Dear Dr. SONG,

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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We look forward to receiving your revised manuscript.

Kind regards,

Tai Dinh

Academic Editor

PLOS ONE

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[This work was supported by the Trinity College Dublin-China Scholarship Council PhD Scholarship (Grant Number 202406920021). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.].

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[This work was supported by the Trinity College Dublin-China Scholarship Council PhD Scholarship (Grant Number 202406920021). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.]

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If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise. 

Additional Editor Comments:

Reviewer #1

Song and colleagues are planning to perform a systematic review and meta-analysis, here outlining their planned work in an overall well-written and constructed protocol. A PROSPERO version of the protocol is available, and as of 10th of July, it appears as if the work is at the stage of screening. Preferrably, the authors should have waited for at least the initial reviewer feedback before commencing the formal search and screening, but it is, at the same time, fully understandable that they have now, and in practical terms, this is often the reality. The topic is clinically relevant, with a novel angle, and I applaud the authors for submitting a detailed protocol! In general, I see no major issues with this protocol or the methodological approaches outlined; however, there are bits here and there that can benefit from some polishing and revision. I've outlined those below. Please apologize the many points, some of them are relatively trivial and have more the nature of questions.

PROSPERO (just three trivial questions)

- why did you switch the author order (between the PROSPERO protocol and this protocol)?

is any of the authors a methodologist (in meta-research/evidence synthesis)/librarian, or has a person with such competence been consulted throughout the planning of this SR/MA? (e.g., for double-checking the search queries or the like)

- is the "Current review stage" indeed up-to-date? Because as I see, the first three steps have been marked as "started", but neither of the first two have been marked as "completed"...

Title

- Why is the focus/(choice of word) on *mitigating* life-style factors? Usually, from what i see, life-style factors investigated are rather *risk* factors...

Abstract

- From the Background, it's not clear why a SR/MA is needed. Is it because the results from primary studies are conflicting? Is it that it's unclear which *specific* cognitive outcomes the associations are actually robust/consistent in? Something else?

- In Methods, you write "[...] in older adults with CMM"... but what's the control group then? Please clarify/specify this part

- In Methods, you write about two independent reviewers doing screening, but what about data extraction and quality assessment? Those should be performed in pairs as well

Introduction

- Please clarify the difference between cognitive decline and cognitive impairment

- I'd simplify line 61 to "two-fold"/"twice"

- The sentence on lines 66-68 feels unfinished..

- For the part on lines 88-93, please add country and mean age at baseline where it's missing

- On line 97, is it meant "[...] between CMM and cognitive outcomes [...]"?

- Wouldn't the sentence on lines 100-102 be better suited in the very beginning of that paragraph?

- Technically speaking (regarding lines 103-104), Alzheimer's disease is also a type of dementia.. So maybe just "dementia"? why limit yourselves in that regard?

- Again, on line 104, "[...] among older individuals with CMM [...]"... then who is the control group?

- Finally, on line 104, "[...] and 2) Identify [...]"... i think what you mean is to investigate? Also, again, I understand completely the interest in healthy lifestyle factors to adopt, but what about modifiable *risk* factors that can be avoided? it sounds mostly comprehensive when reading your text, but at times quite limiting (what you mean)...

Methods

- Which translation tools will be employed, and why?

- How will you deal with Google Scholar, given that it may easily return enormous amounts of records? Usually, SR/MA take the first 200-300 records or so; how is your plan, and why?

- Including gray literature is very good! but i wonder, is OpenGrey even searchable/indexed? It was more or less de facto defunct last time i checked... How about ProQuest Dissertations and Theses, OAIster, etc...

- I'd strongly recommend searching PubMed instead of Medline, as the former contains ALL of Medline-indexed records PLUS some preprints and other material that could potentially be relevant. Although Medline admittedly offers richer search syntax (e.g., NEAR/x), I'd argue that comprehensiveness outweighs in this case

- Any plans about ensuring non-western inclusion? E.g., i see you plan to use Web of Science, which is great. Please consider also searching KCI and SciELO through WoS (as i recall it doesn't search those by default, just the "core collection"). Also, please consider WHO Global Index Medicus, CABI Direct...

- I'm missing a search query for Google Scholar/OpenGrey

- Why the cut-off of ≥50 years (at baseline, i assume)?

- Hmm, reading the Comparators section, it remains a bit unclear to me, what will *actually* be investigated.. because based on lines 147-149, you are not searching for studies with control groups being without (as many) cardiometabolic diseases... so are you indeed *only* interested in populations where ≥2 CMDs are present?

- Are you sure that case-control studies qualify as longitudinal? Judging by the ROBINS-E paper, it's also not exactly geared for it ("Future work will produce variants of the tool for other epidemiologic study designs (e.g. case-control studies)."; https://pmc.ncbi.nlm.nih.gov/articles/PMC11098530). To strenghten the rigor and clinical utility of this SR/MA, i'd refrain from including case-control studies and keep it at prospective cohort studies, historical cohort data, case-cohort studies, nested case-control studies (i.e., within a cohort), etc..

- Please reconsider excluding letters to the editor. At least from my experience, the trend in some high-impact journals recently is to downgrade many good-quality articles to letters. Some of the authors then opt for putting most of the now "extra" material/data to suppl. material and online repositories (thus, the same data and rigor/detail is actually there, as in a "full-length" article)...

- Will you employ any definition of minimum follow-up length? Would it make sense for some outcomes, given how slowly they develop? Or is this something that you'll simply just comment on, if you see fit?

- I'd place (and also *do*) Data Extraction prior to Assessment of methodological quality

- I assume you might want to revise the estimated deadline on line 197?

- I agree that HR ≈ RR in case the outcome is rare (<15% or so), but i would say it's not quite the case otherwise (please see Table 2 in https://doi.org/10.7326/M16-2607)

- Please clarify (or rather, specify) the meta-analysis models you want to employ. I assume random-effects, although you specifically mention "mixed" modelling multiple times; what's the rationale and what setup are you expecting? Which method of assessment of between-study variance etc? Also, please consider looking into tau(2), as it's more robust than I2 for small sample sizes, if you fear such scenarios in particular

- Why meta-regression for RQ2? Do you really expect such data?

- Subgroup/sensitivity analyses seem fine, but why no sensitivity analysis excluding low-quality studies (for example)?

- Please consider making your R code publicly available, together with collected data (for meta-analysis); a great example/inspiration can be found here: https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1003731

Discussion

- Is there a reference or a further specified rationale for what is said about IPD MA on lines 256-258? My personal point of view is that the heterogeneity seen in clinical context is so great that MAs in and of themselves are by default quite "rough" and always need to be examined cautiously, and i haven't seen proof of IPD MA making things better per se (in this context)

Reviewer #2

This is a well structured manuscript from abstract to reference. But, the author did not include any tables or diagram to show what was done to back up the analysis. No evidence of the research carried out was involved in this manuscript.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

Reviewer #1: Yes

Reviewer #2: Yes

**********

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses??>

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable??>

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors described where all data underlying the findings will be made available when the study is complete??>

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: No

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #1: Yes

Reviewer #2: Yes

**********

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

Reviewer #1: Song and colleagues are planning to perform a systematic review and meta-analysis, here outlining their planned work in an overall well-written and constructed protocol. A PROSPERO version of the protocol is available, and as of 10th of July, it appears as if the work is at the stage of screening. Preferrably, the authors should have waited for at least the initial reviewer feedback before commencing the formal search and screening, but it is, at the same time, fully understandable that they have now, and in practical terms, this is often the reality. The topic is clinically relevant, with a novel angle, and I applaud the authors for submitting a detailed protocol! In general, I see no major issues with this protocol or the methodological approaches outlined; however, there are bits here and there that can benefit from some polishing and revision. I've outlined those below. Please apologize the many points, some of them are relatively trivial and have more the nature of questions.

PROSPERO (just three trivial questions)

- why did you switch the author order (between the PROSPERO protocol and this protocol)?

is any of the authors a methodologist (in meta-research/evidence synthesis)/librarian, or has a person with such competence been consulted throughout the planning of this SR/MA? (e.g., for double-checking the search queries or the like)

- is the "Current review stage" indeed up-to-date? Because as I see, the first three steps have been marked as "started", but neither of the first two have been marked as "completed"...

Title

- Why is the focus/(choice of word) on *mitigating* life-style factors? Usually, from what i see, life-style factors investigated are rather *risk* factors...

Abstract

- From the Background, it's not clear why a SR/MA is needed. Is it because the results from primary studies are conflicting? Is it that it's unclear which *specific* cognitive outcomes the associations are actually robust/consistent in? Something else?

- In Methods, you write "[...] in older adults with CMM"... but what's the control group then? Please clarify/specify this part

- In Methods, you write about two independent reviewers doing screening, but what about data extraction and quality assessment? Those should be performed in pairs as well

Introduction

- Please clarify the difference between cognitive decline and cognitive impairment

- I'd simplify line 61 to "two-fold"/"twice"

- The sentence on lines 66-68 feels unfinished..

- For the part on lines 88-93, please add country and mean age at baseline where it's missing

- On line 97, is it meant "[...] between CMM and cognitive outcomes [...]"?

- Wouldn't the sentence on lines 100-102 be better suited in the very beginning of that paragraph?

- Technically speaking (regarding lines 103-104), Alzheimer's disease is also a type of dementia.. So maybe just "dementia"? why limit yourselves in that regard?

- Again, on line 104, "[...] among older individuals with CMM [...]"... then who is the control group?

- Finally, on line 104, "[...] and 2) Identify [...]"... i think what you mean is to investigate? Also, again, I understand completely the interest in healthy lifestyle factors to adopt, but what about modifiable *risk* factors that can be avoided? it sounds mostly comprehensive when reading your text, but at times quite limiting (what you mean)...

Methods

- Which translation tools will be employed, and why?

