Dear Dr. Friedman,

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.

Congratulations on your engaging and well-written paper on the “Human Disharmony Loop.”

Please address all reviewer comments, focusing on the following:

• Clarify that the study is retrospective and update the abstract’s purpose accordingly.
• State clearly that the absence of a control group is a major limitation.
• Specify which statistical tests were used for each comparison.
• Indicate the patient enrolment period and the time from symptom onset to surgery.
• Provide more details on parameter changes at each follow-up point.

Please submit your revised manuscript by Sep 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 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,

Emil George Haritinian, M.D, Ph.D.

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 amend your list of authors on the manuscript to ensure that each author is linked to an affiliation. Authors’ affiliations should reflect the institution where the work was done (if authors moved subsequently, you can also list the new affiliation stating “current affiliation:….” as necessary).

3. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information.

4. Please remove all personal information, ensure that the data shared are in accordance with participant consent, and re-upload a fully anonymized data set.

Note: spreadsheet columns with personal information must be removed and not hidden as all hidden columns will appear in the published file.

Additional guidance on preparing raw data for publication can be found in our Data Policy (https://journals.plos.org/plosone/s/data-availability#loc-human-research-participant-data-and-other-sensitive-data) and in the following article: http://www.bmj.com/content/340/bmj.c181.long .

5. 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:

Congratulations on your engaging and well-written paper on the “Human Disharmony Loop.”

Please address all reviewer comments, focusing on the following:

- Clarify that the study is retrospective and update the abstract’s purpose accordingly.

- State clearly that the absence of a control group is a major limitation.

- Specify which statistical tests were used for each comparison.

- Indicate the patient enrolment period and the time from symptom onset to surgery.

- Provide more details on parameter changes at each follow-up point.

[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: Partly

Reviewer #3: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: 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

Reviewer #3: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

Reviewer #1: First, I would like to thank you for the opportunity to review the article "Validation of The Human Disharmony Loop: Pectoralis minor tenotomy significantly reduces pain and improves function in historically challenging patients who meet reproducible and explicit diagnostic criteria."

I confirm that the article is clearly written, with logical conclusions.

Therefore, I accept the publication of this article.

Sincerely,

Dr. João Paulo Barile

Reviewer #2: The authors present an interesting and thought-provoking manuscript on the "Human Disharmony Loop" (HDL), a novel conceptual framework for a challenging patient population with chronic upper extremity pain. The proposed diagnostic criteria are explicit, and the reported outcomes following pectoralis minor (PM) tenotomy are impressive. The paper is well-written and the model is clearly explained. However, there are several major concerns that need to be addressed before this manuscript can be considered for publication.

Major Concerns:

Study Design and Inconsistency: The most critical issue is a major inconsistency regarding the study design. The abstract states the purpose is to "validate this model prospectively" , whereas the Methods section and main body repeatedly describe the study as a "retrospective chart review". This is a fundamental contradiction that must be corrected throughout the manuscript. The entire framing of the paper depends on it.

Lack of a Control Group: As a retrospective case series, the study lacks a control group. This is a significant limitation. The dramatic improvements could be influenced by the placebo effect, which is known to be substantial in surgical interventions for pain. The authors should more thoroughly discuss this limitation in the Discussion section and acknowledge how it might temper the interpretation of the results. Without a comparison group (e.g., patients meeting HDL criteria treated with conservative therapy alone for the same duration), it is difficult to definitively attribute the outcomes solely to the PM release.

Reliance on the Scratch-Collapse Test: The diagnosis of multiple neuropathic lesions relies on the scratch-collapse test. As the authors rightly note in their limitations, this test is not part of the formal diagnostic criteria for these conditions. While useful as a clinical tool, its reliability and specificity can be debated. This reliance weakens the claims regarding the resolution of specific nerve compressions (e.g., carpal, cubital tunnel). The authors should further contextualize these findings and be more cautious in their conclusions about "curing" these neuropathies.

The "Double Crush" Phenomenon and Secondary Surgery: The finding that 25% of patients required a secondary neurolysis is clinically very important and adds credibility to the report. However, the discussion could explore this further. Does this high rate of secondary surgery suggest that the HDL model, while valuable, may be incomplete? Or does it position PM release as simply the

first critical step in a multi-stage treatment for a more complex regional pathology? Expanding on this would add significant depth to the discussion.

Minor Concerns:

Statistical Methods Description: In the Methods section, please specify the exact statistical tests used to generate the p-values (e.g., Wilcoxon signed-rank test for pre- vs. post-operative median scores, Chi-squared or Fisher's exact test for categorical variables).

Role of Preoperative PM Block: The data shows that 89% of patients who received a PM block reported improvement. This implies 11% had a "negative" block but still proceeded to surgery and, presumably, had good outcomes. The discussion could briefly touch on the potential reasons for a false-negative block and why it should not be an absolute contraindication for surgery, as this has important clinical implications.

Figure 5: The bar chart in Figure 5 is effective for showing the magnitude of change. However, it would be strengthened by the inclusion of error bars (e.g., interquartile range for the medians) to visually represent the variance in the data.

Reviewer #3: The authors provided a new concept-Human Disharmony 5 Loop (HDL) as a model that anatomically explains a mix of intractable shoulder pain, persistent 3 impingement/loss of shoulder motion, neck pain, headaches, and distal neuropathy. pectoralis minor release was an effective method to reduce shoulder pain, headaches, 24 concomitant neuropathic lesions and improved shoulder range of motion. This article will provide some suggestion to treat patients with similar symptoms. But there are some questions need to be revised or explained.

1. The authors studied 115 patients in this article, but the patient enrollment period was not mentioned.

2. Some figures (figure 1-4) in this article were similar with the previous paper (reference 10-The Human Disharmony Loop: A Case Series Proposing the Unique Role of the Pectoralis Minor in a Unifying Syndrome of Chronic Pain, Neuropathy, and Weakness, PMID: 40095905). Dr. James M Friedman was the co-author in both articles. I think the authors need explain the two articles' connections and distinctions and add the reference in the figure 1, figure 2, figure 3, and figure 4.

3. In the method part, Patients were evaluated pre-operatively, and at 2, 6, 12, and 24 weeks, so what’s the changing trend of pain scores, clinical neuropathic lesions, rotator cuff impingement 13 signs, shoulder range of motion, and complications at these time points.

4. How about the duration of the 115 patients before operation? If the duration of illness influences the surgical outcome, especially for the neuropathic symptoms?

**********

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

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.]

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.

Validation of The Human Disharmony Loop: Pectoralis minor tenotomy significantly reduces pain and improves function in historically challenging patients who meet reproducible and explicit diagnostic criteria

PONE-D-25-26406R1

Dear Dr. Friedman,

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. For questions related to billing, please contact billing support .

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,

Emil George Haritinian, M.D, Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions??>

Reviewer #2: Yes

Reviewer #3: Yes

**********

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

Reviewer #2: Yes

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #2: Yes

Reviewer #3: Yes

**********

Reviewer #2: Thank you once again for the opportunity to review your manuscript titled “Validation of The Human Disharmony Loop.” I appreciate the thoughtful revisions you have made following the initial round of feedback.

The updated version addresses the key concerns raised previously, including clarification of the study design, acknowledgment of limitations such as the absence of a control group, and refinement of the discussion around diagnostic tools and secondary procedures. These changes have strengthened the manuscript and improved its clarity and scientific rigor.

I particularly commend the way you have contextualized the role of the scratch-collapse test, expanded on the implications of secondary neurolysis, and clarified the diagnostic value of the PM block. The figures and data presentation are also improved, notably with the addition of interquartile ranges.

In summary, I find the revised manuscript well-structured, clearly written, and clinically relevant. I have no further concerns and support its publication.

Thank you again for your valuable contribution.

Reviewer #3: Human Disharmony 29 Loop (HDL) was a model that explained a mix of intractable shoulder pain, persistent

27 impingement/loss of shoulder motion, neck pain, headaches, and distal neuropathy. This article provide a new sight to treat the complex shoulder and upper extremity pain and functional disorder for clinal doctors.

**********

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

Reviewer #3: No

**********