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PONE-D-23-40113Rebamipide prevents upper gastrointestinal bleeding in NSAID use for orthopaedic conditions: A nested case-control study using the LIFE Study databasePLOS ONE

Dear Dr. Hamai,

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.

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ACADEMIC EDITOR:

Thank you for submitting your manuscript, titled "[Rebamipide prevents upper gastrointestinal bleeding in NSAID use for orthopaedic conditions: A nested case-control study using the LIFE Study database]," to PLOS ONE. Your work has now been reviewed by two experts in the field, and I have carefully considered their evaluations.

After a thorough assessment, I have decided that your manuscript could potentially be suitable for publication, but it requires major revisions. Both reviewers have acknowledged the importance and relevance of your study but have raised significant concerns that need to be addressed to meet our publication standards.

We encourage you to resubmit your revised manuscript. Please include a detailed response letter outlining how you have addressed each of the reviewers' comments.

Best regards

==============================

Please submit your revised manuscript by Mar 08 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'.
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• 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,

Mahmoud Kandeel

Academic Editor

PLOS ONE

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“This work was supported by the Japan Society for the Promotion of Science KAKENHI (Grant Numbers JP19K21590 and JP20H00563) and by Japan Science and Technology Agency FOREST (Fusion Oriented REsearch for disruptive Science and Technology) program (Grant Number JPMJFR205J).”

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I have read the journal's policy and the authors of this manuscript have the following competing interests:Yasuharu Nakashima received research grants from Chugai Pharmaceutical Co., Ltd., AYUMI Pharmaceutical Corporation, EA Pharma Co., Ltd., KYOCERA Corporation, and Zimmer Biomet G.K. All other authors have no conflicts of interest to disclose.”

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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

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

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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: No

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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

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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: Estimated Editor and Authors,

First, I would like to thank you for the opportunity to review this manuscript. This is a nested case-control that evaluated the effectiveness of the prescription of rebamipide for prevention of upper gastrointestinal bleeding in NSAIDs users living with orthopedic conditions. The manuscript is well written and is relevant in the scope of patient safety, considering the high morbidity and mortality related to gastrointestinal bleeding as an adverse drug event. However, methodological reporting is somewhat confusing and needs to be improved for a better understanding of the study and to be reproducible.

Follow my feedback below to help you improve the quality and clarity of your manuscript:

- Title: The authors report as if the rebamipide prevents upper gastrointestinal bleeding on any NSAIDS user, but the authors' findings only identified this protection in occasional users. Therefore, it is important to review the title so that it is harmonious with the findings of the study.

- At many times the occasional use of NSAIDS is cited, but this is not defined. It is very important to define how stratified the consumption of NSAIDS and what was considered in each stratum.

Introduction

- Page 5, Line 60: Is there no more current data on the rebamipide prescription?

- The most appropriate terminology is "adverse drug events" and not "effects".

- Important to define what was considered "low risk of NSAIDs induced ulcers".

- Page 6, lines 86 and 87 do not fit in the introduction: "We used medical claims data for the analysis we consider it a useful approach for tracking cats across specialties in the real world."

Methodology

- The methodology should follow the reporting of checklist Strobe, because in many moments this section is confused. Strobe should be used to guide the methodology report.

I understand, for example, that the methodology should start by presenting the study and setting design and not the database used to consult the data.

- Page 6, Line 103: Do two public insurance systems cover the entire country?

- How many researchers conducted data collection? Were pre-delineated forms used for this data collection?

- Why was the Time Window (T.W.) from 90 days before t0 to 1 day before t0 the exclusion criteria?

- Were the life habits of patients, such as smoking and consumption of beverages, which depending on the amount consumed may be associated with gastrointestinal problems?

- Pages 8 and 9, lines 151 - 153: This sentence is not clear. What refers to censorship in line 153?

- The definition of cases is not clear. Patients diagnosed with osteoarthritis or back pain who were prescribed from NSAIDs were follow-up until these patients undergoing endoscopy and developed upper gastrointestinal bleeding? This flow of recruitment of participants was not clear to me.

- If the patient had in his medical record the reporting of endoscopic findings such as "duodenal ulcer" or "gastric ulcer", would it be considered case? As already reported in the limitations of the study, the non-analysis of endoscopic reports consists of an important bias.

Another aspect, the intention was to evaluate upper gastrointestinal bleeding as an adverse event of the use of NSAIDS, right? Therefore, this excludes the non-variceal etiology. How was the control of the etiologies of the upper gastrointestinal bleeding? Was it possible to identify if the patient was bleeding by neoplasia, cirrhosis, varicose veins, or other conditions? This aspect needs to be better reported.

- I was also in doubt in the following excerpt "However, we assume that the fictitious disease name of "upper gastrointestinal bleeding" would be rarely assigned to a patent without any symptoms of gastrointestinal ulcer." Was it considered cases only patients with upper with gastrointestinal bleeding or just with ulcer as well? Were evaluated if these patients had signs of recent bleeding?

- Page 10, line 176: define what was considered "1) continuous user, 2) occasional user, and 3) non-user".

- Page 11, line 206: the following sentence is confusing: "the analytical results are planned to be disseminated to the public through these participating municipalities."

- One piece of information that would greatly enrich the results would be to assess the defined daily dose of NSAIDs consumed by the participants. I suggest that the authors assess the feasibility or relevance of including this data.

- Was it possible to control whether patients self-medicated with NSAIDs, in addition to the medical prescription they received? How are NSAIDs sold in Japan? In many patients, there is free access to this class.

Results

- When reporting averages or medians, I suggest including the standard deviation or quartiles, respectively.

- In table 1, the data presented in the last rows is not clear. Is it the dose of each NSAID and the respective quartiles? Why are most of the drugs set to 0? I think this form of presentation is a bit confusing. I apologize if I'm not understanding the presentation correctly.

Discussion

- As the authors cite the importance of variants in the CYP2C19 gene, which can impact the metabolism of proton pump inhibitors, it is also worth highlighting variants in the CYP2C9 gene, as the *2 and *3 alleles are responsible for the slow metabolism of NSAIDs, which increases the risk of gastrointestinal bleeding.

- The authors could further highlight the clinical implications and contributions of these findings to clinical practice and patient safety.

Reviewer #2: This is a worthwhile study as there is a paucity of clinical trial data of rebamipide for this indication.

Methods are sound. Inclusion criteria are quite narrow but this helps to avoid confusing.

The discussion about the adverse effects of PPIs compared to those of rebamipide is not equitable. More types of adverse effects have been reported with PPIs, but they have also been used more widely than rebamipide.

It is necessary to make more mention of the adverse effects of rebapimide. The labels list leukopenia and liver dysfunction as adverse effects; although rare (I checked Malaysian and Philippine labels).

The results are than continuous use of rebamipide was associated with less GI bleeding than no use, but the occasional use was associated with a higher risk than no use

The conclusion than rebamipide may be more beneficial than PPIs is unsound since the effect of PPIs has not be addressed in this study.

Some issues need to be addressed:

In the abstract, it should be specified that the patients are at low risk of NSAIDs induced ulcers.

Enteric infections and hypomagnesemia should be mentioned as adverse effects of PPI

Line 78: “[Rebamipide] and may be superior to PPIs as a prophylactic agent for patients at low risk of NSAID induced ulcers.” This statement is not supported by a reference.

Line 80 “The prevention of NSAID-induced ulcers can be achieved from the initial prescription of NSAIDs, such as in an orthopaedic outpatient clinic; however…”

This phrase is strange. From the initial prescription of NSAIDs, prevention is established, it is not yet achieved.

The methods should make it clear whether it is a calendar month or a 30-day period.

Why is ICD-10 code B98.0 (H. pylori as a cause of diseases classified in other chapters) not used as an exclusion criterion?

Line 138: Anticoagulants are associated with bleeding rather than ulcer risk.

Authors should provide unadjusted estimates of the main analysis. (STROBE item 16)

Line 162: “However, we assumed that the fictitious disease name…”

The phrase is strange. The name is not fictitious.

Line 170: the total number of NSAID tablets “prescribed” instead of “administered”.

Line 320: “the study sample was limited to low-risk patients”. This is not a limitation since the research question was about low risk patients

S2 Figure The duration of upper gastrointestinal bleeding after the first prescription of NSAIDs

Figure title is wrong. Data are days to bleeding.

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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: Yes: Marcela Forgerini

Reviewer #2: Yes: Javier Garjon

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[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.

PONE-D-23-40113R1Continuous co-prescription of rebamipide prevents upper gastrointestinal bleeding in NSAID use for orthopaedic conditions: A nested case-control study using the LIFE Study databasePLOS ONE

Dear Dr. Hamai,

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 Jun 21 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,

Mahmoud Kandeel

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.

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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: (No Response)

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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: Partly

**********

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: No

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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: Dear Editor and Authors,

Firstly, I thank you for the opportunity to review again this manuscript.

The authors carried out a carefully review and attended all my suggestions. Hence, I am delighted with the revised version and have no other suggestions.

Minor comment: genes should be written in italics.

Finally, I congratulate the authors for their careful review.

Reviewer #2: Continuous-user is defined as one whom rebamipide was co-prescribed from t0 with the same number of tablets as NSAIDs. However, as dosage of rebamipide is one tablet 3 times/day and dosage of celecoxib is one tablet/day, the same number of tablets covers fewer days with rebamipide than with celecoxib. This not fit with figure 1.

In which group is someone who is prescribed more rebamipide tablets than NSAIDs (as they should be in the case of celecoxib or meloxicam for being a continuous user)? It is necessary to clarify this issue.

I am sorry, but I disagree with reviewer #1. “Adverse drug event” is not a standard term; I consider “adverse effect” or “adverse drug reaction” more accurate terms because a causal relationship between the drug and an occurrence is suspected.

Please see: European Medicines Agency and Heads of Medicines Agencies, 2017. Guideline on good pharmacovigilance practices (GVP) Annex I - Definitions (Rev 4). https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-good-pharmacovigilance-practices-annex-i-definitions-rev-4_en.pdf

Lines 292-296

There is a duplicity:

prescribers should be aware of the risk of pulmonary adverse drug events associated with rebamipide [44], and leukopenia might occur in rare cases [5], meaning that rebamipide is not entirely risk-free. However, prescribers need to be aware of the potential for pulmonary adverse events associated with rebamipide [44] and rare instances of leukopenia [5], highlighting that it is not without risks.

Line 323

"Using PPIs to prevent NSAID-induced ulcers in patients with no risks should be discussed"

“with no risk factors” or “at low risk” are better expressions.

Lines 345 346

"While we found that NSAIDs might unexpectedly cause upper gastrointestinal bleeding, this conclusion is based on studies with low-risk patients."

I do not understand the sentence. NSAIDs, expectedly, cause upper gastrointestinal bleeding even in low-risk patients. This is a finding from the present study. What studies are the authors referring to?

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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: Yes: Marcela Forgerini

Reviewer #2: No

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[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.

PONE-D-23-40113R2Continuous co-prescription of rebamipide prevents upper gastrointestinal bleeding in NSAID use for orthopaedic conditions: A nested case-control study using the LIFE Study databasePLOS ONE

Dear Dr. Hamai,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Jul 11 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,

Mahmoud Kandeel

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.

[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 #2: (No Response)

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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 #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 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 #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 #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 #2: Line 240.

I think what is meant is “The median time to upper gastrointestinal bleeding after the first prescription of NSAIDs was 134 days (S2 Figure).”

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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 #2: Yes: Javier Garjon

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Continuous co-prescription of rebamipide prevents upper gastrointestinal bleeding in NSAID use for orthopaedic conditions: A nested case-control study using the LIFE Study database

PONE-D-23-40113R3

Dear Dr. Hamai,

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.

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Kind regards,

Mahmoud Kandeel

Academic Editor

PLOS ONE

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