Optimal measurement method for anterior instability on stress radiographs in anterior cruciate ligament tear: Considering the effect of static anterior tibial subluxation

Joo Hyung Han; Chong-Hyuk Choi; Min Jung; Kwangho Chung; Sungjun Kim; Taeho Ha; Sung-Hwan Kim

doi:10.1371/journal.pone.0310428

Peer Review History

Original SubmissionFebruary 20, 2024
21 Jun 2024 Decision Letter - Ismail Tawfeek Abdelaziz Badr, Editor PONE-D-23-39613Optimal Measurement Method for Anterior Instability on Stress Radiographs in Anterior Cruciate Ligament Tear: Considering the Effect of Static Anterior Tibial SubluxationPLOS ONE Dear Dr. Kim, 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. Please submit your revised manuscript by Jul 28 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at 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 include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. 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The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf 2. In the online submission form, you indicated that information and datasets analyzed during the current study available from the corresponding author on reasonable request. All PLOS journals now require all data underlying the findings described in their manuscript to be freely available to other researchers, either 1. In a public repository, 2. Within the manuscript itself, or 3. Uploaded as supplementary information. This policy applies to all data except where public deposition would breach compliance with the protocol approved by your research ethics board. If your data cannot be made publicly available for ethical or legal reasons (e.g., public availability would compromise patient privacy), please explain your reasons on resubmission and your exemption request will be escalated for approval. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: I Don't Know ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: 1.It is possible that ACL injuries may be combined with other conditions, such as knee osteoarthritis and synovitis. It is therefore important to consider whether the patients enrolled in this study were excluded from the disturbances caused by these possible co-morbidities. Were the patients enrolled in this study with ACL confounders excluded? 2.Whether the two measurements mentioned in the paper, "the traditional load-unload method" and "the load method", are routine in clinical practice. 3.This is a retrospective study, the control group of 28 healthy patients was matched to 340 patients who underwent surgical procedures other than ACL reconstruction, did the surgical operations the patients underwent interfere with the results of this study? These patients also underwent the same assessment components as ACL patients, are these measurements also routine in the clinic? 4.This study concludes,“In conclusion, the measurement method for anterior instability using load SSD showed superior diagnostic accuracy compared to the load-unload SSD method, which is susceptible to false negatives owing to static anterior tibial subluxation in ACL tear cases”,does static anterior tibial subluxation also influence the diagnosis of anterior instability in patients with ACL injuries when using the load-unload SSD method? Reviewer #2: Firstly, I want to congratulate the authors for the efforts to do this article. Althogut there are limitations, it has a good methodology that support its results. However, I have some considerations and suggestions. Line 27: "...and 28 healthy patients (control group)". However, in Figure 1, I have observed 30 patients in the control group Line 92: "...486 patients". However, in Figure 1, I have observed 456 patients Line 121-126: I suggest you include a figure to better visualize the patient's position for the test. This way, it is easier to reproduce your study. Conclusion The purpose of the article in the abstract is "to investigate whether tibial subluxation in the neutral position affects the diagnosis of anterior instability in patients with ACL injuries, potentially impacting the reliability and diagnostic accuracy of stress radiography". I suggest that you include a clearer answer to this question in your discussion and conclusion. ****** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: No ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. Attachments Attachment Submitted filename: review.docx https://doi.org/10.1371/journal.pone.0310428.r001
Revision 1
