Effectiveness of adding inspiratory muscle training to a cardiac rehabilitation program in people with acute myocardial infarction revascularized by percutaneous coronary intervention (CARDIOINSPIRE): Study protocol for a randomized controlled trial

Jose M. Zuazagoitia-Lama-Noriega; A. M. Gómez-González; Jose A. Moral-Munoz

doi:10.1371/journal.pone.0343947

Peer Review History

Original SubmissionSeptember 29, 2025
19 Nov 2025 Decision Letter - Mansueto Neto, Editor Dear Dr. Zuazagoitia-Lama-Noriega, 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 Jan 03 2026 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. 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'. 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Please amend either the abstract on the online submission form (via Edit Submission) or the abstract in the manuscript so that they are identical. 6. Please upload a copy of Supporting Information Figure S1, S2, which you refer to in your text on page 36. 7. If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise. Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions? Reviewer #1: Yes Reviewer #2: Yes ******** 2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses??> Reviewer #1: Yes Reviewer #2: Partly ****** 3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable??> Reviewer #1: Yes Reviewer #2: No ****** 4. Have the authors described where all data underlying the findings will be made available when the study is complete??> The PLOS Data policy Reviewer #1: Yes Reviewer #2: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: Yes Reviewer #2: Yes ****** Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics. You may also provide optional suggestions and comments to authors that they might find helpful in planning their study. Reviewer #1: Interesting protocol. Some issues should be added. A primary end point should be clearly stated and sample size calculation performed on it Abstract: in the conclusion I would not put numbers Methods: probably more details about rehabilitation should be added in the appendix methods: ways of blinding should be better detailed methods: it should be added if block sizes were exploited Reviewer #2: Comments to the Author Overall, the protocol presents a relevant clinical question and outlines a study with potential to produce meaningful and applicable findings. However, as a study protocol, it is essential that all methodological components are described with complete transparency and precision to ensure reproducibility. Several elements—particularly the eligibility criteria, randomization procedures, allocation concealment, and statistical analysis plan—require clearer operational definitions and greater detail. Additionally, the rationale for specific intervention parameters—such as the choice of inspiratory muscle training at 70% of MIP—should be explicitly justified and supported by evidence to ensure appropriateness and feasibility. Strengthening these sections will enhance the robustness of the protocol and increase the reliability of the future trial. Major Comment — Eligibility Criteria and Terminology (“Myocardial Ischemia”) Page 6, line 121: The term “myocardial ischemia (MI)” is potentially ambiguous and requires clearer definition. It is not evident whether the authors refer to individuals with acute myocardial infarction or to those with conditions involving reduced myocardial perfusion (e.g., stable coronary artery disease). Please specify the objective inclusion criteria (e.g., diagnostic biomarkers, ECG findings, imaging evidence) to ensure accurate characterization of the study population. Additionally, clarify whether the sample includes participants undergoing elective procedures, emergency procedures, or both. If a more precise descriptor is warranted, please apply the updated terminology consistently throughout the manuscript, including the title, abstract, introduction, and the “Participants and Study Setting” section. Major Comment — Terminology: “Functional Capacity” vs. “Cardiorespiratory Fitness” Page 9, lines 169–170: In the Outcomes section, the term “functional capacity” is used to describe VO₂max obtained during maximal exercise testing. These measures are more accurately characterized as indicators of cardiorespiratory fitness rather than functional capacity in the clinical sense. I recommend replacing “functional capacity” with “cardiorespiratory fitness” in this section and ensuring that any earlier or subsequent uses of the term are revised for consistency and conceptual clarity. Major Comment — Clarification of Revascularization Terminology (PTCA vs. PCI) Page 6, line 109: The terminology used to describe the revascularization procedure (“percutaneous transluminal coronary angioplasty – PTCA”) appears potentially inaccurate or incomplete. Contemporary cardiology literature typically uses the broader term percutaneous coronary intervention (PCI), which encompasses both balloon angioplasty (PTCA) and stent implantation. Because the manuscript title and several sections refer specifically to PTCA, it remains unclear whether the study will include only patients treated with balloon angioplasty, those treated with PCI involving stents, or both types of coronary interventions. This distinction should be clearly specified in the Eligibility Criteria section. If the intention is to include all forms of PCI, the terminology should be updated consistently throughout the manuscript, including the title, abstract, introduction, and the Participants and Study Setting section, as well as all subsequent occurrences. Conversely, if the study is designed to include