Hearing loss is a highly prevalent condition that affects around 1 in 6 people in the UK alone. This number is predicted to rise by the year 2031 to a staggering 14.5 million people due to the ageing population of the UK. Currently, the most common intervention for hearing loss is amplification with hearing aid(s) which serve to address the issue of audibility due to hearing loss, but cannot reverse its effects. The consequences of hearing loss are multifaceted, as it is a complex condition that can detrimentally affect various aspects of an individual's life, including communication and personal relationships. The scope of these reported issues is so broad that it calls on the need for patient-centred management plans that are tailored to each patient as well as appropriate measures to assess intervention benefit. It is unclear whether current outcome instruments adequately match what patients report as the most important problems for them.The systematic review aims to capture existing knowledge about patients and their communication partner's perspective on the everyday impact of hearing loss. Methods are defined according to the Preferred Reporting Items for Systematic reviews and Meta-analyses for Protocols (PRISMA-P) 2015.No ethical issues are foreseen. Findings will be reported in student's thesis as well as at national and international ENT/audiology conferences and in a peer-reviewed journal.PROSPERO CRD42015024914. The protocol poses a clearly formulated question about what patients (and communication partners) consider to be the problems related to hearing loss. A systematic review of these domains will help to inform the potential scope for patient-centred management plans and notably selection of outcome measures to assess intervention efficacy and effectiveness.The protocol includes a clear methodology for data collection and synthesis with distinct objectives.Limitations include a foreseen language bias where articles will only be included in the review if written or obtainable in English.et al8In the UK, hearing loss affects about 8 million people.et alIn addition to the uncertainties regarding which types of outcome measures are to be used, the more fundamental concepts of what aspects of adult functioning with hearing loss are considered important also remain ambiguous.et al: ‘those with whom the person with hearing impairment communicates with on a regular basis. The term communication partner has been used to refer to the significant others which may include their spouse, siblings, children, friends, relatives, colleagues, and carers’.13The present systematic review aims to collate the existing knowledge about patient and their communication partner's perspective on the negative consequences of hearing loss on everyday life. This includes studies that have reported individual symptoms from patients and communication partners, as well as studies that have categorised individual symptoms into domains. Communication partners are defined as per Manchaiah The purpose of the systematic review is to develop a list of domains on the impact of hearing loss using data from individuals who have been diagnosed with hearing loss or are in regular contact with someone who has. This objective translates into the primary research question: ‘What are the domains reported by adults with hearing loss and their communication partner(s) considered to be problematic in relation to their hearing loss?’ This would include reported problems with aided and non-aided listening, but not with using listening devices themselves. The domains of symptoms could be used to inform patient-centred management plans, as well as to inform the choice of outcome measures to assess treatment benefit.The systematic review will collate independent evidence from studies that have reported what adults with hearing loss and communication partners report as problematic in everyday life.After domains relating to the everyday impact of hearing loss have been generated from the data, secondary objectives will:Identify similarities and differences in the evidence collected from patients and their communication partner(s).Compare reported difficulties with existing standardised frameworks for clinical assessment, including the ICF.Investigate the reported symptoms in relation to severity of hearing loss, where hearing status is adequately specified.Secondary analyses will be conducted only where there is a sufficient number of records for a meaningful synthesis of the data.Methods are reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses for Protocols 2015 (Prisma-P) 2015.Given the large number of closed-set questionnaires in use, eligible study designs span quantitative, as well as qualitative, methodologies. Eligible studies must have employed questionnaires (closed or open questions), focus groups or interviews  to elicit the data relating to our primary question. Only interventional, observational and cross-sectional studies will be considered for inclusion. The exclusion criteria are (1) studies that do not report hearing loss as the primary condition of interest, (2) case reports, articles for professional magazines and (3) web-based discussion forums due to their limited scientific value.Participants eligible for inclusion in the review are men and women who have been diagnosed with mild-to-profound hearing loss . Eligible participants will also include communication partner(s) or those whom communicate with an individual on a regular basis. Only articles that include a study sample of participants ≥18 years old will be considered.The systematic review will include evidence from any intervention studies that assess and report included data collected at the initial assessment (prior to intervention).The systematic review does not assess specific interventions.There will be no restrictions by type of setting. All settings will be considered, including clinical and academic sites.Articles that are not written in English will be excluded as the research team does not have the resource to support translation.et al6All records to be included in the systematic review will have been published on or after 1982. This date was chosen because Granberg All published journals will be included where they can be identified through the following electronic databases: PubMed, EMBASE, Web of Knowledge, the Cochrane Central Register of Controlled Trials (CENTRAL) and CINAHL. Conference proceedings will be searched using Cos Conference Papers Index (ProQuest) and Web of Science (Thomas Reuters). Case reports will be excluded from the search due to their low scientific value.Google Scholar will be searched using the specified search terms through every web page that contains eligible records. We will discontinue the Google Scholar search when one page contains no relevant articles. Records that have not been published in peer-reviewed journals, such as book chapters and conference abstracts, will be considered for inclusion, regardless of publication, in order to avoid publication bias.Hearing loss associations representing patients  will also be contacted to enquire about commissioned reports.In order to ensure that literature identified is comprehensive and rigorous, the present study comprises three steps outlined by PRISMA: identification of records, screening and eligibility assessment. The search process will identify records and the results will be documented. The search process will be reported in sufficient detail so that it is repeatable. This will include details, the search strategy and the number of records retrieved and excluded. Should any changes to the search process be made, then these will be recorded and explained. All internet database searches and contact with hearing loss associations will also be recorded.The electronic database search will require ‘hearing’ in the article title or abstract, in conjunction with additional relevant search terms such as keywords or in the title or abstract. The search strategies for each database have been designed to be highly sensitive in order to pull as many potentially relevant records as possible, but not too restrictive that records that could be included are missed. To help structure the search, the Population, Intervention, Comparator and Outcomes elements from PICOS were used.The search terms for PubMed and EMBASE will be guided by: ‘(hearing) AND (problem OR complain* OR symptom OR impairment OR difficult*OR concern* OR impact OR effect)’ OR ‘(hearing) AND (patient OR communication partner OR partner OR significant OR famil*OR spouse)’.An example search from PubMed is as follows:(((((((hearing(Title/Abstract)) AND (‘1982/05/01’(Date—Publication) : ‘3000’(Date—Publication)))) AND (((((((((((((((((problem(Title/Abstract)) OR