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: ANTIMICROBIAL AND MICRONUTRIENT INTERVENTIONS FOR THE MANAGEMENT OF INFANTS UNDER 6 MONTHS OF AGE IDENTIFIED WITH SEVERE MALNUTRITION: A LITERATURE REVIEW
Review round: 1
Reviewer: 1

Output:
Basic reporting: I have put everything in one doc and pasted under each; I had no time to recategorize it in your format.
The review is dealing with a very interesting topic that needs more attention and is therefore very timely.
This review attempts to do a lot in one review:  It might want to do too much and therefore the reader gets easily lost. The title is promising but possibly misleading. It is more about interventions related to impact on nutritional status than medical interventions as such.

Though it is  a very courageous attempt to do this literature study it would benefit from perhaps less ambitious goals. The authors opt to look for interventions and what is known in adjacent age groups in relation to ‘severe malnutrition’. It is not fully clear what the authors anticipated as the terminology varies in this document. The authors use sometimes ‘severe malnutrition’  but it is unclear whether they refer to severe acute malnutrition or any type of severe malnutrition. It becomes more confusing when terms like
‘Acute wasting, severe malnutrition, acutely malnourished, SAM’ (the first and third include moderate acute malnutrition) are used. The authors seem occasionally to use this mix of terms  interchangeably.

The authors use various age groups/terms (infant, child) without precisely defining these. What is the definition of an infant in this context:  0-12 months? 0-6 months? What is the definition in this context of a “child”? Do they mean anyone 6 months to 18 years? or 6-59 months? In line 163 it is stated children of any age. This leads to confusion.

Though this is not a ‘must’ but the authors could consider not to take the intervention as a starting point but the physiological group: and list all what is known for that group related to malnutrition: e.g. LBW through pre-term; LBW through SGA; 0-6 months (malnourished and non malnourished – ideally more specific: SAM and/or MAM); 6-59 months (malnourished and non malnourished – ideally more specific: SAM and/or MAM). It is unclear why the authors included information on any child older than 59 months. For example: references are made to 5-12 years or 2-12 years but the purpose is to look at adjacent age groups  (e.g. line 440-441). It is questionable to consider a child  5 years and older as an adjacent group.

The authors describe the efficacy of various interventions (line 120) but as the efficacy is related to a desired outcome it is not always clear what outcome is referred to in the different sections.
It would have been helpful to have the results marked in a table and not just a summary table:
 e.g. a table with column headings such as:
subject/age group/biological group, intervention, sort of study, objective intervention,  description of subjects (SAM, MAM, stunted, etc), outcomes, etc
The authors do not discuss any neonatal period and put everything <6 months in one group. The neonatal period is a distinctive period and should be acknowledged as such. Also, the nutritional needs in that group in infants that are preterm are different from other neonates.
It is unclear why the authors decided to exclude the impact of breastmilk fortifiers.

The paper reads more like a report from a lit review than a manuscript for a peer reviewed journal. Sometimes it reads like a long list of citations from the reviewed journals causing lack of uniformity and cohesion. The introduction is not very clear and many passages raise questions on what the authors exactly meant to say. It would benefit to summarize what is known about the 0-6 months and SAM (or both SAM and MAM) in a table.
This manuscript needs thorough editing and text can be written more concise. There are various paragraphs where words are missing.
Additionally, the manuscript would benefit from some clarifications/ corrections:
The dosages of various interventions are not always clear daily, single intake/bolus e.g. lines 359-361. The references need some additional reviewing by the authors: here and there missing pages, missing journal  (e.g. references 4, 8, 16, 19, etc).
Line 422: <12.6-150mg/day in children:  150 mg per day???
Table 1 : do the authors mean >6 months until 18 years, or 6-59 months?
The titles of the tables/figures are not always clear and would benefit with some more precise description.

