PONE-D-25-03031Pharmacoinvasive strategy versus fibrinolytic therapy in adults with ST-elevation myocardial infarction: a systematic review and meta-analysisPLOS ONE

Dear Dr. Goicochea-Lugo,

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.

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PLOS ONE

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Additional Editor Comments:

As explained below, I listed required and recommended changes for further considering this manuscript.

Required changes  primarily stem from Reviewer #1's concerns regarding the misinterpretation and misrepresentation of findings. Specifically, the authors must correct all instances where non-statistically significant differences are described as "possible" or "important" reductions. They should accurately reflect the null hypothesis findings and, if desired, discuss potential type II errors or the need for larger studies. Additionally, the manuscript must address the unclear prevalence statement on page 10 and remove unnecessary uses of "important" for statistically significant differences. Recommended changes , from Reviewer #2, involve clarifying methodological choices. While these are not strictly required for technical soundness, they would significantly strengthen the manuscript. These include justifying database selection, addressing the handling of studies with high risk of bias, explaining the chosen risk of bias threshold, clarifying heterogeneity assessment, detailing the application of MID thresholds in GRADE assessment, justifying the two-level downgrading of 30-day mortality, and discussing the impact of variability in time to PCI and gender distribution.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited 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

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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

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: PONE-D-25-03031 PLOS ONE Pharmacoinvasive strategy versus fibrinolytic therapy in adults with ST-elevation myocardial infarction: a systematic review and meta-analysis

Review

This is a systematic review and meta-analysis of randomised trials investigating a pharmaco-invasive strategy (fibrinolysis plus early coronary angiography with a view to angioplasty) versus a fibrinolytic therapy (fibrinolysis alone). Seven RCTs were identified, including a total of 3053 patients. No statistically significant difference in mortality was identified, but there was a reduction in reinfarction, unplanned revascularization and angina favouring the pharmaco-invasive strategy.

The systematic review appears to have been rigorously conducted and the statistical analyses sound. The results are however presented and interpreted incorrectly. Even in the abstract the authors state the following:

The PS [pharmaco-invasive strategy], compared to fibrinolysis, may have an important reduction on mortality (-5 per 1000; 95% CI: -16 to +10)

The manuscript is littered with these misrepresentations of findings where the null hypothesis cannot be rejected, described as ‘possible’ reductions. It seems to be a problem with interpretation and misrepresentation rather than a fatal flaw in the analysis, as such I think it can be remedied with what would be quite an extensive re-write. To be suitable for publication in any journal there needs to be a major revision. I would also suggest that some of the important forest plots are put into the main manuscript rather than the supplementary appendix.

Specific comments/questions:

1) On page 10, line 51-53 the authors state:

STEMI is a public health problem in both industrialized and developing countries with a prevalence that can reach up to 40%.

I am not sure what the authors mean here. This suggests that 40% of the population are having a STEMI at any one time. This needs to be corrected.

2) The repeated use of the word important for statistically significant differences between treatment groups is unnecessary and should be changed.

3) Where a statistically significant difference has not been identified stating that there may be an important difference between groups does not mean anything. It might be discussed that a larger patient population would be required to identify a difference and that there is a possibility of type II error. This requires correction in the results and discussion section.

4) Some of the forest plots for the important outcomes should be included in the main manuscript and not just in the supplementary appendix.

Reviewer #2: In this study, the authors conducted a systematic review and meta-analysis comparing the pharmacoinvasive strategy with fibrinolysis in adults with ST-elevation myocardial infarction. The study provides insights into the potential benefits and limitations of pharmacoinvasive management, particularly regarding reinfarction, revascularization, angina, and hospital stay length. My comments and suggestions to the authors are as follows:

1) While the review focuses exclusively on randomized controlled trials, observational studies could provide valuable real-world insights, particularly for safety outcomes such as bleeding and stroke. Could the authors clarify whether observational studies were considered at any stage of the study selection process?