complain*(Title/Abstract)) OR symptom(Title/Abstract)) OR impairment(Title/Abstract)) OR difficult*(Title/Abstract)) OR concern*(Title/Abstract)) OR impact(Title/Abstract)) NOT child*) NOT p*pediatric) NOT hearing screening) NOT hearing protection) NOT hearing conservation) NOT hearing prevalence) NOT hearing incidence) NOT hidden hearing) NOT ‘hidden’ hearing loss) NOT dementia))) AND Humans(Mesh) AND English(lang) AND adult(MeSH))) OR ((((((hearing(Title/Abstract)) AND (‘1982/05/01’(Date—Publication):‘3000’(Date—Publication)))) AND ((((((((((((((((patient(Title/Abstract)) OR communication partner(Title/Abstract)) OR partner(Title/Abstract)) OR significant other (Title/Abstract)) OR famil*(Title/Abstract)) OR spouse(Title/Abstract)) NOT child*) NOT p*ediatric) NOT hearing screening) NOT hearing protection) NOT hearing conservation) NOT hearing prevalence) NOT hearing incidence) NOT hidden hearing) NOT ‘hidden’ hearing loss) NOT dementia))) AND Humans(Mesh) AND English(lang) AND adult(MeSH)).The first category is combined with the second category as an ‘AND’ statement and similarly, the first category is combined as an ‘AND’ statement with the third category. Records are filtered by English language, human, date and age categories where possible.VV (first author) will be responsible for data management and will be the only member of the research team to have editorial rights. A list of records excluded from the review will be reported together with the reasons for exclusion. Reasons as to why any potentially relevant records have been excluded will be highlighted in the document, rather than all of the research evidence identified. Records that have been included will be assigned an ID code to link each record in the master file with along with the full article text. A system of recording decisions made about each article will be produced in Excel.The study is part of a PhD project. VV will have overall responsibility for the study and shall oversee all study management. VV will have day-to-day responsibility for the study and study conduct. The study will be overseen by two academic supervisors (DAH and MAA).Duplicate records will be removed to avoid biased data synthesis.The first selection step will consider the title information and determine inclusion according to the PICOS and other eligibility criteria. The second stage of selection will consider the abstract for all potentially relevant records that appear to meet the inclusion criteria or for which there is insufficient information in the title to assure inclusion. Articles with a potentially relevant title, but with no available abstract, will be retained and taken through to full-text screening. The third stage of selection will consider the full text of articles that met inclusion or where there is still uncertainty in eligibility. VV and DAH will independently carry out a screen of the titles and abstracts.Box 1Eligibility criteria: abstract screening▸ Research aims and objectives of study are appropriate to addressing question(s) of systematic review▸ Hearing status▸ Study sample of participants age ≥18 years old▸ Abstract available in English▸ Hearing loss is the primary condition of interestIf a disagreement arises between the two reviewers (VV and DAH), then the citation of the record will be retained. During the full article screening stage, the full-text papers of the queried citations will be obtained and checked according to the data extraction criteria. If the article is deemed to be ineligible at this stage, then the reasons for exclusion will be documented. Given the large time period of the search citation (33 years), the lead author of the article will not be contacted by email to seek clarification for any missing data. Missing data will be marked as ‘not stated’. During the abstract screening stage, reviewers will assess the potential eligibility of the records using a screening tool :Box 1ElIf it can be determined that the article does not meet the inclusion then it can be excluded straight away, specifically, those that are clearly not relevant and those that address the outcome of interest but fail on another criteria, such as population. For those in this latter category, reason for exclusion will be noted.Box 2General informationResearcher performing data extraction Record number (to uniquely identify study)Author Article titleYear of publicationType of publication Country of originStudy characteristicsStudy design Is hearing the primary condition of interest? Primary method for collecting individual hearing loss symptoms Type of questions Sample size Theoretical framework (if stated)Participant characteristicsMean ageGenderSetting Hearing status Domains describing patient-reported symptomsMeasure Author examples or patient quotes describing their symptomsPerspective Domains describing communication partner-reported symptomsMeasure Author examples or communication partner quotes describing their symptomsPerspective Free-field text The parallel screening of the article titles and abstracts will assure the reliability of the decision process, and for the decision outcomes to be reproducible. A flow chart showing the number of articles remaining at each stage of the selection process will be created to document the study process. A record of any amendments made to the data extraction will be kept for reference. The data extraction form  serves tThe data extraction form  will incA list of questions and measures  that were used by the authors to the patients and communication partner(s) to obtain the information will be compiled.Studies may report a mixture of domains of patient-reported symptoms, authors' examples to explain each domain or quotes given by individual patients or their significant others. All of this information will be extracted in the data extraction form.The domains of symptoms reported by patients and their communication partner could be used to inform the choice of outcome measures to assess the consequences of hearing as well as treatment benefit.13A risk of bias assessment will not be carried out as the scope of the review does not involve investigating the effects of a particular intervention for adults with hearing loss.The purpose of this systematic review is to develop a list of domains on the impact of hearing loss using data given by individuals who have been diagnosed with hearing loss or are in regular contact with someone who has been diagnosed. For all included quantitative and qualitative studies, the data items of interest are equivalent . For included records that have used closed-set questionnaires to assess the impact of hearing loss, only those domains or items of the questionnaire that have been highlighted by the authors because they reflect experienced symptoms will be extracted. For any included records that explicitly report domains, the authors' terminology will be extracted wherever possible. We will also extract any authors' examples or quotes given by individual patients or their significant others relating to the experience of hearing loss. This information will help us to understand the authors' epistemological frame and hence to interpret their concept of each domain. All included records will be used in a narrative synthesis guided by techniques from meta-ethnography and grounded theory to form domains using the domain terms, as well as being informed by the author examples and participant quotes as described above.The next step of the synthesis will analyse and compare the findings between the included records. Conditional on the amount of relevant data extracted, emerging relationships between studies investigating the secondary objectives will also be carried out. A table will summarise and display the main findings.Main findings from included records that contain evidence from the perspective of patients that report the everyday impact of hearing loss will be presented in a summary table, and all reported symptoms will be identified.Main findings from included records of the impact of hearing loss reported from communication partners will be presented in a summary table, and all reported symptoms will be identified.To address the other secondary objectives, we will directly compare the reported domains of hearing loss symptoms from each study population. We will devise a table that presents the reported domains of hearing loss-related symptoms corresponding to hearing loss severity , and we will compare reported symptoms between subgroups.We intend to carry out the following prespecified subgroup analyses:We will compile a comprehensive list of the questions that were asked by the researchers involved in the study to obtain information from patients and their communication partner(s). We will also review the questions the authors used to elicit information from both study populations, to determine how well the questions were suitable and open enough to elicit unbiased information. We anticipate that not all articles included in the review will report hearing levels of study participants. Therefore, only data from articles that have reported hearing loss will be included in the secondary question, which will seek to associate particular domains with hearing loss severity.We expect that most of the included records will report narrative data that would have employed qualitative analysis to identify themes or domains. Where appropriate therefore, a quality analysis will be performed using tools designed for qualitative research; Critical Appraisal Skills Programme (CASP).Study results and discussion will be written up in the student's thesis and made accessible via an institutional repository.Results will be widely disseminated at conference by the student and academic supervisors.Public and patient engagement .A peer-reviewed journal publication complying with Open Access policy.No ethical issues are foreseen. Reports will be guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA-P) 2015. We will employ the following dissemination strategies:


