Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: REGIONAL INFECTIOUS RISK PREDICTION OF COVID-19 BASED ON GEO-SPATIAL DATA
Review round: 2
Reviewer: 2

Output:
Basic reporting: -
Experimental design: -
Validity of the findings: -
Additional comments: The manuscript is substantially improved but the English language needs to improve further. The use of zero epidemic data is relatively common in predicting the risk of a disease or disease outbreak in epidemiology. The authors have added and cited literature works in the Introduction, however, the related work surveyed needed to be connected together and discussed in an organized and concise manner. The background on the COVID-19 timeline in mainland China in Introduction should be succinctly described with the essential facts to highlight the problem the paper would like to address only. The synthesized information on the problem described in the introduction, the findings from the current study with the supporting literature, should be wrapped up in both the discussion and conclusion sections.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: REGIONAL INFECTIOUS RISK PREDICTION OF COVID-19 BASED ON GEO-SPATIAL DATA
Review round: 3
Reviewer: 1

Output:
Basic reporting: The revised has been correctly and the manuscript is suitable for publication
Experimental design: it is good
Validity of the findings: it is good
Additional comments: the revised has been correctly and the manuscript is suitable for publication


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: IDENTIFICATION OF L-ASPARAGINASES FROM STREPTOMYCES STRAINS WITH COMPETITIVE ACTIVITY AND IMMUNOGENIC PROFILES: A BIOINFORMATIC APPROACH
Review round: 1
Reviewer: 1

Output:
Basic reporting: Good
Experimental design: Good
Validity of the findings: Good
Additional comments: Further genetic engineering studies on L-aspa is highly appreciable!


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: IDENTIFICATION OF L-ASPARAGINASES FROM STREPTOMYCES STRAINS WITH COMPETITIVE ACTIVITY AND IMMUNOGENIC PROFILES: A BIOINFORMATIC APPROACH
Review round: 1
Reviewer: 2

Output:
Basic reporting: The manuscript by Gonzales-Torres et al addresses an important need, namely, that of identifying a new asparaginase (ASNase) that would have clinical advantages over the currently approved ASNases (which are anti-leukemic biologic drugs). However, the work has major deficiencies that detract from its impact.

This same group proposed in 2012 that an ASNase from Rhizobium etli (ReAII) has ‘therapeutic potential’ (Lines 84-88). This assertion is perplexing since according to the 2012 paper, ReAII has a Km value 600-fold higher than that of EcAII (Table 2 of the 2012 paper) – see point #4 below of ‘Major Issues’ section. In line 214 the authors write that ‘ReAII hydrolyzes L-asparagine as similar levels to EcAII, but with lower activity’ (and site the 2012 paper). This statement gives this reviewer pause, since it demonstrates a total misunderstanding of what type of activity is required for clinical efficacy. We need to care less about the rate of Asn hydrolysis when [Asn] is in the millimolar range. The only relevant number is the rate of Asn hydrolysis at physiological [Asn], which is 50 micromolar.

Major issues
1.	The authors fail to be explicit about what properties would make an asparaginase a suitable anti-cancer drug. They note, correctly, the importance of identifying new ASNases that are ‘less toxic and less immunogenic’ (line 90). However, the authors throughout the manuscript fail the mention the concept of ‘Km value’ and that it is imperative for the ASNase to have a Km value in the low micromolar range.
2.	When searching for less immunogenic ASNases, it is puzzling that the authors do not discuss searching mammalian genomes. What is the rationale for focusing on yet another bacterium, when the current ASNases are bacterial and are highly immunogenic? Why not include mammalian ASNases in the search, since, one can make the assumption, that a more human-like ASNase would likely be less immunogenic than a more distant ASNase.
3.	E. coli has several ASNases. The clinically used one, EcAII is structurally very similar to EcAI. However, whereas EcAII has the required low Asn Km value, EcAI does not. Therefore, any bioinformatic search for a new ASNase must be able to distinguish between a low Km (clinically relevant) and a high Km (clinically irrelevant) ASNase. The authors need to include a section on how the bioinformatic tools that they use make this differentiation (if they do). If the tools do NOT make this differentiation, that this work is largely not helpful since it misses the top criterium for an efficient ASNase. If the authors believe that by adding EcAI to the phylogenetic analysis this was actually done, they are asked to be more explicit about it. Also, please discuss the presence of a periplasmic secretion sequence in EcAII but not in EcAI, and whether this can act as a differentiator between Type I and Type II ASNases (and as such, predict ASNases with low Km value). The authors hint at this (Line 198), but if so, it needs more explicit discussion.
4.	As discussed above, Km is the most important parameter for clinical relevance. It is unclear why the authors include ReAII in their analysis since it has a Km that is way too high.
5.	The authors write that ASNases with sequences homologous to that of ScAII (S. coelicolor type II) are in the same family as that of ReAII. In other words, those ASNases in family PF06089.11 are, to my understanding, not suitable for clinical use based on a predicted high Asn Km value. So why are these even considered in this work?
6.	The authors find that the ReAII family (PF06089.11) is predicted to be less immunogenic than the EcAII family (PF00710.11). Assuming this is correct, it does not suggest that PF06089.11 family members be tested since they would be predicted to have a high Km, and hence, clinically, irrelevant.
7.	This reviewer sees no value in the protein structure predictions. Can these predictions say something about the Km value? I think not. If the authors disagree, please explain how these data would inform the selection of an ASNase to test.
8.	At the end of the day, the proof of the pudding is in the eating. In other words, the authors need to pick the ‘best’ ASNase based on the predictions of all of the programs that they ran, express it, and confirm that it has the required low Km value. Without such confirmatory work, the value of this report is deemed low.

Minor issues
1.	Line 51: there are actually 4, not 3 ASNase formulations currently available. A new PEGylated EcA formulation, which is different to Oncaspar by only having a different linker between enzyme and PEG, has been recently approved.
2.	Line 53: In the US, Elspar (EcAII) is not used anymore, and Oncaspar (EcAII-PEG) has become the first line treatment.
3.	Line 61: please look into liver toxicity as well.
4.	Line 71: please explain why you connect the glutaminase co-activity with allergic reactions. I can understand why the bacterial origin would cause an allergic reaction, but why do you include the glutaminase activity. Of course, the glutaminase activity is likely to be behind many of the other toxicities seen with asparaginases (but not immunogenicity).

Grammar/English suggestions
1.	The word ‘Selection’ in the title is misleading since it implies some sort of an experimental selection assay. A more appropriate word would be ‘Identification’.
2.	Line 27; move ‘predicted’ to the front; i.e. ‘Based on it predicted low immunogenicity…..’
3.	Line 69; these ‘enzymes’ should be these ‘antibodies’
4.	Line 84; typo; ASNasa  ASNase
5.	Line 138; DRB1*11:01 is listed twice.
Experimental design: Included above
Validity of the findings: Included above
Additional comments: No additional comments


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: IDENTIFICATION OF L-ASPARAGINASES FROM STREPTOMYCES STRAINS WITH COMPETITIVE ACTIVITY AND IMMUNOGENIC PROFILES: A BIOINFORMATIC APPROACH
Review round: 1
Reviewer: 3

Output:
Basic reporting: The authors use appropriate concise language and provide a relevant introduction discussion that describes the current state of the field and limitations to current asparaginase therapy during the treatment of leukemias. The figure legends and labels are appropriate and clear.
Experimental design: The authors use sophisticated methods for their research objective aiming to identify a new asparaginase source that can be less immunogenic relative to currently used preparations. However, there are a few areas of opportunity to clarify their approach using the Immune Epitope Database (IEDB). In particular, with regards to the following:

1.	For epitope density (ED) estimation, the equation used includes a parameter “Predicted epitope” which is not clear. Is this the CPR of the predicted epitope? If so, it should be clarified.

2.	For Table 2:
a.	The authors should clarify whether “epitope number” refers to the number of epitopes with CPR < 1.
b.	For HLA “Allele number” on table 2, the authors should clarify whether this refers to the # of HLA alleles (out of 8) where that particular epitope has a CPR < 1.

Generally, the antigenicity/HLA binding data is used clearly to compare to E. coli asparaginase (EcAII). The manuscript would benefit by including the same analysis for Erwnia asparaginase (ErAII), as both preparations are used clinically. Furthermore, demonstrating that epitopes of EcAII and ErAII don’t cross-react with asparaginase from Streptomyces scabrisporus is key for recommending it as a therapeutic option after immune responses to both agents (not clear from Fig. 3).
Validity of the findings: The authors’ conclusions are supported by their results. However, an important limitation of the study is that the stability of asparaginase from Streptomyces scabrisporus in plasma or serum was not assessed or estimated. The authors should acknowledge importance of PK properties/clearance for identifying a suitable alternative asparaginase preparation that can be used clinically. Note that an asparaginase with high clearance will have low immunogenicity due to decreased immune cell presentation.
Additional comments: The manuscript by Gonzales -Torres et al. presents a computational approach for identifying less immunogenic forms of the chemotherapeutic agent asparaginase. The authors use a novel approach that screens candidates for antigenicity and binding to MHC class II alleles, which is an important consideration for therapeutic asparaginases. Based on their search and approach, they identify a previously uncharacterized L-asparaginase from Streptomyces scabrisporus as a promising therapeutic candidate that can be used after human immune responses to PEGylated E. coli asparaginase and/or Erwinia asparaginase.

