Clinical characteristics, comorbidities, and correlation with advanced lipedema stages: A retrospective study from a Swiss referral centre

Xhyljeta Luta; Giacomo Buso; Enrica Porceddu; Roxani Psychogyiou; Sanjiv Keller; Lucia Mazzolai

doi:10.1371/journal.pone.0319099

Peer Review History

Original SubmissionDecember 12, 2024
12 Dec 2024 Author Response https://doi.org/10.1371/journal.pone.0319099.r001
29 Dec 2024 Decision Letter - Tanja Grubić Kezele, Editor PONE-D-24-57104Clinical characteristics, comorbidities, and predictors of disease severity in lipedema: A retrospective study from a Swiss referral centrePLOS ONE Dear Dr. Xhyljeta, 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. ============================== Based on the reviewers' suggestions, the paper needs major revision. The reviewers' comments can be found below.<o:p></o:p> ============================== Please submit your revised manuscript by Feb 12 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. 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, Tanja Grubić Kezele, Ph.D., M.D. Academic Editor PLOS ONE Journal requirements: When submitting your revision, we need you to address these additional requirements. 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 2. 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. b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of recommended repositories, please see https://journals.plos.org/plosone/s/recommended-repositories. You also have the option of uploading the data as Supporting Information files, but we would recommend depositing data directly to a data repository if possible. Please update your Data Availability statement in the submission form accordingly. [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? 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: Partly Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 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: No Reviewer #2: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 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: The big strength of the article is indeed the fact that it uses existing data of participants who have been diagnosed with lipedema.However, I have some comments that in my opinion may improve this article: 1. Title: you mention predictors of lipedema in the title, and later on in the text, and those predictors are age and BMI - I think taking into account the fact that this is retrospective and not longitudinal study it is really hard to say to what extent these are predictors, especially that BMI is such a problematic measurement. Maybe saying that these are correlates would just be safer and closer to the truth. Abstract:You mention: "Descriptive statistics and logistic regression were used for analysis." Descriptive statistics in my opinion cannot be used to analyze but to describe - maybe you can rephrase this sentence?"Severe lipedema" - you use that term very often, I am not so sure if that's the best statement, maybe advanced lipedema? or some other term?I'd also rewrite the conclusions - I am not quite sure to what extent your study demonstrates clinical burden of lipedema and the sentence about overlooking symptoms is not clear to me - do you mean other studies or your study? IntroductionAlthough there is not international consensus about management of lipedema - there are several guidelines in different countries, e.g. all of them mention the need for a complex approach, taking into account lifestyle management. Results,It is unclear to me what p-value means in Table one. Is the difference significant between all of the group, only one of them? What was the statistics used to calculate that, is it chi square? If so, then it should maybe be briefly explained in the text. Also, sometimes is reported, sometimes not, so it is just unclear why.Same in prevalence of comorbidities and differences between groups, was it calculated with chi-square? "The most common was compression therapy198 (55.9%), followed by contraception (18.4%), manual lymphatic drainage (15.2%), psychotropic199 medications (12.6%), and hormonal therapy (11.0%). "Was contraception prescribed for lipedema? It is unclear to me why you report this, same with psychotropic drugs and hormonal therapy. Especially under the title conservative treatment. Maybe you need to clarify why you report this data and which of those treatments are for lipedema. Discussion In the discussion you mention depression, however in the results you report that 64% reported anxiety, and 24 % depression, and you never refer to the anxiety in the discussion. It would be good to include this. You mention that "Most studies link lipedema to psychological distress, though one study found it preceded lipedema symptoms in 80% of participants [52]"In the cited study the authors interviewed patients already diagnosed with ipedema and based on that concluded that stress preceded some symptoms (especially pain), I don't think we can say that stress or depression preceds lipedema symptoms based on such methodology. Or maybe we can say that is precedes pain occurrence. So I'd suggest to rephrase that. Based on your study you can safely say that there is a correlation, or that depression is frequent comorbidity. " Moreover, the older age of those with severe disease supports the view that lipedema is progressive, contrary to some suggestions " I think this might be a correlation - it is hard to say unless you conduct a longitudinal study. " In our cohort, pain, fatigue, anxiety, and depression levels did not differ significantly293 between stages, suggesting that current classifications fail to capture symptom severity and QoL" I think this is an important conclusion that could be emphasized Reviewer #2: the authors tackle a topic that is little researched, so the report is certainly of interest. - I would use different words than "genetic transmission", being for sure a mutlifactorial disease - In conservative treatment right nutrition must be considered, particularly ketogenic diet, that even in a case report, positively impacts QoL 10.3390/life11121402 - criteria (2) is a poor indicator, in clinical practice there are good results reported if right nutritional plan are applied, not the case of "classical" scheme with 50% of calories from carbohydrate or more - two comorbidities are often reported: PCOS and insulin resistance, have you been screened? ****** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean? ). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy . Reviewer #1: No 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. https://doi.org/10.1371/journal.pone.0319099.r002
Revision 1
16 Jan 2025 Author Response We thank the editor and the reviewers for their time and thoughtful comments that have helped us to improve our manuscript. Our detailed responses below are bolded directly underneath each Editor/Reviewer comment. Corresponding changes are made in the main body of the manuscript. We have ensured that our revised manuscript adheres to PLOS ONE's style requirements. We have referred to the style templates provided at the suggested links. Our study involves sensitive human participant data, and ethical restrictions prevent us from sharing de-identified datasets publicly. These restrictions were imposed by Research Ethics Committee. Requests for data access can be directed to the following contact referencing our project ID: CER-VD, BASEC 2023-02221: Commission cantonale d'éthique de la recherche sur l'être humain Avenue de Chailly 23 1012 Lausanne Tel: + 41 21 316 18 36 E-Mail: scientifique.cer@vd.ch We have updated our Data Availability Statement in the submission form to reflect this restriction and provide clear instructions for requesting data access. Reviewers' comments: Authors’ response to Reviewer #1 The big strength of the article is indeed the fact that it uses existing data of participants who have been diagnosed with lipedema. However, I have some comments that in my opinion may improve this article: We thank the reviewer for the detailed and valuable suggestions. Title: you mention predictors of lipedema in the title, and later on in the text, and those predictors are age and BMI - I think taking into account the fact that this is retrospective and not longitudinal study it is really hard to say to what extent these are predictors, especially that BMI is such a problematic measurement. Maybe saying that these are correlates would just be safer and closer to the truth. We agree with the reviewer and have revised the title to replace "predictors" with "correlates" to better reflect the nature of our analysis. Clinical characteristics, comorbidities, and correlation with advanced lipedema stages: A retrospective study from a Swiss referral centre Abstract: You mention: "Descriptive statistics and logistic regression were used for analysis." Descriptive statistics in my opinion cannot be used to analyze but to describe - maybe you can rephrase this sentence? We have revised the sentence in the abstract to clarify that descriptive statistics were used to summarise the data, while logistic regression was employed for analysis. Descriptive statistics were used to summarise the data, and logistic regression was employed for analysis (Page 2, lines 31-32). "Severe lipedema" - you use that term very often, I am not so sure if that's the best statement, maybe advanced lipedema? or some other term? We agree with the suggestion and have replaced "severe lipedema" with "advanced lipedema" throughout the manuscript. I'd also rewrite the conclusions - I am not quite sure to what extent your study demonstrates clinical burden of lipedema and the sentence about overlooking symptoms is not clear to me - do you mean other studies or your study? We have rephrased the conclusions in the abstract to represent our findings, emphasizing the correlation more accurately between advanced disease stages and quality of life and clarifying the reference to overlooked symptoms . Our study highlights frequent comorbidities in patients with lipedema, including chronic venous disease, obesity, and mental health conditions such as anxiety and depression. The distribution of comorbidities supports the need for tailored management. The correlation between disease stages, age, and BMI suggests potential progression, warranting confirmation through prospective studies (Page3, lines 46-49). Introduction: Although there is not international consensus about management of lipedema - there are several guidelines in different countries, e.g. all of them mention the need for a complex approach, taking into account lifestyle management. We have expanded the introduction to reference international guidelines on lipedema management and emphasized the importance of a multifaceted approach. Although there is no international consensus on the management of lipedema, several guidelines exist across different countries. These guidelines universally emphasise the importance of a comprehensive approach that includes lifestyle management (Page 4, lines 71-74). References • Reich-Schupke S, Schmeller W, Brauer WJ, Cornely ME, Faerber G, Ludwig M, Lulay G, Miller A, Rapprich S, Richter DF, Schacht V, Schrader K, Stücker M, Ure C. S1 guidelines: Lipedema. J Dtsch Dermatol Ges. 2017 Jul;15(7):758-767. • Faerber G, Cornely M, Daubert C, et al. S2k guideline lipedema. JDDG: Journal der Deutschen Dermatologischen Gesellschaft. 2024; 22: 1303–1315. • Hardy D, Williams A. Best practice guidelines for the management of lipoedema. Br J Community Nurs. 2017 Oct 1;22(Sup10):S44-S48. doi: 10.12968/bjcn.2017.22.Sup10.S44. PMID: 28961048. • Herbst KL, Kahn LA, Iker E, Ehrlich C, Wright T, McHutchison L, Schwartz J, Sleigh M, Donahue PM, Lisson KH, Faris T, Miller J, Lontok E, Schwartz MS, Dean SM, Bartholomew JR, Armour P, Correa-Perez M, Pennings N, Wallace EL, Larson E. Standard of care for lipedema in the United States. Phlebology. 2021 Dec;36(10):779-796. doi: 10.1177/02683555211015887. Epub 2021 May 28. PMID: 34049453; PMCID: PMC8652358. • Cannataro R, Michelini S, Ricolfi L, Caroleo MC, Gallelli L, De Sarro G, Onorato A, Cione E. Management of Lipedema with Ketogenic Diet: 22-Month Follow-Up. Life (Basel). 2021 Dec 15;11(12):1402. doi: 10.3390/life11121402. PMID: 34947933; PMCID: PMC8707844. Results: It is unclear to me what p-value means in Table one. Is the difference significant between all of the group, only one of them? We apologise for any confusion. The p-value in Table 1 represents the differences between individual groups rather than an overall comparison. To make this clearer, we have added a note in Table 1 explaining the interpretation of the p-values provided (Page 9, lines 160-161). What was the statistics used to calculate that, is it chi square? If so, then it should maybe be briefly explained in the text. Also, sometimes is reported, sometimes not, so it is just unclear why. Same in prevalence of comorbidities and differences between groups, was it calculated with chi-square? The statistics used to calculate the p-values in Table 1 were indeed derived from chi-square tests. We have added a brief explanation of the statistical method in the text to provide clarity. Comparisons across lipedema stages were conducted using chi-square tests for categorical variables (e.g., BMI classification, lipedema type, and comorbidities) (Page 7, lines 138-140). "The most common was compression therapy198 (55.9%), followed by contraception (18.4%), manual lymphatic drainage (15.2%), psychotropic199 medications (12.6%), and hormonal therapy (11.0%). "Was contraception prescribed for lipedema? It is unclear to me why you report this, same with psychotropic drugs and hormonal therapy. Especially under the title conservative treatment. Maybe you need to clarify why you report this data and which of those treatments are for lipedema. We acknowledge the confusion and have clarified that these treatments were part of the participants' reported medical history and not specifically prescribed for lipedema. Additionally, we have updated the heading title to: Concomitant medications, conservative treatments, and surgical therapy (Page 11, line 203). Table 4 summarises the most commonly reported concomitant medications and treatments from the medical history. Among conservative treatments, the most frequent was compression therapy (55.9%), followed by manual lymphatic drainage (15.2%). Other commonly prescribed medications, beyond conservative treatments, included contraception (18.4), psychotropic drugs (12.6%), and hormonal therapy (11.0%) (Page 11, lines 204-208). Discussion In the discussion you mention depression, however in the results you report that 64% reported anxiety, and 24 % depression, and you never refer to the anxiety in the discussion. It would be good to include this. Thank you for your observation. We have expanded the discussion to incorporate the data on anxiety and highlighted its significance in relation to previous research. The high prevalence of depression and anxiety in our study population aligns with previous literature (Page 15, lines 289-290). You mention that "Most studies link lipedema to psychological distress, though one study found it preceded lipedema symptoms in 80% of participants [52]"In the cited study the authors interviewed patients already diagnosed with lipedema and based on that concluded that stress preceded some symptoms (especially pain), I don't think we can say that stress or depression precedes lipedema symptoms based on such methodology. Or maybe we can say that is precedes pain occurrence. So I'd suggest to rephrase that. Thank you for bringing this to our attention. We agree with your observation and have revised the statement to clarify that the cited study suggests stress may precede the occurrence of certain symptoms, particularly pain, rather than lipedema symptoms more broadly. Most studies link lipedema to psychological distress, though one study found it preceded pain occurrence in 80% of participants (Page 15, lines 291-293). Based on your study you can safely say that there is a correlation, or that depression is frequent comorbidity. We agree that our study demonstrates a correlation and confirms that depression and anxiety are frequent comorbidities. We have updated the text to reflect this and further emphasised the importance of addressing the psychological burden in lipedema patients through timely assessment and specialist support. In our study, depression and anxiety were common comorbidities, highlighting the importance of assessing the psychological burden in lipedema patients and ensuring timely referral to specialist support when necessary (Page 15, lines 294-296). " Moreover, the older age of those with severe disease supports the view that lipedema is progressive, contrary to some suggestions " I think this might be a correlation - it is hard to say unless you conduct a longitudinal study. We have revised the discussion to clarify that our findings suggest a correlation between age and advanced disease stage, without implying definitive evidence of disease progression. The older age observed in individuals with advanced disease suggests a potential progression of lipedema, which contrasts with some previous suggestions. However, due to the design of our study, we cannot establish a causal relationship (Pages 15-16, lines 299-301). " In our cohort, pain, fatigue, anxiety, and depression levels did not differ significantly293 between stages, suggesting that current classifications fail to capture symptom severity and QoL" I think this is an important conclusion that could be emphasized. We have highlighted this finding more prominently in conclusions, stressing the limitations of current classification systems in capturing symptom severity and quality of life. Pain, fatigue, anxiety, and depression levels showed no significant differences between stages, suggesting that current classifications may not adequately reflect symptom severity and QoL emphasising the need for clinical tools that integrate these parameters (Page 17, lines 328-331). Authors’ response to Reviewer #2 Reviewer #2: the authors tackle a topic that is little researched, so the report is certainly of interest. We thank the reviewer for the supportive comments. - I would use different words than "genetic transmission", being for sure a mutlifactorial disease . We have replaced "genetic transmission" with "genetic predisposition" to better align with the multifactorial nature of lipedema. Genetic predisposition is possible, as lipedema often runs in families (Page 3, lines 57-58). - In conservative treatment right nutrition must be considered, particularly ketogenic diet, that even in a case report, positively impacts QoL 10.3390/life11121402 We acknowledge the potential role of nutrition, particularly the ketogenic diet, in improving the quality of life for lipedema patients, as highlighted in the cited case report. While our study did not specifically explore dietary interventions, we agree that this is an important area for further research to better understand its impact on symptom management and overall quality of life. To highlight the significance of nutrition in conservative treatment approaches, we have incorporated the following references into the introduction: • Cannataro R, Michelini S, Ricolfi L, Caroleo MC, Gallelli L, De Sarro G, et al. Management of Lipedema with Ketogenic Diet: 22-Month Follow-Up. Life (Basel). 2021;11(12). • Lundanes J, Sandnes F, Gjeilo KH, Hansson P, Salater S, Martins C, Nymo S. Effect of a Low-Carbohydrate Diet on Pain and Quality of Life in Female Patients with Lipedema: A Randomized Controlled Trial. Obesity (Silver Spring). 2024 Jun;32(6):1071-1082. doi: 10.1002/oby.24026. Epub 2024 Apr 16. PMID: 38627016. • We appreciate the perspective on the benefits of tailored nutritional plans over traditional dietary approaches. In addition, we have revised Criterion 2 to reflect these considerations and to emphasize the potential effectiveness of specific nutritional interventions: (2) Minimal improvement with conventional weight loss strategies (excluding ketogenic diets) (Page 5, lines 94-95). - two comorbidities are often reported: PCOS and insulin resistance, have you been screened? We acknowledge the importance of screening for PCOS and insulin resistance in the context of lipedema. However, these comorbidities were not screened for in our study. We appreciate your suggestion and will consider including such assessments in future research to provide a more comprehensive analysis. Attachments Attachment Submitted filename: Response_to_Reviewers.pdf https://doi.org/10.1371/journal.pone.0319099.r003
28 Jan 2025 Decision Letter - Tanja Grubić Kezele, Editor Clinical characteristics, comorbidities, and correlation with advanced lipedema stages: A retrospective study from a Swiss referral centre PONE-D-24-57104R1 Dear Dr. Xhyljeta, 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. If you have any questions relating to publication charges, please contact our Author Billing department directly at authorbilling@plos.org. 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, Tanja Grubić Kezele, Ph.D., M.D. Academic Editor PLOS ONE Additional Editor Comments (optional): 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 ******** 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 ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: (No Response) Reviewer #2: The authors addressed engough my comments ****** 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: No Reviewer #2: No ******** https://doi.org/10.1371/journal.pone.0319099.r004
Formally Accepted
Acceptance Letter - Tanja Grubić Kezele, Editor PONE-D-24-57104R1 PLOS ONE Dear Dr. Luta, 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 If revisions are needed, the production department will contact you directly to resolve them. If no revisions are needed, you will receive an email when the publication date has been set. At this time, we do not offer pre-publication proofs to authors during production of the accepted work. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few weeks 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. 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 Prof. dr. Tanja Grubić Kezele Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0319099.r005

Open letter on the publication of peer review reports

PLOS recognizes the benefits of transparency in the peer review process. Therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. Reviewers remain anonymous, unless they choose to reveal their names.

We encourage other journals to join us in this initiative. We hope that our action inspires the community, including researchers, research funders, and research institutions, to recognize the benefits of published peer review reports for all parts of the research system.

Learn more at ASAPbio .