Dear Dr. Xiang,

Thank you very much for submitting your manuscript "Clonorchis sinensis on the prognosis of patients with spontaneous rupture of Hepatocellular Carcinoma: an inverse probability of treatment weighting analysis" for consideration at PLOS Neglected Tropical Diseases. As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. In light of the reviews (below this email), we would like to invite the resubmission of a significantly-revised version that takes into account the reviewers' comments.

We cannot make any decision about publication until we have seen the revised manuscript and your response to the reviewers' comments. Your revised manuscript is also likely to be sent to reviewers for further evaluation.

When you are ready to resubmit, please upload the following:

[1] A letter containing a detailed list of your responses to the review comments and a description of the changes you have made in the manuscript. Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

[2] Two versions of the revised manuscript: one with either highlights or tracked changes denoting where the text has been changed; the other a clean version (uploaded as the manuscript file).

Important additional instructions are given below your reviewer comments.

Please prepare and submit your revised manuscript within 60 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email. Please note that revised manuscripts received after the 60-day due date may require evaluation and peer review similar to newly submitted manuscripts.

Thank you again for your submission. We hope that our editorial process has been constructive so far, and we welcome your feedback at any time. Please don't hesitate to contact us if you have any questions or comments.

Sincerely,

Javier Sotillo

Academic Editor

PLOS Neglected Tropical Diseases

Uriel Koziol

Section Editor

PLOS Neglected Tropical Diseases

***********************

Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #1: The paragraph "Study Population" should be re-written like this: Of 328 patients with ruptured HCC, 171 were excluded (17 with previous treatment, 95 receiving TAE or TACE, 33 without treatment, and 26 without complete follow up data). In addition, the prognosis-related clinical factors including MVI, BCLC stage, tumor size, and HBV DNA should be compared between 157 included patients and 171 excluded patients. This will let readers know if the 157 patients represent the 328 patients in total. Others are OK.

Reviewer #2: (No Response)

Reviewer #3: 1. It would be better if the authors can provide the information of IPTW in the introduction or method, including the advantages, and how it important and improve the result or previous reports.

2. To obvious, please describe separately between the baseline characteristics and the result that comparison of before and after using IPTW. Importantly, please use Chi-square to compare the different between before and after using IPTW. Could you please explain more about the statistical analysis of this part?

--------------------

Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #1: The results are fully and clearly presented. Tables and Figs need to be polished. HBV infection between the two groups should be included in the survival analysis because HBV replication has been proven to be an independent risk factor of HCC prognosis.

Reviewer #2: (No Response)

Reviewer #3: 1. Are the results clearly and completely presented in Table 1?

2. This finding did not show the significant data of C. sinensis and no C. sinensis group when no using IPTW, could you please explain and discussion in this point.

--------------------

Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #1: The significance was found in patients adjusted by inverse probability of treatment weighting (IPTW). Pls discuss how this kind of matching might avoid potential bias?

Reviewer #2: (No Response)

Reviewer #3: 1. Please elucidate how srHCC differ from HCC, what is the significant point to study?

2. Please add more risk factors of HCC and/or srHCC, relationship of HBV, HCV and C. sinensis with HCC.

3. It would be good if the author can add more discuss about C. sinensis in HCC when compare with srHCC.

--------------------

Editorial and Data Presentation Modifications?

Use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. If the only modifications needed are minor and/or editorial, you may wish to recommend “Minor Revision” or “Accept”.

Reviewer #1: No more comment.

Reviewer #2: (No Response)

Reviewer #3: (No Response)

--------------------

Summary and General Comments

Use this section to provide overall comments, discuss strengths/weaknesses of the study, novelty, significance, general execution and scholarship. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. If requesting major revision, please articulate the new experiments that are needed.

Reviewer #1: In this study, authors evaluated the association of Clonorchis sinensis infection with the risk of ruptured HCC in Guangxi, an endemic province of Clonorchis sinensis infection in China. Previously, this group characterized the association of Clonorchis sinensis infection with the risk of HCC. This is a new study not being reported. The study design is right. The outcomes are important in this field. However, minor revision is needed focusing on following aspects.

1. The paragraph "Study Population" should be re-written like this: Of 328 patients with ruptured HCC, 171 were excluded (17 with previous treatment, 95 receiving TAE or TACE, 33 without treatment, and 26 without complete follow up data). In addition, the prognosis-related clinical factors including MVI, BCLC stage, tumor size, and HBV DNA should be compared between 157 included patients and 171 excluded patients. This will let readers know if the 157 patients represent the 328 patients in total.

