Dear Dr. Mao,

Thank you very much for submitting your manuscript "Nationwide and long-term epidemiological research of snake envenomation in Taiwan during 2002–2014: a study utilizing National Health Insurance Database" 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.

The manuscript adds important information to the field. It will be great to add actual epidemiological data on snakebite envenomation rather than the surrogates used.

Because of its importance I recommend that the authors revise the manuscript after major revision and resubmit.

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,

R. Manjunatha Kini

Academic Editor

PLOS Neglected Tropical Diseases

Justin Remais

Section Editor

PLOS Neglected Tropical Diseases

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The manuscript adds important information to the field. It will be great to add actual epidemiological data on snakebite envenomation rather than the surrogates used.

Because of its importance I recommend that the authors revise the manuscript after major revision and resubmit.

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: Please refer the comments under Summary and General Comments

Reviewer #2: -the incidence of venomous snakebite being extrapolated from hospital insurance payouts maybe fallacious as many of the envenomed may actually land up with alternate therapies which fall below the insurance radar as so commonly happens in South-East Asian countries and whether these numbers reporting for treatment in modern medical facilities are thus truly representative enough

- it is not stated as to whether the e Taiwan National Health Insurance covers for all individuals and all diseases or in short whether the health system is uniformly insured for all

- There would be instances of victims being given ASV for a presumptive bite which would finally turn out as non-venomous or other bites which could only be confirmed with study of the individual case notes

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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: Please refer the comments under Summary and General Comments

Reviewer #2: The incidence of venomous snakebite may not be truly representative but a pointer towards the results given

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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: Please refer the comments under Summary and General Comments

Reviewer #2: Reasonably well, yes

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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: None

Reviewer #2: this manuscript on a Neglected Tropical disease is presented well given that it has all the negatives that come alongside retrospective data analysis using an Insurance database

I would think it could be accepted with revisions and of modest interest to readers

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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: Suggest to change the “snake envenomation” as “snakebite envenomation” in the title and throughout the manuscript.

The terms “envenoming” and envenomation” have been used is different parts of the manuscript. Suggest to use single terminology throughout the manuscript.

Abstract: Reword the introduction of the abstract to highlight the lack of long-term epidemiological data of snakebite envenomation (SBE). It is not necessary to include the names of the venomous snakes with in the limited word count in the abstract.

This is not a true prospectively conducted SBE epidemiology study. All epidemiological results were generated based on the distribution and used of different antivenoms in different parts of Taiwan. Therefore, reword this sentence “This study aimed to explore the epidemiology of snake envenomation in Taiwan to facilitate the development of prevention strategies and resource allocation.” to highlight that this study is based on Antivenom data.

Add thousand separators in all the numerical values more than 999. (throughout the manuscript).

Authors summary: Include the common names of the listed snake species.

Authors summary: “The low case-fatality rate observed might be due to easy access to modern medicine, immediate availability of antivenoms in healthcare facilities, few adverse effects of antivenoms, and prompt surgical intervention.”

Lack of highly venomous snakes have highly potent venom is a leading factor for low case fatality. Please include that in this sentence.

Under introduction: Following details on Taiwan and related to SBE have to be included.

Total land area, total population, proportion of people in rural areas, proportion of people in agricultural sector, type of snake antivenom used, antivenom manufacturers, details of the snakebite management guidelines used to treat patients, basis of deciding type of antivenom, how snakes are identified in hospitals.

At the end of introduction: Aims and objectives of this study have not been stated.

Under study population and setting: include the details of antivenom manufacturers.

Under study population and setting: “We assumed that patients who received specific snake antivenom were envenomed by relevant snakes”. Majority of the data analysis of this study depends on accurate identification of snake bitten by and correct used of antivenom. Therefore, it is important to provide more details about how bitten snakes were identified and antivenom selection procedure.

The presented epidemiological data on SBE is based on antivenom usage database and which is far from the actual SBE epidemiology described by a prospective observation study. There is a possibility of some envenomated patients may not seek hospital admissions, some patients may not give the antivenom, some patients may have received antivenom inappropriately. Therefore, I would like to suggest to present this data as “use of snake antivenom in Taiwan”. This factor has not been highlighted because of using “epidemiology of snake envenomation” in several places. I suggest to reword the title and other relevant sections accordingly.

Discussion: Highlight that all these epidemiological data is based on the Antivenom distribution and used data and the actual SBE epidemiology would be somewhat different and explain the reasons for the difference.

Provide some SBE epidemiology figures in some Asian countries and discuss the Taiwan values with the values of some Asian countries.

Limitations:

Describe the issues of accurate snake identification and decision of use of different type of Antivenom based on that.

“Second, the epidemiology of individual snakebites….” Here this is not on snakebites, snakebite envenomation based on antivenom using data.

Conclusions: Second line “clinical features”

This study has not described the detailed clinical features of SBE. Presented overall local and systemic effects such as neurotoxicity, renal injury, and so on. Hence, this has to be modified as “local and overall systemic toxin effects”

Table 1. Caption: “Characteristic distributions of venomous snakebites, and calculation of…”

This is not snakebites, this has to be modified as “Characteristic distributions of SBE cases based on use of snake antivenom, and calculation of….

Reviewer #2: I read the manuscript written by Jen-Yu Hsu et al with a lot of interest and have the following remarks to make

-in the author summary he states that venomous snakebite is a tropical disease and should not be neglected, whilst venomous snakebite is already listed as a neglected tropical disease (NTD)

- Bungarus multicinctus multicinctus is I believe not distributed in India

- ‘Wound infection and antibiotic use were defined as having erysipelas, cellulitis, fasciitis, or myositis and receiving oral or intravenous antibiotics within 7 days, respectively’, would not hold true for all fasciitis or myositis as a lot of it could be attributed directly to the venoms of viperid, crotalid and even elapid species as well

- I wonder how many of the envenomed actually land up with alternate therapies which fall below the insurance radar as so commonly happens in South-East Asian countries and whether these numbers reporting for treatment in modern medical facilities are thus truly representative enough

- Given the constraints placed by retrospective analysis of data and that it being based on insurance pay-outs I think that the manuscript is structured well and makes for a good read.

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Reviewer #1: Yes: Kalana Maduwage

Reviewer #2: Yes: Jaideep Menon

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

Dear Dr. Mao,

Thank you very much for submitting your manuscript "Nationwide and long-term epidemiological research of snakebite envenomation in Taiwan during 2002–2014 based on the use of snake antivenoms: a study utilizing National Health Insurance Database" 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.

The revised manuscript satisfactorily responds to all the questions, queries and corrections suggested by the reviewers. Some parts of their rebuttal will help improve the manuscript. For example, segments in the rebuttal letter such as "We agree with you that diagnosing wound infections in SBEs can be difficult and may be overestimated if deep tissue or biopsy cultures are not performed for the wound. However, we observed that 76.8% to 80.9% of N. atra bite patients developed wound infections in studies conducted by Mao et al. Out of the 59 and 87 patients, 50 and 73, respectively, had positive wound bacterial cultures [1,2]. In addition, 22 out of 27 and 30 out of 33 had positive deep tissue or biopsy cultures, respectively [2,3]. Furthermore, necrotizing soft tissue infections, including necrotizing fasciitis, were observed in 42.1% to 44.7% of N. atra bites [2,3]. On the other hand, wound infections are less common in T. s. stejnegeri and P. mucrosquamatus (crotaline) bites, with rates of 11.4% and 27.4%, respectively [4,5]. In this study, which utilized the National Health Insurance database, we used criteria similar to those in a recent report to identify SBE wound infections [6]. Our findings indicate that 20.3% of patients who received FH antivenom (i.e., antivenom for T. s. stejnegeri and P. mucrosquamatus) developed wound infections, which is consistent with previous studies conducted by Mao et al. [4,5], and lower than the study conducted by João Victor Soares Coriolano Coutinho et al. [6]. Although the incidence of wound infection might still have been overestimated in this study, such overestimation is much smaller" along with the references. You could use such answers to reviewers' comments to improve the revised manuscript.

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,

R. Manjunatha Kini

Academic Editor

PLOS Neglected Tropical Diseases

Justin Remais

Section Editor

PLOS Neglected Tropical Diseases

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

The revised manuscript satisfactorily responds to all the questions, queries and corrections suggested by the reviewers. Some parts of their rebuttal will help improve the manuscript. For example, segments in the rebuttal letter such as "We agree with you that diagnosing wound infections in SBEs can be difficult and may be overestimated if deep tissue or biopsy cultures are not performed for the wound. However, we observed that 76.8% to 80.9% of N. atra bite patients developed wound infections in studies conducted by Mao et al. Out of the 59 and 87 patients, 50 and 73, respectively, had positive wound bacterial cultures [1,2]. In addition, 22 out of 27 and 30 out of 33 had positive deep tissue or biopsy cultures, respectively [2,3]. Furthermore, necrotizing soft tissue infections, including necrotizing fasciitis, were observed in 42.1% to 44.7% of N. atra bites [2,3]. On the other hand, wound infections are less common in T. s. stejnegeri and P. mucrosquamatus (crotaline) bites, with rates of 11.4% and 27.4%, respectively [4,5]. In this study, which utilized the National Health Insurance database, we used criteria similar to those in a recent report to identify SBE wound infections [6]. Our findings indicate that 20.3% of patients who received FH antivenom (i.e., antivenom for T. s. stejnegeri and P. mucrosquamatus) developed wound infections, which is consistent with previous studies conducted by Mao et al. [4,5], and lower than the study conducted by João Victor Soares Coriolano Coutinho et al. [6]. Although the incidence of wound infection might still have been overestimated in this study, such overestimation is much smaller" along with the references. You could use such answers to reviewers' comments to improve the revised manuscript.

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. Mao,

We are pleased to inform you that your manuscript 'Nationwide and long-term epidemiological research of snakebite envenomation in Taiwan during 2002–2014 based on the use of snake antivenoms: a study utilizing National Health Insurance Database' 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.

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

Best regards,

R. Manjunatha Kini

Academic Editor

PLOS Neglected Tropical Diseases

Justin Remais

Section Editor

PLOS Neglected Tropical Diseases

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The authors have revised the manuscript to include all suggestions/clarifications.