PONE-D-24-27274Use of a cooling pack to reduce subcutaneous vaccine injection pain in children : a two-group, single-blind, randomized, parallel-group multicenter studyPLOS ONE

Dear Dr. Okafuji,

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.

==============================

Dear Authors,

Thank you for your submission. Please revise the manuscript thoroughly, addressing each of the reviewers' comments point by point in detail, ensuring that all concerns and suggestions are adequately resolved. If you are unable to revise the paper according to the reviewers' expectations, I would be open to considering it as a letter for publication.

Best,

==============================

Please submit your revised manuscript by Oct 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'.

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,

Academic Editor

PLOS ONE

Journal Requirements: When submitting your revision, we need you to address these additional requirements. 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf 2. In the online submission form, you indicated that "Deidentified individual participant data (including data dictionaries) will be made available, in addition to study protocols, the statistical analysis plan, and the informed consent form. The data will be made available upon publication to researchers who provide a methodologically sound proposal for use in achieving the goals of the approved proposal. Proposals should be submitted to the corresponding author via email (okafuji@kcho.jp)" All PLOS journals now require all data underlying the findings described in their manuscript to be freely available to other researchers, either 1. In a public repository, 2. Within the manuscript itself, or 3. Uploaded as supplementary information.This policy applies to all data except where public deposition would breach compliance with the protocol approved by your research ethics board. If your data cannot be made publicly available for ethical or legal reasons (e.g., public availability would compromise patient privacy), please explain your reasons on resubmission and your exemption request will be escalated for approval. 3. PLOS requires an ORCID iD for the corresponding author in Editorial Manager on papers submitted after December 6th, 2016. Please ensure that you have an ORCID iD and that it is validated in Editorial Manager. To do this, go to ‘Update my Information’ (in the upper left-hand corner of the main menu), and click on the Fetch/Validate link next to the ORCID field. This will take you to the ORCID site and allow you to create a new iD or authenticate a pre-existing iD in Editorial Manager.

Additional Editor Comments:

The abstract should be structured

P-values should be included in the results section of the abstract

In terms of pain assessment, using only the FLACC scale may not provide a comprehensive view

The term "two-group" in the title is unnecessary

Consider adding a row in the tables to compare median scores between guardians and third-party evaluators would improve the strength of the results, especially if no statistical significance is found between the two groups.

The sample size calculation should reference the article it is based on, ensuring proper citation.

The use of a cooling pack may seem outdated and Im not sure about the novelty of this work. Consider discuss it in the introduction first

Different vaccines have varying pain levels, so generalizing across all vaccines is inappropriate.

Tables should not be placed in the introduction

The delay in submitting the study, conducted three years ago, should be explained.

A rationale for including children aged 3–6 years is needed, particularly since not all age groups were included. The age range should also be mentioned in the title.

The inclusion and exclusion criteria need more detail, especially regarding skin diseases, which could impact the effect of the cooling pack.

It’s important to confirm whether the normality of variables was assessed.

When reporting median and IQR, use the format *median [IQR]*

Ensure consistent P-value formatting throughout the manuscript (e.g., *P-value = 0.08* or *P-value < 0.05*).

Each table should include a footer explaining abbreviations and tests used for P-values. The claim that this study is the "first" to investigate local cooling during vaccinations should be reconsidered, as there are many existing studies on this topic.

If the focus is on "childhood anxiety and fear of pain," baseline anxiety should be measured and controlled for, as this can influence the results.

Finally, update the manuscript with recently published studies to reflect the current state of research.

[Note: HTML markup is below. Please do not edit.]

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

Reviewer #3: Yes

**********

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

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

**********

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

Reviewer #3: Yes

**********

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

Reviewer #3: Yes

**********

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: The rationale for not employing the Wilcoxon test for sample size calculation remains unclear.

For assessing reliability, it would be more appropriate to utilize either Spearman's rank correlation coefficient or Cohen's kappa statistic.

Figure 4: the cooling group has less than 15 data points.

Reviewer #2: The article evaluates the effectiveness and safety of using a cooling pack to reduce pain during subcutaneous vaccine injections in children aged 3-6 years. The study was conducted in two pediatric clinics in Japan. Sixty children were randomly assigned to either a cooling group or a non-cooled group. The primary pain assessment checklist was the FLACC scale, rated by a third party who viewed videos of the vaccination. The study found that the cooled group had significantly lower FLACC scores compared to the non-cooled group.

The article discuss a innovative approach to pediatric pain management by introducing a simple, non-pharmacological method using a cooling pack to reduce vaccine injection pain in children but after carefully reviewing the submitted article following points are provided for consideration.

Areas for Consideration:

1) While the components (solutions) of vaccines could differ in various regions, it is important that the brand names of the vaccines used in the study be specified. This is an important omission because different formulations, even for the same type of vaccine, can have varying components or solvents that might influence the level of pain experienced during injection. Additionally, the discussion section mentions that pneumococcal vaccines are known to cause severe pain. Providing this information would be beneficial for future studies to investigate the solvents and other components of the vaccines used in this study as potential contributors to pain. Understanding the role of these components could provide insights into pain management strategies during vaccination.

2) The terminology used in the article should be double-checked and unified. For example, the abstract states, “Local cooling during subcutaneous vaccine administration is a safe and effective pain-relief method and can be implemented in infants receiving subcutaneous vaccines,” while the study actually focuses on children aged 3-6 years. Inconsistency should be corrected to ensure clarity and accuracy throughout the manuscript.

3) The structure of the introduction in the manuscript requires revision to better align with standard scientific practices. The final paragraph of the introduction should focus on clearly stating the objectives and main aim of the study, rather than discussing methodological details or presenting a table. Currently, the introduction ends with a table (Table 1) that details the FLACC scale, which is more appropriate for the Methods section. I recommend that the authors transfer this table to the Methods section and revise the introduction to emphasize the study's objectives more clearly. This adjustment will help maintain the logical flow of the manuscript and ensure that the introduction provides a concise and focused overview of the study's purpose.

4) The FLACC scale, while widely used, is not without its limitations, particularly in a population as young as 3 years old, where subjective pain expression can be highly variable and influenced by factors other than pain itself, such as fear or fatigue. The reliance on a third-party assessment based on video footage further complicates the interpretation, as subtle cues that could indicate discomfort might be missed or misinterpreted. In this case, to enhance the reliability of the results, it would be beneficial to double-check the videos and scoring with another independent assessor. Comparing the scores from multiple assessors could help ensure reproducibility and minimize potential bias or errors in the interpretation of the pain levels observed in the children.

Reviewer #3: In this paper, the author evaluated the pain-relieving effect and safety of local cooling during subcutaneous vaccine injection in young children (3 to 6 years old). This two-group, single-blind, randomized, parallel-group multicenter study demonstrated that a simple and easy method of local cooling could significantly alleviate pain associated with vaccination in young children. It is a well written paper that needs a minor revision and below are my comments:

1. There is strong evidence supporting the effectiveness of topical anesthetics in preventing pain in individuals ≤ 12 years of age. The author did not mention the advantage of current cooling method compared with topical anesthetics or the disadvantage of topical anesthetics in the current treatment in the introduction.

2. In this paper, the author mentioned that PURU CURE Ice Pack® was modified to be small enough to fit the infant’s upper arm. It would be great if the author could compare the price between current Ice pack and the topical anesthetics or spray cooling.

3. Regarding the experiment design, some children may find the cold uncomfortable and thus may show some FLACC behavioral pain after the local cooling. They may show less FLACC behavioral pain for subcutaneous injection in this situation. It would be more convincing if the author could provide the data showing no FLACC difference before and after the local cooling.

4. As author mentioned in the paper, there’re some limitations in the experiment design such as big age differences (3 to 6 ages), 2 different vaccine types and single-blind trial design. There are some other factors that have been demonstrated in reducing the pain need to consider in real situations such as the positioning for needle and the surroundings environment for the children (parents or other people who can distract the child).

5. The pain-relieving effect was tested in Japanese encephalitis virus vaccine or the influenza virus vaccine. In the future study, it would be interesting to see the effects of local cooling on more painful vaccinations such as MMR and HPV.

**********

6. 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: No

Reviewer #2: No

Reviewer #3: No

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment 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. 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-24-27274R1Use of a cooling pack to reduce subcutaneous vaccine injection pain in children aged 3-6 years: A single-blind, randomized, parallel-group multicenter studyPLOS ONE

Dear Dr. Okafuji,

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.

I appreciate your efforts in addressing the comments. However, as part of the editorial process, it is essential to provide a point-by-point response to the reviewer comments. I kindly request you to:

1. Provide a point-by-point response to the comments in the same order as they were provided.
2. Indicate the specific parts of the manuscript where changes were made , with detailed references to line and page numbers.

Please submit your revised manuscript by Jan 10 2025 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,

Seyedeh Yasamin Parvar, M.D., M.P.H.

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.

Additional Editor Comments:

I appreciate your efforts in addressing the comments. However, as part of the editorial process, it is essential to provide a point-by-point response to the reviewer comments. This facilitates a clear understanding of how each point has been addressed.

To ensure clarity and consistency, I kindly request that you:

Provide a point-by-point response to the comments in the same order as they were provided.

Indicate the specific parts of the manuscript where changes were made, with detailed references to line and page numbers.

Additionally, while the manuscript is well-prepared overall, there are a few minor revisions required:

1- Ensure that all typographical issues mentioned previously have been resolved throughout the manuscript.

2- Replace "fig" with "figure" in full and bold this term consistently in the text.

3- In terms of pain assessment, using ONLY the FLACC scale may not provide a comprehensive view.

4- Provide references for this part in the introduction: “A gel-based cooling pack, which maintains its softness even when frozen, may provide a less intimidating alternative for pediatric patients; thus offering a more comfortable and effective pain-relief method during vaccination.”

5- Explain the delay in submitting the study, conducted three years ago, in the “limitations.”

6- Confirm whether the normality of variables was assessed and specify this in detail in the statistical part of the methods section.

7- Rewrite the first sentence of the discussion for clarity.

8- I couldn’t find answer and revisions for this comment. If the focus is on "childhood anxiety and fear of pain," baseline anxiety should be measured and controlled for, as this can influence the results.

9- UPDATE the manuscript with recently published studies to reflect the current state of research.

10-Provide references for this part in the discussion: “While cooling packs are reusable and cost-effective in the long term, they require upfront investment and preparation by hospitals, and the cost may fall on families if purchased individually (3,200 yen per unit).”

11- Avoid using references in the conclusion.

[Note: HTML markup is below. Please do not edit.]

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

Reviewer #3: 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: (No Response)

Reviewer #2: Yes

Reviewer #3: Yes

**********

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

Reviewer #1: (No Response)

Reviewer #2: Yes

Reviewer #3: 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: (No Response)

Reviewer #2: Yes

Reviewer #3: 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: (No Response)

Reviewer #2: Yes

Reviewer #3: 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: All my concerns are addressed.

Reviewer #2: (No Response)

Reviewer #3: In this paper, the author demonstrated local cooling could significantly alleviate pain associated with subcutaneous vaccine injection in young children (3 to 6 years old). Compared with topical anesthetics, local cooling offers rapid pain relief within 30 to 60 seconds, making it a more practical option for pediatric use. Although FLACC scale has the limitation for young children, this gel-based cooling pack still demonstrated the effectiveness of local cooling in pain-relief in clinical settings, which is of great importance. I would recommend this paper to be published in PLOS ONE journal.

**********

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: No

Reviewer #2: No

Reviewer #3: No

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment 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. 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.

Use of a cooling pack to reduce subcutaneous vaccine injection pain in children aged 3-6 years: A single-blind, randomized, parallel-group multicenter study

PONE-D-24-27274R2

Dear Dr. Okafuji,

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.

An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager®  and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, please contact our Author Billing department directly at authorbilling@plos.org.

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,

Seyedeh Yasamin Parvar, M.D., M.P.H.

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

**********

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)

**********

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

Reviewer #1: (No Response)

**********

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)

**********

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)

**********

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: All my comments have been addressed.

**********

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: No

**********