exclusively patients treated with PTCA, this should be explicitly stated and adequately justified, given that isolated PTCA is less common in contemporary clinical practice. Major Comment — Adoption of the CONSORT, SPIRIT, and CERT Frameworks In addition to the SPIRIT checklist for study protocols and the CONSORT guidelines for the forthcoming randomized clinical trial, I recommend incorporating the Consensus on Exercise Reporting Template (CERT) (doi:10.1136/bjsports-2016-096651). CERT will help ensure comprehensive reporting of exercise-related components in both the protocol and the final trial manuscript. Major Comment — Allocation Concealment Not Adequately Ensured The description of the allocation process suggests that group assignment may be predictable, which raises concerns regarding allocation concealment. Concealment must be ensured so that neither participants nor investigators involved in enrollment can foresee upcoming assignments. Please clarify the allocation procedure and describe the mechanism used to maintain adequate concealment (e.g., central randomization, sealed opaque envelopes). Notably, allocation concealment is conceptually distinct from blinding and must be addressed separately. This concern arises from the paragraph describing group allocation. Major Comment — Clarity in Random Sequence Generation The manuscript does not provide sufficient detail on how the random allocation sequence will be generated. Although Epidat 3.1 is mentioned, the specific method used (e.g., computer-generated random numbers, block randomization, stratification) is not described. Please specify how the software generates the random sequence, including any parameters used. Major Comment — Statistical Analysis The current statistical plan relies on multiple independent tests for within- and between-group comparisons. For a randomized trial with pre–post measurements, this approach does not adequately evaluate the group × time interaction. I recommend specifying a unified model (e.g., repeated-measures ANOVA or a linear mixed-effects model) to assess differential changes between groups over time. Additionally, the authors should explicitly state that analyses will follow the intent-to-treat principle and that the significance level will be set at 5% with 95% confidence intervals. Minor Comments — Clarifications and Reference Updates Page 4, line 79: Endurance and strength training are mentioned, but no supporting reference is provided. Please include an appropriate citation. Page 5, line 88: The citation of the study by Fabero-Garrido may give the impression that the sample included only individuals undergoing PTCA. However, the original study included optimally treated individuals with ischemic heart disease, regardless of revascularization status. Please revise to ensure accurate representation. Page 5, line 94: The abbreviation “MIP” appears for the first time. Please define it as “maximal inspiratory pressure (MIP)” at first mention. Minor Comment — Specification of Exercise Contraindications Pages 6–7, lines 126–127: The manuscript states that contraindications to exercise will be considered but does not list them. Please provide the specific contraindications or cite the guideline used to define them. Minor Comment — Justification of the IMT Protocol Intensity Page 8, lines 155–157: The inspiratory muscle training protocol (70% of MIP, 3 sets of 10 repetitions performing one daily training session four days a week) requires clearer justification. This intensity appears relatively high, and it is not clear whether this configuration has been tested in similar populations or shown to be effective and well tolerated. If supported by previous evidence, please cite the relevant studies. Otherwise, consider whether a more gradual progression of the training load—particularly during the initial sessions—might improve tolerance and adherence. Minor Comment — Appropriateness of the NYHA Scale Page 15, line 305: It is not clear whether all participants will have a diagnosis of heart failure. If not, the NYHA classification may not be the most appropriate tool for assessing dyspnea, as it is designed specifically for heart failure populations. For a broader cardiac sample, I recommend using an alternative validated instrument, such as the modified Medical Research Council scale (mMRC), which is applicable across different etiologies of dyspnea and may provide a more suitable assessment for this study. ****** 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: Fabrizio D'Ascenzo 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". 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Revision 1
31 Dec 2025 Author Response REVIEWER #1 RV: Some issues should be added. RV: 1. A primary end point should be clearly stated and sample size calculation performed on it. AA: We appreciate this observation and have clearly stated the primary endpoint, which is “Cardiorespiratory Fitness” The sample size calculation was performed according to the meta-analysis by Fabero-Garrido et al. (2024). This study established that people with ischemic heart disease who have undergone an Inspiratory Muscle Training program have a mean difference of 2.18 ml O2/kg/min with respect to the control group, and we want to find a deviation of 1 MET (3.5 ml O2/kg/min). The calculations were performed using the statistical software GPower 3.1, considering a confidence level of 95% and power of 80% in all cases. - Fabero-Garrido R, Del Corral T, Plaza-Manzano G, Sanz-Ayan P, Izquierdo- García J, López-De-Uralde-Villanueva I. Effects of Respiratory Muscle Training on Exercise Capacity, Quality of Life, and Respiratory and Pulmonary Function in People With Ischemic Heart Disease: Systematic Review and Meta-Analysis. PTJ: Physical Therapy & Rehabilitation Journal \| Physical Therapy [Internet]. 2024; RV: 2. Abstract: in the conclusion I would not put numbers. AA: Thank you very much for your suggestion. We have reviewed the entire abstract and have only left the number corresponding to the Clinical Trials registry, as this is a requirement of the journal's guidelines. RV: 3. Methods: probably more details about rehabilitation should be added in the appendix. AA: We have incorporated the Consensus on Exercise Reporting Template (CERT) as supporting information (S10 File) to include all the details of the rehabilitation and ensure that the exercise intervention can be replicated. RV: 4. Methods: ways of blinding should be better detailed. AA: In a specific section entitled “Blinding” (pages 19-20, lines 383-395), we have adequately detailed the blinding of all parties involved: participants, rehabilitation physicians, evaluators, physical therapist and nurse who will perform the intervention, and statistician who will analyze the data. The following text was added to the main document: “Participants will receive instruction about IMT from one of the rehabilitation physicians, who will be different from the one performing the assessments. Furthermore, none of the participants will know to which group they belong, since all of them will be given the same IMT device, but with a different training load. The physiotherapist and nurse who will conduct the CRP training sessions will not be involved in the allocation of participants. The statistical analysis will be carried out by a statistician of the research team who will not participate in the allocation, assessment or intervention process. In addition, the participants’ data will be provided anonymously. In the event of any adverse effect or circumstance that endangers the health of the participants, the researchers will be unblinded. If such a contingency arises, both a paper-based and an electronic record are always maintained and remain accessible to all authorized investigators.” RV: 5. Methods: it should be added if block sizes were exploited. AA: We thank the reviewer for this important observation. We have revised and significantly expanded the description of the random sequence generation process (page 18, lines 368-381). Each patient will be randomly assigned to either the intervention or control group (1:1 ratio) using a random sequence of numbers generated with the Simple Random Sampling module of Epidat 3.1 (open-access epidemiological analysis software developed by the Xunta de Galicia, Dirección Xeral de Saúde Pública). Specifically, to reach a sample size of N = 72, the software will generate random numbers that will identify the participants. Participants will be randomly assigned to the intervention group or control group based on the list of random numbers generated by the software. Although block sizes will not be exploited, this simple random assignment will ensure maximum unpredictability in the assignment of participants, preventing any prediction of future assignments. REVIEWER #2 Major Comments RV: 1. Major Comment — Eligibility Criteria and Terminology (“Myocardial Ischemia”). Page 6, line 121: The term “myocardial ischemia (MI)” is potentially ambiguous and requires clearer definition. It is not evident whether the authors refer to individuals with acute myocardial infarction or to those with conditions involving reduced myocardial perfusion (e.g., stable coronary artery disease). Please specify the objective inclusion criteria (e.g., diagnostic biomarkers, ECG findings, imaging evidence) to ensure accurate characterization of the study population. Additionally, clarify whether the sample includes participants undergoing elective procedures, emergency procedures, or both. If a more precise descriptor is warranted, please apply the updated terminology consistently throughout the manuscript, including the title, abstract, introduction, and the “Participants and Study Setting” section. AA: We greatly appreciate your feedback. We have replaced the term “myocardial ischemia” with “acute myocardial infarction” (code: BA41 from the International Classification of Diseases, 11th revision), which specifically defines the study population and, therefore, as you suggest, is more accurate. In addition, we have added as an inclusion criterion (page 6, line 124) that an emergency percutaneous coronary intervention has been performed. With these changes, it is clear that people with stable angina or those who have undergone a scheduled procedure will not be included. We have also updated all sections of the manuscript accordingly. RV: 2. Major Comment — Terminology: “Functional Capacity” vs. “Cardiorespiratory Fitness” Page 9, lines 169–170: In the Outcomes section, the term “functional capacity” is used to describe VO₂max obtained during maximal exercise testing. These measures are more accurately characterized as indicators of cardiorespiratory fitness rather than functional capacity in the clinical sense. I recommend replacing “functional capacity” with “cardiorespiratory fitness” in this section and ensuring that any earlier or subsequent uses of the term are revised for consistency and conceptual clarity. AA: Thank you very much for your comment. Indeed, the term “cardiorespiratory fitness” is more consistent, so we have replaced “functional capacity” with “cardiorespiratory fitness”. We have also revised the term throughout the rest of the document. RV: 3. Major Comment — Clarification of Revascularization Terminology (PTCA vs. PCI) Page 6, line 109. The terminology used to describe the revascularization procedure (“percutaneous transluminal coronary angioplasty – PTCA”) appears potentially inaccurate or incomplete. Contemporary cardiology literature typically uses the broader term percutaneous coronary intervention (PCI), which encompasses both balloon angioplasty (PTCA) and stent implantation. Because the manuscript title and several sections refer specifically to PTCA, it remains unclear whether the study will include only patients treated with balloon angioplasty, those treated with PCI involving stents, or both types of coronary interventions. This distinction should be clearly specified in the Eligibility Criteria section. If the intention is to include all forms of PCI, the terminology should be updated consistently throughout the manuscript, including the title, abstract, introduction, and the Participants and Study Setting section, as well as all subsequent occurrences. Conversely, if the study is designed to include exclusively patients treated with PTCA, this should be explicitly stated and adequately justified, given that isolated PTCA is less common in contemporary clinical practice. AA: We appreciate your suggestion and agree with it. We have changed the term “percutaneous transluminal coronary angioplasty (PTCA)” to “percutaneous coronary intervention (PCI)”. This clarifies the group of people we want to study which encompasses both balloon angioplasty (PTCA) and stent implantation. The terminology used in the manuscript in this regard has been modified accordingly. RV: 4. Major Comment — Adoption of the CONSORT, SPIRIT, and CERT Frameworks In addition to the SPIRIT checklist for study protocols and the CONSORT guidelines for the forthcoming randomized clinical trial, I recommend incorporating the Consensus on Exercise Reporting Template (CERT) (doi:10.1136/bjsports-2016-096651). CERT will help ensure comprehensive reporting of exercise-related components in both the protocol and the final trial manuscript. AA: We have incorporated the Consensus on Exercise Reporting Template (CERT) as Supporting Information (S10 File) to ensure comprehensive reporting of exerciserelated components. RV: 5. Major Comment — Allocation Concealment Not Adequately Ensured The description of the allocation process suggests that group assignment may be predictable, which raises concerns regarding allocation concealment. Concealment must be ensured so that neither participants nor investigators involved in enrollment can foresee upcoming assignments. Please clarify the allocation procedure and describe the mechanism used to maintain adequate concealment (e.g., central randomization, sealed opaque envelopes). Notably, allocation concealment is conceptually distinct from blinding and must be addressed separately. This concern arises from the paragraph describing group allocation. AA: We greatly appreciate your comments. We have rewritten the “Allocation Concealment” section (pages 18-19, lines 367-381) and separated it from the “Blinding” section (pages 19-20, lines 383-395) as you requested. We agree that a robust allocation concealment mechanism is fundamental to preventing selection bias. To ensure that the assignment is unpredictable and independent of the investigators involved in recruitment, we will implement the following actions: a) The randomization sequence will be generated by a team member who will not be involved in the clinical recruitment or assessment of participants, using Epidat 3.1 software. b) This independent researcher will prepare a set of identical, opaque, and carbon-lined envelopes. Each envelope will be sequentially numbered on the outside and it will contain the group assignment on a folded card inside. c) The envelopes will be opened by the rehabilitation physician only after the patient meets all eligibility criteria and provides written informed consent. The envelopes will be opened in strict numerical order, ensuring that the assignment for the next participant will remain unknown until the previous one is fully enrolled. RV: 6. Major Comment — Clarity in Random Sequence Generation. The manuscript does not provide sufficient detail on how the random allocation sequence will be generated. Although Epidat 3.1 is mentioned, the specific method used (e.g., computer-generated random numbers, block randomization, stratification) is not described. Please specify how the software generates the random sequence, including any parameters used. AA: Thank you very much again for the improvements you requested. Accordingly, the following text was added (page 18, lines 370-377): “Once included, each patient will be randomly assigned to either the intervention or control group (1:1 ratio) using a random sequence of numbers generated with the Simple Random Sampling module of Epidat 3.1 (open-access epidemiological analysis software developed by the Xunta de Galicia, Dirección Xeral de Saúde Pública). Specifically, to reach a sample size of n = 72, the software will generate a sequence that determines the group for each participant according to their order of enrollment. This simple random assignment will ensure maximum unpredictability in the assignment of participants, preventing any prediction of future assignments.” RV: 7. Major Comment — Statistical Analysis The current statistical plan relies on multiple independent tests for within- and betweengroup comparisons. For a randomized trial with pre–post measurements, this approach does not adequately evaluate the group × time interaction. I recommend specifying a unified model (e.g., repeated-measures ANOVA or a linear mixed-effects model) to assess differential changes between groups over time. Additionally, the authors should explicitly state that analyses will follow the intent-to-treat principle and that the significance level will be set at 5% with 95% confidence intervals. AA: Thank you for your valuable comment. We have specified that the data will be analyzed using a mixed-design ANOVA to assess differential changes between groups over time. And we have also established that an intention-to-treat analysis with multiple imputation will be implemented for missing data exceeding 5%; otherwise, a complete case analysis will be conducted. Furthermore, we have specified that the significance level will be set at 5% with 95% confidence intervals. Minor Comments — Clarifications and Reference Updates RV: 8. Page 4, line 79: Endurance and strength training are mentioned, but no supporting reference is provided. Please include an appropriate citation. AA: We have included the following reference that clearly highlights the obligation to include strength training and aerobic exercise in cardiac rehabilitation programs. - Brown TM, Pack QR, Aberegg E, Brewer LC, Ford YR, Forman DE, et al. Core Components of Cardiac Rehabilitation Programs: 2024 Update: A Scientific Statement From the American Heart Association and the American Association of Cardiovascular and Pulmonary Rehabilitation. Circulation [Internet]. 2024 Oct 29;150(18):e328–47. RV: 9. Page 5, line 88: The citation of the study by Fabero-Garrido may give the impression that the sample included only individuals undergoing PTCA. However, the original study included optimally treated individuals with ischemic heart disease, regardless of revascularization status. Please revise to ensure accurate representation. AA: Thank you very much for your comment. We have rewritten that sentence (page 5, line 87), specifying that Fabero-Garrido's study includes patients with ischemic heart disease so as not to give the impression that it only includes patients undergoing PTCA. RV: 10. Page 5, line 94: The abbreviation “MIP” appears for the first time. Please define it as “maximal inspiratory pressure (MIP)” at first mention. AA: We appreciate you pointing that out, and we have defined “maximal inspiratory pressure” for the first time. Minor Comment — Specification of Exercise Contraindications RV: Pages 6–7, lines 126–127: The manuscript states that contraindications to exercise will be considered but does not list them. Please provide the specific contraindications or cite the guideline used to define them. AA: Thank you for your insightful comment. We have added the main specific contraindications for starting cardiac rehabilitation in patients who have suffered an acute myocardial infarction and have added the corresponding bibliographic reference: - Protoview P, Vol B, Ringgold B. Guidelines for Cardiac Rehabilitation Programs, 6th Edition. ProtoView [Internet]. 2020 [cited 2025 Dec 19];2020(19):1–2. Minor Comment — Justification of the IMT Protocol Intensity RV: Page 8, lines 155–157: The inspiratory muscle training protocol (70% of MIP, 3 sets of 10 repetitions performing one daily training session four days a week) requires clearer justification. This intensity appears relatively high, and it is not clear whether this configuration has been tested in similar populations or shown to be effective and well tolerated. If supported by previous evidence, please cite the relevant studies. Otherwise, consider whether a more gradual progression of the training load— particularly during the initial sessions—might improve tolerance and adherence. AA: The next three studies, which involved coronary artery bypass graft surgery and coronary artery disease patients and used fairly similar IMT protocols in terms of sets, repetitions, weekly sessions, and inten Attachments Attachment Submitted filename: Response to Reviewers.pdf* https://doi.org/10.1371/journal.pone.0343947.r002
12 Feb 2026 Decision Letter - Mansueto Neto, Editor Effectiveness of adding inspiratory muscle training to a cardiac rehabilitation program in people with acute myocardial infarction revascularized by percutaneous coronary intervention (CARDIOINSPIRE): Study protocol for a randomized controlled trial PONE-D-25-40583R1 Dear Dr. Zuazagoitia-Lama-Noriega 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. For questions related to billing, please contact billing support . 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, Mansueto Gomes Neto, Ph.D Academic Editor PLOS One Additional Editor Comments (optional): Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions? Reviewer #1: Yes ******** 2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses??> Reviewer #1: Yes ****** 3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable??> Reviewer #1: Yes ****** 4. Have the authors described where all data underlying the findings will be made available when the study is complete??> The PLOS Data policy Reviewer #1: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: Yes ****** Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics. You may also provide optional suggestions and comments to authors that they might find helpful in planning their study. Reviewer #1: All comments have been addressed. authors should be complimented for performing a such complete review. I have no firther comments ****** 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: fabrizio d'ascenzo ******** https://doi.org/10.1371/journal.pone.0343947.r003
Formally Accepted
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