2) The search strategy included PubMed, Web of Science, Embase, and Cochrane Library (CENTRAL), but no justification was provided for excluding other potentially relevant databases such as Scopus, LILACS, or CINAHL. Given that broader searches could reduce publication bias and increase comprehensiveness, could the authors clarify the rationale for limiting the search to these four databases?

3) The manuscript states that publication bias could not be statistically assessed due to the small number of studies (7 RCTs, 3,053 patients). However, the absence of a formal statistical assessment does not preclude a qualitative evaluation. Did the authors conduct any qualitative assessment of publication bias (e.g., reviewing asymmetries in reported outcomes, searching for unpublished trials, or assessing selective reporting)?

4) Figure 2 illustrates that some studies presented a high risk of bias, particularly in blinding of participants and allocation concealment. However, there is no explicit mention of whether studies with high risk of bias were automatically excluded or included in the meta-analysis without restrictions. The Discussion states that most studies had a low risk of bias, but it does not clarify how studies with high risk were handled. Were these studies included in the main analysis? If so, was any sensitivity analysis performed to assess their impact on the overall results?

5) The study considers a trial as 'low risk of bias' if at least 5 out of 7 domains in the Cochrane RoB 1.0 tool are classified as low risk. However, Cochrane guidelines do not recommend a fixed numerical threshold for determining overall risk, as certain domains (e.g., allocation concealment or outcome blinding) can have a disproportionately high impact on validity. Could the authors clarify why this specific threshold was chosen instead of a more qualitative domain-based assessment?

6) The manuscript defines I² <40% as 'not important heterogeneity.' However, according to Cochrane guidelines, an I² between 30-60% can indicate moderate heterogeneity. Could the authors clarify the rationale behind this threshold? Was this classification based on an alternative reference, such as the GRADE Working Group or specific cardiovascular studies? Additionally, some outcomes with I² >40% (e.g., long-term angina, I² = 76%) were not downgraded in certainty. Could the authors clarify why heterogeneity was not consistently considered when assessing the certainty of evidence?

7) The 'Certainty of Evidence' section states that imprecision was assessed according to GRADE guidelines, considering confidence intervals crossing MID thresholds and the number of events. While Table 2 presents the MID values used, it does not specify how they were determined or applied in the downgrading process. Could the authors clarify whether these MID thresholds were based on predefined literature standards, expert consensus, or empirical data from the included studies? Additionally, what specific criteria led to downgrading by one or two levels for each outcome?

8) In Table 2, the certainty of evidence for 30-day mortality was downgraded by two levels due to very serious imprecision. However, the reported risk ratio (RR 0.87, 95% CI: 0.59–1.27) suggests a potentially beneficial effect, though the confidence interval includes 1. Other outcomes with similarly wide confidence intervals were downgraded only one level. Could the authors clarify the rationale for downgrading mortality by two levels instead of one? Additionally, the Discussion states that the pharmacoinvasive strategy 'may have an important reduction on mortality,' yet the certainty of evidence for this outcome is classified as low. Could the authors clarify how they reconcile this conclusion with the statistical uncertainty in the mortality estimate?

9) The time from fibrinolysis to PCI varied significantly across studies (135 minutes to 16.7 hours), which could influence clinical outcomes. Considering that timely reperfusion is a key determinant of efficacy, did the authors assess whether this variability had any impact on treatment effect? If no formal stratified analysis was performed, could the authors clarify whether exploratory approaches (e.g., narrative assessment of trends across studies) were considered to address this clinically relevant issue?

10) The proportion of male participants varied widely across studies (20.4% to 85.9%), and prior research (e.g., the TRANSFER-AMI trial) has suggested potential gender-based differences in treatment response. Given this known variability, did the authors consider any assessment—either quantitative or qualitative—of how gender distribution might have influenced the results? If not, could the authors clarify how this potential confounder was accounted for in the overall interpretation?

