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PONE-D-20-06583

Rapid glycemic regulation in poorly controlled patients living with diabetes, a new approach <gwmw class="ginger-module-highlighter-mistake-type-3" id="gwmw-15856881875558206946191">in</gwmw> understanding the pathophysiology of Charcot's acute <gwmw class="ginger-module-highlighter-mistake-type-1" id="gwmw-15856881875558947104717">neuroarthropathy</gwmw>

PLOS ONE

Dear dr dardari,

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Manal S. <gwmw class="ginger-module-highlighter-mistake-type-1" id="gwmw-15856882053484411390607">Fawzy</gwmw>, Ph.D., M.D.

Academic Editor

PLOS ONE

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Additional Editor Comments (if provided):

Based on the constructive and valued reviewers’ comments, the authors should address, in addition, the following concerns:

- Provide more information about the inclusion and exclusion process, screening of cases etc. A flow chart would be most helpful as the patient-group in question is a heterogenous one and too little data are presented regarding this issue.

- Provide a fully plausible and validated biological model for the described association. Otherwise, the authors should point to this issue in the study shortcomings for the readers.

- Acknowledge the fact that data speak describe an association and not a causality.

- Sufficiently address in their study limitations all the possible pitfalls that stem from drawing conclusions from retrospective data.

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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

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

Reviewer #1: I Don't Know

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 <gwmw class="ginger-module-highlighter-mistake-type-3" id="gwmw-15856882206899974495972">to</gwmw> 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<gwmw class="ginger-module-highlighter-mistake-type-6" id="gwmw-15856882223699625479975">.</gwmw>g. <gwmw class="ginger-module-highlighter-mistake-type-1" id="gwmw-15856882229505033897090">participant</gwmw> privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

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. <gwmw class="ginger-module-highlighter-mistake-type-6" id="gwmw-15856882280618318727862">(</gwmw>Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: To the authors:

Thank you for the opportunity to review this <gwmw class="ginger-module-highlighter-mistake-type-1" id="gwmw-15856882294543587272824">intersting</gwmw> paper by Dardari et al.

The paper touches upon a very interesting and largely overlooked problem in <gwmw class="ginger-module-highlighter-mistake-type-1" id="gwmw-15856882307373516530623">glycaemic</gwmw> regulation, namely the complications that can arise from too rapid/aggressive blood glucose treatment.

While the issues regarding cardiovascular and retinal disease in this regard <gwmw class="ginger-module-highlighter-mistake-type-3" id="gwmw-15856882316763224509431">is</gwmw> <gwmw class="ginger-module-highlighter-mistake-type-1" id="gwmw-15856882316764421058823">wellknown</gwmw>, the problems with <gwmw class="ginger-module-highlighter-mistake-type-1" id="gwmw-15856882316763873544039">neuropathic</gwmw> patients are more elusive.

Below, I have listed my comments on the paper as a whole. Unfortunately, my copy does not contain line <gwmw class="ginger-module-highlighter-mistake-type-6" id="gwmw-15856882331351905120624">numbering and</gwmw> so I cannot address my comments to any specific line.

1) More information about the data collection and quality of the database would be helpful. Considering the time period and multiple sites, one wonders about the <gwmw class="ginger-module-highlighter-mistake-type-1" id="gwmw-15856882346266953796452">homogenicity</gwmw> of the charts/electronic systems. How were data logged and retrieved?

2) In the same <gwmw class="ginger-module-highlighter-mistake-type-6" id="gwmw-15856882366210285016844">vein it</gwmw> would be helpful if the paper included a <gwmw class="ginger-module-highlighter-mistake-type-1" id="gwmw-15856882366218889101846">flowchart</gwmw> of patients screened, excluded and so on. How were the data <gwmw class="ginger-module-highlighter-mistake-type-1" id="gwmw-15856882384425905003395">entried</gwmw> validated/controlled? How was the diagnosis confirmed?

The 44 cases have been gathered over a 10 year time period, which makes me think that a lot of borderline cases were removed (unless we're talking about smaller hospitals). Thus, it appears the authors had a good and solid screening of cases. However, this is not apparent in the manuscript.

3) What timeline was used to give the diagnosis acute Charcot foot? When was it considered chronic instead? What was the temperature spread? Any bilateral feet? Recurrences?

4) What was the spread in dates from HbA1c analyses at each time point?

5) Since all the patients had Charcot, they probably all had neuropathy before onset. Is it possible that only 3 cases with registered painful neuropathy is due to insufficient data quality.

6) Were there any of the cases with other <gwmw class="ginger-module-highlighter-mistake-type-6" id="gwmw-15856882457538292147058">possible plausible</gwmw> listed causes of Charcot foot? For instance trauma, physical stress or surgery?

7) It would be helpful to list HbA1c values in IFCC units as well as DCCT.

8) Did every single patient decrease in HbA1c, or did someone increase as well? If so, were there any differences between the two groups?

9) A change from 66.7 mmol/<gwmw class="ginger-module-highlighter-mistake-type-1" id="gwmw-15856882488674427369829">mol</gwmw> to 57.4 mmol/<gwmw class="ginger-module-highlighter-mistake-type-1" id="gwmw-15856882488672406722665">mol</gwmw> is relatively small, and unavoidable in clinical practice. Do you have any indication about <gwmw class="ginger-module-highlighter-mistake-type-3" id="gwmw-15856882503155184797133">frequency</gwmw> of Charcot arthropathy being associated with such a change in HbA1c? Do you have any suggestions about how to effectively mitigate this issue in high risk patients?

10) Why did the patients get a better HbA1c before Charcot onset? You write that 26<gwmw class="ginger-module-highlighter-mistake-type-6" id="gwmw-15856882522164014636389">(</gwmw>27) of 44 patients with altered medication – what happened to the rest? Maybe expand the table to say a bit more about these cases. Did they for instance get hospital control instead of GP control? Did they change lifestyle/lose weight? Is it possible to elaborate further since it's very important?

11) It seems that <gwmw class="ginger-module-highlighter-mistake-type-3" id="gwmw-15856882552605569563017">data</gwmw> support an association to better regulation especially in T1DM group. What happens if you remove the T2DM patients from the analysis completely. Why do you think this is the case? Could it be a different <gwmw class="ginger-module-highlighter-mistake-type-3" id="gwmw-15856882564132405105517">mechanisms</gwmw>?

12) The authors have found an interesting association between acute Charcot foot and <gwmw class="ginger-module-highlighter-mistake-type-2" id="gwmw-15856882572213929706917">resent</gwmw> decrease in HbA1c. But of course association does not mean causality. Could you speculate about other factors that might contribute to this <gwmw class="ginger-module-highlighter-mistake-type-2" id="gwmw-15856882582869979896254">find</gwmw>?

Would you be able to design a model to predict or adjust for any such confounding factors to your dataset?

13) At the bottom of page 8, the authors write that the reduction is mainly due to insulin intensification. Has any analysis done <gwmw class="ginger-module-highlighter-mistake-type-3" id="gwmw-15856882602814557116714">of</gwmw> this and/or i.e. <gwmw class="ginger-module-highlighter-mistake-type-1" id="gwmw-15856882605807033556421">contributing</gwmw> factors?

14) Do you know if any of the patients complained about TIND?

Reviewer #2: Introduction

1- Definition of Charcot neuroarthropathy is needed

2- Clear statement to describe why this research is important.

Methods

1-More justification why the authors select <gwmw class="ginger-module-highlighter-mistake-type-3" id="gwmw-15856882635276213516370">retrospective approach</gwmw> and more information about selection of participants

Findings and discussion

Can the authors discuss more about the contributions the study makes to existing knowledge or literature?

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Reviewer #1: No

Reviewer #2: No

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Rapid glycemic regulation in poorly controlled patients living with diabetes, a new associated factor in the pathophysiology of Charcot's acute neuroarthropathy

PONE-D-20-06583R1

Dear Dr. dardari,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

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With kind regards,

Manal S. Fawzy, Ph.D., M.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

The authors have adequately addressed the concerns raised by the reviewers.

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

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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

**********

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

Reviewer #1: Yes

Reviewer #2: 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

**********

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

**********

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: The authors have addressed my previous comments and I am happy with their responses. I accept this paper to be published.

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Reviewer #1: No

Reviewer #2: Yes: Amer Al-Sahouri

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