PONE-D-20-33347

Helicobacter pylori eradication improves motor fluctuations in advanced Parkinson's disease patients: A prospective cohort study (HP-PD trial)

PLOS ONE

Dear Dr. Lolekha,

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We look forward to receiving your revised manuscript.

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Wan-Long Chuang, M.D., Ph.D.

Academic Editor

PLOS ONE

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spectrophotometer for the study."

We note that you have provided funding information that is not currently declared in your Funding Statement. 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.

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"This study was supported by a grant from

Thammasat University Research Fund (TU Research Scholar, Contract No. 2/4/2562) and Thai Parkinson’s Disease and Movement Disorder Society (Thai-PDMDS). "

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

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

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This is an interesting and important study. My comments are as follows:

1. The authors reported the changes of UPDRS motor scores and GI symptoms scores after H. pylori eradication (before and after). It is suggested that the authors may add a table to compare patients receiving eradication therapy versus those not receiving eradication therapy (HP negative group).

2. The case number of patients receiving eradication therapy is small (N=17), whereas the authors conducted multiple comparisons in the statistical analysis. Multiple testing correction might be needed or at least should be addressed in the discussion.

3. Whether the improvement of UPDRS score is directly related to the disappearance of H. pylori or alterations in gut microbiota may be addressed in the discussion section.

Reviewer #2: The article describes clearly about the effect of Helicobacter pylori (HP) eradication on the motor and non-motor performance in Parkinson's disease (PD). The authors concluded that HP eradication may increase "on" time and decrease "off" time and also significantly improved the end-of-dose score and GI symptoms including bloating and dysphagia. The article is well written with useful information. However, there are several questions needed to be clarified.

1.

Is there any difference of all the profiles in patients who failed the eradication therapy? Because PD patients had high placebo effects when receiving the treatment, the data may help clarify the effects of eradication therapy.

2.

Please provide the difference of LED and the percentage of relevant medications of PD patients with successful HP eradication with and without motor fluctuations. Because motor fluctuations may be improved by the adjustment of antiparkinsonian medications, the data may elucidate the effects of the eradication therapy.

3.

The International Movement Disorder Society has verified wearing-off questionnaires as WOQ-19 and WOQ-9, which are frequently used. The end-of-dose questionnaire in the article seemed to be similar to the questions of WOQ-9 or WO1-19. Could the authors explain the reasons why using the end-of-dose questionnaire? Please provide the all the profiles of questionnaires and the reference of the questionnaire.

4.

It’s very interesting and plausible to know the improvement of bloating symptoms in PD patients receiving eradication therapy. The authors mentioned there was no significant difference of motor scores and NMSQ scores, could the authors provide the evidence and explain the possible mechanism of the improvement of dysphagia symptoms?

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Reviewer #1: No

Reviewer #2: No

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PONE-D-20-33347R1

Helicobacter pylori eradication improves motor fluctuations in advanced Parkinson's disease patients: A prospective cohort study (HP-PD trial)

PLOS ONE

Dear Dr. Lolekha,

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

Please submit your revised manuscript by Apr 23 2021 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: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Wan-Long Chuang, M.D., Ph.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.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

Reviewer #3: (No Response)

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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: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

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

Reviewer #1: Yes

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: Yes

Reviewer #2: Yes

Reviewer #3: No

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

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

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: This is an interesting and important study. The authors have responded to the comments from the reviewer.

Reviewer #2: The great efforts of the authors to answer the question are appreciated. I think their work may help the clinicians and scientists to uncover the complex mechanism between HP and PD.

Reviewer #3: Abstract: There are two percentages mentioned, and it isn't quite clear how these are calculated - 22 patients (55%) and 17 patients (77.3%) - the higher number has the lower percentage, so, to be correct the denominator must be different, but it isn't clear what it is from this text. Could you please clarify, perhaps by stating what the denominator was (22/40 and then 17/22?)?

Study design - pg 3, line 74 - what was the effect size or mean and standard deviation of change in daily on-off time, L-dopa onset or peak time used in the power calculation? What was the difference in groups the study aimed to test? or was it only in those patients who eradicated HP that were of interest? Why were the patients who were HP negative at baseline included? How were the numbers reduced from 163 to 40?

It is unclear how the various groups were recruited from the text, but it is clearer once Figure 1 is examined - could the text be cleared up?

pg 9, line 190 - mention multiple testing correction method with statistical methods (as "p<0.05 was considered to be statistically significant") on page 6 isn't the full story. Include the Bonferroni corrected p-values where they were calculated.

Table 4: It needs to be clear that this is baseline HP negative results and after treatment HP eradication results. For the statistically significant results - it may have been that the results were just different at baseline between these two groups of patients - would it have been of interest to see if there was a difference in the later time point data for the two groups, adjusted for the baseline variables?

Could be 4 columns of results be presented? Pre and post treatment for those who were HP negative at baseline and those who ended up as HP negative after treatment?

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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.

Helicobacter pylori eradication improves motor fluctuations in advanced Parkinson's disease patients: A prospective cohort study (HP-PD trial)

PONE-D-20-33347R2

Dear Dr. Lolekha,

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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Kind regards,

Wan-Long Chuang, M.D., Ph.D.

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 #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 #3: (No Response)

**********

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

Reviewer #3: (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 #3: (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 #3: (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 #3: (No Response)

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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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 #3: No