The authors focus on an important research question related to asparaginase therapy, which is an essential component of pediatric leukemia treatment protocols worldwide. Their approach using bioinformatic tools to assess whether a particular asparaginase would have a high probability of a human immune response is novel and provides a new tool or strategy for screening potential therapeutic enzymes. The strength of the manuscript is the approach used for identifying their proposed asparaginase. The most important issue is providing a more detailed discussion and conclusion on whether Streptomyces scabrisporus asparaginase would cross-react after E. coli or Erwinia asparaginase.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: IDENTIFICATION OF L-ASPARAGINASES FROM STREPTOMYCES STRAINS WITH COMPETITIVE ACTIVITY AND IMMUNOGENIC PROFILES: A BIOINFORMATIC APPROACH
Review round: 2
Reviewer: 1

Output:
Basic reporting: Good
Experimental design: Good
Validity of the findings: Good
Additional comments: Further molecular characterization of L-asparaginase is highly appreciable


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: IDENTIFICATION OF L-ASPARAGINASES FROM STREPTOMYCES STRAINS WITH COMPETITIVE ACTIVITY AND IMMUNOGENIC PROFILES: A BIOINFORMATIC APPROACH
Review round: 2
Reviewer: 2

Output:
Basic reporting: The author’s revised manuscript is definitely improved over the original submission. Yet, some issues that need attention remain.

Major required change:
Section 2.7. Here the authors discuss the molecular docking results for S. scabrisporus ASNase (SsAII), with the goal of identifying the active site. The result is shown in Figure 8. From this figure, it is not clear how this enzyme would catalyze the hydrolysis of asparagine. Specifically, for the predicted Site A, the amide group of the asparagine side chain is predicted to be close to Gly237; the carbonyl to Asn141; neither of these amino acids are likely to participate in catalysis. The predicted binding to Site B also fails to show the type of amino acids that could catalyze the hydrolysis reaction.

For example, for the EcA ASNase, conserved threonine residues, a tyrosine, and a lysine participate in catalysis. The authors need to re-examine the predicted binding of asparagine to SsAII to see if it is consistent with being near to residues that can catalyze the reaction. And are the identified putative catalytic residues conserved in this family of ASNases? If not, then this prediction is likely to be false.

Minor required changes:
Title: Identification of L-asparaginases from Streptomyces strains with competitive activity and immunogenic profiles: a bioinformatic approach  Identification of L-asparaginases from Streptomyces strains with a predicted competitive activity and immunogenic profiles: a bioinformatic approach

Abstract: In this work, a bioinformatic approach was used to identify, select and characterize L-asparaginases from Streptomyces through sequence…. In this work, a bioinformatic approach was used to identify, select and computationally characterize L-asparaginases from Streptomyces through sequence….

Page 3:…as well as pegylated E. chrysanthemi ASNase (EcAI-PEG).  as well as pegylated E. chrysanthemi ASNase (ErAI-PEG).
Experimental design: see above
Validity of the findings: see above
Additional comments: No additional comments


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: IDENTIFICATION OF L-ASPARAGINASES FROM STREPTOMYCES STRAINS WITH COMPETITIVE ACTIVITY AND IMMUNOGENIC PROFILES: A BIOINFORMATIC APPROACH
Review round: 2
Reviewer: 3

Output:
Basic reporting: See previous comments
Experimental design: See previous comments
Validity of the findings: See previous comments
Additional comments: Thanks for adding clarifications.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: CLINICAL IMPACT OF LENVATINIB IN PATIENTS WITH UNRESECTABLE HEPATOCELLULAR CARCINOMA WHO RECEIVED SORAFENIB
Review round: 1
Reviewer: 1

Output:
Basic reporting: No issues
Experimental design: 1) in the abstract and results, it is stated AFP >400 ng/mL is a risk factor: when was this AFP measured? Upon commencement of lenvatinib?

2) In the abstract, methods and results: it is not stated when the mRECIST treatment response is measured- is it 1 month after commencement of lenvatinib? Or maybe 3 months after commencement of lenvatinib?

3) The aims in line 93 are inadequate. They need to be expanded upon, especially with regard to the data about PFS and OS risk factors.

4) In line 99, it is stated "First, only patients who received sorafenib were enrolled." Don't the authors mean "only patients who received sorafenib followed by lenvatinib were enrolled?" Lenvatinib is not mentioned at all in this paragraph!

5) in Line 128, in the statistical analysis, it is stated that "Statistical analyses of group differences were performed using the t-test, Fisher’s exact test, and chi-square test for categorical variables." This is not correct. Firstly, the t-test is a test of continuous, not categorical variables, when means of groups are being compared. Secondly, I see no evidence throughout the rest of the manuscript that the t-test, Fisher’s exact test, and chi-square test are ever applied. The statistical analyses of group differences appear to be performed purely on PFS and OS, for which the log-rank test was used.

6) Similarly, in line 133, it is not stated what test is used to calculate multivariate analysis of the Kaplan-Meier curves. I assume this is Cox proportional hazards testing? But the authors need to make it clear.
Validity of the findings: 1) In table 4, there are no statistical analyses (to find p-values) performed between  any of the between-group comparisons. Could the authors have done a Chi-square test of 6-month PFS rates, between groups according to response to lenvatinib, with Bonferroni correction? And similarly a Chi-square test of 12-month OS rates, between groups according to response to lenvatinib, with Bonferroni correction? And then log-rank comparisons of PFS and OS between groups according to treatment lines?

2) In table 5, there are no statistical analyses (to find p-values) performed between any of the between-group comparisons. Could the authors have done a Chi-square test, between groups according to response to previous sorafenib, with Bonferroni correction?
Additional comments: No additional comments


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: CLINICAL IMPACT OF LENVATINIB IN PATIENTS WITH UNRESECTABLE HEPATOCELLULAR CARCINOMA WHO RECEIVED SORAFENIB
Review round: 1
Reviewer: 2

Output:
Basic reporting: 1)	English language should be implemented. There are some grammatical mistakes especially in the Introduction section

2)	In line 114, you wrote that patients >60 kg have been treated with 10 mg of lenvatinib daily. I’m quite sure that this is a typing error, because the correct dose should be 12 mg (based on data from REFLECT trial). If it is not, why did you choose this dose?

3)	In line 209, you wrote “Es”, probably instead of “AEs”. This should be corrected
Experimental design: 4)	In lines 107-108, you wrote that HCC diagnosis was made according to pathology, AFP levels and CT/MRI. Firstly, you should put the reference(s) of guideline(s) you use for HCC diagnosis; secondly, international guidelines have removed AFP levels from diagnosis algorithm, why did you use it?

5)	According to international guidelines and phase III trials, second-line treatment after sorafenib should be represented by regorafenib or cabozantinib. Why did you use lenvatinib? In the rationale of the study this is not actually clear

6)	Are all 40 patients cirrhotic? This should be reported in population characteristics. If there are non-cirrhotic patients, this characteristic should be added in univariate and multivariate analysis.

7)	What type of systemic treatment did patients assume before treatment with lenvatinib in third and fourth-line?

8)	The result concerning relationship between the type of response to lenvatinib and type of response to sorafenib is really interesting. It is not clear the reason of discontinuation of sorafenib in the cohort of responder patients (n=26). Have they all developed a radiological progression of disease under sorafenib before initiating lenvatinib? Were there definitive sorafenib discontinuations due to intolerance/toxicity?

9)	How did you deal with patients who died before first radiological evaluation of response to lenvatinib? After who many weeks was performed the first CT/MRI of evaluation?

10)	AEs incidence is presented for the entire population. Are there significant differences in AEs incidence between second, third and fourth-line cohorts?
Validity of the findings: 11)	It is not correct making OS analysis on the entire population. Patients receiving lenvatinib as third and fourth-line therapy have been exposed to different drugs that could change tumor molecular characteristics and microenviroment.
It is interesting to note significant differences between second-line cohort OS (8.1 mo) and third/fourth-line cohort OS (11.5 and 12.0 mo, respectively). This could be related to tumor molecular changes due to previous drugs (first of all immunotherapy, as mentioned in the article).

12)	As mentioned in Materials and Methods, OS was calculated from the date of lenvatinib initiation to death or last living contact. Probably, lots of patients underwent to a further line therapy after lenvatinib discontinuation. In case of response to the new treatment, we will see an improvement in OS that is not actually related to lenvatinib efficacy. OS data should be presented as general OS and corrected OS by censoring at further line treatment initiation.
Additional comments: Lenvatinib as “non-first-line” therapy for advanced HCC is an interesting field of study. Nowadays, several new drugs are emerging and this study focuses on the future challenge of multistep pharmacological treatment of HCC.
As mentioned in the discussion section, this study has the limitation to be retrospective, monocentric, with a very small sample size and with a short follow-up period. Unfortunately, these are also a number of critical points. First of all the excessive heterogeneity of the population of study. My advertisement is to focus the research on a single cohort of patients (i.e. lenvatinib as second-line after sorafenib? Lenvatinib as third-line after sorafenib and checkpoint inhibitors?) in order to provide data with impact on real clinical practice.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: CLINICAL IMPACT OF LENVATINIB IN PATIENTS WITH UNRESECTABLE HEPATOCELLULAR CARCINOMA WHO RECEIVED SORAFENIB
Review round: 2
Reviewer: 1

Output:
Basic reporting: No further issues
Experimental design: No further issues
Validity of the findings: No further issues
Additional comments: No additional comments


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: A COMBINATION OF TWO ELISA TESTS FOR NASOPHARYNGEAL CARCINOMA SCREENING IN ENDEMIC AREAS BASED ON A CASE-CONTROL STUDY
Review round: 1
Reviewer: 1

Output:
Basic reporting: No comments
Experimental design: See comments below
Validity of the findings: See comments below
Additional comments: In this study, the authors evaluated the performance of EBV VCA and EBNA1 IgA antibody screening for NPC detection.  Using data from over 550 NPC hospital-based cases and over 10,000 individuals who participated in an NPC screening program, the authors evaluate the performance characteristics of VCA IgA alone, EBNA1 IgA alone and a multiplicative combination of these 2 assay results for the identification of NPC.  This is a large effort that explores a question of public health importance in regions with high incidence of NPC.  Of note, performance of these same antibody tests has previously been evaluated/published using a combination risk score based on a logistic model, as appropriately noted by the authors.

The following suggestions/questions are offered to the authors:
1.	It is unclear how many of the 550+ hospital cases included in this study derived from individuals who participated in the 10,000+ screening program.  Assuming a subset of the 550+ cases were identified via screening, an additional analysis that restricts to individuals who participated in the screening study would be of interest (i.e., exclude NPC cases identified via self-referral of symptomatic individuals).  Such an analysis would more accurately evaluate the performance of EBV-based antibody screening for the detection of NPC in the study population.
2.	Since the same two assays have been previously used for NPC screening using a scoring system defined using a logistic model, it would be of interest to directly compare the performance of the published logistic model score to the present multiplicative score.  Such an analysis would be highly informative to determine whether the multiplicative approach has improved performance compared to the already existent logistic model-based score.
3.	It is unclear why a multiplicative score was chosen.  The choice of such an approach should be further justified/explained.  In addition, other methods of defining the VCA/EBNA1 combined risk score could be considered.  At a minimum, an approach that considered the additive effect of the 2 assays could be considered.
4.	While 70% of cases were male, <40% of controls were male.  Given that rates of NPC differ considerably by sex, an analysis that evaluates the performance of the antibody-based score separately for men and women would be informative.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: A COMBINATION OF TWO ELISA TESTS FOR NASOPHARYNGEAL CARCINOMA SCREENING IN ENDEMIC AREAS BASED ON A CASE-CONTROL STUDY
Review round: 1
Reviewer: 2

Output:
Basic reporting: 1) literature reference is needed for the multiplication model.

2) Figure 1 and Figure 2 should be converted to boxplot with marker cut-off value indicated in graphs.
Experimental design: 1) Line 226 to 232 in manuscript - The description of results in these lines seems more appropriate to be under the Results sub-title "Diagnostic value of the markers" than under the Results sub-title "Diagnostic accuracies of the markers". For results that come under diagnostic accuracy, it is hoped that findings related to true positive (TP), false positive (FP), true negative (TN), false negative (FN), accuracy [formula = (TP + TN)/(TP + TN + FP + FN)] would be reported.

2) Diagnostic values of combined VCA/IgA and EBNA1/IgA markers had been reported by other case-control and prospective studies and shown to have higher diagnostic values than single markers (Gao et al., 2017; Liu et al., 2012; Yu et al., 2018). These studies utilized probability calculated by logistic regression while the authors of this manuscript applied multiplication model. This manuscript could provide a bit more justification about the usage of multiplication model and also perhaps conduct more analysis to cover the knowledge gap - compare the performance of these two modeling methods using same data set and discuss about their practicability and limitations.
Validity of the findings: 1) In discussion, the authors mentioned that "The cost of NPC screening with EBV DNA test was expensive (Harris et al., 2019)...". However, this sentence is referencing to a report that made estimation from non-endemic area (Harris et al., 2019).

2) In discussion, the authors mentioned that "The diagnostic performance of EBV DNA test for early-stage NPC patients was not satisfactory (Ji et al., 2014)". The authors should include more recent studies in discussion (for examples, PMID: 28792880 and PMID: 31469434).
Additional comments: No additional comments


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: A COMBINATION OF TWO ELISA TESTS FOR NASOPHARYNGEAL CARCINOMA SCREENING IN ENDEMIC AREAS BASED ON A CASE-CONTROL STUDY
Review round: 2
Reviewer: 1

Output:
Basic reporting: No new comment
Experimental design: No new comment
Validity of the findings: No new comment
Additional comments: I have reviewed the changes made to the manuscript and thank the authors for taking the time to respond to my previous comments.  I have a couple remaining comments related to the new results summarized in Table 3.

1. Could the authors please confirm that the p-value comparing the AUC for the multiplicative (0.978; 95% CI = 0.969-0.986) and PROB (0.972; 95% CI = 0.962-0.982) models is <0.01?  The 2 AUC estimates differ only in the 3rd decimal place so it is strange that the p-value reported is so small.

2. Regardless of whether or not the AUC for these 2 approaches is statistically significantly different, the difference is very minor and the authors should therefore comment on the practical implications of such a small change when deciding whether or not the multiplicative model truly improves performance over the currently used PROB model.

3.  In responding to #2 above, please account for the fact that the sensitivity for the 2 approaches is very similar (91% and 88%) and that the specificity is lower for the multiplicative model (92%) than for the PROB model (96%).  Since every 1% decrement in Specificity has a big impact on false(+) and programmatic costs, the fact that the PROB model has improved specificity over the newly evaluated multiplicative approach should be discussed.  It is important for both the Abstract and Discussion to reflect the important finding that the PROB model is still likely the preferred way to utilize VCA/EBNA1 IgA antibody results for NPC screening and that the multiplicative model does not greatly improve on that approach overall and, in fact, has worst specificity and positive predictive value than the PROB approach.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: A COMBINATION OF TWO ELISA TESTS FOR NASOPHARYNGEAL CARCINOMA SCREENING IN ENDEMIC AREAS BASED ON A CASE-CONTROL STUDY
Review round: 2
Reviewer: 2

Output:
Basic reporting: 1) Raw data of this study (peerj-48783-raw_data.xls):
column B title "NA1-IgA rOD" should be "EBNA1-IgA rOD"
list "PROB" values for each individual

2) change whiskers of box plots in Figure 1 and 2 to indicate the 10th percentile and 90th percentile and describe this in figure legend.

3) when describing the serological results, be consistent in using "/" or "-" (e.g. VCA-IgA or VCA/IgA)

4) Sensitivity and specificity values are stated using percentage in Table 3 but mentioned as fractions in manuscript (line 227 to 235).

5) are Figure 3, Table 3, Table 4 and Table 5 showing results from all or just samples the training stage? please state this in the manuscript
Experimental design: no comment
Validity of the findings: no comment
Additional comments: 1) Serological results for male NPC patients and female NPC patients are not shown but VCA-IgA was reported as having higher sensitivity in detecting male NPC patients as compared to female NPC patients (Table 5). There should be some explanation or speculation about this difference in Discussion.

2) Serological results may or may not be affected by other factors stated in Table 1 (age, NPC family history and smoking history). The authors should analyse and report the findings.

3) As compared to the logistic regression model ("PROB"), the multiplication model ("combination") developed in this study had small decrease in specificity to detect all NPC (Table 3), but slight increase in sensitivity to detect all NPC (Table 3) and remarkable improvement in sensitivity to detect early stage NPC (Table 5). Are these results consistent in the training stage as well as in the verification stage? If so, what are the implications?

4) The results of verification stage were mentioned twice in separate paragraphs within Discussion.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: A COMBINATION OF TWO ELISA TESTS FOR NASOPHARYNGEAL CARCINOMA SCREENING IN ENDEMIC AREAS BASED ON A CASE-CONTROL STUDY
Review round: 3
Reviewer: 1

Output:
Basic reporting: The authors mentioned that "The verification sample data set was used to make Table 4 ,Table 5,Table 6,Table 7 and Table 8". Therefore in the manuscript, line 243 starting from "The differences in the sensitivities of the markers between early-stage and advanced-stage NPC patients were not significant by using verification samples(p>0.05, Table 4)..." to the end of line 255 should be moved to line 263 under the Results sub-topic "Verifying the effect of the combination on NPC screening".
Experimental design: no comment
Validity of the findings: no comment
Additional comments: No additional comments


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: EFFECTS OF DIET AND GIZZARD MUSCULARITY ON GRIT USE IN DOMESTIC CHICKENS
Review round: 1
Reviewer: 1

Output:
Basic reporting: New literature on gastroliths and grit use in birds is rare and every new paper is a very welcomed addition to our yet limited understanding of this matter.
The manuscript by Takasaki & Kobayashi reports a very interesting but relatively short-termed experiment with grit use in chicken, focusing on gastroliths development depended on diet and muscularity of the gizzard.
I found the language of the manuscript sometimes cumbersome. For example, the presentation of results in the abstract could be shorter and written more clearly, with a focus on just the significant results.
There are three major problems I have with the manuscript as it stands:
1)	there is virtually no detailed information about the grit used in this study (except its shape)
2)	these is not enough relevant literature regarding grit use in domestic chicken cited and discussed
3)	the visual presentation of data is poor, it could be very much improved with more easily accessible figures and diagrams
If these issues are remedied, the paper would be a valuable addition to research on bird digestion, gizzards, and gastroliths.
Experimental design: My main issue is with the short duration of the experiment and the validity of its results. See detailed comments below.

