To assess the feasibility of radiologic measurements and find out whether hearing outcome could be predicted based on computer tomography (CT) scan evaluation in patients with temporal bone fractures and suspected ossicular joint dislocation.We assessed 4002 temporal bone CT scans and identified 34 patients with reported ossicular joint dislocation due to trauma. We excluded those with no proven traumatic ossicular dislocation in CT scan and patients with bilateral temporal bone fractures. We measured four parameters such as malleus-incus axis distance, malleus-incus angle at midpoints, malleus- incus axis angle and ossicular joint space. The contralateral healthy side served as its own control. Hearing outcome 1–3 months after the index visit was analyzed. We assessed diagnostic accuracy and performed a logistic regression using radiologic measurement parameters for outcome prediction of conductive hearing loss (defined as >20dB air-bone gap).p = .006). A cut-off value for the axis deviation of 0.25mm showed a sensitivity of 0.778 and a specificity of 0.94 (p < .001) for discrimination between poor and good hearing outcome in terms of conductive hearing loss.We found excellent inter-rater agreement on the measurement of axis deviation between incus and malleus in CT scans (interclass correlation coefficient 0.81). The larger the deviation of incus and malleus axis, the higher probability of poor hearing outcome (odds ratio (OR) 2.67 per 0.1mm, Adequate assessment of high resolution CT scans of temporal bone in which ossicular chain dislocation had occurred after trauma was feasible. Axis deviations of the incus and the malleus were strongly predictive for poor hearing outcome in terms of air conduction 1–3 months after trauma. We propose a 3-level classification system for hearing outcome prediction based on radiologic measures. Ossicular chain dislocation is often associated with a traumatic fracture of the temporal bone –3. OftenTransverse fractures often affect the labyrinth, the vestibular, and cochlear systems, as well as the facial nerve. Longitudinal fractures (sparing the otic capsule) commonly involve the external auditory canal, tympanic membrane, and the middle ear including the ossicular chain, which often results in conductive hearing loss , 7, 8. IWe sought to perform a retrospective analysis of patients with a radiologically suspected ossicular chain dislocation and to assess the radiologic CT parameters and their association with conductive hearing outcome.This retrospective single-center cohort study included patients admitted to the emergency department (ED) with an ossicular injury caused by trauma and a fully documented audiometric examination at the time of the traumatic event in the period January 2010 to December 2017. All patients underwent a CT scan of the head as part of our standard emergency procedure for trauma patients.In a primary screening of the radiological database, head trauma cases including petrous bone injury were identified using key words like “ossicular dislocation” “ossicular dehiscence” “petrous bone” by an experienced head and neck neuroradiologist (FW). In the second-stage screening conducted by a medical student (NS), only patients with a reported or suspected traumatic ossicular chain dislocation were included. All images were reviewed and assessed by 2 blinded neuroradiologists; one was a very experienced head and neck neuroradiologist (FW) and the other was a neuroradiology trainee (MK).We excluded patients whose scans showed no proven dislocation of the ossicular chain in CT or had no head trauma. We further excluded patients with bilateral temporal bone fracture since the contralateral healthy side served as its own control. S1 Fig in ® Definition Edge; Siemens Healthcare, Erlangen, Germany). A certified reporting workstation  was used for evaluation by the 2 neuroradiologists, who were blinded to outcomes. Slight motion artifacts were considered acceptable. All the images collected were of sufficiently good quality to allow an accurate assessment of the middle ear.All CT examinations were performed with the patient in a supine position using a 128-slice CT scanner  and a bone window (kernel J70h) of the acquired CT scan of the head; each in the axial, coronal, and sagittal plane. For our retrospective data analysis, we additionally reconstructed the CT scans in 3-D to provide a different view of the ossicular chain anomalies in our trauma cohort. Both, 2-D and 3-D views have been used for the measurements .The acquisition parameters of our standard trauma CT scan of the head were: slice thickness 1.0 mm, matrix 512 × 512, field of view 200 mm, total acquisition time of 1 second by tube current-time product of 240 mA, and tube voltage 100 kV. This resulted on average in a computed tomography dose index of 35 mGy and a dose-length product of 650 mGycm.Assessment of the presence of an ossicle fracture was followed by the evaluation of ossicle dislocation or luxation based on visual identification of a discernable gap between ossicles. The distance ‘D’ between malleus and incus was measured by drawing a virtual line between the long axis of the incus and the middle of the head of the malleus, and the offset of the incus in medial or lateral deviation measured in mm were reported . The preThe degree of the offset between malleus and incus dislocation was separately measured, and the malleus–incus axis angle ‘α’ measured at midpoints (degrees) and the malleus–incus axis angle ‘β’ (degrees) were documented . FurtherWe assessed hearing outcome 1–3 months after the index ED visit and after resorption of any hemotympanon confirmed by tympanometry and otoscopy. Mixed hearing loss was not an exclusion criterion, however, sensorineural hearing loss due to labyrinthine concussion was not assessed since it was not considered a primary or secondary endpoint in this study. We used data from pure tone audiometry with air and bone conduction. The pure tone average including frequencies of 500Hz, 1000Hz, 2000Hz, and 3000Hz was calculated following the guidelines of the American Academy of Otolaryngology Committee on Hearing and Equilibrium . An averWe used SPSS (IBM Version 25) for statistical analysis. We calculated the inter-rater agreement for each variable, Cohen’s kappa for categorical variables and the intraclass correlation coefficient for continuous data. A logistic regression was applied for the assessment of independent variables that might determine a poor hearing outcome with an air-bone gap of ≥20dB. Hearing outcome was coded as a binary, dependent variable.A receiver operator characteristics (ROC) curve was constructed using the radiological variables. We assessed the diagnostic accuracy and calculated the optimal cut-point (Youden’s index) for the discrimination of poor hearing outcome. Normative data from the contralateral healthy ear (2 standard deviations from the mean) and data from the ROC curve served as a basis for the classification of traumatic ossicular chain luxations.The institutional review board and the local ethics committee  gave approval for the access to and use of the data collected with the intention of using it for retrospective clinical research. Data have been fully anonymized. Informed consent was waived by the ethics committee.We included 34 patients  with a mean age of 44.7 years (SD 24.9), 20 with a dislocation of the incudomalleolar joint, 1 with involvement of the incudostapedial joint, 4 with a joint distension , and 9 with a complex dislocation involving all 3 ossicles. All patients had a history of head trauma, 56% reported a fall from height, 27% were involved in a traffic accident, 11% had a blunt head trauma and 6% had an unknown trauma mechanism. Fifteen of the 34 patients had a severe brain injury with a Glasgow Coma Scale (GCS) score of 3–8, 5 patients had a moderate (GCS 9–12), and 6 patients a minor brain injury (GCS 13–15). The state of consciousness remained unknown for 8 patients. The main complaints at the index ED visit were dizziness (6 out of 34) and hearing loss (7) followed by nausea (3), vomiting (3), headache (3), facial palsy (2), otorrhea (2), and gait disturbance (1).One-third of the patients had facial nerve palsy (12 out of 34). Twenty-two patients suffered from bloody ear discharge, 10 had a hemotympanon, and 1 patient a perforation of the tympanic membrane; however, only 7 patients complained of hearing loss. Nine of the 22 patients who underwent follow-up hearing tests 1–3 months after the initial trauma had a hearing loss ≥20dB  for discrimination between poor and good hearing outcome in terms of conductive hearing loss. The axis angle measured at the midpoints ‘α’ was also a significant predictor  with a high sensitivity  but lower specificity (0.743).The angle ‘α’ and the distance ‘D’ between the 2 measured axes also had the highest sensitivity and specificity for predicting a poor hearing outcome . A cut-oAlmost half of the patients suffered from conductive hearing loss 1–3 months after temporal bone fracture with associated luxation/dislocation of middle ear ossicles. High resolution temporal bone CTs with narrow slice widths allowed accurate radiologic measurements with high inter-rater agreement. The distance ‘D’ between the 2 axes through the short process of the incus and the midpoint of the malleus was an accurate predictor for hearing outcome. Each deviation difference of 1/10mm increased the odds for a poor predicted hearing outcome by 2.6. A cut-off value of 0.25mm had a statistically significant high sensitivity