Peer Review History

Original SubmissionFebruary 12, 2023
Decision Letter - Masaki Mogi, Editor

PONE-D-23-04083Corneal confocal microscopy demonstrates sensory nerve loss in children with autism spectrum disorderPLOS ONE

Dear Dr. Malik,

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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The manuscript was evaluated by two reviewers.There are several minor revisions existed in the present form. 

See the suggestions carefully, and respond them appropriately.

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We look forward to receiving your revised manuscript.

Kind regards,

Masaki Mogi

Academic Editor

PLOS ONE

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2. We noticed you have some minor occurrence of overlapping text with the following previous publication(s), which needs to be addressed:

- https://doi.org/10.1002/ana.26484

- https://doi.org/10.1161/STROKEAHA.117.018289

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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

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

Reviewer #1: Yes

Reviewer #2: Yes

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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

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

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

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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: Summary

Overall, the paper is well and clearly written. This is an interesting study where authors for the first time demonstrate corneal nerve fibre loss in children with autism spectrum disorder (ASD).

Questions

1. It’s interesting that no reduction in IWL was observed in children with ADS. Perhaps the reason for this could be the fact that only 6 children had IW captured.

2. Were the IW images captured for 6 or 7 children? Figure 2E seems to show that there where 7 children with captured IW.

3. Have you considered to quantify Langerhans cells for the same images? This would be interesting to see if there are any differences between both groups.

4. Perhaps it would be beneficial for readers to add IW images as well even there was no significant difference between both groups.

Reviewer #2: The authors have demonstrated a reduction in corneal nerve fibers in children with autism spectrum disorder. This paper represents an important contribution to the literature since this is the first report of corneal nerve loss in ASD. The paper is very well written and the methodology is sound.

I have two minor comments:

1. In the Methods section (page 4, line 24), the authors stated that inferior whorl length parameter was available for six participants, which I think should have been seven – as it appears in Figure 2E.

2. Page 9, line 20; please edit as “… an alteration”

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Reviewer #1: No

Reviewer #2: No

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Revision 1

Reviewers

Reviewer:#1: Summary

Overall, the paper is well and clearly written. This is an interesting study where authors for the first time demonstrate corneal nerve fibre loss in children with autism spectrum disorder (ASD).

Questions

It is interesting that no reduction in IWL was observed in children with ASD. One possible reason for this could be the fact that only 6 children had IW captured.

Answer: Thank You. We agree that with IW data from only 7 individuals may well have limited the power of the study. An alternate explanation is that lack of change in the IW reflects less distal nerve involvement and therefore provides insights into the underlying pathology of neurodegeneration in ASD. This differs from greater IW involvement in patients with diabetic neuropathy who typically have a distal dying back neuropathy. We have now expanded the discussion to clarify this on page 9.

“We show no loss of corneal nerves at the more distal inferior whorl which may indicate a unique pattern of neurodegeneration affecting proximal rather than distal nerves. This differs from our previous studies in adults with diabetic neuropathy showing greater loss of nerves at the inferior whorl compared to the central cornea, which is consistent with a dying back neuropathy [43].”

Were the IW images captured for 6 or 7 children? Figure 2E seems to show that there were 7 children with captured IW.

Answer: Thank you. We apologize for this error. The inferior whorl length was assessed in seven participants as per the figure. We have now corrected this in the text.

Have you considered quantifying Langerhans cells for the same images? It would be interesting to see if there are any differences between the two groups.

Answer: We agree that quantification of LC’s may provide insights into the underlying mechanisms of neurodegeneration in ASD. However, the variability in LC assessment if very large and with the small numbers we do not feel we would generate meaningful results. We are planning a larger study where we will quantify LC’s.

It might be beneficial for readers to add IW images as well, even if there was no significant difference between the two groups.

Answer: Thank you for your suggestion. We have now added IW images in Fig 1.

“Fig 1. Central corneal nerve image from a healthy control (A) and child with ASD (B) showing a reduction in main nerve fibers and branches (red arrows) in children with ASD and Inferior whorl (IW) image from a healthy control (C) and child with ASD (D) showing no difference.

Reviewer #2: The authors have demonstrated a reduction in corneal nerve fibers in children with autism spectrum disorder. This paper represents an important contribution to the literature as it is the first report of corneal nerve loss in ASD. The paper is very well-written, and the methodology is sound.

I have two minor comments: In the Methods section (page 4, line 24), the authors stated that the inferior whorl length parameter was available for six participants, which I believe should have been seven, as it appears in Figure 2E.

Answer: Thank you. We apologize for this error. The inferior whorl length was assessed in seven participants as per the figure 2E. We have now corrected this in the text.

Page 9, line 20; please edit as "... an alteration."

Answer: Thank you. We have edited the sentence accordingly.

Attachments
Attachment
Submitted filename: ASD Rebutal Letter.docx
Decision Letter - Masaki Mogi, Editor

Corneal confocal microscopy demonstrates sensory nerve loss in children with autism spectrum disorder

PONE-D-23-04083R1

Dear Dr. Malik,

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 for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, 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,

Masaki Mogi

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

The authors well responded to the Reviewers' suggestions. No further comment.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

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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 #2: (No Response)

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

Reviewer #2: (No Response)

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

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: (No Response)

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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 #2: (No Response)

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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 #2: (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 #2: No

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Formally Accepted
Acceptance Letter - Masaki Mogi, Editor

PONE-D-23-04083R1

Corneal confocal microscopy demonstrates sensory nerve loss in children with autism spectrum disorder

Dear Dr. Malik:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

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 plosone@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. Masaki Mogi

Academic Editor

PLOS ONE

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