Estimating the uncertain effect of the COVID pandemic on drug overdoses

Ali Moghtaderi; Mark S. Zocchi; Jesse M. Pines; Arvind Venkat; Bernard Black

doi:10.1371/journal.pone.0281227

Peer Review History

Original SubmissionJanuary 17, 2023
12 Mar 2023 Decision Letter - Vincenzo Alfano, Editor PONE-D-23-01497Estimating The Uncertain Effect of the COVID Pandemic on Drug OverdosesPLOS ONE Dear Dr. Moghtaderi, 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 address the comments of reviewer 2, with special attention to ecological fallacy and the composition of the sample. Please submit your revised manuscript by Apr 26 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. 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This will take you to the ORCID site and allow you to create a new iD or authenticate a pre-existing iD in Editorial Manager. Please see the following video for instructions on linking an ORCID iD to your Editorial Manager account: https://www.youtube.com/watch?v=_xcclfuvtxQ 5. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information. [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 ******** 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: No 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: This manuscript examined if increases in overdose deaths and ED visits were associated to the COVID-19 pandemic, increased synthetic-opioid use or both. The study takes into account pre-pandemic estimations to determine the effect of COVID-19 on Opioid overdose deaths and ED visits, which is novel and accurate comparing previous studies. Nonetheless, the manuscript needs clarity, as at times redundant and is not concise, which dilutes the findings. For example, there paragraphs: “Figure 1, Panel A, presents 12-month rolling average rates for all drug-related overdose deaths, synthetic-opioid-related deaths, and other overdose deaths, per 100,000 population”, but this type of information pertains to the figure, and results should be concise and state the statistical significance of what is added in the tables/figures, which is lacking in this section. Additionally, the authors tend to be speculative at times in their discussion, for example using words like (i.e. somewhat lower), but don't back up these statements (is it statistically significant?) Finally, there are moments where the authors state causality, but acknowledge that there could be other potential factors (such as the pandemic) that could be contributing to the predicted trends. With that said, the authors should avoid any causal jargon (even though the statistical model considers counterfactuals) and focus their study on the predictions found. Reviewer #2: The authors provide an in-depth and thorough review of the literature in their introduction that is relevant to their research question, and they provide adequate rationale for their study at hand. What was the definition of death or non-death opioid presentations. Was this data determined from diagnosis codes used for ED visits, was this a clnical diagnosis, post-mortem, utilizing confirmatory blood levels? May be worth specifying. Adequate explanation of limitations provided throughout, which is appreciated. I believe the author's conclusions to be sound, and not overstated. There are limitations to the data presented, as the author's suggest; however, they do not drive their conclusions too far. ****** 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 ******** [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.0281227.r001
Revision 1
27 Apr 2023 Author Response Dear Professor Alfano, Thank you for consideration of our paper, “Estimating The Uncertain Effect of the COVID Pandemic on Drug Overdoses.” We would like to thank the reviewers for their thoughtful comments. We believe our paper has substantially improved because of their comments. Below, we outline our responses to the comments. Please address the comments of reviewer 2, with special attention to ecological fallacy and the composition of the sample. Reply. We respond to the referees below. Ecological fallacy. Neither referee mentions an ecological fallacy issue, and we do not believe our study has this problem. This term is usually applies to situations where one infers individual-level characteristics from group results. We do not do this. Sample composition. We rely partly on CDC data and partly on data from US Acute Care Solutions. We reviewed what we said about each data source, and revised for clarity. For overdose deaths, the national data is complete. For national emergency department (ED) visit data, the CDC draws on EDs from 42 states that submit data to it. The sample should be reasonably representative of larger EDs, but we don’t want to claim that because the CDC does not disclose which EDs participate. For both of our sources for ED visit data (CDC and the ED staffing company), we added information about visit counts to the text. 2. In your Data Availability statement, you have not specified where the minimal data set underlying the results described in your manuscript can be found. PLOS defines a study's minimal data set as the underlying data used to reach the conclusions drawn in the manuscript and any additional data required to replicate the reported study findings in their entirety. All PLOS journals require that the minimal data set be made fully available. For more information about our data policy, please see http://journals.plos.org/plosone/s/data-availability. Reply. We now provide the data on drug overdose mortality and the national CDC data on non-fatal drug ED visits, as well as our codes in our resubmission package. We are not allowed to share the data from the national emergency staffing group based on the data use agreement in place. 5. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information. Reply. Done. 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 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: No 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: This manuscript examined if increases in overdose deaths and ED visits were associated to the COVID-19 pandemic, increased synthetic-opioid use or both. The study takes into account pre-pandemic estimations to determine the effect of COVID-19 on Opioid overdose deaths and ED visits, which is novel and accurate comparing previous studies. Nonetheless, the manuscript needs clarity, as at times redundant and is not concise, which dilutes the findings. Reply. We reread the manuscript, and tried to eliminate redundancy. For example, there paragraphs: “Figure 1, Panel A, presents 12-month rolling average rates for all drug-related overdose deaths, synthetic-opioid-related deaths, and other overdose deaths, per 100,000 population”, but this type of information pertains to the figure, and results should be concise and state the statistical significance of what is added in the tables/figures, which is lacking in this section. Reply. We added additional explanation to the text of the implications of this figure. This figure reports national totals as reported by the CDC; there are no associated confidence intervals. The CDC does not report them and we cannot compute them from the data that the CDC provides. We added an explanation to the limitations section that confidence intervals around the CDC-reported data are not available. Additionally, the authors tend to be speculative at times in their discussion, for example using words like (i.e. somewhat lower), but don't back up these statements (is it statistically significant?) Reply. We compare predicted deaths from our models (based on pre-pandemic trends) at different points in