8 Jul 2024 Author Response We are grateful for the effort that the reviewer has put into the review process. Thanks to the detailed comments provided by the reviewer, we were able to advocate our argument for this paper with improved logical progression. Additionally, in terms of format, we were able to revise the entire manuscript to be more concise and clearer, which has allowed us to convey our conclusion more effectively. Our responses to the reviewer are provided below. Thank you again for your valuable feedback. GENERAL Reviewer #1: 1. It is possible that ACL injuries may be combined with other conditions, such as knee osteoarthritis and synovitis. It is therefore important to consider whether the patients enrolled in this study were excluded from the disturbances caused by these possible co-morbidities. Were the patients enrolled in this study with ACL confounders excluded? -> In this study, factors that could act as confounding variables in measuring anterior instability due to ACL rupture—such as previous surgical history of the affected knee, stiff knee or limited range of motion due to pain, concomitant injuries to other ligaments in the affected knee, and concomitant meniscal tears involving displaced portions—were set as the exclusion criteria. (Revised page #5/lines 106-111) As suggested by the reviewer, we also considered osteoarthritis as a factor influencing the patient's symptoms and added it to the exclusion criteria, subsequently reviewing the patients again. The reviewer's advice was very helpful in setting the factors that could influence the interpretation of the results, and we are grateful for that. (Revised page #5/lines 108-109) 2. Whether the two measurements mentioned in the paper, "the traditional load-unload method" and "the load method", are routine in clinical practice. -> In the measurement of anterior instability using stress radiography, a common approach in clinical practice with the Telos device is to measure the displacement of the tibia under load only, which we have referred to as the “load method" in this study. This method is routine in clinical practice. However, static-predisposed tibial subluxation is believed to be a potential confounding factor in the assessment of anterior instability using stress radiography. Therefore, in contrast, the “load-unload method" is the method we attempted, which measures the difference between the load and unload positions (page #4/lines 87-90). This method was used to take into account the degree of tibial subluxation. We have revised the introduction to provide a clearer explanation of these two methods. (Revised page #3/lines 58-61) (Revised page #6/lines 135) 3.This is a retrospective study, the control group of 28 healthy patients was matched to 340 patients who underwent surgical procedures other than ACL reconstruction, did the surgical operations the patients underwent interfere with the results of this study? These patients also underwent the same assessment components as ACL patients, are these measurements also routine in the clinic? -> As you pointed out, this study was retrospective, and the control group consisted of patients who had undergone different types of knee arthroscopic surgery rather than healthy subjects. The measurements used in this study were conducted before surgery, so the operations themselves did not interfere with the results. However, the preoperative diagnoses could have influenced the outcomes. Therefore, it should be noted that not undergoing ACL reconstruction in the control group does not necessarily imply normal ACL function. To minimize differences in ACL function influenced by factors such as average age and other demographics, we performed propensity score matching. Consequently, considering the average age, we believe the concern is minimal. We have added these points to the limitations. The measurements used in this study are routinely conducted with the same protocol for patients undergoing knee arthroscopic surgery at the institution where this research was carried out. Therefore, we believe there is little concern regarding the differences in measurement methods among patients included in this study, including the control group. These points are important limitations of the study and should be addressed in future research with new designs. We appreciate the reviewer's comments, which allowed us to add this interpretation to the manuscript. Thank you for your valuable feedback. (Revised page #10/lines 253-266) 4.This study concludes, “In conclusion, the measurement method for anterior instability using load SSD showed superior diagnostic accuracy compared to the load-unload SSD method, which is susceptible to false negatives owing to static anterior tibial subluxation in ACL tear cases”, does static anterior tibial subluxation also influence the diagnosis of anterior instability in patients with ACL injuries when using the load-unload SSD method? -> To explain the conclusion of this study, it is crucial to understand how much static anterior tibial subluxation influences the diagnostic ability of the load-unload SSD method. As reported by Almekinders et al.,[1] there is a tendency for anterior tibial subluxation in patients with chronic untreated ACL rupture. Static anterior tibial subluxation itself reduces the difference between the load and unload states of the affected knee, which seems to decrease the diagnostic ability of the load-unload method in the chronic group. Consequently, while the influence on diagnostic ability for acute injuries is small, static anterior tibial subluxation appears to significantly reduce the diagnostic ability of the load-unload method for chronic injuries. This point has been added to the discussion, and thanks to the reviewer's comment, we were able to include an important argument to support the conclusion of this study. We appreciate this input. (Revised page #9/lines 234-235) Reviewer #2: Firstly, I want to congratulate the authors for the efforts to do this article. Although there are limitations, it has a good methodology that support its results. However, I have some considerations and suggestions. Line 27: "...and 28 healthy patients (control group)". However, in Figure 1, I have observed 30 patients in the control group -> The control group consisted of 30 patients, and the content has been corrected. (Revised page #2/lines 26-28) Line 92: "...486 patients". However, in Figure 1, I have observed 456 patients -> As you pointed out, 456 patients is correct. The content has been corrected in Figure 1. (Revised Figure 1) Line 121-126: I suggest you include a figure to better visualize the patient's position for the test. This way, it is easier to reproduce your study. -> A photo of the actual imaging process has been added to visualize the patient's position for the test. (Revised Figure 2) Conclusion The purpose of the article in the abstract is "to investigate whether tibial subluxation in the neutral position affects the diagnosis of anterior instability in patients with ACL injuries, potentially impacting the reliability and diagnostic accuracy of stress radiography". I suggest that you include a clearer answer to this question in your discussion and conclusion. -> As you pointed out, there was a lack of detailed information on how tibial subluxation in the neutral position affects the diagnosis of anterior instability. Almekinders et al.[1] reported that patients with chronic untreated ACL rupture tend to have anterior tibial subluxation. This static anterior tibial subluxation reduces the difference between the load and unload states of the affected knee, which appears to decrease the diagnostic accuracy of the load-unload method in the chronic group. We have added the above content to the discussion to provide a clearer answer on the impact of tibial subluxation. (Revised page #9/lines 225-230) The main message of this study was the comparison of the two methods for measuring anterior instability, so this content has been left in the conclusion. Your comments have greatly helped us draw a clear conclusion that aligns with the stated purpose of the paper. Additionally, your detailed feedback allowed us to correct some errors in the manuscript. Thank you for your valuable input. References 1. Almekinders LC, Pandarinath R, Rahusen FT. Knee stability following anterior cruciate ligament rupture and surgery. The contribution of irreducible tibial subluxation. J Bone Joint Surg Am. 2004;86(5):983-7. doi: 10.2106/00004623-200405000-00014. PubMed PMID: 15118041. Attachments Attachment Submitted filename: loading_laxity_reviewer_answer_0707.docx https://doi.org/10.1371/journal.pone.0310428.r002
13 Aug 2024 Decision Letter - Ismail Tawfeek Abdelaziz Badr, Editor PONE-D-23-39613R1Optimal Measurement Method for Anterior Instability on Stress Radiographs in Anterior Cruciate Ligament Tear: Considering the Effect of Static Anterior Tibial SubluxationPLOS ONE Dear Dr. Kim, 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. Please submit your revised manuscript by Sep 27 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at 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 include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We look forward to receiving your revised manuscript. Kind regards, Ismail Tawfeek Abdelaziz Badr, M.D. Academic Editor PLOS ONE Journal Requirements: Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: All comments have been addressed Reviewer #3: (No Response) Reviewer #4: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #3: Yes Reviewer #4: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #3: Yes Reviewer #4: N/A ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #3: Yes Reviewer #4: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #3: Yes Reviewer #4: Yes ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: (No Response) Reviewer #3: This is the second version of this manuscript that was resubmitted after considering the comments of previous 2 Reviewers. The article is about comparing 2 radiological methods for diagnosing the anterior instability in patients with ACL injuries using the Telos device: The load side to side difference (SSD) and the load unload (SSD). The authors found that the load SSD method has a higher diagnostic value specially in chronic cases. They aue this for the static anterior translation occurs in patients with chronic ACL Injuries. The authors considered all comments of the previous reviewers