explain some variation in findings. Studies included tests of a range of cognitive domains including attention, processing speed, executive functioning, short-term memory, working memory and long-term memory. Some used screening tests for cognitive impairment such as the Mini Mental Status Exam  that mayWith respect to dementia outcomes, all research to date concerning hearing loss and risk of dementia has made no differentiation according to type of cognitive pathology and focused on ‘all-cause’ dementia. Dementia is a symptomatic description of cognitive impairment that impacts on functioning in daily life.There are many types of dementia with different pathological causeshttp://www.hic.nihr.ac.uk/) including information on dementia subtypes and hearing may facilitate this sort of research in future.But there are many types of dementia with different pathological causes. Future research should differentiate between dementia types and test specific hypotheses concerning how hearing impairment may contribute causally to specific dementias. Lack of information about dementia subtype and/or small numbers of people with subtypes of dementia in existing data sets is a limitation. Nevertheless, availability of routinely collected clinical data for large numbers of people , which If hearing loss is causally implicated in dementia risk, then effective prevention, identification and treatment of hearing loss may be critically important to reduce the cumulative incidence of dementia.Hearing loss is a marker of risk for cognitive decline and dementia.Controlled hearing intervention studies of long-term cognitive outcomes are challenging, and thus the evidence for the impact of hearing interventions comes from observational studies.Further studies are needed to assess the benefit of hearing interventions on long-term cognitive outcomes and to guide public health efforts to lower the incidence and prevalence of dementia.


There is concern that some generic preference-based measures (GPMs) of health-related quality of life may be insensitive to interventions that improve hearing. Establishing where sensitivity arises could contribute to the design of improved measures. Accordingly, we compared the sensitivity of four widely used GPMs to a clinically effective treatment—cochlear implantation—which restores material degrees of hearing to adults with little or no functional hearing.N = 147) received implants in any of 13 hospitals in the UK. One month before implantation and 9 months after, they completed the HUI2, HUI3, EQ5D3L, and SF-6D questionnaires, together with the EuroQoL visual-analogue scale as a direct measure of health, a performance test of speech reception, and a self-report measure of annoyance due to tinnitus.Participants  contains supplementary material, which is available to authorised users. Generic preference-based measures (GPMs) of health-related quality of life (HRQL) play important roles in the allocation of resources in health care because they provide the utility component of cost–utility analyses. Such analyses inform prioritisation of treatments by third-party payers in many jurisdictions and are mandated in England when the National Institute for Health and Care Excellence (NICE) commissions the appraisal of a health technology .There is concern that some GPMs are insensitive to interventions which improve hearing –5. The iThe development of GPMs begins with researchers identifying dimensions on which good function corresponds to good health. Discrete levels of function are defined on each dimension ranging from poor to good. A subset of the possible combinations of levels is valued by a representative sample of the public. These informants use methods for measuring preferences  such thaMobility, Self-care, Usual Activities, Pain/Discomfort, and Anxiety/Depression. The version of the system until recently preferred by NICE [Sensation, Mobility, Emotion, Cognition, Self-care, and Pain, each with 4–6 levels. In the Mark-3 version (HUI3) [Sensation was decomposed into Seeing, Hearing, and (being understood when) Speaking. Self-care was re-worked as Dexterity. The Short-Form-6D (SF-6D) [Physical functioning, Role limitations, Social functioning, Pain, Mental health, and Vitality, each with 4–6 levels. The dimensions are a subset of those in the Medical Outcomes Study Short-form Health Survey (SF-36) [We examined four widely used GPMs –11. The  by NICE  defines  by NICE , 13 incln (HUI3) , Sensati (SF-36) , such thGiven differences in wording, dimensions, and methods of valuation, it is not surprising that the GPMs differ in their sensitivity to interventions , includiWe made such a comparison by investigating the sensitivity of the four GPMs to cochlear implantation—a clinically effective intervention  which reThe rationale for the study was that the categorical change from dysfunctional hearing to viable hearing that is brought about by implantation would allow scope for GPMs to show improvement if they were sensitive to hearing. The study adds to those in the systematic review  of whichAgainst that background, we identified reasons why the four GPMs differed in their sensitivity to implantation. We distinguished their response to impaired speech reception from their response to tinnitus, and we considered the implications for the choice of GPM to use in studies of hearing.Participants were adults who met criteria of candidacy for implantation in the United Kingdom (UK): they had developed a severe-to-profound sensorineural hearing loss in both ears after acquiring spoken language; they had at least one patent cochlear nerve; they could identify no more than 50% of the content words in pre-recorded sentences presented in quiet without lipreading when using hearing aids. Their demographic and audiological characteristics are listed in Table EQ-5D-3L.Five measures of HRQL and two functional measures of hearing were derived from four questionnaires and a performance test. The questionnaires were presented on touch screens. The performance test was conducted in audiological test rooms. The measures are described below where the name given to each derived variable is italicised, e.g. EQ-5D-3L) using the valuation function described by Dolan [EQ-VAS). For the Health Utilities Index Mark 2 and 3, a