Dear Dr. Clery,

Thank you very much for submitting your manuscript "The trends in prevalence of acute stroke impairments: Analysis using the South London Stroke Register" (PMEDICINE-D-20-02083) for consideration at PLOS Medicine.

Your paper was evaluated by a senior editor and discussed among all the editors here. It was also discussed with an academic editor with relevant expertise, and sent to independent reviewers, including a statistical reviewer. The reviews are appended at the bottom of this email and any accompanying reviewer attachments can be seen via the link below:

[LINK]

In light of these reviews, I am afraid that we will not be able to accept the manuscript for publication in the journal in its current form, but we would like to consider a revised version that addresses the reviewers' and editors' comments. Obviously we cannot make any decision about publication until we have seen the revised manuscript and your response, and we plan to seek re-review by one or more of the reviewers.

In revising the manuscript for further consideration, your revisions should address the specific points made by each reviewer and the editors. Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments, the changes you have made in the manuscript, and include either an excerpt of the revised text or the location (eg: page and line number) where each change can be found. Please submit a clean version of the paper as the main article file; a version with changes marked should be uploaded as a marked up manuscript.

In addition, we request that you upload any figures associated with your paper as individual TIF or EPS files with 300dpi resolution at resubmission; please read our figure guidelines for more information on our requirements: http://journals.plos.org/plosmedicine/s/figures. While revising your submission, please upload your figure files to the 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. 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 us at PLOSMedicine@plos.org.

We expect to receive your revised manuscript by Jul 23 2020 11:59PM. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

***Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***

We ask every co-author listed on the manuscript to fill in a contributing author statement, making sure to declare all competing interests. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. If new competing interests are declared later in the revision process, this may also hold up the submission. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT. You can see our competing interests policy here: http://journals.plos.org/plosmedicine/s/competing-interests.

Please use the following link to submit the revised manuscript:

https://www.editorialmanager.com/pmedicine/

Your article can be found in the "Submissions Needing Revision" folder.

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see http://journals.plos.org/plosmedicine/s/submission-guidelines#loc-methods.

Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

We look forward to receiving your revised manuscript.

Sincerely,

Emma Veitch, PhD

PLOS Medicine

On behalf of Clare Stone, PhD, Acting Chief Editor,

PLOS Medicine

plosmedicine.org

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Requests from the editors:

*In the Abstract Methods and Findings section, please include a brief note summarising any key limitations of the study methods.

*At this stage, we ask that you include a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract. Please see our author guidelines for more information: https://journals.plos.org/plosmedicine/s/revising-your-manuscript#loc-author-summary

*Please clarify in the paper if the analytical approach followed here corresponded to one laid out in a prospective study protocol or analysis plan? Please state this (either way) early in the Methods section.

a) If a prospective analysis plan (from your funding proposal, IRB or other ethics committee submission, study protocol, or other planning document written before analyzing the data) was used in designing the study, please include the relevant prospectively written document with your revised manuscript as a Supporting Information file to be published alongside your study, and cite it in the Methods section. A legend for this file should be included at the end of your manuscript.

b) If no such document exists, please make sure that the Methods section transparently describes when analyses were planned, and when/why any data-driven changes to analyses took place.

c) In either case, changes in the analysis-- including those made in response to peer review comments-- should be identified as such in the Methods section of the paper, with rationale.

*We'd suggest using an appropriate reporting guideline (eg STROBE - https://www.equator-network.org/reporting-guidelines/strobe/) - to guide reporting of study methods and findings; if doing this please ensure you upload the completed STROBE checklist as supporting information alongside the revised paper.

*At the moment the Discussion section doesn't explicitly include a clear Strengths and Limitations section; with respect to the latter this should include a summary of any specific biases inherent in the study methods which might have prevented the observed effects from closely approximating the "real" effects, and if so in what direction those biases might have have affected observed outcomes (eg towards null or away from null).

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Comments from the reviewers:

Reviewer #1: I confine my remarks to statistical aspects of this paper. These were well done and I recommend publication

Peter Flom

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Reviewer #2: Clery et al. report the trends of acute stroke impairments overtime using population-based data. Limb motor deficits, dysphagia and incontinence declined between 2001 and 2018. Interestingly, the prevalence of all pre-stroke risk factors, except for vascular disease, increased over time. The authors hypothesize that the increased use of anticoagulants and statins could count, at least in part, for the decrease of acute impairments.

- This study analyzes ischemic stroke, ICH and SAH. These diseases are different in etiology, severity and prognosis. The article is mostly focused on ischemic stroke. The authors may want to consider concentrating in ischemic stroke solely.

- Can the authors provide data on gaze paresis and dysarthria?

- Why did the authors exclude the data from 1995 to 2001?

- The decrease in the use of anti platelets may be related to new data showing that there is no benefit on its use for primary prevention

- The results are important for policy makers, but I believe these data are population specific and cannot be extrapolated. also, the decrease in stroke severity, and its association with the use of antithrombotics has already been shown.

- "We have found that strokes of undetermined aetiology have high levels of impairments comparable to that of LAAs and CEs." Stroke of undetermined source (aka ESUS) are mostly due to covert afib or carotid plaques < 50%. This may also explain the reported findings.

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Reviewer #3: This paper describes the trends in prevalence of acute stroke impairments in a large stroke registry. The results are interesting, and the analysis is convincing. I have just a few minor questions and comments to Authors.

1) page 6, line 83. Please give values in mg, most of us readers do not use mmols.

2) page 7 line 88. Despite relevant negative comments about (see for instance Stroke 36(4):902-4 · May 2005 "Time to burn Toast"), Toast classification is still widely used. However, I suggest Authors, if at all possible, to use OCSP classification, and also to look at Esus cases, which could have different level of impairment.

3) page 7 line 92. As for haemorrhages, could Authors differentiate between typical and atypical forms? It seems that the latter are increased in recent years, and the impact on impairment may well be different.

4) page 8 line 112. Authors did not adjust for smoking and cholesterol levels. Is there a specific reason for that? If not, could they add these two factors to their analysis?

5) Results line 134. Mean age looks quite low, as compared to the one found in different European studies. Do Authors think that this fact could limit the external validity of their results?

6) Results line 152. The decrease in severity is evident. Hower, could it be due to more mild cases being admitted, or to less severe cases being admitted? is any other facility available for stroke patient in the study area? Have Authors any information on the number of patients staying at home with their stroke?

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Any attachments provided with reviews can be seen via the following link:

[LINK]

Dear Dr. Clery,

Thank you very much for re-submitting your manuscript "The trends in prevalence of acute stroke impairments: A population-based cohort study using the South London Stroke Register" (PMEDICINE-D-20-02083R1) for review by PLOS Medicine.

I have discussed the paper with my colleagues and the academic editor and it was also seen again by reviewers. I am pleased to say that provided the remaining editorial and production issues are dealt with we are planning to accept the paper for publication in the journal.

The remaining issues that need to be addressed are listed at the end of this email. Any accompanying reviewer attachments can be seen via the link below. Please take these into account before resubmitting your manuscript:

[LINK]

Our publications team (plosmedicine@plos.org) will be in touch shortly about the production requirements for your paper, and the link and deadline for resubmission. DO NOT RESUBMIT BEFORE YOU'VE RECEIVED THE PRODUCTION REQUIREMENTS.

***Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***

In revising the manuscript for further consideration here, please ensure you address the specific points made by each reviewer and the editors. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments and the changes you have made in the manuscript. Please submit a clean version of the paper as the main article file. A version with changes marked must also be uploaded as a marked up manuscript file.

Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. If you haven't already, we ask that you provide a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract.

We expect to receive your revised manuscript within 1 week. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

We ask every co-author listed on the manuscript to fill in a contributing author statement. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT.

Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

If you have any questions in the meantime, please contact me or the journal staff on plosmedicine@plos.org.

We look forward to receiving the revised manuscript by Aug 19 2020 11:59PM.

Sincerely,

Clare Stone, PhD

Managing Editor

PLOS Medicine

plosmedicine.org

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Requests from Editors:

Competing interests: Please mention the YW is a paid statistical referee for PLOS Medicine, but had no role in the peer review of this paper.

Title – I suggest removing ‘The’

Abstract – Please include summary demographic information and provide p values for 95% Cis (here and elsewhere). Also, Please quote one further limitation in the abstract

Author Summary – briefly please say what the 5 conditions are that were unaffected.

Please include a space before the opening square brackets for refs.

STROBE – please submit supp files individually, including this one and also sections and paragraphs should be used instead of pages as these change during formatting and revisions.

- at line 35, suggest "In this study, we found that stroke patients in the SLSR had a complexity ..." (also similar amendments at line 56)

- Poor punctuation at line 312; in fact, this whole paragraph on ethnic disparities is quite hard to understand. Do you mean that the proportion of Black people in the relevant population has not changed, and therefore that a higher proportion of Black people than White have risk factors and suffer strokes in South London? Please clarify.

Comments from Reviewers:

Reviewer #2: My concerns have been appropriately addressed.

Thank you for the opportunity of reviewing your paper.

Reviewer #3: Authors were kind enough to consider all my points, and, as far as possible, to follow my suggestions. I have no further question or comment.

Any attachments provided with reviews can be seen via the following link:

[LINK]

Dear Dr Clery,

On behalf of my colleagues and the academic editor, Dr. Joshua Willey, I am delighted to inform you that your manuscript entitled "Trends in prevalence of acute stroke impairments: A population-based cohort study using the South London Stroke Register" (PMEDICINE-D-20-02083R2) has been accepted for publication in PLOS Medicine.

PRODUCTION PROCESS

Before publication you will see the copyedited word document (in around 1-2 weeks from now) and a PDF galley proof shortly after that. The copyeditor will be in touch shortly before sending you the copyedited Word document. We will make some revisions at the copyediting stage to conform to our general style, and for clarification. When you receive this version you should check and revise it very carefully, including figures, tables, references, and supporting information, because corrections at the next stage (proofs) will be strictly limited to (1) errors in author names or affiliations, (2) errors of scientific fact that would cause misunderstandings to readers, and (3) printer's (introduced) errors.

If you are likely to be away when either this document or the proof is sent, please ensure we have contact information of a second person, as we will need you to respond quickly at each point.

PRESS

A selection of our articles each week are press released by the journal. You will be contacted nearer the time if we are press releasing your article in order to approve the content and check the contact information for journalists is correct. If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact.

PROFILE INFORMATION

Now that your manuscript has been accepted, please log into EM and update your profile. Go to https://www.editorialmanager.com/pmedicine, log in, and click on the "Update My Information" link at the top of the page. Please update your user information to ensure an efficient production and billing process.

Thank you again for submitting the manuscript to PLOS Medicine. We look forward to publishing it.

Best wishes,

Clare Stone, PhD

Managing Editor

PLOS Medicine

plosmedicine.org