PONE-D-22-29971The Risk of Ischemic Stroke Significantly Increases in Individuals with Blepharitis: A Population-based Study Involving 424,161 PatientsPLOS ONE

Dear Dr. Chiang,

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Redoy Ranjan, MBBS, MRCSEd, Ch.M., MS (CV&TS), FACS

Academic Editor

PLOS ONE

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Reviewers' comments:

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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: Yes

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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: Yes

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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: This pioneering study needs to be replicated but at a prospective design, with inclusion of surrogate markers like Il-6 and with severity of blepharitis included. the inclusion of odontogenic bacteria can be further done . A noteworthy citation that may aid in the future is this: Pyysalo MJ, Pyysalo LM, Pessi T, Karhunen PJ, Öhman JE. The connection between ruptured cerebral aneurysms and odontogenic bacteria. J Neurol Neurosurg Psychiatry. 2013 Nov;84(11):1214-8. doi: 10.1136/jnnp-2012-304635. Epub 2013 Jun 12. PMID: 23761916.

Reviewer #2: It is a new idea. however, what about the type of infarction? Is it large vessel or small vessel disease. In addition,is it thrombosis or embolic stroke. And what do you recommend after getting these results about the relation between blepharitis and stroke?

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Reviewer #1: Yes: Mohamed Mostafa

Reviewer #2: No

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PONE-D-22-29971R1The risk of ischemic stroke significantly increases in individuals with blepharitis: A population-based study involving 424,161 patientsPLOS ONE

Dear Dr. Chiang,

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.

ACADEMIC EDITOR: The authors are thanked for this submission to PLOS ONE. After a critical external peer review by three experts, I reinforce improving the clarity and presentation of your paper and adding recent references with in-text citations. Please see the attached reviewer comments detail below.

Please submit your revised manuscript by Feb 25 2023 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Redoy Ranjan, MBBS, MRCSEd, Ch.M., MS (CV&TS), FACS

Academic Editor

PLOS ONE

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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: All comments have been addressed

Reviewer #3: All comments have been addressed

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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: Yes

Reviewer #3: Partly

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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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

Reviewer #3: Yes

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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: I would like to thank the honorable authors for including my comments in the manuscript and look forward to future prospective version of similar works.

Reviewer #2: Thanks for addressing the comments. And one last comment on the word" causal " as it is written "casual" in discussion section please correct.

Reviewer #3: 1．The authors statistically demonstrated an association between ischemic stroke (IS) and blepharitis. However, some points were difficult to understand, probably due to my lack of ability.

My understanding may be wrong, but, in this study, the subjects were all patients with NHIRD from 2008 to 2018 who were excluded from the exclusion criteria. Authors created two cohorts with or without blepharitis under the assessment of matching criteria, and examined the incidence of new IS in a follow-up up to 2019.

But, for example, the following 1) and 2) questions arise in the description of ‘Methods’, I think it is better to use Fig. 1 to organize and describe 'Methods' in an easy-to-understand manner.

1) Study Design:

① Are the following patients followed until Dec. 31, 2019? : Patients diagnosed with IS during the 10-year period between Jan. 1, 2008 and Dec. 31, 2018 among those diagnosed with blepharitis.

② Does the history of stroke, transient ischemia attack on line 6 mean past history before 2008?

2) Procedures:

The content of the blepharitis cohort and the non-blepharitis cohort on the third line is unclear. Is the blepharitis cohort the IS patients with blepharitis? Is the non-blepharitis cohort the IS patients without blepharitis? Alternatively, are the blepharitis cohorts the blepharitis patients other than the exclusion criteria patients? Are the non-blepharitis cohort patients with all diseases other than blepharitis and exclusion criteria patients?

2．More importantly, the definition of IS, which is the basis of this research, is unclear. Please clarify the following questions.

　The diagnosis of IS is made according to the ICD-9 and ICD-10 classifications, but the definition of IS in this study is unclear. ICD-9-CM 433 and 434 also include 'without mention of infarction'. ICD-10-CM I65 and I66 are 'not resulting in cerebral infarction'. It is necessary to clarify whether the IS criteria are infarction, include CBF reduction without infarction, or include arterial occlusion without CBF reduction. They will change the results and considerations.

3．The definition of 'IS' in the paper cited in ‘Discussion’ may be different from the definition of 'IS' in reference papers. For example 'IS' in reference [20] is ICD-10-CM I63, that is ‘cerebral infarction’.

4．In ‘Discussion’, the relationship between stroke risk factors and inflammatory processes is fully described using reference papers. However, there are few reference papers on the inflammatory process in blepharitis, and reference [32] is a small number patients (7 cases) study of chronic blepharitis. Reference [39] described the result of IL in uveitis, and not a study in blepharitis. It would be desirable to cite more reference papers on inflammatory processes in blepharitis and discuss the relationship between blepharitis and ischemic stroke via inflammatory processes more concisely.

5.　On line 13 of 'Strengths and Limitation', isn't 'can' in 'Finally, the severity of blepharitis can be defined' 'cannot'?

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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: Mohamed Mostafa

Reviewer #2: No

Reviewer #3: No

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The risk of ischemic stroke significantly increases in individuals with blepharitis: A population-based study involving 424,161 patients

PONE-D-22-29971R2

Dear Dr. Chiang,

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,

Redoy Ranjan, MBBS, MRCSEd, Ch.M., MS (CV&TS), FACS

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

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: Thank you for the review opportunity. I would like to see reproducible articles including intracerebral aneurysm/ hemorrhagic infarction.

Reviewer #3: The authors kindly answered my questions to compensate for my lack of understanding. And they accepted some of my comments and revised part of their manuscript. I greatly appreciate the efforts of the authors.