Risk factors of phlebitis in patients admitted to the intensive care unit vary according to the duration of catheter dwelling: A post-hoc analysis of the AMOR-VENUS study

Yutaro Shinzato; Hideto Yasuda; Takashi Moriya; Haruka Taira; Yuki Kishihara; Masahiro Kashiura; Yuki Kotani; Natsuki Kondo; Kosuke Sekine; Nobuaki Shime; Keita Morikane; on behalf of the AMOR-VENUS study group

doi:10.1371/journal.pone.0320583

Peer Review History

Original SubmissionDecember 18, 2023
18 Dec 2023 Author Response https://doi.org/10.1371/journal.pone.0320583.r001
15 Jul 2024 Decision Letter - Ioannis Savvas, Editor PONE-D-23-30822Risk factors of phlebitis in patients admitted to the intensive care unit vary according to the duration of catheter dwelling: A post-hoc analysis of the AMOR-VENUS studyPLOS ONE Dear Dr. Yasuda, 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 Aug 29 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. 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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: Thank you for your informative article. I have a few questions about the analyses. line 99: what was the purpose of the analysis of variance and Kruskal-Wallis test? line 101: what was the purpose of the Fisher exact est of Pearson's chi-square test, as the association of interest is with phlebitis, and this is assessed with Cox regression analyses? Clarify if it is to test for differences according to duration of catheter dwelling group. Should the patient and/or hospital effects be considered in these tests? Should a mixed hierarchical model be better placed to assess these differences? Is the endpoint really time to phlebitis from insertion of PIVC (rather than phlebitis which is presumably incidence of phlebitis)? How was patient and ICU accounted for in the Cox regression analyses? Does this need to be a hierarchical model too? Reviewer #2: Shinzato and colleagues have performed a further post-hoc analysis of this study of phlebitis in 23 ICUs in Japan. Although they report factors that may be associated with phlebitis, there is little justification for the dichotomisation of 24 vs > 72 hours, and I note that many of their findings have been previously reported in their three other papers from this dataset. In particular, the biological plausibility of why certain drugs but not others may be associated with later phlebitis is not well explored, and also the discrepant findings reported here from their previous paper which found a shorter dwell time with phlebitis positive patients vs phlebitis negative patients (Duration of catheter dwell, median (IQR), hour 37.0 (19.2–57.6) with phlebitis vs 44.8 (21.0–81.5) without phlebitis p < 0.01) is also not discussed. How does the confounder of catheter removal in the case of suspected phlebitis (with a commensurate shorter dwell time) affect their findings? Reviewer #3: The authors conducted a post-hoc study of the AMOR-VENUS study to identify risk factors for PIVC-related phlebitis in intensive care patients, according to catheterization duration. 3348 PIVCs inserted in 1335 patients were included. Several independent variables were identified, depending on the duration of catheter dwell. Overall, the manuscript is clear and well-written. The present study raises no ethical issues, as the ethical approval of the AMOR-VENUS study included post-hoc analyses. I am not a statistician. My analysis does not include the statistical methods used by the authors. Several catheters (2.5 on average) were inserted per patient. How did the authors consider this in their statistical analyses? Similarly, patients with missing data were excluded from the analysis. How many patients/catheters does this represent? My main limitation is the implication of the results in clinical practice. The duration of catheterization is rarely known when the catheter is inserted. How the identification of phlebitis risk factors according to catheterization dwell time will change practices deserves to be widely developed in the manuscript. ****** 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: Olivier MIMOZ ******** [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. 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Revision 1
11 Dec 2024 Author Response December, 2024 Ioannis Savvas, DVM, Ph.D. Academic Editor PLOS ONE Dear Dr. Savvas, We are pleased to be given an opportunity to resubmit our manuscript titled "Risk factors of phlebitis in patients admitted to the intensive care unit vary according to the duration of catheter dwelling: A post-hoc analysis of the AMOR-VENUS study" for further consideration in PLOS ONE. The Manuscript ID is: PONE-D-23-30822. We would like to thank you and the reviewers for the valuable feedback and insightful suggestions, which have helped us improve the quality of our manuscript. I look forward to working with you and the reviewers to move this manuscript closer to publication in the PLOS ONE. In response to the reviewers' comments, we have made significant revisions, which we believe have strengthened our work. A detailed point-by-point response to each reviewer’s comment is included below. Additionally, the revisions made in the manuscript have been highlighted in the track-changes version. We hope