- How will you deal with Google Scholar, given that it may easily return enormous amounts of records? Usually, SR/MA take the first 200-300 records or so; how is your plan, and why?

- Including gray literature is very good! but i wonder, is OpenGrey even searchable/indexed? It was more or less de facto defunct last time i checked... How about ProQuest Dissertations and Theses, OAIster, etc...

- I'd strongly recommend searching PubMed instead of Medline, as the former contains ALL of Medline-indexed records PLUS some preprints and other material that could potentially be relevant. Although Medline admittedly offers richer search syntax (e.g., NEAR/x), I'd argue that comprehensiveness outweighs in this case

- Any plans about ensuring non-western inclusion? E.g., i see you plan to use Web of Science, which is great. Please consider also searching KCI and SciELO through WoS (as i recall it doesn't search those by default, just the "core collection"). Also, please consider WHO Global Index Medicus, CABI Direct...

- I'm missing a search query for Google Scholar/OpenGrey

- Why the cut-off of ≥50 years (at baseline, i assume)?

- Hmm, reading the Comparators section, it remains a bit unclear to me, what will *actually* be investigated.. because based on lines 147-149, you are not searching for studies with control groups being without (as many) cardiometabolic diseases... so are you indeed *only* interested in populations where ≥2 CMDs are present?

- Are you sure that case-control studies qualify as longitudinal? Judging by the ROBINS-E paper, it's also not exactly geared for it ("Future work will produce variants of the tool for other epidemiologic study designs (e.g. case-control studies)."; https://pmc.ncbi.nlm.nih.gov/articles/PMC11098530). To strenghten the rigor and clinical utility of this SR/MA, i'd refrain from including case-control studies and keep it at prospective cohort studies, historical cohort data, case-cohort studies, nested case-control studies (i.e., within a cohort), etc..

- Please reconsider excluding letters to the editor. At least from my experience, the trend in some high-impact journals recently is to downgrade many good-quality articles to letters. Some of the authors then opt for putting most of the now "extra" material/data to suppl. material and online repositories (thus, the same data and rigor/detail is actually there, as in a "full-length" article)...

- Will you employ any definition of minimum follow-up length? Would it make sense for some outcomes, given how slowly they develop? Or is this something that you'll simply just comment on, if you see fit?

- I'd place (and also *do*) Data Extraction prior to Assessment of methodological quality

- I assume you might want to revise the estimated deadline on line 197?

- I agree that HR ≈ RR in case the outcome is rare (<15% or so), but i would say it's not quite the case otherwise (please see Table 2 in https://doi.org/10.7326/M16-2607)

- Please clarify (or rather, specify) the meta-analysis models you want to employ. I assume random-effects, although you specifically mention "mixed" modelling multiple times; what's the rationale and what setup are you expecting? Which method of assessment of between-study variance etc? Also, please consider looking into tau(2), as it's more robust than I2 for small sample sizes, if you fear such scenarios in particular

- Why meta-regression for RQ2? Do you really expect such data?

- Subgroup/sensitivity analyses seem fine, but why no sensitivity analysis excluding low-quality studies (for example)?

- Please consider making your R code publicly available, together with collected data (for meta-analysis); a great example/inspiration can be found here: https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1003731

Discussion

- Is there a reference or a further specified rationale for what is said about IPD MA on lines 256-258? My personal point of view is that the heterogeneity seen in clinical context is so great that MAs in and of themselves are by default quite "rough" and always need to be examined cautiously, and i haven't seen proof of IPD MA making things better per se (in this context)

Reviewer #2: This is a well structured manuscript from abstract to reference. But, the author did not include any tables or diagram to show what was done to back up the analysis. No evidence of the research carried out was involved in this manuscript.

**********

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:  Daniil Lisik

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.

Dear Dr. SONG,

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 30 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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

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

We look forward to receiving your revised manuscript.

Kind regards,

Tai Dinh

Academic Editor

PLOS ONE

Journal Requirements:

If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise. 

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:

Please further revise the manuscript to address all comments raised by the reviewer.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

Reviewer #1: Yes

Reviewer #2: Yes

**********

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses??>

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable??>

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors described where all data underlying the findings will be made available when the study is complete??>

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #1: Yes

Reviewer #2: Yes

**********

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

Reviewer #1: The authors have provided thorough and professional responses and appropriate revisions. I am happy.

Reviewer #2: Thank you for your response. But, you only attached a checklist for the analysis and not the analysis itself, which do not suffice in my opinion, I understand your point about availability at the moment. You also need to know that, the analysis is important for your research paper.

**********

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:  Daniil Lisik

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

The role of lifestyle in mitigating cognitive decline in older adults with cardiometabolic multimorbidity (CMM): A protocol of systematic review and meta-analysis

PONE-D-25-25646R2

Dear Dr. SONG,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager®  and clicking the ‘Update My Information' link at the top of the page. For questions related to billing, please contact billing support .

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Tai Dinh

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

The authors have revised the paper according to the reviewers’ suggestions, and I have therefore decided to accept it.

Reviewers' comments: