PONE-D-23-14246Traditional Herbal Medicine Use Tripled the Risk of Multi-organ Dysfunction Syndrome in a Pediatric Intensive Care Unit in Ethiopia: A Prospective Cohort Study.PLOS ONE

Dear Dr. Teshager,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

The manuscript has been evaluated by two reviewers, and their comments are available below. The reviewers have raised a number of major concerns. They feel that the limitations of the manuscript have not been sufficiently discussed. Given the limitations of the study design, care must be taken to ensure that conclusions - including the title - are presented appropriately and not overstated. The reviewers also note concerns about the reporting of the Methods and Results, including statistical analyses presented, and in particular they request clarifications regarding the sample size calculation.

Could you please carefully revise the manuscript to address all comments raised?

Please submit your revised manuscript by Oct 21 2023 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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Marianne Clemence

Staff Editor

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: 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?

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: I found it very interesting topic and it is thoroughly studied with an exhaustively analyzed data. If the paper gets published many of the public health experts will work on the mitigation strategy through public awareness. However I have some comments

1. The title seems exaggerated. Although the patients who used THM had a 2.45 (95% CI: 1.29, 4.65 ) risk of developing MODS, the authors are trying to exaggerate the output. Hence it has to be said doubled the occurrence of MODS instead of a threefold increase in risk of MODS.

2. In the abstract, under the result section, the last sentence is repeatedly mentioned and has to be deleted. The word keyword has to be written as one word and has to be corrected.

3. In the material and methods section, the study area description is needed. Information regarding the area coverage of the hospital, patient types attending the hospital has to be provided.

4. In the calculation of the sample size, the formula yields 376 not 260. If 10% contingency is used it will be 414. Rather, you can estimate the number of admissions based on a three month data and then you can use a sample adjustment formula for finite population.

5. In the discussion section (paragraph 2, line 4), the justification you indicated has to be accompanied by references.

6. In the discussion section paragraph 3, the justification you raised on the increased risk of MODS in critically ill children who take traditional herbal medicines has to be supported by references.

7. In the introduction (on the last paragraph) and data processing and analysis part, avoid using first-person pronouns ("we").

Reviewer #2: summary of the research:

The study provides important insights into the incidence and predictors of multi-organ dysfunction syndrome (MODS) in a pediatric intensive care unit (PICU) in Ethiopia. The finding that traditional herbal medicine (THM) use is associated with a threefold increased risk of MODS is particularly concerning, given the widespread use of such medicines in Ethiopia and other low- and middle-income countries. The study's strengths include its rigorous methodology and focus on a vulnerable population, and its findings have important implications for clinical practice and public health policy.

However, there are some limitations to consider. The study was conducted at a single center, which may limit the generalizability of the findings to other settings. The sample size was relatively small, which may have limited the ability to fully explore the association between THM use and MODS. The study did not examine the specific types of THM used, which may have different risks and benefits.

General Comments:

Comments on title and abstract:

1. Title not specific to study area: I will suggest that the authors revise the title to make it more specific to the study area. This could help readers quickly understand what the study is about and whether it is relevant to their interests.

2. Lack of background of the study: I suggest that the authors include more information about the background of the study in the background section of the abstract. This could help readers understand the context of the research and why it is important.

3. It is not explicitly stated in the abstract where the single center study took place. To improve the readers' understanding of the study's limitations and generalizability, I suggest that the authors include a sentence in the abstract specifying that the study was conducted at Gondar Comprehensive Specialized Hospital, Gondar, Ethiopia

The authors should provide a more detailed explanation of the following:

Population and sample part (p.4):

The sample size for the study appears to have been determined using a standard formula for incidence proportion with finite population correction, taking into account the expected incidence proportion of MODS, margin of error, confidence level, and follow-up period. However, there is some discrepancy in the reported sample size calculation, with the statement indicating a sample size of 260 patients, while later indicating that a total of 310 patients were included in the final analysis. Moreover, there is no explicit mention of sampling techniques

Variables of the study part (p.5)

1. There is no explicit mention of a variable related to traditional herbal medicine (THM) use in the list of independent variables considered in the study.

2. The authors of a study on Multiple Organ Dysfunction Syndrome (MODS) should include information about the criteria used for the diagnosis of MODS in their manuscript.

Data processing and analysis (p.6)

The statistical methods used in the study should be reviewed to ensure that appropriate methods were used for the type of data analyzed. For analyzing time-to-event data, such as the time to development of MODS, survival analysis techniques such as bivariate and multivariate Cox proportional hazards models are appropriate, while the chi-square test and simple linear regression are not. Therefore, the chi-square test and simple linear regression should be replaced with appropriate statistical methods like bivariate and multivariate Cox proportional hazards models. However, it appears that the appropriate statistical methods were used in the results section of the manuscript.

Results part:

1. As the objective of the study is to examine the incidence and predictors of Multi-Organ Dysfunction Syndrome (MODS) in a Pediatric Intensive Care Unit (PICU) in Ethiopia, the Cox proportional hazards model can be utilized to investigate the association between predictor variables and the likelihood of developing MODS over time, rather than the mortality of patients (p.10). Mortality of patients should be removed.

2. Patients who used THM had an increased risk of MODS AHR of 2.45 (95% CI: 1.29, 4.65). Therefore, a hazard ratio of 2.45 is slightly lower than a three-fold increase in risk. It will be better nearly three-fold.

Regarding figures:

Figures 3, 4, and 5 are likely to be important components of the study and should be properly described, labeled, and cited in the text to ensure that readers can fully understand and interpret the results presented. It is important that the author reviews the manuscript and ensures that figures are properly integrated into the text to support the study's findings and conclusions.

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Reviewer #1: Yes: Dr. Dawit Kassaye Getaneh (Assistant Prof. of Epidemiology)

Reviewer #2: No

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PONE-D-23-14246R1Traditional Herbal Medicine Use Doubled the Risk of Multi-organ Dysfunction Syndrome in a Pediatric Intensive Care Unit in the University of Gondar Comprehensive Specialized Hospital, Northwest Ethiopia: A Prospective Cohort Study.PLOS ONE

Dear Dr. Teshager,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please revise your Title: 1. shorten it; 2. remove the institution name.

Please submit your revised manuscript by Jan 28 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

The Title is too long.  Please revise it.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Robert Jeenchen Chen, MD, MPH

Academic Editor

PLOS ONE

Journal Requirements:

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.

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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

********** 

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

********** 

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

********** 

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

********** 

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: The manuscript is technically sound and written in standard English. They used appropriate statistical analysis and concluded based on their core findings. The declare that the authors addressed all the comments and revised it accordingly. However, I have seen few inconsistency and editorial issue on certain points and I recommend the authors/editors to see carefully those areas.

1. In the abstract section before the last sentence, "A threefold increase in the risk of MODS....) has to be stated consistently as " A more than twofold increase in the risk of MODS was seen in patients who used TMH".

2. In the competing interest section, it is stated that "---patients/public were not involved in the research". However, the study is a prospective cohort and needs patients follow-up. How it is said that patients were not involved?

3. In the data processing and analysis section, the first sentence has to be edited as of the following. "After ensuring consistency and completeness, the data was imported into EpiData V.3.1, then exported to Excel and subsequently to R 4.2.2 for cleaning and analysis."

4. In the data processing and analysis section, the authors has to replace the term multivariate by Multivariable, since the study has only one dichotomous outcome.

Reviewer #2: I hereby endorse the publication of the manuscript titled “Traditional Herbal Medicine Use Doubled the Risk of Multi-organ Dysfunction Syndrome in a Pediatric Intensive Care Unit in the University of Gondar Comprehensive Specialized Hospital, Northwest Ethiopia: A Prospective Cohort Study”. I believe that the findings of this study provide valuable insights into the association between traditional herbal medicine use and the risk of Multi-organ Dysfunction Syndrome in pediatric patients.

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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: Yes: Dr. Dawit Kassaye Getaneh

Reviewer #2: No

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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. Registration is free. 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 PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PONE-D-23-14246R2Traditional Herbal Medicine Use Doubled the Risk of Multi-organ Dysfunction Syndrome in Children in Gondar, Ethiopia: A Prospective Cohort Study.PLOS ONE

Dear Dr. Teshager,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please revise the Title.  Is it necessary to specify the location in the Title?

Please submit your revised manuscript by Mar 01 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Robert Jeenchen Chen, MD, MPH

Academic Editor

PLOS ONE

Journal Requirements:

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.

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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

**********

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

**********

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

**********

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

**********

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: I found it well organized and technically sound research paper. All my concerns are addressed properly and it is well edited.

Reviewer #2: Re-review comment of Reviewer 2

I believe that the findings of this study offer valuable insights into the association between the use of traditional herbal medicine and the risk of Multi-organ Dysfunction Syndrome in pediatric patients. However, I do have some minor comments.

1. In the Data processing and analysis section, the statement "Statistical tests such as the chi-square test and simple linear regression were used when they are found to be necessary" should be removed. These tests are not appropriate for survival data analysis in this study, and the statement is inaccurate. Instead, please include only the methods that were actually employed for analysis.

2. The section currently titled “Predictors of Mortality in the PICU” should be renamed to “Predictors of Incidence of MODS in the PICU”. Furthermore, all instances of the term “mortality” should be replaced with “incidence of MODS” in this section. This is because the primary objective of this study is to investigate the incidence and predictors of MODS in a PICU, not mortality. Additionally, please note that Table 2 does not discuss mortality.”

3. In the Discussion section, the statement “The finding that patients with critical illness diagnoses had a 2.45 times increased risk of developing MODS in critically ill patients is supported by multiple other studies” should be corrected. The correct value is not 2.45, but rather 2.68.

4. In the Author Contributions section, the roles of the authors need to be clearly defined.

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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: Yes: Dr. Dawit Kassaye Getaneh (DVM. BPharm, MPH)

Reviewer #2: Yes: Leykun Getaneh Gebeye

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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. Registration is free. 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 PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Traditional Herbal Medicine Use Doubled the Risk of Multi-organ Dysfunction Syndrome in Children: A Prospective Cohort Study.

PONE-D-23-14246R3

Dear Dr. Teshager,

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,

Robert Jeenchen Chen, MD, MPH

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

**********

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

**********

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: The manuscript is technically sound, well edited and presented following a scientific methods using a standard English.

Reviewer #2: The manuscript titled “Traditional Herbal Medicine Use Doubled the Risk of Multi-organ Dysfunction Syndrome in Children: A Prospective Cohort Study” is approved for publication. The revisions have enhanced its quality, and no further changes are required.

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Reviewer #1: Yes: Dr. Dawit Kassaye Getaneh (MPH, Assist. professor)

Reviewer #2: Yes: Leykun Getaneh Gebeye

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