The cardiac autonomic response to acute psychological stress in type 2 diabetes

Nelly Lou Monzer; Mechthild Hartmann; Magdalena Buckert; Kira Wolff; Peter Nawroth; Stefan Kopf; Zoltan Kender; Hans-Christoph Friederich; Beate Wild

doi:10.1371/journal.pone.0265234

Peer Review History

Original SubmissionSeptember 28, 2021
1 Nov 2021 Decision Letter - Yih-Kuen Jan, Editor PONE-D-21-31231The Cardiac Autonomic Response to Acute Psychological Stress in Type 2 DiabetesPLOS ONE Dear Dr. Monzer, 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 16 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. 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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. We note that you have stated that you will provide repository information for your data at acceptance. Should your manuscript be accepted for publication, we will hold it until you provide the relevant accession numbers or DOIs necessary to access your data. If you wish to make changes to your Data Availability statement, please describe these changes in your cover letter and we will update your Data Availability statement to reflect the information you provide. 3. Please ensure that you refer to Figure 3 in your text as, if accepted, production will need this reference to link the reader to the figure. [Note: HTML markup is below. Please do not edit.] 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: N/A ****** 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 ****** 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 ****** 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: ABSTRACT 1. Line 22: The abbreviation for HRV should come from "heart rate variability". 2. Line 27-28: Although the SDNN activity of diabetic patients was lower than that of the healthy group, there was no statistical difference in the response of SDNN and RMSSD to the stress test between the two groups. Therefore, the description of "impaired autonomic flexibility pattern" does not seem appropriate. INTRODUCTION This part is well written. MATERIALS & METHODS 1. Line 120-134, page 6-7: It may be easier for the readership if the authors provided a diagram of experimental procedure, so that the reader can more clearly know the time points of the six experimental phases. And confirm the time taken by the participants to complete the entire experiment. Was it 56 minutes (Line 225-227)? Moreover, it can also integrate the point-in-time correlation of various parameters such as HR, HRV, VAS, and TSST. 2. Line 145-146, page7: Generally, the basic unit of HRV analysis, whether it is time domain analysis or frequency domain analysis, is based on a 5-minute period. Why is the 3-minute ECG record used here for analysis? Please explain the reason. 3. Line 156-160, page8: Generally, time-domain analysis is more commonly used to analyze periodic or longer-period records. Frequency domain analysis seems to be more commonly used to observe autonomic changes in a short period of time. It also uses 3-5 minutes as the unit for analysis, which seems to be more in line with the author's design of 6 sampling and 3-minute analysis (Line 1458-146). In addition, frequency domain analysis can additionally observe changes in sympathetic activity, because according to the literature, the sympathetic activity of diabetic patients will also be affected. Based on the above two factors, it is suggested that the author can try to observe the results of this research data by frequency domain analysis. RESULTS Overall, this section reads well. DISCUSSION 1. Line 260-261, page 15: The data in Figures 3 and 4 cannot support the description of “impaired autonomic flexibility”. Because there was no difference in HRV response between the two groups after the TSST test. 2. Line 263, page 15: What does "Cardiac response pattern" refer to? The meaning here is unclear, please specify exactly which physiological parameter response? 3. Line 277-279, page 16: This sentence means that age and diabetes have a bottoming effect on the reduction of RMSSD activity. Is there any evidence in the literature? Isn't their influence cumulative? 4. Line 310-313, page 17: The effects of exercise training and breathing exercise intervention on autonomic flexibility mentioned in this paragraph seem to be irrelevant to this study? CONCLUSION The conclusions of the paper were very general and deserve better specificity. The conclusion of the paper should say more about how to use this information to make a change in practical application, and comment on the specific research that is suggested to move the science forward. Reviewer #2: 1. In the subsection “Participants”, the number of the participants and their demographic data should be clearly described. Also, the exclusion criteria were not well described. 2. For the subsection “ECG Sampling and HRV Analysis”, the major concerns are as follows. (1) The authors used SDNN and RMSSD of HRV to indicate the “sympathovagal balance” and “cardiac vagal outflow”, respectively. How about the frequency domain indices of HRV? (2) What types of signals were recorded using the ECG logger? The ECG signals or “Heart rate and heart rate variability samples”? (3) Why a sampling frequency of 8000 Hz was used? (4) The positions of five ECG electrodes. (5) How to perform the procedure “artifact correction”? what does the term “artifact rate” mean? (line 155) 3. The “Results” section was not well organized. 4. There are a lot of incorrect or inappropriate expressions. Only in the abstract, the meanings of many terms such as “Multilevel analyses”, “attenuated HR”, “decreased HR curvature”, “HR recovery”, and “stress system” are ambiguous. ****** 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:** Fuyuan Liao [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. https://doi.org/10.1371/journal.pone.0265234.r001
Revision 1
25 Nov 2021 Author Response Reviewer #1: ABSTRACT 1. Line 22: The abbreviation for HRV should come from "heart rate variability". Thank you for pointing out this mistake. We have corrected it. (s. line 22) 2. Line 27-28: Although the SDNN activity of diabetic patients was lower than that of the healthy group, there was no statistical difference in the response of SDNN and RMSSD to the stress test between the two groups. Therefore, the description of "impaired autonomic flexibility pattern" does not seem appropriate. Thank you. We have replaced the expression in question (s. line 27-28) INTRODUCTION This part is well written. MATERIALS & METHODS 1. Line 120-134, page 6-7: It may be easier for the readership if the authors provided a diagram of experimental procedure, so that the reader can more clearly know the time points of the six experimental phases. And confirm the time taken by the participants to complete the entire experiment. Was it 56 minutes (Line 225-227)? Moreover, it can also integrate the point-in-time correlation of various parameters such as HR, HRV, VAS, and TSST. Thank you for this suggestion. We have provided a supplementary figure depicting the experimental procedure including point-in-time correlations between the VAS and the physiological variables. As depicted in the figure, the study procedures took approximately 2 hours. 2. Line 145-146, page7: Generally, the basic unit of HRV analysis, whether it is time domain analysis or frequency domain analysis, is based on a 5-minute period. Why is the 3-minute ECG record used here for analysis? Please explain the reason. We used 3-min intervals to achieve a more detailed assessment of the stress response during the stress test. The stress test lasted only approximately 14 minutes and we aimed for 3 samples assessing the HR and HRV response to stress anticipation, the speech task and the surprise arithmetic task. Due to participants varying reactions to the stress test, there was a (small) variance in the exact timing of the stress test. Using 3-minute samples ensured three non-overlapping ECG samples for all participants. To ensure comparability, we wanted to keep all ECG-samples the same length and therefore only used 3-minute samples. We have inserted a short explanation of the ECG sample length in the Methods section (s. lines 151-152). As suggested in your third comment below, we have replaced RMSSD and SDNN with HF and LF HRV. For both HF and LF HRV, samples of <5 min. have been shown to be reliable. See for example: Castaldo, R., Montesinos, L., Melillo, P., James, C., & Pecchia, L. (2019). Ultra-short term HRV features as surrogates of short term HRV: a case study on mental stress detection in real life. BMC medical informatics and decision making, 19(1), 1-13. Baek, H. J., Cho, C. H., Cho, J., & Woo, J. M. (2015). Reliability of ultra-short-term analysis as a surrogate of standard 5-min analysis of heart rate variability. Telemedicine and e-Health, 21(5), 404-414. Salahuddin, L., Cho, J., Jeong, M. G., & Kim, D. (2007, August). Ultra short term analysis of heart rate variability for monitoring mental stress in mobile settings. In 2007 29th annual international conference of the ieee engineering in medicine and biology society (pp. 4656-4659). IEEE. 3. Line 156-160, page8: Generally, time-domain analysis is more commonly used to analyze periodic or longer-period records. Frequency domain analysis seems to be more commonly used to observe autonomic changes in a short period of time. It also uses 3-5 minutes as the unit for analysis, which seems to be more in line with the author's design of 6 sampling and 3-minute analysis (Line 1458-146). In addition, frequency domain analysis can additionally observe changes in sympathetic activity, because according to the literature, the sympathetic activity of diabetic patients will also be affected. Based on the above two factors, it is suggested that the author can try to observe the results of this research data by frequency domain analysis. We have replaced RMSSD and SDNN with HF and LF power. RMSSD was highly correlated with HF power and SDNN with LF power and our results did not change when using frequency domain analysis (s. results section). Correlations and results of both frequency and time-domain analysis can be compared below on page 5 and 6 of the document "Response to Reviewers". RESULTS Overall, this section reads well. DISCUSSION 1. Line 260-261, page 15: The data in Figures 3 and 4 cannot support the description of “impaired autonomic flexibility”. Because there was no difference in HRV response between the two groups after the TSST test. Thank you. We have replaced the expression in question (s. line 281). 2. Line 263, page 15: What does "Cardiac response pattern" refer to? The meaning here is unclear, please specify exactly which physiological parameter response? Thank you for pointing this out. We have revised the sentence. (s. line 281) 3. Line 277-279, page 16: This sentence means that age and diabetes have a bottoming effect on the reduction of RMSSD activity. Is there any evidence in the literature? Isn't their influence cumulative? As we found no conclusive evidence for neither a floor effect, nor a cumulative effect, we revised the section deleted the sentence. 4. Line 310-313, page 17: The effects of exercise training and breathing exercise intervention on autonomic flexibility mentioned in this paragraph seem to be irrelevant to this study? Thank you. We have deleted the paragraph in question. CONCLUSION The conclusions of the paper were very general and deserve better specificity. The conclusion of the paper should say more about how to use this information to make a change in practical application, and comment on the specific research that is suggested to move the science forward. Thank you for your suggestion. We expanded the respective paragraphs (s. lines 334-339 and 345-347). Reviewer #2: 1. In the subsection “Participants”, the number of the participants and their demographic data should be clearly described. Also, the exclusion criteria were not well described. Thank you for pointing this out. We have revised the section (s. lines 78-81). Number of participants and demographic data can be found in the Results section (sample description, s. lines 211-215 and table 1). We have expanded this section as well. 2. For the subsection “ECG Sampling and HRV Analysis”, the major concerns are as follows. (1) The authors used SDNN and RMSSD of HRV to indicate the “sympathovagal balance” and “cardiac vagal outflow”, respectively. How about the frequency domain indices of HRV? We have replaced RMSSD and SDNN with HF and LF power. RMSSD was highly correlated with HF power and SDNN with LF power and our results did not change when using frequency domain analysis (s. Results section). Correlation and results of both frequency and time-domain analysis can be compared on page 5 and 6 of the document "Response to Reviewers". (2) What types of signals were recorded using the ECG logger? The ECG signals or “Heart rate and heart rate variability samples”? Thank you for pointing out this inaccuracy. We have revised the paragraph in question (s. line 144-145). (3) Why a sampling frequency of 8000 Hz was used? The ECG system we used uses oversampling to improve resolution and signal-to-noise ratio. We have included an explanation in the respective section (s. line 145-146). (4) The positions of five ECG electrodes. Thank you for your suggestion. We have included a description of the placement of the electrodes in line 146-148. (5) How to perform the procedure “artifact correction”? what does the term “artifact rate” mean? (line 155) Thank you for your suggestion. We have expanded this section and included a more detailed description of the procedure (s. lines 160-170). 3. The “Results” section was not well organized. Thank you for pointing this out. We have reorganized the results section. Results on HR and HRV are now placed before the results on psychological tension. 4. There are a lot of incorrect or inappropriate expressions. Only in the abstract, the meanings of many terms such as “Multilevel analyses”, “attenuated HR”, “decreased HR curvature”, “HR recovery”, and “stress system” are ambiguous. Thank you for pointing this out. We have tried to be more specific (s. lines 26-29, 34-35, 189, 230, 279, 281) Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0265234.r002
13 Jan 2022 Decision Letter - Yih-Kuen Jan, Editor PONE-D-21-31231R1The Cardiac Autonomic Response to Acute Psychological Stress in Type 2 DiabetesPLOS ONE Dear Dr. Monzer, 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 Feb 27 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, Yih-Kuen Jan, PhD 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) ******** 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: Partly ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: 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 ****** 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 ****** 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: Thanks for your reply to my questions. Your revisions were generally accepted. There are still some minor issues that require your reply. The questions are as follows: LINE 28 & 279: The sentence described in the text (Line 28 & 279) appears to be misleading: "This pattern was accompanied by significantly decreased low frequency HRV ..... between the groups." The term "decreased" to describe the LF HRV response in the text appears to be misleading. Because there was no difference in LF HRV in group-by-time interaction in the stress response, only the LF HRV in the DM group was consistently lower than that in the healthy group. Therefore, it is suggested that the word "lower" is more appropriate to replace "decrease" here. LINE 32-33 & 341-342: "The impairment of the autonomic nervous system commonly found in people with type 2 diabetes likely affects the stress response." This sentence in the conclusion is too excessive and vague. In fact, the difference in ANS was only in the LF, and the stress response only affected the heart rate and subjective perception, however, there was no significant difference in the ANS response. Therefore, it is recommended to make more specific and precise conclusions to avoid misunderstandings. ****** 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 [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. https://doi.org/10.1371/journal.pone.0265234.r003
Revision 2
11 Feb 2022 Author Response LINE 28 & 279: The sentence described in the text (Line 28 & 279) appears to be misleading: "This pattern was accompanied by significantly decreased low frequency HRV ..... between the groups." The term "decreased" to describe the LF HRV response in the text appears to be misleading. Because there was no difference in LF HRV in group-by-time interaction in the stress response, only the LF HRV in the DM group was consistently lower than that in the healthy group. Therefore, it is suggested that the word "lower" is more appropriate to replace "decrease" here. Thank you for your suggestion! We have replaced the word “decreased” with the word “lower” in Line 28 and 279. LINE 32-33 & 341-342: "The impairment of the autonomic nervous system commonly found in people with type 2 diabetes likely affects the stress response." This sentence in the conclusion is too excessive and vague. In fact, the difference in ANS was only in the LF, and the stress response only affected the heart rate and subjective perception, however, there was no significant difference in the ANS response. Therefore, it is recommended to make more specific and precise conclusions to avoid misunderstandings. Thank you! We have replaced the sentence in question with a more precise conclusion. See lines 32-34 & 342-344 Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0265234.r004
28 Feb 2022 Decision Letter - Yih-Kuen Jan, Editor The Cardiac Autonomic Response to Acute Psychological Stress in Type 2 Diabetes PONE-D-21-31231R2 Dear Dr. Monzer, 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, Yih-Kuen Jan, PhD Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: 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: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: 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 ****** 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 ****** 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: Thanks to the author's revision, this paper appears to have been improved. This article is now suitable for acceptance and publication. ****** 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 https://doi.org/10.1371/journal.pone.0265234.r005
Formally Accepted
10 Mar 2022 Acceptance Letter - Yih-Kuen Jan, Editor PONE-D-21-31231R2 The Cardiac Autonomic Response to Acute Psychological Stress in Type 2 Diabetes Dear Dr. Monzer: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. 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. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Yih-Kuen Jan Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0265234.r006

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