Repeated rebiopsy for detection of EGFR T790M mutation in patients with advanced-stage lung adenocarcinoma: Associated factors and treatment outcomes of Osimertinib

Taeyun Kim; Junsu Choe; Sun Hye Shin; Byeong-Ho Jeong; Kyungjong Lee; Hojoong Kim; Se-Hoon Lee; Sang-Won Um

doi:10.1371/journal.pone.0310079

Peer Review History

Original SubmissionApril 8, 2024
18 Jun 2024 Decision Letter - Hamidreza Montazeri Aliabadi, Editor PONE-D-24-12639Repeated rebiopsy for detection of EGFR T790M mutation in patients with advanced-stage lung adenocarcinoma: associated factors and treatment outcomes of OsimertinibPLOS ONE Dear Dr. Um, 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 Aug 02 2024 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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In the online submission form, you indicated that "The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request." All PLOS journals now require all data underlying the findings described in their manuscript to be freely available to other researchers, either 1. In a public repository, 2. Within the manuscript itself, or 3. Uploaded as supplementary information. This policy applies to all data except where public deposition would breach compliance with the protocol approved by your research ethics board. If your data cannot be made publicly available for ethical or legal reasons (e.g., public availability would compromise patient privacy), please explain your reasons on resubmission and your exemption request will be escalated for approval. [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: Partly ******** 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: This is an interesting study about the T790M yield of repeated biopsies under EGFR TKI progression and their association with patient outcomes. I have the following comments: 1. It would have been helpful to give some information about the entire patient population: 100% had T790M after max 3 biopsies, but how many received biopsies (i.e. how many other patients had all biopsies negative) in the same time period? 2. It would be important to add the type of EGFR mutation in Table 1 (del19 vs. L858R vs. other rare mutations) 3. Regarding the analysis of survival: it would be important to also check other prognostic parameters, like the type of EGFR mutation. It is known that the type of EGFR mutation and presence of brain metastases are independent predictors of OS for these patients, which should be taken into account in the analysis, see for example https://pubmed.ncbi.nlm.nih.gov/32871455/, which could also be added in the Discussion. Reviewer #2: Um et al reported implications of repeated rebiopsy for T790M detection in patients with EGFR-mutant NSCLC and associated factors and treatment outcomes of osimertinib. Their manuscript includes several interesting points for readers. However, there is a critical methodologic problem in their study, and major modification is necessary. Major points: 1. Their study population focused on only osimertinib-administered patients. They insisted T790M detection rate on first rebiopsy of 69.9%. This is absolutely incorrect. As they mentioned, many studies reported clinical T790M detection rate on first rebiopsy of 30-50%. These previous studies consecutively examined all patients who received rebiopsy to detect T790M in their hospitals. The authors should also consecutively examine all rebiopsied patients in their institute. This is a critical problem in their study. 2. Similarly, T790M detection rates on second and third rebiopsies were incorrect. They excluded cases without T790M, since their study only examined T790M-positive cases. 3. They described “The median interval between the first and second rebiopsy was 12.5 days (IQR: 8.5-21.0 days).” This is astonished. After failure of first rebiopsy, was second rebiopsy performed on the same target? or another target? Their manuscript did not show detailed information on rebiopsy targets. Minor point: 1. EGFR should be italicized when they express a gene. (e.g., EGFR mutation) ****** 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: Petros Christopoulos 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. 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Revision 1
30 Jul 2024 Author Response Reviewer 1 Comment 1: It would have been helpful to give some information about the entire patient population: 100% had T790M after max 3 biopsies, but how many received biopsies (i.e. how many other patients had all biopsies negative) in the same time period? Response 1: Thank you for the valuable comment. In response to the comments from both reviewers, we re-checked the entire patient population who received rebiopsies during the study period. Therefore, we have also revised the patient selection process. In brief, a total of 443 patients received rebiopsies, with the cumulative rate of T790M detection increasing as follows: 14.2% after the first rebiopsy, 31.8% after the second, 38.8% after the third, 41.1% after the fourth, 41.5% after the fifth, and 42.0% after the sixth. We summarized these results as Fig 1 and Table 1. Also, we have revised the related sections: Abstract (Results), Materials and Methods, 1st paragraph of Results, and 1st and 3rd paragraph of Discussion. Comment 2 & 3: It would be important to add the type of EGFR mutation in Table 1 (del19 vs. L858R vs. other rare mutations). Regarding the analysis of survival: it would be important to also check other prognostic parameters, like the type of EGFR mutation. It is known that the type of EGFR mutation and presence of brain metastases are independent predictors of OS for these patients, which should be taken into account in the analysis, see for example https://pubmed.ncbi.nlm.nih.gov/32871455/, which could also be added in the Discussion. Response 2 & 3: Thank you for the comment and sharing a valuable reference. First, we have added numbers and percentages of EGFR mutation in Table 2. Second, we have re-estimated odds ratio from multivariable analyses additionally considering EGFR mutation status. Results are summarized in Table 5: however, in this analysis we could not find EGFR mutation as a distinguishing parameter in terms of number of rebiopsy and method for rebiopsy. Please refer to the Results section. Reviewer 2 Major points: Comment 1 & 2: Their study population focused on only osimertinib-administered patients. They insisted T790M detection rate on first rebiopsy of 69.9%. This is absolutely incorrect. As they mentioned, many studies reported clinical T790M detection rate on first rebiopsy of 30-50%. These previous studies consecutively examined all patients who received rebiopsy to detect T790M in their hospitals. The authors should also consecutively examine all rebiopsied patients in their institute. This is a critical problem in their study. Similarly, T790M detection rates on second and third rebiopsies were incorrect. They excluded cases without T790M, since their study only examined T790M-positive cases. Response 1 & 2: Thank you for the valuable comment. In response to the comments from both reviewers, we have re-checked the entire patient population who received rebiopsies during the study period. Therefore, we have also revised the patient selection process. In brief, a total of 443 patients received rebiopsies, with the cumulative rate of T790M detection increasing as follows: 14.2% after the first rebiopsy, 31.8% after the second, 38.8% after the third, 41.1% after the fourth, 41.5% after the fifth, and 42.0% after the sixth. We have summarized these results as Fig 1 and Table 1. Also, we have revised the related sections: Abstract (Results), Materials and Methods, 1st paragraph of Results, and 1st and 3rd paragraph of Discussion. Comment 3: They described “The median interval between the first and second rebiopsy was 12.5 days (IQR: 8.5-21.0 days).” This is astonished. After failure of first rebiopsy, was second rebiopsy performed on the same target? or another target? Their manuscript did not show detailed information on rebiopsy targets. Response 3: Thank you for the comment. The next target for rebiopsy was based on the clinician’s decision rather than on a protocolized approach. Therefore, we clarified this point in the method section. Minor point: Comment 1: EGFR should be italicized when they express a gene. (e.g., EGFR mutation) Response 1: We have italicized EGFR when it expresses the gene. Attachments Attachment Submitted filename: Response to Reviewers_revised_240727.docx https://doi.org/10.1371/journal.pone.0310079.r002
16 Aug 2024 Decision Letter - Hamidreza Montazeri Aliabadi, Editor PONE-D-24-12639R1Repeated rebiopsy for detection of EGFR T790M mutation in patients with advanced-stage lung adenocarcinoma: associated factors and treatment outcomes of OsimertinibPLOS ONE Dear Dr. Um, 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 make sure to specifically address the concerns raised by Reviewer 2. Please submit your revised manuscript by Sep 30 2024 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, Hamidreza Montazeri Aliabadi Academic Editor PLOS ONE Journal Requirements: 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 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: The authors have addressed all reviewers' comments and improved the manuscript accordingly. There are no further comments Reviewer #2: Um et al revised and resubmitted their manuscript with major modifications. Although their manuscript has several interesting and clinically meaningful points, there are still some unresolved critical problems in the manuscript. I feel Figure 1 was well modified and easy to understand for readers and their conclusions are excellent. Major points: 1. Results of abstract is inappropriate for a scientific paper. They exhibited little numeric data. Guide for authors of PLOS ONE describes, “Results – What did you find? Briefly give the key findings of your study. Include key numeric data (including confidence intervals or p values), where possible.”. They should thoroughly modify it. Table 1 is impressive and easy to understand for readers, and the findings should be included in the Results section. 2. S3 Table appears first in the Discussion. Also, sentences on lines 256-259: “In our institution, liquid biopsy was used as the primary method for T790M detection (73.7%, 330/448), likely due to the simplicity of blood sampling compared to tissue acquisition. Meanwhile, tissue biopsy was the predominant method for the second rebiopsy (59.2%, 215/363).” appear first in the Discussion. Such expressions are really inappropriate for scientific papers. What the authors did not mention in the Result should not be used in the Discussion. They must mention these results in the Result section, previously. 3. T790M-positive rate at first rebiopsy was only 14%. This is lower than former pivotal reports on T790M-positive rate: 30-50%. They considered high rate of liquid biopsy caused this lower T790M-positive rate. So, they should demonstrate rates of liquid and histologic biopsies from first to sixth rebiopsy in the Result section. 4. On lines 146-147, they described, “For the final analysis, 143 patients were included and they received a maximum of three repeated rebiopsies.”. This is confusing. Table 1 shows some patients received sixth rebiopsy. What? ****** 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: Yes: Petros Christopoulos 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.0310079.r003
Revision 2
19 Aug 2024 Author Response Response to Reviewer’s comments Um et al revised and resubmitted their manuscript with major modifications. Although their manuscript has several interesting and clinically meaningful points, there are still some unresolved critical problems in the manuscript. I feel Figure 1 was well modified and easy to understand for readers and their conclusions are excellent. Major points: Comment 1: Results of abstract is inappropriate for a scientific paper. They exhibited little numeric data. Guide for authors of PLOS ONE describes, “Results – What did you find? Briefly give the key findings of your study. Include key numeric data (including confidence intervals or p values), where possible.”. They should thoroughly modify it. Table 1 is impressive and easy to understand for readers, and the findings should be included in the Results section. Response 1: Thank you for the comment. We have added key numerical data with p values to the Results section of Abstract as follows. “Progression-free survival was not significantly different in terms of the methods (tissue: 13.3 months, 95% confidence interval [CI]: [9.4, 23.5] vs plasma: 11.1 months, 95% CI: [8.1, 19.4], p=0.33) and numbers (one: 13.4 months, 95% CI: [9.4, 23.5] vs two or more: 11.0 months, 95% CI: [8.1, 14.8], p=0.51) of repeated rebiopsies. Longer overall survival (OS) was found in patients in whom T790M was detected by tissue specimens rather than by plasma ctDNA (2-year OS rate: 81.7% for tissue vs 63.9% for plasma, p = 0.0038).” We have also added the key numerical data in the Results section. Comment 2: S3 Table appears first in the Discussion. Also, sentences on lines 256-259: “In our institution, liquid biopsy was used as the primary method for T790M detection (73.7%, 330/448), likely due to the simplicity of blood sampling compared to tissue acquisition. Meanwhile, tissue biopsy was the predominant method for the second rebiopsy (59.2%, 215/363).” appear first in the Discussion. Such expressions are really inappropriate for scientific papers. What the authors did not mention in the Result should not be used in the Discussion. They must mention these results in the Result section, previously. Response 2: Thank you for your comments. We have added following sentences in the Results section (Clinical characteristics associated with detection of T790M in plasma ctDNA). “The characteristics of patients according to the sites of T790M detection are summarized in S3 Table. Stage 4B, brain metastasis, bone metastasis and pleural metastasis were more common in the group with T7900M confirmation using plasma ctDNA compared to those with T790M confirmation using tissue biopsy.” We have also added following sentences in the Results section (Baseline Characteristics). “The majority of patients (74.5%) received their first rebiopsy using a liquid biopsy, while most patients at the second rebiopsy received a tissue biopsy (59.2%).” Comment 3: T790M-positive rate at first rebiopsy was only 14%. This is lower than former pivotal reports on T790M-positive rate: 30-50%. They considered high rate of liquid biopsy caused this lower T790M-positive rate. So, they should demonstrate rates of liquid and histologic biopsies from first to sixth rebiopsy in the Result section. Response 3: Thank you for your insightful comment. We have added the data on the rates of liquid and tissue biopsies from first to sixth rebiopsy in Table 1 and have described the content in the Results section Comment 4: On lines 146-147, they described, “For the final analysis, 143 patients were included and they received a maximum of three repeated rebiopsies.”. This is confusing. Table 1 shows some patients received sixth rebiopsy. What? Response 4: We apologize for the confusion. To be clear, we have revised the sentence as follows: “For the final analysis, 143 patients were included” https://doi.org/10.1371/journal.pone.0310079.r004
26 Aug 2024 Decision Letter - Hamidreza Montazeri Aliabadi, Editor Repeated rebiopsy for detection of EGFR T790M mutation in patients with advanced-stage lung adenocarcinoma: associated factors and treatment outcomes of Osimertinib PONE-D-24-12639R2 Dear Dr. Um, 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, Hamidreza Montazeri Aliabadi 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 #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 #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? 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 #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 #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 #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 #2: No ******** https://doi.org/10.1371/journal.pone.0310079.r005
Formally Accepted
10 Sep 2024 Acceptance Letter - Hamidreza Montazeri Aliabadi, Editor PONE-D-24-12639R2 PLOS ONE Dear Dr. Um, 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 Dr. Hamidreza Montazeri Aliabadi Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0310079.r006

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