Borrelia burgdorferi is a spirochetal bacterium transmitted by the Ixodes tick that causes Lyme disease in humans due to its ability to evade the host immune response and disseminate to multiple immunoprotective tissues. The pathogen undergoes dynamic genetic alterations important for adaptation from the tick vector to the mammalian host, but little is known regarding the changes at the transcriptional level within the distal tissues they colonize. In this study, B. burgdorferi infection and gene expression of the essential virulence determinant ospC was quantitatively monitored in a spatial and temporal manner utilizing reporter bioluminescent borrelial strains with in vivo and ex vivo imaging. Although expressed from a shuttle vector, the PospC-luc construct exhibited a similar expression pattern relative to native ospC. Bacterial burden in skin, inguinal lymph node, heart, bladder and tibiotarsal joint varied between tissues and fluctuated over the course of infection possibly in response to unique cues of each microenvironment. Expression of ospC, when normalized for changes in bacterial load, presented unique profiles in murine tissues at different time points. The inguinal lymph node was infected with a significant B. burgdorferi burden, but showed minimal ospC expression. B. burgdorferi infected skin and heart induced expression of ospC early during infection while the bladder and tibiotarsal joint continued to display PospC driven luminescence throughout the 21 day time course. Localized skin borrelial burden increased dramatically in the first 96 hours following inoculation, which was not paralleled with an increase in ospC expression, despite the requirement of ospC for dermal colonization. Quantitation of bioluminescence representing ospC expression in individual tissues was validated by qRT-PCR of the native ospC transcript. Taken together, the temporal regulation of ospC expression in distal tissues suggests a role for this virulence determinant beyond early infection. Borrelia burgdorferi, the etiological agent of Lyme disease, causes a multistage infection resulting in cardiac, neurologic and arthritic symptoms .,80.E. coospC reporter shuttle vector, pJH410, was generated through the PCR amplification of the native ospC promoter including 250 bp upstream from the ATG start codon for ospC and borrelial codon optimized luc . PospC was cloned into pJSB161 .,81.ospC  pJSB161  at the Neviously ,83. Trance assay ,76.ospC expression was generated by amplifying a region of cp26 containing ospC, cloning into pCR2.1 TOPO (Life Technologies), and transforming this construct into Mach-I E. coli cells  and flagellum  or goat polyclonal antisera to Firefly luciferase , followed by incubation with rabbit anti-mouse IgG conjugated to horseradish peroxidase (HRP) or rabbit anti-goat IgG HRP, respectively .in vivo ospC expression during experimental infection utilizing the PospC-luc reporter strain and, based on our prior work ; (B) heart [P = 0.0008)]; (C) inguinal lymph node [P = 0.0381)]; (D) bladder [P = 0.0056)]; and (E) tibiotarsal joint [P = 0.0009)].Bioluminescence of Balb/c tissues infected with 10(TIF)Click here for additional data file.S2 FigospC transcript of individual B. burgdorferi infected murine tissues. Four mouse skin, heart, bladder and tibiotarsal joints from day 10 (dark circles) and 21 (open squares) post-infection were evaluated for the total number of ospC transcripts for each tissue sample based on a standard curve. qRT-PCR for each sample and mouse was performed in triplicate and averaged. The error bars indicate standard error.Quantitative RT-PCR shows the total native (TIF)Click here for additional data file.


Hearing loss is a growing public health issue of global concern. Although more hearing loss could be prevented and most people who live with unaddressed hearing loss could benefit from cost–effective interventions, the subject is often ignored.Many causes of hearing loss that could be prevented persist or are on the rise. These include ear infections, the use of ototoxic medicines and noise exposure.,Despite the overwhelming predictions, neither policy-makers nor the public prioritize hearing loss. This may be because hearing loss is a non-life-threatening, invisible disability.Acknowledging the growing importance of this issue, the World Health Assembly (WHA) adopted a resolution for the prevention of deafness and hearing loss in 2017.WHO hopes that this resolution will have an impact in the global health arena. Well-planned strategies need to be implemented in all parts of the world, including low- and middle-income countries, where most people with hearing loss reside.–Wilson et al. highlighted the need for a global initiative that facilitates efforts to stem and eventually reduce the rising prevalence of hearing loss.An alliance would have a cohesive body of stakeholders whose main purpose is to undertake advocacy and develop networks that facilitate knowledge sharing and foster opportunities for collaboration. With strong leadership, a diverse membership and sound financial backing, such an alliance would be well positioned to drive a global initiative. This alliance and its initiative could provide the impetus for implementing the WHA resolution on the prevention of deafness and hearing loss.Such collaborative and determined action would enable protection of the hearing for over the billion people who are at risk, as well as allowing those who experience hearing loss to achieve their potential through equitable access to the required services and rehabilitation.


This study aims to investigate loss of hearing among drivers in Zahedan, southeastern Iran.This study carried out on a total of 1836 drivers in Zahedan in 2013. Loss of hearing in both ears was measured at 250, 1000, 2000, 3000, 4000, 6000, and 8000 Hertz. The demographic variables, blood parameter and anthropometric data were recorded through interview and examinations. Data were analyzed in Stata.12 software using paired t-tests, McNemar test and Multiple Logistic Regression.The mean age was 38.2±9.8 years. The highest mean hearing thresholds in the right and left ears were 25.7±9.1 and 27.7±9.1, respectively at 250 Hz. There was significant difference between left and right ears hearing threshold at all frequencies (P<0.001), and the highest difference occurred at 250 Hz. Hearing threshold in the left ear was greater than in the right ear at all frequencies. Hearing threshold was correlated to marital status, type of license, and vehicle, smoking, age, and driving history at all frequencies (P<0.01), and also significantly correlated to blood sugar and cholesterol levels at 250 and 500 Hz in both left and right ears (P<0.01).In conclusion, high levels of noise increase hearing threshold with greatest damage to the left ear. Therefore, drivers should be periodically examined for ear damage in accordance to variables affecting loss of hearing. Moreover, drivers must be educated about usage of appropriate ear-plugs during driving, especially for the left ear. Noise is a health-threatening factor, which can affect safety and efficiency of people in their workplace . ThroughThe most important complication associated with loud noise is loss of hearing, which can lead to masking noise and impaired communication, resulting in accidents. Thus, preventing hearing loss and screening those at risk can potentially reduce accidents. Currently, it is considered a major health issue and one of the 10 work-related