As for the animal usage: I consider the chicken experiments necessary and ethical, the necessary approval statements have been provided.
Validity of the findings: See detailed comments below.
Additional comments: Here are some specific comments referring to the line of the manuscript:

14 – To my knowledge there is no plural for grit (the term always incorporates several small stones). “Grits” is a term rather used for groats.
20 – there are well-established and well-defined terms for clast shapes in the geological literature. what do you mean by solidity? hardness?
22 – larger than what? are these changes significant?
39/40 – after reading the complete manuscript, I am not sure you can make such a statement because your experiment with grit only lasted a week!
51 – perhaps mention the other relevant functions of grit (reviewed in: Wings O. A review of gastrolith function with implications for fossil vertebrates and a revised classification. Acta Palaeontologica Polonica. 2007;52(1):1-16.)
83 – I am not sure that three weeks will make such a big difference in the development of (or lack of) gizzard muscles. Please explain why you did not choose a longer period for this experiment? Anyhow, there often is a high plasticity of gizzard muscles in birds.
106 – What was the lithological composition of grit used? This is perhaps the most important factor for development of grit shape changes!  Was it a mixture of rock types with different hardnesses? Or was it just quartz or a similarily hard rock type? With hard lithologies, the changes on the grit would only have been minimal after one week (see Wings & Sander 2007). Another example: if you had some limestone pieces in your grit (often incorporated in the commercially used grit for poultry), these clasts would simply dissolve in the stomach juices…
what was the shape variety in initial grit?
112 – Ok, here you define the term solidity. Please provide references for this use in the literature.

170 – What was the reason that chicks had to be euthanized prematurely?
175 – This makes me wonder if the chicks would have chosen even larger grit particles if you would have supplied them. On what basis did you choose the upper grit size limit?

General comments for the results: it would be good if you could illustrate the original shape variety of your initial grit in a diagram. you could also illustrate all other grit samples (ingested, excreted, remaining) in the same way. perhaps with area diagramms? or scatter plots? this would make your main results far easier to compare and comprehend.
Also, it would be helpful to have photographs of the different grit samples. at least in the supplements. also, I would be interested to see photographs of a typical gizzard from each group.

259 – what do you mean with “dull? less polished? or less sharp? be specific
261 – of course gastroliths are heavily abraded in the gizzard. this has been documented by several studies see Wings & Sander 2007
269 – grit abrasion is also strongly dependent on the lithology
273 – this is very strongly dependent on the duration gastroliths remain in the gizzard
278 – I am not sure this really is the first attempt. There is a vast number of papers about grit use in commercial chicken out there. Here are just some from my database which could be incorporated in your discussion:
Balloun, S. L., and Phillips, R. E.: Grit feeding affects growth and feed utilization of chicks and egg production of laying hens, Poult. Sci., 35, 566-569, 1956.
Bgatov, V. I., Motovilov, K. Y., and Speshilova, M. A.: Фyнкции пpиpoдныx минepaлoв в oбмeнныx пpoцeccax ceльcкoxoзяйcтвeннoй птицы [Functions of natural minerals in the metabolic processes of poultry], C.-x. биoлoгия [Agricultural Biology], 7, 98-102, 1987.
Buckner, G. D., and Martin, J. H.: The function of grit in the gizzard of the chicken, Poult. Sci., 1, 108-113, 1922.
Combs, G. F., G.L., R., and Nicholson, J. L.: Studies on the evaluation of insoluble grit for broilers, Maryland Agr. Exp. Sta. Misc.Publ., 210, 1954.
Cooney, W. T.: Influence of various grits on battery-raised broilers, Station circular / Agricultural Experiment Station / Oregon State Agricultural College, 139, 1941.
Curtis, M. R.: On the ability of chickens to digest small pieces of aluminum, Ann. Rept. Maine Agric. Exper. Sta. Bull, 221, 314-318, 1913.
Ferber, K. E., and Brüggemann, H.: Die Zugabe von Kalksteingrit und Flintgrit zum Futter bei der Jungmast von Hähnchen, Archiv für Geflügelkunde, 7, 363-368, 1933.
Heuser, G. F., and Noms, L. C.: Calcite grit and granite grit as supplements to a chick starting ration, Poult. Sci., 25, 195-198, 1946.
Kaupp, B. F., and Ivey, J. E.: Digestive coefficients of poultry feeds and the rapidity of digestion and fate of grit in the fowl, North Carolina Agr. Exp. Sta. Tech. Bul., 22, 1923.
Platt, C. S., and Stephenson, A. B.: The influence of commercial limestone and mica grits upon growth, feed utilization, and gizzard measurements of chicks, New Jersey Agr. Exp. Sta. Bul., 587, 1935.
Rau, G. J., and Platt, C. S.: The effect of size of limestone grit particles in poultry rations, Poult. Sci., 28, 232-235, 1949.
Scott, M. L., and Heuser, G. F.: The value of grit for chickens and turkeys, Journal of Poultry Science, 36, 276-283, 1957.
Tepper, A. E. R., Durgin, R. C., and Botorff, C. A.: Fine versus coarse grit as a feed ingredient for poultry, New Hampshire Agr. Exp. Sta. Circ., 56, 1939.
Titus, H. W., and Fritz, J. C.: The Scientific Feeding of Chickens, 5th ed., Interstate, Danville, Ill.,, 336 pp., 1971.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: EFFECTS OF DIET AND GIZZARD MUSCULARITY ON GRIT USE IN DOMESTIC CHICKENS
Review round: 1
Reviewer: 2

Output:
Basic reporting: The manuscript describes a very interesting experiment that is of high biological interest in my view.
The language is not acceptable, and requires extensive revision, including the involvement of a professional in avian biology/nutrition in my view. I made extremely detailed language corrections in the abstract in the attached pdf, and a lot of the detailed criticism can be transferred to the whole manuscript from there. Examples are the use of plural for grit ("grits"), the use of the word "regulation" when a word like "response" or "effect" would be adequate, or "remained grit" for leftovers. Correcting the language of the whole article is beyond the scope of work a reviewer can do.
The literature references are sufficient, incl. the background. I made one comment in the attached pdf on literature use in the introduction, where – in chicken – the fermentation of fibre is not the sole function of the caeca (I think fermentation of uric acid is at least also important) and using a citation on a very different species (kiwi) appears inappropriate to me.
The article structure is professional, raw data is provided (albeit in a strange way – split across many different files – there is no reason why the data cannot be provided in a single file in my view, and I would recommend/demand that). This should include both size-specific information per individual (for grit of a certain particle size range) as well as summative information of «all grit».
The manuscript is self-contained with relevant results to hypotheses.
Experimental design: The research is original, and primary. The question is well defined, relevant and meaningful, and the knowledge gap is evident.
The ethical standard is ok, and I guess the investigation methods are ok as well, but the way that the methods are worded precludes a thorough judgement.
In particular, the following method issues are relevant in my view:
The diets need to be described in detail, in terms of composition, and form (pelleted? meal? grain size? etc).
Data that is summative for an individual, such as body weight, gizzard weight, total amount of grit ingested, total amount of grit in the gizzard, total amount of grit in the faeces, should be evaluated by statistical models (either using the raw data, or transformed/ranked data as appropriate) with diet and gizzard muscle state as cofactors, incl. their interaction. This should also be done with relative measures (grit or gizzard weights in % of body mass).
Data on mean grit particle size should be calculated (this is possible, there are methods for this, e.g. in Fritz J, Streich WJ, Schwarm A, Clauss M (2012) Condensing results of wet sieving analyses into a single data: a comparison of methods for particle size description. Journal of Animal Physiology and Animal Nutrition 96:783-797.
ideally, one single value per animal for shape measures would be calculated (using a weighted average approach), and these would be compared between ingested grit, gizzard grit and faecal grit using repeated measures (or, individual as random factor), and diet and gizzard type as covariates.
Some statistical metods and results mentioned in the discussion are never explained in methods or results (see pdf).
The methods of shape need to be explained in detail, ideally with example graphs. Later, in the discussion, «sharpness» is used to describe these measures, but that is not explained in methods. It is also not clear how the measurements in ImageJ were done – how was it achieved that particles did not lie against each other, how were measurements taken (manually, algorithm)?
Sieving was done – and the number of samples for video analysis (n=500 individual stones) was explained for the offered grit. Sieving is not mentioned for gizzard, or faeces, but I assume it was done as well? How many stones did you use for leftover grit/gizzard grit/ faeces grit – 500 per sample as well – or did you measure all particles? How were they arranged for video analysis?
What sieving did you use – wet or dry sieving – what machine was used?
There is a general conceptual issue that influences the methods. Evidently, grit in the gizzard is not only modified in terms of shape, but it is also REDUCED IN SIZE. Hence, even if the ingested grit is never <0.5 mm, the grit in gizzard and especially faeces will definitely contain a lot of material <0.5 mm. How do you deal with this? It seems that this fraction was ignored? That is no problem in terms of methods as long as you discuss it, and the implications. For example, you could calculate the daily ingestion of grit, the daily excretion of grit, and calculate the difference (which, due to your methods, one would have to assume to represent material <0.5 mm). How much would that be? What proportion of the ingested grit would that represent?
I would expect graphical representations of body mass, relative gizzard mass, grit ingestion mass, gizzard grit mass (%BM), mean particle size of ingested/gizzard/faeces grit (e.g. as column charts), i.e. not only charts that represent each individual sieve fraction.
Comparisons should not be made between gizzard/faeces and initial grit, but with ingested grit.
Specific procedures, such as correcting for body mass or using cube root of body mass for relationship with particle size should be stated in the methods.
Validity of the findings: The results are given without selective reporting in my view. Underlying data have been provided. In conclusions, particle size reduction in the gizzard is not mentioned. Most other conclusions are sound, but some are illogical (see pdf).
Additional comments: This is a fascinating study!


