The relationship between heart rate variability and glucose clearance in healthy men and women

Abigail Nickel; Robert Buresh; Cherilyn McLester; Andre Canino; Gabe Wilner; Keilah Vaughan; Pedro Chung; Brian Kliszczewicz

doi:10.1371/journal.pone.0303346

Peer Review History

Original SubmissionSeptember 27, 2023
30 Jan 2024 Decision Letter - Hidetaka Hamasaki, Editor PONE-D-23-28922The relationship between heart rate variability and glucose clearance in healthy men and womenPLOS ONE Dear Dr. Nickel, 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 15 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. 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If you are unable to adhere to our open data policy, please kindly revise your statement to explain your reasoning and we will seek the editor's input on an exemption. Please be assured that, once you have provided your new statement, the assessment of your exemption will not hold up the peer review process. 3. Please include your full ethics statement in the ‘Methods’ section of your manuscript file. In your statement, please include the full name of the IRB or ethics committee who approved or waived your study, as well as whether or not you obtained informed written or verbal consent. If consent was waived for your study, please include this information in your statement as well. Additional Editor Comments: Thank you for submitting your valuable work to PLOS ONE. The editor also has a concern for the small sample size. I would appreciate it if you could address the issues raised by the reviewers. [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: Partly Reviewer #2: Partly ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 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: 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: The authors have found significant correlations between heart rate variability (HRV) markers and fasting blood glucose levels in healthy individuals. However, they did not find any significant correlations between HRV markers and the area under the curve (AUC) of glucose. When analyzing by sex, only men showed significant correlations between AUC and RMSSD, SDNN, and LF. There were no sex differences for fasting blood glucose levels, AUC, RMSSD, SDNN, HF, and LF. However, it is important to note that this is a small study with a limited sample size. a sample size of at least 30 is recommended for statistical tests because it is large enough to approximate the true distribution of the population being studied. Was the HRV derived from ECG with your own algorithm, or it was just getting from the ECG monitor? authors should explain why they chose the statistical measures. The study you provided does not mention the use of a menstrual cycle survey in the correlations of measures, why did the authors performed that suevey, the same for the Urine Specific Gravity? Reviewer #2: The study by Nickel et al. investigated the impact of oral glucose on the extent of HRV, considered an important biomarker for metabolic health. The participants were given a 75-g glucose load, and HRV was measured before its ingestion. Different HRV calculations/parameters were used to determine its association with the OGTT response (assessed as the AUC). The results showed that HRV parameters were correlated with capillary glucose concentration. Considering sex in the statistical model, correlations disappeared in women but not in men. Furthermore, HRV and AUC parameters were also correlated in the group of men. The research was properly conducted; methods are appropriate, and results might have certain implications regarding the HRV field. I have the following constructive comments that hopefully can further increase the quality of this manuscript. Method section: The study was carefully designed and conducted. However, the sample size was small (n=18; 10 men and 8 women). Could authors mention this issue (I missed this information in the Method section)? As the small sample size included in the study might impact data interpretation. Thank you. Could the authors better explain what “apparently healthy individuals” is? Did authors determine that using blood samples, personal/medical interviews, questionnaires or is self-reported? Please provide more information as the paper is focused on “healthy individuals.” Was glucose metabolism impairment established as an inclusion/exclusion criterion? If yes, how was it determined? Regarding glucose concentration, authors should mention they are measuring “capillary blood glucose” instead of “blood glucose.” Could authors provide the exact fasting time (e.g., mean and SD). Thank you. Was a commercial glucose drink used, or "homemade" - please state the source and volume (this information was not provided). Does the participant have an “acclimation period” prior to the HRV assessment, or did the HRV assessment start immediately after participants were placed in bed/stretcher? I noticed authors used the low artifact correction filter in the Kubios software. Could the authors better explain why they used this filter? In a relatively recent study (PMID: 31979367), the authors proposed the medium filter for young adults. In this regard, did the authors check whether the results are independent of the Kubios filter used? AUC calculation: I understood the rationale for computing the AUC using the Tai’s Mathematical Model; however, I wonder whether that AUC calculation provides glucose values as “arbitrary units” or “no units” (as certain AUC calculations [e.g., PMID: 14756916]). Could authors mention this aspect? The thermic effect of a 75g bolus of glucose was unlikely to have been completed within the 3-hour measurement window - therefore it is possible that some differences in the response may have been missed by not capturing the downward tail of the HRV response curve. Should this not warrant a mention? Moreover, did capillary glucose concentration values return to baseline? If not, do the authors believe this issue could partially explain the results (e.g., absence of associations)? If capillary glucose did not return to baseline levels after 2-h, glucose-stimulation could be influencing the results. I would suggest mention this issue. Finally, could authors provide a figure showing the capillary glucose concentration and across time (i.e., the curve)? Thank you. Does a protocol of repeated finger-prick collection add to within-subject variability? Capillary blood is notoriously difficult to standardize at each time point of collection, though it may relate to venous values. Lines 133-135: No information regarding missing data is provided. Although Table 2 included 18 participants, I noticed that Figures (1 – 3) showed 15 participants instead of 18. Please mention this issue. Why was the menstrual cycle recorded/registered if it was not used for analyses? Did the authors include the menstrual cycle in the analyses (e.g., as a confounder factor for correlations)? If not, I would suggest placing Table 1 as supplementary material or embed it in Table 2. New analysis: I would suggest repeating the analyses, including heart rate (in beats per minute). Discussion section: Lines 173-175: This could be related to the low statistical power/sample size, rather than not an effect was observed. This issue deserves a mention. Lines 179-181: This threshold is commonly used when blood glucose concentration (i.e., vein samples) is obtained. As I mentioned previously, I would recommend emphasizing that capillary instead of vein glucose concentration was assessed. Limitation section: In my opinion, the following should be included: The small sample size should be mentioned in this section. The menstrual cycle should be mentioned as a potential limitation, as women were at different menstrual cycle statuses which could impact the results in an unknown manner. Glucose concentration was assessed by a finger-prick instead of vein collection. I hope you find these suggestions helpful for refining your manuscript. Kind regards, ****** 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: Yes: GILBERTO IVAN PERPINAN ISEDA Reviewer #2: No ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. 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Revision 1
27 Feb 2024 Author Response Reviewer #1: The authors have found significant correlations between heart rate variability (HRV) markers and fasting blood glucose levels in healthy individuals. However, they did not find any significant correlations between HRV markers and the area under the curve (AUC) of glucose. When analyzing by sex, only men showed significant correlations between AUC and RMSSD, SDNN, and LF. There were no sex differences for fasting blood glucose levels, AUC, RMSSD, SDNN, HF, and LF. However, it is important to note that this is a small study with a limited sample size. a sample size of at least 30 is recommended for statistical tests because it is large enough to approximate the true distribution of the population being studied. The following was changed in the limitations: “Though this study was a novel attempt to evaluate glucose regulation, it was not without limitations. This study used a small sample size, which is an inherit limitation regardless of significant findings. Future studies should use a more robust sample size to better corollate physical and physiological contributors to HRV based OGTT relationship. Furthermore, this study was not designed to control for menstrual cycle. Future studies should enroll female participants in a fashion to control for stage of menstrual cycle. This study used single-day HRV to predict same-day metabolic function; though appropriate for comparing to same-day OGTT, this value may be stronger when compared to a weekly average, given the levels of variability we observed in these markers. The measurement of glucose concentration in this study was performed using finger-prick, future projects should use vein collection to reduce standard error. Lastly, plasma insulin may provide additional insight for this study.” 1) Was the HRV derived from ECG with your own algorithm, or it was just getting from the ECG monitor? HRV was derived using Kubios software (version 3.0.5). The files collected from the Finapres NOVA were transferred to Kubios for analysis. The following was edited in the methods to clarify this more. “Measurements for the current study were collected using the Finapres NOVA, and ECG files were transferred to Kubios software (version 3.0.5).” 2) authors should explain why they chose the statistical measures. “We used parametric stats appropriate for the nature of our data. Because parametric stats assume that data are distributed normally, performed a test for normality, to ensure that our data were indeed distributed normally. We performed two-tailed correlation analysis to be conservative in our conclusions. Likewise, we did a two-tailed independent samples t-test to conservatively compare results between sexes.” 3) The study you provided does not mention the use of a menstrual cycle survey in the correlations of measures, why did the authors performed that survey, the same for the Urine Specific Gravity? Menstrual cycle information was not entered into the correlation due to the low sample size and was used as observational data. Previous work in our lab suggested a relationship between HRV and menstrual cycle, so we collected the phase data as a participant characteristic in the event we observed a sex-based difference. USG was collected for the BIA hydration Reviewer #2: The study by Nickel et al. investigated the impact of oral glucose on the extent of HRV, considered an important biomarker for metabolic health. The participants were given a 75-g glucose load, and HRV was measured before its ingestion. Different HRV calculations/parameters were used to determine its association with the OGTT response (assessed as the AUC). The results showed that HRV parameters were correlated with capillary glucose concentration. Considering sex in the statistical model, correlations disappeared in women but not in men. Furthermore, HRV and AUC parameters were also correlated in the group of men. The research was properly conducted; methods are appropriate, and results might have certain implications regarding the HRV field. I have the following constructive comments that hopefully can further increase the quality of this manuscript. Method section: The study was carefully designed and conducted. However, the sample size was small (n=18; 10 men and 8 women). Could authors mention this issue (I missed this information in the Method section)? As the small sample size included in the study might impact data interpretation. Thank you. This information we added to the limitation section. Could the authors better explain what “apparently healthy individuals” is? Did authors determine that using blood samples, personal/medical interviews, questionnaires or is self-reported? Please provide more information as the paper is focused on “healthy individuals.” “Inclusion and exclusion criteria were determined through self-report through the health history questionnaire” Was glucose metabolism impairment established as an inclusion/exclusion criterion? If yes, how was it determined? Known metabolic conditions were a part of the exclusion criteria and determined through the self-report HHQ. Regarding glucose concentration, authors should mention they are measuring “capillary blood glucose” instead of “blood glucose.” Fixed Could authors provide the exact fasting time (e.g., mean and SD). Thank you. We only confirmed that they had not eaten prior to 12 hours before arriving to the lab, so we do not have exact times. Was a commercial glucose drink used, or "homemade" - please state the source and volume (this information was not provided). OGTT beverage containing 75 grams of glucose (Trutol TM ) Does the participant have an “acclimation period” prior to the HRV assessment, or did the HRV assessment start immediately after participants were placed in bed/stretcher? The following was added: “on an examination bed” was added to the Experimental Design section. “The first five minutes of the 10-minute recording were discarded for acclimatation. The last five minutes of resting time points were analyzed.” I noticed authors used the low artifact correction filter in the Kubios software. Could the authors better explain why they used this filter? In a relatively recent study (PMID: 31979367), the authors proposed the medium filter for young adults. In this regard, did the authors check whether the results are independent of the Kubios filter used? We visually inspected each recording for artifact when applying the filters and used the lowest filter setting possible to avoid augmenting the recording beyond the natural variations that may occur. The citations we used warned against too strong of filters as it may “over filter” the recording and lose natural variation. The following was added for clarification: The Kubios “low artifact correction” filter with a � 0.35 sec sensitivity to R-R abnormalities compared to the local average was used [12,13]. AUC calculation: I understood the rationale for computing the AUC using the Tai’s Mathematical Model; however, I wonder whether that AUC calculation provides glucose values as “arbitrary units” or “no units” (as certain AUC calculations [e.g., PMID: 14756916]). Could authors mention this aspect? The reviewer brings up a good point, the unit used in this model was “arbitrary units”, this has been added into the manuscript and is expressed as AU. The thermic effect of a 75g bolus of glucose was unlikely to have been completed within the 3- hour measurement window - therefore it is possible that some differences in the response may have been missed by not capturing the downward tail of the HRV response curve. Should this not warrant a mention? The reviewer makes a good point. The duration of the OGTT used was the standard two hours. However, we added the following to the limitation section: Future studies should extend the number of measures glucose time points beyond the two-hour mark in order to capture the downward tail of the OGTT and capture full glucose clearance. Moreover, did capillary glucose concentration values return to baseline? If not, do the authors believe this issue could partially explain the results (e.g., absence of associations)? If capillary glucose did not return to baseline levels after 2-h, glucose-stimulation could be influencing the results. I would suggest mention this issue. Capillary glucose concentration values did not return to baseline (Figure 4). We believe this was addressed with the change we made with the previous comment. Finally, could authors provide a figure showing the capillary glucose concentration and across time (i.e., the curve)? Thank you. Figure 4 was added for capillary glucose over time Does a protocol of repeated finger-prick collection add to within-subject variability? Capillary blood is notoriously difficult to standardize at each time point of collection, though it may relate to venous values. This is a good comment and we added the limitation of finger sticks with future work utilizing venipuncture. Lines 133-135: No information regarding missing data is provided. Although Table 2 included 18 participants, I noticed that Figures (1 – 3) showed 15 participants instead of 18. Please mention this issue. Three participants were dropped due to ECG error, they were removed from analysis and we accidentally left the total group in the table. Table 2 has been updated and the following was added: “Eighteen apparently healthy volunteers completed the study: ten males and eight females. Two males and one female were removed from data analysis due to artifact or ECG recording error, 15 total participants were analyzed, eight males and seven females.” Why was the menstrual cycle recorded/registered if it was not used for analyses? Did the authors include the menstrual cycle in the analyses (e.g., as a confounder factor for correlations)? If not, I would suggest placing Table 1 as supplementary material or embed it in Table 2. Menstrual cycle information was not entered into the correlation due to the low sample size and was used as observational data. Previous work in our lab suggested a relationship between HRV and menstrual cycle, so we collected the phase data as a participant characteristic in the event we observed a sex-based difference. New analysis: I would suggest repeating the analyses, including heart rate (in beats per minute). RHR correlation data was added to table 3 and results. Discussion section: Lines 173-175: This could be related to the low statistical power/sample size, rather than not an effect was observed. This issue deserves a mention. Sample size was added as a limitation to the limitation section. Lines 179-181: This threshold is commonly used when blood glucose concentration (i.e., vein samples) is obtained. As I mentioned previously, I would recommend emphasizing that capillary instead of vein glucose concentration was assessed. The following was edited: “The participants in this study were considered healthy, normal weight individuals with an average capillary FBG of 89.9 ± 8.2 mg/dL.” Limitation section: In my opinion, the following should be included: The small sample size should be mentioned in this section. The menstrual cycle should be mentioned as a potential limitation, as women were at different menstrual cycle statuses which could impact the results in an unknown manner. Glucose concentration was assessed by a finger-prick instead of vein collection. The following was changed in the limitations: “Though this study was a novel attempt to evaluate glucose regulation, it was not without limitations. This study used a small sample size, which is an inherit limitation regardless of significant findings. Future studies should use a more robust sample size to better corollate physical and physiological contributors to HRV based OGTT relationship. Furthermore, this study was not designed to control for menstrual cycle. Future studies should enroll female participants in a fashion to control for stage of menstrual cycle. This study used single-day HRV to predict same-day metabolic function; though appropriate for comparing to same-day OGTT, this value may be stronger when compared to a weekly average, given the levels of variability we observed in these markers. The measurement of glucose concentration in this study was performed using finger-prick, future projects should use vein collection to reduce standard error. Lastly, plasma insulin may provide additional insight for this study.” Attachments Attachment Submitted filename: PlosOneReviewer.docx https://doi.org/10.1371/journal.pone.0303346.r002
2 Apr 2024 Decision Letter - Hidetaka Hamasaki, Editor PONE-D-23-28922R1The relationship between heart rate variability and glucose clearance in healthy men and womenPLOS ONE Dear Dr. Nickel, 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 May 17 2024 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, Hidetaka Hamasaki 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 #2: 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 #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? 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 #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 #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 #2: I would like to thank the authors for taking the time to make revisions based on my comments and suggestions. Please find below my minor comments and suggestions: 1. I would suggest adding the lack of an exact fasting time to the limitations section, as the authors 'recommended' fasting for ≥ 12 hours, but cannot confirm it. 2. References 12 and 13 are cited to justify Kubios artifacts 'over filter' correction. I would suggest including the following citation (PMID: 31979367) as it addresses this issue. 3. How resting heart rate (RHR) was derived from the ECG signal should be added to the methods section. Additionally, please check the units of RHR in Table 3 (should be bpm instead of bmp). 4. I noticed that information concerning detrending, lambda, and interpolation rate was not provided in the Kubios software description. 5. In the Methods section, when referring to the Fast Fourier Transformation technique, I would suggest changing 'technique' to 'algorithm' for clarity. ****** 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 ******** [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.0303346.r003
Revision 2
22 Apr 2024 Author Response We have addressed the most recent revisions in the newest 'Reviewer comments' attachment: We re-examined the data files and found the participant fasting times were Total - 13.1 +/- 1.8 hours, Males - 12.6 +/- 2.1 hours, and Females - 13.7 +/- 1.2 hours. The following citation was added: Alcantara JMA, Plaza-Florido A, Amaro-Gahete FJ, Acosta FM, Migueles JH, Molina-Garcia P, et al. Impact of Using Different Levels of Threshold-Based Artefact Correction on the Quantification of Heart Rate Variability in Three Independent Human Cohorts. J Clin Med. 2020 Jan 23;9(2):325. The following was changed: Methods: HRV Analysis section The last five minutes of resting time points were analyzed for HRV and RHR. Bmp was changed to bpm. Detrending was set to smoothing priors with a smoothing parameter of 500, lambda of 0.035 Hz, and Interpolation rate of 4 Hz Attachments Attachment Submitted filename: Reviewer comments 2.docx https://doi.org/10.1371/journal.pone.0303346.r004
24 Apr 2024 Decision Letter - Hidetaka Hamasaki, Editor The relationship between heart rate variability and glucose clearance in healthy men and women PONE-D-23-28922R2 Dear Dr. Kliszczewicz, 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 will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, 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, Hidetaka Hamasaki Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0303346.r005
Formally Accepted
14 May 2024 Acceptance Letter - Hidetaka Hamasaki, Editor PONE-D-23-28922R2 PLOS ONE Dear Dr. Kliszczewicz, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset If revisions are needed, the production department will contact you directly to resolve them. If no revisions are needed, you will receive an email when the publication date has been set. At this time, we do not offer pre-publication proofs to authors during production of the accepted work. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few weeks to review your paper and let you know the next and final steps. Lastly, 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 customercare@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. Hidetaka Hamasaki Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0303346.r006

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