PONE-D-21-01310

Does Fibersol-2 efficacious in reducing duration of watery diarrhea and stool output in children 1-3 years old? a randomized, parallel, double-blinded, placebo- controlled, two arm clinical trial

PLOS ONE

Dear Dr. Shahid,

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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Ivan D. Florez; MD, MSc, PhD

Academic Editor

PLOS ONE

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"This research study was funded by Matsutani Chemical Industry Company Limited, Japan on behalf of ADM/Matsutani LLC, USA. The International Centre for Diarrhoeal Disease Research, Bangladesh, receives unrestricted support from the Government of the People's Republic of Bangladesh, Global Affairs Canada, the Swedish International Development Cooperation Agency and the UK Department for International Development."

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Additional Editor Comments:

Your manuscript has been reviewed by three experts in the field, and they have found some points that need to be addressed before this manuscript is considered for publication. Please go through the reviewers' comments and consider addressing these points, and prepare a revised version.

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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: Partly

Reviewer #2: Yes

Reviewer #3: No

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

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: 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: No

Reviewer #3: 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: No

Reviewer #2: Yes

Reviewer #3: 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: 1. On the assessment of patient´s response: In the introduction section, the authors mention in a rather casual way that they wanted to study this compound's effect on the duration of diarrhea and the stool output (lines 88-89 of the manuscript). In another paragraph, under the "measurements" section (lines 201- 202), the authors indicate that the primary outcomes are diarrhea duration, the proportion of patients recovered within 72 hours, and daily stool output. Therefore, this clinical trial has not one but three primary criteria of response. To measure diarrhea duration, the authors indicate that they did count the number of hours elapsed from randomization to the last watery stool (lines 196-197). The authors need to clarify if they were recording the physical characteristics of every single stool passed during the study. It looks to me that only the stool volume was measured and recorded. This clarification will also be useful for understanding how they calculated the proportion of patients recovered from diarrhea. Enrolled patients stayed in the hospital for some days and then discharged and followed up at home. This design introduces a potential major problem in measuring the stool volume. While in the hospital, stools were collected in buckets placed beneath a cholera cot (line 186); once the patients were at home, the stools were collected in plastic bags (lines 192-193). These are two different ways of measuring this study outcome. At best, the authors should calculate the stool output during the hospital stay separated from that collected at home and compare this variable between the two groups looking for inconsistencies.

2. On the required size of study: The authors do not provide a sample size calculation, which should include the study power and the Type I and Type II error levels for any of the three selected study outcomes; they only mention the number of subjects included in the trial (line 108). I suspect that the necessary number of subjects to ascertain the study hypothesis would differ for each study outcome since each uses a different metric (hours, proportion, and volume).

3. On the method used to prepare a list of random treatment assignements: The authors inform that this is a placebo-controlled, randomized, double-blind, parallel clinical trial (line 105). A person not involved otherwise in the study prepared the list of random treatment assignments using a random number table (lines 114-115). The treatment's name was written on a piece of paper and then placed inside a sealed envelope (lines 115-116). The authors must clarify whether the person who prepared the sealed envelopes wrote the sequential study number outside these envelopes.

4. On the allocation concealment: The study researcher had the envelopes containing the treatment assignments (line 117) and opened the correspondent envelope only after the next patient was enrolled and gave the consent (lines 118-120). However, the authors need to explain the procedure followed in greater detail.

5. On the double-blind nature of this study: This is not a double-blind clinical trial. In this study, the enrolled patients received either the experimental treatment (digestion resistant maltodextrin) or the control treatment (regular maltodextrin) in the form of a drinking solution, twice a day for seven days (lines 109-112). The study was not blinded for the research physician since he or she was in charge of opening the sealed envelopes containing the name of the treatment allocated to the next patient (lines 118-119). We do not know if the study was blinded to the caregivers and how. The authors need to clarify this. The authors also should explain why they did not opt for a double-blind design, which would be feasible if the sequential study drinking solutions were provided already prepared by the hospital's pharmacy labeled only with the sequential study number.

6. On the statistical analysis: Mean (standard deviation), and median (IQR) for continuous variables and OR (95% CI) for categorical variables are provided in the tables presenting the data analysis results. Since this study is negative (no superiority of the experimental treatment over the control treatment), the authors must estimate how large the type II error is for this study's size.

7. On the evaluation of safety: There is no section in the manuscript, neither in methods or results, that explicitly presents what and how to monitor the intervention's side effects. Table 5 shows the comparative results between the two treatment groups of four variables observed during the seven days of the study: abdominal distension, abdominal pain, abdominal rumbling, and abdominal bloating. The authors need to clarify if these were the variables selected to monitor the safety of the trial. I do not understand the difference between abdominal distension and abdominal bloating.

8. On the registration of this trial: I have verified that this trial is registered at ClinicalTrials.gov with the number NCT03565393

9. On the accessibility of the study protocol and primary data records: The study protocol is available as an annex (supporting information). The authors declared that this study's primary data records would be public with some restrictions and only upon request.

10. On the sources of funding and the role of funders: The sponsor of this study is mentioned in the manuscript. However, the authors do not note whether or not the funder had a role in designing the study protocol, data analysis, decision to publish, and preparing this manuscript.

Reviewer #2: Title: There's a typo in the title; did you intend for it to be; "Is Fibersol-2 efficacious..."

Abstract: The presentation of the numerical results should be improved, for example for the continuous outcomes you should report the mean, standard error, difference, 95% confidence intervals for the difference and p-value: "The mean (SE) duration of watery diarrhoea in the fibserol and control groups respectively were XX(xx) and YY(yy) respectively, a difference of ZZ, 95%CI zz to zz, p-value zzzz." For the binary outcome: "The proportions of children who recovered from watery diarrhoea within 72 hours in the fibersol and control arms were AA and BB respectively, odds/risk ratio/difference CC, 95%CI cc to cc, p-value cccc."

Introduction:

- there's a missing space between "fibre" and "produced" in line 60.

- first word of line 61 should be plural "prebiotics", or begin with "A prebiotic..."

- line 70: "the evidence", not plural.

- line 78: do you mean "in children admitted to hospital with diarrhoea and dehydration" or "dehydration due to diarrhoea", rather than "dehydrated diarrhoea"?

- line 84, you mean "healthy" not "healthful".

Methods

Although most of the required information is present, the reporting of the methods does not follow the order of sections recommended in the CONSORT guidelines, and the methods therefore feels rather jumbled up. For example, lines 108 to 112 under 'study design' belong to 'randomisation and masking', and the description of the eligibility criteria after randomisation and masking seems odd. Please have a look at the CONSORT statement at http://www.consort-statement.org/checklists/view/32--consort-2010/66-title and try to reorganise the methods to follow the suggested order.

Please include a clear description of how the sample size was determined - this is not currently reported. The numbers of children in each arm is a result and should not be included anywhere in the methods, e.g. in lines 121 and 123.

For the analysis, first, a table of descriptive characteristics of the sample, without any statistical tests comparing the groups, should be presented. These should be means and standard deviations for continuous variables, and counts and proportions for categorical ones, in each group and overall. This should be Table 1. It should be followed by a table showing the mean and SE of continuous outcomes in each group and the difference in means, 95% confidence intervals and p-values, both crude and adjusted, from a linear regression model. For the binary outcome the table should have the counts of events and proportions in each arm and the odds ratio or risk ratio or risk difference with the 95% confidence intervals and p-values, both crude and adjusted. It is these results that should then be summarised in the text and abstract.

Please avoid using the ± designation anywhere in the text as it implies a range of values which is not what you seem to mean in each case where it is used.

Please include the sources of funding and other support and the role of funders as a sub-section in the methods (e.g. the last subsection of methods).

Reviewer #3: Dear Editor

This study is a good example for the effects of different kind of supplementation to ORS for children with acute infectious diarrhea. Randomization, patient selection and end-points are great for pediatric diarrhea study. However I can not understand why the authors prefer to use this prebiotic for the treatment of diarrhea. Prebiotics have some beneficial effects on health (not innumerable), and majority of the effects of fiber are increased transit time (mainly proposed in children with constipationd or other FGIDs). This may be beneficial for diarrhea if combined with probiotic strains.

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Reviewer #1: Yes: Eduardo Salazar-Lindo

Reviewer #2: No

Reviewer #3: No

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PONE-D-21-01310R1Is Fibersol-2 efficacious in reducing duration of watery diarrhea and stool output in children 1-3 years old? A randomized, parallel, double-blinded, placebo- controlled, two arm clinical trialPLOS ONE

Dear Dr. Shahid,

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 Mar 03 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,

Ivan D. Florez, MD, MSc, PhD

Academic Editor

PLOS ONE

Journal Requirements:

Additional Editor Comments:

Reviewers have provided some comments that need to be addressed. Please prepare a revised version with a point-by-point response to their comments.

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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 #2: (No Response)

Reviewer #3: All comments have been addressed

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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 #2: Partly

Reviewer #3: Yes

**********

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

Reviewer #2: No

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 #2: No

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 #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 #2: In the abstract, the lines reporting numerical results (41-42) should (1) for duration of watery diarrhoea and total watery stool output, instead of the statistics reported using ± which the authors don't indicate what they are, should report the difference in means with 95% confidence intervals in addition to the p-values; (2) for proportion recovered, the odds ratio (as stated in your statistical analysis section) with 95% confidence intervals in addition to the p-value. These can be obtained from appropriate regression models.

The statistical analysis is not appropriately described or presented. It should focus on (1) presenting the characteristics of participants in each treatment arm. Categorical variables should be presented as counts and proportions, and continuous ones as means with standard deviations or medians with IQRs as approporiate (this is usually reported in Table 1 and seems to have been done well). It is not normally necessary to conduct tests of normality of covariates; (2) the methods for estimating the treatment effects on the outcomes, with 95% confidence intervals and p-values. These would normally be appropriate regression models. The results tables coming out of these should report the count and proportion of binary outcomes in each arm, with unadjusted and adjusted effects, here odds ratios, with their 95% confidence intervals and p-values; for continuous outcomes, the means and standard errors (NOT standard deviations) of the outcome in each arm, along with the unadjusted and adjusted effect estimates (mean differences) with 95% confidence intervals and p-values; (3) how the sample size was determined - this is critial!

Thus, the results presented in Tables 2 to 4 are not appropriate. Please see https://www.sciencedirect.com/science/article/pii/S0140673618317823 for examples of typical approaches to presenting the results tables.

The statement in the statistical methods section about the power of the study is a result, and should be reported in the last paragraph of the results section.

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.

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

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-21-01310R2Is Fibersol-2 efficacious in reducing duration of watery diarrhea and stool output in children 1-3 years old? A randomized, parallel, double-blinded, placebo- controlled, two arm clinical trialPLOS ONE

Dear Dr. Shahid,

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.

A number of outstanding concerns have been expressed regarding the statistical reporting in your study. Please respond carefully to these comments when preparing your revision.

Please submit your revised manuscript by Dec 02 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,

Jamie Males

Editorial Office

PLOS ONE

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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 #2: (No Response)

Reviewer #3: All comments have been addressed

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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 #2: Partly

Reviewer #3: Yes

**********

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

Reviewer #2: No

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 #2: No

Reviewer #3: Yes

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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 #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 #2: There are still some problems with the statistical reporting in this manuscript. First, the sample size determination is repeated in two places: in lines 133 to 149 and again in lines 252 to 254.

That aside, the sample size determination is poorly reported. For example, when the authors say they anticipated a 25% relative reduction in 48-hour stool output, they do not indicate the anticipated stool output before or after the 48 hour period which would be useful in attempting to replicate their calculations; so it is not possible to do so. Furthermore, when they say that they assumed the proportion of children recovered within 72 hours would be 35% in the placebo group compared to 70% in the fibersol-2 group (or even the information about the duration of watery diarrhoea), there is no external information to justify why they thought these would be the case; it almost seems as if these numbers have been plucked out of thin air to justify the study size post-hoc.

The description of the statistical analysis is still quite poor. For example, the authors say in line 256: "in qualitative variables, differences in proportions were compared by the chi-squared test." I'm assuming this refers to categorical variables. First of all, the authors need to be clear whether these were the descriptive variables of the participants - in which case there would be no need for tests of significance - or outcome variables, in which case in my previous review I recommended performing regressions and reporting the magnitudes of association (odds ratios/risk ratios/risk differences - only one of these) with 95% confidence intervals and p-values, both unadjusted and adjusted where possible. This point also applies to the next statement in line 256 about 'quantitative data' (which I assume means continuous outcomes) - again here, if these were descriptive, then means and standard deviations are to be reported; if these are the outcomes, then means and standard errors in each group, followed by mean differences from linear regression models with 95% confidence intervals and p-values should be reported.

(adding this after reading the rest of the manuscript - some of the information I have asked for above is present in the manuscript, but the current description of the methods makes it seem like it has been done incorrectly)

Tables 1, 2, 3 and 4 are well-reported, and consistent with what one would expect - but not consistent with the statistical methods described, given my comments above. Table 5 is also useful additional information, but no mention of this in the statistical methods.

Reviewer #3: Recent version of the manuscript would be pıublish in PLos One, if Editorial Board also agree to publish.

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Reviewer #2: No

Reviewer #3: No

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Is Fibersol-2 efficacious in reducing duration of watery diarrhea and stool output in children 1-3 years old? A randomized, parallel, double-blinded, placebo- controlled, two arm clinical trial

PONE-D-21-01310R3

Dear Dr. Shahid,

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.

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PLOS ONE

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Reviewer #2: All comments have been addressed

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Reviewer #2: (No Response)

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Reviewer #2: (No Response)

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Reviewer #2: (No Response)

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Reviewer #2: (No Response)

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Reviewer #2: (No Response)

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Reviewer #2: No

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