diseases, and it is a major occupational disease in Europe . A studyThe noise is considered the third leading dangerous pollutant in major cities , and roaDrivers are exposed to many physical and physiological stresses such as environmental noise, vibration, temperature fluctuations (due to opening and closing of door and working outside home in different seasons), ergonomic problems and safety risks such as accidents . TherefoMany studies have been conducted in industrial environments on occupational hearing loss in Iran and around the world , but onlSince in the Western countries, vehicles are much more advanced and create very little noise, only a few studies have been conducted on loss of hearing in drivers. However, a number of studies have been conducted in this area in developing countries. In a study in India, hearing loss in HGV drivers was 3 times more compared to taxi drivers . AnotherOn the other hand, there is no comprehensive study regarding drivers in South-East of Iran, Sistan & Bluchestan province. Furthermore, this province has been located at the border of Pakistan and Afghanistan where thousands of HV drivers transport goods from Iran to Pakistan or Afghanistan and vice versa. Therefore, study of hearing status and its related factors among drivers could be of utmost importance. Accordingly, the present study aimed to provide useful evidences on HV drivers’ hearing status and to identify groups at greater risk.A total of 1836 inner and intercity drivers in Zahedan with a minimum of 5 years driving history were studied in terms of physical ear examination and audiometry in 2013. Study exclusion criteria were diseases of the ear, work history in noisy environments and subsequent loss of hearing. Participants included drivers with license class A and B (a classification of driving license in Iran), selected according to convenient sampling method. The demographic variables, history of hearing problems and work in other environments, blood parameter and anthropometric data were recorded in data registry forms through in-depth interviews and medical examinations and tests. Indeed, drivers were interviewed in predefined Health Center (Hanane) and a questionnaire on abovementioned information was completed by trained interviewers, for each subject. As we wanted to evaluate the relation between hearing loss and some blood parameters, so, they were asked to refer to the regional laboratory. The drivers additionally provided with an introduction letter for blood sampling (12-h overnight fasting). One day after the interview, a blood sample was taken from each driver at the laboratory and blood parameters were tested. The weight of the subjects was measured by standardized and reliable scale and height of them was measured in centimeter scale in standing position by height gauge.After ear examination by an ear, nose and throat specialist, audiometry was performed by an audiometric clinician, and loss of hearing in both right and left ears was measured at 250, 500, 1000, 2000, 3000, 4000, 6000, and 8000 Hz, and recorded in audiogram sheets. The presence of a hearing loss was defined as a pure-tone average of threshold at 250, 500, 1000, 2000, 3000, 4000, 6000, and 8000 Hz greater than 25 dB of HL in the worse ear and the worse ear was chosen in order to include people with at least one affected ear .To ensure correct answers, study objective were explained for participants, and they were assured of confidentiality of data. Additionally, informed consent was obtained from all study participants. Data were analyzed using Paired t-test, McNemar and Chi-square test. Furthermore, a binary logistic regression was carried out with the Stata.12 software to clarify the predictors of HL. Normal distribution of data was confirmed using Kolmogrov-Smirnov test. P < 0.05 was considered significant.A total of 1836 inner and intercity drivers in Zahedan were studied, of whom, 385 drivers (21%) were younger than 30 years of age. 47 drivers (2.6%) were illiterate, and only 42 (2.3%) had university education. A total of 115 drivers (6.3%) were single, and 632 (34.4%) were HG drivers. 288 drivers (15.8%) (95% confidence: 8.8-3.2) were cigarette smokers.Of all drivers, 438  had hearing loss in both ears, 77  had hearing loss in the right ear, and 187  had hearing loss in the left ear, with statistically significant differences (P=0.041). Permanent hearing loss was found in 45 drivers (2.4%) in the right ear, 69 (3.8%) in the left, and 28 (1.5%) in both ears, and at all frequencies, their hearing loss was greater than 25 Hz.Frequency distribution of hearing loss in the right, left and both ears was found separately, and the relationship of hearing loss with demographic parameters and some blood factors was studied using logistic regression test . The preAlthough HGV drivers more than non-HGV drivers, and illiterate drivers more than highly educated ones suffered loss of hearing, no significant relationship was found between loss of hearing and education level or type of vehicle (P>0.05). Similarly, the relationship of hearing loss with marital status was not significant (P>0.05). Hearing loss in smoker drivers was greater than in non-smokers, with a significant difference (P=0.038) .Although odds of hearing loss reduced with increasing blood sugar, cholesterol and triglyceride, none of these factors had a significant relationship with hearing loss (P>0.05). The odds of hearing loss increased with increasing BMI, but not significantly (P>0.05) . It mustFrequency distribution of hearing loss and mean hearing threshold in both ears in drivers at different frequencies are shown in The present study showed the prevalence of bilateral hearing loss in 23.8% of drivers, and about a quarter of drivers had hearing loss, which is higher than that previously reported in Iran . There aClearly, the prevalence of hearing loss depends on how it is defined, diagnostic methods, frequencies studied, age and gender, and socioeconomic status of drivers and study population in epidemiological studies, which limits comparison between studies. However, the previous studies conducted on the general population in Norway and USA  have repAlthough hearing loss reduces with increasing blood sugar, cholesterol, and triglyceride, in multivariate analysis with controlled age, none of these parameters was significantly related to hearing loss. The odds of hearing loss increased with increasing BMI, but not significantly. This is somewhat in agreement with a previous study in Iran . It appeIn the present study, haring loss in both ears increased with aging, which is in line with previous domestic and international studies  in driveIn this study, education level and marital status were not significantly related to hearing loss, but it was greater in passenger vehicle drivers than other drivers. Passenger vehicle drivers appear to spend more time driving and are more exposed to noise and stress, which adversely affects their hearing loss. Moreover, hearing loss was greater in smoker drivers than non-smokers. Although there are few studies on the effect of smoking on hearing loss, smokers appear to have higher stress and mental preoccupation. Generally, greater stress and noise have mutual effect on hearing loss. On the other hand, this result might be explained by the need to open the window when smoking, which in turn increases the exposure to noise.This study showed greater hearing loss in the left ear than in the right one, and this agrees with studies in Iran  and worlStrong points in the present study included a large sample size, measuring demographics and blood factors, controlling confounding factors, and being the first study of its kind in the Southeast of Iran. Study limitations included being cross-sectional and not determining cause and effect relationship.In conclusion, considering that proper hearing in drivers can have an important role in reducing preventing road accidents, it is essential that greater attention be paid to this occupation in terms of professional and occupational health, so that as well as preventing progress of hearing loss, safety of these and other people can be improved. It is recommended that drivers be periodically and regularly examined in terms of damage to the ear; and screening can be conducted according to parameters affecting hearing loss. Given the relationship between some blood factors and hearing loss, it is highly important to educate drivers about complications of hearing loss and use of appropriate ear-plugs during driving. Clearly, vehicle manufacturers can play a substantial role in reducing occupational hearing loss in drivers by standardization of production in terms of lower noise and air-conditioning to prevent opening of the window.