Though a good attempt to provide more clarity on what is known/needed for the 0-6 months old malnourished children, this review needs more work to make the information it found more accessible.
Experimental design: The review is dealing with a very interesting topic that needs more attention and is therefore very timely.
This review attempts to do a lot in one review:  It might want to do too much and therefore the reader gets easily lost. The title is promising but possibly misleading. It is more about interventions related to impact on nutritional status than medical interventions as such.

Though it is  a very courageous attempt to do this literature study it would benefit from perhaps less ambitious goals. The authors opt to look for interventions and what is known in adjacent age groups in relation to ‘severe malnutrition’. It is not fully clear what the authors anticipated as the terminology varies in this document. The authors use sometimes ‘severe malnutrition’  but it is unclear whether they refer to severe acute malnutrition or any type of severe malnutrition. It becomes more confusing when terms like
‘Acute wasting, severe malnutrition, acutely malnourished, SAM’ (the first and third include moderate acute malnutrition) are used. The authors seem occasionally to use this mix of terms  interchangeably.

The authors use various age groups/terms (infant, child) without precisely defining these. What is the definition of an infant in this context:  0-12 months? 0-6 months? What is the definition in this context of a “child”? Do they mean anyone 6 months to 18 years? or 6-59 months? In line 163 it is stated children of any age. This leads to confusion.

Though this is not a ‘must’ but the authors could consider not to take the intervention as a starting point but the physiological group: and list all what is known for that group related to malnutrition: e.g. LBW through pre-term; LBW through SGA; 0-6 months (malnourished and non malnourished – ideally more specific: SAM and/or MAM); 6-59 months (malnourished and non malnourished – ideally more specific: SAM and/or MAM). It is unclear why the authors included information on any child older than 59 months. For example: references are made to 5-12 years or 2-12 years but the purpose is to look at adjacent age groups  (e.g. line 440-441). It is questionable to consider a child  5 years and older as an adjacent group.

The authors describe the efficacy of various interventions (line 120) but as the efficacy is related to a desired outcome it is not always clear what outcome is referred to in the different sections.
It would have been helpful to have the results marked in a table and not just a summary table:
 e.g. a table with column headings such as:
subject/age group/biological group, intervention, sort of study, objective intervention,  description of subjects (SAM, MAM, stunted, etc), outcomes, etc
The authors do not discuss any neonatal period and put everything <6 months in one group. The neonatal period is a distinctive period and should be acknowledged as such. Also, the nutritional needs in that group in infants that are preterm are different from other neonates.
It is unclear why the authors decided to exclude the impact of breastmilk fortifiers.

The paper reads more like a report from a lit review than a manuscript for a peer reviewed journal. Sometimes it reads like a long list of citations from the reviewed journals causing lack of uniformity and cohesion. The introduction is not very clear and many passages raise questions on what the authors exactly meant to say. It would benefit to summarize what is known about the 0-6 months and SAM (or both SAM and MAM) in a table.
This manuscript needs thorough editing and text can be written more concise. There are various paragraphs where words are missing.
Additionally, the manuscript would benefit from some clarifications/ corrections:
The dosages of various interventions are not always clear daily, single intake/bolus e.g. lines 359-361. The references need some additional reviewing by the authors: here and there missing pages, missing journal  (e.g. references 4, 8, 16, 19, etc).
Line 422: <12.6-150mg/day in children:  150 mg per day???
Table 1 : do the authors mean >6 months until 18 years, or 6-59 months?
The titles of the tables/figures are not always clear and would benefit with some more precise description.

Though a good attempt to provide more clarity on what is known/needed for the 0-6 months old malnourished children, this review needs more work to make the information it found more accessible.
Validity of the findings: The review is dealing with a very interesting topic that needs more attention and is therefore very timely.
This review attempts to do a lot in one review:  It might want to do too much and therefore the reader gets easily lost. The title is promising but possibly misleading. It is more about interventions related to impact on nutritional status than medical interventions as such.

Though it is  a very courageous attempt to do this literature study it would benefit from perhaps less ambitious goals. The authors opt to look for interventions and what is known in adjacent age groups in relation to ‘severe malnutrition’. It is not fully clear what the authors anticipated as the terminology varies in this document. The authors use sometimes ‘severe malnutrition’  but it is unclear whether they refer to severe acute malnutrition or any type of severe malnutrition. It becomes more confusing when terms like
‘Acute wasting, severe malnutrition, acutely malnourished, SAM’ (the first and third include moderate acute malnutrition) are used. The authors seem occasionally to use this mix of terms  interchangeably.

The authors use various age groups/terms (infant, child) without precisely defining these. What is the definition of an infant in this context:  0-12 months? 0-6 months? What is the definition in this context of a “child”? Do they mean anyone 6 months to 18 years? or 6-59 months? In line 163 it is stated children of any age. This leads to confusion.

Though this is not a ‘must’ but the authors could consider not to take the intervention as a starting point but the physiological group: and list all what is known for that group related to malnutrition: e.g. LBW through pre-term; LBW through SGA; 0-6 months (malnourished and non malnourished – ideally more specific: SAM and/or MAM); 6-59 months (malnourished and non malnourished – ideally more specific: SAM and/or MAM). It is unclear why the authors included information on any child older than 59 months. For example: references are made to 5-12 years or 2-12 years but the purpose is to look at adjacent age groups  (e.g. line 440-441). It is questionable to consider a child  5 years and older as an adjacent group.

The authors describe the efficacy of various interventions (line 120) but as the efficacy is related to a desired outcome it is not always clear what outcome is referred to in the different sections.
It would have been helpful to have the results marked in a table and not just a summary table:
 e.g. a table with column headings such as:
subject/age group/biological group, intervention, sort of study, objective intervention,  description of subjects (SAM, MAM, stunted, etc), outcomes, etc
The authors do not discuss any neonatal period and put everything <6 months in one group. The neonatal period is a distinctive period and should be acknowledged as such. Also, the nutritional needs in that group in infants that are preterm are different from other neonates.
It is unclear why the authors decided to exclude the impact of breastmilk fortifiers.

The paper reads more like a report from a lit review than a manuscript for a peer reviewed journal. Sometimes it reads like a long list of citations from the reviewed journals causing lack of uniformity and cohesion. The introduction is not very clear and many passages raise questions on what the authors exactly meant to say. It would benefit to summarize what is known about the 0-6 months and SAM (or both SAM and MAM) in a table.
This manuscript needs thorough editing and text can be written more concise. There are various paragraphs where words are missing.
Additionally, the manuscript would benefit from some clarifications/ corrections:
The dosages of various interventions are not always clear daily, single intake/bolus e.g. lines 359-361. The references need some additional reviewing by the authors: here and there missing pages, missing journal  (e.g. references 4, 8, 16, 19, etc).
Line 422: <12.6-150mg/day in children:  150 mg per day???
Table 1 : do the authors mean >6 months until 18 years, or 6-59 months?
The titles of the tables/figures are not always clear and would benefit with some more precise description.

Though a good attempt to provide more clarity on what is known/needed for the 0-6 months old malnourished children, this review needs more work to make the information it found more accessible.
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: ANTIMICROBIAL AND MICRONUTRIENT INTERVENTIONS FOR THE MANAGEMENT OF INFANTS UNDER 6 MONTHS OF AGE IDENTIFIED WITH SEVERE MALNUTRITION: A LITERATURE REVIEW
Review round: 1
Reviewer: 2

