-->PONE-D-25-31923-->-->Targeted Muscle Reinnervation (TMR) or Regenerative Peripheral Nerve Interface (RPNI) for pain prevention in patients with limb amputation: a protocol for a systematic review and meta-analysis-->-->PLOS ONE

Dear Dr. Gurpegui,

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.

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We look forward to receiving your revised manuscript.

Kind regards,

Simone Ranaldi, Ph.D.

Academic Editor

PLOS ONE

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2. 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.

Additional Editor Comments:

The two independent reviewers identified issues with the level of detail that is included in the manuscript, the list of reference and the general grammar and syntax. All of these issues should be solved fully before publication in the Journal.

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Reviewers’ comments:

Reviewer’s Responses to Questions

-->Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.-->

Reviewer #1: Yes

Reviewer #2: Partly

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-->2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.-->

Reviewer #1: Yes

Reviewer #2: Partly

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-->3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.-->

Reviewer #1: Yes

Reviewer #2: No

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-->4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. 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

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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 #1: Yes

Reviewer #2: No

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-->6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)-->

Reviewer #1: Summary of Key Recommendations

Area Recommendation

Method clarity Define “classical amputation” more precisely

Data synthesis Clarify standardization for different pain scales

Limitations Add a dedicated limitations section

Figures Include a PRISMA-P diagram

Supplementary Include the full search strategy as a supplement

Language Minor editorial corrections for grammar and clarity

Reviewer #2: Extent of my review

My review put the overall content of this manuscript in perspective with previous works involving qualitative and quantitative assessment of clinical outcomes.

I have also focused mainly on the strength of the argumentation, the validity of the study protocol and overall coherence of the manuscript.

Relevance of this work

The authors aim to address genuine and important clinical questions: what are the true clinical benefits of surgical reinnervations and what are difference of outcomes between TMR and RNPI?

The study protocol including systematic review and meta-analysis is conventional.

Clearly, there is a need for this type of publication that will be critical to all stakeholders, including consumers, practitioners and decision makers.

Limitations of this work

My overall impression is that the manuscript is written conservatively providing only the minimal required information. Consequently, it does fail short of providing comprehensive description and, sometime, critical elements of the study protocol.

For example:

• Outcome measures are not categorized according to safety and efficacy,

• Examples of searches syntaxes in online supplemental material 1 not available with the submission,

• The data extraction form is missing,

• The table for the timeline is not referenced,

• The heading for “references” is missing,

• Nearly half of the references are more than 10-year-old,

Altogether, the manuscript will benefit from professional editing to improve the overall English writing style (e.g., wording and syntax).

Outcomes

Despite these concerns, I do believe that the core work of the study can be original and worthwhile publishing provided that the authors address the points below. I am confident that a substantial publication that will be well-cited could come out of the work.

Selected specific comments

1. L 25: Consider adding the lower time limit for the reference selection, if any.

2. L 24: Re-word “what each technique offers” in terms of efficacy and safety of RPNI and TMR.

3. L 38: Verify if RPNI and TMR are acknowledged MeSH terms (e.g., need to spell them out).

4. L 43: Modify this statement about “high-quality articles” given the proposed selection criteria including not only randomized and quasi-randomized with high level of evidence, but also observational studies which could potentially include case series with low level of evidence. The next point is also referring to including gray literature with low level of evidence

5. L 49: Replace “superior or inferior limb amputation” by more commonly used “upper or lower limb amputation”.

6. L 54: Add “Classical amputation without reinnervation”.

7. L 56: Categorize outcomes according to measure of efficacy and safety to aligned with the objectives in L 158.

8. L 71: Rewrite the sentence as “being age, renal disease, proximal amputation, diabetes, and peripheral vascular disease the risk factors” is unclear.

9. L 77-80: Add some statistical data to support these points.

10. L 82: Verify if “(the process of)” should be between brackets.

11. L 90: Verify if the sentence is completed.

12. L 92: Table 1 should include the spelling of US and MRI

13. L 95: Describe what is the “100%” in these stats (e.g., percentage of what).

14. L 111: Include information about other treatments for PLP such as mirror therapies.

15. L 123: Provide references looking at one or the other or both interventions.

16. L 165: Included other critical confounders such as time since amputation, time since reinnervation, daily usage of prosthesis.

17. L 200: Indicate clearly to outcomes related to efficacy and safety.

18. L 212: Provide list of keywords used to conduct the searches and examples of searches syntaxes (Online supplemental material 1 not available with the submission).

19. L 226: Reference the Table for timeline

20. L 239: Provide the draft of the data extraction form.

21. L 266: Spell IPC in caption of Table

22. L 314: Add heading for “References”,

23. L 315: Verify if any of 41 references more than 10-year old can be replaced by newer references.

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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 #1: Yes: Vaikunthan Rajaratnam

Reviewer #2: No

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Targeted Muscle Reinnervation (TMR) or Regenerative Peripheral Nerve Interface (RPNI) for pain prevention in patients with limb amputation: a protocol for a systematic review and meta-analysis

PONE-D-25-31923R1

Dear Dr. Gurpegui,

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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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,

Yee Gary Ang, MBBS MPH

Academic Editor

PLOS One

Additional Editor Comments (optional):

Reviewers’ comments:

Reviewer’s Responses to Questions

-->Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.-->

Reviewer #2: Yes

**********

-->2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.-->

Reviewer #2: Yes

**********

-->3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.-->

Reviewer #2: Yes

**********

-->4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. 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: No

**********

-->6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)-->

Reviewer #2: Overall comments

General Comments

My overall impression is that the authors have carefully read the comments and genuinely made significant efforts to address all comments thoroughly both in the manuscript and the supplement material. The authors addressed satisfactorily all my initial comments. I have made a few new suggestions to address some minor points in the revised manuscript.

Outcomes

I believe that the core of this study is original and worthwhile publishing. In my view, the manuscript is ready for publication upon consideration of the comments below.

Selected specific comments

Introduction

1.L 46: Consider replacing “patients” by more accepted term such as “individuals”, “users” or “participants” throughout the manuscript depending on the context.

2.L 45: Make sure the term “Black” and “White” participants are correct. Consider using “Caucasian” rather than “White”

3.L 48: Verify if the term “morbidity” should be replaced by “comorbidity”. This will make more sense to me.

4.L 72: Replacing “stump” by more accepted clinical term “residuum” throughout the manuscript

Methods

5.L 112: Consider naming “case series” for studies with n<10 and “cohort studies” for studies with N>10. This will simply the description of the limitations.

6.L 118: Consider adding a sentence about the inclusion of all ethnic background to clearly show the link with the objective about Black and Caucasian backgrounds.

7.L 133: Correct “benefit and risk” by “benefits and risks”.

8.L 142: Spell out “Patient-Reported Outcomes Measurement Information System (PROMIS)”.

9.L 209: Clarify if the analysis should also be stratified by ethnic background.

Discussion

10.L 247: Rephrase the sentence to avoid confusion with the study excluded. See previous comments about “cohort studies” vs “case series”.

References

11.L 200: Provide publication details for Ref 13.

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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 #2: No

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