PONE-D-24-46307Gynecologic health of women with multiple sclerosis: An overview on the current status and findings of Pap tests in a low-income settingPLOS ONE

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Mohammad Reza Fattahi, M.D., M.P.H.

Academic Editor

PLOS ONE

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Additional Editor Comments:

Thank you for submitting your manuscript entitled "Gynecologic health of women with multiple sclerosis: An overview on the current status and findings of Pap tests in a low-income setting." You have selected a highly relevant and underexplored topic that holds significant importance in the literature.

However, after a thorough review, I have identified several essential aspects that need to be addressed to enhance the clarity, depth, and impact of your manuscript. Please refer to the detailed comments and suggestions provided to guide your revisions. Addressing these points will significantly strengthen the manuscript's contribution to the field.

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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?

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Reviewer #1: Yes

Reviewer #2: No

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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: This manuscript titled; Gynecologic health of women with multiple sclerosis: An overview on the current status and findings of Pap tests in a low-income setting

Thank you for your valuable contribution to the field. Early diagnosis of gynecological issues is critical for patients with MS, and the authors have provided an analysis to highlight this in their tables.

To further enhance the value of this manuscript, I would like to suggest additional points to help strengthen it.

Below are my comments for improvement:

Methods:

The authors haven't reported the total number of pregnancies in patients with MS, which may have a significant impact on the course of MS, particularly concerning the EDSS and disease progression. However, the manuscript does not specify the MS subtypes in the patients, such as relapsing-remitting (RR), primary progressive (PP), or secondary progressive (SP) MS. This lack of stratification is important, as the type of MS could influence both disease progression and potentially the results of Pap smears. It would be valuable for the authors to include an analysis of the MS subtype with Pap smear results, as this could reveal important patterns or associations. I would also suggest including a detailed analysis of the relationship between MS subtype and the Pap smear results, as this would offer more insight into the possible interactions between disease type and cervical health.

Additionally, in the exclusion criteria, patients with MS who have had intercourse within 48 hours of the Pap smear should be excluded from the study. This recommendation is based on established guidelines in gynecological research, as recent intercourse may interfere with test accuracy by causing irritation or altering the cells on the cervix. The authors should address this consideration more explicitly in the study design.

Tables:

Each table should have a clear and concise title placed above the table. Additionally, all abbreviations used within the tables should be listed below the table for clarity and ease of reference.

The percentages in each column should add up to exactly 100%, with no exceptions, to ensure accuracy in data presentation.

Furthermore, demographic data for the HC group are currently missing, I mean that all of the demographic data for MS patients in the first table must be provided for the HC group, too. This information is essential for making meaningful comparisons between the MS patients and the HC group. Including demographic data for both groups in the tables and within the body of the manuscript would enhance the comprehensibility and rigor of the study's findings.

Reviewer #2: 1. Some claims made in the discussion and introduction sections are unsupported by references. Please provide adequate citations to strengthen the credibility of these statements. For instance:

Introduction:

*For instance, HPV vaccination could be offered to the wwMS if they are shown to bear an additional risk for HPV infection. Other instances could be offering behavioral consultation, sanitary products, as well as routine screening for, and treating of infections in both wwMS and their partners, if they are shown to bear an additional risk for such diseases.

Discussion:

*Interestingly, a recent Mendelian randomization study on the UK biobank cohort

found an association between MS and related factors (e.g., use of DMT) with cervical cancer but none of the other 14 investigated cancers.

*These results may be explained by an impairment in the immune response to cervical pathogens, possibly mediated by DMT.

*Furthermore, higher-grade inflammatory changes were more frequent in wwMS treated with aCD20 – a DMT class acting mainly on B cells.

*Another explanation could be the impairment of afferent pathways in wwMS. Particularly, impairment of afferent pathways in the wwMS with infection could render them asymptomatic.

2.About income:

*What is the methodology or scale for classifying income levels into mild, moderate, or severe categories?

*One critical aspect that required evaluation was the correlation between a patient's income level and their genital health. Unfortunately, this analysis is absent from the results and discussion sections. The study's methodology primarily just focused on matching MS patients with a control group for comparative analysis. → (Pap test results of wwMS were compared with a 1:2 age- and socioeconomic status (SES)-matched group of healthy controls (HC) who underwent Pap tests for cervical cancer screening in the same laboratory and in the same period)

3. Please specify in the methods section who provided the Pap smear samples: a gynecologist or another healthcare professional. This information is crucial for ensuring the adequacy and quality of the samples.

4. In certain instances please provide both the numerical count and the corresponding percentage together.

5. To enhance relevance, consider relocating this sentence ((Further of note, among all, only one of the wwMS with evidence of yeast infection showed severe inflammatory changes, whereas all HC with evidence of infection showed severe inflammatory changes)) and adding to the subsequent sentence ((As seen, the observed reactive/inflammatory changes differed between the participants with MS and matched HC; such changes were less frequently observed in the wwMS (OR: 0.3; 95% CI: 0.2, 0.4; p < 0.001)).

6. When analyzing (Pap test results), it would be insightful to rank DMTs based on their associated odds ratios (ORs), from highest to lowest. This ranking would facilitate the identification of DMTs potentially linked to increased risk of infection or inflammatory. changes in MS patients. Also for better understanding you can mention as sentences which of DMT can cause more infection or inflammatory reaction?

7. In paragraph 3 of the discussion, please add the word (neural) before (afferent pathway) for better understanding.

8. please add (Benign) word before all phrases (inflammatory/reactive changes) for more comprehension.

9. As comorbidities such as diabetes can significantly impact susceptibility to infection in MS patients, it is crucial to explore the relationship between specific comorbidities and the risk of infection in wwMS. please explain the relationship or impact of comorbidities on infection in wwMS.

10. please mention the mean (SD) or median of duration of DMT.

11. Please provide more detailed information on the prevalence of Human Papillomavirus (HPV) infection in wwMS. If the prevalence of HPV is elevated compared to the general population, please elucidate the potential factors contributing to this increased risk. Additionally, please discuss the cervical malignancy presentation associated with HPV infection in MS patients.

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Reviewer #1: No

Reviewer #2: No

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Gynecologic health of women with multiple sclerosis: An overview on the current status and findings of Pap tests in a low-income setting

PONE-D-24-46307R1

Dear Dr. Sedaghat

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,

Mohammad Reza Fattahi, M.D., M.P.H.

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 #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: Yes

**********

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

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 #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 #2: 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 #2: The manuscript was excellently revised. Only two minor points are considered:

1. In the abstract: Please expand (women with MS (wwMS) to (women with multiple sclerosis)

2. Please put the point after the reference number at the end of sentences in your manuscript : .[] to [].

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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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