PONE-D-22-05529Adapted “Break The Cycle for Avant Garde” Intervention to Reduce Injection Assisting and Promoting Behaviours in People Who Inject Drugs in Tallinn, Estonia: A Pre- Post Trial.PLOS ONE

Dear Dr. Uusküla,

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.

 Your manuscript has been reviewed by two peer-reviewers and their reports are appended below. The reviewers comment that the study could be strengthened by additional detail on the study's methodology and further explanation on the experimental design. Furthermore, the reviewers have commented that the statistics used in this study could be more clearly described, justified, and reported. Could you please revise the manuscript to carefully address the concerns raised?

Please submit your revised manuscript by Oct 08 2022 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,

Maria Elisabeth Johanna Zalm, Ph.D

Editorial Office

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. Please include a complete copy of PLOS’ questionnaire on inclusivity in global research in your revised manuscript. Our policy for research in this area aims to improve transparency in the reporting of research performed outside of researchers’ own country or community. The policy applies to researchers who have travelled to a different country to conduct research, research with Indigenous populations or their lands, and research on cultural artefacts. The questionnaire can also be requested at the journal’s discretion for any other submissions, even if these conditions are not met.  Please find more information on the policy and a link to download a blank copy of the questionnaire here: https://journals.plos.org/plosone/s/best-practices-in-research-reporting. Please upload a completed version of your questionnaire as Supporting Information when you resubmit your manuscript.

3. Thank you for stating the following financial disclosure: 

AU - grant # IUT34-17 from the Estonian Ministry of Education and Research, Estonia

DDJ - grant 1DP1DA039542 from the National Institutes of Health, USA

Please state what role the funders took in the study.  If the funders had no role, please state: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript." 

If this statement is not correct you must amend it as needed. 

Please include this amended Role of Funder statement in your cover letter; we will change the online submission form on your behalf.

4. Thank you for stating the following in the Acknowledgments Section of your manuscript: 

This work was supported by grant 1DP1DA039542 from the National Institutes of Health, USA, and by grant # IUT34-17 from the Estonian Ministry of Education and Research.

However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form. 

Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows: 

AU - grant # IUT34-17 from the Estonian Ministry of Education and Research, Estonia

DDJ - grant 1DP1DA039542 from the National Institutes of Health, USA

Please include your amended statements within your cover letter; we will change the online submission form on your behalf.

5. Thank you for stating the following in your Competing Interests section:  

None

Please complete your Competing Interests on the online submission form to state any Competing Interests. If you have no competing interests, please state "The authors have declared that no competing interests exist.", as detailed online in our guide for authors at http://journals.plos.org/plosone/s/submit-now 

 This information should be included in your cover letter; we will change the online submission form on your behalf.

6. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For more information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. 

In your revised cover letter, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially sensitive information, data are owned by a third-party organization, etc.) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories.

We will update your Data Availability statement on your behalf to reflect the information you provide.

7. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information. 

8. We note that the original protocol file you uploaded contains a confidentiality notice indicating that the protocol may not be shared publicly or be published. Please note, however, that the PLOS Editorial Policy requires that the original protocol be published alongside your manuscript in the event of acceptance. Please note that should your paper be accepted, all content including the protocol will be published under the Creative Commons Attribution (CC BY) 4.0 license, which means that it will be freely available online, and any third party is permitted to access, download, copy, distribute, and use these materials in any way, even commercially, with proper attribution.

Therefore, we ask that you please seek permission from the study sponsor or body imposing the restriction on sharing this document to publish this protocol under CC BY 4.0 if your work is accepted. We kindly ask that you upload a formal statement signed by an institutional representative clarifying whether you will be able to comply with this policy. Additionally, please upload a clean copy of the protocol with the confidentiality notice (and any copyrighted institutional logos or signatures) removed.

[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: Partly

Reviewer #2: Yes

**********

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

Reviewer #1: No

Reviewer #2: I Don't Know

**********

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

**********

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

**********

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 objective of this pre-post study is to assess changes to injection initiation assisting and promoting behaviours in participating PWID, during the six months following an adapted BTC session. The study was approved by the respective Ethics/IRB board and has a valid NCT number. The study objectives sound interesting. I have the following questions.

1. A pre-post study is like a quasi-experimental design. The manuscript is submitted as a Clinical Trial. What is the justification here?

2. Sample size/power shoiuld be generated using the "primary response variable". It was never clearly mentioned what's the primary response.

3. The subsection on Outcome variables do not mention the nature of the responses; are they continuous, discrete, proportions?

3. The statistical methods are straightforward; during the sign test application, what was the null hypothesis under consideration? Write clearly.

4. A significant number of covariates are available; it is not clear why a formal regression analysis was not conducted. The sample size looks decent enough to conduct a regression analysis.

5. Any statement of significance/non-significance in the Results section should be accompanied by a p-value. This needs to be properly checked throughout.

6. The Conclusions section should allude to future studies (with larger sample sizes), often from multicenter scenarios combining other populations, to properly validate the effect of the BEATVIC group sessions.

Reviewer #2: Preventing transitions into injection drug use is likely to have significant benefits including reductions in bacterial and infectious diseases and risk for these diseases. The study, using a pre- post-design examined the impact of the Break the Cycle intervention. While this intervention has been around since the late 1990s it has not been subject to rigorous evaluation. The proposed study improves on prior studies by using a larger sample size. I have noted a number of concerns below. One deserves more attention. Specifically, the authors need to better example how they conducted the comparison between those who were followed and those who were not. I wonder if the authors could control for the few variables that were found to differ in the final model of intervention effects. Lastly, given that there were recent changes in the drug use pattern in the study community that authors might want to examine if secular trends (or time) influenced the results.

Minor/specific comments

Page 3, line 50/51. The authors might consider removing the mention to Scott County, Indiana since there have been multiple HIV outbreaks in the USA. See:

Lyss, S.B., Buchacz, K., McClung, R.P., Asher, A., Oster, A.M., 2020. Responding to Outbreaks of Human Immunodeficiency Virus Among Persons Who Inject Drugs—United States, 2016–2019: Perspectives on Recent Experience and Lessons Learned. The Journal of Infectious Diseases 222(Supplement_5), S239-S249.

Page 5, line 100/101. The sentence beginning, “The same,…” seems incomplete. I think the authors are indicating that the adaption process and study protocol are described in citation 9. Please clarify.

Page 6, line 127. I think SIEMENS should be in [ ].

Page 6, line 139. I think this section should just begin with a statement about what survey instrument was used and perhaps a statement about its validity and reliability if available. The sentence suggest that the same questionnaire was used throughout the study, which is assumed. So I would recommend removing “In both years” as well.

Page 10, lines 226/227. I think the paraphenthical statement can be removed or if it stays, the authors should revise it to read “injecting with used syringes and give used syringes to others to inject with.”

Table 1. Not sure why p-values are shown for some variables but not others (age, gender, education among others).

Page 13,lines 241/244. According to Table 1, other variables were also found to differ (p<0.05) by follow-up including housing status, currently on methadone among other items. Not sure why only 3 are discussed here. My guess is that the authors conducted some type of multivariate regression analysis to identify factors independently associated with follow-up. If that is the case, the authors should add a sentence or two describing there approach here. I’m also a bit worried about the results reported. The bivariate p between followed and not followed for HIV status was p=0.95 and the percentages of people followed and not followed are pretty close. So some explanation about what they did here would be helpful. Whatever statistical approach they used to account to loss to follow-up should be described in the statistical methods section.

**********

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

**********

[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.

Adapted “Break The Cycle for Avant Garde” Intervention to Reduce Injection Assisting and Promoting Behaviours in People Who Inject Drugs in Tallinn, Estonia: A Pre- Post Trial.

PONE-D-22-05529R1

Dear Dr. Uusküla,

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 for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, 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,

Ricky N. Bluthenthal

Guest Editor

PLOS ONE

Additional Editor Comments (optional):

The revised manuscript has been very responsive to comments from the prior review. Issues raised by reviewer 2 are minor and can be addressed during the proofing process.

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: (No Response)

Reviewer #2: Yes

**********

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

Reviewer #1: (No Response)

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: (No Response)

Reviewer #2: (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)

Reviewer #2: No

**********

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 #2: The revised manuscript looks good. I noticed a few minor issues that can be addressed quickly. See below.

Line 26, spell out PWID the first time it appears in the abstract and in the paper (line 47).

Line 79 add (BTC) after “Break The Cycle” as this abbreviation is used later in the paper. The authors can delete the BTC in line 174 since the abbreviation will have been defined earlier in the paper.

Line 157, spell out RDS the first time it appears.

Line 205, spell out “OR” and “CI” the first time they appear.

Line 230, remove Second “%”

Line 249, spell out “aOR” the first time it appears.

250, remove the second aOR in this line.

Table 2, page 15 the cell with “Any unprotected sex” has unnecessary “..” in it.

Line 299, previous the authors have used “injection drug use” and not intravenous drug use. Not sure why they changed the language in this line.

**********

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

**********