The efficacy of preoperative evolocumab-rosuvastatin combination therapy in patients with ST-elevation myocardial infarction

Hongxu Li; Huawei Dong; Shilin Bao; Xuemei Wang; Zuolin Fu

doi:10.1371/journal.pone.0339501

Peer Review History

Original SubmissionJune 29, 2025
29 Jul 2025 Decision Letter - Hean Teik Ong, Editor Dear Dr. fu, Please submit your revised manuscript by Sep 12 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. 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'. 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Please amend your manuscript to include your abstract after the title page. 5. Please include a caption for figure 1. 6. If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise. Additional Editor Comments: Please make major revision to the article to address reviewer comments. [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? 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 Reviewer #1: Yes Reviewer #2: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: Yes Reviewer #2: Yes ****** Reviewer #1: Was a baseline LDL cholesterol level available before treatment of statin and evolocumab was initiated? Even though there is a difference in LDL after treatment, whether it could be accounted for by differences in baseline LDL cholesterol level. Was other markers of cardiac injury like CK/CKMB measured and were they different between the groups. IL 6 is not easily measured - was CRP measured and if so, was there any difference between groups. A possible reason for the results to be less significant is because only 1 dose of evolocumab was given. If this was continued, then the LDL lowering effect should still be significant and this could translate into better outcomes for the treatment arm. Any explanation why only 1 dose was given. Reviewer #2: Interesting paper. Some issues should be added Abstract: probably for a misprint problem shoild be totally rewritten methods: primary end point is the end point on which sample size calculatio is performed. Please check methods/reults: more details about assessment of angina should be stated. discussion: recently bempedoic acid has shown some potentiality. Please quote on PMID: 38017541 and discuss also the potential itneraction of this treatment. ****** 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? 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Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0339501.r001
Revision 1
28 Aug 2025 Author Response PONE-D-25-32807 The efficacy of preoperative evolocumab-rosuvastatin combination therapy in patients with ST-elevation myocardial infarction Dear Editor and Reviewers, We sincerely appreciate the time and effort dedicated to reviewing our manuscript and providing constructive feedback. We have carefully addressed each comment to improve the quality and clarity of our work. Below, we provide a point-by-point response to the editor reviewers’ comments, with corresponding revisions highlighted in the revised manuscript (tracked changes file). Response to Editor : 1.deposit laboratory protocols in protocols.io: It's a good suggestion to deposit laboratory protocols in protocols.we have deposited our laboratory protocols in protocols.io to enhance the reproducibility of results. DOI: dx.doi.org/10.17504/protocols.io.n2bvje6mwgk5/v1 (Private link for reviewers:https://www.protocols.io/private/107F70C8702E11F08A690A58A9FEAC02 to be removed before publication.) 2.meets PLOS ONE's style requirements� We have tried to ensure that our manuscripts meet PLOS ONE's style requirements, including document naming requirements and modified accordingly. However, due to our limited ability, please assist in correcting any inadequacies, thank you again for your efforts. 3.data will be submitted to a repository: Thanks for the reminder, We have now uploaded our complete minimal dataset to Figshare, a PLOS-approved repository: · Repository: Figshare · DOI: 10.6084/m9.figshare.29986402 4.Clinical Trial registered and provide the complete date range for participant recruitment and follow-up We have stated the name of the registry and the registration number in the submission data and on the title page of the manuscript and the reasons for not registering this study before enrolment of participants started in the Methods section. we confirm that all related trials are registered by stating: The authors confirm that all ongoing and related trials for this drug/intervention are registered. The trial was registered at the Chinese Clinical Trial Registry (ChiCTR2500099498). This trial was not pre-registered due to initial failure to fully recognize the importance of early registration and lack of familiarity with the registration process. However, a retrospective registration was conducted at the Chinese Clinical Trials Registry (ChiCTR2500099498) before data was analysised, and all data were ensured complete, transparent, and non-selective reporting.The authors confirm that all ongoing and related trials for this drug/intervention are registered. We have provided the complete date range for participant recruitment and follow-up in the methods section. The dates of start and end of the recruitment period for this study are July 23, 2023 and April 22, 2024, respectively. The last follow-up date was October 26, 2024. 5.amend manuscript to include your abstract after the title page� Thank you for the reminder, we have done as you reminded. 6.include a caption for figure 1� Thank you for your suggestion, we have added a caption for figure 1. Flow of participants through each stage of the randomized trial. The diagram adheres to the CONSORT 2010 statement.A total of 112 acute ST-elevation myocardial infarction (STEMI) patients were screened between July 2023 and April 2024 at Liaocheng People's Hospital. After exclusions (n=32), 80 patients were randomized to intervention (n=40) or control (n=40). All participants completed the 6-month follow-up and were included in the intention-to-treat�ITT� analysis. Ethical approval: Institutional Ethics Committee of Liaocheng People's Hospital (LCSY-2023009). Trial registration: Chinese Clinical Trial Registry (ChiCTR2500099498). 7.the reviewer comments include a recommendation to cite specific previously published works,� We have reviewed and evaluated the publication and determine that it is partly relevant and should be cited. “Recent trials with bempedoic acid (13) have demonstrated additional LDL-C lowering options for statin-intolerant patients. While our study focused on PCSK9 inhibition, the potential synergistic effects of combining bempedoic acid with evolocumab warrants investigation, particularly given their complementary mechanisms targeting cholesterol biosynthesis and clearance respectively. Future studies should explore whether triple therapy (statin+bempedoic acid+PCSK9 inhibitor) could provide incremental benefits in acute coronary syndromes." Response to Reviewer 1: 1.Baseline LDL Cholesterol Levels: Thank you for raising this important point. Due to the acute onset of acute myocardial infarction, the patient's diet was uncertain at the time of visit, and the emergency examination items in our hospital did not include LDL cholesterol, and LDL-C testing was not performed before starting statin and elolumab treatment. Considering that the grouping was randomized and there was no significant difference in basic data between the two groups, it is speculated that there may be no significant difference in baseline LDL-C between the two groups, and the difference in LDL-C after treatment is mainly related to treatment. Of course, if there is baseline data, it may be more illustrative, and we will take this into account in future studies. 2. Markers of Cardiac Injury (CK/CKMB) and Inflammation We agree that additional biomarkers could provide further insights. TNI instead of CK and CK-MB levels was measured during the study, and no significant differences were observed between the groups�CRP was also assessed as a more accessible inflammatory marker, and no significant differences were observed between the groups (data now included in Table 6). Table6: CRPand TNI Changes on Day 1 control group treatment group z p CRP(mg/L) 7.52�3.24�20.10� 10.14�3.01�17.69� -0.178 0.859 TNI(ng/ml) 8.00(4.70�14.00) 7.55(3.03�14.25) -0.236 0.814 3. Single-Dose Evolocumab and Treatment Duration: Thanks for the suggestion. A possible reason for the results to be less significant is because only 1 dose of evolocumab was given. If this was continued, then the LDL lowering effect should still be significant and this could translate into better outcomes for the treatment arm. This has been confirmed by the FORIER study which supports sustained treatment. On the basis of guideline-guided drug therapy, elolumab combined with statin intensive lipid-lowering and anti-inflammatory therapy was applied before emergency PCI to observe the efficacy of a single dose. This is the novelty of this study. Response to Reviewer 2: 1. Abstract Misprint: We apologize for the typographical errors in the abstract. We have completely rewritten the abstract to eliminate any potential misprints and improve clarity. The revised version now follows a structured format with clear Background/Methods/Results/Conclusions sections, includes all key numerical findings with precise P-values, and maintains balanced interpretation of results. The clinical trial registration number has been prominently displayed. 2. Primary Endpoint Clarification: Thank you for this important methodological observation. We confirm that the primary endpoint (6-month MACE) was indeed the basis for our sample size calculation, as stated in the Methods section (2.5 Statistical Analysis). We have now added explicit confirmation: "Sample size was calculated based on the primary endpoint of 6-month MACE incidence, assuming 80% power to detect a 25% absolute reduction between groups (α=0.05, two-sided). 3. Angina Assessment Details: Additional details on angina assessment (e.g., CCS classification, symptom diaries) have been included in the Methods and Results sections to improve transparency. We have expanded both Methods and Results sections regarding angina assessment: - Methods (2.4 Outcome Measures): Added "Angina was assessed according to CCS classification criteria through scheduled clinic visits and documented using standardized case report forms." - Results (3.2.4): Added "All reported angina episodes were physician-adjudicated and required typical symptoms of ischemia with or without objective evidence of ischemia (ECG changes or imaging evidence 4. Bempedoic Acid and Novel Therapies: We appreciate this valuable suggestion and have substantially expanded the Discussion section to incorporate recent evidence on bempedoic acid: - Added new paragraph: "Recent trials with bempedoic acid (PMID: 38017541) have demonstrated additional LDL-C lowering options for statin-intolerant patients. While our study focused on PCSK9 inhibition, the potential synergistic effects of combining bempedoic acid with evolocumab warrants investigation, particularly given their complementary mechanisms targeting cholesterol biosynthesis and clearance respectively. Future studies should explore whether triple therapy (statin+bempedoic acid+PCSK9 inhibitor) could provide incremental benefits in acute coronary syndromes." Additional Revisions 1. Provide rationale for the chosen rosuvastatin dose (10 mg). We added justification in the Introduction (page 3, paragraph 2): Medium-dose rosuvastatin (10 mg) was selected to balance efficacy and safety in Chinese populations, as higher doses may increase hepatotoxicity risk without proven incremental benefits in acute settings [4]. 2. Discuss the clinical relevance of early LDL-C reduction in STEMI. Expanded in Discussion (page 9, paragraph 2): Rapid LDL-C reduction within 24 hours may attenuate plaque inflammation and microvascular dysfunction, potentially explaining the observed STR improvement. 3.Grammar/Clarity: Polished language throughout (e.g., "postoperative day 1" → "post-PCI day 1"). 4. All changes are tracked in the revised manuscript, and new references/citations have been added as appropriate. We believe these revisions have strengthened the manuscript and addressed all critiques. Thank you for considering our work for publication in PLOS ONE. Thank you again for your time and expertise. Sincerely, Zuo-lin Fu, on behalf of the authors Email: fzl04@163.com Attachments: 1. Revised Manuscript with Track Changes 2. Manuscript (clean version) 3. Response to Reviewers Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0339501.r002
14 Nov 2025 Decision Letter - Kamal Sharma, Editor Dear Dr. fu, Please submit your revised manuscript by Dec 29 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. 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 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, Kamal Sharma Academic Editor PLOS ONE Journal Requirements: 1. If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise. 2. 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: Hello, As all the reviewer has accepted the changes made in the manuscript, revised manuscript can be accepted after the minor revision has been addressed of one of the reviewers. Thanks [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author Reviewer #1: All comments have been addressed Reviewer #2: All comments have been addressed Reviewer #3: (No Response) Reviewer #4: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions??> Reviewer #1: Yes Reviewer #2: (No Response) Reviewer #3: Yes Reviewer #4: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? -->?> Reviewer #1: I Don't Know Reviewer #2: (No Response) Reviewer #3: Yes Reviewer #4: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available??> The PLOS Data policy Reviewer #1: Yes Reviewer #2: (No Response) Reviewer #3: Yes Reviewer #4: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: Yes Reviewer #2: (No Response) Reviewer #3: Yes Reviewer #4: Yes ****** Reviewer #1: No additional comments Reviewer #2: (No Response) Reviewer #3: (No Response) Reviewer #4: The authors have presented a well-structured and comprehensive study that have clinical relevance. The findings are relevant for both cardiology and nursing audiences. Grammatical/Typos: • Proof read the overall article again, and correct any grammatical error that might be in place. Narrative: • Page 1-3, line 25-84: The introduction builds good context on CAD and PCI but lacks specific evidence linking psychological adaptation to clinical outcomes. Add a few sentences citing studies that report the poor resilience leading to worse cardiac rehabilitation adherence or higher anxiety. • Page 18, 174-178: Conclusion is good but could be more impactful via adding statements like uture longitudinal studies should evaluate how interventions that strengthen coping skills can enhance resilience and reduce cardiovascular event recurrence. Methods/Results: • Page 13, Line 66: Clear structure but lacks details on scale validation and sampling. Needs to inform the handling of missing data or incomplete questionnaire. ****** 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: Fabrizio D'Ascenzo Reviewer #3: No Reviewer #4: No ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] To ensure your figures meet our technical requirements, please review our figure guidelines: https://journals.plos.org/plosone/s/figures You may also use PLOS’s free figure tool, NAAS, to help you prepare publication quality figures: https://journals.plos.org/plosone/s/figures#loc-tools-for-figure-preparation. NAAS will assess whether your figures meet our technical requirements by comparing each figure against our figure specifications. https://doi.org/10.1371/journal.pone.0339501.r003
Revision 2
19 Nov 2025 Author Response PONE-D-25-32807R1 The efficacy of preoperative evolocumab-rosuvastatin combination therapy in patients with ST-elevation myocardial infarction Dear Dr. Kamal Sharma and Reviewers, Thank you for giving us the opportunity to submit a revised version of our manuscript titled "The efficacy of preoperative evolocumab-rosuvastatin combination therapy in patients with ST-elevation myocardial infarction" (Manuscript ID: PONE-D-25-32807R1). We sincerely appreciate the editors and reviewers for your time and valuable comments, which have greatly helped us in improving the quality of our manuscript. We have carefully addressed the points raised by the reviewers. The changes made in the manuscript are highlighted in the "Revised Manuscript with Track Changes" file. An additional clean version of the revised manuscript has also been submitted. Response to Editor : 1.deposit laboratory protocols in protocols.io: It's a good suggestion to deposit laboratory protocols in protocols.we have deposited our laboratory protocols in protocols.io to enhance the reproducibility of results. DOI: dx.doi.org/10.17504/protocols.io.n2bvje6mwgk5/v1 (Private link for reviewers:https://www.protocols.io/private/107F70C8702E11F08A690A58A9FEAC02 to be removed before publication.) 2.review reference list to ensure that it is complete and correct� We have reviewed the references in our manuscript. While the reference list is well-structured and as of November 17, 2025, no articles have been marked as “Retracted” or “Expression of Concern”� one minor error is identified and corrected in the author list in Reference 10. Response to Reviewer #4: We thank the reviewer for their positive feedback and valuable suggestions to further strengthen our manuscript. We have addressed the specific comments as follows: 1. Comment: "Page 1-3, line 25-84: The introduction builds good context on CAD and PCI but lacks specific evidence linking psychological adaptation to clinical outcomes. Add a few sentences citing studies that report the poor resilience leading to worse cardiac rehabilitation adherence or higher anxiety." · Response: We thank the reviewer for this insightful suggestion. While our study primarily focuses on the pharmacological intervention, we recognize the importance of the patient's psychological state in overall recovery. We have now added a sentence in the Introduction section to acknowledge this aspect and cite relevant literature: "Beyond pharmacological therapy, a patient's psychological adaptation, such as low resilience, has been linked to poorer adherence to cardiac rehabilitation and higher levels of anxiety, which may indirectly influence long-term clinical outcomes [2]" [2] Bertolín-Boronat C, Marcos-Garcés V, Merenciano-González H, Martínez Mas ML, Climent Alberola JI, Perez N, López-Bueno L, Esteban Argente MC, Valls Reig M, Arizón Benito A, Payá Rubio A, Ríos-Navarro C, de Dios E, Gavara J, Jiménez-Navarro MF, Chorro FJ, Sanchis J, Bodi V. Depression, Anxiety, and Quality of Life in a Cardiac Rehabilitation Program Without Dedicated Mental Health Resources Post-Myocardial Infarction. J Cardiovasc Dev Dis. 2025 Mar 4;12(3):92. doi: 10.3390/jcdd12030092. 