PONE-D-22-10523Long-term outcome of tibial plateau leveling osteotomy using an antimicrobial silver-based coated plate in dogsPLOS ONE

Dear Dr. Pages,

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 23 2022 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,

Ashraf M. Abu-Seida, Ph.D.

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

Additional Editor Comments:

There are few grammatical issues throughout the manuscript, please correct them and follow up the format of the journal

[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

Reviewer #3: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

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: The authors have submitted a simple and clean evaluation and are to be commended. I relatively few comments:

line 53 - change preferred to recommended

line 62 - complications should be complication

line 63 - delete "the most"

line 69 - change claiming to designed for

line 72 - delete designed

line 74 - change "to protect" into "as providing protection"

Line 75 - add "of this study" after objective

line 95 - clarify that additional surgery due to complication (explant) was not cause for exclusion. At this early point in the manuscript the point isn't clear.

line 98 (or somewhere before discussion) - the authors need to describe how complications were classified and what exactly constituted a complication. They cover some of this in the discussion but it should be here also. Why is patellar tendinitis listed as both a minor and a major complication?

line 114 - of should be to

line 144 - ModTPA should be explained as ReTPA minus PostTPA (thus the positive values)

line 155 - this might be the place to further describe the application of Cook's system

line 184 - previous values for ModTPA should be reported (probably in the discussion)

Figures 1, 2, 3 - perhaps better positioned after the section discussing the statistical analysis

line 255 change demonstrates t supports

line 308 - efficiency should be evidence of efficacy

OVERALL - despite the brief discussion in lines 315-324, the major deficiency of this study is the lack of a control group relative to this hospital. The data alluded to should be incorporated into this study, or, preferably, a similar cohort population from previous years using a different plate should be evaluated identically. Obviously there is a variable introduced about time, but this data would still be preferable to the historical/literature comparisons currently presented. This will be annoying, but will dramatically improve the manuscript.

Reviewer #2: This paper (PONE-D-22-10523) discusses the outcome including surgical site infection (SSI) after tibial plateau levering osteotomy (TPLO) using the BioMedtrix TPLO Curve®︎ plate. This paper provides the interesting data. However, it is concerned the evidence level of this paper is weak to conclude that the antimicrobial silver-based (HyProtect®︎) coating plate does not reduce SSI, because of no control group, retrospective style, and a single surgeon study at a single institution. In addition, some revisions are necessary to improve the quality of your manuscript as follows.

Major points:

1. Study design (L.94-95): You should describe the exclusion criteria, in more detail (ex. other orthopedic diseases of affected limb, dermatitis, or infections of other area...).

2. Surgical procedure (L.126): Add details about the type and trade name of sterile wound dressings used in this study because of their impact on the occurrence of SSI.

3. Surgical procedure (L.130-131): The postoperative cefalexin dosage seems a little low. Please recheck it.

4. Radiographic evaluation (L.140): The relationship between the person who performed TPLO surgery and the person who evaluated the radiographs is unclear. Please clarify it.

5. Results: Add the percentage (or number) of partial and complete tears of the cranial cruciate ligament.

6. Results (L201-202): Are all intraoperative minor complications the fibula fractures?

7. Results (L216-217) and Table 2: Are patellar fracture and tibial crest fracture minor complication? Please recheck them.

8. Results (L246): Other titles are preferable (ex. Differences in radiographic measurements between observers or Intraobserver variability).

9. Are the screws inserted in these cases coated with the same coating as the TPLO Curve®︎ plates? If not, you need to discuss the effect of non-coating screws on SSI in the Discussion.

10. Discussion (L.305-309): Briefly describe the antimicrobial mechanism of silver-based coated implants.

11. Ref 16 is inappropriate as a reference paper. Please delete it.

Minor points:

1. L.66: 3,6% to 16,5%→3.6% to 16.5%

2. L.166: observers’ mean→observer’s mean?

3. L.333: authors ’opinion→author’s opinion?

4. Figure 1: ”0°” added to vertical axis.

5. Figure 2: ”0°” added to vertical axis.

Reviewer #3: This is a manuscript that investigates a newer implant that offers a special coating which in theory should reduce the incidence of surgical site infection. Such plate coatings are being advertised more aggressively, and their effectiveness should be studied. The results of this smaller scale report indicate a similar infection rate to previous studies and thuse the coating does not appear to offer a clinical benefit.

Overall this manuscript could use some editorial assistance as there are some minor grammatical issues interspersed throughout the manuscript.

Line 53- tibial plateau leveling osteotomy.... not plate

Need to define the minor, major, and catastrophic complications. Referencing the cook paper is appropriate, but those definitions still need to be present within the manuscript

Line 204- cranial tibial artery?

Line 204- the retention of a K-wire is not considered a complication to this reviewer as its presence is not in a direct response to complication such as tibial tuberosity fracture, it was just left in place for perceived increase in construct stability. This is also questionable given reports exist which indicate a retained K wire does not provide significant increase in stability

Line 215-222: Need to better define what is major vs. minor complication. For example, a patella fracture is defined as minor which was likely treated conservatively with rest and NSAIDs. Why is patellar tendinitis classified as a major complication when it would have likely also been treated with rest and NSAIDS. The consistency between these issues is not apparent to this reviewer, again clearly defining the criteria used in this report and reason conditions were categorized as major or minor needs to be clarified

Line 240- where all SSI confirmed by positive culture? If not then what definition and criteria were used. If culture was used for all then consider summary of the bacterial culture results as it would be interesting to see if there is any difference in bacteria isolates with regard to plate coating

Line 315-325- this reviewer is uncertain how to feel about this data being contained in the discussion, if it is from the authors' centers then it could be included in the study design and should be added to the material methods and statistical analysis, essentially changing the study design to a retrospective cohort comparison and potentially strengthening the article. This reviewer would recommend major revision to include this information. If not desired, then it would be better to compare study data results to previous reports (i.e historical data) as previous TPLO reports using non-coated implants are abundant and the study results are comparable to reach the same conclusion. As written, the authors attempt to 'backdoor' data that is not fully explained to strengthen their conclusion. A retrospective cohort study design with direct comparison would be best as it improves the strength of study design.

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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: Yes: Kazuya Edamura

Reviewer #3: No

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Attachments

Attachment

Submitted filename: Review PONE_D_22_10523.docx

PONE-D-22-10523R1Long-term outcome of tibial plateau leveling osteotomy using an antimicrobial silver-based coated plate in dogsPLOS ONE

Dear Dr. Pages,

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 July 5, 2022. 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,

Ashraf M. Abu-Seida, Ph.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.

Additional Editor Comments (if provided):

Please follow up the format of the journal

Please respond to all reviewers comments

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: (No Response)

**********

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: Yes

Reviewer #3: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

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: The authors have addressed my concerns. I maintain (i assume they agree) that a better control population would be far superior, but i accept that is not going to happen. In recognition of the time concern, i recommend publication

Reviewer #2: This manuscript has been appropriately revised. Before completing the manuscript, please recheck the following minor points.

1. You should include the numbers in the BioMedtrix TPLO Curved plate and Synthes TPLO plate groups in the Abstract.

2. Abstract (Line 39): 7→6?, 31→32? Please final check them (and also others)!

3. Abstract (Results): Please describe which group results.

4. Line 159: “ModTPA was calculated (ReTPA minus PostTPA)”→”ReTPA minus PostTPA (ModTPA) was then calculated”

5. Results (Line: 210-218): Each data such as age, breed, body weight, affected stifle joint, type of rupture etc. should be listed separately for each group.

6. I found that the cases with combined caudal cruciate ligament rupture was included in this revised manuscript. Did you perform only TPLO surgery in these cases? Or did you perform a combination of extracapsular stabilization technique, etc.?

7. Line 261-262: Names of bacteria should be in italics.

8. Line 282: Another title is preferable (from “Statistical analysis” to another title). You did not change it, although you described “These have been changed” in revision letter.

9. Line 392: Others limitations→Other limitations?

10. Figures: “0°” on the vertical axis has not been improved...

Reviewer #3: The authors have revised this manuscript and while improved still needs to better incorporate the control group with thorough analysis and better description of analysis in the materials in methods.

Line 96-100: add the information from lines 109-113 to this region of the paragraph

Data analysis: need to add statistical methods for comparison of the population statistics between the biomedtrix and synthes groups for continuous and categorical data, also need to add post hoc power analysis performed

Line 218-219 : need to expand information of the synthes group similar to the biomedtrix group, add median values and ranges for data of the synthes group and statistically compare between groups using the methodology in the data analysis section. must ensure there is not a bias in one group that would predispose to SSI

Line 288-290: add in the post hoc power analysis information contained in the discussion at lines 385-388. this is data

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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: Yes: Kazuya Edamura

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.

Attachments

Attachment

Submitted filename: Review PONE-D-22-10523R1.docx

PONE-D-22-10523R2Long-term outcome of tibial plateau leveling osteotomy using an antimicrobial silver-based coated plate in dogsPLOS ONE

Dear Dr. Pages

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 02 2022 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,

Ashraf M. Abu-Seida, Ph.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.

Additional Editor Comments:

Line 234-235: caudal cruciate ligament tear→caudal cruciate ligament partial? tear

Line 260-267: The number of major intraoperative complications is 11 (4.4%) or 9 (3.6%)? Which is correct?

Table 2: Sort the major complications in order of number of occurrences.

Reviewers' comments:

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: This submitted paper (PONE-D-22-10523R2) are appropriately revised in response to the reviewer's remarks. I think that this paper is worthy of acceptance in the PLOS ONE. When you send final manuscript, please recheck the following points.

Line 234-235: caudal cruciate ligament tear→caudal cruciate ligament partial? tear

Line 260-267: The number of major intraoperative complications is 11 (4.4%) or 9 (3.6%)? Which is correct?

Table 2: Sort the major complications in order of number of occurrences.

**********

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: Yes: Kazuya Edamura

**********

[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.

Long-term outcome of tibial plateau leveling osteotomy using an antimicrobial silver-based coated plate in dogs

PONE-D-22-10523R3

Dear Dr. Pages

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,

Ashraf M. Abu-Seida, Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments: