PONE-D-24-34354Oral zinc sulphate reduces recurrence rate and provides significant therapeutic effects for viral warts: a systematic review and meta-analysis of randomized controlled trialsPLOS ONE

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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: Partly

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: Partly

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

Reviewer #1: I Don't Know

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: I Don't Know

Reviewer #5: 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: No

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: No

Reviewer #5: 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: No

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: 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: Thank you for inviting me to review the paper on the effect of oral zinc sulfate on viral warts. My main concern is why the authors pooled the Akhavan study, which has a different drug dosage, with other studies.

Other points:

Title:

Reduces "the" recurrence rate...

Abstract:

The abstract needs to be structured. The search date and the databases searched should be mentioned (method).

The number of included studies and the number of studies in your primary search should be mentioned (result).

Method:

Lines 96-98: Did the authors use MeSH words and other synonyms?

Was any language restriction applied?

Result:

Summarize the number of studies at each step of the selection of eligible studies in the study selection part.

A funnel plot should not be used for studies with fewer than 10 inclusions.

Add the list of excluded studies at the full-text review step and the reasons for exclusion in the supplementary materials.

A table should be added summarizing the results of the statistical analyses of the included studies, such as RR, RD, etc.

Data regarding double/single blinding of the studies should be added to Table 1.

The inclusion criteria of the RCTs should be added to the table.

Discussion:

Why were these studies only conducted in the Middle East and North Africa region?

Reviewer #2: Strengths: This systematic review and meta-analysis offers robust and comprehensive insights into the therapeutic effects of oral zinc sulphate for viral warts. By conducting subgroup analyses based on plasma zinc levels and treatment modalities, the study provides more detailed insights into the efficacy of zinc sulphate under various conditions. The use of statistical methods such as random-effects models, sensitivity analyses, and Egger’s test for publication bias ensures that the conclusions are not only statistically significant but also reliable. Clinically relevant information is particularly highlighted for patients with low plasma zinc levels or those resistant to conventional treatments.

Limitations: Some studies included in the meta-analysis had small sample sizes, which may reduce the statistical power of the conclusions. Additionally, the study population was predominantly female (72.6%), and the impact of zinc supplementation may differ across sexes.

Reviewer #3: The authors conducted an interesting study on zinc and viral wart.

It would be better if you could provide evidence for the statement "However, the conclusions of these studies are inconsistent, and comprehensive research has been lacking in recent years.".

Reviewer #4: 1. English writing is generally not indented at the beginning of the line.

2. L67-68, please add to the preamble the inconsistent specifics of the oral zinc findings and add references, which is what is needed to do this study.

3. there are ethnographic differences in the incidence of warts, and although the literature is limited, the reason why this was not subgrouped needs to be stated in the limitations

4. please provide a specific search strategy for each database

5. the search strategy mentions references to included literature as sources for inclusion, this needs to be reflected in the flowchart

6. Please add the specific number of literature screening entries in the text.

7. The small amount of literature included is still a major concern, especially when the amount of literature is small for regression.

8. Two systematic evaluations have been conducted, and the strengths of this study are not fully described in the discussion.

9. Why were subgroup analyses of gender not conducted, and if the gender differences were so large, was it possible to extract data for secondary analysis?

Reviewer #5: Comments to PLOS ONE PONE-D-24-34354

Title:

Oral zinc sulphate reduces recurrence rate and provide significant therapeutic effects for viral warts: a systematic review and meta-analysis of randomized controlled trials

Comments to authors

Thank you for your hard work. I appreciate the efforts of the authors.

• Through a systematic review and meta-analysis, this study has reported an evidence on the efficacy of oral zinc sulphate, whether monotherapy or as a combined with traditional therapies compared to placebo or other oral therapies for the treatment of viral warts.

Recommendation for improvement:

• The study provided new insights, however there are several weaknesses still need to be considered.

• Deciding to conduct a systematic review, meta-analysis, and meta-regression to produce new, more accurate and valid evidence, however, the interpretations of the findings are not clearly presented. Therefore, the authors are asked to discuss with biostatistician or epidemiologist to enriched the presentation of findings.

• The writing style needs to be considered to make it easier for readers to understand and to implement the findings of this study.

Introduction

• The background that has become the basis for this research is not strong enough to describe the existing problems. What are the research questions that the authors want to answer? Are all parts (population, intervention, comparison, outcome) that have become the target of the authors supported by data, for example from results of previous research or from existing theories are to be tested? The authors are asked to consider on how is this background related to the research conducted that can help strengthen the authors’ hypotheses. Therefore, the authors are advised to explain the relevance of the background presented.

• Line 48: The authors stated, “… with the highest prevalence observed in school-aged children and young adults”. Are the results of your study in line with this statement? The results you have reported are the mean (+SD) age of 31.64+12.49. If it is in accordance with the results of previous research that is us as a reference, then it needs to be emphasized in the discussion section.

• Line 66: “According to the current literature, both topical and oral zinc formulations may be effective as primary or adjunct therapies for viral warts”. However, this systematic review and meta-analysis only analyzed the effectiveness of oral administration. The authors are asked to explain the reason why this study only focused on oral administration.

• In this background section, it would be better to also explain the results of previous primary studies that describe of how effective the zinc sulphate can be as monotherapy or combined therapy, or how the intervention might work compared with others.

Methods

• Line 80: “P, human participants with skin or external genital warts”. The authors are asked to provide scientific reasons why only skin warts and external genital warts are included in the criteria, while all types of warts need to be treated.

• Line 90: The authors stated “the exclusion criteria were..1) non-RCTs; 2) RCTs not involving oral zinc sulphate supplementation , 4) non-placebo-controlled,,,” Explanation of the things that were exclusion criteria are actually already described as inclusion criteria. For example, in the inclusion criteria it is clearly written that studies with RCTs design will be included. This means (without needing to be written again) that studies with designs other than RCTs will be excluded, so it may not need to be sharpened again by writing it in the exclusion criteria section.

• Line 95: In the literature search strategy, the authors only limited the search by using 5 electronic databases. The authors should explain this, as well as explain whether they used grey literature or hand-searching to recruit includes study in this systematic review.

• Line 96: The keywords compiled by the authors seem to describe only intervention and outcome. Therefore, authors are asked to consider developing a search strategy by enriching the keywords that include participants and comparisons as well. Boolean technique and the use of more alternative words need to be considered.

• The authors are asked to explain if there is any language restriction, and the reasons to limit it.

• Line 102: “If the two authors had different opinions during the process, a third author was conducted to resolve any disagreements”. There, the authors are asked to explain if there is any disagreement, what are them, and how to solve them.

• Line 116: The secondary outcome was defined as the rate of relapse occurring within six months after treatment as well as any treatment-related side effects. Please be explained clearly if you analyses only for studies reported rate of relapse at least 6 months after intervention.

• Line 112, to consistent with the results especially for randomization (in line 185: “..three studies were classified as having some risk of bias in the randomization process because they did not describe the concealment of random allocation”), the authors are suggested to define clearly about the randomization.

Results

• Line 153: “Articles without full-text availability were excluded”. Please be explained if any effort in finding out this article, or how the authors solve this issue.

• Line 153: “… and we ensured that all zinc sulphate studies were administered orally..”. This statement should be in line with inclusion criteria

• Line 161: “27.4% of whom were male”. In this part, why are male highlighted, usually what is highlighted is the dominant characteristic, in this case are women. Unless there is a specific reason of male participation.

• Line 162: “Based on the available data, the average age was 31.64+12.49” It would be better if these findings are explained briefly in the discussion section, if necessary, because in the introduction section, the authors pay attention to the age variable so that it will be seen whether your results support the explanation in the introduction.

• Table 1: The authors stated that data from the Akhavan, 2014 study (either Cryotherapy or Imiquimod) the comparator was a cream, not an oral preparation. It would be better if this be explained in the methods or inclusion criteria that the comparator is not limited to oral preparations only.

• Line 261: “Unexpectedly, longer disease duration was associated with better treatment outcomes”. The authors are mentioned this issue in the Discussion as disagreement with only one RCT. Therefore, the authors are asked to suggest in Conclusion section what kind of research could be done to strengthen this finding.

• Figure 2: Process of randomization was less than 60%, and overall low risk of bias of included studies was less than 50%. The authors are asked to explain about the risk of bias of included studies, in line with decided to do meta-regression. That may affect the methodological quality of the study.

• Figure 6: the authors are asked to explain on the reasons to combine the combined therapy and monotherapy in one.

• Supplement figure 4: the authors are asked to explain the results, where 5 out of 8 studies are outside the line.

• The high heterogeneity may also be caused by inconsistent of operational definition of variables, design, or dosage of zinc sulphate, and duration for therapies.

Discussion:

• The Discussion section are provided insight findings. However, the authors are lacking in explanation of the agreement and disagreement of this findings with previous studies or literature theories. The authors are asked to clearly distinguish finding gap in the background and how your results contribute to the field.

• The authors are suggested to enriched their arguments, incorporate multiple viewpoints from existing literature to provide a balanced understanding of the topic.

• The authors are also advised to discuss deeply about the potential of the limitations of the study in the end of Discussion section.

Conclusions

• The authors are suggested to explain any unique contributions, potential applications, or scientific and policy implementation of the findings.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

Reviewer #4: No

Reviewer #5: Yes:  Windy Mariane Virenia Wariki

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Oral zinc sulphate reduces the recurrence rate and provides significant therapeutic effects for viral warts: a systematic review and meta-analysis of randomized controlled trials

PONE-D-24-34354R1

Dear Dr.Po-Yan,

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.

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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 #4: All comments have been addressed

Reviewer #5: 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 #1: (No Response)

Reviewer #4: Yes

Reviewer #5: Yes

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

Reviewer #1: (No Response)

Reviewer #4: Yes

Reviewer #5: Yes

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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: (No Response)

Reviewer #4: Yes

Reviewer #5: 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: (No Response)

Reviewer #4: Yes

Reviewer #5: 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: (No Response)

Reviewer #4: The authors have made appropriate revisions based on the reviewers' suggestions and all issues have been addressed without further suggestions.

Reviewer #5: I would like to express my heartfelt gratitude for the authors' hard work and dedication in revising the manuscript on the basis of the feedback provided. The authors' commitment to improving the quality of the manuscript is truly commendable. The revisions made reflect a deep understanding of the subject matter and show the willingness to engage with constructive criticism.

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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: No

Reviewer #4: No

Reviewer #5: No

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