The purpose of this study was to examine the difference between self-reported hearing status and hearing impairment assessed using conventional audiometry. The associated factors were examined when a concordance between self-reported hearing and audiometric measures was lacking.In total, 19,642 individuals ≥20 years of age who participated in the Korea National Health and Nutrition Examination Surveys conducted from 2009 through 2012 were enrolled. Pure-tone hearing threshold audiometry (PTA) was measured and classified into three levels: <25 dB ; ≥25 dB <40 dB (mild hearing impairment); and ≥40 dB (moderate-to-severe hearing impairment). The self-reported hearing loss was categorized into 3 categories. The participants were categorized into three groups: the concordance (matched between self-reported hearing loss and audiometric PTA), overestimation (higher self-reported hearing loss compared to audiometric PTA), and underestimation groups (lower self-reported hearing loss compared to audiometric PTA). The associations of age, sex, education level, stress level, anxiety/depression, tympanic membrane (TM) status, hearing aid use, and tinnitus with the discrepancy between the hearing self-reported hearing loss and audiometric pure tone threshold results were analyzed using multinomial logistic regression analysis with complex sampling.Overall, 80.1%, 7.1%, and 12.8% of the participants were assigned to the concordance, overestimation, and underestimation groups, respectively. Older age , abnormal TM (2.17 [1.46–3.23] and 1.59 [1.17–2.15]), and tinnitus (2.44 [2.10–2.83] and 1.61 [1.38–1.87]) were positively correlated with both the overestimation and underestimation groups. Compared with specialized workers, service workers, manual workers, and the unemployed were more likely to be in the overestimation group , and service workers were more likely to be in the underestimation group (AOR = 1.42 [1.01–1.99]). Higher education level (0.77 [0.59–1.01] and 0.43 [0.33–0.57]) and hearing aid use (0.36 [0.17–0.77] and 0.23 [0.13–0.43]) were negatively associated with being in the underestimation group (0.43 [0.37–0.50]). Compared with males, females were less likely to be assigned to the underestimation group (0.43 [0.37–0.50]). Stress (1.98 [1.32–2.98]) and anxiety/depression (1.30 [1.06–1.59]) were associated with overestimation group.Older age, lower education level, occupation, abnormal TM, non-hearing aid use, and tinnitus were related to both overestimation and underestimation groups. Male gender was related to underestimation, and stress and anxiety/depression were correlated with overestimation group. An understanding of these factors associated with the self-reported hearing loss will be instrumental to identifying and managing hearing-impaired individuals. The estimated prevalence of hearing loss is as high as approximately 16.1% and increases with age . SimilarSeveral previous studies have demonstrated that only 43–71% of individuals show concordance between their self-reported hearing loss and audiometric pure-tone audiometry (PTA) results . Some inSeveral factors are associated with biases in self-reported hearing loss. It has been reported that age, sex, ethnicity, education level, and the degree of measured hearing impairment are associated with the self-reported hearing loss ,8. The oThe present study aimed to evaluate the factors associated with discrepancies between self-reported hearing loss and audiometric PTA results. There are several studies examining the factors associated with the discrepancy between self-reported hearing loss and audiometric findings, however most of these studies have been confined to the elderly population, ages 50 and older,15,16.FeThe present study was approved by the institutional review board of the Korea Centers for Disease Control and Prevention . Written informed consent was obtained from each participant prior to the survey.This investigation was a cross-sectional study that utilized data from the Korea National Health and Nutrition Examination Survey (KNHANES), which included participants who were representative of the South Korean population. The survey included a health interview, a nutritional survey, and physical examinations. The applied statistical methods were based on the sampling design and utilized weighted values. The KNHANES data collected by the Centers for Disease Control and Prevention of Korea from 2009 to 2012 were analyzed. Each year, 192 districts were selected by a panel, and 20 households in each of these districts were further identified to allow sampling that reflected the entire Korean population. The surveys evaluated data from the civilian, non-institutionalized South Korean population using a stratified, multistage, clustered sampling method based on the national census data. The sample was weighted by statisticians who performed post-stratification and accounted for the non-response rates and extreme values.Among the 36,067 total participants, we excluded the following: participants younger than 20 years old , because children and adolescents were not surveyed regarding their social economic status; participants who refused or failed a PTA test ; and participants who reported incomplete data regarding educational level, occupation, stress level, anxiety/depression, TM, hearing aid use, and tinnitus history (453 participants). Ultimately, 19,642 participants  were included in this study. The survey participants ranged in age from 20 to 97 years. The mean age of the overall population was 50.4 ± 16.2 years. All the enrolled individuals had sufficient cognitive function to complete the questionnaire, the physical examination, and PTA.In this study, age, sex, education, occupation, stress level, anxiety/depression, TM status, hearing aid use (including implantable devices), and tinnitus were used as independent variables. The discrepancy between self-reported hearing loss and the audiometric PTA results  was used as the dependent variable.The patients were divided into the following three groups based on education level: middle school or less (low), high school or junior college (middle), and college or graduate school (high). Ten types of occupations based on the Korean standard occupation classification were used . The tenThe participants were asked about their stress level (“How much do you feel stress in ordinary life?”) and presented with 4 possible answers: “I feel little stress”, “I feel some stress”, “I feel much stress”, and “I feel very stress”. The participants were asked questions about their anxiety/depression level using a translated EQ-5D-3 L question . They seAfter the completion of the questionnaire and physical examination, the audiometric PTA were measured in a soundproofing booth using an audiometer , and included frequencies of 500, 1000, 2000, 3000, 4000, and 6000 Hz in both ears in accordance with the American National Standards Institute (ANSI) standard. The hearing threshold was defined as the mean hearing threshold of the better ear on PTA tests at 500, 1000, 2000, and 4000 Hz. Hearing loss in this study was defined as follows: <25 dB , ≥25 dB and <40 dB (mild hearing loss), and ≥40 dB (moderate-to-severe hearing loss).The participants were instructed to “Please select one answer below that most accurately expresses your hearing status without hearing aids”. The possible answers were “I feel no difficulty”, “I feel some difficulty”, “I feel much difficulty”, and “I cannot hear”. Next, we grouped the participants who responded “I feel much difficulty” and “I cannot hear” together into one group, which is subsequently referred to as the “much difficulty” group.Next, we divided the participants into three groups according to the difference between their perception of their hearing impairment and their audiometric PTA results . The conThe differences in general characteristics according to the discrepancy between self-reported hearing loss and measured audiometric evaluation were calculated using analysis of variance (ANOVA) tests for age and hearing threshold and chi-square tests for education level, occupation, stress level, anxiety/depression, TM status and tinnitus.The associations of the examined factors (independent variables) with the discrepancy between self-reported hearing loss and audiometric PTA  were analyzed using multinomial logistic regression with complex sampling. Multinomial logistic regression is an extension of logistic regression for use when a nominal