-->PONE-D-26-01189-->-->Evaluation of analgesic and anti-inflammatory activities of the root extract of Grewia schweinfurthii Burret and its major chemical constituents-->-->PLOS One

Dear Dr. Gemechu,

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 Apr 12 2026 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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We look forward to receiving your revised manuscript.

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Eshetie Melese Birru, PhD

Academic Editor

PLOS One

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Additional Editor Comments:

Thank you for submitting your manuscript entitled “Evaluation of analgesic and anti-inflammatory activities of the root extract of Grewia schweinfurthii Burret and its major chemical constituents.”While the study uses established in vivo pharmacological models, several substantive concerns must be addressed before further consideration.

Major Concerns

Ethical and Scientific Justification for Animal Use

The manuscript does not clearly demonstrate sufficient prior in vitro, in vivo, or species-specific literature supporting analgesic or anti-inflammatory activity of G. schweinfurthii. In the absence of robust preliminary evidence, direct multi-dose in vivo testing of a crude extract raises concerns under the animal ethics framework. The authors must provide stronger literature-based or experimental justification for progressing to animal experimentation.

Insufficient Chemical Characterization

The structural elucidation of the isolated compound lacks HRMS confirmation, detailed 2D NMR correlation discussion, and purity assessment prior to biological testing. Stronger analytical validation is required.

Unusually High Anti-inflammatory Efficacy

The reported 93% inhibition at 400 mg/kg, comparable to indomethacin, is unusually high for a crude extract. The edema calculation method, raw ΔV data, and statistical handling should be clarified to ensure accuracy.

Mechanistic Overinterpretation

Claims regarding COX inhibition, prostaglandin suppression, and ROS modulation are speculative and not supported by mechanistic assays. These interpretations should be reframed cautiously.

Data Availability Compliance

Full underlying individual-level data must be made available in accordance with PLOS ONE policy.

[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: No

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 study investigates the analgesic and anti-inflammatory activities of the 80% methanolic root extract of Grewia schweinfurthii and its isolated compound (AL-03) using established in vivo models. The results demonstrate dose-dependent peripheral and central analgesic effects, as well as significant inhibition of carrageenan-induced paw edema, comparable to standard drugs. Overall, the manuscript addresses an important area of ethnopharmacology, although improvements in data presentation, mechanistic interpretation, and chemical characterization are needed.

Comments

Abstract: Include key numeric results (e.g., % inhibition of writhing or edema, IC₅₀ if applicable).

Introduction: Clearly state the research gap. Introduce the importance of tannins, flavonoids, saponins, etc., in analgesic and anti-inflammatory activity to strengthen the rationale.

Materials and Methods: Include voucher specimen number for reproducibility. Report yield (%) of crude extract. Include storage conditions (temperature, light protection). Phytochemicals screening: Flavonoids mentioned twice — remove redundancy. Acute Toxicity:Clarify which OECD guideline was followed (423 vs 425). Correct inconsistencies in dose explanation. Hot plate assay: state baseline latency, maximum cutoff time clearly. Carrageenan assay: clarify early/late phase interpretation and injection site. Correct TLC plate thickness (200 μm vs 200 μg). Standardize units (mg/kg, µL, mL, °C).

Results and Discussion: Compound isolation: Report yield (mg, %) of AL-03. Confirm purity (TLC/HPLC/melting point). Acute Toxicity:Include quantitative body weight data. Discuss OECD toxicity category. Compound AL-03: Include full characterization data. Report yield (%). Clarify novelty — first isolation from this species? Analgesic Activity (Writhing & Hot Plate): Provide numerical data: mean ± SEM writhes, latency (s), % inhibition, statistical significance. Include time-course figure for hot plate assay. Avoid mechanistic claims without direct evidence. Anti-inflammatory Activity: Provide paw volume data ± SEM for all time points. Include time-course figure with statistical annotation.Mechanistic statements (COX-2, prostaglandin inhibition) should be phrased as plausible or literature-supported. Discuss contribution of flavonoids, terpenoids, and steroids to analgesic/anti-inflammatory effects. Integrate peripheral (writhing) and central (hot plate) analgesic findings with anti-inflammatory results for a cohesive pharmacological narrative. Integrate peripheral (writhing) and central (hot plate) analgesic findings with anti-inflammatory results for a cohesive pharmacological narrative. Add study limitaions and recommendations for the future.

Reviewer #2: Review Report:

Manuscript Number: PONE-D-26-01189

The manuscript Title: Evaluation of analgesic and anti-inflammatory activities of the root extract of Grewia schweinfurthii Burret and its major chemical constituents.

Detailed Comments/Recommendations:

Title: The title could be slightly misleading if the isolated compound was not tested in vivo, because the phrase “and its major chemical constituents” might imply that their pharmacological activity was directly evaluated. If the compound was only characterized chemically and not tested separately, it would be more accurate to say something like:

“…and characterization of its major chemical constituents”

Abstract:

 The objective should be clearly and directly stated in the abstract.

 The animal model used should be mentioned in the abstract.

 The study design along dosages (treatment protocols) are lacking.

 The name of statistical analysis should be briefly mentioned.

 The authors should also mention which OECD guidelines were used.

 Results lack the numerical data. Few numeric data must be mentioned to attract the reader’s interest.

 The conclusion must directly reflect the findings and avoid overstated claims like “can be developed as a drug” etc.

Introduction:

 In 3rd paragraph the sentence “It has a minimally helpful effect, especially when faced with pathogenic difficulties; instead, it makes infections worse” is difficult to understand. Please rephrase it.

 In 5th paragraph please briefly summarize adverse effects in 1–2 sentences instead of listing multiple drug classes and complications.

 In 7th Paragraph, consider shortening botanical and morphological details (height, leaves) unless directly relevant to pharmacological study.

 Please clarify which traditional uses specifically relate to analgesic and anti-inflammatory activity (e.g., joint pain, headache).

 References could be integrated more smoothly; currently the long list of species may distract the reader.

 In last paragraph please clarify which traditional uses specifically relate to analgesic and anti-inflammatory activity (e.g., joint pain, headache).

 There is vague gap statement with mentions that “few species evaluated” but does not clearly say what exactly is missing about G. schweinfurthii. Similarly, the aim of study is too much broad. Rewrite the specified aims of study.

Materials and Methods:

 Under the heading of Isolation of the major compound, please explain choice of solvents for elution (CHCl3-MeOH).

 The name/code of the isolated compound (AL-03) is given, but no brief description of its identity is provided in Methods (could state structure elucidation will follow using NMR).

 Please clarify species and strain of mice used for toxicity testing.

 Please provide justification for using 2000 mg/kg as initial dose.

 Explain if ethical approval was obtained for animal experiments.

 Please Provide route of administration consistently for all groups.

 Mention randomization method used to allocate animals to groups.

 In Acetic Acid-Induced Writhing, please specify ethical considerations (minimizing animal suffering) and mention replication or whether multiple experiments were conducted.

 In Hot Plate method, please indicate sample size justification.

 For Carrageenan-Induced Paw Edema, please Include precise measurement technique for paw volume (plethysmometer vs. water displacement).

 Please M=mention if the experiment was performed blind to treatment groups.

 Please include statements regarding sample size (n), F-statistic with degrees of freedom, and exact p-values for ANOVA in the section of Statistical Analysis and apply this stat as well in the results.

Results and Discussion:

 LD50 was not determined exactly and claimed result is a preliminary acute toxicity assessment. This prevents misinterpretation as a formal LD50 study. Please find LD50 and give its detailed methodology as well in methods section.

 In section “TLC Analysis of 4-(2''-(4'-isopropylphenyl)propan-2''-yl)-2,3-dihydrofuran” please clarify whether the reported Rf values correspond to a purified compound or crude fraction.

 Please provide the rationale for selecting the two solvent systems (chloroform:methanol and chloroform:ethyl acetate).

 Consider reporting TLC plates’ reproducibility and whether co-TLC with related compounds was performed.

 Results in section “Analgesic activity of root extract using acetic acid-induced writhing method” It is unclear whether the 100 mg/kg dose showed any statistically significant effect compared to the negative control. This should be clarified.

 Please include in result paragraph with proper df and F-values along with P values.

 Please improve the discussion by clearly separating the results from explanations, avoiding strong assumptions about how the extract works, and making a clearer comparison with morphine and previous studies to better explain the central pain-relieving effects.

Conclusion:

 Rewrite the conclusion by keeping in mind that the results come from animal experiments, not human studies and also the isolated compound’s effects are not proven because it was not tested on its own.

 Include study limitations and recommend further experiments to confirm the findings.

References:

 Well documented

Concluding Remarks:

The manuscript has potential, but it can only be considered for publication after major revisions addressing the issues highlighted above.

**********

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Reviewer #1: Yes: Dr. Kanwal Ashiq

Reviewer #2: Yes: Dr. Aamir Mushtaq

**********

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-->PONE-D-26-01189R1-->-->Evaluation of analgesic and anti-inflammatory activities of the root extract of Grewia schweinfurthii Burret and its major chemical constituents-->-->PLOS One

Dear Dr. Gemechu,

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 Jun 20 2026 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:-->

• A letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If 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.

As the corresponding author, your ORCID iD is verified in the submission system and will appear in the published article. PLOS supports the use of ORCID, and we encourage all coauthors to register for an ORCID iD and use it as well. Please encourage your coauthors to verify their ORCID iD within the submission system before final acceptance, as unverified ORCID iDs will not appear in the published article. Only  the individual author can complete the verification step; PLOS staff cannot  verify ORCID iDs on behalf of authors.

We look forward to receiving your revised manuscript.

Kind regards,

Eshetie Melese Birru, PhD

Academic Editor

PLOS One

Journal Requirements:

If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise.

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 #3: (No Response)

**********

-->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 #3: Yes

**********

-->3. Has the statistical analysis been performed appropriately and rigorously? -->

Reviewer #1: Yes

Reviewer #3: 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 #3: 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 #3: 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: This manuscript presents a well-designed experimental pharmacological study with a strong methodological framework and meaningful biological outcomes. The investigation appropriately evaluates both the crude extract and isolated compound of Grewia schweinfurthii, which adds scientific depth and enhances the overall value of the work. The study demonstrates good use of validated in vivo models for analgesic and anti-inflammatory assessment, supporting the reliability of the findings.

Minor comments are given below:

The research gap and novelty justification could be more sharply defined at the end of the introduction to better position the study.

Justification for selection of isolated compound (AL-03) needs clarification in methods.

Limited integration between phytochemical constituents and observed biological activities, along with insufficient comparative discussion within the Results section.

The conclusion is appropriate and consistent with the study findings. It correctly highlights analgesic and anti-inflammatory potential of the extract and isolated compound. However, the unique contribution of dual evaluation (extract + compound) should be explicitly stated as the key highlight of the study.

Reviewer #3: (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: Yes: Dr. Kanwal Ashiq

Reviewer #3: 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.]

To ensure your figures meet our technical requirements, please review our figure guidelines: https://journals.plos.org/plosone/s/figures

You may also use PLOS’s free figure tool, NAAS, to help you prepare publication quality figures: https://journals.plos.org/plosone/s/figures#loc-tools-for-figure-preparation.

NAAS will assess whether your figures meet our technical requirements by comparing each figure against our figure specifications.

Attachments

Attachment

Submitted filename: Peer Review.docx

-->PONE-D-26-01189R2-->-->Evaluation of analgesic and anti-inflammatory activities of the root extract of Grewia schweinfurthii Burret and its major chemical constituents-->-->PLOS One

Dear Dr. Gemechu,

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 Jul 19 2026 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:-->

• A letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If 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.

As the corresponding author, your ORCID iD is verified in the submission system and will appear in the published article. PLOS supports the use of ORCID, and we encourage all coauthors to register for an ORCID iD and use it as well. Please encourage your coauthors to verify their ORCID iD within the submission system before final acceptance, as unverified ORCID iDs will not appear in the published article. Only  the individual author can complete the verification step; PLOS staff cannot  verify ORCID iDs on behalf of authors.

We look forward to receiving your revised manuscript.

Kind regards,

Eshetie Melese Birru, PhD

Academic Editor

PLOS One

Journal Requirements:

If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise.

[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 #3: (No Response)

**********

-->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 #3: Yes

**********

-->3. Has the statistical analysis been performed appropriately and rigorously? -->

Reviewer #1: Yes

Reviewer #3: 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 #3: 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 #3: 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 #3: (No Response)

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Reviewer #1: Yes: Dr. Kanwal Ashiq

Reviewer #3: Yes: Wêndeo Kennedy Costa

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Attachments

Attachment

Submitted filename: Peer_Review_declet_2.docx

Evaluation of analgesic and anti-inflammatory activities of the root extract of Grewia schweinfurthii Burret and its major chemical constituents

PONE-D-26-01189R3

Dear Dr. Gemechu,

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.

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Kind regards,

Eshetie Melese Birru, PhD

Academic Editor

PLOS One

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 #3: All comments have been addressed

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-->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 #3: Yes

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-->3. Has the statistical analysis been performed appropriately and rigorously? -->

Reviewer #3: Yes

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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 #3: Yes

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-->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 #3: Yes

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-->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 #3: (No Response)

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-->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 #3: Yes: Wêndeo Kennedy Costa

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