PONE-D-22-13485The Off-Hour Effect on Mortality in Traumatic Brain Injury According to Age Group

PLOS ONE

Dear Dr. ryu,

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.

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

Dear Eujene, Jung and Hyun Ho, Ryu

Your manuscript “The Off-Hour Effect on Mortality in Traumatic Brain Injury According to Age Group” has now been assessed by our reviewers.

You have applied a simple analysis to the traumatic brain injury patients, and even though your findings may not be revolutionary – no insult intended – it is still of general interest.

The manuscript is therefore still considered for publication, although not in its current form. The two reviewers have raised some valid points, that may improve the manuscript and allow a revised version to be published. Please address all points, as well as the following:

• Please ensure your names are spelled correctly throughout the manuscript (Ro is mentioned in Author Contributions, which I hope is a typo)
• Funding Acknowledgement: Please indicate whether the grant had an influence or otherwise restricted the research.
• Could you provide I little more information on EMT level-1 and level-2 differences in competencies?

Please submit your revised manuscript by Oct 07 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,

Tim Alex Lindskou

Academic Editor

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

"This study was supported by a grant (BCRI-20022) of Chonnam National University Hospital Biomedical Research Institute"

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. 

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: 

"The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript"

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

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.

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

********** 

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

Reviewer #1: Yes

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: No

Reviewer #2: No

********** 

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: In a single center population of TBI patients between 2017-2020, the authors found no significant difference in mortality in patients visiting ED during off hours. The effect measure of ED admission during off hours on mortality was significant in patients aged 0-17 years compared to other age groups. Additionally, 85% of TBI patients presented during off hours and there were no differences in the proportion of surgical intervention between on- and off- hours.

Abstract:

- Would not state TBI is a surgical emergency, as 80% are mild and even moderate to severe may not always require surgery.

- Please include N. Please include how TBI was defined at the study institution. Please include more relevant data in the results section.

- I'm not sure the conclusion supports that any differences are currently present between daytime and nighttime emergency care.

Introduction:

- Would not state TBI is a surgical emergency, similar to above.

Methods:

- Authors need to define what constitutes "TBI" at their site. This alone could be a limitation depending on how it is defined.

- Per the authors, "The main outcome measure was mortality at hospital discharge. The secondary outcome was surgical intervention within 6 hours of ED admission. The main exposure variable was arrival time at ED admission (off-hour vs. working-hour). We defined daytime as 09:00 AM to 17:59 PM and nighttime as 18:00 PM to 08:59 AM; weekdays as Monday to Friday; and weekends as Saturday, Sunday, and national holidays, based on a previous study." As such, there should be a limitation discussed as 6 pm and 9 am are hardly accepted as "nighttime" at most institutions.

- Unclear why the authors controlled for so few variables while using a multivariable regression despite evaluating much larger initial cohorts. We know variables such as psychiatric history, history of prior TBIs, etc, can lead to poorer outcome.

- The Pediatric cohort is usually a completely separate population in characteristics and (in part) response to TBI, however were included as part of the main analysis in this study.

Limitations:

- Need to be augmented per comments above.

Discussion:

- The statement "EDs should, thus, be designed such that patients can expect the same quality of emergency care regardless of admission time." should be tempered/revised, as there is no recent evidence that ER care changes based on the hour.

- How can the results of this study change and/or improve practice?

Reviewer #2: 1. term seniors is. not universal (my pdf page 11)

2. weekdays and holidays are combined...are there Monday holidays like the US ?

3. am I correct these patients have isolated head injury. if they have a wrist fracture that only required splint, or a isolated ribfracture, were they excluded ?

4. is time from ED presentation to OR different in the weekday vs weekend group. are neurosurgeons available in the hospital during the day and night ? do they need to travel during these times from another office or home. I assume the OR staff/OR are 24/7/365.

5. maybe the important variable

6. table 1 ..what does intentionality mean

7. the p value ...what comparisons do they represent ...so age ...is it the 3 categories 0-17, 18-64 and ≥65 vs day and night? are these multiple comparisons still significant after a multiple comparison (Bonferroni) correction? same is true for all these other 3x2 , 5x2 ,4x2 comparisons

8. seems like there is overlaps in table 1 and 2....there is day vs night, weekday vs weekend, then in table 2 its really the same but now defined as off hours vs working hours. Why have the two and not just simply with on hours and off hours ?

9. it looks like these multiple comparisons also exist in other tables

so for example table 4 , mortality at hospital dc is p < .05. for a 3x2 table , 6 comparisons the level of significance is not .05 , but actually .05 /6 , significance adjusted 0.01250.

so your report of significance if not corrected at < .05 actually is. not significant between .01250 and .05.

********** 

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: Yes: Pierre Borczuk

**********

[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-22-13485R1The Off-Hour Effect on Mortality in Traumatic Brain Injury According to Age GroupPLOS ONE

Dear Dr. ryu,

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 Dec 15 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,

Tim Alex Lindskou

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.

[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 #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 #1: No

Reviewer #3: Yes

**********

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

Reviewer #1: 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 #1: 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 #1: 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: I appreciate the authors' time investment to address the Reviewer comments. However, a number of concerns remain:

1) The authors state in the Methods that TBI patients over the age of 18 were included, however the paper reports on patients aged 0-17 years.

2) I don't understand the rationale of doing a subgroup analysis in patients only with subdural hemorrhage. What about other types of intracranial injury?

3) I do not understand the rationale of having multiple significant differences in predictors on univariate analysis, and only including age and arrival time in multivariable analysis.

4) The study found that patients aged 0-17y had increased odds of mortality (Table 4) compared to other age groups when arriving during off-hours, yet in the conclusion does not provide a tangible explanation or actionable next step.

5) Off hour presentation with TBI, as the authors show, is associated with dangerous mechanisms (assaults, alcohol use) which require in depth discussions, especially relating to care received. While more 18-64yo patients presented during off hours, 0-17yo's had increased mortality. Why?

6) There were more SDH's during off hours than working hours. What about other forms of intracranial hemorrhage? This must be analyzed, controlled for and discussed thoroughly.

7) Are there differences in hospital lengths of stay between the two groups? This requires an adequate multivariable analysis.

Minor comments:

1) "The inclusion criteria are... and had intracranial hemorrhage and/or diffuse axonal [? injury]..."

Reviewer #3: Dear Editor,

Thank you for asking me to comment on the Revision -1 of this submission, although as you know I was not invited for the original review. So , my comments are brief since I see that the questions made by original reviews are being answered properly.

The only part that I am concerned is that the authors Excluded the patients under 18 ( inclusion of 18 and older). However their data and results are bout children less than 18 / How is this possible?

{{{{ The inclusion criteria are patients with TBI over 18 years of age who visited trauma center using

emergency medical services (EMS) within 72 hours of injury and had intracranial hemorrhage and/or

diffuse axonal confirmed by a radiological examination.}}}}

Best,

Ali Seifi Seifi, MD, FACP, FNCS, FCCM

Associate Professor of Neurocritical Care

University of Texas Health Science Center at San Antonio

**********

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 #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-22-13485R2The Off-Hour Effect on Mortality in Traumatic Brain Injury According to Age GroupPLOS ONE

Dear Dr. ryu,

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.

I do apologize for the long process time and understand the importance of publication this year. Therefore, I am sending you the comments following only a single review.

Please briefly address the last reviewers three comments, and then I am certain we can aim for a quick publication.

Please submit your revised manuscript by Jan 28 2023 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,

Tim Alex Lindskou

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.

[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 #4: (No Response)

**********

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 #4: Yes

**********

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

Reviewer #4: 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 #4: 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 #4: 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 #4: Retrospective single center review examining outcomes for TBI patients by time off day and day of week of presentation. The authors demonstrate that outcomes are similar for all patients regardless of when they present. There is a signal for patients 0-17 where mortality seems to be increased at off-hours time, although this is based on only 3 deaths - and may statistically significant but clinically less so.

In general, outcomes are dependent on anatomic injury, presenting physiology, and comorbidities. Do the authors have any data on comorbidities in their study population (especially the older patients).

For the 0-17 age group, the findings are of interest, but the authors need to better describe specifically who cares for this patient population during the day as well as during off hours. Do you use pediatric specialists (and especially pediatric neurosurgeons and / or neurointensivists) and are any specialists available 24/ 7 or only during the workdays?

Finally, the conclusions should include the equivalent outcomes for the vast majority of patients. This speaks well of the trauma center / system that you have set up and should not be minimized.

**********

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 #4: 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.

The Off-Hour Effect on Mortality in Traumatic Brain Injury According to Age Group

PONE-D-22-13485R3

Dear Dr. ryu,

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,

Tim Alex Lindskou

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Thank you for the revised manuscript.

It appears there have been some latency from your submission of the latest revision, to I received it. This is completely out of my hands, but still unfortunate.

Well done on your article and for your patience.

Reviewers' comments: