PONE-D-21-02242

Applicability and safety of discontinuous ADVanced Organ Support (ADVOS) in the treatment of patients with acute liver failure (ACLF) outside of intensive care.

PLOS ONE

Dear Dr. Julia Weinmann-Menke,

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.

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We look forward to receiving your revised manuscript.

Kind regards,

Tatsuo Kanda, M.D., Ph.D.

Academic Editor

PLOS ONE

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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

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

Reviewer #1: Yes

Reviewer #2: Yes

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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

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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

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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: Authors concluded discontinuous ADVOS treatment outperformed hemodialysis in reducing protein-bound metabolites. The data of the article is attractive. However, authors need to be more careful not to mislead. Revisions required are as follows:

Major revisions

#1: There is no significant difference between 28-days survival in ADVOS treated cohort and HD treated cohort. Avoid misleading expressions and keep the content that it was possible to indicate non-inferiority.

#2: Concerning 44% (IQR 30; 85), is 28-days ‘survival’ correct or 28-days ‘mortality’ correct? The description in the text and the description in the table do not match.

#3: It would be better if there is a comparison between predicted 28-days survival in the ADVOS treated cohort and HD treated cohort.

Minor revisions

#1: In Abstract, in line 19, the correct one is ‘‘stronger’’, not ‘‘stringer’’.

#2: In Results, in line 2, the correct one is ‘‘65.3%’’, not ‘‘53.5%’’.

#3: Concerning main etiology of cirrhosis in three patients, is ‘a mixed etiology (HBV, alcohol or NASH)’ correct or ‘viral hepatitis (HBV, HCV)’ correct? The description in the text and the description in the table do not match.

#4: In Results, in line 8, what is ‘hydropy’?

#5: In Results, in line 12, and In Table 2 and In Supplementary table 3, the correct one is ‘‘prothrombin time-INR’’, not ‘‘INR’’.

Reviewer #2: To evaluate the effect of ADVOS as discontinuous treatment for patients with ACLF outside intensive care unit, Leonard Kaps et al. conducted retrospective study including 26 patients with ACLF and HRS-AKI. Comparing with hemodialysis performed in a matched cohort, ADVOS achieved a stringer decrease in bilirubin (p=0.01), while detoxification of watersoluble catabolites’ including creatinine and BUN was comparable.

They concluded that discontinuous ADVOS treatment was safe and effective in patients with ACLF outside intensive care and outperformed hemodialysis in reducing protein-bound metabolites.

This is an interesting and valuable paper reporting on the effect of discontinuous ADVOS treatment for patients with ACLF and HRS-AKI. Although the paper is well written and clearly presented, the authors should reconsider the following issues.

Major comments:

1. The authors described in the summary that ‘The 28-days survival rate in the ADVOS group was 56% (14/26) exceeding the expected survival time according to 12% (predicted median 28-days survival was 44%, IQR 30; 85)’ and in the conclusion section ‘we found a trend that ADVOS carries a survival advantage in patients with ACLF.’

These sentences seem to be sophistical argument. Predicted 28-days survival was calculated in each patient by the CLIF-C ACLF calculator. It should not be described that the 28-days survival rate in the ADVOS group exceeded the expected value by 12%.

The effect of ADVOS on the 28-days survival of patients with ACLF should be assessed statistically according to the result of case control study: 56% (14 of 25) in the ADVOS group vs 40% (10 of 25) in the HD group. Log-rank test is also able to be used for survival analysis.

2. In Table 2, the data of ACLF grade should be shown in numbers of patients belonging to each grade: grade 1, 2, 3, instead of median and IQR.

3. Long-term outcome of 26 patients with ACLF was not disclosed. It should be shown whether any patient received liver transplantation or not.

4. Urine volume could be assessed before and after treatment with ADVOS and with HD.

5. The title should be corrected partially: patients with acute liver failure (ACLF)⇒patients with acute-on-chronic liver failure (ACLF).

6. The authors should ensure that tables are the best format to present their data.

7. The description of matching criteria 1 in Table 4 is insufficient. How many patients were male?

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Reviewer #1: Yes: Hidehiro Kamezaki

Reviewer #2: Yes: Nobuaki Nakayama

[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.]

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PONE-D-21-02242R1

Applicability and safety of discontinuous ADVanced Organ Support (ADVOS) in the treatment of patients with acute liver failure (ACLF) outside of intensive care.

PLOS ONE

Dear Dr. Julia Weinmann-Menke,

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 Apr 22 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

We look forward to receiving your revised manuscript.

Kind regards,

Tatsuo Kanda, M.D., 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.

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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: All comments have been addressed

Reviewer #2: All comments have been addressed

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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 #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: 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: Yes

Reviewer #2: 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 #2: 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: Leonard Kaps et al. revised their manuscript carefully and adequately.

They disclosed that only one patient in the ADVOS cohort received liver transplantation and created supplementary figure1.

They should describe whether a liver-transplanted patient was censored at the time of transplantation in the long-term survival analysis or not (Log-rank test, supplementary figure 1, p=0.08).

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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: Hidehiro Kamezaki

Reviewer #2: Yes: NOBUAKI NAKAYAMA

[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.

Applicability and safety of discontinuous ADVanced Organ Support (ADVOS) in the treatment of patients with acute-on-chronic liver failure (ACLF) outside of intensive care.

PONE-D-21-02242R2

Dear Dr. Julia Weinmann-Menke,

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.

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Kind regards,

Tatsuo Kanda, M.D., Ph.D.

Academic Editor

PLOS ONE

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