Association between long COVID and nonsteroidal anti-inflammatory drug use by patients with acute-phase COVID-19: A nationwide Korea National Health Insurance Service cohort study

Ye-Seul Lee; Heejun Kim; Sunoh Kwon; Tae-Hun Kim

doi:10.1371/journal.pone.0312530

Peer Review History

Original SubmissionAugust 7, 2024
26 Aug 2024 Decision Letter - Seth Kwabena Amponsah, Editor PONE-D-24-33236Association between long COVID and acute usage of nonsteroidal anti-inflammatory drugs (NSAIDs) in COVID-19 patients: a nationwide cohort study from the National Health Insurance Service in KoreaPLOS ONE Dear Dr. Kim, 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 Oct 10 2024 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, Seth Kwabena Amponsah, PhD Academic Editor PLOS ONE Journal Requirements: When submitting your revision, we need you to address these additional requirements. 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf 2. Thank you for stating the following in the Acknowledgments Section of your manuscript: "This study was supported by the Korea Institute of Oriental Medicine [grant number KSN2121220]." We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form. Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows: "This study was supported by the Korea Institute of Oriental Medicine [grant number KSN2121220]." Please include your amended statements within your cover letter; we will change the online submission form on your behalf. 3. Thank you for stating the following financial disclosure: "This study was supported by the Korea Institute of Oriental Medicine [grant number KSN2121220]." Please state what role the funders took in the study. If the funders had no role, please state: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript." If this statement is not correct you must amend it as needed. Please include this amended Role of Funder statement in your cover letter; we will change the online submission form on your behalf. 4. In the online submission form, you indicated that "The data is available upon request and review by the National Health Insurance Service of Korea." All PLOS journals now require all data underlying the findings described in their manuscript to be freely available to other researchers, either 1. In a public repository, 2. Within the manuscript itself, or 3. Uploaded as supplementary information. This policy applies to all data except where public deposition would breach compliance with the protocol approved by your research ethics board. If your data cannot be made publicly available for ethical or legal reasons (e.g., public availability would compromise patient privacy), please explain your reasons on resubmission and your exemption request will be escalated for approval. 5. Please ensure that you refer to Figure 2 in your text as, if accepted, production will need this reference to link the reader to the figure. 6. Please remove your figures from within your manuscript file, leaving only the individual TIFF/EPS image files, uploaded separately. These will be automatically included in the reviewers’ PDF. 7. 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. 8. 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 : Authors are requested to address all comments from reviewers. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Partly ******** 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: 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: This is a very interesting paper. Introduction: Concise and well written. Methods: It was well written To improve this manuscript, there should be some recommendations for policy and practice. References: Referencing style should be consistent. Reviewer #2: Concerns 1. The manuscript will benefit from a grammar check. 2. Rephrase your conclusion in the abstract. Should be straightforward….eg., Both NSAIDS and APAP are robustly associated with reduced risk of Long-term COVID-19….. 3. How and where were the controls recruited? Why did the controls have more medical conditions (covariates) than the cases? Could this have affected the outcomes observed in model 5 of Table 2? Could this potential protective effect be due to chance? 4. Your recommendations should be more specific and not generalized. Which specific molecular or biochemical aspects are required to expand on observed relationships? ****** 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. Attachments Attachment Submitted filename: Comments_PONE-D-24-33236.docx https://doi.org/10.1371/journal.pone.0312530.r001
Revision 1
18 Sep 2024 Author Response Answer to the editor and reviewers’ comments Editor’s comment • 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'. Thank you for your comments. We did this. • 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'. Thank you for your comments. We did this. • An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. Thank you for your comments. We did this. 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. We didn’t change to our financial disclosure. 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. Thank you for your comments. 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf We followed the Plos one’s recommendation for formatting. 2. Thank you for stating the following in the Acknowledgments Section of your manuscript: "This study was supported by the Korea Institute of Oriental Medicine [grant number KSN2121220]." We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form. Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows: "This study was supported by the Korea Institute of Oriental Medicine [grant number KSN2121220]." Please include your amended statements within your cover letter; we will change the online submission form on your behalf. We don’t want to change funding information. We removed the description on fuding at acknowledgment section. We added it in the online submission system. 3. Thank you for stating the following financial disclosure: "This study was supported by the Korea Institute of Oriental Medicine [grant number KSN2121220]." Please state what role the funders took in the study. If the funders had no role, please state: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript." If this statement is not correct you must amend it as needed. Please include this amended Role of Funder statement in your cover letter; we will change the online submission form on your behalf. Funders of this study did noting so we added following statement in the submission system. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. 4. In the online submission form, you indicated that "The data is available upon request and review by the National Health Insurance Service of Korea." All PLOS journals now require all data underlying the findings described in their manuscript to be freely available to other researchers, either 1. In a public repository, 2. Within the manuscript itself, or 3. Uploaded as supplementary information. This policy applies to all data except where public deposition would breach compliance with the protocol approved by your research ethics board. If your data cannot be made publicly available for ethical or legal reasons (e.g., public availability would compromise patient privacy), please explain your reasons on resubmission and your exemption request will be escalated for approval. The database data from the National Health Insurance Service undergoes a special procedure for anonymization and can only be accessed at a designated location for a limited time period. As of September 2024, the access rights to the data we requested have already been revoked, making it inaccessible. Considering that health insurance data contains sensitive personal information and access is not always permitted to protect privacy, we have described it as follows: The data included in this study from the National Health Insurance Service in Korea can only be accessed at a designated location for a limited time period for protection of personal information so it is available upon request and review by the National Health Insurance Service of Korea. 5. Please ensure that you refer to Figure 2 in your text as, if accepted, production will need this reference to link the reader to the figure. We added it in the manuscript. 6. Please remove your figures from within your manuscript file, leaving only the individual TIFF/EPS image files, uploaded separately. These will be automatically included in the reviewers’ PDF. We removed them. 7. 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. We added captions for Supporting information files as follows: Supporting Information files Supplementary Table 1. Study information COVID, coronavirus disease-2019; NSAIDs, non-steroidal anti-inflammatory drugs; AIDS, acute immunodeficiency syndrome; HIV, human immunodeficiency virus. Supplementary Table 2. Univariate and multivariate logistic models of medication exposure between long COVID cases and controls with duration of COVID as a covariate Model 1, univariate; Model 2, adjusted for COVID duration; Model 3, adjusted for COVID duration, sex, and age group; Model 4, adjusted for COVID duration, sex, age group, and region; Model 5, adjusted for duration, sex, age group, region, and CCI; Model 6, adjusted for COVID duration, sex, age group, region, CCI, and underlying comorbidities 1Day of COVID diagnosis - 14 days after COVID diagnosis 215 days since COVID diagnosis - end of follow-up (diagnosis of long COVID, diagnosis of other COVID episodes, or end of observation period p <0.05; p <0.01; *p <0.001 NSAIDs, nonsteroidal anti-inflammatory drugs; CI, confidence interval; OR, odds ratio; APAP, acetaminophen or paracetamol Supplementary Table 3. Univariate and multivariate logistic models comparing single NSAID users with acetaminophen or paracetamol (APAP) users and combined nonsteroidal anti-inflammatory drugs + APAP with APAP users Model 1: univariate; Model 2: adjusted for sex and age group; Model 3: adjusted for sex, age group, and region; Model 4: adjusted for sex, age group, region, and CCI; Model 5: adjusted for sex, age group, region, CCI, and underlying comorbidities 1Day of COVID diagnosis - 14 days after COVID diagnosis 215 days since COVID diagnosis - end of follow-up (diagnosis of long COVID, diagnosis of other COVID episodes, or end of observation period p <0.05; p <0.01; p <0.001 NSAIDs, nonsteroidal anti-inflammatory drugs; CI, confidence interval; OR, odds ratio; APAP, acetaminophen or paracetamol 8. 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. There is no retracted reference. Thank you for your comments. Reviewer Comments Association between long COVID and acute usage of nonsteroidal anti-inflammatory 2 drugs (NSAIDs) in COVID-19 patients: a nationwide cohort study from the National 3 Health Insurance Service in Korea Concerns 1. The manuscript will benefit from a grammar check. Thank you for your comments. We already edited our manuscript before submission through a professional English editing service. But as you commented, we checked grammar once again. 2. Rephrase your conclusion in the abstract. Should be straightforward….eg., Both NSAIDS and APAP are robustly associated with reduced risk of Long-term COVID-19….. Dear reviwer, We added this point based on your comments as follows: Conclusion: While this study suggests a possible links between NSAID use in acute infection stage and higher risk of long COVID as well as both NSAIDs and acetaminophen uses during the chronic period and lower risk of long COVID, the association was not statistically significant. 3. How and where were the controls recruited? Why did the controls have more medical conditions (covariates) than the cases? Could this have affected the outcomes observed in model 5 of Table 2? Could this potential protective effect be due to chance? Dear reviewer, Thank you for your valuable comments. First of all, the control group was not radomly selected; rather, it was selected through propensity score matching from the same database and within the same time period as the observational group. These individuals had COVID-19 but did not take NSAIDs, and they were chosen in a way that controlled for other confounding factors to ensure comparibility between the two groups. The mathing method allowed three controls per patient, matching for the exact age group, sex, CCI score, and the year and month of COVID-19 episode. For the underlying disease severity, we used the CCI score as an exact condition; this allows for a variation in the type of the underlying disease, which in our study encompassed a wide range of diseases, while matching the overall severity. The result showed that there was no difference between the two groups except for anemia (SMD = 0.2). It is true that anemia may cause symptoms which