Correlation study of FGF23/D-serine in maintenance hemodialysis patients with combined hearing impairment

Dunlu Yuan; Jiaqing Li; Min Guo; Qing Yang; Jingjing Huang; Jingwen Nie; Ruomei Li; Qing Li

doi:10.1371/journal.pone.0280378

Peer Review History

Original SubmissionNovember 6, 2022
28 Nov 2022 Decision Letter - Gulali Aktas, Editor PONE-D-22-30210Correlation study of FGF23/D-serine in end-stage renal disease patients with combined hearing impairmentPLOS ONE Dear Dr. Li, 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 Jan 12 2023 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. 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Additional Editor Comments: Authors studied association between FGF23/D-serine in end-stage renal disease patients with hearing loss in the manuscript titled "Correlation study of FGF23/D-serine in end-stage renal disease patients with combined hearing impairment". FGF23 is an inflammatory marker and on the other hand, chronic kidney disease, especially diabetic kidney injury is also characterized with change in serum levels of inflammatory cytokines. I recommend authors discussing this issue. [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: Yes 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: Yes 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: Dear Authors Thank you very much for the opportunity of reviewing the manuscript entitled ‘Correlation study of FGF23/D-serine in end-stage renal disease patients with combined hearing impairment’ for your journal. The article is about clinically significant FGF23/D-serine on hearing impairment in patients with CRD. Indeed, the article is very interesting and of utmost importance to the field. Title is appropriate for article, summary abstracted the manuscript adequately, the keyword is enough. The background and the rationale of the study sufficiently expressed in introduction. Study cohort, laboratory and statistical analyses are well issued in methodology. Results of the study are interesting and given in an easy to read way. Discussion is faultless and is the most perfect section of the manuscript. It does not require any more revisions. References are accurate. Figures are clear. Table is informative. As a result, the article should be accepted for publication in the journal. Sincerely Reviewer #2: There are a few comments or questions that need clarification from the authors: 1. Why is the title ... in ESRD patients, not CKD patients with routine HD (MHD)? Given that HD plays an important role in phosphate removal, and influences fluctuations in phosphate levels, PTH, and possibly serum FGF-23 levels. 2. OR must be accompanied by 95% CI, because it can describe the accuracy of the data. 3. It is known that FGF-23 plays an important role in the metabolism of vitamin D and phosphate by increasing phosphate excretion with the end result being inhibition of secondary hyperparathyroidism. In this regard, is the presence of FGF-23 serum not just a marker or does it have a direct pathological effect? 4. To be able to bind to its receptor, FGF-23 requires the presence of Klotho. Why wasn't Klotho's serum level evaluated? 5. This study was conducted on patients with GFR < 15 mL/min/1.73 m2. Are all ESRD patients on dialysis? 6. Regarding point 5, it is important to inform the average eGFR and duration of HD in the data on the characteristics of the research subjects. 7. Considering that the HD process can affect the results of laboratory examinations directly or indirectly, the timing of blood sampling is very important related to the HD therapy itself, so further explanation is needed. 8. Similarly, laboratory data is dynamic in nature, whereas hearing loss is a relatively more static condition. Is sampling for laboratory examination carried out once or several times? ****** 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: Yes: mehmet zahid kocak 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.0280378.r001
Revision 1