and specificity for discriminating poor from normal hearing outcome and served as the threshold for a new proposed classification.The most frequent trauma mechanism was falls from height followed by traffic accidents. A rapid deceleration or high energetic trauma was the cause of temporal bone fractures with consecutive injury to the ossicular chain. This result is congruent with that of a recent study by Delrue et al. , but in There was a high proportion of longitudinal fractures in our cohort. The classical classification of temporal bone fractures into longitudinal, transverse, or mixed fractures, however, has a poor correlation with clinical symptoms , 16. TheOssicular chain dislocation or luxation is a frequent complication of temporal bone fracture. In this study, incudomalleolar dislocation was by far the most common type, as has been reported in other CT-based studies , 21. HowOur study data suggest that a latero-medial dislocation of the incus is more likely than a longitudinal traction. A lateral displacement changes the axis angle and axis distance, whereas traction leads to a widening of the joint space. The configuration of the ligamentous apparatus of the middle ear ossicles supports the observed mechanism of dislocation and the vulnerability of the incus. While the malleus is attached by 3 ligament folds , the incus is only kept in place by a strong posterior incudal ligament fold, which is attached at the apex of the short incus process  S2 Fig . The latTo our knowledge, this is the first study to propose a grading system for predicting conductive hearing outcome based on CT in patients with traumatic dislocations of the middle ear ossicles. This classification of hearing outcome prediction is limited to patients with conductive or mixed hearing loss after trauma. Sensorineural hearing loss due to labyrinthine concussion is not covered; however, sensation levels might be screened by the Weber tuning fork test at the bedside  or assessed by bone conduction hearing tests. Patients classified as grade II had a pathological axis deviation in the index CT but still had normal hearing after 1–3 months; however, no follow-up imaging or surgical reports were available to confirm recovery in terms of anatomy.CT spatial resolution was limited to 0.2–0.3mm, however, distance measurements close to the resolution limits were not performed between anatomical structures but were restricted to distances between two marked axis. Some calculated mean distances in our classification table were smaller than the spatial CT resolution which is the result from statistical analysis including values with zero millimeters (no dislocation). Further studies using the proposed classification system and its radiologic measuring techniques are necessary to detect possible technical limitations regarding the measurements. Overall, the inter-rater agreement was excellent indicating a reproducible and accurate radiologic measurement, which was also found by Maillot et al, provided that assessments were done by senior readers and taking into account 3D CT reconstructions .Finally, luxations of the incudostapedial joint were not measured quantitatively due to the low frequency of occurrence in our cohort; however, qualitative radiological assessment was still possible. It is unclear whether such isolated joint luxations remain limited to the incudostapedial joint or—more likely—affect the entire ossicular chain.This proposal for a grading system is a first attempt to classify patients according to whether a normal or poor hearing outcome is likely after temporal bone fractures. Future prospective studies are essential for its validation. Prospective studies with hearing assessments after resorption of the hemotympanon, long-term hearing results and intraoperative findings might give more insights about the mechanism and morphology of dislocations. Information about prognosis and encouragement might improve the follow-up of these patients.Assessment of high-resolution CT scans of temporal bone with respect to ossicular chain dislocations after traumatic temporal bone fractures was feasible. Axis distance ‘D’ of the short incus process and the middle point of the malleus body were strongly predictive for hearing outcome in terms of air conduction 1–3 months after trauma. We propose a new 3-level classification system for the prediction of poor or normal hearing outcome in patients with ossicular chain dislocation caused by trauma based on radiologic measures.S1 Appendix(PDF)Click here for additional data file. 13 Oct 2020PONE-D-20-27974Traumatic Dislocation of Middle Ear Ossicles: A New Computed Tomography Classification Predicting Hearing OutcomePLOS ONEDear Dr. Mantokoudis,Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.Please submit your revised manuscript by Nov 27 2020 11:59PM. 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Reviewer #1: I congratulate the authors for this interesting paper.How unfortunate that the study managed to analyze only 34 exams in a universe of more than 4000 CT scans. Anyway, the authors managed to adequately point out the limitations of the study and I believe that the idea should follow so that other studies use the same method to validate the tomographic correlation with the potential to predict the audiometric results.Reviewer #2: This is a review of the temporal bone CT scans of patients with a radiologically suspectedossicular chain dislocation and their association with conductive hearing outcome. It states that Figure S1 in the Appendix shows how patients were included in the analysis, although I failed to find this figure in my copy of the manuscript. The severity of incudomalleal joint disruption was assessed with 1 mm slices of standard trauma CT scan of the head. Aside from the inter rater agreement, logistic regression was used to assess the association between 4 CT scan parameters with poor hearing outcome defined as conductive hearing loss of ≥20dB air-bone gap. The authors then found that the malleus-incus axis distance and malleus-incus angle measured at midpoints were statistically correlated with conductive hearing loss.Here are some of my questions:1. Was the patient selection process blinded to outcomes? Who did the selection, how was this done and how were disagreements to include patients addressed?2. Were the 2 neuroradialogists blinded to outcomes?3. I am concerned that the distance of 0.25 mm was found significant when the cuts were 1 mm in thickness. The “ice cream cone” constituting the incus and the malleal head appears discernible enough from the sample CT scan picture but how were differences in measurements settled? And how high were the inter rater agreements in each of the 4 radiologic parameters? (I did not find Appendix Table S1 in my copy).4. I am not clear as to how the authors determined the ranges of the malleus-incus axis distances of 0-0.07, 0.08-0.25 and >0.25 for each category. I may have missed how they have correlated these ranges with normal or abnormal hearing.I appreciate how the discussion attempts to explain the results in terms of the ligamentous attachments of the malleus and incus may explain the vulnerability of the incudomalleal joint to trauma. An illustration may more clearly drive home the point.I also appreciate the limitations part and agree with all the points raised by the authors, particularly with their statement that “some calculated mean distances in our classification table were smaller than the spatial CT resolution which is the result from statistical analysis”. Given this potential technical difficulty in measurement, I think they should point out that their new classification system should be applied into another set of trauma patients to understand how well it performs.Reviewer #3: The authors perform a study to determine the association between CT findings of post-traumatic ossicular injuries and conductive hearing outcome. They also propose a classification system to predict audiometric outcomes based on radiological measurements. Although this is an interesting area of research to explore, there are some major concerns that need to be addressed, as listed below:1. The abstract should be revised to include more detail about methodology, such as summary of inclusion/exclusion criteria, measurements taken  and how good/poor hearing was defined by the authors. “CT” abbreviation should be provided in the Objectives.2. Also, in the abstract — The authors write in the conclusion: “Adequate assessment of high resolution CT scans of temporal bone in which ossicular chain dislocation had occurred after traumatic fractures of temporal bone was feasible.” — did you mean your new radiological parameters (measurements) for assessment were feasible and reproducible? If the authors also wanted to assess their feasibility, it should be included in the aims (objectives).3. Lines 80-83: Patients should also acknowledge the fact that hearing dysfunction is often overlooked in polytrauma patients because other trauma-related physical/brain injuries that take medical priority.4. Lines 84: fractures are OFTEN associated with a hemotympanum.5. Material and Methods: Inclusion criteria is confusing — were considered cases with ossicular chain injury following head trauma regardless of presence of TBF? Or was presence of TBF determinant for study inclusion? I also suggest providing # of excluded cases within each criterion in Figure 1S .6. Line 152: What does “more than one direction” mean? More than one joint? Please clarify.7. Did any patient have a history of