2. Comment: "Page 18, 174-178: Conclusion is good but could be more impactful via adding statements like 'Future longitudinal studies should evaluate how interventions that strengthen coping skills can enhance resilience and reduce cardiovascular event recurrence.'" · Response: We agree that this is an important direction for future research. We have expanded the Conclusion section to include this perspective: "Furthermore, future longitudinal studies should explore how interventions combining intensive lipid-lowering therapy with psychosocial support, such as those aimed at strengthening coping skills and resilience, could potentially enhance overall patient outcomes and reduce cardiovascular event recurrence." 3. Comment: "Page 13, Line 66: Clear structure but lacks details on scale validation and sampling. Needs to inform the handling of missing data or incomplete questionnaire." · Response: We thank the reviewer for pointing this out. We have added details in the Methods section (2.5 Statistical Analysis) regarding data handling: "The analysis followed the intention-to-treat principle. For the primary and secondary endpoints, there were no missing data as all 80 randomized participants completed the 6-month follow-up. Any incomplete questionnaire items in the case report forms were clarified by direct contact with the attending physician before database locking." 4. Comment: "Proof read the overall article again, and correct any grammatical error that might be in place." · Response: We have thoroughly proofread the entire manuscript to correct grammatical errors and improve language clarity. This has been done throughout the "Revised Manuscript with Track Changes." Response to Reviewers #1, #2, and #3: We thank the reviewers for their previous comments,which have been adequately addressed in the prior revision round, and for their current acceptance of the manuscript. We believe these revisions have strengthened the manuscript and addressed all critiques. Thank you for considering our work for publication in PLOS ONE. Thank you again for your time and expertise. Sincerely, Zuo-lin Fu, on behalf of the authors Email: fzl04@163.com Attachments: 1. Revised Manuscript with Track Changes 2. Manuscript (clean version) 3. Response to Reviewers Attachments Attachment Submitted filename: Response to Reviewers1.docx https://doi.org/10.1371/journal.pone.0339501.r004
9 Dec 2025 Decision Letter - Kamal Sharma, Editor The efficacy of preoperative evolocumab-rosuvastatin combination therapy in patients with ST-elevation myocardial infarction PONE-D-25-32807R2 Dear Dr. fu, 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. For questions related to billing, please contact billing support . 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, Kamal Sharma Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: Reviewer's Responses to Questions Comments to the Author Reviewer #2: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions??> Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? -->?> Reviewer #2: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available??> The PLOS Data policy Reviewer #2: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #2: Yes ****** Reviewer #2: all comments have been addressed and authors should be complimented for performing such an interesting study ****** 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 #2: Yes: Fabrizio D'Ascenzo ******** https://doi.org/10.1371/journal.pone.0339501.r005
Formally Accepted
Acceptance Letter - Kamal Sharma, Editor PONE-D-25-32807R2 PLOS One Dear Dr. fu, 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. You will receive an invoice from PLOS for your publication fee after your manuscript has reached the completed accept phase. If you receive an email requesting payment before acceptance or for any other service, this may be a phishing scheme. Learn how to identify phishing emails and protect your accounts at https://explore.plos.org/phishing. 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. Kamal Sharma Academic Editor PLOS One https://doi.org/10.1371/journal.pone.0339501.r006

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