Predictors for one-year outcomes of cardiorespiratory fitness and cardiovascular risk factor control after cardiac rehabilitation in elderly patients: The EU-CaRE study

Prisca Eser; Thimo Marcin; Eva Prescott; Leonie F. Prins; Evelien Kolkman; Wendy Bruins; Astrid E. van der Velde; Carlos Peña Gil; Marie-Christine Iliou; Diego Ardissino; Uwe Zeymer; Esther P. Meindersma; Arnoud W. J. Van’tHof; Ed P. de Kluiver; Matthias Wilhelm

doi:10.1371/journal.pone.0255472

Peer Review History

Original SubmissionOctober 28, 2020
14 Apr 2021 Decision Letter - Gerson Cipriano Jr., Editor PONE-D-20-33363 Predictors for one-year outcomes of cardiorespiratory fitness and cardiovascular risk factor control after cardiac rehabilitation in elderly patients: the EU-CaRE study PLOS ONE Dear Dr. ESER, 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 read and respond to all of the peer review comments. You should provide a point-by-point response to explain any changes you have (or have not) made to the original article and be as specific as possible in your responses. Please submit your revised manuscript by May 29 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://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, Gerson Cipriano Jr., PT, MsC, 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 2. Thank you for including your ethics statement: "The study was approved by all relevant medical ethics committees of all participating centres, and registered at trialregister.nl (NTR5306". a. Please amend your current ethics statement to include the full name of the ethics committee/institutional review board(s) that approved your specific study. b. Once you have amended this/these statement(s) in the Methods section of the manuscript, please add the same text to the “Ethics Statement” field of the submission form (via “Edit Submission”). For additional information about PLOS ONE ethical requirements for human subjects research, please refer to http://journals.plos.org/plosone/s/submission-guidelines#loc-human-subjects-research 3. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. In your revised cover letter, please address the following prompts: a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent. b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. We will update your Data Availability statement on your behalf to reflect the information you provide. 4. Thank you for stating the following in the Competing Interests section: 'AWJvH reports grants from Medtronic, grants and personal fees from Astra Zeneca, outside the submitted work, UZ reports grants and personal fees from Astra Zeneca, grants and personal fees from Bayer, personal fees from Boehringer Ingelheim, grants and personal fees from BMS, personal fees from Daiichi Sankyo, personal fees from Eli Lilly, grants and personal fees from Novartis, grants and personal fees from MSD, personal fees from Trommsdorf, personal fees from Amgen, outside the submitted work.' a. Please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials, by including the following statement: "This does not alter our adherence to PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests). If there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared. b. Please include your updated Competing Interests statement in your cover letter; we will change the online submission form on your behalf. Please know it is PLOS ONE policy for corresponding authors to declare, on behalf of all authors, all potential competing interests for the purposes of transparency. PLOS defines a competing interest as anything that interferes with, or could reasonably be perceived as interfering with, the full and objective presentation, peer review, editorial decision-making, or publication of research or non-research articles submitted to one of the journals. Competing interests can be financial or non-financial, professional, or personal. Competing interests can arise in relationship to an organization or another person. Please follow this link to our website for more details on competing interests: http://journals.plos.org/plosone/s/competing-interests 5. Please amend the manuscript submission data (via Edit Submission) to include author P. de Kluiver. 6. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: Yes ******** 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: No ****** 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: Interesting paper. Abstract; at firsr glance it remains unclear how patients were selected. Which were inclusion criteria? methods: definition of elderly should be added methods/results>a relevant difference between patients after CABG/cardiac surgery and after PCI is present methods: it should be added how variavles were selected methods: primary end point and secondary end points should be added methods: sample size calculation should be added Reviewer #2: This is a powerful paper which contributes to expand the knowledge about cardiovascular rehabilitation in elderly patients. In this paper, the authors analyzed the effect of cardiac rehabilitation in the enhancement of traditional cardiovascular risk factors – LDL-cholesterol, blood pressure, weight, and HbA1c in patients with DM - and improvement of functional capacity (peak oxygen consumption – peak VO2). (Also see attached document with comments) Reviewer #3: I commend the authors on this work and after having reviewed the manuscript have the following queries: General comments: Please verify first expansion of all abbreviations and ensure that is done only once Specific comments: 1. Did the sites of recruitment have an influence on your results? This could be a confounder 2. I understand the numbers of those not completing CR are small - but did you attempt to identify any factors within that group as well (if they have CPET values)? 3. Were any functional test performed in the elderly? This could be used as surrogates among those in whom CPET was not possible ****** 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: Yes: Fabrizio D'Ascenzo Reviewer #2: Yes:** Alexandra Correa Gervazoni Balbuena de Lima 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 Comments.docx https://doi.org/10.1371/journal.pone.0255472.r001
Revision 1
5 May 2021 Author Response Point-by-point responses to reviewers’ comments We thank the reviewers for their constructive comments and hope we have addressed them accordingly. Please find below our responses to the reviewers’ comments in italic font. 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: Interesting paper. Abstract; at firsr glance it remains unclear how patients were selected. Which were inclusion criteria? Detailed inclusion criteria have been published previously in: Prescott E, Meindersma EP, van der Velde AE, Gonzalez-Juanatey JR, Iliou MC, Ardissino D, Zoccai GB, Zeymer U, Prins LF, Van't Hof AW, Wilhelm M, de Kluiver EP. A EUropean study on effectiveness and sustainability of current Cardiac Rehabilitation programmes in the Elderly: Design of the EU-CaRE randomised controlled trial. Eur J Prev Cardiol. 2016 Oct;23(2 suppl):27-40. And Prescott E, Mikkelsen N, Holdgaard A, Eser P, Marcin T, Wilhelm M, et al. Cardiac rehabilitation in the elderly patient in eight rehabilitation units in Western Europe: Baseline data from the EU-CaRE multicentre observational study. European journal of preventive cardiology. 2019;26(10):1052-63. Additionally, we have amended the following sentence on line 97, page 6, as follows: “Briefly, elderly (65+) patients participating in CR of one of the eight European centres after coronary artery bypass grafting (CABG), percutaneous coronary intervention (PCI) or without revascularization as well as after percutaneous or surgical valve replacement (HVR) were included.” methods: definition of elderly should be added Elderly was defined as patients aged ≥65 years (please see sentence cited above). methods/results>a relevant difference between patients after CABG/cardiac surgery and after PCI is present methods: it should be added how variavles were selected Selection of variables is described on page 8, line 138: “Robust linear mixed models were performed for change in peak VO2 [ml/min/kg] between T0 and T2 (function rlmer from package robustlmm version 2.3). The following factors were included as predictor variables: Age, sex and peak exercise capacity at T0, comorbidities, cardiovascular risk factors and characteristics of CR, namely, lag time of CR and CR duration and self-reported physical activity level during follow-up. Centre was entered into the model as a random factor. Further factors from a list of cardiovascular risk factors and comorbidities (provided in S 1 Table) by backward selection. Non-significant variables were eliminated from the model manually by individually removing the variable with the largest p-value until any insignificant (p>0.01) parameters were removed from the model. This was done to avoid removing non-significant variables which had a large effect on other significant variables.” methods: primary end point and secondary end points should be added Primary and secondary end points were the predictors for the following primary and secondary outcomes (page 7, line 130): “Predictors were sought for the primary outcome, changes in CRF (T2-T0), namely change in peak VO2 [ml/kg/min]. Predictors were also sought for secondary outcomes, namely for CVRF control at T1 and T2, including the achievement of target levels according to current guidelines [15] as follows: BPsys < 140 mmHg, LDL-C < 1.8 mmol/l, BMI < 30 kg/m2 (non-obesity) or lowering body weight by ≥5%, and HbA1c in diabetic patients < 53 mmol/mol.” methods: sample size calculation should be added The sample size calculation for the EU-CaRE observational study is stated on page 6, line 93. “We aimed at including a total of 1760 patients equivalent of 220 patients from each site..” Reviewer #2: This is a powerful paper which contributes to expand the knowledge about cardiovascular rehabilitation in elderly patients. In this paper, the authors analyzed the effect of cardiac rehabilitation in the enhancement of traditional cardiovascular risk factors – LDL-cholesterol, blood pressure, weight, and HbA1c in patients with DM - and improvement of functional capacity (peak oxygen consumption – peak VO2). (Also see attached document with comments) Reviewer #3: I commend the authors on this work and after having reviewed the manuscript have the following queries: General comments: Please verify first expansion of all abbreviations and ensure that is done only once Thank you for pointing this out, we have corrected some missing or duplicated abbreviations. Specific comments: 1. Did the sites of recruitment have an influence on your results? This could be a confounder This is a good comment, yes, sites were a confounder, because CR programmes differed in duration and intensity from each other. Further, patient inclusion time into the programmes differed as well, with some centres starting patients in their programmes within days after interventions (stationary programmes) and several weeks or months (ambulatory programmes). However, we wanted to find predictors with regard to patient characteristics, not centre characteristics, which is why we included centres as random factors. The influence of site has been addressed in the publication of the main study results: Prescott E, Eser P, Mikkelsen N, Holdgaard A, Marcin T, Wilhelm M, Gil CP, González-Juanatey JR, Moatemri F, Iliou MC, Schneider S, Schromm E, Zeymer U, Meindersma EP, Crocamo A, Ardissino D, Kolkman EK, Prins LF, van der Velde AE, Van't Hof AW, de Kluiver EP. Cardiac rehabilitation of elderly patients in eight rehabilitation units in western Europe: Outcome data from the EU-CaRE multi-centre observational study. Eur J Prev Cardiol. 2020 Nov;27(16):1716-1729. 2. I understand the numbers of those not completing CR are small - but did you attempt to identify any factors within that group as well (if they have CPET values)? Unfortunately, none of the centres had CPET data from patients not undergoing CR. 3. Were any functional test performed in the elderly? This could be used as surrogates among those in whom CPET was not possible Indeed, 6-minute-walking tests were performed in patients who were too weak to perform CPETs. We have presented detailed results in: “A CPET was performed by 1534 patients, 48 performed a 6MWT and 51 patients did not have a baseline functional test available.” We have presented these results in detail in: Prescott E, Eser P, Mikkelsen N, Holdgaard A, Marcin T, Wilhelm M, Gil CP, González-Juanatey JR, Moatemri F, Iliou MC, Schneider S, Schromm E, Zeymer U, Meindersma EP, Crocamo A, Ardissino D, Kolkman EK, Prins LF, van der Velde AE, Van't Hof AW, de Kluiver EP. Cardiac rehabilitation of elderly patients in eight rehabilitation units in western Europe: Outcome data from the EU-CaRE multi-centre observational study. Eur J Prev Cardiol. 2020 Nov;27(16):1716-1729. Attachments Attachment Submitted filename: Responses to reviewers.docx https://doi.org/10.1371/journal.pone.0255472.r002
1 Jun 2021 Decision Letter - Gerson Cipriano Jr., Editor PONE-D-20-33363R1 Predictors for one-year outcomes of cardiorespiratory fitness and cardiovascular risk factor control after cardiac rehabilitation in elderly patients: the EU-CaRE study PLOS ONE Dear Dr. ESER, 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. Although the authors have adequately responded to all reviewers' comments, a complete proofreading review is required. Please submit your revised manuscript by Jul 16 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://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, Gerson Cipriano Jr., PT, MsC, 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.] [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.0255472.r003
Revision 2
1 Jun 2021 Author Response Responses to reviewer 2 Thank you very much for your supportive comments. Please find below our responses to your comments and questions. We hope that we have addressed them according to your expectations. Questions Line 92. “We aimed at including a total of 1760 patients equivalent of 220 patients from each site”. How was the sample size calculated? In the design paper of the study - A EUropean study on effectiveness and sustainability of current Cardiac Rehabilitation programmes in the Elderly: Design of the EU-CaRE randomised controlled trial. European journal of preventive cardiology. 2016;23(2 suppl):27-40 – it is described the sample size of the Eu-Care RCT (randomised controlled trial) based on the improvement of peak O2 consumption, but not from the observational study. The EU-CaRE study consisted of an observational study and an RCT. For the observational study, sample size was based on number of expected eldery patients seen each year and consisted of 220 patients per centre. In the methods section on p. 6 it reads: We aimed at including a total of 1760 patients equivalent of 220 patients from each site. The CR program offered at each site has been described previously [12]. Ref. 12 (see above) refers to the description of the CR program only, not to the sample size calculation. Suggestion of citation Kim KH, Jang YC, Song MK, Park HK, Choi IS, Han JY in the recent paper “Changes in Aerobic Capacity Over Time in Elderly Patients with Acute Myocardial Infarction During Cardiac Rehabilitation. Ann Rehabil Med. 2020 Feb;44(1):77-84. doi: 10.5535/arm.2020.44.1.77. Epub 2020 Feb 29. PMID: 32130841; PMCID: PMC7056327” found a similar no improvement in functional capacity in elderly patients in CR. Thank you for pointing out this reference, we have included it in the Discussion section. Suggestion of limitation Almost 50% of CR participants are older adults (>65 years), many of whom are frail or deconditioned. We need to start looking for frailty in elderly patients entering CR programmes and become more familiar with the tools to recognize and evaluate the severity of this condition. Furthermore, we need to better understand whether exercise-based cardiac rehabilitation may change the course and the prognosis of frailty in cardiovascular patients. The benefits of CR are well-suited to counteract the deficits of frailty such as sarcopenia, inactivity, fatigue, cognitive decline, and depression. We couldn’t agree more! Attachments Attachment Submitted filename: Responses to Review Comments_2.docx https://doi.org/10.1371/journal.pone.0255472.r004
19 Jul 2021 Decision Letter - Gerson Cipriano Jr., Editor Predictors for one-year outcomes of cardiorespiratory fitness and cardiovascular risk factor control after cardiac rehabilitation in elderly patients: the EU-CaRE study PONE-D-20-33363R2 Dear Dr. ESER, 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, Gerson Cipriano Jr., PT, MsC, Ph.D. Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0255472.r005
Formally Accepted
28 Jul 2021 Acceptance Letter - Gerson Cipriano Jr., Editor PONE-D-20-33363R2 Predictors for one-year outcomes of cardiorespiratory fitness and cardiovascular risk factor control after cardiac rehabilitation in elderly patients: the EU-CaRE study Dear Dr. Wilhelm: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. 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 plosone@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 Professor Gerson Cipriano Jr. Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0255472.r006

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 .