time, to actual mortality data from the CDC. The CDC data does not provide confidence intervals, so our models do not have them either. Thus, terms like “somewhat lower” are the best we can do, in describing how the prediction compares to the actual data. We tried to be clear that any comparison of actual to predicted mortality is speculative. Finally, there are moments where the authors state causality, but acknowledge that there could be other potential factors (such as the pandemic) that could be contributing to the predicted trends. With that said, the authors should avoid any causal jargon (even though the statistical model considers counterfactuals) and focus their study on the predictions found. Reply. We tried to avoid any causal claims. For example, the draft stated that “Our model is not causal. Thus, we can neither rule out nor rule in a causal effect of fentanyl access or the pandemic on overdose deaths.” We added a similar statement to the introduction, saying we do not have a control group and therefore cannot have a causal research design. We reviewed the draft and the words used and revised for clarity. We believe that readers will understand that we are not making causal claims. Reviewer #2: The authors provide an in-depth and thorough review of the literature in their introduction that is relevant to their research question, and they provide adequate rationale for their study at hand. What was the definition of death or non-death opioid presentations. Was this data determined from diagnosis codes used for ED visits, was this a clinical diagnosis, post-mortem, utilizing confirmatory blood levels? May be worth specifying. Reply. Deaths come from the CDC, which relies on the text fields included in death certificates. The National Center for Health Statistics, within the CDC, received these death certificates, and assigns ICD-10 codes for primary cause of death and secondary causes based on the text fields. How accurate the death certificates are, and what blood tests or other laboratory results they are based on, is not known, and may vary based on who fills out the death certificate and customary practice where the person died. We explain this in the revised draft. For ED visits, counts are based on diagnosis codes assigned by the clinician (usually an ED physician) at the time of the visit. We revised the draft to add details on this dataset. Adequate explanation of limitations provided throughout, which is appreciated. Reply. We added a limitation with regard to the accuracy of death certificates. I believe the author's conclusions to be sound, and not overstated. There are limitations to the data presented, as the author's suggest; however, they do not drive their conclusions too far. Attachments Attachment Submitted filename: Response to reviewers.docx https://doi.org/10.1371/journal.pone.0281227.r002
22 May 2023 Decision Letter - Vincenzo Alfano, Editor PONE-D-23-01497R1Estimating The Uncertain Effect of the COVID Pandemic on Drug OverdosesPLOS ONE Dear Dr. Moghtaderi, 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 Jul 06 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, Vincenzo Alfano 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: (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: 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 ****** 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 ****** 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: The authors addressed most of the requests from the first review, which is appreciated. But the manuscript is still too long and needs to be concise and clear. For example, the first five and a half pages are introduction (even though the authors tried to use different headings). This information can be summarized in half of the length and some of this information (for example evidence on overdose mortality) can be use in the discussion, which in comparison is short and should be the focus of the paper along the results (half the length). Same with the methodology. The authors describe the different analyses performed in pages 9-10, but then go into detail in the statistical analysis. This is repetitive. Results are showing the same issue, and it was not accounted from the previous review. For example: "Fig 1, Panel A, presents 12-month rolling average rates for all drug-related overdose deaths, synthetic-opioid-related deaths, and other overdose deaths, per 100,000 population, from 2015-2021". should be considered a footnote in the figure and not be in the main results. This just distract the reader from the main findings (which would be: ...rise during the pandemic period continues a trend toward rising synthetic opioid deaths that accelerated in mid-2019. In contrast, other overdose deaths were basically flat from mid-2019 on). ****** 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.0281227.r003
Revision 2
29 Jun 2023 Author Response 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: The authors addressed most of the requests from the first review, which is appreciated. But the manuscript is still too long and needs to be concise and clear. For example, the first five and a half pages are introduction (even though the authors tried to use different headings). This information can be summarized in half of the length and some of this information (for example evidence on overdose mortality) can be use in the discussion, which in comparison is short and should be the focus of the paper along the results (half the length). Reply. We moved the detailed description of the prior literature to the Appendix; the introduction is now substantially shorter. Same with the methodology. The authors describe the different analyses performed in pages 9-10, but then go into detail in the statistical analysis. This is repetitive. Reply. We combined these two sections. The new “Methods” section describes the databases we use first, then provides information about the outcomes we study, and finally describes the statistical analysis. Results are showing the same issue, and it was not accounted from the previous review. For example: "Fig 1, Panel A, presents 12-month rolling average rates for all drug-related overdose deaths, synthetic-opioid-related deaths, and other overdose deaths, per 100,000 population, from 2015-2021". should be considered a footnote in the figure and not be in the main results. This just distract the reader from the main findings (which would be: ...rise during the pandemic period continues a trend toward rising synthetic opioid deaths that accelerated in mid-2019. In contrast, other overdose deaths were basically flat from mid-2019 on). Reply. We revised and shortened this section. https://doi.org/10.1371/journal.pone.0281227.r004
17 Jul 2023 Decision Letter - Vincenzo Alfano, Editor Estimating The Uncertain Effect of the COVID Pandemic on Drug Overdoses PONE-D-23-01497R2 Dear Dr. Moghtaderi, 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, Vincenzo Alfano Academic Editor 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: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: 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 ****** 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: (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.0281227.r005
Formally Accepted
31 Jul 2023 Acceptance Letter - Vincenzo Alfano, Editor PONE-D-23-01497R2 Estimating The Uncertain Effect of the COVID Pandemic on Drug Overdoses Dear Dr. Moghtaderi: 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. Vincenzo Alfano Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0281227.r006

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