and modified the article accordingly in a positive way; Yet there are still improvement potential in the article as follows : • Lines 26-28 (Abstract): the authors included 30 patients in acute group, 28 Patients in the chronic group and 30 patients in the control group. The sum should be 88 not 86 as the authors mentioned. • Line 90: the authors mentioned that they reviewed 486 patients operated in the their center to choose the included patients, but in the flow chart (Figure 1) they mentioned that the reviewed patients were 456 patients. Please unify this number. • Line 252: the authors mentioned the abbreviation ALL. Please write it formal because it was not mentioned previously in the . I suppose they mean the anterolateral ligament. Reviewer #4: Thank you very much for allowing me to review your manuscript. I appreciate the effort you have made performing this study and submitting it to plos one. I think this is appropriate for publishing. ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #3: Yes: Ayman F. AbdelKawi Reviewer #4: No ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0310428.r003
Revision 2
14 Aug 2024 Author Response We are grateful for the effort that the reviewer has put into the review process. Thanks to the detailed comments provided by the reviewer, we were able to correct the remaining typographical errors in this paper and further improve its overall quality. Our responses to the reviewer are provided below. Thank you again for your valuable feedback. GENERAL Reviewer #1: (No Response) Reviewer #3: This is the second version of this manuscript that was resubmitted after considering the comments of previous 2 Reviewers. The article is about comparing 2 radiological methods for diagnosing the anterior instability in patients with ACL injuries using the Telos device: The load side to side difference (SSD) and the load unload (SSD). The authors found that the load SSD method has a higher diagnostic value specially in chronic cases. They aue this for the static anterior translation occurs in patients with chronic ACL Injuries. The authors considered all comments of the previous reviewers and modified the article accordingly in a positive way; Yet there are still improvement potential in the article as follows : Lines 26-28 (Abstract): the authors included 30 patients in acute group, 28 Patients in the chronic group and 30 patients in the control group. The sum should be 88 not 86 as the authors mentioned. -> We have corrected this number to 88. (Revised page #2/lines 26) Line 90: the authors mentioned that they reviewed 486 patients operated in the their center to choose the included patients, but in the flow chart (Figure 1) they mentioned that the reviewed patients were 456 patients. Please unify this number. -> The correct number is 456 patients. We have revised the text accordingly. (Revised page #4/lines 91) Line 252: the authors mentioned the abbreviation ALL. Please write it formal because it was not mentioned previously in the . I suppose they mean the anterolateral ligament. -> We intended to refer to the anterolateral ligament. We have revised the text to include both the full term and the abbreviation. (Revised page #10/lines 254) Reviewer #4: Thank you very much for allowing me to review your manuscript. I appreciate the effort you have made performing this study and submitting it to plos one. I think this is appropriate for publishing. Attachments Attachment Submitted filename: loading_laxity_reviewer_answer_0814.docx https://doi.org/10.1371/journal.pone.0310428.r004
2 Sep 2024 Decision Letter - Ismail Tawfeek Abdelaziz Badr, Editor Optimal Measurement Method for Anterior Instability on Stress Radiographs in Anterior Cruciate Ligament Tear: Considering the Effect of Static Anterior Tibial Subluxation PONE-D-23-39613R2 Dear Dr. Kim, 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. An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Ismail Tawfeek Abdelaziz Badr, M.D. Academic Editor PLOS ONE ********** https://doi.org/10.1371/journal.pone.0310428.r005
Formally Accepted
5 Sep 2024 Acceptance Letter - Ismail Tawfeek Abdelaziz Badr, Editor PONE-D-23-39613R2 PLOS ONE Dear Dr. Kim, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset If revisions are needed, the production department will contact you directly to resolve them. If no revisions are needed, you will receive an email when the publication date has been set. At this time, we do not offer pre-publication proofs to authors during production of the accepted work. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few weeks to review your paper and let you know the next and final steps. Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. If we can help with anything else, please email us at customercare@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Ismail Tawfeek Abdelaziz Badr Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0310428.r006

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