single questionnaire allowed both indices to be calculated. The words “hearing aid” were replaced with “cochlear implant” in the version of the questionnaire presented post-operatively. Reported levels of the dimensions were converted to weights which were combined to yield composite indices for HUI2 [HUI2, HUI3). For the Short-Form-6D, responses to the UK SF-36 questionnaire [(SF-6D).The EQ-5D-3L questionnaire and visual-analogue scale of the EuroQoL Descriptive System were presented. Reported levels of the five dimensions were converted to a composite index .Speech). A measure of annoyance due to tinnitus was obtained by presenting 13 questions [Tinnitus).A measure of speech reception was obtained by presenting recordings of sentences to participants at an intensity typical of conversational speech and counting the percentage of content words reported correctly , 29  were assessed with the Standardised Response Mean  and, forTo establish which dimensions of each GPM were sensitive to implantation, and to determine whether positive changes on some dimensions were offset by negative changes on others, we identified dimensions on which there was a significant change—either positive or negative—between the levels to which participants assigned themselves before and after implantation using a Wilcoxon signed-rank test.Speech and Tinnitus and changes in each composite index. We also examined whether values of Speech and Tinnitus before and, separately, after implantation were correlated with the pre- and post-operative values of the composite indices.A composite index could be sensitive to variation in both speech reception and tinnitus, to one, or to neither. To determine which pattern of sensitivity was shown by each GPM, we calculated Kendall rank correlation coefficients between changes in Speech and Tinnitus, we calculated Kendall rank correlation coefficients between changes in the levels of each dimension and changes in Speech and Tinnitus. We also tested whether values of Speech and Tinnitus before and after implantation were correlated with the pre- and post-operative levels of individual dimensions.To determine which individual dimensions underpinned correlations between composite indices and HUI2 displayed a moderate significant change and HUI3 a large significant change. EQ-5D-3L displayed a small significant change. SF-6D and EQ-VAS did not show significant changes. Analysis of variance showed that the four changes differed significantly  = 45.3, p < 0.001); all pair-wise comparisons were significant (p < 0.001), except the comparison between EQ-5D-3L and SF-6D.Table Speech, increased from 3.8% correct to 56.1% correct with a large effect size. The second functional measure, Tinnitus, declined from 23.9 to 16.8 with a small effect size. Thus, implantation was associated with a large primary effect of improved speech reception and a small secondary effect of reduced annoyance due to tinnitus. Online Resource 3 provides additional support for the interpretation of speech reception as the primary outcome and annoyance due to tinnitus as the secondary outcome.The first functional measure of hearing, Anxiety/Depression dimension of EQ-5D-3L which is at top-right in the table. Before implantation, 83 participants placed themselves at the best level of this dimension, 52 at the middle level, and 12 at the worst level, summarised as . After implantation, the pattern had improved significantly to  .Table Sensation (HUI2), Hearing (HUI3), and Speaking (HUI3); improvements in Anxiety/Depression (EQ-5D-3L) and Mental Health (SF-6D); and a worsening of Pain . Thus, each GPM included at least one dimension that displayed a significant improvement, while HUI2 and SF-6D also included dimensions that worsened significantly.Implantation was associated with three types of change: improvements in Speech and Tinnitus and change in each measure of HRQL. Change in Speech was correlated with change in HUI2 and HUI3, but not with change in EQ-5D-3L or EQ-VAS. Change in Tinnitus showed the opposite pattern; it was correlated with change in EQ-5D-3L and EQ-VAS, but not with change in HUI2 or HUI3. Change in neither functional measure was correlated with change in SF-6D. Thus, none of the composite indices was sensitive to the improvements in both speech reception and tinnitus associated with implantation. Online Resource 4 includes multiple regression analyses which corroborate these patterns of correlation.The upper panel of Table HUI2 was correlated with Speech before implantation, and only HUI2 and HUI3 were correlated with Speech after implantation. In contrast, each measure of HRQL was correlated with Tinnitus, both before and after implantation.The middle and lower panels of Table Speech and Tinnitus. The results corroborate the implication of Table Tinnitus than in Speech. The four GPMS together contain 25 dimensions. Variation in Speech was correlated significantly with the levels of only four of them before or after implantation, while variation in Tinnitus was correlated with 15.Table The data reported here were gathered in the late 1990s. Improvements in cochlear implants and changes in candidature might have rendered the results irrelevant to today’s outcomes. Two considerations counter those concerns. First, criteria of candidacy for unilateral implantation of adults in England  remain tWith those caveats, the study provides evidence at three levels of detail to inform the choice of GPM to use in assessments of interventions for hearing disorders. First, at the level of composite indices, the results corroborate previous demonstrations –5 that GHowever, limitations in all of the GPMs emerge at the second level of detail where the changes associated with implantation on individual dimensions are considered Table . SignifiSensation (HUI2) and Hearing (HUI3) dimensions ask about the ability to “hear what is said” in conversation. More surprising may be that neither Usual Activities (EQ-5D-3L) nor Role Limitations or Social Functioning (SF-6D) were similarly sensitive. However, participants had been severely profoundly hearing impaired for nearly 15 years on average , pain , and mental health . This pattern  can be see also , that tisee also , 40, andsee also  or anxiesee also .Tinnitus, not the change in Speech