Sex-Specific Inflammatory Profiles Affect Neuropsychiatric Issues in COVID-19 Survivors

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Recommendation:
The article titled “Sex-specific inflammatory profiles affect neuropsychiatric issues of COVID19” presents an insightful investigation into the interplay between inflammation, depression,
and cognitive impairment in post-COVID-19 patients, with a strong emphasis on sex-specific
differences. The use of path modeling on a robust inflammatory biomarker panel provides a
nuanced understanding of the mechanisms underlying neuropsychiatric outcomes post-COVID.
The study is timely, well-structured, and presents a valuable contribution to the field of
neuroimmunology and post-COVID research. However, the manuscript would benefit from
minor revisions to improve clarity, organization, and formatting consistency, particularly in
grammar and language usage.

Major Comments:
Scientific Significance:
The study addresses a novel and clinically significant topic—sex-specific differences in
inflammatory pathways associated with post-COVID neuropsychiatric symptoms. The
comprehensive biomarker panel and application of path modeling add methodological rigor.
However, the manuscript would benefit from explicitly emphasizing how these findings
advance current knowledge compared to existing studies in the field.

Specific Comments and Suggested Revisions:
1. Abstract:
o The sentence: “Cognitive impairment in males was primarily influenced by
depression, not inflammation.” could be revised for clarity.
Suggested: “In males, cognitive impairment appeared to be driven mainly by
depressive symptoms, with minimal influence from inflammatory markers.”
o The term “residual dysregulated immune-inflammatory response” is somewhat
unclear. Consider simplifying or defining it briefly.

2. Line 35–38 (Introduction):
Original: “Inflammation is a point of convergence between mood regulation and
cognitive functioning…”
Suggested: “Inflammation represents a common pathway influencing both mood
regulation and cognitive functioning, with cytokines playing key roles in learning,
memory, and emotional processing.”

3. Line 53–56:
Original: “…some inconsistent studies indicating that inflammation predicts depressive
symptoms in women but not in men, and vice versa.”
Suggested: “Previous findings on sex differences in inflammation-related depressive
symptoms have been inconsistent, with some studies suggesting stronger associations
in women and others in men.”

4. Tables and Figures: Ensure all tables and figures are referenced in numerical order and
contain informative captions.

5. Grammar and Readability:
o Revise for minor grammatical issues and wordiness. For example: Abstract:
“also showing a trend of association with depressive burden…”with
“and showed a trend toward association with depressive symptoms.”
o Replace informal or vague expressions such as “to our surprise” with neutral
language like “interestingly” or “notably.”

6. References:
o Ensure all references conform to Biomolecules formatting guidelines. Use
consistent formatting for journal names, issue numbers, and page ranges.

7. Conclusion:
o The conclusion is well-aligned with the results but could be sharpened slightly for
impact:
Suggested: “These findings highlight the growing importance of recognizing sex
differences in immunological and neuropsychiatric responses to COVID-19.
Future studies should further explore how hormonal and immune interactions
may inform personalized, sex-specific treatment approaches in post-COVID
care.”

Summary:
The manuscript presents a compelling and methodologically solid investigation into sex-specific
inflammatory profiles and their impact on post-COVID depression and cognitive impairment.
The integration of biomarker data and psychological assessments through path modeling offers
strong analytical value. While the manuscript is generally well-written, minor revisions to
improve clarity, grammar, and methodological transparency are recommended.

Comments on the Quality of English Language

Enclosed here are my revision!

Author Response

Please see the attachment.

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

The article highlights an important aspect of physiology, namely describing the differences in the immunological profile in males and females and the relationship of cytokines and inflammation to depression and cognitive impairment. The authors conclude that the causes of depression at the physiological level are different in males and females. The study has undoubted novelty. The purpose of the study is clearly enough formulated. The advantage of this work is the use of PLS-PM method, which provides valuable results. The results obtained are in line with the aim of the study. However, there are some remarks:

1. The study lacks a control group and it is not clear how depression and cytokines are related to COVID-19.
2. What exactly was the expression of the post-COVID syndrome in the examined persons?
3. The BDI-13 was used to assess depression, it is necessary to give interpretation of this scale in the text, it is not clear whether there is depression in the examined persons. Also for the ZSDS index.
4. The reliability of the data presented in Table 1 is questionable. For example, it shows significant differences in Basic_FGF in female and male, while the medians are 12.5 ± 3 and 13 ± 3 respectively. The same is true for other indicators. It is necessary to verify all the data presented.

Author Response

Please see the attachment.

Author Response File: Author Response.docx

Reviewer 3 Report

Comments and Suggestions for Authors

This is an interesting and relevant study however there are several concerns that should be addressed.

1. The title is not worded correctly. It is unclear how inflammatory profiles "affect" neuropsychiatric issues
2. There are several instances where the authors claim the findings show that inflammation in the brain impacts neuropsychiatic issues. However, the data show at best an association of peripheral inflammatory factors and psychiatic issues. No measure of inflammation in the brain. 
3. The lack of control subjects is a weakness.
4. The font in the figures is too small
5. There are several instances in the results section where findings are not significant yet stated as "approached" significance or "positive trend"; simply state not significant. Discussing these trends may be appropriate in discussion section but must not be overstated. Also, in the results section, data are described as "detrimental" (pg. 9, line 217) however there is no evidence that the measurement results in detrimental effect. Similar statements are found in the discussion (lines 276, 278, 281, 310, 311).
6. Discussion starts by restating results rather than discussing results
7. Discussion includes  

Author Response

Please see the attachment.

Author Response File: Author Response.docx

Round 2

Reviewer 3 Report

Comments and Suggestions for Authors

All concerns have been adequately addressed.