Neurological outcomes and predictive factors in traumatic spinal cord injury patients in the intensive care unit

Danqin Yuan; Yaling Jin; Lihui Chen; Min Tang; Jiuzhou Lin; Weiting Chen

doi:10.1371/journal.pone.0323433

Peer Review History

Original SubmissionFebruary 22, 2025
22 Feb 2025 Author Response https://doi.org/10.1371/journal.pone.0323433.r001
18 Mar 2025 Decision Letter - Osama Farouk, Editor PONE-D-25-08324Neurological Outcomes and Predictive Factors in Traumatic Spinal Cord Injury Patients in the Intensive Care UnitPLOS ONE Dear Dr. Chen, 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 May 02 2025 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. 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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. Please provide a complete Data Availability Statement in the submission form, ensuring you include all necessary access information or a reason for why you are unable to make your data freely accessible. If your research concerns only data provided within your submission, please write "All data are in the manuscript and/or supporting information files" as your Data Availability Statement. 3. Your ethics statement should only appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please delete it from any other section. [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: No 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: Yes 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: Thanks for the opportunity to review this manuscript. major comments: 1. Depending on the ASIA scale to determine neurological recovery is depatable, so the authors should mention in the abstract that they used this scale as a method of measurement of neurological improvement. 2. A limitation section should be written to address the following issues: 1: using ASIA scale as a measure of functional recovery. 2: the limited number of patients in the improvement group (39) compared to no improvement (236). 3: including patients with craniocerebral injury is a significant bias as the authors can include patients with TBI that should have impacts on functional recovery as well. 3. The authors mentioned using multivariate analysis, while the presented tables included only univariate and logistic regression analysis. I cannot trust the results based on univariate analysis in a heterogenous problem like SCI. The authors should perform multivariate analysis to adjust for age, gender, ASIA scale, and combined injuries to see the exact impact of blood pressure management and early surgery on neurological recovery. minor comments: 1. In Table 6, please revise the number of patients without improvement throughout all factors. The authors said in the first row that the number is 236 (non-improvement group), while for example, at early surgery and after adding patients with and without early surgery, the total is 238. Reviewer #2: I have reviewed this interesting manuscript and have the following questions and comments: The authors stated that “Data was accessed for research purposes between 12/4/2023 and 12/4/2025” putting in mind that we are still in march 2025!!?? Why were patient with grade E ASIA scale excluded from the study putting in mind the possibility of deterioration along the course of treatment? Why were some patient given high dose steroids and others given regular dose and how did this impact the results? ****** 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.0323433.r002
Revision 1
20 Mar 2025 Author Response Response to Reviewers Manuscript ID: PONE-D-25-08324 Title: Neurological Outcomes and Predictive Factors in Traumatic Spinal Cord Injury Patients in the Intensive Care Unit Dear Academic Editor and Reviewers, Thank you very much for your valuable comments and insightful suggestions on our manuscript. We have carefully revised our manuscript according to your feedback. Below, we provide point-by-point responses to each comment: Reviewer #1: Major comments: 1. Depending on the ASIA scale to determine neurological recovery is debatable. Authors should mention clearly in the abstract that they used this scale as a method of measurement of neurological improvement. Response: We appreciate your point regarding the debate surrounding the ASIA scale as a measure of neurological recovery. To clarify our methodology, we have revised the abstract to explicitly state that the ASIA scale was used to assess neurological improvement (see revised Abstract). Additionally, we have added a discussion of its strengths and limitations in the newly included Limitations section (see Discussion). 2. A limitation section should address these issues clearly: a. Using ASIA scale as a measure of functional recovery. b. The limited number of patients in the improvement group compared to the non-improvement group. c. Including patients with craniocerebral injury. Response: A clear limitation section has been added to address these points explicitly: "This study has several limitations: First, the ASIA scale, though commonly used, may not comprehensively reflect functional recovery. Second, the relatively small number of patients in the improvement group (n=39) compared to the non-improvement group (n=238) may affect statistical robustness. Third, The inclusion of patients with craniocerebral injuries as a potential source of bias, with an explanation that these patients were included to reflect real-world ICU populations, though we now discuss how traumatic brain injury (TBI) could confound functional outcomes." (Discussion, Limitations paragraph) 3. Authors mentioned using multivariate analysis, but the presented tables included only univariate and logistic regression analysis. Perform multivariate analysis adjusting for age, gender, ASIA scale, and combined injuries. Response: We have clarified our statistical methods and performed multivariate logistic regression analyses, clearly adjusting for age, gender, ISS, The level and severity of the injury, Steroid treatment, The use of mannitol, combined injuries and Surgical approach. The revised methods section states: "Univariate and multivariate logistic regression analyses were conducted to identify significant factors. Multivariate analyses adjusted for age, gender, ISS, The level and severity of the injury, Steroid treatment, The use of mannitol, combined injuries and Surgical approach were conducted to evaluate the impact on neurological recovery." (Methods section) Results from adjusted analyses have been updated in Table 7. Minor comments: 1. In Table 6, revise the number of patients without improvement (from 238 to 236). Response: The number of patients has been corrected from 236 to 238 in Table 6. This was a typographical error, and we appreciate your attention to detail. Reviewer #2: 1. Clarify the correct period for data access. Response: We have corrected the data access date to read: "Data was accessed for research purposes between December 4, 2023, and December 4, 2024." (Methods section) 2. Explain why ASIA Grade E patients were excluded. Response: We have clarified the exclusion reason: "Patients classified as ASIA grade E were excluded due to the lack of neurological deficits, with minimal risk of functional deterioration significant enough for inclusion in this study." However, we acknowledge your concern about potential deterioration. We have clarified this rationale in the Methods section and added a note in the Limitations section discussing the possibility of deterioration and its exclusion from our primary outcome. 3. Clarify why patients were given different steroid dosages and how this might impact results. Response: We clarified this issue in the discussion: "Patients received different steroid dosages based on clinical judgment, but no patient received high-dose steroid pulse therapy, and the specific impact of these dosing differences on neurological outcomes requires further investigation." (Discussion section) Additional Revisions per Journal Requirements: 1.PLOS ONE style requirements: We have reviewed and adjusted the manuscript to comply with PLOS ONE’s formatting guidelines, including file naming conventions. 2.Data Availability Statement: We have updated the submission form with the statement: “All data are in the manuscript and/or supporting information files,” as all relevant data are included in the submission. 3.Ethics statement placement: The ethics statement has been moved to the Methods section and removed from other sections as requested. Thank you again for your valuable feedback. We hope our revisions adequately address your concerns and look forward to your further evaluation. Sincerely, Weiting Chen, M.D. Corresponding author https://doi.org/10.1371/journal.pone.0323433.r003
15 Apr 2025 Decision Letter - Osama Farouk, Editor PONE-D-25-08324R1Neurological Outcomes and Predictive Factors in Traumatic Spinal Cord Injury Patients in the Intensive Care UnitPLOS ONE Dear Dr. Chen, 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 May 30 2025 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. 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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, Osama Farouk Academic Editor PLOS ONE Journal Requirements: Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. Additional Editor Comments (if provided): [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: (No Response) ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: (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: Yes Reviewer #2: Yes Reviewer #3: (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: Yes Reviewer #2: Yes Reviewer #3: (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: - Thanks for addressing the previous comments. Please consider also the following suggestions: 1. Add the effect size for your multivariate analysis so we can determine how much stronger that early surgery and blood pressure management can be to determine neurological recovery. 2. Can you adjust the title of Table 7 to clearly identify your adjustment? 3. For your limitation section, can you add references and elaborate more on the limitations of the ASIA scale? 4. Did you consider any questionnaire for autonomic recovery as well? It will be important to elaborate on this. 5. From your record, what is the shape of spinal fracture that was associated with the best neurological recovery, and what was the type of spinal fracture that was associated with the worst recovery? 6. Please clearly identify in the abstract that you used the ASIA scale as a measure of neurological recovery. Reviewer #2: (No Response) Reviewer #3: All looks well statistically. The revisions have been addressed and additions to the paper included, especially with the multivariate logistic addition. Some typos noticed and important: Authors abstract: Result section: 'Multivariate logistic regression analysis demonstrated that early targeted blood pressure management (MAP≥ 85mmHg) (OR=2.296, 95% CI: 1.036–5.086, P=0.040) and early surgery (≥24h) (OR=2.841, 95% CI: 1.088–7.419, P=0.033) were protective factors for neurological improvement.' Correction, ‘and early surgery (≥24h)’ should be,’ and early surgery (<= 24h).’ Also 'Treatment of TSCI and Status at Discharge' section , Correction, At very end two lines before the ‘Discussion’ section ‘and early surgery (≥24h)’ should be ‘and early surgery (<=24h’)'. Please check and edit any other typos in the paper. ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean? ). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy . Reviewer #1: No Reviewer #2: No Reviewer #3: No ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/ . PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org . Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0323433.r004
Revision 2
17 Apr 2025 Author Response Response to Reviewers Manuscript ID: PONE-D-25-08324R1 Title: Neurological Outcomes and Predictive Factors in Traumatic Spinal Cord Injury Patients in the Intensive Care Unit Dear Academic Editor and Reviewers, We sincerely appreciate the reviewers' positive feedback and the opportunity to further improve our manuscript. We have carefully addressed all the comments and suggestions as outlined below: Reviewer #1: 1.Add the effect size for your multivariate analysis so we can determine how much stronger that early surgery and blood pressure management can be to determine neurological recovery. Response: We have added effect size data in the Results section and in Table 7, including standard errors (SE) for each covariate. Specifically, we report the odds ratios (OR), 95% confidence intervals (CI), and SEs from the multivariate logistic regression model, which demonstrate the strength of association between early surgical intervention and targeted blood pressure management. These findings suggest that both early hemodynamic optimization and timely surgical intervention are independently associated with improved neurological recovery. For instance, early surgery (OR = 2.841, 95% CI: 1.088–7.419, SE = 0.490) and early blood pressure management (OR = 2.296, 95% CI: 1.036–5.086, SE = 0.406) were found to be significant predictors of favorable neurological outcomes. 2.Can you adjust the title of Table 7 to clearly identify your adjustment? Response: We have revised the title of Table 7 to: "Multivariate Logistic Regression Analysis of Postoperative Neurological Improvement in Traumatic SCI Patients (Adjusted for age, gender, ISS, injury level/severity, steroid use, mannitol use, combined injury, and surgical approach)." 3.For your limitation section, can you add references and elaborate more on the limitations of the ASIA scale? Response: We have expanded the Limitations section to include a more detailed discussion of the limitations of the ASIA scale and added relevant references to support these points. We also clarified in the Methods section that patients classified as ASIA grade E were excluded due to the lack of neurological deficits, with minimal risk of functional deterioration significant enough for inclusion. However, we acknowledge the concern that some of these patients could deteriorate, and this limitation has now been explicitly noted in the revised Limitations section. 4.Did you consider any questionnaire for autonomic recovery as well? It will be important to elaborate on this. Response: We acknowledge this important aspect. We have now added a sentence in the Discussion noting that autonomic recovery was not assessed using standardized questionnaires such as the Spinal Cord Independence Measure (SCIM) or the International Standards to document remaining Autonomic Function after Spinal Cord Injury (ISAFSCI) , which is a limitation of our study and should be addressed in future research. 5.From your record, what is the shape of spinal fracture that was associated with the best neurological recovery, and what was the type of spinal fracture that was associated with the worst recovery? Response: We appreciate the reviewer’s interest in the association between spinal fracture morphology and neurological recovery. However, our current dataset did not include sufficient detail on fracture shape classification to allow for a reliable analysis of fracture patterns and their correlation with outcomes. Therefore, we are unable to provide conclusive observations regarding which fracture types were associated with the best or worst neurological recovery. We have clarified this in the Discussion section and suggested it as an important area for future research, which we plan to investigate in subsequent studies with dedicated radiographic data collection and classification. We are particularly interested in exploring how specific fracture morphologies may influence spinal cord damage and recovery trajectories in different clinical scenarios. 6.Please clearly identify in the abstract that you used the ASIA scale as a measure of neurological recovery. Response: This has been clearly stated in the Methods portion of the Abstract: “Neurological recovery was assessed using the American Spinal Injury Association (ASIA) impairment scale.” Reviewer #2: (No additional comments provided.) Reviewer #3: 1.Abstract Result section: 'early surgery (≥24h)' should be corrected to 'early surgery (≤24h).' Response: Thank you for identifying this. We have corrected this typo in both the Abstract and the main Results section. 2.Also in the 'Treatment of TSCI and Status at Discharge' section, ‘early surgery (≥24h)’ should be ‘early surgery (≤24h).’ Response: This error has been corrected. 3.Please check and edit any other typos in the paper. Response: We have conducted a thorough proofreading of the entire manuscript and corrected typographical and grammatical errors to improve readability and precision. We appreciate the thoughtful and constructive feedback from the reviewers and editor. We believe that the revised manuscript has been significantly improved and hope it now meets the criteria for publication in PLOS ONE. Sincerely, Weiting Chen, M.D. Corresponding Author Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0323433.r005
8 May 2025 Decision Letter - Osama Farouk, Editor Neurological Outcomes and Predictive Factors in Traumatic Spinal Cord Injury Patients in the Intensive Care Unit PONE-D-25-08324R2 Dear Dr. Chen, 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 will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, 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, Osama Farouk 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 Reviewer #3: 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 Reviewer #3: (No Response) ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #3: (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: Yes Reviewer #3: (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: Yes Reviewer #3: (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: Thanks a lot for the opportunity to review this paper. The authors addressed my comments appropriately. Reviewer #3: (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 Reviewer #3: No ******** https://doi.org/10.1371/journal.pone.0323433.r006
Formally Accepted
Acceptance Letter - Osama Farouk, Editor PONE-D-25-08324R2 PLOS ONE Dear Dr. Chen, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset You will receive further instructions from the production team, including instructions on how to review your proof when it is ready. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few days to review your paper and let you know the next and final steps. Lastly, 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 customercare@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. Osama Farouk Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0323433.r007

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