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Reviewer #1: No

Reviewer #2: No

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PONE-D-25-03031R1Pharmacoinvasive strategy versus fibrinolytic therapy in adults with ST-elevation myocardial infarction: a systematic review and meta-analysisPLOS ONE

Dear Dr. Goicochea-Lugo,

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 Aug 30 2025 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,

Parisa Fallahtafti

Academic Editor

PLOS ONE

Journal Requirements:

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. 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

Reviewer #3: (No Response)

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

Reviewer #3: Yes

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

Reviewer #2: Yes

Reviewer #3: No

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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

Reviewer #3: Yes

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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

Reviewer #3: No

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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: After reviewing the authors’ responses, I would like to highlight remaining gaps that have not been adequately addressed and require further clarification.

The authors acknowledged the impossibility of performing a statistical assessment of publication bias due to the limited number of studies, and added in lines 129-130 that no qualitative suspicion of bias was observed. This revision is constructive; however, the qualitative assessment remains limited, as it was based solely on the absence of small industry-funded studies.

The criterion of considering “low risk of bias” as meeting 5 out of 7 domains was justified by referencing previous systematic reviews, with an appropriate citation (p. 15, lines 116-122), thus demonstrating alignment with established methodological precedents. Nonetheless, the authors’ response and the manuscript fail to discuss the relevance of critical domains such as random sequence generation or allocation concealment, whose qualitative weighting could influence the overall risk classification.

The correction to the definition of heterogeneity to align with Cochrane standards (I² 0–40% as “might not be important”) demonstrates responsiveness and adherence to current guidelines. However, the manuscript does not explain why outcomes with substantial heterogeneity – such as long-term angina (I² = 76%, p. 58, lines 241–247) – did not result in a downgrade of the certainty of evidence within the GRADE assessment (Table 2, p. 56).

The justification of MIDs was based on the literature, with citation of reference [19] (Armstrong et al., 2013; p. 65, line 137), a clinical trial comparing fibrinolysis and primary PCI, in an effort to align with GRADE guidance. However, reference [19] does not explicitly define MIDs or describe the process for determining them, and neither the response to the reviewer nor the manuscript (p. 16, lines 142–144) provides sufficient detail on how MID values were selected or derived. While data from [19] (e.g., a 1.9% difference in the composite outcome) may have been used to infer MID thresholds, the lack of transparency regarding this derivation process compromises methodological clarity.

Reviewer #3: Thank you dear editor for the opportunity to review this systematic review and meta-analysis comparing pharmacoinvasive strategy (PS) with fibrinolysis in ST-elevation myocardial infarction (STEMI). The topic is clinically relevant, particularly in resource-limited settings.

1. Title & Abstract

Title

The title implies a direct comparison between PS and fibrinolysis, but the PS intervention includes fibrinolysis followed by PCI. This could mislead readers into thinking PS excludes fibrinolysis (Page 1, Title).

Abstract

No mention of registration (PROSPERO) or risk of bias assessment tool (Page 1, Abstract).

Absolute effects lack context without baseline risks (Page 1, Lines 35–36).

The statement "PS has trivial or no effect on major bleeding" (Line 41) is overstated; the CI (-17 to +13) includes both trivial harm and benefit, making "no effect" speculative.

The abstract claims "high certainty" for reinfarction but omits downgrading reasons for other outcomes (Page 1, Lines 35–46).

Conclusion: States PS "may have an important reduction of mortality and stroke" but does not clarify that CIs include null effects (Mortality 95% CI: -16 to +10; Stroke: -10 to +2) (Page 1, Lines 44–46).

2. Introduction

Fails to justify why PS (fibrinolysis plus PCI) is compared to fibrinolysis alone instead of primary PCI, the gold standard (Page 13, Lines 66–72).

The response to Reviewer #1 (Page 2, Lines 1–3) revised STEMI prevalence to "over 3 million cases per year," yet the manuscript retains "prevalence that can reach up to 40%" (Page 46, Line 54).

The objective ("to compare PS versus fibrinolysis") is vague; it should specify efficacy/safety outcomes (Page 14, Line 77).