outcome has more than two unordered categories/levels. In this analysis, concordance group was set as the reference. Two-tailed analyses were conducted, and P values below 0.05 were considered significant. The adjusted odds ratios (AORs) and 95% confidence intervals (CIs) were calculated. All the results are presented as weighted values. The results were statistically analyzed using SPSS version 21.0 .In total, the 19,642 participants exhibited various degrees of hearing impairment (including no hearing impairment); specifically, 81.20% , 12.92% , and 5.89%  of the participants exhibited mean hearing thresholds <25 dB HL, ≥25 dB HL and <40 dB HL, and ≥40 dB HL, respectively. Overall, 80.1% , 7.1% , and 12.8%  of the participants were in the concordance, overestimation, and underestimation groups, respectively. Regarding hearing levels, the concordance decreased with increasing hearing thresholds, and 92.2% and 7.7% of the normal-hearing participants were in the concordance and overestimation groups, respectively. Among the participants with mild hearing impairment based on audiometric PTA, 28.1%, 5.8%, and 66.1% were in the concordance, overestimation, and underestimation groups, respectively. Of the participants with moderate-to-severe hearing impairment, 27.4% and 72.5% were in the concordance and underestimation groups, respectively .We investigated several characteristics that were potentially associated with the discrepancy between self-reported hearing loss and audiometric PTA. Age, sex, education level, occupation, stress level, anxiety/depression, TM abnormalities, and tinnitus were correlated with the discrepancy between self-reported hearing loss and audiometric PTA . Males .The multinomial logistic regression analysis revealed that older participants tended to show less concordance between their self-reported hearing loss and audiometric PTA results in age from 20 to 97 years. The discrepancy between self-reported hearing loss and audiometric PTA increased with age; for every 10 years of age, the rate of overestimation of hearing loss increased 1.28-fold (95% CI = 1.19–1.37), and the rate of underestimation of hearing loss increased 2.80-fold . Females were less likely than males to have underestimation of hearing loss . A high level of education was associated with the concordance of hearing impairment results, and the dose-response relationship was significant . Service workers, manual workers, and the unemployed were more likely than specialized workers to experience overestimation of hearing loss . As stress levels increased, greater proportions of participants presented overestimation of hearing loss . A moderate level of anxiety/depression was associated with overestimation of hearing loss . The participants with abnormal TMs were more likely to have a discrepancy between their self-reported hearing loss and audiometric PTA results compared with participants with normal TMs . Tinnitus was related to the discrepancy between self-reported hearing loss and audiometric PTA results with respect to both overestimation and underestimation of hearing loss , a subgroup analysis was performed using logistic regression analysis. The results revealed that old age, occupation, and stress level were significantly associated with discrepancies only in the individuals with < 25 dB HL. TM abnormality and tinnitus were associated with a discrepancy between self-reported hearing loss and audiometric PTA in all the hearing threshold groups . FurtherIn our cohort, 80.1% belonged to the concordance group. This value is higher than those presented in previous studies, which reported rates of 43–71% . The higOld age was related to overestimation and underestimation of hearing loss. The elderly tend to be more accepting of hearing difficulty than young individuals because their needs for communication in daily work and meetings are reduced . AdditioAnxiety and depression were significantly related to overestimation of hearing loss in the present study. A series of studies has suggested the adverse effects of hearing impairments on depression and cognition, especially in the elderly ,32. In aIn the present study, specialized workers showed significantly least discrepancy between self-reported hearing loss and audiometric PTA results. On the other hands, unemployed showed significantly more overestimation of hearing loss. This result may be explained by the fact that individuals with hearing loss have more difficulty obtaining employment and are more frequently injured on the job . A higheTinnitus was related to both overestimation and underestimation of hearing loss. Like stressed individuals, those with tinnitus are vulnerable to anxiety regarding and hypersensitivity to hearing difficulty, which may result in their high discrepancy between measured audiometric hearing loss and self-reported hearing loss observed in this study. However, individuals with tinnitus may be confused about their hearing abilities because loud tinnitus can mask real sounds. Moreover, even tinnitus patients with a normal audiogram occasionally have hidden hearing impairment ,40. ConsThe presence of a TM abnormality was associated with a discrepancy between self-reported hearing loss and audiometric PTA results. TM perforations, middle ear effusion, and other miscellaneous lesions associated with inflammatory conditions and can disturb sound conduction through the middle ear account for the majority of TM abnormalities. Such inflammatory reactions cause other complaints, such as middle ear discharge, otalgia, and facial nerve palsy. These complications may disturb the accurate perception of hearing impairment besides of the increased audiometric PTA air conduction threshold. Furthermore, inflammation and infection are temporary rather than permanent events. Middle ear pathologies can be gradually improved or aggravated, and such changes result in the improvement or aggravation of hearing impairments. This perturbation of hearing may impede the concordance of hearing ability. Furthermore, a histories of middle ear infection has been suggested to increase tinnitus independently from audiometric measures .Hearing aid users exhibited significantly less overestimation  and underestimation  of hearing loss compared with non-hearing aid users. The overestimation of hearing loss of hearing aid users may be the result of the hearing aid users receiving information on hearing difficulty prior to the survey at previous hearing evaluations. In contrast, regarding the underestimation of hearing loss of hearing aid users, the audiometric PTA threshold may also influence the self-reported hearing loss and could be attributed to the relief of hearing difficulty as a result of wearing a hearing aid.Our results showed that old age, occupation, and stress level were associated with the patterns of self-reported hearing loss in the individuals with<25 dB HL. However, because most of our study population (81.2%) had a hearing threshold of <25 dB HL, we could not find a discrete, statistically significant discrepancy between self-reported hearing loss and audiometric PTA in the ≥ 25 dB subgroup .The current study has strengths relative to previous investigations in the comprehensive adjustments for various factors and the large representative population-based study design. We used the hearing thresholds from the better-hearing ears, which minimized the possibility of underestimation of hearing loss. The selection of the better ear was based on the classification of World Health Organization, which was adopted in many prior studies ,15.Despite these strengths, our study has limitations. There are conflicting opinions regarding the use of a reference for hearing thresholds ,41,42. WFurther studies to clarify the predictive values and patterns of self-reported hearing loss across a wide range of ages are warranted. Additional factors will be comprehensively investigated to determine their associations with the patterns of self-reported hearing loss. By helping to predict the patterns of self-reported hearing loss, these results will greatly aid the identification of hearing-impaired individuals. In addition, knowledge regarding self-reported hearing loss in association with patient characteristics and audiometric PTA thresholds will advance the management of hearing problems.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 Table(DOCX)Click here for additional data file.S5 Table(DOCX)Click here for additional data file.


Military musicians are working in a noisy environment with high sound exposure levels above the international standards. Aim of the current study is to find out, whether they develop the expected hearing impairments. Adherence to the regulations for prevention in musicians is more difficult than in other occupational fields.In an interval of 13.3 years, 36 out of 58 male military musicians of a German army music corps were subjected twice to an audiometric audit. There were no exclusion criteria apart from acute ENT infections (three musicians). These results were compared with one another and evaluated by means of statistical methods for relationships with several factors.p < 0.05) in hearing loss, whereas the influence of the instrument and the acoustic traumata were not.At frequencies below 3 kHz, the follow-up audiograms were up to 5 dB better than the preliminary examination. From 4 kHz up to 8 kHz the preliminary investigations showed less hearing impairment. Averaging all frequencies the improvement of hearing ability was around 1 dB. Above 1 kHz the average hearing of the right ear was up to 7 dB better than that of the left ear. Age-induced hearing loss was 3 to 8 dB lower than predicted by ISO standards over the entire frequency range. The side of the ear (right/left) and the frequency  were significant . Music may be less harmful than industrial noise, or the long-term auditory training of the musicians leads to a delayed presbycusis. At the time of the old Israelites, trumpets are said to have been able to bring whole city walls to collapse, according to the relevant account in the Old Testament of the Bible, in Joshua 6. Even today, brass orchestras are able to produce a significant sound pressure, which may be felt in a larger radius. While lovers of military music appreciate these brass instruments and the sound, the usually excessive volume encounters refusal, especially with gentler natures. But not only military orchestras can produce high sound pressure levels but even ballet orchestras are suspected of hearing hazard .EX > 90 dB(A).The musicians as parts of the sound source themselves are more exposed to these sounds than the audience in some distance and should therefore take a greater risk to develop noise induced hearing loss. In order to determine these sonic loads, appropriate measurements were made in some studies. These relate predominantly to classical orchestras. Since the number of military musicians on the whole seems rather small, their hearing is rarely subject of published investigations. A search in PubMed with the search query: <“military musicians” AND “hearing”> provides only three matches. One of these articles  complainOverall, there is a rather heterogeneous picture regarding the hearing of musicians in the literature, which presents partly contradictory results and is not always comparable in terms of methodology. An important step towards standardization could be the application of a new parametric method by Bo et al. 2016) for the noise risk assessment of professional orchestral musicians . The pre6 for theAll microphone positions, with values up to 93 dB (A), show equivalent sound exposure well above the upper exposure action values .The comparison of two audiograms to the same persons should enable to make reliable statements about the development of hearing or the development of a hearing damage in these persons under sound exposure far above the upper exposure action values .Out of a total of 58 male military musicians of the army music corps in Bremerhaven 39 musicians could be tested a second time after about 13 years. Only complete data sets were evaluated. Three musicians who suffered from a cold were excluded. A total of 36 musicians could be evaluated in the present longitudinal study. Existing hearing damage was not an exclusion criterion, as only the development of hearing was of interest, whilst comparing the two hearing tests.For the audiometry 4 audiometers of the company Hortmann type CA540 and an audiometer of the company Maico type MA53 in connection with circum-aural transducers type HDA200 of the company Sennheiser were used. These transducers were calibrated according to ISO 389–8  and ISO The first audiometry tests were performed with audiometers from Siemens type T31 and Beomat 2005 SR with supra-aural transducers from Beyer type DT 48 with sinusoidal tones. The tranducers were calibrated according to ISO 389–1 . The audThe acoustic measurements during the rehearsal were carried out by the technicians of Pfander . The meaThe data processing was carried out with the Office programs Access and Excel Microsoft Office 2010, whereby even simple T-tests were used. The age-related hearing loss from ISO 7029 (2nd and 3rd editions) , 25 was At intervals of about 13.3 years (mean age of the groups 31.4 and 44.7 years) military musicians of the German Federal Armed Forces were checked twice by means of audiometry and questioning.In Fig. Figure p = 0.036. A clear trend towards larger deviations at higher frequencies can be seen.The average differences between the hearing thresholds of the right and left ear are shown in Fig. N = 14) and the history of the experienced acoustic shocks, both mentioned in the questionnaire, represent between-subjects factors.The statistical verification of relationships was performed with a multifactorial analysis of variance (ANOVA) with repeated measurements based on 5 factors and their interactions. Three factors: the frequency with three measurement levels , The ear (right / left) and the audiogram (first and second) are the inner-subjects factors (repeated measures) and two factors: the musician’s instrument 2 from the ISO 1999  * LEX,h - L02 ft = 13.3 years. The average sound load LEX,8h = 91.4 dB(A) as well as determined at microphone position A  persisted for each musician and every working day during the 13.3 years without using ear protection devices or any other protective measures., and 8 kHz frequencies, the auditory curves are parallel, with the auditory thresholds being better for the first audiogram than the second, as might be expected. Together with the 3 kHz frequency, this range is the most sensitive to the harmful effects of noise. The hearing threshold at 10 kHz behaves contrary to expectations. Although the presbyacusis is most pronounced at high frequencies, better thresholds are seen in the later study of military musicians. For clarification, these differences in the threshold values in Fig. When comparing the two studies with an average interval of 13.3 years in Fig. Musicians in classical orchestras (Chicago Symphony)  have higFinnish members of the National Opera are exposed to sound levels above the upper action exposure values of 85 dB (A) .EX levels for the brass section could be measured up to 90.7 dB(A) and peak levels for the percussion section reached 146,9 dB(C).In an Australian study  mean LEXIn a Canadian study , the aveIn his measurements Fig.  Pfander p = 0.270 (audiogram) are not significantly different between the two examinations over 13.3 years of exposure. ISO 1999 [Nevertheless, the hearing thresholds at 3, 4 and 6 kHz with ISO 1999  predictsISO 1999  nor presISO 1999 , 27. TheISO 1999 , averageN = 5) of all observed/suspected acoustic traumata (N = 17) are identified by the survey. Therefore, the missing statistically significant correlation of the hearing thresholds with acoustic trauma (yes/no) (p = 0.402) can be explained. Sonic events that lead to clearly visible sinks in the audiogram are usually kept in mind by those affected, especially since their consequences can have an impact on the performance of the musicians. The discrepancy between the anamnestic questionnaire and the audiometric findings on acoustic trauma may well be the result.In addition to the music played during working hours, additional exposure is added by playing music during leisure time and other noisy hobbies . Furtherp < 0.001). Since the thresholds at 8 kHz are better than at 6 kHz, we can speak of a sink in the audiogram indicating a history of noise exposure.The frequency-dependent differences at 3, 4 and 6 kHz, which statistically describe the observed drop in the hearing curve are highly significant , which is surprising in view of the large differences between the instruments in terms of maximum volume and their frequency spectrum. In the statistical review, the factor instrument had no significant influence nor possible interactions with the ear (not listed in Table he factor instrument also was not significant (Possible reasons for only small differences in the two investigations could be the different measurement techniques and the use of pulsed test tones in the second study with better measurement results, compared to continuous tones in the first study. However, there is no evidence in the literature, on the contrary, only marginal differences were found . SimilarOverall, the musician’s hearing has remained largely unchanged during the period under review, just over 13 years. The effect of noise on hearing remains far behind the predictions of ISO 1999 . Similar


Purpose. This study aimed to examine whether plasma levels of cathepsin S or its inhibitor, cystatin C, may serve as biomarkers for COPD. Patients and Methods. We measured anthropometrics and performed pulmonary function tests and chest CT scans on 94 patients with COPD and 31 subjects with productive cough but no airflow obstruction . In these subjects and in 52 healthy nonsmokers (NS) and 66 healthy smokers (HS) we measured plasma concentrations of cathepsin S and cystatin C using an ELISA. Data were analyzed using simple and logistic regression and receiver operating characteristic analyses. Results. Cathepsin S and cystatin C plasma levels were significantly higher in the COPD and AR groups than in the NS and HS groups (p < 0.01). Among the COPD patients and AR subjects, plasma cathepsin S levels and cathepsin S/cystatin C ratios, but not cystatin C levels, were negatively related to severe airflow limitation  and severe emphysema as assessed by low attenuation area (LAA) score on chest CT scans . Conclusion. Plasma cathepsin S and cathepsin S/cystatin C ratios may serve as potential biomarkers for COPD. Consequently, there is an urgent need to identify and validate sensitive and reliable biomarkers for COPD in compartments that are easy to sample, such as blood, to more quickly assess the efficacy of novel therapies for COPD in clinical trials. In particular, it will be crucially important to identify reliable biomarkers for early stage COPD, the stage at which novel therapies might have the most impact on successfully modifying the course of the disease and preserving lung function.COPD is characterized by narrowing of small airways and lung parenchymal destruction, partly caused by chronic lung inflammation including increased numbers of neutrophils, macrophages, and CD8-positive T lymphocytes, oxidative stress, and alveolar septal cell apoptosis –3. ChangRecent research has identified a number of potential molecules and pathways that could serve as potential biomarkers and be targeted to develop novel therapies . One sucCO) measurements.We hypothesized that plasma concentrations of cathepsin S and cystatin C would differ between COPD patients, subjects with cough and sputum, and healthy smokers and nonsmokers. To test this hypothesis, we measured the plasma concentrations of cathepsin S and cystatin C and explored the association between levels of these biomarkers with degree of airflow obstruction and emphysema severity as assessed by low attenuation areas on chest CT scans and diffusing capacity of the lung for carbon monoxide (DLn = 94) were diagnosed based on airflow obstruction as defined by a ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) lower than 0.7 and an % FEV1 predicted value lower than the 95% confidence interval for this population by PFT. One group of 31 subjects  was defined as having chronic respiratory symptoms  but no airflow limitation as assessed by PFT. Enrolled healthy volunteers were classified into two groups by smoking history: 52 healthy nonsmokers (NS) and 66 healthy smokers (HS). This study was approved by the Ethics Committee of Keio University Hospital and informed consent was obtained from each subject.This study subjects included 125 patients suggestive of COPD consecutively visiting the outpatient clinic of Keio University Hospital from 2000 through 2003 and also included 118 healthy volunteers (age ≥ 50 years). All patients underwent pulmonary function tests (PFT) and chest CT. The patients suspected of having clinically stable COPD fulfilled the following criteria: (1) smoking history of ≥ 10 pack-years or more; (2) age ≥ 40 years old; and (3) having chronic respiratory symptoms including cough, sputum, and dyspnea on exertion. The patients were excluded if they were (1) having any pulmonary disease other than COPD; (2) having serum creatinine level > 1.5 mg/dL with renal dysfunction; (3) having serious comorbidities including unstable cardiovascular or cerebral diseases and treated malignant tumors; (4) having self-reported asthma; and (5) having an exacerbation for at least one month prior to recruitment or being treated with oral corticosteroids. The COPD patients  kit  after diluting the samples 1 : 100 using the diluent supplied by the kit manufacturer. The lower detectable limit of cathepsin S using these kits was 15.6 pg/mL. Plasma concentrations of cystatin C were determined in duplicate using a sandwich ELISA as previously described . GT 13 wCO was estimated by 10 s breath holding in most patients of the COPD (n = 83) and AR (n = 20) groups (n = 103) . Chest CT was also performed in all patients of the COPD and AR groups .Spirometry was performed in all patients of the COPD and AR groups using an electronic spirometer . Regular treatment was not changed prior to spirometric testing. DLTo calculate emphysema severity, the entire lung was divided into six zones . Low attenuation areas (LAA) were visually scored in each zone on a scale from 0 to 4: 0, no LAA; 1, 1–25%; 2, 26–50%; 3, 51–75%; 4, 76–100%. The total (0–24) was assessed by three pulmonologists in a blinded manner and the mean score was defined as the LAA score, a quantitative indicator of emphysematous change , 15. Dia1 predicted < 50%) or emphysematous change (LAA ≥ 8.0) were determined using logistic regression analysis. Logistic regression analysis models were prepared to avoid the influence of potential confounders, including age, sex, body mass index (BMI), smoking status, serum creatinine levels, the presence of hypertension, and treatment with inhaled corticosteroid (ICS). Inclusion of variables was based on existing knowledge of risk factors for COPD and on the factors related to plasma cystatin C levels according to previous reports . Also, the cathepsin S/cystatin C ratio  and age  correlated to severe airway obstruction (p = 0.001. OR = 0.28) and the cathepsin S/cystatin C ratio  were the strongest factors associated inversely with the presence of severe emphysema  when the threshold was set at ≥ 12.1 ng/mL. The specificity improved from 62% to 80% if the threshold was set at ≥ 16.2 ng/mL but the sensitivity decreased to 74%. These additional analyses suggest that plasma cathepsin S levels may serve as a useful biomarker for COPD. Rokadia et al. also reported that active smokers with COPD had significantly higher plasma levels of cystatin C than healthy controls in accordance with our results . These o1/FVC and % FEV1 predicted is positively associated with BMI and malnutrition in a large number of COPD patients [An unexpected result from our study was that, among the COPD patients and AR subjects, plasma cathepsin S and cathepsin S/cystatin C ratios were inversely correlated with the extent of airflow obstruction and emphysema severity, as assessed by LAA on CT scans, even after normalizing for various confounding factors including age, gender, BMI, renal function, smoking history, the presence of hypertension, and treatment with ICS. Thus, plasma cathepsin S levels, but not cystatin C levels, were significantly increased in patients with AR and with mild COPD when compared with patients with severe airflow limitation and emphysema. One possible explanation for the inverse correlation between plasma cathepsin S and severity of disease among the COPD patients is that cathepsin S is produced in lung tissue including activated macrophages , and as patients , and plapatients . Also, ppatients . Additiopatients . A priorpatients .Taken together, we speculate that the inverse correlation between plasma cathepsin S and cathepsin S/cystatin C ratios and severity of airflow limitation and emphysema in patients suggestive of COPD that we observed in this study might reflect these complex processes in the pathophysiology of this disease. However, additional cohorts of COPD and asthma will be needed to confirm these findings. Symptomatic smokers without pulmonary function decline are classified as Stage 0 disease and reported to have an increased susceptibility to COPD in GOLD 2001. AR, that is Stage 0 disease, develops COPD in 50% . In addiThere are several limitations in our study. First, it was impossible to obtain pulmonary function data from subjects in the NS and HS groups. The healthy volunteers (NS and HS) were differentiated from the patients (COPD and AR) since they had no chronic respiratory symptoms leading to visiting hospitals. Second, the mean age of the COPD group was significantly higher than AR and the healthy subjects. However, our results indicate that cathepsin S levels are not affected by age . Third, We have demonstrated significantly elevated plasma levels of cathepsin S and cystatin C, and plasma cathepsin S/cystatin C ratios, in COPD patients versus healthy subjects. Our results suggest that plasma cathepsin S concentrations and cathepsin S/cystatin C ratios may serve as potential biomarkers for COPD.