PONE-D-20-10447

Lung-protective properties of expiratory flow-initiatedpressure-controlled inverse ratio ventilation:  A randomised controlled trial

PLOS ONE

Dear Dr. Hirabayashi,

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.

Specifically, the reviewers have raised overlapping concerns about the reporting of the statistical methodology and study design in the manuscript.

Please submit your revised manuscript by Sep 14 2020 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

We look forward to receiving your revised manuscript.

Kind regards,

Richard Hodge

Associate 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.During our internal evaluation, the in-house editorial staff noted that the clinical trial was registered at ClinicalTrials.gov

'It was approved by the Ethical Committee of Teikyo University School of Medicine, Tokyo, Japan on 12 September 2017 (No. 17-063) and was registered at ClinicalTrials.gov UMIN000029552' (line 82-84).

However, the trial registration provided in the manuscript is a UMIN Clinical Trials Registry number. At this time, we ask that you also provide the ClinicalTrias.gov trial registration number in your Methods section.

3. In the Methods section, please confirm that the study protocol provided in Supplementary Figure 1 is the original study protocol that was specifically submitted to and approved by the Ethical Committee of Teikyo University School of Medicine.

4. In your Methods section, please provide additional information about the participant recruitment method and the demographic details of your participants. Please ensure you have provided sufficient details to replicate the analyses such as: a) the recruitment date range (month and year).

5. Please provide a sample size and power calculation in the Methods, or discuss the reasons for not performing one before study initiation.

6.Thank you for stating the following financial disclosure:

 [The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.].

At this time, please address the following queries:

1. Please clarify the sources of funding (financial or material support) for your study. List the grants or organizations that supported your study, including funding received from your institution.
2. State what role the funders took in the study. If the funders had no role in your study, please state: “The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.”
3. If any authors received a salary from any of your funders, please state which authors and which funders.
4. If you did not receive any funding for this study, please state: “The authors 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.

[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: Partly

Reviewer #2: Yes

Reviewer #3: Partly

**********

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

Reviewer #1: I Don't Know

Reviewer #2: Yes

Reviewer #3: No

**********

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: No

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: It is thought that the results of previous studies suggesting that the serum cytokines selected in this study could was used as a surrogate marker for lung injury should be included in the introduction or discussion. In addition, I think it is necessary to consider why there were no differences of cytokines between the two groups although EF-initiated PC-IRV reduce dead space. The primary endpoint of this study was not change of respiratory mechanics but the change of serum cytokines.

Page 4, 91-93. Has the same surgeon performed surgery on all enrolled patients?

Page 6, 158-160. Please add references about the cytokines selected in this study.

Page 6, 172-175. Was there data regarding serum cytokine obtained from previous studies or preliminary study for calculating the sample size? Please describe the sample size calculation in more detail.

Page 6, 175-178. What are the criteria for using non-parametric and parametric methods differently depending on the type of variable? Did you perform a normality test?

Page 9, 231-233. In this study, correlation analysis was performed between IL-6 and the duration of surgery. Did your group conduct correlation analysis between cytokine and duration of the Trendelenburg position?

Page 10, 270-272. The meaning of the sentence regarding permissive hypercapnia is not clear. Can permissive hypercapnia in two patients observed only in VCV give special significance compared to PC-IRV?

Page 11, 280-282. Isn't the duration of the Trendelenburg position and pneumoperitoneum more meaningful than simply duration of surgery?

Page 11, 303-308. The meaning of this paragraph is unclear. It was noted that the peak inspiratory pressure was lower in the PCV group than that in the VCV in patients with laparoscopy and robot surgery. Why were there advantages in maintaining respiratory mechanics?

Reviewer #2: It is well written and well designed study

These are my suggestions

It would be better to give the ventilator strategy as a scheme in to the method part

It would be better to add VDshunt/VTE , ETCO2 , PaCO2-PetCO2 in results and table 2

Is PVC statement in line 306 actually PCV ?

Reviewer #3: A prospective two-arm randomized clinical trial was conducted to compare differences in serum cytokine levels in men undergoing robot-assisted laparoscopic radical prostatectomy. No significant differences in IL-6 levels at the end of surgery were observed between the two arms.

Minor revisions:

1- Line 91: Provide specific details on how the randomization list was generated. If randomized blocks were used, indicate the block size.

2- Line 172: Provide more complete details for the statistical power calculation. The power calculation should include: sample size, alpha level (indicating one or two-sided), minimal detectable difference and statistical testing method.

3- Line 175 states, “The Mann–Whitney U test was used to compare differences in the serum

cytokine levels between the two groups.” To clarify, was the Mann-Whitney U test used to compare differences only at the end of surgery?

4- Line 187: Clarify that the patients were randomized rather than simply divided.

5- Table 1: In the statistical analysis section, state the statistical methods used to compare patient and surgery characteristics shown in Table 1. If data is normally distributed, summarize the results using mean and standard deviation. If the data is not normally distributed provide the median, first and third quartiles. Use nonparametric tests (Mann-Whitney U-test) to compare groups when the distribution of the data is not normally distributed. Use parametric tests (t-tests) to compare groups with normally distributed data.

6- Table 2: Tests of the interaction of arm by time is more appropriate than repeatedly applying t-tests when comparing the data shown in Table 2.

7- Line 232: Clarify the rs notation. There appears to be a typographical error “rs=0,082”.

8- The p-value associated with a correlation is a test of the null hypothesis: correlation equal to zero; however, the absolute magnitude of the coefficient indicates the strength of the linear relationship between two variables. In general, the strength or correlation coefficient is the more important statistic to reflect upon.

Below is a table for interpreting correlation coefficients:

Coefficient (absolute value) Interpretation

0.90 - 1.0 Very Strong

0.70 - 0.89 Strong

0.40 - 0.69 Moderate

0.10 - 0.39 Weak

less than 0.10 Negligible correlation

9- Indicate if adverse events were collected according to a standardized method.

10- Add the correlation coefficients to Figures 2 and 3.

11- Indicate the funding source(s), and the role of the funder(s)?

12- All acronyms and abbreviations must be spelled out in first use.

**********

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: revision suggestions.docx

PONE-D-20-10447R1

Lung-protective properties of expiratory flow-initiated pressure-controlled inverse ratio ventilation:  A randomised controlled trial

PLOS ONE

Dear Dr. Hirabayashi,

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 Dec 03 2020 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

We look forward to receiving your revised manuscript.

Kind regards,

Steven Eric Wolf, MD

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

Editor - Thank you for resubmitting your paper. As promised, I sent it back to the original referees who are now almost completely satisfied save a few minor issues. Please carefully consider the comments below and reply directly to each in a cover letter with appropriate marked and linked changes to the manuscript. I look forward to receiving the next version which I will handle personally for timeliness.

If data is normally distributed, summarize using mean (SD) and compare using parametric methods, possibly t-tests. However, if data is non-parametic summarize using median (first and third quartiles) and compare using non-parametic method such as Mann Whitney U tests.

[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 #2: All comments have been addressed

Reviewer #3: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: (No Response)

Reviewer #2: Yes

Reviewer #3: Yes

**********

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

Reviewer #1: (No Response)

Reviewer #2: N/A

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: (No Response)

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: (No Response)

Reviewer #2: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

Reviewer #2: (No Response)

Reviewer #3: If data is normally distributed, summarize using mean (SD) and compare using parametric methods, possibly t-tests. However, if data is nonparametic summarize using median (first and third quartiles) and compare using nonparametic method such as Mann Whitney U tests.

**********

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

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

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

Reviewer #1: No

Reviewer #2: 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.

Lung-protective properties of expiratory flow-initiated pressure-controlled inverse ratio ventilation:  A randomised controlled trial

PONE-D-20-10447R2

Dear Dr. Hirabayashi,

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,

Steven Eric Wolf, MD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments: