Transfer Alert

This paper was transferred from another journal. As a result, its full editorial history (including decision letters, peer reviews and author responses) may not be present.

PONE-D-21-08610

Impact of Gender on Use of Low Tidal Volume Ventilation in Invasively Ventilated ICU Patients – a mediation analysis using two observational cohorts

PLOS ONE

Dear Dr. Swart,

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 28 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,

Aleksandar R. Zivkovic

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

1. Please provide additional details regarding participant consent. For each patient cohort, in the ethics statement in the Methods and online submission information, please ensure that you have specified (1) whether consent was informed and (2) what type you obtained (for instance, written or verbal, and if verbal, how it was documented and witnessed). If your study included minors, state whether you obtained consent from parents or guardians. If the need for consent was waived by the ethics committee, please include this information.

If your study includes an analysis of retrospectively collected data, please ensure that you have discussed whether all data/samples were fully anonymized before you accessed them and/or whether the IRB or ethics committee waived the requirement for informed consent. If patients provided informed written consent to have data/samples from their medical records used in research, please include this information.

1. Thank you for stating the following in the Acknowledgments/Funding Section of your manuscript:

Amsterdam University Medical Centers, location ‘AMC’, Amsterdam, The Netherlands

We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form.

Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows:

The author(s) received no specific funding for this work.

Please include your amended statements within your cover letter; we will change the online submission form on your behalf.

1. Thank you for stating the following in the Competing Interests section:

Ary Serpa Neto reported receiving personal fees from Dräger outside of the submitted work. Marcelo Gama de Abreu reported receiving grants and personal fees from Drägerwerk AG and GlaxoSmithKline and receiving personal fees from GE Healthcare outside of the submitted work. No other disclosures were reported.

We note that you received funding from a commercial source: Drägerwerk AG, GlaxoSmithKline, GE Healthcare

Please provide an amended Competing Interests Statement that explicitly states this commercial funder, along with any other relevant declarations relating to employment, consultancy, patents, products in development, marketed products, etc.

Within this Competing Interests Statement, 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.

Please include your amended Competing Interests Statement within 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

1. We noted in your submission details that a portion of your manuscript may have been presented or published elsewhere. „Gender Differences in Tidal Volume Limitation – an ICU database analysis. Oral presentation at European Respiratory Society Annual International congress 2020, Online”

Please clarify whether this conference proceeding or publication was peer-reviewed and formally published. If this work was previously peer-reviewed and published, in the cover letter please provide the reason that this work does not constitute dual publication and should be included in the current manuscript.

1. 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:

6a) 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.

6b) 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.

1. 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.

8. 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 #1: This is a pot joc analysis of two large longitudinal projects from 59 ICUs in USA including 8207 patients with mechanical ventilation >48 hours . Temporal changes of Vt and gender differences were analyzed during the period 2001-2015 . The authors did not included more recent data (2015-2020) with probably higher implementació of protective ventilation . Vt declines over the years in both sex but with a persistent difference between females (Vt 10.2 to 8.2) vs males ( Vt 9.2 to 7.3 ) ml/Kg PBW. What is the real clinical impact and relevance of a gender difference of median Vt 0.9 ml/KgIBW among both groups ? What is the Vt atributable mortality considering that the majority of respiratory mechanical parameters were in the recommended level of protective mechanical ventilation and no gender differences were observed except for Minute ventilation ? What was ventilatory ratio in both groups ? Additional Comments :

1. How and when actual body weigth and heigth were messured ?

2. The authors used a hight resolution data base . Could you please explain what you mean by high resolution ? What is the quality control of the data base ?

3. Table S2. Body weigth should be vidu heigth

4. Sepsis including pneumònia was the most frequent Initial diagnosis that increases overtime associated with a lower Pa/FiO2 . What was the gender Vt difference in this group of patients with probably a lower lung compliance ?

Reviewer #2: The authors report an interesting and clinically relevant study in a retrospectively mode on the use of low tidal volume ventilation (LTVV) in female versus male patients over the past years. The main finding was, that the use of LVVT improved over years, but less consequent in women compared to men, but this finiding is more due to the miscalculation of body height than of the gender per se.

The study is adequately performed in design, statistics and presentation of results. The findings are important and should be recognized by intensivists. I have just a few minor comments:

1. abstract p4, l 88: it should read "...using the correctly assessed body height for calculation of ideal body weight."

2. Introduction, p 5, l 91: "in the past..." is not correct, since the ARDSNet study is now 21 years old, may be it could read: "Although a landmark study regarding the benefit of LTVV was published in 2000, int hte past..."

3. p 6, l117-118: misphrase"...over recent years over the years..."

4. the references are mostly unstructured and not formatted to journals style

5. p7, l 140-150: Since the variation of VT is very dependent from the mode of MV (controlled vs. augmented spontaneously) the authors should add in a senternce which ventiklation mode was used in the early phase of MV in the studies.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: Yes: Prof. Dr. Thomas Bein, MD

[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.

Impact of sex on use of low tidal volume ventilation in invasively ventilated ICU patients - A mediation analysis using two observational cohorts

PONE-D-21-08610R1

Dear Dr. Swart,

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,

Aleksandar R. Zivkovic

Academic Editor

PLOS ONE