Peer Review History
Original SubmissionMarch 2, 2020 |
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PONE-D-20-06139 Dual versus single vessel normorthermic ex vivo perfusion of rat liver grafts using metamizole for vasodilatation. PLOS ONE Dear Prof. Dr. Sauer, 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. We would appreciate receiving your revised manuscript by May 14 2020 11:59PM. When you are 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. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols Please include the following items when submitting your revised manuscript:
Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out. We look forward to receiving your revised manuscript. Kind regards, Michael Bader 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 http://www.journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and http://www.journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf 2. Thank you for stating the following in your manuscript: "This work was funded by institutional financial support of the Charité – Universitätsmedizin Berlin, the German Research Foundation and by a Kickbox Seed Grant of the Einstein Center for Regenerative Therapies. Nathanael Raschzok is fellow of the BIH Charité Clinician Scientist Program funded by the Charité – Universitätsmedizin Berlin and the Berlin Institute of Health." 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." [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: Partly ********** 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: 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: 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: This study was performed in a rat model of ex vivo liver perfusion using dual versus single vessel perfusion. The authors evaluate these effects after the use of metamizole. Although the authors showed a relationship between the use of metamizole and the protection against the arterial vasospasm with is important because one of the main complications associated with liver transplantation is related to bile duct ischemia. Despite these, I sent my comments: The heterogeneous etiologies for liver transplantation and methodology were problematic. In this study, the time of cold ischemia and warm ischemia is very short. One of the main problems of this work is that it is barely reproducible since cannulating a rat's hepatic artery is technically demanding. I suggest placing an image in the article. During this study, the liver was flushed via the aorta and the portal vein with HTK solution supplemented with glycine. Given the variability of liver preservation solutions, will this finding be transversal to other preservation solutions? UW or Celsior? The underlying molecular mechanism was not well suggested in this study. What is the effect in the mitochondrial function, the principal cellular source of energy? For example, the content of ATP? How do you think it could be used in liver transplantation? Reviewer #2: This paper provides a novel technique at delivering metamizole through the hepatic artery during single or dual vessel ex vivo perfusion of the rat liver to improve perfusion outcomes. Those livers perfused with metamizole, whether through pressure control or hourly administration, appeared to have less ischemic injury as evidenced by greater urea production and lower AST and ALT levels as well as more physiologic pH values. My critique of this paper is that this medication appears to be banned in the United States for human use by the FDA. Therefore, I recommend a major revision of your conclusion portion of the manuscript. Namely, I caution you in your statement that "metamizole is a widely used drug in human medicine" as well as your notations qualifing its limited risks of agranulocytosis. The main limitation of this paper, while well designed, is that the drug used has limited clinical utility. Reviewer #3: In this study, the authors present a comparison between dual vessel vs. single vessel normothermic liver perfusion in a small animal model. The authors also focused on a known perfusion pressure issue associated with hepatic artery perfusion by introducing metamizole as an agent to mitigate arterial vasospasm. They hypothesized based on previous research, that since metamizole has been shown to decrease vasospasm in the rat femoral artery, that these findings may also decrease pressure related issues during hepatic artery perfusion. As a result, the authors conclude dual vessel liver perfusion to be superior to single vessel perfusion in the presence metamizole for use in arterial pressure control for perfusions that last 6 or more hours. This is a well-designed and rigorous study with one main exception: The work is persuasive for the use of metamizole improving arterial pressures during dual vessel perfusion in small animal models; however there appears need of significant data and likely another experimental group to back up the claims that dual vessel perfusion is superior to single vessel perfusion in this small animal model. There are also some questions regarding the methods employed in liver recovery and perfusion which may need clarifications or corrections. It is unclear as to how a definitive conclusion can be reached that dual vessel perfused livers perform better than single vessel perfusion. First, unless I am missing it there was no single vessel perfusion with metamizole group, which makes comparisons difficult. It would have been a better comparison if single vs dual perfusion groups compared without metamizole, as it would be an apples to apples comparison. Still, a question that rises is if metamizole would have had similar beneficial effects in single vessel perfusion, and if the results would then be comparable to dual+ metamizole group. In addition, oxygen consumption and oxygen saturation levels at inlet and effluent would be important to evaluate, since providing oxygen via both vessels is a key benefit of dual perfusion based on human liver perfusion literature. Supplemental data shows some lactate clearance, but it is unclear if the dialysis cartridge used removes lactate from the perfusate. Other indicators that come to mind are edema and ATP levels; another suggestion is to use some of the clinical perfusion viability criteria already used, such as the one published by Mergental et al to compare the viability of the perfused grafts. A more technical concern that could potentially influence the perfusion metrics and overall outcome was ligating the SHVC and cannulating the IVC. This can restrict the outflow of the perfusate and can increase the overall pressure within the liver. Research has shown that even partial occlusion of veins in the liver can lead to diffused hepatic congestion and enlargement (ie. sinusoidal thrombosis). This effect may have several different downstream consequences, all of which could alter the evaluation of the grafts. The results of the graft assessment given (pressure (both arterial and portal), histological analysis, biochemical markers ALT/AST), could be influenced by complications arising from the methodology of the experimental design itself. Have the authors considered such issues, and if so how did they avoid it affecting their results? The final technical concern is the flow rates that were used in this study. For dual vessel perfusion the flow was set to 1.1mL/min/g (paragraph 201-202) generating a flow of 1ml/min/g liver through the portal and 0.1 ml/min/g liver through the hepatic artery. These flow rates are very low, compared with other papers in literature which listed the arterial flow from 0.21 +/- 0.02 to 3.5 +/- 0.2 mL/min/g liver, and portal flow 1.53 +/- 0.19 to 32.1 +/- 1.6 mL/min/g liver. The flow rates stated in the manuscript are consistent with mouse liver perfusions. With such low flow rates, the concern is about the availability of oxygenated perfusate to the liver and if the flow rates were high enough to fully oxygenate the organ. Without data on the oxygen consumption and saturation values, it is not possible to ascertain if the organ was oxygenated sufficiently. Minor issues in the manuscript: 1. 1 mL Lactated Ringers that is supplemented with 500 IE Heparin is injected into the IVC. This concentration of Heparin in rats weighing between 280-350g will subsequently euthanize the rat exposing the liver to warm ischemic time (WIT). The portal and aorta are then cannulated and flushed after with 20 mL of 4C HTK, however the liver is still within the body cavity, and in the subjected to room temperature while the hepatic artery SHVC, right suprarenal vein, esophageal veins are ligated and the IVC is cannulated. Even though the WIT time is likely minimal, it should be clarified in the manuscript. 2. Average initial pressure was 5.65 mmHg. This pressure seems awfully high given that the temperature of the liver is close to 4C at the time of connection? This could cause damage to the endothelial layer within the vasculature of the liver and subsequently cause further complications during the length of perfusion. 3. There are various spelling and grammatical errors throughout the manuscript, which could use a thorough review by the authors. ********** 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: Corey Eymard 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 to be viewed.] 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 us at figures@plos.org. Please note that Supporting Information files do not need this step. |
Revision 1 |
PONE-D-20-06139R1 Dual versus single vessel normorthermic ex vivo perfusion of rat liver grafts using metamizole for vasodilatation. PLOS ONE Dear Dr. Sauer, 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 by reviewer 3, in particular please comment on edema. Please submit your revised manuscript by Jul 23 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:
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, Michael Bader Academic Editor PLOS ONE [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: All comments have been addressed 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: Yes Reviewer #2: Yes Reviewer #3: Yes ********** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: I Don't Know Reviewer #2: Yes 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: Yes 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: Yes 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: I was satisfied with the answers given by the authors that meet my questions. The placement of the figures values the work. Congratulations. Reviewer #2: (No Response) Reviewer #3: The authors did address some key comments that were raised in the original manuscript, and the detail provided in the responses is appreciated. I also appreciated the nuances observed in human vs rat comparisons. I have two minor comments: First, the question re. ATP from two reviewers was not addressed. I do appreciate that performing such analyses may require repeat of most if not all experiments which in my opinion is not necessary and would likely be unnecessary duplication that would not justify the use of research animals; one reason the Mergenthal criteria was recommended as an alternative to ATP is it can be evaluated practically. Since the authors have already done this in the revision, I would have recommended the authors to note this in their rebuttal so it does not appear like an ignored comment to the reviewers. My second comment would be if the authors could shed some light on if they noticed any difference in relation to edema (or lack thereof) between the groups? Noting that pressures in dNEVLP in the metamizole on-demand group were better, I would be interested to see if this correlates in the context of edema as well. Overall, I consider the manuscript is acceptable for publication with very minor revisions. ********** 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: Yes: Rui Miguel Martins 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. |
Revision 2 |
Dual versus single vessel normothermic ex vivo perfusion of rat liver grafts using metamizole for vasodilatation. PONE-D-20-06139R2 Dear Dr. Sauer, 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, Michael Bader Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: |
Formally Accepted |
PONE-D-20-06139R2 Dual versus single vessel normothermic ex vivo perfusion of rat liver grafts using metamizole for vasodilatation. Dear Dr. Sauer: 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 Prof. Michael Bader Academic Editor PLOS ONE |
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