Robotic versus laparoscopic total mesorectal excision with lateral lymph node dissection for advanced rectal cancer: A systematic review and meta-analysis

Mohamed Ali Chaouch; Mohammad Iqbal Hussain; Adriano Carneiro da Costa; Alessandro Mazzotta; Bassem Krimi; Amine Gouader; Eddy Cotte; Jim Khan; Hani Oweira

doi:10.1371/journal.pone.0304031

Peer Review History

Original SubmissionJanuary 16, 2024
24 Mar 2024 Decision Letter - Tsutomu Kumamoto, Editor PONE-D-24-01676Robotic Versus Laparoscopic Total Mesorectal Excision with Lateral Lymph Node Dissection for Advanced Rectal Cancer: A Systematic Review and Meta-AnalysisPLOS ONE Dear Dr. Chaouch, 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 May 08 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, Tsutomu Kumamoto 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: The authors are conducting a very important review in rectal cancer surgery. However, there are several issues. 1. Regarding postoperative complications, more detailed descriptions are required for definitions and grades. 2. Will this review focus on both short-term and long-term results? It would be better to make a clear description of these. 3. There are no RCT or PS matching studies, and the review contains considerable selection bias. Considering this, the review must not mislead the readers. [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: Partly ******** 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: No 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 compared postoperative short course outcomes between robotic and laparoscopic TME+LPLND. The authors concluded that the robotic approach is a safe and feasible alternative in advanced rectal cancer. This is appealing to some physicians, but I have the following issues: 1. As described in discussion, the studies including in this analysis are all retrospective studies, which lead to selection bias. 2. The BMI of the cases is low (mean 21-23), so it should be described that this study is based on a biased case. 3. The definition of each complication is not stated. The grade of the complication should also be described. 4. There are many typographical errors. Reviewer #2: This study is a meta-analysis conducted to investigate the advantages of robotic surgery over laparoscopic surgery in performing Lateral Pelvic Node Dissection (LPND). Appropriate studies were identified and analyzed. However, I would like to inquire about a few points: 1. The introduction states that while the benefits of postoperative outcomes are identified, the oncological safety has not been clarified. However, the abstract states that this study will clarify postoperative outcomes. If the objective is to compare short-term outcomes, the introduction in the text needs to be refined. 2. In the introduction, the citation for the following sentence needs to be corrected: "The overall risk of recurrence following this strategy increases from 10 (2) to 30% in cases of lateral node involvement (2)." 3. In the introduction, the citation for the following sentence needs to be replaced with a more appropriate one: "In the East, promising results have been demonstrated when LPN metastasis (LPNM) is treated with TME and Lateral Pelvic Node Dissection (LPND) (1)." 4. In the methods, the paragraph on eligibility criteria's studies needs clarification: "We included all randomized controlled trials (RCTs) and controlled clinical trials (CCTs) that compared robotic Total Mesorectal Excision (RTME) with Laparoscopic Pelvic Lymph Node Dissection (LPND), and laparoscopic Total Mesorectal Excision (LTME) with LPND." Please verify if the term 'laparoscopic pelvic lymph node dissection' is incorrectly written instead of 'lateral pelvic lymph node dissection.' 5. To analyze differences in anastomotic leakage, it would be beneficial to add the stoma rate to the results. 6. In the results, it would be advisable to include lymphocele, which is an LPND-specific complication. 7. Regarding the third paragraph of the discussion: "Because LPND requires only lymphatic tissue dissection, the lateral pelvic vascular and nervous complexes should be preserved during skeletonization." I disagree with this statement. I believe that if LPN has to be removed in proximity to certain structures, some vessels and nerves may need to be sacrificed. I would like to hear your opinion on this. 8. The use of abbreviations needs to be systematically reviewed throughout the text. Especially since LPN is described in the fifth paragraph of the discussion, it should have been detailed earlier. And as previously mentioned, the abbreviation "Laparoscopic Pelvic Lymph Node Dissection (LPND)" is inappropriate. There is a need for a clear review and arrangement of the abbreviations used throughout the text. Reviewer #3: Thank you for the opportunity to review this study. My comments are as follows: 1. This review covers a relevant and interesting topic. 2. The introduction is rather wordy and covers many different concepts. This should be further summarised in shortened paragraphs to discuss the pertinent issues related to the topic at hand. 3. The statistical analysis appears to be sound and well conducted. 4. The major limitation of the study is the lack of mature data and paucity of randomized trials, prospective studies, or propensity score matched studies which can control for confounding and selection bias. 5. Several RCTs and meta-analyses already exist comparing Lap vs Robotic TME. The authors should decide if the study is to compare Lap TME + LPND vs RTME + LPND as currently is, or to focus on the Lap LPND vs Robotic LPND aspect – this is an important distinction as several important quality control and oncological parameters are missing should TME be included, such as rates of complete TME, distal resection margin, CRM positivity, and conversion rates. I suggest that the authors focus on the LPND aspect as this is relatively novel while there is an abundance of data on approaches to TME. 6. Table 2 is quite challenging to compare and interpret – I suggest there be an additional row demonstrating the pooled frequencies and proportions. 7. It should be strongly emphasized that the grade of evidence is low to very low across all measures of outcomes resulting in an inability to draw definite conclusions. ****** 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: 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.pdf https://doi.org/10.1371/journal.pone.0304031.r001