3. Methods

Eligibility Criteria

"Primary PCI performed 2–24 hours after fibrinolysis" (Page 14, Line 85) is ambiguous. Does "primary PCI" imply immediate PCI, conflicting with the 2–24h window?

"Cardiac failure," "angina," and "stroke" lack standardized diagnostic criteria (Page 14, Lines 88–92).

Search Strategy

Database Justification: No rationale for excluding Scopus/LILACS/CINAHL despite Reviewer #2's query (Page 15, Lines 96–99; Page 2, Response #2).

Study Selection & Data Extraction

The "diriment author" (Page 15, Line 105) role is not defined.

Risk of Bias (RoB)

Using a fixed threshold (5/7 low-risk domains = "low RoB") contradicts Cochrane guidelines, which discourage numerical thresholds (Page 15, Lines 121–122; Page 3, Response #5).

Figure 2 (Page 35) uses "+" and "○" without a legend.

Statistical Analysis

Defining I² <40% as "not important" conflicts with Cochrane (30–60% = moderate heterogeneity) (Page 49, Line 127; Page 3, Response #6).

Minimal important differences (MIDs) for outcomes (mortality: ±2/1000) lack justification. No citation or method for deriving MIDs is provided (Page 22, Lines 192–194; Page 3, Response #7).

Qualitative assessment ("no suspicion of bias") is inadequate without funnel plots or registry searches (Page 49, Lines 128–129).

Subgroup Analysis

Pre-specified subgroups ("bled at time of fibrinolysis") are not supported by included studies, yet this is not acknowledged (Page 50, Lines 134–135).

4. Results

Study Characteristics

Table 1 Errors:

"Time from fibrinolysis to PCI" for GRACIA-1 is listed as "16.7 hours (5.6)" without units (Page 20).

Rescue PCI rates in the fibrinolysis group (14–34.9%) are reported but not contextualized (Page 17, Line 180).

Risk of Bias

4/7 studies had high RoB in ≥1 domain, but sensitivity analysis (Page 26, Lines 257–261) was limited to supplemental material, not main text.

Meta-Analysis Results

Revascularization outcomes (30-day/longest) are labeled "high certainty" despite being based on only 2–3 studies (Page 22, Table 2).

Angina at longest follow-up had I²=76% but was not downgraded for inconsistency (Page 25, Line 251).

Mortality is downgraded twice for imprecision (RR 0.87, 95% CI: 0.59–1.27), but the Discussion claims PS "may have an important reduction" (Page 23, Table 2; Page 27, Line 271).

5. Discussion

Highlights PS benefits but downplays null findings (major bleeding: RR 0.91, 95% CI: 0.66–1.26) (Page 27, Lines 276–278).

Studies were from high-income countries (Canada, Europe), but implications are extended to LMICs without caveats (Page 28, Line 285).

Limitations

Time-to-PCI Variability: The impact of widely varying fibrinolysis-to-PCI times (135 min–16.7 hours) on outcomes is not discussed (Page 28, Lines 293–295).

Despite known gender disparities in STEMI, subgroup analysis was not performed due to "insufficient studies," but TRANSFER-AMI reported gender-specific data (Page 26, Lines 263–268; Page 4, Response #10).

6. Conclusion

Claims PS reduces mortality and stroke despite low certainty and CIs including null effects (Page 30, Lines 348–351).

Does not address uncertain evidence for cardiac failure/cardiogenic shock (very low certainty).

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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

Reviewer #3: No

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[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.

Pharmacoinvasive strategy versus fibrinolytic therapy alone in adults with ST-elevation myocardial infarction: a systematic review and meta-analysis

PONE-D-25-03031R2

Dear Dr. Goicochea-Lugo ,

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.

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Kind regards,

Parisa Fallahtafti

Academic Editor

PLOS ONE

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

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #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

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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

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6. Review Comments to the Author

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Reviewer #2: All points raised by the reviewers have been addressed, and the necessary clarifications have been incorporated into the manuscript. I am in favor of the manuscript being accepted for publication after this round of revision.

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Reviewer #2: No

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