PONE-D-21-24377Do manual therapies have a specific autonomic effect? An overview of systematic reviews.PLOS ONE

Dear Dr. Roura,

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. Having intensively reviewed your revised draft, our external reviewers differed with their final recommendations, at least to some extent. Thus, I have double checked your revised version, to come to a more balanced decision (see R #1). All in all, our  identified shortcomings are considered reasonable with regard to both PLOS ONE’s quality standards and our readership's expectations. Therefore, we invite you to submit a carefully revised version of the manuscript that addresses EACH AND EVERY point raised during the current review process. Please note that a non-convincing revision (not considered acceptable with regard to language, content, reviewers' constructive criticisms, generalizable conclusions, and/or Authors' Guidelines) must lead to outright reject. 

Please submit your revised manuscript by Oct 21 2021 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,

Andrej M Kielbassa

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. 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. Thank you for stating the following financial disclosure: 

 [Funding for the publication of this article was provided by Registro de Osteopatas de España (ROE) www.osteopatas.org].  

Please state what role the funders took in the study. If the funders had no role, please state: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript." 

If this statement is not correct you must amend it as needed. 

Please include this amended Role of Funder statement in your cover letter; we will change the online submission form on your behalf.

3. We note that you have stated that you will provide repository information for your data at acceptance. Should your manuscript be accepted for publication, we will hold it until you provide the relevant accession numbers or DOIs necessary to access your data. If you wish to make changes to your Data Availability statement, please describe these changes in your cover letter and we will update your Data Availability statement to reflect the information you provide.

4. Please include a separate caption for each figure in your manuscript.

5. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information. 

[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: No

Reviewer #3: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: N/A

Reviewer #3: Yes

**********

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

Reviewer #3: 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

Reviewer #3: 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: This is a review of systematic reviews. I have no comments to the authors. The only thing is checking the file uploading since tables are mixed with text and it has been difficult to review the paper. Authors could explain why they have not conducted an umbrella meta-analysis.

Reviewer #2: General remarks

- In formulating the scope for a review of reviews, the PICOS (participants, interventions, comparators, outcomes, and study design) structure is considered helpful. Please revise accordingly.

- Please note that there are various evidence levels with recent research papers. Consequently, a Systematic Review of Level I would include only Level-I Randomised Controlled Studies. No doubt, a Level-I Overview of Systematic Reviews must include Level-I Systematic Reviews only. It would not make sense to re-repeat poor RCTs, and to re-repeat poor Systematic Reviews based on poor RCTs.

- Please remember that Plos One's mission is "to publish methodologically and ethically rigorous research". Would it be sound from a methodological point of view to include papers based on poor quality? No, it wouldn't. Would it be sound from an ethical point of view to draw any conclusions based on such papers? Again, no, it wouldn't, too. But this clearly would render your "rigorous" research doubtful.

- What about using the AMSTAR tool as a means to assess the methodological quality of systematic reviews?

- What about using the GRADE approach with your ‘Summary of Findings’?

Abstract

- Please note that the allowed maximum word count with this section is 300. Please shorten considerably.

- Note all repositories have been used. Please provide reasons.

- "Two overview authors independently applied the selection criteria (...)." Please define the "selection criteria".

- "Our search identified 557 records, from which we included 12 reviews." No word about the quality of those 12 papers? Remember that just including 12 retrievable papers would not seem satisfying.

- "Moreover, the clinical relevance of those results are still unclear." Reasons remain unclear.

- "Future research should consider some key elements proposed to overcome common shortcomings and include ways to improve the quality and applicability of the results." This is not considered a conclusion referring to your aims; instead (as with most other topics), this would have been clear prior to the start of your project.

Intro

- Again, please stick to the Authors' Guidelines. "(...) body’s internal environment (homeostasis) (1,2)." must read "(...) body’s internal environment (homeostasis) [1,2]." Revise thoroughly.

- "Recent systematic reviews have shown that the MT approach is clinically effective (...)." and "iMoreover, several clinical studies have shown the effectiveness of MT (...)." Please see comments given above, and add information on the quality level of the referenced papers. Just "being published" is not considered a quality aspect.

- Same with "Evidence about autonomic effects of manual therapy interventions is synthesized within many reviews (41–46,48,49)." Again, provide detailed information, and revise carefully.

Meths

- Did you note that your "Objectives" (aims) do not fully correspond to your Abstract section?

- regarding your inclusion criteria, please see comments given above. Revise carefully, and include aspects of utmost quality.

- "Cochrane Library, PubMed, EPISTEMONIKOS, and SCOPUS" would not seem exhaustive. Why didn't you include other databases? What about foreign languages? What about the grey literature?

- "Two authors (SR and GA) independently assessed titles and abstracts of records identified by the electronic searches according to the inclusion criteria and decided on eligibility obtaining a full text copy from relevant references." Indeed, the two authors obviously simply searched. Again, what about the quality level of the included papers?

- "We solved disagreements involving a third author (FC) to reach a consensus through discussion." What kind of "disagreements" are you talking about? How often have there been "disagreements"? Was a consensus possible in all cases? And, again, what about the agreements regrading the quality levels?