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: EFFECTS OF DIET AND GIZZARD MUSCULARITY ON GRIT USE IN DOMESTIC CHICKENS
Review round: 2
Reviewer: 1

Output:
Basic reporting: Thank you for your revision, there definitely has been an improvement in this manuscript, however, I still think it is not ready for publication yet.

Please excuse the delay, but it is holiday and field season right now and due to time constraints I was unable to look at the manuscript with the scrutiny I would have preferred. Especially, I had not the time to check on the statistics. Also, I did not find the figure captions.

I am not a native English speaker, but for me there are still many language issues which need fixing, for example in line 26: How can the ingested grit be sharper (do you mean more angular?) than the offered grit. I thought the ingested grit is part of the offered grit? Do you mean that the proportion of the grit ingested compared to all grit particles that were offered had on average a more angular outline? Also, I would rather limit the use of the term “sharp” here since it is commonly used in connection to sharp edges on tools. Why not use the term “angular”? If you do not wish to use the established geological terminology for roundness, please explain why and at least compare your findings with the six standard categories (Very angular; Angular; Sub-angular; Sub-rounded; Rounded; Well-rounded) at least once.

123: what are silicastic stones? do you mean siliciclastic? if so, do you mean that the stones were composed of siliciclastic sediments (i.e. quartz sandstone) or were they rather composed as one solid vein quartz clast? After looking at fig. S2, I assume that latter, but please be precise as this strongly affects the outcome of your experiments. Also, some clasts on S2 look like chert to me, there might even be a difference in the abrasion rate between vein quartz and chert, at least the development of polish on the surface of chert gastroliths indicate this.

210: I do not understand. 3g were ingested on average, 1g was found in the gizzard, and 2.52g were excreted? where does that additional mass of 0.52g of grit come from? also, with “excreted grit on the last day” you mean the total excreted grit, right?
or do you mean that the combined excreted grit of all chicks on only the last day had this mass? if so, why do you give that amount here when discussing average amounts? and why did you only check the excreted grit mass on the last day?

272 Why did you not check the feces of at least a few chicks during the complete experiment?

294 ability? I am not convinced, they probably just had no need to retain the grit with this diet

301 I am not sure this is entirely true. From hundreds of sets of bird gastroliths I have seen, the fast majority has rather rounded gastroliths. I think it was a rather artificial setting to allow them access to so many angular clasts. This is not what birds usually find in their natural habitats and also not the standard in bird gastroliths. I assume that rounded gastroliths also allow effective trituration of foodstuffs, not by cutting, but by squashing and grinding. Which shape is indeed more effective still needs to be demonstrated.

308-310  Well this is definitely caused by your artificially angular shape of grit particles. Virtually no depositional environment in natural habitats provides birds with such angular stones. I am sure if an ostrich would get access to similarly very angular stones as gastroliths, you would also see an identical very fast change in grit shape. For how fast even the surfaces of quartz gastroliths are altered, see https://www.researchgate.net/publication/307758683_A_simulated_bird_gastric_mill_and_its_implications_for_fossil_gastrolith_authenticity

310-312 I highly doubt that, see above.

319-323 I disagree, as stated above are such angular grit shapes not natural. Also, less muscular gizzards are virtually non-existant in free-ranging herbivorous birds including chicken. For that you would have needed another experimental setting, providing the chicks also access to “normal” rounded grit. All you can say is that in addition to the valid conclusions of Ginofriddo & Best gastroliths shape is also dependent on diet and the strength of gizzard muscles.
Also, if you would have continued your experiment for more than a week (i.e. several months) you would surely have seen that the roundness of the gastroliths would have increased. Not all gastroliths are excreted or replaced within such a short time span.

329 digesting tuff?

Figure S1 – Please crop the images and add a scale bar.
Figure S2  -Please bring all images to the same scale.
Experimental design: see above
Validity of the findings: see above
Additional comments: No additional comments


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: EFFECTS OF DIET AND GIZZARD MUSCULARITY ON GRIT USE IN DOMESTIC CHICKENS
Review round: 2
Reviewer: 2

Output:
Basic reporting: In my view, this is generally fine. I made some changes in the attached mmanuscript to more accurately reflect the results in my view.
I also make suggestions, both in the word file and in the pdf file, for improvements to the figures. I would include Fig. S2 in the main paper, because it is a very cool and impressive figure - but irrespective of whether it is in supplement or in main document, the scale of all sub-figures needs to be the same, otherwise its effect is lost (right now, it looks as if uningested grit was larger than offered grit, due to the difference in scale).
Supplementary files all need legends in the documents themselves (e.g., all excel tables lack a legend in the excel, and they need units, explanation of abbreviations etc.).
Experimental design: This is fine. There is one thing that is a pity - when the authors counted the 500 pieces of grit from offered or leftover grit, they could have weighed these as well so that they could have made an estimate of the total number of pieces in the offered and uningested grit, which would have allowed them to calculate mean sizes as they did for gizzard and excreted grit. In case this data is available, that should be added and done. But if it is not available, this is not a problem. I added a statement on this in the methods.
Validity of the findings: no comment
Additional comments: please see both the annotated word file (for text and comments on supplements) and the annotated pdf file (for comments on figures and tables of the main text).
This was in my view a very good revision and it is a very nice paper. Thank you for heeding the previous comments so well. In my view, further review is not necessary.
sincerely    m clauss

ps: I just noted that I cannot attach the annotated word file, so I will send it via email to the corresponding author and the editor.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: EFFECTS OF DIET AND GIZZARD MUSCULARITY ON GRIT USE IN DOMESTIC CHICKENS
Review round: 3
Reviewer: 1

Output:
Basic reporting: Thank you for implementing the changes.
I make some additional language and technical remarks in the attached pdf, which should be made at the proofing stage in my view. No further review needed.
Experimental design: fine
Validity of the findings: very good
Additional comments: Thank you for the fine work. m clauss


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: RADON AND THORON EXHALATION RATE, EMANATION FACTOR AND RADIOACTIVITY RISKS OF BUILDING MATERIALS OF THE IBERIAN PENINSULA
Review round: 1
Reviewer: 1

Output:
Basic reporting: The manuscript has been presented in a Good manner by quoting some of the references of importance. The structure of the manuscript is also acceptable as per the quality of the work.
Experimental design: The authors should specifically mention the energy of the Gamma peaks used for the assessment of Radium and Thorium in the soil samples. I would suggest that the Radium equivalent activity must be mentioned instead of Radium and Thorium and the doses should be calculated by taking into consideration the Radium equivalent.
Validity of the findings: I would like to see the graph of Gamma Spectrometry using HPGe and if possible the FWHM values as it is very important that what software is used for the curve fitting and finding FWHM values for finding the areas under the peak.
Additional comments: Figure 1 is very vague, it must be drawn wrt dome coordinates.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: RADON AND THORON EXHALATION RATE, EMANATION FACTOR AND RADIOACTIVITY RISKS OF BUILDING MATERIALS OF THE IBERIAN PENINSULA
Review round: 1
Reviewer: 2

Output:
Basic reporting: The article is well written. The language of the manuscript is fluent and understandable.  But there are some writting errors. These errors were corrected on the manuscript (attached as revised manuscript pdf file). The introduction section reflects the general text of the article and adequately explains why the study was done. Figures and tables are relevant and well labeled and described. However, the article was not prepared according to the rules of the journal. The authors need to rearrange the article according to the instructions for authors.
Experimental design: Research question was well defined, relevant and meaningful. Methods were described with sufficient detail. The experimental methods used in this study are very well known.
Validity of the findings: In this study, (1) the activity concentrations of 226Ra and 232Th naturally occurring in 41 building materials (structural, covering and raw materials) manufactured in the Iberian Peninsula (Portugal and Spain), exported and used in all countries of the world were measured using a gamma-ray spectrometry with an HPGe detector, (2) radon (222Rn) and thoron (220Rn) exhalation rates (mass and surface) and emanation coefficients of these materials were determined using active radon and thoron monitor, and (3) the annual effective dose due to inhalation of radon and thoron was estimated to assess the radiological risks associated the use of these building materials. These findings are important for assessing the radon and thoron concentrations in buildings, environmental radioactivity, and health hazards of individuals. For this reason, the manuscript can be considered for publication in International PeerJ.
Additional comments: But there are some writting errors. These errors were corrected on the manuscript (attached as revised manuscript pdf file).


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: RADON AND THORON EXHALATION RATE, EMANATION FACTOR AND RADIOACTIVITY RISKS OF BUILDING MATERIALS OF THE IBERIAN PENINSULA
Review round: 1
Reviewer: 3

Output:
Basic reporting: Specific comments
Page in MS (Line)	Written	Change to 	Comments
L 48-49	Radon is the second leading cause of increase
49 of the probability of lung cancer after tobacco smoke (Torres-Durán et al., 2014).		This citation is not correct. This fact was established much before 2014. Find original reference
L.55	is 3.8	3.825
L.55	equivalent radiation dose		Usually we talk about effective dose.

