Regadenoson for the treatment of COVID-19: A five case clinical series and mouse studies

Joseph Rabin; Yunge Zhao; Ezzat Mostafa; Manal Al-Suqi; Emily Fleischmann; Mark R. Conaway; Barbara J. Mann; Preeti Chhabra; Kenneth L. Brayman; Alexander Krupnick; Joel Linden; Christine L. Lau

doi:10.1371/journal.pone.0288920

Peer Review History

Original SubmissionJune 24, 2022
14 Nov 2022 Decision Letter - Maria Elisabeth Johanna Zalm, Editor 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-22-17321Regadenoson for the treatment of COVID-19: a five case clinical series and mouse studiesPLOS ONE Dear Dr. Lau, 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. Your manuscript has been assessed by two peer-reviewers and their reports are appended below. The reviewers comment that the manuscript could be strengthened with additional detail and clarifications. One of the reviewers comments that the manuscript may present incorrect information regarding the delivery of adenosine by V infusion. The statistical referee has commented on the statistical analysis reported, and indicates that the statistical limitations of the study should be discussed further in the discussions section. Could you please carefully revise the manuscript to address all comments raised? Please submit your revised manuscript by Dec 28 2022 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: https://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, Maria Elisabeth Johanna Zalm, Ph.D Editorial Office 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 stating the following in the Acknowledgments Section of your manuscript: "We are grateful to Dr. Xiaoxuan Fan in the Flow Cytometry Core Laboratory (University of Maryland, Baltimore) for assistance with Flow Cytometry and Dr. Lisa Hester in the Cytokine Core Laboratory at UMB. This study was supported by NIH R01HL128492-05S1, the Manning Fund for COVID-19 Research, MC10, and Astellas Pharma US, Inc., ISR005923. Patent pending for this manuscript." 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: "This study was supported by NIH R01HL128492-05S1 (CLL), the Manning Fund for COVID-19 Research, MC10 (JL), and Astellas Pharma US, Inc., ISR005923 (CLL & JL). The sponsors or funders play NO role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript" 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: Yes Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: 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: No Reviewer #2: 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 ****** 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: Well written manuscript, however I feel the focus is much on outcomes of more interest in the larger trial as opposed to the safety focus that this manuscript should focus on. Here are some comments: Why are the primary and secondary endpoints of the randomized trial included as primary and secondary in this study of the five non-randomized patients treated with focus on the safety, tolerability and toxicity? Regarding the statistical analyses of the continuous outcomes, they should in the larger trial account for the baseline value i.e. include the baseline value as a covariate. Change scores, normalization etc. does not appropriately adjust for baseline values as including it as a covariate does (much has been written about this in the literature). In merely 5 individuals there are not that many degrees of freedom to play with hence the results can be left as is. However, many of the results can simply be regression towards the mean e.g. if you have a high baseline value you will most likely have a lower value at the next measure and this should somehow be mentioned under limitations. Please write under limitations that there is a risk of spurious results due to the number of statistical tests (it could somehow be combined with my previous comment) The two way anova under figure 2 is not mentioned under methods Reviewer #2: Overall this is an interesting paper describing the beneficial effects of a single infusion of Regadenoson, an A2A adenosine receptor agonist, on patients with COVID and murine data which further confirms the beneficial effects of this infusion. Moreover, the authors report that the principal antiinflammatory effects of regadenoson in this setting is mediated via inhibition of NKT cells. Overall, the clinical data remain quite preliminary and little can be said regarding efficacy of treatment in patients although the murine data is suggestive and prior clinical data using adenosine, a non-selective agonist, provides some evidence of efficacy in patients with COVID. There is one issue that should be corrected. The authors repeatedly note that adenosine cannot be given by IV infusion because of its effects on the heart (via A1 receptor stimulation). Adenosine is currently on the market for use as an infusion agent for pharmacologic stress testing so all of the references to A1 inhibitors and the contraindications to use of IV adenosine, etc should be eliminated. ****** 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: Bruce N. Cronstein, 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. https://doi.org/10.1371/journal.pone.0288920.r001
Revision 1