Results

- "All the reviews included randomized clinical trials (RCTs), one also included quasi-RCTs, four included non-randomized trials and two other designs." Again, see comments given above. "Quasi-RCTs, non-randomized trials and other designs" would not confirm Level-I research. Why did you include such papers?

- With your Table 2 ("Characteristics of the included reviews"), please add your quality assessment. Again, please do not simply add the published papers; instead provide a sound, a valid, and a reasonable quality assessment, to allow to distinguish high- from poor-level papers.

- Do not use Authors' names with your text, see "Schmid et al. found conflicting evidence (69).".

- There would seem some errors to be evident. See "and after mobilisations (41,45) and in the diastolic blood pressure after neck manipulations (Schmid et al. 2008)."

- Same with "Galindez et al. found a decrease in systolic BP in hypertensive type I subjects but not in healthy participants (Galindez et al 2016). Two studies found an increase in HR after mobilisations (49,67), and one found no effect after cervical manipulation (Galindez et al 2017)." revise carefully.

- "Different quality assessment tools were used among the SRs (Appendix 4), showing a high heterogeneity of the studies' quality." See comments given above. First, the quality of the reviews would seem more important than the contents, to decide whether the paper will be included. Second, the results of your quality assessment must be provided here, and NOT somewhere in an Appendix.

- From your Table 9 (!) it finally becomes clear that you ONLY found 1 (!) paper of "high quality". This would not seem convincing, not at all.

- Revise thoroughly for minor typos, see ""(...) are considered. (30,76,112)."

- Again, do not use Authors' names, see "This tool is highly recommended when performing overviews or clinical guidelines (Whiting et al.)."

- "The difference between those with low risk of bias and those with unclear risk of bias was due to the poor reporting of information, lack of protocol registration and methodological deficiencies." OK, but this would not seem an acceptable excuse.

- "Our overview identified a high heterogeneity in regards to the quality of the articles included." Again, this would mean that papers with poor quality have been included. This must be elaborated more clearly. Moreover, it does not make sense to re-re-repeat those poor quality papers. With your revision, please stick exclusively to the Level-I papers. This refers to your conclusions. Papers with poor quality might be mentioned, but the drawbacks must be elucidated clearly.

- "Consistent with the literature, the studies included in the present overview revealed the same issues, such as high heterogeneity, reporting deficiencies and the same articles rated differently." So please explain why you have included those papers? What about excluding such RCTs/systematic reviews? Remember that your write for the readers. What should a reader think after having swallowed your overview?

- Please separate your "Suggestions" from the "Conclusions".

- Do not mix "Conclusions" and "Recommendations". All these aspects might be right, but do not mix it up, please.

Refs

- Stick exclusively to the Journal style, and revise for uniform formatting. Again and again, you state "[Internet]" and "Available from"; please delete. Consult some recently published Plos One papers. Provide doi and PMID numbers.

Concl

- With your Conclusions, please stick exclusively to your revised aims. Do not simply repeat your results here. Do not give a further literature review here. Instead, provide a reasonable and generalizable extension of your outcome.

All in all, this submitted draft would seem interesting, is considered easily intelligible and would seem worth following after a thorough revision, considering all the aspects indicated above.

Reviewer #3: I congratulate the authors for their work. The review addresses a relevant topic with important gaps in the literature. The compression of the mechanisms of effect of manual techniques is fundamental for the most adequate clinical reasoning and for the scientific advance in this subject. In fact, the relationship between autonomic effects and clinical improvement is an important gap in the literature. The large number of reviews on the subject can confuse readers and the authors knew how to unify the main findings of the studies in a very adequate way. However, I suggest better synthesizing the ideas in the introduction and discussion to reduce the scope of the work. Below are other small suggestions

Intro:

1. Overall the introduction is very complete, but excessively detailed and long. Theoretically, readers interested in the topic should already have a basic knowledge of the topic, or they can consult the bibliographic references for further details. I suggest reducing paragraphs, or even unifying some (the second and third could unify action mechanisms - and gaps in these mechanisms - of manual therapy, without the need for so many explanations about the definition and clinical conditions that this area usually deals with - theme of the second paragraph )

Methods:

2. The authors describe that they considered the level of evidence described in the reviews included, as well as the methodological quality of the studies included in the reviews, for the generalization of evidence. However, the criteria used to summarize the level of evidence of the findings were not clear. I suggest defining a better instrument for this, something like the GRADE approach or similar.

Results:

3. Due to the amount of information (due to the large number of studies and variables), I suggest deleting the "newspaper" column from Table 2.

4. Table 5. Review by Araujo et al, it seems that they would be "Intervertebral mobilisations" or "mobilisations" only, and not both. In this same table, some words in the techniques column are capitalized and others are not.

Discussion:

5. As the introduction, the discussion is too long. Due to the number of studies and research questions, the results are already extensive. I suggest summarizing the main topics both in the introduction and in the discussion. Many discussion topics have already been covered in the results. I suggest organizing the discussion more broadly (without so many sections). I suggest organizing the discussion according to the following topics: main findings; strenghts and limitations; comparison with previous studies; meaning of the study (clinical message and future directions).

6. I see no reason for the authors to report results from more recently published RCTs….out of the scope of the study.

**********

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

Reviewer #3: Yes: Francisco Xavier de Araujo

[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.

PONE-D-21-24377R1Do manual therapies have a specific autonomic effect? An overview of systematic reviews.PLOS ONE

Dear Dr. Roura,

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.

Having intensively reviewed your revised draft, our external reviewers agreed with their final recommendations. Additionally, I have double checked your revised version, to come to a final decision (see R #1). All in all, I am convinced that your revised paper will be worth following, even if your revised version still would benefit from minor and major re-edits and some polishing.

Please submit your revised manuscript by Dec 16 2021 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,

Andrej M Kielbassa

Academic Editor

PLOS ONE

[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 #2: (No Response)

Reviewer #3: 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 #2: No

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: N/A

Reviewer #3: Yes

**********

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 #2: Yes

Reviewer #3: 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 #2: Yes

Reviewer #3: 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: All comments have been addressed by the authors making the paper acceptable for publication in its current form

Reviewer #2: General remark

- This revised and re-subitted draft has considerably improved.

- Moreover, the Authors have thoroughly responded to this reviewer's previous comments. Their thoughts would seem comprehensible, even if some few positions are considered debatable. The future readers will decide on those aspects.

- Unfortunately, still some aspects are in need of revision. Please see below, and remember that this is not the right place to persistently insist on prevailing your ideas.

Abstract

- Again, please stick to Journal guidelines. Maximum word count is 300 (but NOT 399!). Please revise carefully. Remember that your answer ("Thank you for this comment, Abstract has been shortened considerably") would not seem satisfying.

- Again, please adapt aims given with the Abstract section and the questions asked in the Introduction section. This reviewer has read your comments ("Thank you for this clarification, corrections have been

amended in the Abstract page 2 lines 20-21"), but still there would be some need to polish this topic.

- Remember that with your conclusions, answers must be given exclusively to your questions.

Introduction

- Please see comments given above.

Materials and Methods

- Heading must read "Materials and methods". Again, please stick to the Journal guidelines, and consult some recently published Plos One papers. "METHODS" would not seem acceptable. Remember that there will not be any thorough copy editing, so only flawless papers will be acceptable.

- As a general recommendation, please stick to Journal style with ALL other aspects. For example, you repeatedly refer to "table 2", "table 3", "table 4", and so on. Again, please consult some recently published Plos One papers, there you will see that this must read "Table (1, 2, 3, or 4)". Same with other minor aspects, please revise carefully, and remember that submitting a flawless manuscript is considered the Authors' task, and that the typesetter will not be able to copy edit your draft.

Conclusions

- Do not give a "summary" here. For example, "There is considerable research (...)" and "This overview summarized the information reported by 12 systematic reviews." are not considered conclusions.

- Again, with your Conclusions section, please stick exclusively to your revised aims. Do not simply repeat your results here. Instead, provide a reasonable and generalizable extension of your outcome.

- Same thoughts are valid for "Implications for research: (...)". These aspects surely would seem right, and should be transferable to the Discussion section. However (and again), those thoughts are not considered Conclusions. Again, please revise carefully.

References

- Again, revise for uniform formatting. Stick to Journal style. Provide doi and PMID numbers. Again, the Authors' response ("We apologise for this inconvenience and references have been amended as suggested.") would not seem satisfying.

- Example would be: "Cheng L, Weir MD, Xu HH, Antonucci JM, Lin NJ, Lin-Gibson S, et al. Effect of amorphous calcium phosphate and silver nanocomposites on dental plaque microcosm biofilms. J Biomed Mater Res B Appl Biomater. 2012; 100(5): 1378–1386. https://doi.org/10.1002/jbm.b.32709 PMID: 22566464" Revise thoroughly, but carefully. Remember that it is not the idea to re-re-review your submitted draft, and another re-submission not considered satisfying would lead to "outright rejection".

In total, this revised and resubmitted draft still is not considered ready to proceed. The Authors should be given another try to re-submit a perfect manuscript considered acceptable,

Reviewer #3: I congratulate the authors for the revised version.

I maintain my comments on the length of the introduction and discussion. I believe the text could be better synthesized. However, I agree with the authors' arguments.

**********

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 #2: No

Reviewer #3: 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.

Do manual therapies have a specific autonomic effect? An overview of systematic reviews.

PONE-D-21-24377R2

Dear Dr. Roura,

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 for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at 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. If you have any billing related questions, 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, congratulations and compliments, and stay healthy

Andrej M Kielbassa, Prof. Dr. med. dent. Dr. h. c.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

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 #2: 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 #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

**********

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 #2: 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 #2: 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 #2: The Co-Authors have satisfyingly revised their draft, according to the previous comments. All other reviewers have agreed to accept this submission, which is considered ready to proceed now.

**********

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 #2: No