PONE-D-23-18279Inflammatory Markers in World Trade Center Workers with Asthma: Associations with Post Traumatic Stress DisorderPLOS ONE

Dear Dr. Agrawal,

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PLOS ONE

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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: Partly

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

Reviewer #1: Yes

Reviewer #2: No

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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: Comments to the Author

Comment: The full form of DSM-5 is not mentioned anywhere in the manuscript

Comment: Line 155: Correct to plasma cytokine levels.

Comment: Line 165: Put space after (J.B.)

Comment: Line 171: Spelling needs to be corrected for Streptavidin-Phycoerythrin.

Comment: As the last part of this study overlaps with the COVID pandemic, did this study consider whether individuals participating in the study was exposed to COVID-19 and whether that would influence the airways and cytokines present?

Comment: Line 201: The P value mentioned in the text and Table 1 are not the same. Which one is correct?

Comment: Line 391, 397, 405 and 411: Correct VEFG to VEGF

Comment: Were any of these samples diluted before testing? RANTES is a marker which needs to be tested after diluting serum/plasma samples using Luminex multiplex assays and usually cannot be tested along with other markers in serum multiplex assays. Were any issues noted with RANTES detection during this study?

Reviewer #2: Overall, this is an interesting work looking to explore whether WTC workers with diagnoses of PTSD and asthma have a specific underlying inflammatory marker profile to explain increased asthma morbidity. Parts of the manuscript, particularly the Introduction and Discussion, do not follow a logical flow to orient the reader to the clinical investigation that was performed. This Reviewer can intuit the line of reasoning in performing some of the secondary analyses, but a more thorough investigation of these factors (particularly the degree of WTC exposure and the outcomes of interest) would strengthen the work substantially in view of the negative findings reported.

Major comments:

1. Please provide rationale for utilizing both blood and sputum samples in the Methods section.

2. Though this reviewer can appreciate why a more thorough statistical analysis was not performed, it seems obvious to investigate some of the other factors collected (such as degree of WTC Exposure) in relation to blood & sputum cytokine levels regardless of PTSD status given that there was no significance in those markers between groups. This would strengthen the paper considerably.

3. Further, this reviewer suggests that if at all feasible, the Authors should include a small control group to understand normative values of this assay for blood & sputum cytokine levels. Please report graphically as a reference in all Tables.

4. It seems theoretically possible that individuals with asthma have upregulation of these values at baseline given that it is a chronic disease. If that is not the case, then justification should be provided in the text of the manuscript in the Discussion.

5. Please further clarify the significance of elevated neutrophils in the sputum cell differential in the Discussion. It is not obvious why this finding is clinically meaningful.

Minor comments:

Line 73: Clarify what is meant by “uncontrolled asthma symptoms” in terms of clinical presentation.

Line 82, Line 87: The role of the cytokines noted in the Introduction are not well-described. Please clarify their roles in relation to PTSD and asthma, respectively.

Line 114: Do the authors mean “opt-in”?

Line 187: Correct to “markers”.

Line 202: Please explain why 29% of individuals were excluded due to lack of blood cytokine measures.

Lines 247-249: Suggest a more thorough review of the literature to include how social and behavioral determinants drive inflammation in chronic conditions. The Authors have not provided a reference for this statement.

Table 2: Please provide reference ranges.

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Reviewer #1: No

Reviewer #2: No

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Inflammatory Markers in World Trade Center Workers with Asthma: Associations with Post Traumatic Stress Disorder

PONE-D-23-18279R1

Dear Dr. Agrawal,

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,

Suresh Pallikkuth

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

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 #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 #1: Yes

Reviewer #2: Yes

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

Reviewer #1: Yes

Reviewer #2: 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 #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: 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 #1: Authors have adequately addressed my comments and I feel that this manuscript is now acceptable for publication.

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 #1: No

Reviewer #2: No

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