2. The significance was found in patients adjusted by inverse probability of treatment weighting (IPTW). Pls discuss how this kind of matching might avoid potential bias?

3. HBV infection between the two groups should be included in the survival analysis because HBV replication has been proven to be an independent risk factor of HCC prognosis.

Reviewer #2: Overview and general recommendation:

This study analyzed the role of C. sinensis infection in the survival outcomes of spontaneous rupture hepatocellular varcinoma patients using inverse probability of treatment weighting and found that C. sinensis infection had an adverse impact on OS in srHCC patients and was independent prognostic factor. This study was novel. However, there still some questions.

Questions and suggestions:

1. As we know, the destiny of tumors and survival outcomes of patients were decided by many factors including the pathological type, size, metastasis of tumors, chemotherapy, patient's physical condition and diet, and so on. However, these factors were not evaluated in this study. Usually, for patients with tumor of late stage, chemotherapy is needed and is a very important factor that will influence the outcomes of patients. Obviously, these factors were not designed and considered.

2. As the author said, most patients in this study were with chronic hepatitis B infection which was another very important virus that destroys the liver function. This should also be evaluated. Line 259, HCV should be HBV.

3. For OS, before IPTW, the median for the C. sinensis group was 17 months while that for the no C. sinensis group was 32 months. There was already a big difference between these two groups. However, the P was below 0.05. Why?

4. From 2013 to 2021, this study lasted for 8 years. When patients had partial hepatectomy and found to be infected with C. sinensis, did not they receive any treatment for this parasite? Any treatment will also have an impact on the results of this study.

5. C. sinensis should be italic.

Reviewer #3: The manuscript entitled “Clonorchis sinensis on the prognosis of patients with spontaneous rupture of Hepatocellular Carcinoma: an inverse probability of treatment weighting analysis” is interesting work, but there are major points need to be addressed before publish as followed;

1. It would be better if the authors can provide the information of IPTW in the introduction part, including the advantages, and how it important and improve the result or previous reports.

2. This finding did not show the significant data of C. sinensis and no C. sinensis group when no using IPTW, could you please explain and discussion in this point.

3. Please Italics for the word “C. sinensis” in the text.

4. To obvious, please describe separately between the baseline characteristics and the result that comparison of before and after using IPTW. Importantly, please use Chi-square to compare the different between before and after using IPTW. Could you please explain more about the statistical analysis of this part?

5. Please elucidate how srHCC differ from HCC, what is the significant point to study?

6. Please add more risk factors of HCC and/or srHCC, relationship of HBV, HCV and C. sinensis with HCC.

7. It would be good if the author can add more discuss about C. sinensis in HCC when compare with srHCC.

--------------------

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.

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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: Yes: Guangwen Cao

Reviewer #2: No

Reviewer #3: No

Figure 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. 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 us at figures@plos.org.

Data Requirements:

Please note that, as a condition of publication, PLOS' data policy requires that you make available all data used to draw the conclusions outlined in your manuscript. Data must be deposited in an appropriate repository, included within the body of the manuscript, or uploaded as supporting information. This includes all numerical values that were used to generate graphs, histograms etc.. For an example see here: http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001908#s5.

Reproducibility:

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Attachments

Attachment

Submitted filename: Comment for authors_PNTD-D-23-00960.pdf

Dear Dr. Xiang,

Thank you very much for submitting your manuscript "Clonorchis sinensis on the prognosis of patients with spontaneous rupture of Hepatocellular Carcinoma: an inverse probability of treatment weighting analysis" for consideration at PLOS Neglected Tropical Diseases. As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. The reviewers appreciated the attention to an important topic. Based on the reviews, we are likely to accept this manuscript for publication, providing that you modify the manuscript according to the review recommendations.

Please prepare and submit your revised manuscript within 30 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email.

When you are ready to resubmit, please upload the following:

[1] A letter containing a detailed list of your responses to all review comments, and a description of the changes you have made in the manuscript.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out

[2] Two versions of the revised manuscript: one with either highlights or tracked changes denoting where the text has been changed; the other a clean version (uploaded as the manuscript file).

Important additional instructions are given below your reviewer comments.