asymmetric hearing loss or ear disease prior to the trauma?8. Line 208, 217 — Keep consistency in terminology while reporting hearing loss (average air-bone gap vs. conductive hearing loss) throughout the Results.9. Audiometric data timeline considered for inclusion in the study needs clarification. Did all patients have audiometric evaluation? Did the authors include audiometric data before 1 mo in addition to those performed 1-3 months after trauma? In the Results, Line 207-208: “Nine of the 22 patients who underwent follow-up hearing tests still had a hearing loss ≥20dB 1-3 months after the initial trauma” gives the impression that audiometric data before 1mo were also reviewed. Please clarify.10. Line 109: Figure 1 does not relate to the sentence/paragraph.11. Line 164-173: It is not clear if cases with mixed hearing loss were also included. Please specify.12. Line 197: “4 with a joint distension” — Please clarify.13. Line 210-211: The total accounts for 33 cases. However, authors report a total of 34 cases in this study. Similar to my question #5 — were cases without TBF included? Please clarify.14. Keep consistency when reporting measurements in the main manuscript, table and figures . Also, consider including symbols  in the tables.15. Line 225: Table 2 indicates that D and α had the highest sensitivity and specificity for predicting a poor hearing outcome instead. Please review/clarify.16. In Methods, authors mention to have performed 3D-CT reconstructions to provide different views of the ossicular chain anomalies — Were both 2D-CT axial and sagittal views and 3D-CT reconstructions used for measurements? It should be clarified in the Methods. Also, were there any ossicle fractures identified in your cohort?17. I suggest including the recent publication from Maillot et al. (2020) — PMID: 28551022 — related to this topic to enrich the discussion.**********what does this mean?). If published, this will include your full peer review and any attached files.6. PLOS authors have the option to publish the peer review history of their article  digital diagnostic tool,  26 Nov 2020Reviewer #1: I congratulate the authors for this interesting paper.How unfortunate that the study managed to analyze only 34 exams in a universe of more than 4000 CT scans. Anyway, the authors managed to adequately point out the limitations of the study and I believe that the idea should follow so that other studies use the same method to validate the tomographic correlation with the potential to predict the audiometric results.AUTHOR REPLY: We would like to thank the reviewer for the thorough review of the manuscript, the positive feedback and the appreciation of the work.Reviewer #2: This is a review of the temporal bone CT scans of patients with a radiologically suspected ossicular chain dislocation and their association with conductive hearing outcome. It states that Figure S1 in the Appendix shows how patients were included in the analysis, although I failed to find this figure in my copy of the manuscript. The severity of incudomalleal joint disruption was assessed with 1 mm slices of standard trauma CT scan of the head. Aside from the inter rater agreement, logistic regression was used to assess the association between 4 CT scan parameters with poor hearing outcome defined as conductive hearing loss of ≥20dB air-bone gap. The authors then found that the malleus-incus axis distance and malleus-incus angle measured at midpoints were statistically correlated with conductive hearing loss.Here are some of my questions:1. Was the patient selection process blinded to outcomes? Who did the selection, how was this done and how were disagreements to include patients addressed?AUTHOR REPLY: Thank you for raising this important question. In a primary screening the radiological database has been searched for key words like “ossicular dislocation” “ossicular dehiscence” “petrous bone” by a experienced head and neck neuroradiologist (FW). In the second-stage screening, all reports of the 4002 CT scans were screened by a medical student (NS) for reported or suspected ossicular chain dislocation associated with trauma. All images were then again reviewed and assessed by 2 blinded neuroradiologists to determine whether a dislocation actually was present or not. Neurologist were blinded to outcomes. We have added this specification to “Material and Methods: Patient Population.2. Were the 2 neuroradialogists blinded to outcomes?AUTHOR REPLY: Both neuroradiologists were blinded to outcomes as stated in Material and Methods under the section “Patient population”.REVISED: “A certified reporting workstation  was used for evaluation by the 2 neuroradiologists, who were blinded to outcomes.”3. I am concerned that the distance of 0.25 mm was found significant when the cuts were 1 mm in thickness. The “ice cream cone” constituting the incus and the malleal head appears discernible enough from the sample CT scan picture but how were differences in measurements settled? And how high were the inter rater agreements in each of the 4 radiologic parameters? (I did not find Appendix Table S1 in my copy).AUTHOR REPLY: Please see appendix table 1S attachedREVISED: Limitations section: Some calculated mean distances in our classification table were smaller than the spatial CT resolution which is the result from statistical analysis including values with zero millimeters (no dislocation).4. I am not clear as to how the authors determined the ranges of the malleus-incus axis distances of 0-0.07, 0.08-0.25 and >0.25 for each category. I may have missed how they have correlated these ranges with normal or abnormal hearing.¨AUTHOR REPLY: Grade I was determined by the mean range of the contralesional, healthy side . For the determination of the cut-off between grad 2 and 3, we used the ROC analysis and calculated the best discrimination cut-off (0.25). We added this information in the manuscript to make it more clear.REVISED: “Grade I represents the normal, non-displaced axis distance of the incudomalleolar joint .”“The discrimination cut-off between Grade II and Grade III was derived from the ROC analysis (Table 2).”I appreciate how the discussion attempts to explain the results in terms of the ligamentous attachments of the malleus and incus may explain the vulnerability of the incudomalleal joint to trauma. An illustration may more clearly drive home the point.AUTHOR REPLY: We added an additional figure in the appendix illustrating the incudal ligament folds (figure S2).I also appreciate the limitations part and agree with all the points raised by the authors, particularly with their statement that “some calculated mean distances in our classification table were smaller than the spatial CT resolution which is the result from statistical analysis”. Given this potential technical difficulty in measurement, I think they should point out that their new classification system should be applied into another set of trauma patients to understand how well it performs.AUTHOR REPLY: We agree with the reviewer that the new classification should be applied to other trauma patients.REVISED: “Further studies using the proposed classification system and its radiologic measuring techniques are necessary to detect possible technical limitations regarding the measurements.”Reviewer #3: The authors perform a study to determine the association between CT findings of post-traumatic ossicular injuries and conductive hearing outcome. They also propose a classification system to predict audiometric outcomes based on radiological measurements. Although this is an interesting area of research to explore, there are some major concerns that need to be addressed, as listed below:1. The abstract should be revised to include more detail about methodology, such as summary of inclusion/exclusion criteria, measurements taken  and how good/poor hearing was defined by the authors. “CT” abbreviation should be provided in the Objectives.AUTHOR REPLY: Thank you for raising these important points. We revised the abstract and added inclusion/exclusion criteria. “CT” abbreviation provided. Radiologic measurements and hearing outcome defined.2. Also, in the abstract — The authors write in the conclusion: “Adequate assessment of high resolution CT scans of temporal bone in which ossicular chain dislocation had occurred after traumatic fractures of temporal bone was feasible.” — did you mean your new radiological parameters (measurements) for assessment were feasible and reproducible? If the authors also wanted to assess their feasibility, it should be included in the aims (objectives).AUTHOR REPLY: We assessed also the feasibility of radiological measurements and added this to the objectives in the abstract.REVISED: “To assess the feasibility of radiologic measurements and find out whether hearing outcome could be predicted based on computer tomography (CT) scan evaluation in patients with temporal bone fractures and suspected ossicular joint dislocation.”3. Lines 80-83: Patients should also acknowledge the fact that hearing dysfunction is often overlooked in polytrauma patients because other trauma-related physical/brain injuries that take medical priority.AUTHOR REPLY: Corrected. We integrated this important fact in the introduction.REVISED: “Often hearing dysfunction is overlooked in polytrauma patients because other trauma-related physical/brain injuries take medical priority.”4. Lines 84: fractures are OFTEN associated with a hemotympanum.AUTHOR REPLY: corrected5. Material and Methods: Inclusion criteria is confusing — were considered cases with ossicular chain injury following head trauma regardless of presence of TBF? Or was presence of TBF determinant for study inclusion? I also suggest providing # of excluded cases within each criterion in Figure 1S .AUTHOR REPLY: We agree that exclusion criteria were not clearly stated. We rephrased this sentence. Yes, we included cases with ossicular chain injury following any head trauma regardless of presence of TBF. However, we did not found any bilateral temporal bone fractures with associated bilateral ossicular dislocation (n=0). We corrected Figure S1. REVISED: “We excluded patients whose scans showed no proven dislocation of the ossicular chain in CT or had no head trauma. We further excluded patients with bilateral temporal bone fracture since the contralateral healthy side served as its own control.”6. Line 152: What does “more than one direction” mean? More than one joint? Please clarify.AUTHOR REPLY: “more than one direction” means a dislocation in several planes (axes). REVISED: or complex if there was a luxation or dislocation in more than one direction . 