10 Jan 2023 Author Response Editor Requirements: 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'. Response: We have included all three required items and named them as “ Response to Reviewers”, “Revised Manuscript with Track Changes”, and “Manuscript”. 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 Response: The revised files have been named to conform with journal requires. We have revised formatting of the main text , title and author affiliations. 2. Thank you for stating the following in the Acknowledgments Section of your manuscript: "We are grateful to Dr. Xiaoxuan Fan in the Flow Cytometry Core Laboratory (University of Maryland, Baltimore) for assistance with Flow Cytometry and Dr. Lisa Hester in the Cytokine Core Laboratory at UMB. This study was supported by NIH R01HL128492-05S1, the Manning Fund for COVID-19 Research, MC10, and Astellas Pharma US, Inc., ISR005923. Patent pending for this manuscript." 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: "This study was supported by NIH R01HL128492-05S1 (CLL), the Manning Fund for COVID-19 Research, MC10 (JL), and Astellas Pharma US, Inc., ISR005923 (CLL & JL). The sponsors or funders play NO role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript" Please include your amended statements within your cover letter; we will change the online submission form on your behalf Response: We have removed the funding information from the Acknowledgments and corrected the funding statement. Reviewer #1: Well written manuscript, however I feel the focus is much on outcomes of more interest in the larger trial as opposed to the safety focus that this manuscript should focus on. Here are some comments: 1. Why are the primary and secondary endpoints of the randomized trial included as primary and secondary in this study of the five non-randomized patients treated with focus on the safety, tolerability and toxicity? Response: Thank you for pointing out that the original manuscript lacked clarity on this point. We state in the revision that only five non-randomized patients are included in this report. In the revised manuscript we note that this five case report and mouse study provide evidence of Regadenoson safety and anti-inflammatory efficacy, although a definitive trial has yet to be completed. 2. Regarding the statistical analyses of the continuous outcomes, they should in the larger trial account for the baseline value i.e. include the baseline value as a covariate. Change scores, normalization etc. does not appropriately adjust for baseline values as including it as a covariate does (much has been written about this in the literature). In merely 5 individuals there are not that many degrees of freedom to play with hence the results can be left as is. However, many of the results can simply be regression towards the mean e.g. if you have a high baseline value you will most likely have a lower value at the next measure and this should somehow be mentioned under limitations. Response: Thank you for raising this important point. We have added a comment in the discussion section (Lines 537-548). This human study did not include untreated patient controls or have sufficient power to determine if RA reduced mortality or length of stay in the hospital, but we did observe promising effects within 24 hours of RA treatment: subjective improvement in all subjects; increased SpO2; a trend toward lower CRP levels; rapidly reduced expression of CD69 on circulating iNKT cells; and a gradual reduction in circulating levels of 11 of 13 pro-inflammatory cytokines. The results are not adjusted for multiple statistical tests and some of the observed reductions in cytokine levels might be explained by regression to the mean. A larger placebo-controlled clinical trial is needed to confirm these findings, but they do suggest that RA will be effective for rapidly reducing cytokine production in inflamed COVID-19 patients. As an aside, we ran the repeated measures models using the baseline value as a covariate and estimated the mean changes from baseline at 30minutes, 4 hours and 24 hours at the average of the baseline values. The results from these analyses were nearly identical to those found from the change point models presented in the paper. Change scores Baseline as covariate Change from baseline SE Change from baseline* SE IL-6 30m 0.178 0.344 0.176 0.311 4.5h 0.204 0.344 0.203 0.311 24h 0.422 0.344 0.421 0.311 MCP-1 30m 0.087 0.077 0.087 0.081 4.5h 0.099 0.077 0.099 0.081 24h 0.278 0.077 0.278 0.081 IL-8 30m -0.126 0.211 -0.125 0.643 4.5h -0.026 0.211 -0.025 0.643 24h -0.022 0.211 -0.021 0.643 IL12p40 30m -0.074 0.123 0.176 0.311 4.5h -0.214 0.123 0.203 0.311 24h -0.279 0.123 0.421 0.311 IL-7 30m -0.034 0.248 -0.034 0.261 4.5h -0.249 0.248 -0.249 0.261 24h -0.222 0.248 -0.222 0.261 IP-10 30m 0.084 0.126 0.084 0.121 4.5h -0.275 0.126 -0.275 0.121 24h -0.268 0.126 -0.268 0.121 IFN-g 30m -0.070 0.183 -0.070 0.175 4.5h -0.313 0.183 -0.313 0.175 24h -0.102 0.183 -0.103 0.175 MIP-1A 30m -0.108 0.409 -0.108 0.447 4.5h -0.356 0.409 -0.356 0.447 24h -0.647 0.409 -0.647 0.447 IL12p70 30m -0.047 0.158 -0.047 0.163 4.5h -0.358 0.158 -0.358 0.163 24h -0.271 0.158 -0.271 0.163 IL-17 30m 0.285 0.401 0.285 0.369 4.5h -0.511 0.401 -0.511 0.369 24h -0.723 0.401 -0.723 0.369 IL-1B 30m 0.017 0.366 0.016 0.353 4.5h -0.685 0.366 -0.686 0.353 24h -0.708 0.366 -0.709 0.353 IL-2 30m 0.035 0.432 -0.028 0.345 4.5h -0.750 0.386 -0.752 0.308 24h -0.795 0.386 -0.796 0.308 TNF-a 30m 0.049 0.355 0.049 0.365 4.5h -0.754 0.355 -0.753 0.365 24h -0.790 0.355 -0.790 0.365 *computed at the average value for the baseline. 3. Please write under limitations that there is a risk of spurious results due to the number of statistical tests Response: We have added discussion regarding the risk of spurious results in the limitation section (lines 543-546) of the revised manuscript. 4. The two way anova under figure 2 is not mentioned under methods. Response: Thank you. The two way anova under figure 2 was added to the Methods section (lines 248). Reviewer #2: Overall this is an interesting paper describing the beneficial effects of a single infusion of Regadenoson, an A2A adenosine receptor agonist, on patients with COVID and murine data which further confirms the beneficial effects of this infusion. Moreover, the authors report that the principal antiinflammatory effects of regadenoson in this setting is mediated via inhibition of NKT cells. Overall, the clinical data remain quite preliminary and little can be said regarding efficacy of treatment in patients although the murine data is suggestive and prior clinical data using adenosine, a non-selective agonist, provides some evidence of efficacy in patients with COVID. There is one issue that should be corrected. The authors repeatedly note that adenosine cannot be given by IV infusion because of its effects on the heart (via A1 receptor stimulation). Adenosine is currently on the market for use as an infusion agent for pharmacologic stress testing so all of the references to A1 inhibitors and the contraindications to use of IV adenosine, etc should be eliminated. Response: The reviewer is absolutely correct. We should have remembered Paracelsus of Ferrara who is famously credited with coining the phrase “the dose makes the poison”. As Paracelsus would have predicted the cardiovascular effects of adenosine are dose-dependent. In the revised manuscript we have revised our comment about adenosine simply to state that absence of any cardiovascular response to inhaled adenosine suggests that little accumulates in blood after inhalation, which is consistent with rapid uptake and metabolism into blood cells and ECs. We have removed the contraindications to use of IV adenosine in the revised manuscript. https://doi.org/10.1371/journal.pone.0288920.r002
10 May 2023 Decision Letter - Emily Chenette, Editor PONE-D-22-17321R1Regadenoson for the treatment of COVID-19: a five case clinical series and mouse studiesPLOS ONE Dear Dr. Lau, Thank you for submitting your manuscript to PLOS ONE. I sincerely apologise for the unusually delayed review timeframe. Your revised manuscript was reviewed by one of the original reviewers, whose comments are appended below. The reviewer commented that their previous concerns were addressed but raised one minor point of concern that must be clarified before we can proceed. 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 Jun 24 2023 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: https://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, Emily Chenette Editor in Chief 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.] 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) ******** 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 ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: I Don't Know ****** 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 ****** 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 ****** 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: All my comments have been adressed but regarding my question and your answer "The two way anova under figure 2 is not mentioned under methods. Response: Thank you. The two way anova under figure 2 was added to the Methods section (lines 248)." A two way anova anlysis is not appropriate since it does not handle the repeated measures over time. Please double check which analysis that was performed or do a correct one. We can clearly see that there will be no effect on blood pressure but still the method for the statistical comparison should be correct. ****** 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 ******** [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.0288920.r003
Revision 2
15 Jun 2023 Author Response Editor Q1: Is the manuscript now acceptable for publication? Reviewer: no response Author response: Please see response to Comment 3. Editor Q2: Is the manuscript technically sound, and do the data support the conclusions? Reviewer: yes Author response: We appreciate that the reviewer found that the experiments had been conducted rigorously. Editor Q3: Has the statistical analysis been performed appropriately and rigorously? Reviewer: I Don't Know. Author response: We have elaborated on statistical methods used in the figure legends. Editor Q4: Have the authors made all data underlying the findings in their manuscript fully available? Reviewer: No Author response: To comply with then PLOS ONE data policy that requires authors to make all data underlying the findings described in their manuscript fully available, we have now added supplemental data tables including all of the data used for the figures. Editor Q5: Is the manuscript presented in an intelligible fashion and written in standard English? Reviewer: yes Reviewer Q6: All my comments have been addressed but regarding my question and your answer "The two-way ANOVA under figure 2 is not mentioned under methods. A two-way ANOVA analysis is not appropriate since it does not handle the repeated measures over time. Please double check which analysis that was performed or do a correct one. We can clearly see that there will be no effect on blood pressure but still the method for the statistical comparison should be correct. Author response: Thank you very much. Our statistician has reviewed and changed to repeated measures applied to changes from baseline. We have updated the manuscript appropriately with statistical explanations. Attachments Attachment Submitted filename: PLOS Response to Reviewers Lau June 2023.docx https://doi.org/10.1371/journal.pone.0288920.r004
7 Jul 2023 Decision Letter - Emily Chenette, Editor Regadenoson for the treatment of COVID-19: a five case clinical series and mouse studies PONE-D-22-17321R2 Dear Dr. Lau, 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. Again, I apologise for the unusually delayed review timeframe for this manuscript. I sincerely appreciate that you and your co-authors chose PLOS ONE as the venue for this study. Kind regards, Emily Chenette Editor in Chief PLOS ONE Additional Editor Comments (optional): 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 ******** 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) ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: (No Response) ****** 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) ****** 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) ****** 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) ****** 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 ******** https://doi.org/10.1371/journal.pone.0288920.r005
Formally Accepted
4 Aug 2023 Acceptance Letter - Emily Chenette, Editor PONE-D-22-17321R2 Regadenoson for the treatment of COVID-19: a five case clinical series and mouse studies Dear Dr. Lau: 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 Dr Emily Chenette Staff Editor PLOS ONE https://doi.org/10.1371/journal.pone.0288920.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 .