Measuring Muscle Post-Exercise Oxygen Consumption in Individuals with a Family History of Diabetes

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Thank you for the interesting and actually reviewed manuscript. The paper addresses a relevant question regarding methodological concerns related to EPOC in muscle measurements taken by NIRS. Several methodological points remain unresolved and impact the acceptability of the conclusions for publication.

A major point concerns the sample size and power statistics. Although power statistics are presented in the context of the a priori power calculations with respect to the mVO₂max variable (lines 135-138), these are not presented in relation to the primary outcomes concerning EPOC. Because extreme variability was noted in the derivation of the mEPOC values presented in this manuscript, the lack of power statistics with respect to these values casts considerable doubt on the interpretation of null results (lines 22-25, 193-195). It should be noted that these values should either be formally incorporated into powerful statistical considerations or this manuscript should be presented as an exploratory pilot study with respect to these values.

The definition of family history of type 2 diabetes can also be made more precise. By including people with family members with either prediabetes, type 1, or type 2 diabetes in a single category (lines 60-63), etiological heterogeneity can potentially obscure relevant metabolic differences. While this caveat is briefly pointed out in a later section (lines 240-242), its relevance to the main comparisons has been overlooked.

There is a methodological issue with respect to how the incomplete EPOC data are handled. In six subjects, EPOC data were not recorded throughout the entire 10 minutes of recovery but were instead extrapolated linearly (lines 143-147). This is difficult to justify given the authors’ own claim that recovery of metabolism after exercise is not a linear process after the initial recovery period (lines 208-210). The authors should provide a clearer method for ascertaining the accuracy of extrapolated data or base the analysis only on what is empirically recorded. The technique utilized in the estimation and subsequent correction of the EPOC component associated with phosphocreatine also needs to be further clarified. Although the underlying reasoning behind the notion of utilizing the recovery constants in mVO₂max has been explained in the manuscript (between lines 213 & 220), the issue of the uncertainty of the estimation, as well as a deviation from the ³¹P-MRS technique, has been inadequately addressed. Furthermore, the protocol used to stimulate EPOC does not have objective controls regarding the intensity exercised by the subjects. The use of vocal cues and self-paced performance in wrist curls (pp. 96-99) does, in fact, introduce variations, and these could be responsible for the large variability observed in EPOC responses.

Crossed and uncrossed use of dominant and non-dominant hands across subjects (lines 68-69) is considered unlikely to affect the outcome, but the evidence is only reported in narrative form in the Discussion section (lines 262-268). Even a minimal quantitative confirmation in the Results section or in the appendix would help substantiate this matter. Some of the explanations of the mechanisms, especially those concerned with lactate build-ups and muscle temperature in the Discussion (lines 225-232), are tentative since corresponding data were not derived. These sections could be improved by distinguishing more clearly the hypotheses for future research and the conclusions derived from the data.

Finally, the conclusions seem somewhat more general than is supported by the results. The claims respecting the possible role of net mEPOC in the understanding of muscle or whole-body health (Conclusions, lines 280-286) could be more closely circumscribed.

Sincerely.

Author Response

Thank you for the interesting and actually reviewed manuscript. The paper addresses a relevant question regarding methodological concerns related to EPOC in muscle measurements taken by NIRS. Several methodological points remain unresolved and impact the acceptability of the conclusions for publication.

Response: We appreciate your interest in our paper.  We have found your suggestions to be useful, and we hope the revised document has been improved as a result. 

A major point concerns the sample size and power statistics. Although power statistics are presented in the context of the a priori power calculations with respect to the mVO₂max variable (lines 135-138), these are not presented in relation to the primary outcomes concerning EPOC. Because extreme variability was noted in the derivation of the mEPOC values presented in this manuscript, the lack of power statistics with respect to these values casts considerable doubt on the interpretation of null results (lines 22-25, 193-195). It should be noted that these values should either be formally incorporated into powerful statistical considerations or this manuscript should be presented as an exploratory pilot study with respect to these values.

Response: We agree that our paper is an exploratory pilot study in terms of evaluating the metabolic consequences of diabetes on muscle metabolism.  We have clarified this in our revised manuscript.  We feel the key importance of our paper is the NIRS method to evaluate post exercise muscle metabolism, which we feel we have adequate sample sizes to demonstrate.  

The definition of family history of type 2 diabetes can also be made more precise. By including people with family members with either prediabetes, type 1, or type 2 diabetes in a single category (lines 60-63), etiological heterogeneity can potentially obscure relevant metabolic differences. While this caveat is briefly pointed out in a later section (lines 240-242), its relevance to the main comparisons has been overlooked.

Response: We have expanded our discussion of family history of diabetes.  We realize the generality of our definition and have addressed this in the revised paper.

There is a methodological issue with respect to how the incomplete EPOC data are handled. In six subjects, EPOC data were not recorded throughout the entire 10 minutes of recovery but were instead extrapolated linearly (lines 143-147). This is difficult to justify given the authors’ own claim that recovery of metabolism after exercise is not a linear process after the initial recovery period (lines 208-210). The authors should provide a clearer method for ascertaining the accuracy of extrapolated data or base the analysis only on what is empirically recorded. The technique utilized in the estimation and subsequent correction of the EPOC component associated with phosphocreatine also needs to be further clarified. Although the underlying reasoning behind the notion of utilizing the recovery constants in mVO₂max has been explained in the manuscript (between lines 213 & 220), the issue of the uncertainty of the estimation, as well as a deviation from the ³¹P-MRS technique, has been inadequately addressed. Furthermore, the protocol used to stimulate EPOC does not have objective controls regarding the intensity exercised by the subjects. The use of vocal cues and self-paced performance in wrist curls (pp. 96-99) does, in fact, introduce variations, and these could be responsible for the large variability observed in EPOC responses.

Response: Several concerns are presented here.  We used a simple linear extrapolation for the missing data as the missing points are in the later stages of the recovery curve.  In this portion of the curve the data are very close to linear and a more complex estimation will not provide markedly different estimates. 

The use of the mVO2max to estimate the contribution of PCr resynthesis to EPOC has been clarified.  Prior studies have shown PCr recovery curves to be exponential and the coefficients of variation for the PCr recovery curves as well as the mVO2 (from NIRS) recovery curves is quite good (8-10%). 

We agree that the exercise chosen was not very precise.  It was voluntary maximal exercise in naïve subjects.  We have addressed this aspect of the study in the revised document.  We do feel that this type of exercise is perhaps more realistic of what people would do in ‘real life’ than more controlled experiments. 

Crossed and uncrossed use of dominant and non-dominant hands across subjects (lines 68-69) is considered unlikely to affect the outcome, but the evidence is only reported in narrative form in the Discussion section (lines 262-268). Even a minimal quantitative confirmation in the Results section or in the appendix would help substantiate this matter. Some of the explanations of the mechanisms, especially those concerned with lactate build-ups and muscle temperature in the Discussion (lines 225-232), are tentative since corresponding data were not derived. These sections could be improved by distinguishing more clearly the hypotheses for future research and the conclusions derived from the data.

Response: We agree that the crossed and uncrossed use of hands should not be important to the results.  We have addressed this issue in the results of the revised paper as well as in the discussion. 

Finally, the conclusions seem somewhat more general than is supported by the results. The claims respecting the possible role of net mEPOC in the understanding of muscle or whole-body health (Conclusions, lines 280-286) could be more closely circumscribed.

Response: This is a preliminary exploratory study and the revised manuscript has softened its conclusions as suggested.

Reviewer 2 Report

Comments and Suggestions for Authors

Dear Authors,

This study have serious flaws that must be improved.

Comments for author File: Comments.pdf

Comments on the Quality of English Language

Grammatical mistakes have been made, and these must be corrected.

Author Response

Better explain study aims and hypotheses

Response: We have revised our introduction to clarify the study aims and hypotheses

Fitness levels of the subjects

Response: We have clarified the discussion of fitness level.  We chose the forearm muscles for this study.  Typically, forearm muscles are not used in regular exercise activities, and thus do not reflect training status.  In the past we have used the forearm muscles as an ‘activity independent’ muscles and the leg muscles as ‘activity dependent’ muscles.  For this reason, we feel the lack of quantification of physical activity level in this study was appropriate.  We can state that all subjects were low to moderately physically active by self-report. 

Type of diabetes is not specified, no mention of gestational diabetes

Response: We have expanded our discussion and rationale for including diabetes in general.  We do not have accurate measures of gestational diabetes, although we agree that this would be a fascinating topic to address in future studies.  

