Cardiovascular risk among middle-aged Japanese adults with atopic dermatitis: A nested case–control study

Misato Maeno; Mami Ishida; Risa Tamagawa-Mineoka; Naoyuki Takashima; Hiroshi Ikai

doi:10.1371/journal.pone.0341337

Peer Review History

Original SubmissionSeptember 25, 2025
25 Sep 2025 Author Response Transfer Alert This paper was transferred from another journal. As a result, its full editorial history (including decision letters, peer reviews and author responses) may not be present. https://doi.org/10.1371/journal.pone.0341337.r001
7 Nov 2025 Decision Letter - Seyed Aria Nejadghaderi, Editor Dear Dr. Ishida, 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 Dec 22 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'. 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If your ethics statement is written in any section besides the Methods, please delete it from any other section. 3. We note that you have indicated that there are restrictions to data sharing for this study. For studies involving human research participant data or other sensitive data, we encourage authors to share de-identified or anonymized data. However, when data cannot be publicly shared for ethical reasons, we allow authors to make their data sets available upon request. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. 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There is no requirement to cite these works unless the editor has indicated otherwise. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? Reviewer #1: Yes Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? -->?> Reviewer #1: Yes Reviewer #2: I Don't Know ****** 3. Have the authors made all data underlying the findings in their manuscript fully available??> The PLOS Data policy Reviewer #1: Yes Reviewer #2: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: Yes Reviewer #2: Yes ****** Reviewer #1: This manuscript investigates the association between atopic dermatitis (AD) and cardiovascular disease (CVD) in a middle-aged population in Japan. The authors employed a nested case-control design, utilizing data from the Kyoto Claim Database spanning ten years (April 2013 to March 2023). The study focuses on individuals aged 40–59 years, comparing first-onset CVD cases with matched controls without prior CVD history. The diagnosis of AD was defined based on both ICD-10 codes and prescribed topical corticosteroids, while logistic regression analysis was used to explore associations between AD, its severity, and CVD outcomes. The results indicate that, among the study population, there was no statistically significant association between AD and CVD onset. The authors report that the odds ratios for CVD occurrence did not support a relationship with either the presence or severity of AD. The paper acknowledges its limitations, particularly around potential misclassification of disease prevalence and severity inherent to claim-based data. comments: The manuscript's similarity index is high. The authors should work to reduce this significantly to ensure originality and clarity. The abstract should encapsulate a stronger public health message to highlight the implications of the findings for broader cardiovascular disease prevention strategies. The introduction would benefit from a clearer transition between the problem statement and the study objectives, helping readers understand the motivation behind the research. Captions for figures and tables should be improved to be more informative, enhancing reader comprehension of the data presented. The manuscript lacks details on the clinical settings in which the findings are applicable. Providing this context is crucial for interpreting risk and deriving meaningful conclusions. The limitations section should be expanded to include: Underreporting and variable data quality Confounding variables and the need for adjustment for comorbidities The inability to establish causality Absence of data on treatment settings and disease severity Lack of advanced stratification to explore heterogeneity in the population Please provide future research direction for the study I encourage the authors to consider performing external validation of their findings using other databases to enhance the robustness of their conclusions. The manuscript should clearly state the study sample size calculation, which is essential for understanding the statistical power of the findings. To improve discoverability, please provide keywords aligned with MeSH (Medical Subject Headings). The authors should elaborate on the specific steps taken in their analysis framework, detailing how model parameters and their corresponding confidence intervals (CIs) were derived. The manuscript needs to clarify how confounding factors were controlled in the analysis, aiding readers in understanding the study's integrity. I suggest that the authors discuss how the findings might apply to other populations or regions with differing contexts, potentially broadening the impact of their research. Reviewer #2: Dear authors: This is a well-organized, clearly written case–control study exploring whether atopic dermatitis is associated with cardiovascular disease risk in a large middle-aged Japanese cohort. However, the following areas need improvement: 1. Abstract could be slightly shortened and should state “no significant association” rather than “no positive association”. 2. The manuscript is clearly written in professional English, though minor grammatical corrections are needed (e.g., “systematic treatment” should be “systemic treatment”; “cardiac artery bypass” is better to be written “coronary artery bypass”). 3. The manuscript includes repetitive content across the Abstract, Results, and Discussion; condensing overlapping information and emphasizing interpretation would enhance clarity and flow. 4. The exclusion of participants with prior cardiovascular disease may introduce selection bias, as some patients with severe atopic dermatitis treated with systemic corticosteroids or JAK inhibitors (both known to increase cardiovascular risk) may have already developed CVD earlier and were therefore excluded from the dataset. This selective exclusion removes individuals at the highest risk, biasing the cohort toward healthier survivors and likely underestimating the true association between atopic dermatitis and cardiovascular disease. 5. The matching strategy (age, sex, major comorbidities) is appropriate; however, key behavioral confounders( smoking, BMI, physical activity, alcohol)are missing. This must be discussed more explicitly in the Limitations as residual confounding may mask true associations. 6. Although PLOS ONE allows format-free initial submission, the current placement of tables, figures, and the Sensitivity Analysis makes the manuscript hard to follow. placing figures and tables near their first mention or and the end would improve readability, while final formatting can follow PLOS ONE guidelines after acceptance. ****** what does this mean? ). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy Reviewer #1: No Reviewer #2: Yes: Shirin Zaresharifi ******** [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.] To ensure your figures meet our technical requirements, please review our figure guidelines: https://journals.plos.org/plosone/s/figures You may also use PLOS’s free figure tool, NAAS, to help you prepare publication quality figures: https://journals.plos.org/plosone/s/figures#loc-tools-for-figure-preparation. NAAS will assess whether your figures meet our technical requirements by comparing each figure against our figure specifications. https://doi.org/10.1371/journal.pone.0341337.r002
Revision 1
24 Dec 2025 Author Response Response to Editor 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf (Response) We confirmed it. 2. Your ethics statement should only appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please delete it from any other section. (Response) We confirmed it. 3. We note that you have indicated that there are restrictions to data sharing for this study. For studies involving human research participant data or other sensitive data, we encourage authors to share de-identified or anonymized data. However, when data cannot be publicly shared for ethical reasons, we allow authors to make their data sets available upon request. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. Before we proceed with your manuscript, please address the following prompts: a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information, data are owned by a third-party organization, etc.) and who has imposed them (e.g., a Research Ethics Committee or Institutional Review Board, etc.). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent. (Response) We updated our Data Availability statement in the submission form accordingly.　This study used data obtained from the Kyoto Prefecture Claims Database, Japan. The data were provided under restricted access and cannot be shared with third parties. Kyoto Prefecture, Japan, is the owner and custodian of the dataset. 4. Please provide a complete Data Availability Statement in the submission form, ensuring you include all necessary access information or a reason for why you are unable to make your data freely accessible. If your research concerns only data provided within your submission, please write "All data are in the manuscript and/or supporting information files" as your Data Availability Statement. (Response) Because we have restrictions on sharing a de-identified data set, we provided this reason in the Data Availability Statement submission form. 5. 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. (Response) There were no recommendations to add specific previously published works. Response to Reviewer #1 (Comment 1) The manuscript's similarity index is high. The authors should work to reduce this significantly to ensure originality and clarity. (Response) Thank you for your comments. We checked the similarity index of the manuscript using iThenticate. As you mentioned, the similarity index was high; however, this was largely due to the frequent use of terminologies common to the subject area in previously published work. Notably, there is an abundance of research papers published in this field. Furthermore, as the Introduction section was thought to rely heavily on citations from review articles, we re-examined whether all sources were appropriately referenced. We assure you that the research design is original, and we have substantially rewritten it to use original terminology as much as possible. (Comment 2) The abstract should encapsulate a stronger public health message to highlight the implications of the findings for broader cardiovascular disease prevention strategies. (Response) Thank you for your comments, but our findings did not strongly suggest that patients with atopic dermatitis (AD) should undergo more thorough cardiovascular disease (CVD) prevention strategies than those without AD. At the same time, we do not believe that CVD prevention should be neglected in patients with AD; we consider it to be just as necessary as it is for the general population. We added the sentence ‘Targeted CVD screening for patients with AD may not be necessary; however, comprehensive management of standard CVD risk factors remains essential, as in the general population.’ in the conclusion. (Comment 3) The introduction would benefit from a clearer transition between the problem statement and the study objectives, helping readers understand the motivation behind the research. (Response) We have substantially rewritten the manuscript for clarity and better readability. (Comment 4) Captions for figures and tables should be improved to be more informative, enhancing reader comprehension of the data presented. (Response) Thank you for your points. We revised the captions for figures and tables. (Comment 5) The manuscript lacks details on the clinical settings in which the findings are applicable. Providing this context is crucial for interpreting risk and deriving meaningful conclusions. (Response) We described the clinical settings in the ’Study design and Data source’ of the Methods. We revised it for clarity and better readability. (Comment 6) The limitations section should be expanded to include: Underreporting and variable data quality Confounding variables and the need for adjustment for comorbidities The inability to establish causality Absence of data on treatment settings and disease severity Lack of advanced stratification to explore heterogeneity in the population (Response) >Underreporting and variable data quality If it refers to limitations based on the characteristics of the insurance claims database, then we amended the first sentence of the limitations as follows: ‘First, defining AD using claims data, without access to clinical severity measures such as EASI or SCORAD, may have introduced misclassification, particularly for individuals who did not seek medical care or whose disease severity was underestimated.’ >Confounding variables and the need for adjustment for comorbidities Confounding factors that could be defined were adjusted for through matching. Factors that were not defined or obtained could not be adjusted for, as stated in the limitation, ‘Fifth, important coronary risk factors, including smoking, alcohol consumption, body mass index, and physical activity, were not captured in the claims data.’ >The inability to establish causality As this is an observational study, it is not designed to establish causality; therefore, it is not considered necessary to explicitly state this as a limitation of the present research. >Absence of data on treatment settings and disease severity We wrote it as a misclassification in the first limitation. We revised it as follows: ‘First, defining AD using claims data, without access to clinical severity measures such as EASI or SCORAD, may have introduced misclassification, particularly for individuals who did not seek medical care or whose disease severity was underestimated. >Lack of advanced stratification to explore heterogeneity in the population We added that ‘Finally, the study population consisted exclusively of Japanese individuals, which may limit the generalizability of the findings to other populations.’ (Comment 7) Please provide future research direction for the study. (Response) Thank you for your comments. We wrote the following: ‘To clarify the nature of this association, future studies should employ prospective designs with detailed clinical information and stratified analyses based on AD severity.’ in the last sentence of the 6th paragraph in the Discussion section. (Comment 8) I encourage the authors to consider performing external validation of their findings using other databases to enhance the robustness of their conclusions. (Response) Thank you for your suggestion. As this is not feasible within the scope of the current research, we will consider it as a future prospect. (Comment 9) The manuscript should clearly state the study sample size calculation, which is essential for understanding the statistical power of the findings. (Response) Thank you for your comments. The entire population in this database was included as the study cohort. Having previously estimated the odds ratio of 1.4, the required case sample size was calculated at 2,368 individuals; therefore, the current case participants of approximately 2,700 individuals were deemed sufficient. We added that in the ‘Case identification: CVD’ in the Method section. (Comment 10) To improve discoverability, please provide keywords aligned with MeSH (Medical Subject Headings). (Response) Thank you for pointing that out. We revised it as follows: “Dermatitis, Atopic, Cardiovascular Diseases, Case-Control Studies, Insurance Claim Review, Middle Aged”. (Comment 11) The authors should elaborate on the specific steps taken in their analysis framework, detailing how model parameters and their corresponding confidence intervals (CIs) were derived. (Response) We revised ‘Statistical analysis’ clearly as follows: To evaluate the association between AD and CVD, we employed a 1:10 matched case–control design, selecting 10 non-CVD controls for each CVD case based on age, sex, index month, hypertension, diabetes mellitus, dyslipidemia, hyperuricemia, and use of anticoagulant or antiplatelet agents. Logistic regression models were used to estimate odds ratios (ORs) with 95% confidence intervals (CIs) for AD prevalence and severity in relation to CVD risk.’ (Comment 12) The manuscript needs to clarify how confounding factors were controlled in the analysis, aiding readers in understanding the study's integrity. (Response) Thank you for your comments. We revised it clearly in the paragraph of ‘Matching factors’ and ‘Statistical analysis’ in the Method section. (Comment 13) I suggest that the authors discuss how the findings might apply to other populations or regions with differing contexts, potentially broadening the impact of their research. (Response) We added that ‘Finally, the study population consisted exclusively of Japanese individuals, which may limit the generalizability of the findings to other populations,’ as the last sentence in the Limitations. RESPONSE TO REVIEWER #2 (Comment 14) Abstract could be slightly shortened and should state “no significant association” rather than “no positive association”. (Response) Thank you for your comments. We revised the abstract. (Comment 15) The manuscript is clearly written in professional English, though minor grammatical corrections are needed (e.g., “systematic treatment” should be “systemic treatment”; “cardiac artery bypass” is better to be written “coronary artery bypass”). (Response) Thank you for pointing that out. We revised them as you mentioned. (Comment 16) The manuscript includes repetitive content across the Abstract, Results, and Discussion; condensing overlapping information and emphasizing interpretation would enhance clarity and flow. (Response) Thank you for your comments. We have rewritten it to clear the content. (Comment 17) The exclusion of participants with prior cardiovascular disease may introduce selection bias, as some patients with severe atopic dermatitis treated with systemic corticosteroids or JAK inhibitors (both known to increase cardiovascular risk) may have already developed CVD earlier and were therefore excluded from the dataset. This selective exclusion removes individuals at the highest risk, biasing the cohort toward healthier survivors and likely underestimating the true association between atopic dermatitis and cardiovascular disease. (Response) Thank you for your comments. As you mentioned, individuals with a diagnosis of CVD who had no episodes of CVD-related angioplasty, surgery, or hospitalization during the observation period were excluded from the study. When comparing the prevalence of AD and the proportion of patients receiving systemic treatment: corticosteroids, cyclosporine, or JAK inhibitors, it was not revealed that the excluded population had severe AD. We added it to the 7th paragraph, shown in S10 Table. (Comment 18) The matching strategy (age, sex, major comorbidities) is appropriate; however, key behavioral confounders (smoking, BMI, physical activity, alcohol) are missing. This must be discussed more explicitly in the Limitations as residual confounding may mask true associations. (Response) Thank you for your comments. We revised the sentence as follows: ‘Fifth, important coronary risk factors, including smoking, alcohol consumption, body mass index, and physical activity, were not captured in the claims data.‘ in the limitations. (Comment 19) Although PLOS ONE allows format-free initial submission, the current placement of tables, figures, and the Sensitivity Analysis makes the manuscript hard to follow. placing figures and tables near their first mention or and the end would improve readability, while final formatting can follow PLOS ONE guidelines after acceptance. (Response) Thank you for your advice. We placed them at the end. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0341337.r003
1 Jan 2026 Decision Letter - Seyed Aria Nejadghaderi, Editor Dear Dr. Ishida, Please submit your revised manuscript by Feb 15 2026 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 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, Seyed Aria Nejadghaderi Academic Editor PLOS One Journal Requirements: 1. 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. 2. 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 Reviewer #1: (No Response) Reviewer #2: (No Response) ******** 2. Is the manuscript technically sound, and do the data support the conclusions??> Reviewer #1: Yes Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? -->?> Reviewer #1: Yes Reviewer #2: I Don't Know ****** 4. Have the authors made all data underlying the findings in their manuscript fully available??> 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 ****** Reviewer #1: (No Response) Reviewer #2: Dear authors Thank you for carefully addressing all comments; the manuscript has improved substantially and all requested points have been satisfactorily met. As a final minor editorial correction, please ensure consistent statistical terminology by replacing “no positive association” with “no significant association” in the opening sentence of the Discussion and in the Conclusion, to align with the Abstract and the reported statistical results. ****** what does this mean? ). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy Reviewer #1: No Reviewer #2: Yes: Shirin Zaresahrifi ******** [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.] To ensure your figures meet our technical requirements, please review our figure guidelines: https://journals.plos.org/plosone/s/figures You may also use PLOS’s free figure tool, NAAS, to help you prepare publication quality figures: https://journals.plos.org/plosone/s/figures#loc-tools-for-figure-preparation. NAAS will assess whether your figures meet our technical requirements by comparing each figure against our figure specifications. https://doi.org/10.1371/journal.pone.0341337.r004
Revision 2
5 Jan 2026 Author Response January 05, 2026 Seyed Aria Nejadghaderi Academic Editor PLOS ONE Dear Editor, We have revised our manuscript in accordance with the detailed suggestions you have graciously provided. Response to Editor 1. 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. (Response) There were no recommendations to add specific previously published works. 2. 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. (Response) We have checked that there are no errors in the list of references. In the twelfth line of the second paragraph of the Introduction, the reference to hypertension has been partially amended. (The citation for reference 35 has been removed.) RESPONSE TO REVIEWER #2 (Comment) Thank you for carefully addressing all comments; the manuscript has improved substantially and all requested points have been satisfactorily met. As a final minor editorial correction, please ensure consistent statistical terminology by replacing “no positive association” with “no significant association” in the opening sentence of the Discussion and in the Conclusion, to align with the Abstract and the reported statistical results. (Response) Thank you for pointing that out. We revised them as you mentioned. Attachments Attachment Submitted filename: Response_to_Reviewers_auresp_2.docx https://doi.org/10.1371/journal.pone.0341337.r005
6 Jan 2026 Decision Letter - Seyed Aria Nejadghaderi, Editor Cardiovascular risk among middle-aged Japanese adults with atopic dermatitis: a nested case–control study PONE-D-25-50839R2 Dear Dr. Ishida, 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, Seyed Aria Nejadghaderi Academic Editor PLOS One Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0341337.r006
Formally Accepted
Acceptance Letter - Seyed Aria Nejadghaderi, Editor PONE-D-25-50839R2 PLOS One Dear Dr. Ishida, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS One. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset You will receive further instructions from the production team, including instructions on how to review your proof when it is ready. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few days to review your paper and let you know the next and final steps. Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. You will receive an invoice from PLOS for your publication fee after your manuscript has reached the completed accept phase. If you receive an email requesting payment before acceptance or for any other service, this may be a phishing scheme. Learn how to identify phishing emails and protect your accounts at https://explore.plos.org/phishing. If we can help with anything else, please email us at customercare@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Seyed Aria Nejadghaderi Academic Editor PLOS One https://doi.org/10.1371/journal.pone.0341337.r007

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