that the revised manuscript meets your expectations, and we look forward to your editorial decision. Thank you again for considering our work for publication in PLOS ONE. Sincerely, Hideto Yasuda Department of Emergency and Critical Care Medicine, 1-847, Amanuma-cho, Omiya-ku, Saitama City, Saitama, 330-8503, Japan Phone: +81-(0)48-647-2111 Fax: +81-(0)48-648-5180 Email: yasudahideto@me.com Our responses to the Reviewers' comments and suggestions are listed below: Reviewer #1 1. Comment: Line 99: What was the purpose of the analysis of variance and Kruskal-Wallis test? Response: Thank you for your question. The Kruskal-Wallis test was performed to compare between the three groups in terms of patient background characteristics to assess whether there were significant differences among the groups categorized by catheter insertion time. Our goal was to assess differences in background characteristics that might impact phlebitis risk, rather than to detect pairwise differences between any specific groups. 2. Comment: Line 101: What was the purpose of the Fisher’s exact test and Pearson’s chi-square test, as the association of interest is with phlebitis, which is assessed with Cox regression analyses? Clarify if it is to test for differences according to duration of catheter dwelling group. Should the patient and/or hospital effects be considered in these tests? Would a mixed hierarchical model be more appropriate for assessing these differences? Response: Thank you for pointing this out. The Fisher’s exact test and Pearson’s chi-square test were used for the univariate analysis to detect differences between the groups rather than to explore associations with phlebitis. These tests aimed to provide an initial understanding of background differences among the groups categorized by catheter dwelling duration. Regarding association testing, we used multilevel Cox regression, which incorporated patient and hospital effects as random effects to account for hierarchical variability. Given the recent advances in analysis techniques, it might indeed have been suitable to omit these background tests entirely, as differences in background characteristics have been less frequently tested in recent literature. 3. Comment: Is the endpoint really time to phlebitis from insertion of PIVC (rather than incidence of phlebitis)? Response: Thank you for this query. As you kindly pointed out, the endpoint in our study was "time to phlebitis from insertion of PIVC." Although the exact time of phlebitis onset may not have been precisely recorded, we monitored the catheter insertion site every four hours, allowing us to estimate the time to phlebitis onset with reasonable accuracy. 4. Comment: How were patient and ICU accounted for in the Cox regression analyses? Should this also be modeled hierarchically? Response: Thank you for pointing this out. In our analysis, we used multilevel Cox regression, incorporating both patient and facility (ICU) as random effects to address potential clustering effects. This hierarchical modeling approach allowed us to account for variability in catheter management practices across facilities and among patients who had multiple catheters. Reviewer #2 1. Comment: There is little justification for the dichotomization of 24 vs >72 hours. Response: Thank you for your comment. We considered categorizing the groups into three distinct categories based on catheter dwelling duration because early infections post-insertion is common in critically ill patients. Although there was no universally accepted cutoff, we selected a 72-hour threshold to achieve a balanced sample size in each group, which could help reduce the risk of overfitting and ensure robust statistical analysis. 2. Comment: The biological plausibility of why certain drugs but not others may be associated with later phlebitis is not well explored. Response: Thank you for your comment. The factors influencing phlebitis onset, particularly medication effects, remain complex and are not fully understood. The existing studies often treat medication as a binary variable (administered or not), which does not capture the timing or dose effects. Ideally, the time-dependent effects of medication on phlebitis onset would require a more sophisticated analysis. In our study, we did not investigate specific timing due to model simplicity; this limitation is noted for future studies. 3. Comment: the discrepant findings reported here from their previous paper which found a shorter dwell time with phlebitis positive patients vs phlebitis negative patients (Duration of catheter dwell, median (IQR), hour 37.0 (19.2–57.6) with phlebitis vs 44.8 (21.0–81.5) without phlebitis p < 0.01) is also not discussed. Response: Thank you for your suggestion. We agree that an explanation was necessary. Accordingly, we have added an explanation to the manuscript (Lines 216-223). 4. Comment: Discrepant findings regarding dwell time and phlebitis. How does the confounder of catheter removal due to suspected phlebitis (with a corresponding shorter dwell time) affect your findings? Response: We appreciate your insightful observation. In our study, early catheter removal due to suspected phlebitis might have led to a shorter dwelling duration, potentially impacting the results. If catheter dwelling duration was reduced due to phlebitis occurrence, this might have influenced the observed relationship between phlebitis incidence and dwelling time. Cases of extended dwelling durations could have shown different phlebitis outcomes. This limitation has been noted in our manuscript, as we recognize the need for further research to clarify this aspect. We have added this meaning to the manuscript (Lines 249-255). Reviewer #3 1. Comment: Several catheters (2.5 on average) were inserted per patient. How did the authors consider this in their statistical analyses? Response: Thank you for your question. Given the possibility that outcomes might be correlated across multiple catheters in the same patient, we performed a multilevel analysis with both patient and facility factors as random effects. This approach helped us account for the nested structure of our data and reduced the risk of inflated associations due to within-patient correlations. 2. Comment: Patients with missing data were excluded from the analysis. How many patients/catheters does this represent? Response: Thank you for your question. We have added a detailed account of the number of patients and catheters excluded due to missing data. This information is reported in the results section (Line 164-167). 3. Comment: Implications for clinical practice: The duration of catheterization is rarely known when the catheter is inserted. How will identifying phlebitis risk factors based on dwell time change practices? Response: We appreciate your insightful query. Our study identified that risk factors for phlebitis onset varied with catheterization duration. For instance, in cases of high risk for phlebitis within the first 24 hours, scheduled replacement might be considered within that period. Conversely, if no risk factors appeared until after 72 hours, the catheter could potentially be monitored until then, delaying replacement. This approach could help estimate optimal replacement timing, which we discussed in the manuscript (Line 232-242). We look forward to your feedback and hope that our revised manuscript is now suitable for publication. Attachments Attachment Submitted filename: Response_to_Reviewers.docx https://doi.org/10.1371/journal.pone.0320583.r003
3 Jan 2025 Decision Letter - Ioannis Savvas, Editor <div>PONE-D-23-30822R1Risk factors of phlebitis in patients admitted to the intensive care unit vary according to the duration of catheter dwelling: A post-hoc analysis of the AMOR-VENUS studyPLOS ONE Dear Dr. Yasuda, 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 Feb 17 2025 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, Ioannis Savvas, DVM, 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. [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: (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 #3: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #3: I Don't Know ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #3: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #3: Yes ****** 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: There was no text change to address the four points that I made in the comments - thus another reader may experience the same confusion as I. Please add some important words to the manuscript to clarify these points (Reviewer 1) Reviewer #3: I thank the authors for having taken all my comments into account. The manuscript is now suitable for publication. ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean? ). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy . Reviewer #1: No Reviewer #3: Yes: Olivier MIMOZ ******** [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.0320583.r004
Revision 2
15 Feb 2025 Author Response February, 2025 Ioannis Savvas, DVM, Ph.D. Academic Editor PLOS ONE Dear Dr. Savvas, We are pleased to be given an opportunity to resubmit our manuscript titled "Risk factors of phlebitis in patients admitted to the intensive care unit vary according to the duration of catheter dwelling: A post-hoc analysis of the AMOR-VENUS study" for further consideration in PLOS ONE. The Manuscript ID is: PONE-D-23-30822. We would like to thank you and the reviewers for the valuable feedback and insightful suggestions, which have helped us improve the quality of our manuscript. I look forward to working with you and the reviewers to move this manuscript closer to publication in the PLOS ONE. In response to the reviewers' comments, we have made substantial and detailed revisions to comprehensively respond to all comments. Specifically, we have: • Elaborated on our statistical methodology, explicitly explaining the rationale for each test used. • Refined the definition of the study endpoint, ensuring clarity regarding how "time to phlebitis" was determined. • Justified the use of hierarchical modeling, with a clear explanation about why this approach was necessary. • Expanded the discussion about clinical implications, outlining how our findings could help establish catheter management strategies in intensive care settings. We sincerely appreciate the reviewers' valuable insights, which have helped us significantly improve our manuscript. For clarity, all revisions have been highlighted in the track-changes version of the manuscript. We hope that the revised manuscript meets your expectations; we look forward to your editorial decision. Thank you once again for considering our work for publication in PLOS ONE. Sincerely, Hideto Yasuda Department of Emergency and Critical Care Medicine, 1-847, Amanuma-cho, Omiya-ku, Saitama City, Saitama, 330-8503, Japan Phone: +81-(0)48-647-2111 Fax: +81-(0)48-648-5180 Email: yasudahideto@me.com Our responses to the Reviewers' comments and suggestions are listed below: Reviewer #1 1. Comment: There was no text change to address the four points that I made in the comments - thus another reader may experience the same confusion as I. Please add some important words to the manuscript to clarify these points. Response: We thank you for your valuable and insightful feedback. We sincerely apologize for any lack of clarity in our previous revision and have now made the necessary modifications to explicitly respond to all four comments. The following revisions have been made to ensure the manuscript is clearer and more comprehensive. 1. Line 99: What was the purpose of the analysis of variance and Kruskal-Wallis test? Response: Thank you for your question. The analyses of variance (ANOVA) and Kruskal-Wallis test were used to compare background characteristics among the three catheter insertion time groups to determine whether significant differences existed. This was necessary for confirming that the groups were comparable before performing further statistical analyses. We have clarified this in the Methods section (Lines 100-102). 2.Line 101: What was the purpose of the Fisher’s exact test and Pearson’s chi-square test, as the association of interest is with phlebitis, which is assessed with Cox regression analyses? Clarify if it is to test for differences according to duration of catheter dwelling group. Should the patient and/or hospital effects be considered in these tests? Would a mixed hierarchical model be more appropriate for assessing these differences? Response: Thank you for pointing this out. In the revised manuscript, we have explicitly stated that Fisher’s Exact Test and Pearson’s Chi-Square Test were used solely for preliminary analyzing background characteristics and were not intended to infer causal relationships with phlebitis risk. Furthermore, we have emphasized that hierarchical modeling (multilevel Cox regression) was applied in the main analysis to appropriately account for both patient- and ICU-level effects. This would ensure that confounding due to clustering at the institutional and patient levels was minimized (Lines 104-108). 3.Is the endpoint really time to phlebitis from insertion of PIVC (rather than incidence of phlebitis)? Response: Thank you for your insightful query. We have now explicitly clarified in the Methods section that the study endpoint was "time to phlebitis from insertion of PIVC," as determined based on regular 4-hour monitoring. This approach ensures that the earliest possible detection of phlebitis onset is made while maintaining consistency in timepoint evaluation across patients (Lines 113-115). 4.How were patient and ICU accounted for in the Cox regression analyses? Should this also be modeled hierarchically? Response: Thank you for pointing this out. We used multilevel Cox regression, incorporating both patient and facility (ICU) as random effects to address potential clustering effects. In the revised manuscript, we have now explicitly justified our choice of this approach, ensuring clarity on why hierarchical modeling was necessary (Lines 106-108). We sincerely appreciate the time and effort invested by the reviewers and editors for evaluating our manuscript. We believe that these revisions have significantly strengthened our study and ensured its clarity, rigor, and clinical relevance. We look forward to your feedback and hope that our revised manuscript now fully meets the criteria for publication in PLOS ONE. Attachments Attachment Submitted filename: Response_to_Reviewers_auresp_2.docx https://doi.org/10.1371/journal.pone.0320583.r005
21 Feb 2025 Decision Letter - Ioannis Savvas, Editor Risk factors of phlebitis in patients admitted to the intensive care unit vary according to the duration of catheter dwelling: A post-hoc analysis of the AMOR-VENUS study PONE-D-23-30822R2 Dear Dr. Yasuda, 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, Ioannis Savvas, DVM, Ph.D. Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0320583.r006
Formally Accepted
Acceptance Letter - Ioannis Savvas, Editor PONE-D-23-30822R2 PLOS ONE Dear Dr. Yasuda, 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 Prof. Ioannis Savvas Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0320583.r007

Open letter on the publication of peer review reports

PLOS recognizes the benefits of transparency in the peer review process. Therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. Reviewers remain anonymous, unless they choose to reveal their names.

We encourage other journals to join us in this initiative. We hope that our action inspires the community, including researchers, research funders, and research institutions, to recognize the benefits of published peer review reports for all parts of the research system.

Learn more at ASAPbio .