L62	to the detriment	neglecting	Sentence is too long and cumbersome
L70	progenies	progeny	There is not plural for progeny.
L99	materials was	materials were
Eq2			Back diffusion was not taken into account in this Eq. Please explain why it was neglected
L. 167	which do not consider	which does not consider
L. 219	from de wall	from the wall
Experimental design: Well done
Validity of the findings: Agree with world wide
Additional comments: Major revision is need for this ms.
Experimental part of this ms is probably well done. Calibration of gamma spectrometer is missing. However, estimation of radon and thoron activity from some construction material obtained by Eq. 6 is not correct. It does not consider amount of material used in some room. So, it was obtained that effective dose (which is usually denoted with E) from zircon is larger than 1 mSv/year. My question, how much zircon can be found in some room, and how is realistic that all room is made by zircon. Formula in Eq.6 should be modified to take into account amount of material used in construction. Then, repeat calculation of effective dose In my, the best knowledge, zircon is used as coating material as very thin layer on ceramic tiles in bathroom or kitchen. Total mass of zircon is very small.  It can be true or similar for some other material.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: RADON AND THORON EXHALATION RATE, EMANATION FACTOR AND RADIOACTIVITY RISKS OF BUILDING MATERIALS OF THE IBERIAN PENINSULA
Review round: 1
Reviewer: 4

Output:
Basic reporting: The paper is interesting and contains data worth to be published. However the English should be substantially improved. I’m not a native English speaker and I don’t feel qualified to do a complete linguistic revision of the text. I just corrected some major mistakes (see the attached annotated pdf). However, in my opinion, the following sentences should be rewritten to improve clarity and comprehensibility:
a)	Lines 60-62
b)	Lines 67-69
c)	Lines 151-153
d)	Lines 164-168
e)	Lines 184-186 (attending ??)
f)	Lines 222-224
g)	Line 236 (the maximum value on average: what do you mean?)

Besides the language issue, the paper contains some problematic points, addressed more specifically in the next sections. These points need to be clarified before making the decision to publish or not
Experimental design: In equation (1) (Material and methods), the mass m of the sample is missing in the denominator: please correct
I have also some questions regarding the experimental set up described in figure 2.
a)	Do you have measured (or estimated) the leakage factor  in equation (2) ?  Its value is negligible for thoron but can substantially affect the radon exhalation estimation
b)	Can you give the asymptotic activity concentration values (for both radon and thoron) reached in the cylindric (not cilindrical, please correct) sealed container?
Validity of the findings: My major concern regarding the findings is related to the use of equation (7) for the calculation of the surface exhalation rate from the measured mass exhalation rate. The relationship between these quantities can be highly affected by the diffusion length (l=√(D⁄lambda)  ;lamba=decay constant;D=coefficiente of diffusion in the material) of radon  and thoron in the different material. Moreover, the exhalation area of your experimental set up can be hardly compared to the exhalation area in real conditions. Actually, being the material crushed, you have increased the effective surface emission area compared to that of the real building material (bric, tile). This fact can affect your results.
Some other minor questions should be addressed. In the tables you take mean values for some materials (zircon, for example) with only 2 samples which show a very large difference: it seems not very informative.
Additional comments: The paper is interesting and worth publishing. I encourage the authors to answer to the above addressed points


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: RADON AND THORON EXHALATION RATE, EMANATION FACTOR AND RADIOACTIVITY RISKS OF BUILDING MATERIALS OF THE IBERIAN PENINSULA
Review round: 2
Reviewer: 1

Output:
Basic reporting: Authors made necessary modifications. I do not have more comments and ms can be accepted for publication.
Experimental design: Well done and well described.
Validity of the findings: Authors found radium/radon/thoron concentration and exhalation in the range similar to other authors world  wide.
Additional comments: MS can be accepted.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: A COMPARISON BETWEEN PREDETERMINED AND SELF-SELECTED APPROACHES IN RESISTANCE TRAINING: EFFECTS ON POWER PERFORMANCE AND PSYCHOLOGICAL OUTCOMES AMONG ELITE YOUTH ATHLETES
Review round: 1
Reviewer: 1

Output:
Basic reporting: No comment
Experimental design: No comment
Validity of the findings: No comment
Additional comments: Comments to the Author
This study can be considered highly original due to the examination of the effects of choice provision over exercise order in strength training sessions on performance and subjective responses of fatigue. The article is well written, novel and with practical applications for S&C coaches who works with multiple players in the GYM at the same time. Thanks for give me the possibility to review this article and I have only few comments in order to help in the final version of the manuscript.

Material and methods
- Line 119, table 1. Please indicate (mm) in the sum of skinfolds. I recommend inform in the legend of the table what are the 8 skinfolds measured.
- Regarding the OPL assessment, could be interesting for the readers to show a table with the information of the load and the mean propulsive velocity at which the optimum power load was estimated for each exercises (mean, SD and range). In addition to this, could you inform about the ICC and CV inter-sessions per variable?
- Power outputs.- Please reflect that the power values were estimated using the linear transducer. The linear transducer does not measure force.
- A sample rate of 25 Hz (lineal encoder of 100 Hz) is more than adequate to record raw speed data during resistance training exercises (Bardella et al. 2016). Higher sampling frequencies provide no increase in the recording precision and may instead have adverse effects on the overall data quality. Why to use a lineal encoder with a sample rate of 1000 Hz during these exercises?

- Line 200. The athletes performed 3 sets of 6 rep for each exercises loaded with the OPL. How did you obtained the power values showed in the table 2? Is the best rep in mean power? The average of the 6 rep? the average of the 18 reps (3x6rep)? You have to explain this information in the methods. Sorry if I didn’t see this explanation.

Discussion
- Line 266 to 272. You don’t need to explain again this information in the discussion. You can describe in a short and precise way the aim of the study, and then the main findings of the investigation.
- Be careful when you are talking about performance in the article… performance is a very global concept. Finally you only measured power performance in 4 exercises, you should be more precise about this. Its also important that you didn’t evaluate longitudinal changes after a training process, therefore you are comparing if power performance within the training session was the same or different in both conditions.

Conclusions
- Don’t talk about the hypothesis again in the conclusions… Stay on topic. Reflect the conclusion of the study and practical applications.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: A COMPARISON BETWEEN PREDETERMINED AND SELF-SELECTED APPROACHES IN RESISTANCE TRAINING: EFFECTS ON POWER PERFORMANCE AND PSYCHOLOGICAL OUTCOMES AMONG ELITE YOUTH ATHLETES
Review round: 1
Reviewer: 2

Output:
Basic reporting: In my opinion, the manuscript seems well written. However, I cannot assess if the English in the present manuscript has the publication quality needed.
The introduction is well documented and written. However, to the best of my knowledge, no previous research was conducted with power training. Nunes (2020) and Simao (2012) reviews only included strength training focus on increasing maximal force and hypertrophy, excluding power training. If that is correct, the authors may include this literature gap in their introduction. On the other hand, if the authors know previous research that performs this type of comparison between self-selected and predefined order in power training, please include in the introduction.
In the discussion section, line 276, the authors have cited Halperin et al., 2015, but this paper doesn't deal with the topic under discussion. Maybe it is a mistake, and the authors want to cite Halperin et al., 2018.
In the same sentence, the authors have used four papers about autonomy from the self-determination framework. In my opinion, we cannot consider that this design with four sessions of training where the participants select the order only on two of them and without control of the rest of conventional training will influence the autonomy supportive.

Regarding tables:

- Please include a space between numbers and ± to improve the readability.
- The authors must use the same level of precision in the mean and the standard deviation.
- Table 1. The authors include the sum of 8 skinfolds as a descriptor of the participants. The authors must include the method of collecting these skinfolds and what the 8 skinfolds are in the method section and describe them in the legend of the table. The authors must also indicate the units of skinfolds on the table (i.e., mm).
- Table 2. The authors must indicate that the results for each exercise and condition are the mean of all repetitions.
- In my opinion, the authors may include a table with the individual data for each repetition and statistical analysis to improve the results section's clarity.
Regarding raw data, the authors only include the ID of the participants in the first sheet. Please indicate it on the other sheets, too.
Regarding supplemental Data, change "control condition" for predetermined order of exercises.
Experimental design: The research question is relevant, meaningful, and well defined. However, the fact that participants select the order of exercises weeks before the sessions is a significant limitation to answer the research question, but the authors describe it well in the discussion section.
Validity of the findings: Although the authors indicate that the participants select different exercise orders and that they had the chance to change the selection one week before the training, they don't specify if any participant changed his/her previous selection and the concrete order of exercises for each participant (at least on the raw data). This information could provide arguments to hypothesize about the validity of select exercise weeks before the training. The concrete order could allow us to identify if one exercise's order is different enough between both conditions.
Additional comments: The authors have used two references from the same authors and year (i.e., Dello lacono, A., Beato, M., & Halperin, I. (2020)). Please, use the letters “a” and “b” to identify them in the text.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: A COMPARISON BETWEEN PREDETERMINED AND SELF-SELECTED APPROACHES IN RESISTANCE TRAINING: EFFECTS ON POWER PERFORMANCE AND PSYCHOLOGICAL OUTCOMES AMONG ELITE YOUTH ATHLETES
Review round: 1
Reviewer: 3

Output:
Basic reporting: The manuscript, for the most part, is written in clear and understandable English.
References and background detail has been provided, however, the final paragraph of the discussion appears to somewhat repeat previous points and does not add a great deal to the manuscript. I suggest that this section is re-evaluated by the authors.

Current figures are suitable but additional ones or information is required. See further comments to authors below. In addition, some additional information and reporting of data would have been useful to improve transparency.

In some sections it is difficult to follow the flow of the study and total number of completed experimental conditions. Suggest further clarity is required in text to avoid potential confusion for the reader. See also comments below.
Experimental design: The general rationale for the study is suitable.
Line 112-122: This section could be more specific and strengthened. For example, it is not clear what 'performance outcomes' refers to in this context. It should also be clearly stated that this is in the context of an acute training session and not over the course of a training intervention.

Some question, or lack of detail provided, regarding the determination of the load for the resistance exercises. This seems somewhat subjective and no report on whether the device used was reliable, or in fact, whether to variable of interest was reliable between trials in repetitions that used the same load. Suggest calculating this from the data or at the very least reporting reliability values of the device from other studies using similar exercises.

Clarity required about the number and order of experimental resistance training sessions. For example, the abstract states 5 experimental sessions, the methods states 'all four sessions', experimental design states 2 resistance training protocols, then line 195-197 seems to imply that there was only one-predetermined condition. Suggest Figure 1 is also presented in a way that more clearly shows the order of sessions.

The statistical approach on line 233-235 is difficult to follow. Please clarify exactly what was conducted here.
Validity of the findings: The authors report similar outcomes across all conditions. However, replicating this study may be difficult and some additional data would help with the transparency of the results and findings.

Some major points to consider:
1. It would be useful to report the load (kg) used for each exercise for each individual.
2. Would be useful to report the order of exercises in some fashion during the self-selected conditions. Perhaps showing this for each individual participant in a table then brief discussion on which was the most popular. This information could be used to develop pre-determined session structures moving forward as it is then informed by athlete preferences.
3. Perhaps the lack of differences between conditions can be somewhat explained by the fact that optimal power loads were used and so effort and fatigue would not be a severe as say a 'heavier' strength training session. If this was the case then more disparate effects between conditions may have been observed. This would make for an interesting point to expand upon in the discussion and highlight the rationale for further research across different types of resistance training sessions. Thus, any conclusions about the effectiveness of ether method is currently confined to this particular type of loading, population etc.
4. Data is collected for each repetition but no presented in this fashion. For example, the decline across reps and exercises may look visually appealing and provide further transparency.
5. Although not possible post-hoc I feel that assessing motivation prior to each resistance training intervention would have been of interest as this is also an important factor in terms of session performance and training adherence in non-supervised settings.
6. Some history on the training programs routinely undertaken by the athletes would be of use. For example, were the experimental conditions different to the exercises they usually perform? Do they normally conduct training using the pre-determined method? If so, the self-selection would be the novel condition but they would be familiarised already with the pre-determined method.
Additional comments: L83: 'can lead to greater'
L104-106: It is unclear what exactly is being referred to in this statement. I.e. how does it account for these factors?
L112: 'when planning'
L116: Suggest removing S&C and using full-term throughout, or at least in the first instance.
L166: Use full term for headings
L184: Please check year of the reference
L229: Was the data normal? It states that normality testing was conducted but the outcome is not presented.
L283: 'may stem...'
L286: Cleary state that the current study is being referred to here.
L315-316: 'our study was an acute design and it...'.
Supp File 1. Please check the reporting of Pearson's r. I think this should be reported as the 'r' value if the correlation is of interest, but 'r2' if the fit of the model is of interest.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: A COMPARISON BETWEEN PREDETERMINED AND SELF-SELECTED APPROACHES IN RESISTANCE TRAINING: EFFECTS ON POWER PERFORMANCE AND PSYCHOLOGICAL OUTCOMES AMONG ELITE YOUTH ATHLETES
Review round: 2
Reviewer: 1

Output:
Basic reporting: No comment
Experimental design: No comment
Validity of the findings: No comment
Additional comments: Congratulations


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: A COMPARISON BETWEEN PREDETERMINED AND SELF-SELECTED APPROACHES IN RESISTANCE TRAINING: EFFECTS ON POWER PERFORMANCE AND PSYCHOLOGICAL OUTCOMES AMONG ELITE YOUTH ATHLETES
Review round: 2
Reviewer: 2

Output:
Basic reporting: The authors have significantly amended the manuscript and as such this is a much improved version. The addition of extra tables and figures helps however, I still have some remaining comments that I have pasted in sections below.
Experimental design: The experimental design is sufficient and sections related to the description of the research questions and methodology have mostly been clarified. However, I have one remaining comment that I do not believe has been adequately addressed yet.
Validity of the findings: Impact and novelty of the study is appealing to the strength and conditioning community and this is now supported by extra data/figures and tables.
Conclusions are adequate but believe a previous comment still needs to be addressed to a higher standard.
Additional comments: In multiple sections the manuscript 'exercise order' now appears as 'exercises order'. However, in the format in most sections it should remain as 'exercise order' or alternatively the authors can say 'order of the exercises'.

L186-187: It is still not clear to the reader that there were four experimental sessions and two of each type when reading this statement. Please revise. Please also highlight somewhere why 2 of each session was conducted and the importance of this.

L242: 'corresponding'

Table 2: Please add unit of measurements for OP and MPV; perhaps kg and m/s?

I could not find anywhere captions for Figure 2, 3 and 4. Please provide.

Although I can appreciate the addition of the new figures in Figure 3 it is difficult to determine which column(s) correspond to which group. Suggest making the symbol a different shape for clarity.

It is still worth highlighting further that similar studies should be trialled with different types of resistance training paradigms (high load/volume etc). I acknowledge this was not part of the study but provides further direction for ongoing research. A line or two to state this would be sufficient.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: USING THE FRAIL SCALE TO COMPARE PRE-EXISTING DEMOGRAPHIC LIFESTYLE AND MEDICAL RISK FACTORS BETWEEN NON-FRAIL, PRE-FRAIL AND FRAIL OLDER ADULTS ACCESSING PRIMARY HEALTH CARE: A CROSS-SECTIONAL STUDY
Review round: 1
Reviewer: 1

Output:
Basic reporting: 1)	I would encourage the authors to redo their literature search. Although the comparison of the three groups (non-frail, pre-frail, and frailty) is not often the primary focus of studies, there are dozens of studies that do report and statistically compare the characteristics of the three groups. Just like the current study does. For example, Hoogendijk et al. 2016 Maturitas, 83, 45-50; Abizanda et al 2011 JAGS, 59, 1356-1359. To mention just a few randomly. I am sure if the authors do a better search they will find 100s of papers.
2)	It would also be good to provide a bit more context of frailty in the introduction. For example, use the recent frailty series in The Lancet (https://www.thelancet.com/series/frailty) or the Clegg 2013 Lancet seminar.
3)	Please avoid the suggestion of longitudinal data. For example: “age, percentage of women and comborbidities increase as frailty progresses” (abstract) is too much suggestive of longitudinal data. Cross-sectional studies are not able to show anything about increase or progress. Please change this across the manuscript. Explanation: the higher percentage women and comorbidity in frail groups may be the result of the current sample selection (primary care visitors), and may say nothing about progress in frailty states.
4)	The title of the manuscript is non-informative. It is not a continuum that is being assessed in this paper, but three categories. Better would be to make a title that covers the content of the study, for example:
5)	Please use “older adults” or “older people” instead of “elderly”. The term “elderly” is nowadays regularly regarded as ageism.
6)	What is “economic income”. Do the authors just mean “income”?
Experimental design: 1)	In the introduction, the authors state that the frailty phenotype (Fried 2001) is measured by the FRAIL scale. This is a wrong assumption. The FRAIL Scale is a questionnaire, with different items than the frailty phenotype. So, I assume the authors were confused? The frailty phenotype is mainly based on clinical performance measurements, and is not the same as the FRAIL scale. This mistake has great implications of the current study, as this requires a major revision throughout the manuscript. Not having the frailty phenotype data available with performance measures is a big limitation of the current study.
2)	Sample selection: From the description of the abstract and the Methods section of the manuscript, it does not really become clear what kind of sample this is. It should be clearly stated that this is a selective primary care sample. There is no random sample selection, and the participants are not representative of a certain population. That limits the generalizability of the findings of this study. For example, it would be different if all primary care patients in a certain area would have been invited for this study. Now it only includes people that already go to the primary care practice with health problems. Therefore, the distribution may be different than in the general older population. This is perhaps why the frailty prevalence rather high for a 60+ population. Please also provide information on non-response, and reasons for non-response (refusal, missing data etc).
3)	What are the implications of having a smaller sample size than needed according to the sample size calculation? Please also provide details on what type of sample size calculation was done?
4)	The number of factors for which associations with frailty was assessed it rather limited. Why were only age, sex, partner status, income and comorbidity assessed? Would it not be a better contribution to the literature if a broader range of factors was assessed?
5)	Primary care is not very strong in Spain. People with acute health problems often go directly to the emergency department in hospitals. This makes it difficult to judge the relevance of the current design. Is primary care in Spain an appropriate place to assess frailty? Please elaborate.
6)	For variables that were not normally distributed, median (IQR) instead of mean (SD) should be reported.
7)	Avoid terms like “nearly statistical significant” (Line 133). Non-significant is non-significant. Please interpret effect size, as the effect size could still be of value sometimes
Validity of the findings: 1)	The description of implications (line 211 etc) goes beyond the findings of the current study. This is a simple cross-sectional study on associations between some factors and frailty. So, please describe the implications that are more close to the findings of the current study. What do these associations tell us? Don`t talk about social relations, when these were not part of the current analysis (social isolation is much more than partner status).
2)	The authors state that the multivariate model has good predictive power (line 222-227). This is wrong! The authors did not develop a prediction model, and did not assess predictive power. That is a completely different statistical approach. Also, variables were pre-selected by the authors, so we do not know anything about whether the chosen variables (age, sex, multimorbidity etc.) provide an optimal model. Please remove this complete paragraph. Also, the sentences on nutritional support come out of nowhere. Please stay more close to the content of the current study.
3)	The interpretation of findings is not always accurate. Without clearly stating the comparison group, the findings have no meaning. For example “income is the only constant factor, with an association only with the robust group” (abstract) has no meaning if we don`t know what the comparison group is.
4)	The reason that pre-frailty is not often studied, is that it is a poorly defined group. Some of these people will never become frail. And the group contains people that suffer from other conditions, like depression (because of the exhaustion question in the frailty measure). So how useful is it to focus on this group? This could be reflected on in the Discussion.
5)	Please add the reference group to all findings, and do this in a consequent way. Now it is unclear what the results exactly mean (Results section), as the reference group is often not mentioned.
6)	A bit more realistic overview of limitations should be provided. Now all limitations are directly presented as strengths. The authors should be a bit more cautious. This is a study with a selective, cross-sectional, sample and a limited data collection. So, calling this a “very rigorous data collection” is maybe a bit overstated (line 162). Another example, the mention of confounding bias (line 163) does not make any sense. Why would an analysis with three categories have less issues of confounding than an analysis of a binary variable? That has nothing to do with the number of categories, but with the appropriateness of the analytical model.
7)	Mentioning the sample size as strong point is not always advisable (line 156). What does a sample size mean if you don`t have the right data? Quality above quantity. Moreover, a sufficient sample size is a prerequisite of performing a study, not a strength!
8)	The comparison with previous studies is limited to very few studies. See my point above: the authors should do a better literature search, and compare with more findings from the European area (even the SHARE study has these data available).
9)	The authors should acknowledge that they used a different frailty measure (FRAIL scale) than the studies they compare their findings with. The best would be to compare only with studies that really use the FRAIL scale.
10)	The main conclusion is non-informative. What does “These factors behaved differently in the three groups, and are of great importance in promoting the detection of factors that characterize the non-frail, pre-frail and frail groups” mean? An unclear sentence. Please change this sentence. Just say something like: Being able to characterize the three groups may help to identify older adults at different frailty stages.
Additional comments: Thank you for the opportunity to review this interesting paper. While the paper is generally well-written, the implications of this cross-sectional descriptive study are somewhat limited. The paper is rather short. Please see my detailed comments above.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: USING THE FRAIL SCALE TO COMPARE PRE-EXISTING DEMOGRAPHIC LIFESTYLE AND MEDICAL RISK FACTORS BETWEEN NON-FRAIL, PRE-FRAIL AND FRAIL OLDER ADULTS ACCESSING PRIMARY HEALTH CARE: A CROSS-SECTIONAL STUDY
Review round: 1
Reviewer: 2