may overlap with chronic fatigue, and the cases show higher morbidity of anemia compared to controls. However, other comorbidities which may cause more severe outcomes were balanced between the two groups, which helps us rule out the potential of confounding due to comorbidities. Furthermore, there is no direct relationship between anemia and use of painkillers, which rules out the potential unmeasured confounding between the baseline characteristics and interventions. Based on the reviewer’s comment, we revised the manuscript as follows: After applying PS matching to create comparable groups, a balance was achieved for demographic factors such as sex and age group, CCI, underlying comorbid conditions except for anemia, which the cases showed higher comorbidity than controls, and the year and month of the COVID-19 episode (Table 1). While there was a slight difference between cases and controls in the comorbidity of anemia (SMD = 0.20), the weak association between anemia and the use of painkillers and balance in the other diseases which may directly be associated with painkiller prescriptions, allowed us to rule out the potential of unmeasured confounding. These individuals did not have more medical conditions, as can be confirmed from Table 1, which shows no differences between the two groups in terms of each medical condition after propensity score matching. When propensity score matching is performed, differences related to those factors between the groups disappear, which means they naturally do not affect the results. Therefore, it is difficult to consider the “potential protective effect” you mentioned as a mere coincidence 4. Your recommendations should be more specific and not generalized. Which specific molecular or biochemical aspects are required to expand on observed relationships? Dear Reviewer, thank you for your comments. In fact, the exact mechanism of how long COVID develops is still not fully understood, and it is also challenging to propose a clear mechanism for how NSAIDs might worsen the symptoms of acute COVID-19 infection while having a protective effect against long COVID with prolonged use. Since this study is based on patient data, it would be difficult to specify a particular molecular or biochemical aspect for future research based solely on our results. However, to avoid any confusion in expression, we would like to clarify that section by rephrasing it as follows. We hope this meets your expectations. Future research is crucial to further explore the effect of NSAID in the acute stage of COVID-19 infection and its molecular mechanism on the incidence of long COVID. Attachments Attachment Submitted filename: renamed_72265.docx* https://doi.org/10.1371/journal.pone.0312530.r002
29 Sep 2024 Decision Letter - Seth Kwabena Amponsah, Editor PONE-D-24-33236R1Association between long COVID and acute usage of nonsteroidal anti-inflammatory drugs (NSAIDs) in COVID-19 patients: a nationwide cohort study from the National Health Insurance Service in KoreaPLOS ONE Dear Dr. Kim, 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 Nov 13 2024 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, Seth Kwabena Amponsah, PhD 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: Whiles the manuscript has improved significantly in terms of scientific content, the entire manuscript will still benefit from English-language editing. The Journal provides such services. I use the Abstract as example; "While this study suggests a possible links between NSAID use in acute infection stage and higher risk of long COVID as well as both NSAIDs and acetaminophen uses during the chronic period and lower risk of long COVID,......" [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 ******** 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 ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes ****** 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 ****** 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) Reviewer #2: (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 #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.0312530.r003
Revision 2
8 Oct 2024 Author Response Reply to the editorial comment Whiles the manuscript has improved significantly in terms of scientific content, the entire manuscript will still benefit from English-language editing. The Journal provides such services. I use the Abstract as example; "While this study suggests a possible links between NSAID use in acute infection stage and higher risk of long COVID as well as both NSAIDs and acetaminophen uses during the chronic period and lower risk of long COVID,......" Dear editor Thank you for your comments. We edited our manuscript in a professional editing service and you can check the certificate by the company in the attached file. We revise the abstract section as you suggested: Although this study suggests a possible link between NSAID use in the acute COVID-19 infection stage and a higher risk of long COVID as well as both NSAID and acetaminophen use during the chronic COVID-19 period and a lower risk of long COVID, the association was not statistically significant. Attachments Attachment Submitted filename: Rebuttal letter_2nd.docx https://doi.org/10.1371/journal.pone.0312530.r004
9 Oct 2024 Decision Letter - Seth Kwabena Amponsah, Editor Association between long COVID and nonsteroidal anti-inflammatory drug use by patients with acute-phase COVID-19: A nationwide Korea National Health Insurance Service cohort study PONE-D-24-33236R2 Dear Dr. Kim, 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, Seth Kwabena Amponsah, PhD Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0312530.r005
Formally Accepted
23 Oct 2024 Acceptance Letter - Seth Kwabena Amponsah, Editor PONE-D-24-33236R2 PLOS ONE Dear Dr. Kim, 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 If revisions are needed, the production department will contact you directly to resolve them. If no revisions are needed, you will receive an email when the publication date has been set. At this time, we do not offer pre-publication proofs to authors during production of the accepted work. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few weeks 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 Prof. Seth Kwabena Amponsah Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0312530.r006

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