Revision 1
31 Mar 2024 Author Response Reviewer queries responses Editor Q1. Regarding postoperative complications, more detailed descriptions are required for definitions and grades. R1. We have added that mortality and morbidity were considered when they occurred within 90 and 30 days after rectal resection, respectively. Q2. Will this review focus on both short-term and long-term results? It would be better to make a clear description of these. R2. We have removed the term “long-term” and we have used “oncological” results only to avoid this doubt. Q3. There are no RCT or PS matching studies, and the review contains considerable selection bias. Considering this, the review must not mislead the readers. R3. Thank you for this valuable remark. We have mentioned this detail in the limitation of the study, reported in the risk of bias assessment of the retained studies, and it was a reason to decrease the level of evidence of the different conclusions after the GRADE assessment in the summary of findings. Reviewers Reviewer #1: Q1. As described in discussion, the studies including in this analysis are all retrospective studies, which lead to selection bias. R1. Thank you for this valuable remark. We have mentioned this detail in the limitation of the study, reported in the risk of bias assessment of the retained studies, and it was a reason to decrease the level of evidence of the different conclusions after the GRADE assessment in the summary of findings. Q2. The BMI of the cases is low (mean 21-23), so it should be described that this study is based on a biased case. R2. Yes absolutely. We have also remarked on this point. However, it is explained by the origin of these studies from Asian countries that were well known with their low BMI. We have added this information in the discussion section and we have highlighted its interest for an external validity of our findings. Thank you for this remark. Q3. The definition of each complication is not stated. The grade of the complication should also be described. R3. We have added a definition of the different complications. Unfortunately, we cannot add additional information regarding the grade because it was not reported in the retained studies. Q4. There are many typographical errors. R4. We have corrected the different errors. Thank you Reviewer #2: Q1. The introduction states that while the benefits of postoperative outcomes are identified, the oncological safety has not been clarified. However, the abstract states that this study will clarify postoperative outcomes. If the objective is to compare short-term outcomes, the introduction in the text needs to be refined. R1. We have removed this sentence from the introduction to alleviate this issue. Q2. In the introduction, the citation for the following sentence needs to be corrected: "The overall risk of recurrence following this strategy increases from 10 (2) to 30% in cases of lateral node involvement (2)." R2. We have corrected the references. Q3. In the introduction, the citation for the following sentence needs to be replaced with a more appropriate one: "In the East, promising results have been demonstrated when LPN metastasis (LPNM) is treated with TME and Lateral Pelvic Node Dissection (LPND) (1)." R3. We have added a reference to this sentence. Q4. In the methods, the paragraph on eligibility criteria's studies needs clarification: "We included all randomized controlled trials (RCTs) and controlled clinical trials (CCTs) that compared robotic Total Mesorectal Excision (RTME) with Laparoscopic Pelvic Lymph Node Dissection (LPND), and laparoscopic Total Mesorectal Excision (LTME) with LPND." Please verify if the term 'laparoscopic pelvic lymph node dissection' is incorrectly written instead of 'lateral pelvic lymph node dissection.' R4. We have corrected it. Q5. To analyze differences in anastomotic leakage, it would be beneficial to add the stoma rate to the results. R5. Unfortunately, the stoma rate was not reported in the included studies. Q6. In the results, it would be advisable to include lymphocele, which is an LPND-specific complication. R6. This outcome was not reported in the different included studies. Q7. Regarding the third paragraph of the discussion: "Because LPND requires only lymphatic tissue dissection, the lateral pelvic vascular and nervous complexes should be preserved during skeletonization." I disagree with this statement. I believe that if LPN has to be removed in proximity to certain structures, some vessels and nerves may need to be sacrificed. I would like to hear your opinion on this. R7. Yes absolutely. In some cases, we found a huge adhesion of metastasis LN and we are obliged to scarify certain structures. We have added this information to this sentence. Q8. The use of abbreviations needs to be systematically reviewed throughout the text. Especially since LPN is described in the fifth paragraph of the discussion, it should have been detailed earlier. And as previously mentioned, the abbreviation "Laparoscopic Pelvic Lymph Node Dissection (LPND)" is inappropriate. There is a need for a clear review and arrangement of the abbreviations used throughout the text. Q9. We have reviewed all the abbreviations. Reviewer #3: Q1. The introduction is rather wordy and covers many different concepts. This should be further summarised in shortened paragraphs to discuss the pertinent issues related to the topic at hand. R1. We have shortened the introduction. Q2. The major limitation of the study is the lack of mature data and paucity of randomized trials, prospective studies, or propensity score matched studies which can control for confounding and selection bias. R2. We have added this information in the limitations of our study. Q3. Several RCTs and meta-analyses already exist comparing Lap vs Robotic TME. The authors should decide if the study is to compare Lap TME + LPND vs RTME + LPND as currently is, or to focus on the Lap LPND vs Robotic LPND aspect – this is an important distinction as several important quality control and oncological parameters are missing should TME be included, such as rates of complete TME, distal resection margin, CRM positivity, and conversion rates. I suggest that the authors focus on the LPND aspect as this is relatively novel while there is an abundance of data on approaches to TME. R3. Thank you for this remark. At the beginning of our study, we performed literature research for all the studies comparing robotic and laparoscopic LPND. We have found studies of urology, digestive disease, and gynaecology. The most relevant issue was that the study population of the PICO that we used was very heterogeneous and it was impossible to pool the outcomes with a huge heterogeneity among the different studies in the majority of the outcomes. We thought that a focus only LPND is an excellent subject of a systematic review and not a meta-analysis. Q4. It should be strongly emphasized that the grade of evidence is low to very low across all measures of outcomes resulting in an inability to draw definite conclusions. R4. Yes, absolutely we have mentioned this information. Attachments Attachment Submitted filename: Reviewers queries responses.docx https://doi.org/10.1371/journal.pone.0304031.r002
29 Apr 2024 Decision Letter - Tsutomu Kumamoto, Editor PONE-D-24-01676R1Robotic Versus Laparoscopic Total Mesorectal Excision with Lateral Lymph Node Dissection for Advanced Rectal Cancer: A Systematic Review and Meta-AnalysisPLOS ONE Dear Dr. Chaouch, 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 Jun 13 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, Tsutomu Kumamoto 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: The authors have addressed most of the reviewers’ comments. However, one reviewer has pointed out a few additional changes that should be made. We recommend reviewing the manuscript again. [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 #2: All comments have been addressed 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 #2: Yes Reviewer #3: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #2: I Don't Know 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 #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 #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 #2: You've worked hard on the revisions. I think your excellent research results have been sufficiently supplemented. I would like to make one request. It seems necessary to review all the citations in the discussion. There are minor issues such as some references having incorrect numbers or duplications. I recommend reviewing them once again. Reviewer #3: =====================================================================================================All comments have been addressed ****** 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 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. https://doi.org/10.1371/journal.pone.0304031.r003
Revision 2
1 May 2024 Author Response Reviewers’ queries responses Reviewer #2: You've worked hard on the revisions. I think your excellent research results have been sufficiently supplemented. I would like to make one request. It seems necessary to review all the citations in the discussion. There are minor issues such as some references having incorrect numbers or duplications. I recommend reviewing them once again. Response : Thank you for the remarks. We have checked all the references to avoid any issues. Attachments Attachment Submitted filename: Reviewers queries.docx https://doi.org/10.1371/journal.pone.0304031.r004
6 May 2024 Decision Letter - Tsutomu Kumamoto, Editor Robotic Versus Laparoscopic Total Mesorectal Excision with Lateral Lymph Node Dissection for Advanced Rectal Cancer: A Systematic Review and Meta-Analysis PONE-D-24-01676R2 Dear Dr. Mohamed Ali Chaouch 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, Tsutomu Kumamoto Academic Editor PLOS ONE Additional Editor Comments (optional): This time, out of three reviewers, one reviewer gave a reject decision, and two reviewer gave a major revision. However, authors have addressed all the points indicated by the two reviewers. There are limitations, but it is a systematic review that will be useful for many colorectal cancer surgeons, and I decided to accept it. https://doi.org/10.1371/journal.pone.0304031.r005
Formally Accepted
16 May 2024 Acceptance Letter - Tsutomu Kumamoto, Editor PONE-D-24-01676R2 PLOS ONE Dear Dr. Chaouch, 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 M.D., Ph.D. Tsutomu Kumamoto Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0304031.r006

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