PONE-D-21-08562

Gastric motility and pulmonary function in children with functional abdominal pain disorders and asthma: a pathophysiological study

PLOS ONE

Dear Dr. Devanarayana,

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 correct or write a detailed rebuttal regarding the corrections suggested by reviewers.

Please submit your revised manuscript by Jun 04 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.

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We look forward to receiving your revised manuscript.

Kind regards,

Davor Plavec, MD, MSc, PhD, Prof.

Academic Editor

PLOS ONE

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4. 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 If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references.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 If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.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:

Dear Authors,

please correct or write a detailed rebuttal regarding the corrections suggested by reviewers.

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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: Partly

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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: Yes

Reviewer #2: 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: Yes

Reviewer #2: No

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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 a good written paper in which Kumari at al. offer a possible explanation for the previously observed association between functional abdominal pain disorders (FAPDs) and asthma. The authors designed a cross-sectional comparative study to test their hypothesis that smooth muscle dysfunction is one of the possible shared pathophysiological mechanisms in both disorders.

They assessed gastrointestinal and bronchial smooth muscle function in four groups of children: FAPDs only, asthma only, both asthma and FAPDs and healthy controls. The authors performed indirect standard tests: real-time ultrasonography, a previously validated method of investigating gastric emptying and antral motility; and spirometry for assessment of lung function parameters and bronchodilator reversibility. The methods and study design are clearly explained and the study is reproducible. The results were obtained using adequate statistical approach and are presented clearly in the text, tables and figures.

This is the first study investigating gastric motor function in children with asthma and the authors showed that gastric motor functions are significantly impaired in children with asthma, similar to children with FAPDs. This suggests gastrointestinal dysmotility could be a possible shared pathophysiological mechanism between these two disorders.

Several studies investigated spirometry findings in adults with FAPDs, but this is the first paper reporting on lung functions in children with FAPDs. The results show normal lung function test in these children. However, in one subgroup of subjects – children with both asthma and FAPDs, the authors were able to demonstrate a significant correlation between parameters that measure airflow limitation (FEV1/FVC ratio, FEF 25-75%) and the motility index, which measures overall gastric motor activity. These correlations suggest simultaneous alteration of airway and digestive tract smooth muscle activity in patients suffering from both diseases and support the hypothesis of shared pathophysiological mechanisms. However, it is worth mentioning that no such correlation was observed in children with only asthma and only FAPDs.

In the discussion section, the authors address how their findings relate to previous research in this area and offer possible explanations of their results. This section needs revision to improve the understanding and better justify the conclusions, as stated below. The authors correctly identify strengths and limitations of their study. Finally, they conclude by suggesting that both asthma and FAPDs might arise because of primary disturbance of smooth muscle activity in the airways and gastrointestinal wall, which could be a possible pathophysiological mechanism for the association between these disorders.

This study could be a foundation for future research to prove the proposed pathophysiological mechanism with more sensitive measures of airway and gut smooth muscle functions and perhaps lead to development of new effective treatment modalities to manage these children more effectively.

Before approving this paper for publication, I suggest that the authors modify the discussion and clarify the following sections to avoid confusion:

1) Why does more severe impairment of gastric motility in children suffering from both asthma and FAPDs, compared to either disease alone further strengthen the association of gut dysmotility and asthma? (page 18, lines 289-291, and repeated in Conclusion, page 21)

2) How do the authors explain the fact that no correlation was documented between motility index and FEV1/FVC ratio or FEF 25-75% in asthmatic children (Results, page 16, paragraph 1), although the subjects did have impaired gastric motility (especially in the context of a positive correlation found among children with both FAPDs and asthma)? Please add comment to the Discussion section.

3) Is the suggested shared pathophysiological mechanism regarding smooth muscle impairment restricted to children with both diseases, or does subclinical pathology (either respiratory or gastrointestinal) exist in all cases? If yes, what would be the reason for inconsistent correlation results among different study groups?

4) The assertion of the conclusion needs toning down/adjustment accordingly to these revisions. Alternatively, the authors should include more information that clarifies and justifies their composition of the conclusion.

Reviewer #2: Dear author, your research and idea of research are really interesting. Unfortunately, this paper is written in bad English and needs proofreading. Also, I partially disagree with the statement in the conclusion - gastrointestinal dysmotility is a possible common pathophysiological mechanism between these two diseases - as gastrointestinal dysmotility cannot really be a part of asthma pathomechanism... Later, it is well said: therefore, these diseases could arise as a result of a primary disruption of smooth muscle activity in the airways and gastrointestinal wall, which could be a possible pathophysiological mechanism for this association between asthma and FAPDs. I suggest you remove or rephrase the first part.

Also, I noticed that you use the same abbreviation for gastric emptying rate and gastroesophageal reflux, which can be confusing.

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Reviewer #1: Yes: Duska Tjesic-Drinkovic

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.

PONE-D-21-08562R1

Gastric motility and pulmonary function in children with functional abdominal pain disorders and asthma: a pathophysiological study

PLOS ONE

Dear Dr. Devanarayana,

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 Sep 28 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. 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,

Davor Plavec, MD, MSc, PhD, Prof.

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 (if provided):

Please revise the manuscript as suggested by reviewer #1.

[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: (No Response)

Reviewer #2: (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: (No Response)

**********

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

Reviewer #1: Yes

Reviewer #2: (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: Yes

Reviewer #2: (No Response)

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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: (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: In the revised manuscript, the authors repeat the statement: “gastric dysmotility is more severe in children having asthma+FAPDs than in having one of those diseases” (Discussion section - line 285), although they acknowledged this is not true (authors’ answer to my Comment 1)

Unfortunately, the authors failed to offer a plausible explanation/answer to my comments 2 and 3. Their conclusions, incorporated in the Discussion section, do not appear sound for several reasons. Specifically, they assume that muscle dysfunction is milder in asthma alone and FAPDs alone than in asthma+FAPDs, but the presented data (Table 2) does not support this assumption. They also suggest that disease progression and the degree of muscle impairment are important for a correlation to exist. They failed to relate to any reference that would back up their point of view. Not being able to find a plausible explanation for a study result is better than offering unsupported or confusing opinions.

Concerning the Reviewer 2 comment – the authors again use the same abbreviation GER for two conditions, what is disappointing. (for example, see lines 290-295).

Therefore, I do not support publishing the work in this form. I encourage the authors to revise the Manuscript once again, mainly the Discussion, following this comment and the previous review comments.

Reviewer #2: (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.

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: Yes: Duska Tjesic-Drinkovic

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.

Gastric motility and pulmonary function in children with functional abdominal pain disorders and asthma: a pathophysiological study

PONE-D-21-08562R2

Dear Dr. Devanarayana,

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,

Davor Plavec, MD, MSc, PhD, Prof.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Ass all the reviewers suggestions have been accepted the manuscript is acceptable for publication in its current form.

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: (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: (No Response)

**********

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

Reviewer #1: Yes

Reviewer #2: (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: Yes

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: Yes

Reviewer #2: (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: (No Response)

Reviewer #2: (No Response)

**********

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: Yes: Duska Tjesic-Drinkovic

Reviewer #2: No