20 Dec 2022 Author Response Dear Editor, Thank you for carefully reviewing our manuscript previously titled “Correlation study of FGF23/D-serine in maintenance hemodialysis patients with combined hearing impairment” for possible publication in the PLOS ONE. We are grateful to you and your reviewers for their constructive critique. We have revised the manuscript, highlighting our revisions in yellow and have attached point-by-point responses detailing how we have revised the manuscript in response to the reviewers' comments below. Thank you for your consideration and further review of our manuscript. Please do not hesitate to contact us with any further questions or recommendations. Yours Sincerely, Qing Li Department of Nephrology, the First Affiliated Hospital of Kunming Medical University, Kunming, 650032, Yunnan, China Position: Associate chief physician E-mail: liqing@kmmu.edu.cn； Tel.: +86-0871-65324888 ORCID of the author: 0000-0001-5452-2734 Reviewer Comments: Manuscript Number: PONE-D-22-30210 Manuscript Title: Correlation study of FGF23/D-serine in maintenance hemodialysis patients with combined hearing impairment Additional Editor Comments Authors studied association between FGF23/D-serine in end-stage renal disease patients with hearing loss in the manuscript titled "Correlation study of FGF23/D-serine in end-stage renal disease patients with combined hearing impairment". FGF23 is an inflammatory marker and on the other hand, chronic kidney disease, especially diabetic kidney injury is also characterized with change in serum levels of inflammatory cytokines. I recommend authors discussing this issue. Response: Done as what you suggested. We deeply appreciate your good suggestion. We have added discussion about this issue. Please see Discussion section: Page 15, Line 232-242, References section: Page23, Line 414-424. Previous studies found that FGF23 regulates the immune response and host defense against bacterial infections. Inflammatory cytokines, such as C-reactive protein and IL-6, increase with FGF23 elevation(20). Inflammatory conditions may also contribute to elevated FGF23 levels in circulation(21). In addition, diabetes mellitus is associated with inflammation and may lead to diabetic nephropathy. Preclinical studies found that insulin deficiency increases serum FGF23 concentration in mice, a process that can be reversed by administering insulin(22). Moreover, the elevation of FGF23 can result in inflammation in diabetic nephropathy. Therefore, FGF23 may be an inflammatory marker in diabetic nephropathy, which triggers a series of pathological changes in renal tissue (23). References 20. Zheng Z, Zheng F. Immune cells and inflammation in diabetic nephropathy. J Diabetes Res. 2016;2016:1841690. 21. Rossaint J, Unruh M, Zarbock A. Fibroblast growth factor 23 actions in inflammation: a key factor in CKD outcomes. Nephrol Dial Transplant.2017; 32(9):1448-53. 22. Bär L,Feger M,Fajol A.Insulin suppresses the production of fibroblast growth factor 23 (FGF23).Proceedings of the national academy of sciences of the United States of America.2018;115 (22):5804-9. 23. David V, Martin A, Isakova T, Spaulding C, Qi L, Ramirez V, et al. Inflammation and functional iron deficiency regulate fibroblast growth factor 23 production. Kidney Int. 2016;89(1):135-46. Reviewer 2 1. Why is the title ... in ESRD patients, not CKD patients with routine HD (MHD)? Given that HD plays an important role in phosphate removal, and influences fluctuations in phosphate levels, PTH, and possibly serum FGF-23 levels. Response: Done as what you suggested. We deeply appreciate your good suggestion. We have corrected the title: Correlation study of FGF23/D-serine in maintenance hemodialysis patients with combined hearing impairment Please see the title section: Page 1, Line 1-3. Title: Correlation study of FGF23/D-serine in maintenance hemodialysis patients with combined hearing impairment 2. OR must be accompanied by 95% CI, because it can describe the accuracy of the data. Response: We deeply appreciate your good suggestion. We have added 95%CI. Please see Abstract section: Page 2, Line40-41. Also, elevated FGF23 and D-serine were identified as risk factors for hearing impairment in ESRD, with ORs of 16.54 (95%CI, 2.75-99.55) and 15.22 (95% CI, 2.59-89.51), respectively. 3. It is known that FGF-23 plays an important role in the metabolism of vitamin D and phosphate by increasing phosphate excretion with the end result being inhibition of secondary hyperparathyroidism. In this regard, is the presence of FGF-23 serum not just a marker or does it have a direct pathological effect? Response: We deeply appreciate your good suggestion. We have added the discussion. Please see Introduction section: Page4-5, Line69-74；Discussion section: Page15, Line 243-249，References：Line 425-427. . Thus, elevated FGF23 is considered a sensitive biomarker for renal and extrarenal adverse effects in patients with CKD (10). Furthermore, abnormally high expression of FGF23 in patients with chronic renal failure accelerates a series of extrarenal damages such as organismal calciphylaxis, atherosclerosis, secondary bone disease, and cognitive impairment of the nervous system. FGF23 neutralization effectively improves bone quality and osseointegration in CKD mice, suggesting FGF23 as a key factor in CKD-related bone diseases (24). In addition, the risk of hearing impairment is significantly higher in ESRD patients with higher FGF23 levels than in those with lower FGF23 levels (2), which is consistent with the results of this study. So, FGF23 not only has an important biomarker in the development of CKD but also has a direct pathological effect on its complications. References 24.Sun N, Guo Y, Liu W, Densmore M, Shalhoub V, Erben RG , et al.FGF23 neutralization improves bone quality and osseointegration of titanium implants in chronic kidney disease mice. Scientific reports. 2015; 5:8304. 4. To be able to bind to its receptor, FGF-23 requires the presence of Klotho. Why wasn't Klotho's serum level evaluated? Response: We deeply appreciate your good suggestion. We have added the explanation. Please see Discussion section: Page15, Line 250-257. References：Line 429-438. FGF23 acts through FGFR and α-Klotho. A combination of Klotho/FGFR/FGF23 regulates FGF signal transduction (25). However, whether a series of pathological changes of FGF23 is essential for Klotho-mediated actions is still under debate (26). Research shows that Klotho and FGF23 are independently associated with concentric hypertrophy in CKD patients (27). Our previous study demonstrated that high levels of FGF23 are associated with hearing impairment in ESRD patients, independently of Klotho (2). So, the Klotho's serum level wasn’t evaluated in this study. References 25. Muñoz-CJR,Rodelo HC, Pendon RMV, Martin MA, Santamaria R, Rodriguez M; Klotho/FGF23 and Wnt Signaling as Important Players in the Comorbidities Associated with Chronic Kidney Disease .Toxins(Basel) , 2020; 12(3): 185. 26.Tanaka S, Fujita S, Kizawa S, Morita H, Ishizaka N. Association between FGF23, α-Klotho, and Cardiac Abnormalities among Patients with Various Chronic Kidney Disease Stages. PLoS ONE , 2016;11, e0156860. 27. Silva AP,Mendes F,Carias E, Gonçalves RB, Fragoso A, Dias C, et al.Plasmatic Klotho and FGF23 Levels as Biomarkers of CKD-Associated Cardiac Disease in Type 2 Diabetic Patients. International journal of molecular sciences,2019;20 (7) :1536. 5. This study was conducted on patients with GFR < 15 mL/min/1.73 m2. Are all ESRD patients on dialysis? Response: Yes，all ESRD patients on dialysis in the present study. Please see Material and Methods section: Page 6, Line98-100. Inclusion criteria were: age ≥ 18 years; glomerular filtration rate (GFR) < 15 mL/min-1.73m2; receiving regular hemodialysis for more than 3 months, four hours per session, 3 times/week 6. Regarding point 5, it is important to inform the average eGFR and duration of HD in the data on the characteristics of the research subjects. Response: Done as what you suggested. We deeply appreciate your good suggestion. We have added the average eGFR and duration of HD in the data on the characteristics of the research subjects. Please see Material and Methods section: Page 6, Line98-100, Results section: Page 10-11, Table 1. Inclusion criteria were: age ≥ 18 years; glomerular filtration rate (GFR) < 15 mL/min-1.73 m2; receiving regular hemodialysis for more than 3 months, four hours per session, 3 times/week; conscious; willing to participate in the study. Characteristic Control