Output:
Basic reporting: Overall a well conducted study with some flaws

1) There is widespread confusing use of both "robust" and "non-frail" to describe one group of study participants. For clarity, the authors should choose one term consistently throughout.

Similarly, in the abstract, it is stated that the study is "measuring robustness". This is erroneous. There is no measurement or quantification of robustness in the already robust population.

I propose the authors abandon the terms "robust" and "robustness" altogether.

2) Similarly, the following sentences are confusingly written in the abstract: "Concerning robustness, the pre-frail individuals were older, with more comorbidities and a lower economic income. Frail and robust participants showed the same differences, except that there was a higher proportion of women in the frail group. Among the frail and pre-frail individuals, the frail individuals were determined to be older, female, and with a greater number of comorbidities."

I suggest, for much more clarity:

"Compared to non-frail individuals, pre-frail individuals were older, with more comorbidities and a lower economic income. Compared to non-frail individuals, frail individuals were more likely to be female, older, with more comorbidities and a lower economic income. Compared to pre-frail individuals, frail individuals were more likely to be female, older and with more comorbidities."

3) The aims of the study are weakly described in lines 55-58. Instead of "factors", I would suggest "pre-existing demographic, lifestyle and medical risk factors". Furthermore, the specific subgroup comparison between pre-frail and frail individuals should be more explicitly highlighted in the aims (especially given the emphasis in the introduction, and in the background section of the abstract, that this comparison has been rarely performed).

4) In line 90-91, the phrases "and the findings of these studies are confirmed with our data. These variables were obtained by personal interview" are redundant and should be deleted.

5) in line 135, "exception" should be "addition".

6) in line 137, "women" should be "more likely to be women"
Experimental design: 1) Somewhere in the statistics section of the methods, it should be explained that in the multivariate logistic regression, income was analysed as a qualitative variable with the lowest income bracket being set as the reference point.

2) Furthermore, the statistical methods used in the "bivariate analysis" in Table 1 are not described in the statistics section of the methods. Is this using Chi-squared and Students T test analysis?
Validity of the findings: 1) Table 1 should also include p values for the between-paired group comparisons, just like Table 2, rather than single omnibus p-values between all three groups. This would be more in keeping with the implicit study aim to determine differences between the pre-frail and frail groups.

2) The summary paragraph in lines 144-149 should also be reworded to focus more strongly on the specific subgroup comparison between pre-frail and frail individuals (especially given the emphasis in the introduction, and in the background section of the abstract, that this comparison has been rarely performed).

3) The conclusions in lines 135-139 section is very weak. Again, it should be reworded to focus more strongly on the specific subgroup comparison between pre-frail and frail individuals. The phrase "these factors behaved differently in the three groups" is inadequate: the conclusion should reiterate the directions and magnitude/significance of these differences.
Additional comments: No additional comments


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: USING THE FRAIL SCALE TO COMPARE PRE-EXISTING DEMOGRAPHIC LIFESTYLE AND MEDICAL RISK FACTORS BETWEEN NON-FRAIL, PRE-FRAIL AND FRAIL OLDER ADULTS ACCESSING PRIMARY HEALTH CARE: A CROSS-SECTIONAL STUDY
Review round: 2
Reviewer: 1

Output:
Basic reporting: All my previous criticisms have been answered, thank you.
Experimental design: All my previous criticisms have been answered, thank you.
Validity of the findings: All my previous criticisms have been answered, thank you.
Additional comments: No additional comments


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: THE FREQUENCY OF COMBINED IFITM3 HAPLOTYPE INVOLVING THE REFERENCE ALLELES OF BOTH RS12252 AND RS34481144 IS IN LINE WITH COVID-19 STANDARDIZED MORTALITY RATIO OF ETHNIC GROUPS IN ENGLAND
Review round: 1
Reviewer: 1

Output:
Basic reporting: Dimitris N. et al. collected allele frequencies from 1000 Genomes Project to calculate the correspondences with ethnic groups in England. A significant correlation was observed between the reported Standardized Mortality Ratios and the frequency of the combined haplotype of both reference alleles, which suggest that the combination of reference alleles of the specific SNPs may be implicated in more severe outcomes of COVID-19. This field is very important for early targeted intervention in those at high risk.
Experimental design: Research question was well defined, while the idea of creating correspondences with ethic groups and the reported standardized mortality ratios was unreliable.
Validity of the findings: The findings and results are quite uncertain, especially there is no precise basic information to support this analysis, for example, age, gender, health status, medical conditions, which were important factors to outcome of COVID-19. Please provide solid evidence to support the study.
Additional comments: The research question is very important and further analysis with more precise data is necessary to support the findings.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: THE FREQUENCY OF COMBINED IFITM3 HAPLOTYPE INVOLVING THE REFERENCE ALLELES OF BOTH RS12252 AND RS34481144 IS IN LINE WITH COVID-19 STANDARDIZED MORTALITY RATIO OF ETHNIC GROUPS IN ENGLAND
Review round: 1
Reviewer: 2

Output:
Basic reporting: The manuscript is written in clear, understandable English however I suggest proof reading of the abstract and introduction for grammatical errors.  Specifically:
- Line 18-19: "Following up to these two developments..." should read "Following up on these two developments..."
- Line 65: "...turned our focus into..." should read "turned our focus to..."

The literature review is well written and clearly introduces all of the necessary information.  I would suggest including previously described data showing IFITM protein restriction of SARS-CoV (Huang et al, Plos Path, 2011).

I would suggest combining the results into one figure with 3 panels as they are repetitive and some are not necessary or unclear.  I also suggest finding a way to show the SMR and h1 ratio with the same ethnic categories to show that they share the same pattern on Figure 1.  You could add SMR with a second y-axis for example.  Figure 2a is unnecessary as it is the same as Figure 1.  Figure 3 does not add anything as the correlation is much more convincing in figure 4.  I suggest having one figure showing (a) ratios, (b) SMR and (c) correlation between h1 ratio and SMR.

I would suggest adding a leading sentence to the results section explaining what you have done briefly.
Experimental design: The design is robust and the authors clearly explain the limitations of their ethnic pools and groupings.
Validity of the findings: The findings seem valid, and the authors discuss how these findings link to previous data well.
Additional comments: The manuscript is well written and presents and interesting observation in regards to the link between COVID-19 mortality and IFITM3.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: THE FREQUENCY OF COMBINED IFITM3 HAPLOTYPE INVOLVING THE REFERENCE ALLELES OF BOTH RS12252 AND RS34481144 IS IN LINE WITH COVID-19 STANDARDIZED MORTALITY RATIO OF ETHNIC GROUPS IN ENGLAND
Review round: 2
Reviewer: 1

Output:
Basic reporting: Grammatical errors previously highlighted have been amended.

The figures have improved slightly but I feel the figure legends do not describe the data well enough and instead try to present results, including those that are not even shown in the figure.  Better description of the figures is required.
Experimental design: Previous comments have been responded to.
Validity of the findings: I feel the discussion would benefit from the acknowledgement that this data only takes into consideration minor allele frequencies and not genotype data.  The association between rs12252 and rs34481144 and viral infection severity is generally linked to genotype not minor allele frequency, with heterozygosity for each SNP generally behaving more similarly to the wild-type homozygous genotype.
Additional comments: No additional comments