7. Did any patient have a history of asymmetric hearing loss or ear disease prior to the trauma?AUTHOR REPLY: These patients had no audiological assessment prior to the trauma, however, any preexisting asymmetric hearing cannot be excluded due to the retrospective nature of our study. 8. Line 208, 217 — Keep consistency in terminology while reporting hearing loss (average air-bone gap vs. conductive hearing loss) throughout the Results.AUTHOR REPLY: corrected9. Audiometric data timeline considered for inclusion in the study needs clarification. Did all patients have audiometric evaluation? Did the authors include audiometric data before 1 mo in addition to those performed 1-3 months after trauma? In the Results, Line 207-208: “Nine of the 22 patients who underwent follow-up hearing tests still had a hearing loss ≥20dB 1-3 months after the initial trauma” gives the impression that audiometric data before 1mo were also reviewed. Please clarify.AUTHOR REPLY: We did not review audiologic data in the time period from trauma until 1 month after trauma. We rephrased this sentence.10. Line 109: Figure 1 does not relate to the sentence/paragraph.AUTHOR REPLY: We agree. This relates to figure S1 in the appendix. 11. Line 164-173: It is not clear if cases with mixed hearing loss were also included. Please specify.AUTHOR REPLY: Thank you for pointing out this ambiguity. Mixed hearing loss was not an exclusion criterion. The study focuses on the ABG, whereas sensorineural hearing loss due to labyrinthine concussion was not assessed since it was not considered a primary or secondary endpoint in this study. We rephrased this in the methods section. We made it more clear in the methods section.12. Line 197: “4 with a joint distension” — Please clarify.AUTHOR REPLY: Joint distension means, that the malleus head was still within in the facet of the incus without axis deviation but the joint space was expanded. We revised accordingly.13. Line 210-211: The total accounts for 33 cases. However, authors report a total of 34 cases in this study. Similar to my question #5 — were cases without TBF included? Please clarify.AUTHOR REPLY: One trauma patient had no TBF. We added this in line 211 and clarified in the methods section. 14. Keep consistency when reporting measurements in the main manuscript, tables and figures . Also, consider including symbols  in the tables.AUTHOR REPLY: Thank you for pointing out these inconsistencies. In the revised manuscript the term “malleus-incus” is now used consistently and we included the symbols  consistently throughout the whole manuscript, including tables, figures and the appendix.15. Line 225: Table 2 indicates that D and α had the highest sensitivity and specificity for predicting a poor hearing outcome instead. Please review/clarify.AUTHOR REPLY: Corrected. It should be ‘D’ and ‘α’». We added labels ‘D’, ‘α’, ‘β’ and ‘d’ to all tables.16. In Methods, authors mention to have performed 3D-CT reconstructions to provide different views of the ossicular chain anomalies — Were both 2D-CT axial and sagittal views and 3D-CT reconstructions used for measurements? It should be clarified in the Methods. Also, were there any ossicle fractures identified in your cohort?AUTHOR REPLY: We used both, 2D and 3D views for the measurements. We clarified this in the methods. One patient had a fracture of the incus. This was added in the results section. 17. I suggest including the recent publication from Maillot et al. (2020) — PMID: 28551022 — related to this topic to enrich the discussion.AUTHOR REPLY: We included the proposed publication in the methods and discussion.AttachmentResponse to Reviewers PONE-D-20-27974.docxSubmitted filename: Click here for additional data file. 8 Jan 2021Traumatic Dislocation of Middle Ear Ossicles: A New Computed Tomography Classification Predicting Hearing OutcomePONE-D-20-27974R1Dear Dr. Mantokoudis,We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. 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Background: Both Guillain–Barré syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) are neurodegenerative and inflammatory demyelination disorders. Sporadic reports showed that the increased levels of thyroid function and autoantibodies are associated with GBS, CIDP, or both, but no systematic study has been reported. We assessed the differences of thyroid function and autoantibodies between GBS and CIDP in a Chinese cohort.Methods: A total of 256 patients were enrolled in this study. 175 clinically confirmed GBS and CIDP patients were selected. Meanwhile, 81 patients hospitalized for diseases other than GBS or CIDP with mild symptoms were enrolled as a control group. Relevant clinical data, including thyroid function, and autoantibody examinations, were collected for statistical analysis.Results: In the comparison of thyroid function and autoantibody parameters, the levels of total thyroxine (TT4), thyroid peroxidase antibody (TPO-Ab), and thyroglobulin antibody (TG-Ab) in the GBS group were all higher than those in the CIDP and Control groups (P < 0.01). The thyroid antibody positive rates in the GBS and CIDP groups were 70.10 and 14.10%, respectively (P < 0.01). In the receiver operating characteristic (ROC) curve analysis, TT4, TPO-Ab, and TG-Ab were higher in the GBS group and lower in the CIDP group (P < 0.01). To achieve a high specificity of 97–99%, the diagnostic cutoff value of TPO-Ab was higher than 133 IU/mL (Sensitivity: 11.34%) or lower than 0.01 IU/mL (Sensitivity: 9.09%), while the diagnostic cutoff value of TG-Ab was higher than 261.1 IU/mL (Sensitivity: 2.06%) or lower than 0.46 IU/mL (Sensitivity: 11.69%). Multivariate logistic regression analysis showed that the differences in TPO-Ab were statistically significant between GBS patients with TPO-Ab was higher than 133 IU/mL and CIDP patients (P < 0.01); the differences in TG-Ab were statistically significant between GBS patients with TG-Ab was higher than 261.1 IU/mL and CIDP patients (P < 0.05).Conclusion: The elevation of thyroid autoantibodies was associated with GBS. TPO-Ab higher than 133 IU/mL or lower than 0.01 IU/mL and TG-Ab higher than 261.1 IU/mL or lower than 0.46 IU/mL had high specificity for differentiating between GBS and CIDP; therefore, TPO-Ab and TG-Ab can be used as biomarkers for the differential diagnosis of GBS and CIDP. Guillain–Barré syndrome (GBS) is an autoimmune peripheral neuropathy characterized by demyelination of peripheral nerves and nerve roots. The clinical manifestation is acute symmetric flaccid limb paralysis, which usually peaks within 4 weeks of disease onset. Respiratory muscle involvement is common, and glucocorticoid treatment alone is not effective in terms of clinical outcomes .Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a disease of the peripheral nervous system (PNS) that is clinically characterized by symmetrical proximal and distal weakness with altered sensation and hyporeflexia/areflexia . CIDP exThyroid peroxidase antibody (TPO-Ab) and thyroglobulin antibody (TG-Ab) are major indicators for the diagnosis of Hashimoto's thyroiditis (HT). The general belief is that TPO-Ab should be measured to identify autoimmune thyroiditis diseases in a manner similar to HT . BairactGBS and CIDP patients who were discharged between October 2014 and February 2020 were enrolled. The inclusion criteria were as follows: GBS or CIDP diagnosed at Beijing Tiantan Hospital, Capital Medical University, and confirmed according to Guillain–Barré and Miller Fisher syndromes—new diagnostic classification  and the The exclusion criteria were as follows: comorbid diseases affecting brain function, such as stroke, transient ischaemic attack, encephalitis, and subarachnoid hemorrhage; systemic infectious diseases, malignant tumors, severe heart, liver, or kidney diseases, or hematological diseases; sequelae of nervous system diseases precluding determination of the severity of GBS; a history of treated or untreated thyroid disease; the use of drugs affecting thyroid function; a history of hypothalamic and pituitary diseases; and ventilator-assisted ventilation or death due to GBS or CIDP.The control group consisted of patients who were discharged between October 2014 and February 2020. The control patients were hospitalized for conditions other than GBS and CIDP with mild symptoms, such as dizziness, primary headache, leukodystrophy, multiple sclerosis, and minor stroke.A blood sample (5 mL) was collected from the median cubital vein of each patient in the morning within 48 h of admission. Blood samples were allowed to stand for 30 min and centrifuged at 3,000 r/min for 10 min. autoantibodies were detected within 1 h of centrifugation. The Abbott automatic biochemical immune analyser (Architectcil6200) and original reagent detection and the chemiluminescence immunoassay method were used to detect serum levels of free triiodothyronine (FT3), free thyroxine (FT4), T3, T4, thyroid-stimulating hormone (TSH), TG-Ab, and TPO-Ab. When the autoantibodies concentration of the sample was below the lower detection limit (or above the upper detection limit), the lower detection limit value  was used.Based on the Clinical Practice Guidelines for Hypothyroidism in Adults:Cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association  and the t-test. Non-normal data are expressed as the median and interquartile range and were compared using the Kruskal–Wallis H-test. Count data are described as a ratio or percentage (%) and were compared between groups with the χ2 test. The GBS or CIDP group assignment was used as the dependent variable, and general patient data that were significantly different between the groups were used as the independent variables for binary multivariate logistic regression analyses. MedCalc19.1 was used to analyse receiver operating characteristic (ROC) curves to evaluate the ability of thyroid functions and autoantibodies to predict GBS and CIDP. P < 0.05 was considered statistically significant.The data were analyzed with SPSS 24.0 statistical software. Measurement data that conformed to or approximated a normal distribution are expressed by x ± s. These means were compared between the groups by the two-independent-sample A total of 256 patients were enrolled in this study. The GBS group (97 cases) included 60 patients with classical acute inflammatory demyelinating polyneuropathy, 19 patients with acute motor axonal neuropathy, 4 patients with acute motor-sensory axonal neuropathy, 11 patients with Miller Fisher syndrome, and 3 patients with acute sensory neuropathy. The CIDP group (78 cases) included 66 patients with classical CIDP, 1 patient with pure motor CIDP, and 11 patients with Lewis-Sumner syndrome. Two acute-onset CIDP (A-CIDP) patients were identified through dynamic patient follow-up and review. There were 81 patients in the control group, and all of them were hospitalized patients with mild disease who did not have GBS or CIDP.P < 0.01), but there was no significant difference between the GBS and CIDP groups (P > 0.05). A comparison of the sex distribution showed that the CIDP group included significantly more males than females (χ2 = 7.69 and P < 0.01). HFGS showed no significant difference between the GBS and CIDP groups . FT4 levels were higher in the GBS group than in the CIDP group (P < 0.05) and Control group (P < 0.01). FT4 levels were higher in the CIDP group than in the control group (P < 0.05). TT3 was lower in the GBS group than in the CIDP and Control groups (P < 0.05). The differences in TSH and FT3 between the three groups did not reach statistical significance (P > 0.05). The comparisons of the above meaningful indicators are depicted in TT4, TPO-Ab, and TG-Ab levels were all higher in the GBS group than in the CIDP and Control groups (2 = 54.75 and P < 0.01). Moreover, the positive rates were significantly different between the GBS and Control groups (χ2 = 68.39 and P < 0.01) although not between the CIDP and Control groups  patients were thyroid autoantibodies positive. Of the 78 patients in the CIDP group, 11 (14.10%) patients were thyroid autoantibody positive. Of the 81 patients in the control group, 7 (8.64%) patients were thyroid autoantibody positive. The positive rates were significantly different between the GBS and CIDP groups (χP < 0.05). The diagnostic cut-off value corresponding to the maximum point of the Youden index was obtained. The diagnostic cut-off value of TPO-Ab was 13.7 IU/mL. At this cut-off value, the sensitivity was 63.92%, and the specificity was 96.15%. The diagnostic cut-off value of TG-Ab was 6.6 IU/mL. At this cut-off value, the sensitivity was 69.07%, and the specificity was 88.46%. The diagnostic cut-off value of TT4 was 89.15 nmol/L. At this cut-off value, the sensitivity was 70.10%, and the specificity was 55.13%. The diagnostic cut-off value of FT4 was 12.23 pmol/L. At this cut-off value, the sensitivity was 71.13%, and the specificity was 48.72%. When the sensitivity was close to 60%, the diagnostic cut-off value of TPO-Ab was 18.6 IU/mL, with a specificity of 97.44%; the diagnostic cut-off value of TG-Ab was 17.36 IU/mL, with a specificity of 94.87%; the diagnostic cut-off value of TT4 was 97.45 nmol/L, with a specificity of 60.26%; and the diagnostic cut-off value of FT4 was 12.71 pmol/L, with a specificity of 58.97%. When >133 IU/mL, TPO-Ab had a sensitivity of 11.34% and a specificity of 98.72% [95% confidence interval (CI): 0.707–0.836]. When >261.1 IU/mL, TG-Ab had a sensitivity of 2.06% and a specificity of 98.72% (95%CI: 0.742–0.864). When >218.25 nmol/L, TT4 had a sensitivity of 1.03% and a specificity of 98.72% (95%CI: 0.567–0.713). When >17.7 pmol/L, FT4 had a sensitivity of 4.12% and a specificity of 98.72% (95%CI: 0.514–0.664)  .P < 0.05). When lower than 0.01 IU/mL, TPO-Ab had a sensitivity of 9.09% and a specificity of 97.96%. When lower than 0.46 IU/mL, TG-Ab had a sensitivity of 11.69% and a specificity of 98.98%. When lower than 69.03 nmol/L, TT4 had a sensitivity of 6.49% and a specificity of 98.98%. When lower than 9.08 pmol/L, FT4 had a sensitivity of 1.30% and a specificity of 97.96% , especially to the TPO-Ab (P < 0.01). When GBS patients with TG-Ab>261.1 IU/mL, the difference in TG-Ab was statistically significant (P < 0.05). However, the difference in HFGS was not statistically significant , prealbumin, and albumin). Changes in the TBG-binding ability and the concentration of T4 under physiological and pathological conditions influence TT4. This study showed that the TT4 and FT4 levels in GBS patients were higher than those in CIDP and Control group patients, especially the TT4 level. The existence of a certain step in the disease course of GBS that affects the binding ability of TBG and leads to an increase in TT4 cannot be ruled out, which still requires further clinical studies for confirmation.Autoimmune thyroid diseases are more common in women, but the incidence and prevalence of GBS among men are both increasing, and genetic and environmental factors likely play a role in this trend . The GBSA limitation of this study is its retrospective design, and we could not ensure that each patient received complete examinations, such as thyroid color Doppler ultrasound and anti-ganglioside antibody detection. Furthermore, the Medical Research Council (MRC) sum score was not assessed for each enrolled patient; therefore, the correlation between the MRC sum score and increased thyroid autoantibodies levels could not be evaluated. In the future, prospective studies should be performed with complete examinations to improve the accuracy of the results.In summary, our study indicated that an elevation of thyroid autoantibodies was associated with GBS. Among the GBS patients, TPO-Ab had higher auxiliary diagnostic value for male GBS patients. The use of thresholds of higher than 13.7 IU/mL for TPO-Ab or higher than 6.6 IU/mL for TG-Ab yielded the best sensitivity and specificity for differentiating GBS from CIDP. When TPO-Ab was higher than 133 IU/mL and TG-Ab was higher than 261.1 IU/mL, a diagnosis of GBS was almost certain. However, when TPO-Ab was lower than 0.01 IU/mL and TG-Ab was lower than 0.46 IU/mL, a diagnosis of CIDP was almost certain. TPO-Ab and TG-Ab may be used as biomarkers for the differential diagnosis of GBS and CIDP. Early detection of thyroid autoantibodies abnormalities in patients has important clinical value for predicting GBS.All datasets presented in this study are included in the article/The studies involving human participants were reviewed and approved by Ethics committee of Beijing tiantan hospital affiliated to capital medical university. Written informed consent from the participants' legal guardian/next of kin was not required to participate in this study in accordance with the national legislation and the institutional requirements.YT managed and collected data and wrote the manuscript. XG researched data and wrote the manuscript. XY conceived and designed the study and contributed to the manuscript. GZ, WZ, and ZL researched the data, contributed to the discussion, and reviewed and edited the manuscript. All authors contributed to the article and approved the submitted version.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.


The Tobacco Control Scale (TCS) was designed for advocacy purposes but has also been used as a research tool. In the present study, we characterized TCS use, its limitations and strengths, and critically assessed its use as a research instrument.We conducted an extensive search of the biomedical databases PubMed and Web of Science for the keyword ‘tobacco control scale’ in all fields. The search was limited to studies published in the period March 2006 to December 2019. Out of 69 hits, 32 studies met the inclusion criteria. Two reviewers independently extracted information from each publication regarding their general characteristics, publication and research aspects, and the characteristics of the use of the TCS.We found that researchers have used the TCS as a tool to monitor tobacco control policies mainly in cross-sectional observational studies with ecological and multilevel designs directed to advocacy and the promotion of further research. Different outcomes, such as smoking prevalence and quit ratios, have been associated with tobacco control policy scores. The main reported limitations of the TCS were a low variance across countries and a failure to express enforcement and to incorporate the most recent legislation.The TCS has been commonly used to assess differences in outcomes according to tobacco control policies. However, there are still areas for improvement in its use in research regarding the lack of comparability of TCS scores across time. The lessons that have been learned should be used to adapt and expand the TCS overseas. Many efforts have been made globally to tackle the tobacco epidemic3, stimulated by the enforcement of the Framework Convention on Tobacco Control. In the European Union (EU), the Tobacco Products Directive has driven the application of stringent tobacco control policies to reduce tobacco use and its negative consequences on health. However, the implementation and enforcement of tobacco control policies still vary greatly across Europe4.Effective tobacco control policies help denormalize smoking, decrease smoking prevalence5 developed the Tobacco Control Scale (TCS) in 2006. The TCS score is determined by a questionnaire based on six cost-effective policy interventions that should be prioritized according to the World Bank. These measures include taxation, smoke-free policies, public spending in information campaigns, advertising bans, health warnings, and treatment. The score assigned to each of these components is weighted by its reported evidence-based effectiveness. Therefore, the score attributed to each country increases with the strength of tobacco control policies up to a maximum of 100 points, indicating full implementation5.Among the initiatives to monitor the implementation of tobacco control policies in Europe, Joossens and Raw5 and to inform the agenda by highlighting the policy components for which progress is lacking, as well as the countries or regions most affected by such delays6. Since 2006, the TCS has been updated every three years .At its inception, the aim of the TCS was to monitor the progress in tobacco control in Europe at a national level by comparing the performance of countries by their rankingEvaluating the impact of tobacco control policies among the population has become an important research area; thus, the TCS has been used as a research tool to measure the implementation of tobacco control policies, though it was not designed for such purposes. However, little is known about the use of the TCS by the tobacco control research community and its advantages and disadvantages as a research tool. Therefore, our aim was to characterize the use of the TCS by researchers and its main limitations and strengths as a research tool in order to critically assess its use as a research instrument.We performed an extensive literature search in the online databases PubMed and Web of Science to identify publications that have used the TCS score(s) as an independent or dependent variable from 27 March 2006, when the first TCS was published, until 1 December 2019. The search was conducted using ‘tobacco control scale’ as the keyword in all fields without any other restrictions to ensure a very sensitive search. The Ethics and Clinical Research Committee of the Hospital Universitari de Bellvitge approved this study (PR247/18).www.scholar.google.com; with search terms in English). These additional searches provided five new publications that met the inclusion criteria and the full-texts were reviewed.We identified 69 publications (32 duplicated in both databases). After removing duplicates, two researchers (AF and AB) screened the titles and abstracts, obtaining 32 studies. The inclusion criteria were quantitative research and inclusion of the TCS score(s) (as dependent or independent variable) in the analysis. We found 27 eligible publications . We compTherefore, we finally included 32 publications that used the TCS score(s) as a dependent or independent variable.® database were designed to extract and register the information from each publication. The evaluation protocol was developed by three researchers who are experts in tobacco control . The protocol describing the main objectives, information sources, search strategy and eligibility criteria, and the data collection was reviewed and approved by all researchers. All variables for which data were described in the publications’ Methods sections were listed.A detailed protocol and Microsoft AccessTwo reviewers independently extracted the data according to the protocol (AF and AB). If any discrepancies emerged, the reviewers discussed the papers until agreement was reached and, when no consensus was met, divergences were solved by discussing them with a third reviewer (CM). The evaluation process was conducted in January 2020.The extracted information included general characteristics, publication characteristics, research characteristics, and characteristics of the use of the TCS .The 32 publications were published between 2008 and 2019. More than two-thirds  were published by research groups from the Netherlands (n=8), Spain (n=9), and the United Kingdom (n=6). Almost all  were original articles published in peer-reviewed journals, 12 of which were Open Access (37.5%). In addition, almost all declared no conflicts of interest  and were financially supported  with public funds , both public and private funds , or private funds .Most of the publications (n=31) were observational studies; 16 used ecological data (50%) with the country as the unit of analysis and 16 used multilevel data (50%) with individual data from surveys as the first-level unit and TCS score by country as second-level aggregated information. Regarding the study design, 23 of the publications were crosssectional studies (78.6%). Most of the articles   included7; however, 46.9% of publications included scores from all EU Member states except Croatia because it was first included in 2013.Twelve out of 21 articles (60%) using individual TCS scores included all six policy components in the analysis. The most frequently used policy components were the individual score on bans in public places  and advertising bans . In contrast, the least used were data on public spending on information campaigns . The publications included data from between 1 and 31 countries; only one publication used scores from all of the countries included in the TCS report, including >30 EU and non-EU countriesHalf (n=16) of the publications were directed towards policymakers with the aim of urging governments to implement more stringent tobacco control policies, 6 publications aimed to foster further research on this topic (18.8%), and the conclusions of 10 papers (31.3%) addressed both aims.7, of hard-core and light smokers8, and of smoking in adolescents10; smoking prevalence and quit ratios11; consumption of rolling tobacco, e-cigarettes, and readiness to quit in adults12; and risk of lung cancer13. Other indicators were smoking in private venues14, self-reported exposure to secondhand smoke (SHS)17, and attitudes towards smoking and tobacco product restrictions21.Almost all of the studies that used the TCS reports as a primary source (n=22) , were ob22, the effects of sales restriction laws on adolescents23, and the factors associated with exposure to tobacco and e-cigarette advertising24. One study assessed the association between smoking prevalence and public sector corruption and other national characteristics25. The main characteristics and results of each article are given in Other publications were focused on exploring the association between the price of tobacco products and infant mortality27 and socio-economic inequalities outcomes in adolescents28 or adults over time31, or to examine political factors that drive tobacco control policy development32. According to the type of data, these publications were half ecological and half multilevel studies.As shown in 33 and providing an overview and comparing the tobacco control progress in Eastern Mediterranean countries34. The main characteristics and results of each study are shown in Two publications computed scores for nonEuropean countries to monitor their tobacco control policy implementation by using the same rationale and methodology. These publications were aimed at measuring the progress after implementation of the WHO-FCTC in Armenia35, except for the smoke-free policies4. Another limitation is that the countries’ rankings have only slightly changed over the years (i.e. the UK has remained in the top position from 2007 to 2016)4. This low variance across countries may reduce the robustness of the results of the studies10. Moreover, some studies reported that the information described by the TCS score(s) does not incorporate the most recent national legislation on tobacco control due to its cross-sectional design13, potentially underestimating the impact of such policies when using the TCS11.Only 11 (34.4%) of all publications included comments on the limitations of using the TCS score as a tool to assess tobacco control policies. The main limitations reported by the studies were that they failed to express the degree to which legislative policies are enforced34 because of potential error in the measurement of their estimates, and inadequate accuracy and comparability of the data33.Finally, among the studies not using data from the original TCS reports, the main limitations were that some policy areas could not be quantified accurately and that some of the policy components assessed by the TCS could not be includedOur results reveal that the TCS has been used mostly in observational, cross-sectional studies with either ecological  or multilevel data . The TCS score has been mainly used as an independent variable to explain the potential variation in outcomes , and mostly employed in European countries, as these countries were the target of the TCS when it was created.This is the first attempt to assess all of the available publications that have used the TCS as a means to measure tobacco control policy implementation since it was developed in 2006. In addition, this is the first study to map out the characteristics of the use of the TCS in scientific research, to understand how this tool has been applied despite its original design as a means to advocate for comprehensive tobacco control policies. Therefore, our findings suggest that the TCS has commonly been used as an indicator of the state of tobacco control policies in Europe.36.Almost all of the studies assessed tobacco control policies through the total TCS score, and most have used the policy components scores from the primary published reports. The policy components most commonly studied were public smoking bans and tobacco product advertising bans, possibly because they are two of the measures that have been most frequently regulated in Europe since the WHO-FCTC came into force in 20055 designed the scale to compare tobacco control policies across countries at a particular time point. Thus, the reference values for scores are sustained across each report. However, these scores are not comparable across years because these standards have changed over time 38; on the other hand, the scale methodology and scoring system changed between 2007 and 201039. Consequently, longitudinal studies to ensure temporal comparability between and within countries require adjusting scores to the highest standards by an escalation process and re-calculating scores from the 2005 and 2007 reports using the newest scoring system and methodology.Another important issue to address is the crosssectional and temporal comparability of the TCS because most of the studies make comparisons across countries and/or over time. Notably, Joossens and Raw32. Few non-European countries have adapted the scale as a proxy to monitor the status of tobacco control policies in non-European countries34. Unfortunately, most of these studies did not clearly explain how they adapted the TCS to estimate new score(s) for each policy component. Therefore, new studies should provide a full description of their adaptation process and the potential limitations and strengths not only to ensure its replication, but also to further develop strategies to adapt the TCS to other contexts overseas.Importantly, most of the studies with a longitudinal design conducted in Europe have adapted the scale rationale and methods to estimate the level of implementation of tobacco control policies to ensure the temporal comparability and include data about years for which the TCS had not been published41. MPOWER’s composite score has some clear advantages over the TCS total score because it is available for all countries, not only European countries, and is comparable over time. However, this proxy also has some disadvantages for research purposes. First, it assigns the same weight to each of the six individual MPOWER scores without taking into consideration that some MPOWER measures have been proven to be more effective than other measures (i.e. taxation). Second, MPOWER’s composite score has a narrower score range than the TCS score , which limits variation across countries and may make it difficult to address variability between countries. Finally, unlike the MPOWER composite score, the TCS score is not affected by the government’s political agenda, as the TCS is built on information from objective databases (i.e. Eurostat) and the Civil Society.These results highlight that the TCS, regardless of its limitations, has been applied as an objective indicator to measure the strength of the implementation of tobacco control policies at the country level. Other studies have used a total score obtained from summing the scores (from 1 to 5) assigned to each MPOWER policy dimension in the WHO’s Reports on the Global Tobacco Epidemic5 already reported some of its major limitations, including difficulties in assessing enforcement versus implementation and its critical dependence on tobacco control experts’ judgement when scoring5. Therefore, such underreporting of limitations makes it difficult to fully describe the limitations that researchers encounter, which is indispensable to moving forward in the field. Among the articles reporting limitations, most of them highlighted the fact that the TCS score(s) did not measure the enforcement of policies except smokefree policies. In this sense, no previous studies have examined the disparity between the implementation and enforcement of tobacco control policies; however, the TCS being predictive of so many outcomes suggests that the implementation of these policies is a good proxy of enforcement. In addition, some studies have questioned the ability of the TCS to incorporate new policies, such as smoke-free outdoor policies, indicating that the authors of the TCS should discuss how to incorporate these new tobacco control policies and which weight they should have in the scale.More than 65% of the reviewed publications did not report any limitation of the TCS as a proxy for measuring tobacco control policies. Nonetheless, Joossens and Raw13 with 54 citations and another paper23 with 103 citations (in Web of Science) up to December 2019.Moreover, our study shows that the TCS has been commonly used in Europe over the last decade, but three research groups from Spain, the Netherlands, and the UK account for more than half of the publications using the TCS for research purposes. This suggests that these groups have led and consolidated the use of this monitoring tool in the tobacco control research field. This is supported by the fact that the publications conducted by these three research groups have received a higher number of citations, including a paper5.More than half of all publications directed their conclusions towards advocacy for improving tobacco control policies. Therefore, most authors find the TCS useful for linking data to policy action, even though the TCS has been commonly used for research purposes. Therefore, the TCS has not lost its intended original purpose for advocacy, as it was developed to detect areas of improvement within each country and to establish comparisons among countries through a ranking, in order to motivate governments to strengthen their weakest polices5.Our results indicate that, despite its potential limitations and lack of a formal validity assessment, the TCS is a good proxy of the strength of tobacco control policies implementation, or at least the best approximation developed so far. However, the TCS has been used at face-value. No attempts have been made to formally validate the scale. Construct validity of the TCS is a complex issue given the composite structure of the TCS itself, though some dimensions are based on objective data (i.e. price and SHS exposure) from population-based surveys and reports of the European Commission; others are based on the answers of one or two informants to an ad hoc questionnaire 42. We searched the available literature in PubMed, the main biomedical database, as well as Web of Science and Google Scholar, and checked all references to identify other articles not published in academic journals. However, the possibility that unpublished manuscripts or other documents addressing the topic of interest may have been missed cannot be ruled out, but it was an a priori decision made by the experienced research team that was composed of tobacco control and policy experts, including the author of the TCS. Under these circumstances, selection (publication) bias seems unlikely to have affected the study.Publication bias is a potential source of error when the units of the investigation are published papersOther potential limitations of our study are linked to the fact that a high number of the publications analyzed here did not include any comment about the limitations and strengths of using TCS scores as a variable to monitor tobacco control policy implementation in research. This missed reporting has hindered the identification of the main limitations and strengths of this tool for different types of study designs, outcomes, or statistical analysis; therefore, our study may have some missing information.However, our study is the first to assess all published articles using the TCS as an indicator of tobacco control policy implementation and to characterize its use in tobacco control research, giving a full and comprehensive overview of how and for which purposes the TCS has been employed in previous studies. This study also presents information on how to best use the TCS as described by the authors in the Limitations sections of the publications. Thus, our study presents the lessons learned from previous research, creating an opportunity for researchers to plan to use the TCS to improve the quality of future studies.This study shows that the TCS has been commonly used in observational, mostly ecological, studies to assess variations in a concrete outcome according to the policies instituted in Europe as a proxy of tobacco control implementation. In addition, the TCS has been employed to detect changes in individual and population outcomes  and establish conclusions about how policies have an effect in specific populations.Our recommendations to researchers and policymakers planning to use the TCS in their future research are as follows. First, the TCS scoring methodology needs to be fully understood, as comparability is not ensured among countries across years. Second, researchers should consider a certain time gap between measuring the TCS score and the outcomes, as the TCS may not include the most recently adopted policies and policies need time to have an effect. Third, knowing the limitations of the TCS in measuring implementation (vs enforcement) of tobacco control policies is important. Fourth, researchers need to take into account the low variance of some tobacco control policies across countries, which may also reduce the robustness of the estimates.A logical next step for future applications of the TCS in research would be to study the impact of tobacco control policy enforcement in terms of several indicators, such as prevalence, SHS, and tobacco sales, and to assess the impact of these policies at the population level. To achieve this goal, more extensive cross-country population-based surveys are needed to include new enforcement measures in future editions of the TCS .Finally, to gain a broader perspective of tobacco control as a public health need and build a stronger tool for tobacco research, we suggest adapting and extending the TCS to other countries of the WHO European Region, and to the reality of other regions of the globe, such as Latin America or Asia, incorporating local and cultural characteristics of these regions while preserving the comparability among countries worldwide.The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none was reported.AF, MF, CM, and EF were supported by the Ministry of Research and Universities from the Government of Catalonia [2017SGR319]. EF was also supported by the Instituto de Salud Carlos III, Government of Spain, co-funded by the European Regional Development Fund (FEDER) [INT16/00211 and INT17/00103]. CM was also supported by the Instituto de Salud Carlos III, Government of Spain, co-funded by the European Regional Development Fund (FEDER) [INT17/00116] and Ministry of Health from the Government of Catalonia [PERIS No. 9015586920/2017]. We thank CERCA Programme/Generalitat de Catalunya for institutional support.Study design: AF, AB, CM, and EF. Collected data and prepared database for analysis: AF and AB. Contributed to strategy of analysis: AF, AB, CM, and EF. Analyzed data: AF. Interpreted data results: AF, AB, CM, LJ, MF, AP, and EF. Drafted manuscript: AF. Critically revised manuscript: All authors. Approved final manuscript version: All authors. Guarantors: EF and CM.Not commissioned; externally peer reviewed.


COCH gene that leads to post-lingual profound sensorineural hearing loss and bilateral vestibulopathy. Carriers of a pathogenic variant leading to DFNA9 can be diagnosed at the pre-symptomatic or early symptomatic stage which creates a window of opportunity for treatment. Preventing hearing loss from occurring or stabilizing progression would provide the opportunity to avoid hearing aids or cochlear implants and would be able to reduce the increased incidence of dementia. While innovative therapies for restoration of hearing have been studied for restoration of hearing in case of severe-to-profound sensorineural hearing loss and congenital hearing loss, further research is needed to study how we can modify disease progression in late-onset autosomal dominant hereditary sensorineural hearing loss. Recently, gene editing strategies have been explored in autosomal dominant disorders to disrupt dominant mutations selectively without affecting wild-type alleles.Hearing loss not only has a significant impact on the quality of life of patients and society, but its correlation with cognitive decline in an aging population will also increase the risk of incident dementia. While current management of hearing loss is focused on hearing rehabilitation , patients are suffering from the burden of progressive hearing loss before hearing aids or cochlear implants are fitted. Although these devices have a significant effect on speech understanding, they do not always lead to normal speech understanding, especially in noisy environments. A significant number of patients suffer from autosomal dominantly inherited disorders that can produce progressive sensorineural hearing loss. This includes DFNA9, a disorder caused by pathologic variants in the  Why the model of autosomal dominant hereditary hearing loss can be of interest.”“Hearing loss has a significant impact on quality of life and society in general. Hearing impairment is the most frequent sensory deficit, affecting 360 million people worldwide and therefore it has been listed by the World Health Organization (WHO) as one of the priority diseases for research into therapeutic interventions to address public health needs . The gloHearing aids and cochlear implants should be regarded as symptomatic treatments that are able to restore functionality  and quality of life to a certain level. Bilateral cochlear implantation has been reported to restore binaural hearing to a certain level and improve speech comprehension, while reducing tinnitus burden and psychological comorbidities –10. HoweOver the past decade the correlation between hearing loss and cognitive decline in the older population has gained more research interest. Large prospective studies have found an independent relationship between hearing loss on the one hand and age-related cognitive decline and incident dementia on the other hand –24. Worlcommon cause hypothesis suggests that hearing impairment and cognitive decline may result from one common mechanism. The cognitive load on perception hypothesis implies that a reduction in cognitive functioning may result in a heavier load on sensory processing. Both hypotheses suggest a top-down correlation. Another hypothesis, the sensory-deprivation hypothesis, implicates peripheral hearing loss as the direct cause of permanent cognitive decline, while the information-degradation hypothesis will point at depression and social isolation resulting from sensorineural hearing loss as the indirect cause. The latter hypotheses rather suggest a bottom-up causality from the periphery. At a pathophysiological level, evidence from rodent studies suggests that sensorineural hearing loss may result in a decreased adult hippocampal neurogenesis, which subsequently leads to impairments of learning and memory  upper airway and central nervous infections, such as acute and chronic otitis media, or meningitis . A signiDFNA9. The DFN is an acronym for DeaFNess, while the A stands for autosomal dominant. DFNA9 is caused by heterozygous gain-of-function mutations or pathogenic variants in the COCH gene. To date, over 25 different variants have been identified worldwide (P51S variant (DFNA9P51S) is the most frequently reported pathogenic variant in Belgium and the Netherlands. The phenotype is characterized by a progressive sensorineural hearing loss, starting from the 3rd−4th decade, followed by a rapid decline to severe-to-profound sensorineural hearing loss by the 6th−7th decade  sensorineural hearing loss where we do know what is happening in the cochlea and what will happen to hearing loss progression in a single adult patient: non-syndromic autosomal dominant hereditary hearing loss. Non-syndromic hearing impairment is a partial or total impairment of hearing not associated with other signs and symptoms. Between 75 and 80 percent of these cases are inherited through an autosomal recessive pattern, while another 20–25 percent of non-syndromic hearing impairment have an autosomal dominant pattern of inheritance , 71. Theorldwide . The P51h decade –74. Progh decade . CurrentTmc1 point mutations were targeted using an adeno-associated virus-mediated delivery to prevent deafness up to 1 year post-injection in mice  to upregulate the atonal gene (ATOH1/MATH1) in supporting cells of the inner ear and to trigger trans-differentiation into functional hair cells . For a r in mice . A simil in mice . RNA inh in mice , 93.P51S, i.e., 3 dBHL per year -in contrast to 1 dBHL per year in age-related hearing loss- and has demonstrated high penetrance, i.e., the occurrence of a phenotype in pathogenic variant carriers , we also know in what area in the inner ear the protein is expressed most abundantly  and what its pathophysiology is  . Earliercarriers . It is iCOCH gene, various hypothetical scenarios were presented while using a Likert scale to study willingness to participate in clinical trials studying potential treatment strategies  prevent hearing loss from occurring at all. Although restoring hearing up to a certain level has become mainstream because of cochlear implantation, little is known on patient attitudes toward preventing, stabilizing or slowing down progression of sensorineural hearing loss by means of such future potentially disease-modifying treatments. In a survey performed in 53 carriers of pathogenic variants in the rategies . OverallAll datasets generated for this study are included in the article/supplementary material.VV designed the work, drafted the manuscript, and approves for publication of the content and agrees to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.