Thank you again for your submission to our journal. We hope that our editorial process has been constructive so far, and we welcome your feedback at any time. Please don't hesitate to contact us if you have any questions or comments.

Sincerely,

Javier Sotillo

Academic Editor

PLOS Neglected Tropical Diseases

Uriel Koziol

Section Editor

PLOS Neglected Tropical Diseases

***********************

Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #1: The methods are clearly described although their English needs to be polished.

Reviewer #2: (No Response)

Reviewer #3: Please the approval ethics number(s)/ID(s) of approval ethics.

--------------------

Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #1: The results are well presented.

Reviewer #2: (No Response)

Reviewer #3: (No Response)

--------------------

Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #1: The outcomes of this study should be reference for understanding the mechanism by which HCC recur.

Reviewer #2: (No Response)

Reviewer #3: (No Response)

--------------------

Editorial and Data Presentation Modifications?

Use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. If the only modifications needed are minor and/or editorial, you may wish to recommend “Minor Revision” or “Accept”.

Reviewer #1: accept

Reviewer #2: (No Response)

Reviewer #3: (No Response)

--------------------

Summary and General Comments

Use this section to provide overall comments, discuss strengths/weaknesses of the study, novelty, significance, general execution and scholarship. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. If requesting major revision, please articulate the new experiments that are needed.

Reviewer #1: No more suggestions

Reviewer #2: The author revised the manuscript. However, there are still some should be addressed before being published.

1. Table 1, the baseline characteristics of the study population were not complete. Such as, for age, why patients only with the age ≤50 years) were analyzed? And, like tumor size, what about patients with tumor size >10 cm? What does the size mean, length or width? All the characteristics in this table were only including some part of patient, not whole population in this study. Will not those characteristics missing in this table influence the results?

2. All C. sinensis were not in italic.

Reviewer #3: (No Response)

--------------------

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: Yes: Guangwen Cao

Reviewer #2: No

Reviewer #3: No

Figure 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. 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 us at figures@plos.org.

Data Requirements:

Please note that, as a condition of publication, PLOS' data policy requires that you make available all data used to draw the conclusions outlined in your manuscript. Data must be deposited in an appropriate repository, included within the body of the manuscript, or uploaded as supporting information. This includes all numerical values that were used to generate graphs, histograms etc.. For an example see here: http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001908#s5.

Reproducibility:

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

References

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article's retracted status in the References list and also include a citation and full reference for the retraction notice.

Dear Dr. Xiang,

We are pleased to inform you that your manuscript 'Clonorchis sinensis on the prognosis of patients with spontaneous rupture of Hepatocellular Carcinoma: an inverse probability of treatment weighting analysis' has been provisionally accepted for publication in PLOS Neglected Tropical Diseases.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. A member of our team will be in touch with a set of requests.

Please note that your manuscript will not be scheduled for publication until you have made the required changes, so a swift response is appreciated.

IMPORTANT: The editorial review process is now complete. PLOS will only permit corrections to spelling, formatting or significant scientific errors from this point onwards. Requests for major changes, or any which affect the scientific understanding of your work, will cause delays to the publication date of your manuscript.

Should you, your institution's press office or the journal office choose to press release your paper, you will automatically be opted out of early publication. We ask that you notify us now if you or your institution is planning to press release the article. All press must be co-ordinated with PLOS.

Thank you again for supporting Open Access publishing; we are looking forward to publishing your work in PLOS Neglected Tropical Diseases.

Best regards,

Javier Sotillo

Academic Editor

PLOS Neglected Tropical Diseases

Uriel Koziol

Section Editor

PLOS Neglected Tropical Diseases

***********************************************************

Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #2: (No Response)

Reviewer #3: (No Response)

**********

Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #2: (No Response)

Reviewer #3: (No Response)

**********

Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #2: (No Response)

Reviewer #3: (No Response)

**********

Editorial and Data Presentation Modifications?

Use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. If the only modifications needed are minor and/or editorial, you may wish to recommend “Minor Revision” or “Accept”.

Reviewer #2: (No Response)

Reviewer #3: (No Response)

**********

Summary and General Comments

Use this section to provide overall comments, discuss strengths/weaknesses of the study, novelty, significance, general execution and scholarship. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. If requesting major revision, please articulate the new experiments that are needed.

Reviewer #2: (No Response)

Reviewer #3: (No Response)

**********

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

Reviewer #3: No