Dear Dr. Yao,

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.

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

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We look forward to receiving your revised manuscript.

Kind regards,

Benjamin Benzon, Ph.D., M.D.

Academic Editor

PLOS ONE

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“The study was supported by the Health Commission of Nan-tong City Health and Family Planning Scientific Research Projects (QNZ2023026).”

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Additional Editor Comments :

Nice randomized controlled trial, reviewers were specific in their questions, in addition to those I also have the following suggestions:

Results section.

Change group labels rom A, B, C, D to actual concentration of sulfentalin, i.e., 5 ug/ml, 1 ug/ml, 0.5 ug/ml and 0 ug/ml group.

Please reorder the sequence of groups on charts in Fig. 2 starting with 5 ug/ml group and ending with 0 ug/mg (i.e. control group).

Please add a scatter plot showing the correlation between total propofol consumption and recovery time.

In first subsection of result please state explicitly which group had exactly what % of moderate and severe pain, please also define in this subsection what pain subcategories did you group when calculating the % of pain relief.

There is no need to repeat the incidences of other side effects when describing the incidence of cough among groups. You can do this informally in Discussion section.

Furthermore, write about hypoxia and bradycardia also in this subsection of results.

When it comes to mediation analysis, can you please explain why should it be used instead of logistic regression with two independent variables

(i.e. total dose of propofol and dose of sulfentalin, as a continous variables). Since propofol and sulfentanil have different mechanism of actions, I do not think that there is much mediation in terms of pharmacodynamics.

Furthermore, if you still think that those two drugs interact, a interaction term can just be added in logistic regression model. Anyways, since logistic regression is far more

used in biomedicine and is easier to interpret I would strongly advise you to replace mediation analysis with logistic regression with drug doses and interaction terms as only independent variables.

The Multivariate analysis subsection, i.e. logistic regression, in which you basically added all other variables is clear and very well written.

Disscusion section

Can you please explain pharmacology behind lower total propofol consumption in sulfentanil treated groups in comparison to control groups?

In conclusion section please talk about analgesic effects first and then about adverse effects.

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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?

Reviewer #1: Partly

Reviewer #2: Partly

Reviewer #3: Partly

Reviewer #4: Partly

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

Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes

Reviewer #4: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

Reviewer #4: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes

Reviewer #4: Yes

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Reviewer #1 : This work is interesting but some chapters need major revision.

Introdoction:

Introduction section: can you explain in text how dilution of sufentanil is making differences in pk/pd (how decreasing drug concentration decrease peak concentration that cause side effects)

55: please explain what other variables

62 Therefore, identifying an optimal concentration of sufentanil that can effectively alleviate injection pain while

63 minimizing adverse effects is of paramount importance. (did this study find optimal concentration of sufentanl? what it aim of study? 

and 67,68, 69 79,80: Can you explain sufentanl pharmacokinetics from injection to the effective organ (brain and spinal dorsal horne) and explain a bit of pharmacodinamic.

What is with albumin transport and red blood cell transport?

75,76.77 Can you explain in text what is negative and positive allosteric modulator?

please explain in text why is clinicly important to treat pain after proporfol induction

please explain in text are other drugs like lidokaine sufficient to decrease pain after propofol induction, also you should in disscusion section find some other clinical trials with lidocaine or other studes and compare results regaridng primary and secondary outcome

please introduce in text why are outcomes in this study relevant to patients

83,84. please in the end of introduction section introduce hypothesis and primary study outcome and secondary outcomes, what is aim of this study.

86 Participants, Study Design and Treatments

You did not asses obstructive sleep apnea scores (Stop-Bang score)?

Did you have gastroscopy and colonoscopy or colonoskopy ?

129-123- So you measure pain every five seconds, and you have chosen the worst score?

Please explain in text why did you choose 30 seconds and not 2 minutes in sequence sufentanl and propofol. It is well known than 2 minutes is time necessary that opioid achieve concentration in effective organ (brain) So analgesia is in 2 or 3 minutes and you did not wait that long.

148- is this Cramer V effect size?

184 please write in text what are primary outcomes and secondary outcomes

In giving results you could write more descriptive statistic that is informative to readers :

Can you put propofol consumtion with mean/ median and +- SD or IQR - descriptive statistis for propofol consumtion or propofol dosage per lean body weight

, in table or in a text becouse propofol consumtion is relevant to propofol side effects.

Table 21, mediatation analysis revealid statisticly significant direct efefct of propofol, so propofol is main cause for recovery time. Is propofol dosage main cause for other adverse effects?

Can you correlate propofol consumtion and side effects beyond your intervention groups?

High dose propofol can cause adverse effects thet are overlapping with sufentanil.

Did sufentanil decrese propofol consumtion? Did different sufentanil concentration decresed propofol consumtion?

210, 284 did you have apnea?

238-243 you have write 2 times propofol consumtion and coefficents

disscusion

please begin with explaining results of the hypotesis ( refute or accepted) and explaine primary outcomes and secondary outcomes and relate yours findings with other clinical trials.

210, 284 did you have apnea?

Reviewer #2: Authors studied using different diluted sufentanil to reduce propofol injection pain. Three dose concentration levels are considered at 5, 1 and 0.5 ug/ml. They studied effectiveness as well as safety, using a clinical trial data with 464 patients.They concluded that the high concentration group 5 ug/ml may be associated with an increased risk of adverse events.

Page 4, more details for patients should be included. Which country? Which city? Which hospital?

You have to write the 4 groups in correct order. Sometimes you put control group first and sometimes last. Try to be consistent. For example, on page 7, it seems control group was before group A. But the effective rates is 70, 85, 90, 85. It seems the last one should correspond to control group if I understand your calculation correctly.

Why do you need bootstrap to build model?

Page 11, the two paragraphs for mediation analysis are the same except different numbers. What’s the difference between the two paragraphs?

Page 13, table 21 should be table 2.

Reviewer #3:  I believe it's important to mention pain in the abstract's conclusion. Also, what is the total propofol consumption of each sufentanil group? There is a significant difference between sufentanil groups in terms of the side effects. I would like further explanations in the discussion section about this. What was the duration of the sufentanil bolus administration? Was this standardized?

What do you mean by "evaporation time" in sections 255-277? I don't agree with that conclusion.

287 "sedation38"

Which cell membrane does sufentanil pass through more quickly, section 294s? Please explain.

304-305 I would consider using clearer language.

307 I would suggest using only "first" or "firsty," not both.

309 This is RCT. I suggest no further explanation about the benefits of RCTs vs. other types of trials.

310 The third strength is a goal of the study. It cannot be a strength.

312, 313 The first limitation is not really an issue. A more significant concern is the large number of patients with cardiovascular diseases who require sedation for gastrointestinal endoscopy. Additionally, the exclusion of patients with severe bronchopulmonary disease, based on specific criteria, further diminishes the generalizability of the study findings.

313 They can be included and are included in multiple other RCTs, so I would recommend removing this sentence: “Future studies are needed to determine if they can be included.”

314 I would not consider that being a single-center study a limitation. Also, the third limitation is not necessarily one. It is more of something that needs further investigation and was not a goal of your study.

Reviewer #4: 1. Gastroscopies were performed by single gastroenterologist?

2. Your primary outcome was pain relief but in conclusion you write about adverse outcomes which are secondary outcomes?

3. You have to numerically define hypoxia and hypotension, also how you decide what is dizziness cause every patient is dizzy while awakeing from analgosedation?

4. Was oxygen administered during procedures?

5. What were total propofol doses per patient? I think all of adverse events were due to propofol not sufentanil because 5mcg is such low dose to produce serious adverse effects.

**********

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

Reviewer #4: Yes:  Ivan Vuković

**********

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Dear Dr. Yao,

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 much improved in the last round of revision, before I accept it for publication I would ask you two address two details:

1) Please add one more scatter plot in Figure 3 in which you will color code patients in each sulfentanil group and fit a regression model for each group

2) Please add a table which models probability of side effect and interaction of Propofol and sulfentalin to your multivariable analysis subsection of Result; you have already showed this table in a response to reviewer 1 (3. interaction analysis), it would be nice to make it a part of manuscript.

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

Please submit your revised manuscript by May 31 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.

• 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 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,

Benjamin Benzon, Ph.D., M.D.

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 :

The manuscript has been much improved in the last round of revision, before I accept it for publication I would ask you two address two details:

1) Please add one more scatter plot in Figure 3 in which you will color code patients in each sulfentanil group and fit a regression model for each group

2) Please add a table which models probability of side effect and interaction of Propofol and sulfentalin to your multivariable analysis subsection of Result; you have already showed this table in a response to reviewer 1 (3. interaction analysis), it would be nice to make it a part of manuscript.

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

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions??>

Reviewer #2: Yes

**********

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

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #2: Yes

**********

Reviewer #2: I appreciate that authors addressed the comments from my previous review. I have read the revised manuscript and concluded that the paper is suitable for publication in this journal.

**********

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 #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

Comparison of pre-treatment with different diluted sufentanil in reducing propofol injection pain in gastrointestinal endoscopy: a randomized controlled study

PONE-D-24-54042R2

Dear Dr. Yao,

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,

Benjamin Benzon, Ph.D., M.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Congratulations on your paper, I hope that it will be of clinical value, especially in China.

Reviewers' comments: