Cancer disrupts sex hormone-inflammation relationships: Analysis of ALI in males from NHANES 2007–2018

Wenyao Xie; Zhenjun Zhang; Dan Zhao; Ya Zhang; Caiting Feng; Yicong Zhou

doi:10.1371/journal.pone.0325796

Peer Review History

Original SubmissionMarch 26, 2025
26 Mar 2025 Author Response https://doi.org/10.1371/journal.pone.0325796.r001
Decision Letter - Akingbolabo Ogunlakin, Editor Dear Dr. Zhou, 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. ============================== Your study on the relationship between sex hormones and inflammation in cancer and non-cancer populations using NHANES data is thoughtful and well-executed. To enhance the clarity and readability of the manuscript, please address the following: • Consider shortening the title for clarity. • Revise the abstract to follow a structured format (Background, Methods, Results, Conclusion). • Clearly define how cancer status was determined in NHANES and provide detailed explanation of how sampling weights across survey cycles were applied in the analysis. • Make minor grammatical and language edits to improve sentence clarity and overall flow. ============================== Please submit your revised manuscript by Jun 18 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols . We look forward to receiving your revised manuscript. Kind regards, Akingbolabo Daniel Ogunlakin, Phd 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. Please include your full ethics statement in the ‘Methods’ section of your manuscript file. In your statement, please include the full name of the IRB or ethics committee who approved or waived your study, as well as whether or not you obtained informed written or verbal consent. If consent was waived for your study, please include this information in your statement as well. 3. 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. Is the manuscript technically sound, and do the data support the conclusions? Reviewer #1: Yes Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? -->?> Reviewer #1: Yes Reviewer #2: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available??> The PLOS Data policy Reviewer #1: Yes Reviewer #2: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: Yes Reviewer #2: Yes ****** Reviewer #1: The study is a well-executed and impactful contribution that provides a compelling exploration between testosterone, inflammation and advanced lung cancer using a robust dataset from NHANES. The research is methodologically sound and clinically relevant, providing insights into sex hormone dynamics in cancer progression. Below are minor suggestions for improvement. Keywords should not repeat words in the title of the manuscript. The term Advanced lung cancer index is ambiguous. Authors should explain explicitly how this index was constructed and justify its validity. A detailed explanation against established standards would improve the study. Reviewer #2: Your study on the relationship between sex hormones and inflammation in cancer and non-cancer populations using NHANES data is thoughtful and well-executed. To enhance the clarity and readability of the manuscript, please address the following: • Consider shortening the title for clarity. • Revise the abstract to follow a structured format (Background, Methods, Results, Conclusion). • Clearly define how cancer status was determined in NHANES and provide detailed explanation of how sampling weights across survey cycles were applied in the analysis. • Make minor grammatical and language edits to improve sentence clarity and overall flow. Thank you. ****** 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 https://doi.org/10.1371/journal.pone.0325796.r002
Revision 1
12 May 2025 Author Response Dear Reviewer 1: We appreciate your careful review of our manuscript and believe that the changes made in response to your suggestions have significantly strengthened the paper. Your expertise and attention to detail have helped us enhance both the technical accuracy and accessibility of our research for readers. Thank you again for your contribution to improving our work. We hope that the revised manuscript now meets your expectations. 1. Keywords should not repeat words in the title of the manuscript. Thank you for this important formatting suggestion. We agree that keywords should complement the title rather than repeat terms already present in it. Based on your recommendation, we have revised our keywords to avoid duplication with the title while still accurately representing the core concepts of our research. The revised keywords are: Androgen, Immunomodulation, Systemic inflammation, Neutrophil-to-lymphocyte ratio, Albumin, Gender differences.是 2. The term Advanced lung cancer index is ambiguous. Authors should explain explicitly how this index was constructed and justify its validity. A detailed explanation against established standards would improve the study. Thank you for this valuable comment highlighting the need for greater clarity regarding the Advanced Lung Cancer Inflammation Index (ALI). We agree that a more detailed explanation would strengthen our manuscript. We have expanded our Methods section to include a more comprehensive explanation of ALI: The ALI was originally developed by Jafri et al. [9] as a prognostic indicator for metastatic non-small cell lung cancer and calculated using the formula: Body Mass Index (BMI, kg/m²) × Serum Albumin (g/dL) / NLR. This index integrates BMI (reflecting nutritional status), serum albumin (a marker of both nutritional status and systemic inflammation), and NLR (neutrophil-to-lymphocyte ratio, an established inflammatory marker). ALI's validity has been confirmed in multiple studies across various cancers, including colorectal cancer (Pian et al., 2022)[12] and intrahepatic cholangiocarcinoma (Catalano et al., 2024)[10], with a low ALI associated with poorer survival outcomes. It offers advantages over single markers by incorporating both inflammatory and nutritional dimensions of cancer pathophysiology. In our study, all ALI components were measured according to standardized NHANES protocols using calibrated equipment and automated analyzers with strict quality control standards. Dear Reviewer 2: We sincerely thank you for the careful review and valuable suggestions on our manuscript. Each point raised is of great value in improving the quality of our paper, and we have carefully considered and made corresponding revisions to address all your concerns. We particularly appreciate your attention to the overall framework of our paper, which has significantly enhanced the quality of our work. Your expert insights have helped us identify key areas for improvement in our manuscript, allowing us to refine our research from a more comprehensive and rigorous perspective. In response to each specific issue you raised, we have made detailed modifications throughout the manuscript. All changes have been highlighted in yellow in the revised manuscript for your easy identification. 1. Consider shortening the title for clarity. Thank you for your thoughtful feedback on our manuscript. We agree that a more concise title would enhance clarity and readability. Following your suggestion, we have revised our title to be more focused while maintaining the core elements of our research. The revised title is "Cancer Disrupts Sex Hormone-Inflammation Relationships: Analysis of ALI in Males from NHANES 2007-2018". This shortened title more efficiently communicates our study's primary finding (the disruption of hormone-inflammation relationships in cancer) while maintaining essential information about the dataset and methodology. The acronym ALI (Advanced Lung Cancer Inflammation Index) is widely recognized in the field and will be fully defined in the abstract and introduction, allowing us to create a more streamlined title without sacrificing clarity. 2. Revise the abstract to follow a structured format (Background, Methods, Results, Conclusion). Thank you for your insightful feedback on our manuscript. We appreciate your attention to detail and constructive suggestions for improving our work. We have revised the abstract to follow the structured format as suggested. The abstract now includes clearly labeled sections for Background, Methods, Results, and Conclusion. 3. Clearly define how cancer status was determined in NHANES and provide detailed explanation of how sampling weights across survey cycles were applied in the analysis. We sincerely appreciate your thoughtful review and the opportunity to clarify important methodological aspects of our study. We have expanded our Methods section to provide more comprehensive information on both cancer status determination and sampling weight application: "Cancer status in our study was determined using the NHANES Medical Conditions Questionnaire (MCQ), which collected self-reported data on medical conditions through personal interviews conducted by trained NHANES staff. Specifically, participants were asked "Has a doctor or other health professional ever told you that you had cancer or a malignancy of any kind?" (variable MCQ220). Those responding "Yes" were classified as having a cancer history, while those responding "No" formed our non-cancer group. Participants with "Don't know" or refused responses were excluded from our analysis. For participants confirming a cancer history, additional information was collected regarding cancer type and age at diagnosis. We excluded individuals with lung cancer to avoid potential confounding with our primary outcome measure." “To account for NHANES complex survey design and ensure nationally representative estimates, we applied appropriate sampling weights following NHANES analytical guidelines. Since our analysis combined data from six survey cycles (2007-2018), we created modified sampling weights by dividing the original 2-year examination weights (WTMEC2YR) by 6. For multivariable analyses, we incorporated the stratification variable (SDMVSTRA) and primary sampling unit (SDMVPSU) along with these modified weights using the svydesign function in R with the following specification: study_design <- svydesign(id = ~SDMVPSU, strata = ~SDMVSTRA, weights = ~WTMEC2YR, data = data, nest = TRUE). This approach accounts for the differential selection probabilities, non-response adjustments, and post-stratification alignments to census population totals while properly adjusting standard errors for the complex sampling design.” 4. Make minor grammatical and language edits to improve sentence clarity and overall flow. We have completed a thorough review of the manuscript and made all necessary grammatical and language edits to improve sentence clarity and overall flow. We carefully addressed each instance of awkward phrasing, refined transition sentences between sections, standardized terminology throughout the text, and ensured consistent verb tense usage. These revisions have enhanced the readability and precision of our work while maintaining the scientific integrity of our findings. We sincerely appreciate the reviewer's attention to these important details, as clear scientific communication is essential for effectively sharing our research contributions with the scientific community. We extend our heartfelt thanks for this valuable feedback, and if there are any remaining concerns about the language or presentation, we would be more than happy to address them in further revisions. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0325796.r003
Decision Letter - Akingbolabo Ogunlakin, Editor Dear Dr. Zhou, 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. Your study on the relationship between sex hormones and inflammation in cancer and non-cancer populations using NHANES data is thoughtful and well-executed. To enhance the clarity and readability of the manuscript, please address the following: • Consider shortening the title for clarity. • Revise the abstract to follow a structured format (Background, Methods, Results, Conclusion). • Clearly define how cancer status was determined in NHANES and provide detailed explanation of how sampling weights across survey cycles were applied in the analysis. • Make minor grammatical and language edits to improve sentence clarity and overall flow. Please submit your revised manuscript by Jun 28 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols . We look forward to receiving your revised manuscript. Kind regards, Akingbolabo Daniel Ogunlakin, Phd 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. Additional Editor Comments: Your study on the relationship between sex hormones and inflammation in cancer and non-cancer populations using NHANES data is thoughtful and well-executed. To enhance the clarity and readability of the manuscript, please address the following: • Consider shortening the title for clarity. • Revise the abstract to follow a structured format (Background, Methods, Results, Conclusion). • Clearly define how cancer status was determined in NHANES and provide detailed explanation of how sampling weights across survey cycles were applied in the analysis. • Make minor grammatical and language edits to improve sentence clarity and overall flow. Thank you. [Note: HTML markup is below. Please do not edit.] [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 https://doi.org/10.1371/journal.pone.0325796.r004
Revision 2
15 May 2025 Author Response ·Dear Reviewer 1: We appreciate your careful review of our manuscript and believe that the changes made in response to your suggestions have significantly strengthened the paper. Your expertise and attention to detail have helped us enhance both the technical accuracy and accessibility of our research for readers. Thank you again for your contribution to improving our work. We hope that the revised manuscript now meets your expectations. 1. Keywords should not repeat words in the title of the manuscript. Thank you for this important formatting suggestion. We agree that keywords should complement the title rather than repeat terms already present in it. Based on your recommendation, we have revised our keywords to avoid duplication with the title while still accurately representing the core concepts of our research. The revised keywords are: Androgen, Immunomodulation, Systemic inflammation, Neutrophil-to-lymphocyte ratio, Albumin, Gender differences.是 2. The term Advanced lung cancer index is ambiguous. Authors should explain explicitly how this index was constructed and justify its validity. A detailed explanation against established standards would improve the study. Thank you for this valuable comment highlighting the need for greater clarity regarding the Advanced Lung Cancer Inflammation Index (ALI). We agree that a more detailed explanation would strengthen our manuscript. We have expanded our Methods section to include a more comprehensive explanation of ALI: The ALI was originally developed by Jafri et al. [9] as a prognostic indicator for metastatic non-small cell lung cancer and calculated using the formula: Body Mass Index (BMI, kg/m²) × Serum Albumin (g/dL) / NLR. This index integrates BMI (reflecting nutritional status), serum albumin (a marker of both nutritional status and systemic inflammation), and NLR (neutrophil-to-lymphocyte ratio, an established inflammatory marker). ALI's validity has been confirmed in multiple studies across various cancers, including colorectal cancer (Pian et al., 2022)[12] and intrahepatic cholangiocarcinoma (Catalano et al., 2024)[10], with a low ALI associated with poorer survival outcomes. It offers advantages over single markers by incorporating both inflammatory and nutritional dimensions of cancer pathophysiology. In our study, all ALI components were measured according to standardized NHANES protocols using calibrated equipment and automated analyzers with strict quality control standards. Dear Reviewer 2: We sincerely thank you for the careful review and valuable suggestions on our manuscript. Each point raised is of great value in improving the quality of our paper, and we have carefully considered and made corresponding revisions to address all your concerns. We particularly appreciate your attention to the overall framework of our paper, which has significantly enhanced the quality of our work. Your expert insights have helped us identify key areas for improvement in our manuscript, allowing us to refine our research from a more comprehensive and rigorous perspective. In response to each specific issue you raised, we have made detailed modifications throughout the manuscript. All changes have been highlighted in yellow in the revised manuscript for your easy identification. 1. Consider shortening the title for clarity. Thank you for your thoughtful feedback on our manuscript. We agree that a more concise title would enhance clarity and readability. Following your suggestion, we have revised our title to be more focused while maintaining the core elements of our research. The revised title is "Cancer Disrupts Sex Hormone-Inflammation Relationships: Analysis of ALI in Males from NHANES 2007-2018". This shortened title more efficiently communicates our study's primary finding (the disruption of hormone-inflammation relationships in cancer) while maintaining essential information about the dataset and methodology. The acronym ALI (Advanced Lung Cancer Inflammation Index) is widely recognized in the field and will be fully defined in the abstract and introduction, allowing us to create a more streamlined title without sacrificing clarity. 2. Revise the abstract to follow a structured format (Background, Methods, Results, Conclusion). Thank you for your insightful feedback on our manuscript. We appreciate your attention to detail and constructive suggestions for improving our work. We have revised the abstract to follow the structured format as suggested. The abstract now includes clearly labeled sections for Background, Methods, Results, and Conclusion. 3. Clearly define how cancer status was determined in NHANES and provide detailed explanation of how sampling weights across survey cycles were applied in the analysis. We sincerely appreciate your thoughtful review and the opportunity to clarify important methodological aspects of our study. We have expanded our Methods section to provide more comprehensive information on both cancer status determination and sampling weight application: "Cancer status in our study was determined using the NHANES Medical Conditions Questionnaire (MCQ), which collected self-reported data on medical conditions through personal interviews conducted by trained NHANES staff. Specifically, participants were asked "Has a doctor or other health professional ever told you that you had cancer or a malignancy of any kind?" (variable MCQ220). Those responding "Yes" were classified as having a cancer history, while those responding "No" formed our non-cancer group. Participants with "Don't know" or refused responses were excluded from our analysis. For participants confirming a cancer history, additional information was collected regarding cancer type and age at diagnosis. We excluded individuals with lung cancer to avoid potential confounding with our primary outcome measure." “To account for NHANES complex survey design and ensure nationally representative estimates, we applied appropriate sampling weights following NHANES analytical guidelines. Since our analysis combined data from six survey cycles (2007-2018), we created modified sampling weights by dividing the original 2-year examination weights (WTMEC2YR) by 6. For multivariable analyses, we incorporated the stratification variable (SDMVSTRA) and primary sampling unit (SDMVPSU) along with these modified weights using the svydesign function in R with the following specification: study_design <- svydesign(id = ~SDMVPSU, strata = ~SDMVSTRA, weights = ~WTMEC2YR, data = data, nest = TRUE). This approach accounts for the differential selection probabilities, non-response adjustments, and post-stratification alignments to census population totals while properly adjusting standard errors for the complex sampling design.” 4. Make minor grammatical and language edits to improve sentence clarity and overall flow. We have completed a thorough review of the manuscript and made all necessary grammatical and language edits to improve sentence clarity and overall flow. We carefully addressed each instance of awkward phrasing, refined transition sentences between sections, standardized terminology throughout the text, and ensured consistent verb tense usage. These revisions have enhanced the readability and precision of our work while maintaining the scientific integrity of our findings. We sincerely appreciate the reviewer's attention to these important details, as clear scientific communication is essential for effectively sharing our research contributions with the scientific community. We extend our heartfelt thanks for this valuable feedback, and if there are any remaining concerns about the language or presentation, we would be more than happy to address them in further revisions. Attachments Attachment Submitted filename: Response_to_Reviewers_auresp_2.docx https://doi.org/10.1371/journal.pone.0325796.r005
Decision Letter - Akingbolabo Ogunlakin, Editor <p>Cancer Disrupts Sex Hormone-Inflammation Relationships: Analysis of ALI in Males from NHANES 2007-2018 PONE-D-25-15723R2 Dear Dr. Yicong Zhou, 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, Akingbolabo Daniel Ogunlakin, Phd Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0325796.r006
Formally Accepted
Acceptance Letter - Akingbolabo Ogunlakin, Editor PONE-D-25-15723R2 PLOS ONE Dear Dr. Zhou, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset You will receive further instructions from the production team, including instructions on how to review your proof when it is ready. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few days to review your paper and let you know the next and final steps. Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. 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. Akingbolabo Daniel Ogunlakin Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0325796.r007

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