group (n=30) MHD+NH group (n=30) MHD+HI group (n=30) P Age(y) mean(SD) 43.17±8.95 43.43±8.79 43.90±10.38 0.954 Male no. (%) 16(53.3) 15(50.0) 22(73.3) 0.139 BMI (Kg/m2) mean(SD) 23.96±3.19 22.30±3.90 22.53±3.61 0.156 History of hypertension no. (%) 12(40.0) 30(100.0) 30(100.0) ＜0.001 History of diabetes mellitus no. (%) 3 (10.0) 3(10.0) 6(20.0) 0.421 CKD etiology no. (%) ＜0.001 Chronic glomerulonephritis 0(0.0) 18(60.0) 14(46.7) Diabetic nephropathy 0(0.0) 3(10.0) 6(20.0) Hypertensive nephropathy 0(0.0) 7(23.3) 9(30.0) Other 0(0.0) 2(6.7) 1（3.3） Creatinine (umol/L) mean(SD) 71.4±11.66 1179±289.28 1104.41±290.44 ＜0.001 BUN (mmol/L) mean(SD) 5.44±1.32 28.83±6.58 28.38±7.65 ＜0.001 e-GFR（mL/min-1.73 m2) 104.42±15.48 3.82±0.97 4.27±1.33 ＜0.001 Duration of dialysis(Month) 0.00±0.00 43.57±25.58 46.83±45.32 0.732 Hb (g/L) mean(SD) 154.37±15.41 104.8±18.03 108.17±18.48 ＜0.001 RBC (1012/L) mean(SD) 5.05±0.54 3.61±0.68 3.64±0.60 ＜0.001 ALB (g/L) mean(SD) 45.67±2.80 41.66±3.58 42.06±5.49 ＜0.001 PTH (pg/mL) mean(SD) 38.52±16.03 609.71±468.27 634.57±657.44 ＜0.001 Phosphorus (mmol/L) mean(SD) 1.22±0.16 2.53±0.62 2.4±0.71 ＜0.001 Calcium (mmol/L) mean(SD) 2.34±0.09 2.31±0.18 2.28±0.20 0.317 FGF23 (pg/ml) mean(SD) 26.62±23.40 96.52±65.07 167.26±81.93 ＜0.001 D-serine(μM）mean(SD) 1.97±0.66 9.09±2.71 12.27±2.18 ＜0.001 Notes. NH, Normal hearing ; HI, Hearing impairment ; ** P < 0.01 7. Considering that the HD process can affect the results of laboratory examinations directly or indirectly, the timing of blood sampling is very important related to the HD therapy itself, so further explanation is needed. Response: Done as what you suggested. We deeply appreciate your good suggestion. We have added the explanation. Please see Data Collection section: Page 7, Line134-137. All subjects fasted for at least 8 h. Then, 5 ml of venous blood was collected before 8:30 am. To avoid the influence of hemodialysis on laboratory data in MHD patients, blood was not collected during and 1 day after hemodialysis. Sampling for laboratory examination was carried out one-time. 8. Similarly, laboratory data is dynamic in nature, whereas hearing loss is a relatively more static condition. Is sampling for laboratory examination carried out once or several times? Response: We deeply appreciate your good suggestion. We have added the explanation. Please see Data Collection section: Page 7, Line135-137. To avoid the influence of hemodialysis on laboratory data in MHD patients, blood was not collected during and 1 day after hemodialysis.Sampling for laboratory examination was carried out one time. We deeply appreciate your constructive comments. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0280378.r002
28 Dec 2022 Decision Letter - Gulali Aktas, Editor Correlation study of FGF23/D-serine in maintenance hemodialysis patients with combined hearing impairment PONE-D-22-30210R1 Dear Dr. Li, 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 for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, 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, Gulali Aktas Academic Editor PLOS ONE Additional Editor Comments (optional): Authors successfully revised the paper in accordance with the reviewers' suggestions. 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: (No Response) ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: No Reviewer #2: (No Response) ****** 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: (No Response) ****** 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: (No Response) ****** 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: (No Response) ****** 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.0280378.r003
Formally Accepted
6 Jan 2023 Acceptance Letter - Gulali Aktas, Editor PONE-D-22-30210R1 Correlation study of FGF23/D-serine in maintenance hemodialysis patients with combined hearing impairment Dear Dr. Li: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. 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 plosone@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 Professor Gulali Aktas Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0280378.r004

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