Should have measured insulin or glucose

Response: We have addressed this limitation in our revised discussion.  While measuring insulin and or glucose levels may have added to the study, we feel in young subjects these values are unlikely to be different enough between groups to be useful. 

Reviewer 3 Report

Comments and Suggestions for Authors

First of all, I would like to thank you for invited to read the document.

The authors have done an excellent job. Each of the comments shared are intended to improve the study.

The comments can be found in the PDF document.

Also, some of the comments on some of the points that need to be reworded in the paper are shared below:

Title

It´s suggested that the title be adapted to comply with the rules.

Furthermore, the title is too general for having evaluated only 14 people.

It is suggested that “exploratory study” be added.

Introduction

The introduction needs to delve deeper into the physiological processes related to COPD and each of the variables analyzed. It should also detail how mitochondrial capacity works when exposed to exercise in healthy people and those with diabetes to provide greater support for the theoretical basis of the research.

It is suggested that the importance of incorporating new technologies such as NIR be highlighted.

In addition, it would be necessary to specify the effects of exercise on women's health and the physiological adaptations that occur when VO2max is assessed.

The introduction needs to be strengthened with greater theoretical foundations from the available scientific evidence. 

Furthermore, the introduction is too short and needs to be expanded.

Line 33-35. It´s suggested that references be added to support the conceptual foundations of the research.

Material and method

Participants

Certain situations need to be specified regarding the participants:

- The women recruited had other health conditions that needed to be taken into account.
- The women recruited had low, moderate, or high levels of physical activity.
- Power tests were performed to determine the sample size.
- They were randomly distributed or assigned to each group. 
- Which institution granted ethical approval
- What is the explanation for recruiting women aged 19-21? Specifying the reasons for selection could help to understand the study more clearly.

Experimental design

It´s suggested that the procedure and experimental design of the study be explored in greater depth.

In other words, explain in detail, step by step, the time taken to perform each test, under what conditions, location, time, etc. If any specific warm-up was performed, it would be necessary to detail it.

Finally, we suggest adding a figure that graphically explains the experiment. This can help the reader understand the objective of the study more clearly.

Analysis

The statistical analysis does not clearly explain the power analyses.

Furthermore, there is no mention of whether the data followed a normal distribution.

Effect size tests were performed.

Results

It´s suggested that a table with all the data be added to the results in order to understand the descriptive statistics and p-values.

Furthermore, it is unclear which results showed statistically significant differences.

In addition, if it was accepted that 7 was a sufficient number for the study to be carried out with each group, this reduced the statistical power, the risk of overfitting, and the lack of representativeness

Discussion

The discussion seems to be more of an introduction that theoretically substantiates the effects of exercise with EPOC.

The discussion needs to be restructured and approached from the perspective of the results, the participants evaluated (women), the variables analyzed, and the small sample size evaluated.

Finally, it is suggested that the conclusions that are not directly derived from the variables and results obtained in this study be revised. It is suggested that the focus be on describing each variable according to the available scientific evidence.

Conclusions

The conclusions overestimate the use of NIR and do not focus on responding to the study's objective, which was to compare EPOC in the forearm muscles of young adults with and without a family history of diabetes.

In addition, the study could benefit from adding some subsections, one on limitations and future prospects and another on practical applications derived from the study.

References

It´s suggest reviewing the guidelines for preparing references according to the MDPI format.

The references do not comply with the format.

 

Finally, the comments made are intended to improve the quality of your work

Comments for author File: Comments.pdf

Author Response

First of all, I would like to thank you for invited to read the document.

 

The authors have done an excellent job. Each of the comments shared are intended to improve the study.

Response: We are glad the reviewer enjoyed reading our paper.  We have used the suggestions to revise the paper, which we feel has been improved as a result.

The comments can be found in the PDF document.

Also, some of the comments on some of the points that need to be reworded in the paper are shared below:

Title

It´s suggested that the title be adapted to comply with the rules.

Response: The title as been revised

Furthermore, the title is too general for having evaluated only 14 people.

Response: The title as been revised

It is suggested that “exploratory study” be added.

Introduction

The introduction needs to delve deeper into the physiological processes related to COPD and each of the variables analyzed. It should also detail how mitochondrial capacity works when exposed to exercise in healthy people and those with diabetes to provide greater support for the theoretical basis of the research.

Response: The introduction has been revised to expand the topic of diabetes and mitochondrial function.  The literature is a bit ‘complex’ and thus we mostly refer to review articles that cover the topic in greater detail. 

It is suggested that the importance of incorporating new technologies such as NIR be highlighted.

Response: We agree that highlighting the NIRS methodology might be highlighted more than it is, and this has been included in the revised paper. 

In addition, it would be necessary to specify the effects of exercise on women's health and the physiological adaptations that occur when VO2max is assessed.

Response: We are not sure how to address this comment.  Clearly women’s health is important (as is mens health) and studies like ours that test women are important.  The effect on health of a single exercise session are perhaps limited, but the benefits of regular exercise are clear.  And in this study the method of evaluating the effects of exercise may be used to better design or understand exercise training programs.

The introduction needs to be strengthened with greater theoretical foundations from the available scientific evidence. 

Response: We have revised the introduction to provide more background for the study. 

Furthermore, the introduction is too short and needs to be expanded.

Response: We have revised the introduction to provide more background for the study.  We do feel that in general introductions should be as short as possible, with most of the background and discussion being presented in the discussion section. 

Line 33-35. It´s suggested that references be added to support the conceptual foundations of the research.

Response: The revised paper includes additional references.

Material and method

Participants

Certain situations need to be specified regarding the participants:

- The women recruited had other health conditions that needed to be taken into account.
- The women recruited had low, moderate, or high levels of physical activity.
- Power tests were performed to determine the sample size.
- They were randomly distributed or assigned to each group. 
- Which institution granted ethical approval
- What is the explanation for recruiting women aged 19-21? Specifying the reasons for selection could help to understand the study more clearly.

Response: We have added more rationale to the methods section concerning the subjects and sample size

Experimental design

It´s suggested that the procedure and experimental design of the study be explored in greater depth.

Response: We have expanded the methods section as recommended.

In other words, explain in detail, step by step, the time taken to perform each test, under what conditions, location, time, etc. If any specific warm-up was performed, it would be necessary to detail it.

Response: We have expanded the methods section as recommended.

Finally, we suggest adding a figure that graphically explains the experiment. This can help the reader understand the objective of the study more clearly.

Response: We have relocated our figure one and provided more information on the experimental protocol.  

Analysis

The statistical analysis does not clearly explain the power analyses.

Response: We have revised our paper to be an pilot exploratory study, and have expanded our power calculations and analysis. 

Furthermore, there is no mention of whether the data followed a normal distribution.

Response: We have addressed this in our revised paper

Effect size tests were performed.

Response: We have discussed effect sizes in our revised paper

Results

It´s suggested that a table with all the data be added to the results in order to understand the descriptive statistics and p-values.

Response: We have not included a table of results because we feel that such a table would duplicate the information included in the figures.  We have included more p values in the revised results.

Furthermore, it is unclear which results showed statistically significant differences.

Response: We have revised the paper to address this concern, and more clearly present the statistical results.

In addition, if it was accepted that 7 was a sufficient number for the study to be carried out with each group, this reduced the statistical power, the risk of overfitting, and the lack of representativeness

Response: We have revised the paper to be a pilot exploratory study and use the current sample sizes to estimate power and sample sizes for future studies.  

Discussion

The discussion seems to be more of an introduction that theoretically substantiates the effects of exercise with EPOC.

Response: We have revised the discussion to include more comparisons of our data to prior studies. 

The discussion needs to be restructured and approached from the perspective of the results, the participants evaluated (women), the variables analyzed, and the small sample size evaluated.

Response: We have revised the paper to address these concerns

Finally, it is suggested that the conclusions that are not directly derived from the variables and results obtained in this study be revised. It is suggested that the focus be on describing each variable according to the available scientific evidence.

Response: We have revised the discussion to include more comparisons of our data to prior studies. 

Conclusions

The conclusions overestimate the use of NIR and do not focus on responding to the study's objective, which was to compare EPOC in the forearm muscles of young adults with and without a family history of diabetes.

Response: We have revised our conclusions to focus on the NIRS methodology, which should help address the concern of the reviewer. 

In addition, the study could benefit from adding some subsections, one on limitations and future prospects and another on practical applications derived from the study.

Response: We have revised the conclusions to address the two main areas suggested by the reviewer.

References

It´s suggest reviewing the guidelines for preparing references according to the MDPI format.

The references do not comply with the format.

Response: We have tried to use the appropriate endnote format for MDPI

 

Finally, the comments made are intended to improve the quality of your work

Response: We appreciate the efforts of the reviewer and hope that the revised paper has been sufficiently improved. 

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Thank you very much for submitting the revised manuscript and for your thoughtful responses to the reviewers. The revisions have significantly improved the work. You've enhanced scientific transparency and interpretability by explicitly framing the study as an exploratory pilot, expanding the discussion of methodological limitations, and appropriately tempering the conclusions. The manuscript now presents a coherent, justified methodological contribution regarding the use of NIRS to assess post-exercise muscle oxygen consumption.

Most of the major concerns from the initial review are now addressed. Remaining issues are minor and mainly relate to clarity in presentation and wording rather than experimental design or data validity.

I have also considered the manuscript suitable for publication after some minor revisions. Please make a final, careful pass to ensure terminological consistency, clarity in the methods, and precision in the language throughout.

I appreciate the opportunity to review your work and wish you success with publication.

Sincerely

Author Response

Thank you very much for submitting the revised manuscript and for your thoughtful responses to the reviewers. The revisions have significantly improved the work. You've enhanced scientific transparency and interpretability by explicitly framing the study as an exploratory pilot, expanding the discussion of methodological limitations, and appropriately tempering the conclusions. The manuscript now presents a coherent, justified methodological contribution regarding the use of NIRS to assess post-exercise muscle oxygen consumption.

Most of the major concerns from the initial review are now addressed. Remaining issues are minor and mainly relate to clarity in presentation and wording rather than experimental design or data validity.

I have also considered the manuscript suitable for publication after some minor revisions. Please make a final, careful pass to ensure terminological consistency, clarity in the methods, and precision in the language throughout.

I appreciate the opportunity to review your work and wish you success with publication.

 

Response: We appreciate the efforts of the reviewer to evaluate our paper.  We have edited the paper to enhance clarity, and we have added a limitations section in the discussion.

 

Reviewer 2 Report

Comments and Suggestions for Authors

Dear authors,

You should provide several references or data to support the claim that fitness level does not influence the metabolic rate of the forearm musculature after exercise. Subjects should have reported whether or not they were involved in activities involving the upper body. Regarding diabetes history, the different types of diabetes are not comparable. The inclusion or exclusion criteria for selecting the number of participants in this study must be much more rigorous than self-reporting data.  

Author Response

You should provide several references or data to support the claim that fitness level does not influence the metabolic rate of the forearm musculature after exercise. Subjects should have reported whether or not they were involved in activities involving the upper body. Regarding diabetes history, the different types of diabetes are not comparable. The inclusion or exclusion criteria for selecting the number of participants in this study must be much more rigorous than self-reporting data.  

 

Response: We appreciate the comments of the reviewer.  We have added references on the differences between the arms and legs of subjects who have not been performing arm training.  The methods have been revised to clearly indicate that none of the participants perform regular arm exercises.

Response: The revised paper also includes a limitations section where we include discussion of the classification of the subjects relative to family history of diabetes. 

Reviewer 3 Report

Comments and Suggestions for Authors

First, I would like to thank you for inviting me to read the document again.

The authors have done an excellent job. They have improved the document with some of the recommendations made.

However, there are certain observations that have not yet been addressed. These are:

- The introduction should go into greater depth on the physiological processes related to COPD and each of the variables analyzed. It should also detail how mitochondrial capacity works when exposed to exercise in healthy people and people with diabetes to better support the theoretical basis of the research.

- In addition, the introduction is still too short and should be expanded to explain the physiological processes in greater detail. 

- What is the reason for recruiting women between the ages of 19 and 21? Specifying the reasons for the selection could help to better understand the study.

- It is suggested that a figure be added to explain the experiment graphically. This may help the reader better understand the objective of the study.

- It is suggested that a table with all the data be added to the results in order to understand the descriptive statistics and p-values. It is unclear which results showed statistically significant differences.

- How statistical power, the risk of overfitting, and the lack of representativeness were addressed with the selected sample.

- The discussion seems to be more of an introduction that theoretically substantiates the effects of exercise with COPD. The discussion needs to be restructured and approached from the perspective of the results, the participants evaluated (women), the variables analyzed, and the small size of the sample evaluated.

- The study could benefit from adding some subsections, one on limitations and future perspectives and another on practical applications derived from the study.

- It is suggested that the guidelines for preparing references according to the MDPI format be reviewed. The references still do not comply with the format.

 

Finally, the comments made are intended to improve the quality of your work

Author Response

First, I would like to thank you for inviting me to read the document again.

The authors have done an excellent job. They have improved the document with some of the recommendations made.

Response: We appreciate the comments of the reviewer. 

However, there are certain observations that have not yet been addressed. These are:

- The introduction should go into greater depth on the physiological processes related to COPD and each of the variables analyzed. It should also detail how mitochondrial capacity works when exposed to exercise in healthy people and people with diabetes to better support the theoretical basis of the research.

Response: We have revised the introduction to include more detail on mitochondria and type 1 or type 2 diabetes (we did not test anything related to COPD). 

- In addition, the introduction is still too short and should be expanded to explain the physiological processes in greater detail. 

Response: We feel the introduction should be as short as possible, while providing enough information to explain to the reader the purpose of the study. 

- What is the reason for recruiting women between the ages of 19 and 21? Specifying the reasons for the selection could help to better understand the study.

Response: We tested young women who where an easily available cohort.  These participants should be healthy and should not have developed diabetic symptoms.  Thus any difference between our groups could be assigned to genetic or epigentic characteristics that could be related to the future development of diabetes. 

- It is suggested that a figure be added to explain the experiment graphically. This may help the reader better understand the objective of the study.

Response: We are not sure how to best answer this question.  We have revised the paper to put figure one in the methods section.  The yellow text boxes in the figure indicate the three protocols performed and the order in which they were performed.  Does the reviewer want a photo of the arm and the experimental equipment?  We currently don’t have an appropriate picture of our set up. 

- It is suggested that a table with all the data be added to the results in order to understand the descriptive statistics and p-values. It is unclear which results showed statistically significant differences.

Response: The text of the results includes p values for comparisons.  We felt we should not repeat data that is in a figure with a new table.  

- How statistical power, the risk of overfitting, and the lack of representativeness were addressed with the selected sample.

Response: We have handled our low statistical power by using terminology that is general enough not to imply strong inferences.  

- The discussion seems to be more of an introduction that theoretically substantiates the effects of exercise with COPD. The discussion needs to be restructured and approached from the perspective of the results, the participants evaluated (women), the variables analyzed, and the small size of the sample evaluated.

Response: The revised paper includes a section on limitations to the study.  This study evaluated a family history of diabetes and did not test people with COPD. 

- The study could benefit from adding some subsections, one on limitations and future perspectives and another on practical applications derived from the study.

Response: This has been done.

- It is suggested that the guidelines for preparing references according to the MDPI format be reviewed. The references still do not comply with the format.

Response: We tried to use the correct endnote reference format.  This can easily be changed once we have the right format.

 

Finally, the comments made are intended to improve the quality of your work

Response: We appreciate the comments of the reviewer

Round 3

Reviewer 2 Report

Comments and Suggestions for Authors

Dear authors,

All the suggestions have been corrected. However, I would like to emphasise that this method is an indirect measurement of oxygen consumption, so strong statements should be avoided.

Author Response

All the suggestions have been corrected. However, I would like to emphasise that this method is an indirect measurement of oxygen consumption, so strong statements should be avoided.

 

Response: We have revised the paper to indicate that the NIRS method is a relative measure of muscle oxygen consumption.  This means that changes in the NIRS signals are a result of muscle metabolism.  However, we do feel that the NIRS method is a direct measure of oxygen consumption, as the signal changes are a result of changes in oxygen concentrations.  We hope this revision is helpful to the reader and is satisfactory to the reviewer. 

 

Reviewer 3 Report

Comments and Suggestions for Authors

First of all, I would like to thank you for invited to read the document.

The authors have done an excellent job. The authors have been able to resolve all of my concerns and observations.

He considered that substantial modifications had been made to the document, which improved its methodological quality. 

I believe the document meets the quality standards for publication in the journal.

 

 

Author Response

We appreciate the time and effort the reviewer made to look at our paper once again.