Output:
Basic reporting: General comments
The manuscript in general well written and well organized, the language also good.
Abstract
Line 1- 3, the title said the study groups are under 6months infants but on the result part (line 45) said “Ninety-four articles were identified for inclusion within this review, none of which
 Studied interventions solely in acutely malnourished infants U6M”, so how the studies were included for review since they weren’t done on U6months?
Experimental design: Survey methodology
In general, the method part lacks a clear description of the objective of the review.
Line 131-132, infants U6M and children with and without malnutrition included. Why without malnutrition children and U6M included?
Line 138-139, anthropometric changes what are these anthropometric changes?  Neurodevelopment = how assessed?
Line 145 149, is not clear and quite hard to understand.
“Where an RCT was included in a subsequent MA, the article was not included unless it contained a subgroup of interest (e.g. malnourished infants and children) that was not the primary population of interest in the MA”
“Similarly, where a study looked at multiple micronutrient interventions, this was
149 included if subgroups were presented analyzing the effect of a single micronutrient.”
Validity of the findings: Result
In general, the result part bulky and can’t relate the review result with the title of the review. As the manuscript described that the review was done on U6M severely malnutrition groups but the reviewed MA, SR, RCT was not in these target groups. Thus, it’s difficult to comment on the result part.
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: ANTIMICROBIAL AND MICRONUTRIENT INTERVENTIONS FOR THE MANAGEMENT OF INFANTS UNDER 6 MONTHS OF AGE IDENTIFIED WITH SEVERE MALNUTRITION: A LITERATURE REVIEW
Review round: 1
Reviewer: 3

Output:
Basic reporting: For infants under 6 months whole management varies whether there is prospects of BF or there is no prospects.
Whole review does not talk about this differentiation
Experimental design: Appropriate
Validity of the findings: Applicable
Additional comments: WHO 2013 updates has given several additional criteria for inpatient care . There is a need to have recommendations for each condition


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: EVOLUTIONARY HISTORY OF DIMETHYLSULFONIOPROPIONATE (DMSP) DEMETHYLATION ENZYME DMDA IN MARINE BACTERIA
Review round: 1
Reviewer: 1

Output:
Basic reporting: Text mostly well presented, though some confusions with the tense.  The Tables and Figures could be better explained with improved and more substantive legends
Experimental design: My expertise is not suited to make accurate judgments on the approaches taken.
Validity of the findings: Fine as far as I can see. This is, however, has a strong theoretical flavour and so, even if their conclusions are not 100% correct, they recognise this and in any event, this work will form the basis for interesting discussions in the field.
Additional comments: Comments on PeerJ MS on DmdA - see also annotated Pdf

On reading this MS, I feel a little like the chap who wanders into the Prado muttering “I don’t know much about art, but I know what I like”. So, the good news is that I liked this paper, with its full-on bioinformatic attack on a single enzyme/gene system. But the bad news is that my abilities to make meaningful judgments on the fine details of these bioinformatic analyses would make Donald Trump blush. So, with that in mind, here goes.
Most of my comments (167 of them) can be seen in situ in the attached Pdf. Many are minor – the English and written presentation are mostly very good, but there are some glitches and these are indicated. One more important problem though, is the need to decide if they are writing in the present or past tense. They start in the former, then switch. There are also some more substantive comments (prefaced with a *** in the Pdf) and these need attention.
Here, I indicate my wider concerns.
I think that my overall worries relate to the fact that the DmdA/dmdA polypeptide/gene (by the way, there are several places where the nomenclature for these is mixed up and wrong) are considered in isolation, addressing them purely in terms of their sequences and their known and proposed structures. Given the terms of reference that they set themselves, that may be fair enough, but, no gene is an island, so maybe they need to bring in other factors.
So, a few things. Of the elephants in the room, the one that gives me most cause for concern is the lack of any mention (I checked) of the worryingly (for some) high Km (~10 mM) values of those DmdA enzymes that have been studied. If the family has had such a long time to evolve, this almost implies that a high Km is an adaptive advantage, perhaps in the context of the high intracellular DMSP concentrations. I think that this point needs to be addressed somewhere. [And, yes, I know that some (though not all) of the Ddd lyases are even less efficient!]
Although they certainly do mention the recent observations that much (maybe most?) of the world’s DMSP is bacterial in origin, I actually feel that this may be a game changer in this field, especially in light of the findings by Williams et al (https://www.nature.com/articles/s41564-019-0527-1) of the range of different bacteria and different pathways that can accomplish this synthesis. This finding may not substantially change the overall line of thinking and the conclusions of this MS, but I do think that it changes the backdrop to the DMSP story and needs to be reflected. (I assure you that this is not a case of “point-scoring”.)
I would like to have seen some consideration of what they think are the features of the Roseobacter lineage (not Roseobacter in italics as repeatedly written in the MS) that makes them so DMSP-philic. If the dmdA functional gene has been around for such a long time, why did it not find its way into a much wider range of marine bacteria? After all, there are very close homologues of the downstream DmdB, C and D polypeptides in a whole host of other bacteria, so these would only require the acquisition of the single dmdA gene for a functional pathway? And that is not all. Emphasising the importance of DMSP in the life and times of the Roseobacters, these bacteria are home to many of the Ddd lyases, and there are links between the two pathways, most obviously that in several Roseobacters, the expression of the dmdA is under the control of the key product (acrylate) of the lyase mediated cleavage. I am not sure what this means in relation to the evolution of the DmdA enzyme, but I suspect that it means something.
I thought that the figure legends could be generally improved, with more information and written more clearly. See my in situ comments on Fig 1 line 329 for example.
Overall, though, I think that this paper will be a useful addition to the DMSP literature and at the very least will set off some productive and interesting discussions.


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: EVOLUTIONARY HISTORY OF DIMETHYLSULFONIOPROPIONATE (DMSP) DEMETHYLATION ENZYME DMDA IN MARINE BACTERIA
Review round: 1
Reviewer: 2

Output:
Basic reporting: Comments on clarity/english in text:

Line 68-69: Consider rewording to make this sentence more accurate to your point, such as: “Compared to genes in the DMS-releasing pathways, dmdA is more frequently found in the genomes of oceanic bacteria.”

Lns 360-363: This doesn’t need to be a separate paragraph. You could add it onto the previous paragraph.

Lns 405-407: I would suggest changing the terms ‘first cluster’ and ‘second cluster’ since these are hard to interpret for finding things where things are on the tree.

Ln528 : What does Fig. 7; “down and up” mean?

Ln 525-528: contradictory phrases “have not a recent common ancestry” and “supports a common recent ancestry” in same paragraph.

Ln 568-569: Are you referring to Figure 4? It would be helpful here and throughout the Discussion to reference the results to which you refer.

Ln 581-584: I cannot understand this sentence.

Ln 600-602: please consider rewording “as well as Ca. P. ubique sequence and this last one has a pI similar to the first” I don’t know what first and last one means.

Ln 605: “degradates” to “degrades”

Ln 616: “experimented” to “experienced”

Ln 444 should say “…selection has influenced the evolutionary history…”

Ln 460 should say “…fits the data better…”

Ln 587 should day “…prior to having been…”

Comments on Figures, Tables, and Supplemental Material:

All Tables (1-6) can be moved to supplemental material.

Supplemental Table 1: I do not understand how to interpret the G+C wobble values, some cells have multiple values, some have decimals and others have commas. Please revise.

Legends for the Supplemental figures and tables are only found on the PeerJ website; final versions of the supplemental materials need to have these legends within the article documents.

Figure 1: In the legend, please define what is meant by ‘closer homologs’ for those with yellow color.

I’m not convinced that Supplemental Figure 6 is necessary. It’s hard to directly compare with Figure 3 because you’re using a different set/number of sequences. You then go on to do the same analysis/comparison with a smaller subset of sequences in Supplemental Figures 7-9 that accomplish your point about HGT.

Legends for the supplemental figures are sometimes too vague. For example, Supplemental Figures 8 and 9 have the exact same title.

There is a fair amount of color switching between figures. DmdA sequences are labeled in blue, red, green, depending on which tree it is – and there are many trees. This leads to reader fatigue. I would suggest trying to make your coloring schemes as consistent as possible.

Supplemental Figure 10b is divided into 4 clades which are supposed to correspond to Figure 4 and Supplemental Figure 10a, but I only see 3 clades. It would also help to include taxonomic labels on Supp. Fig 10b so it’s easier to compare between it and the trees.

Supplemental Figure 10b: what’s the difference between darker and lighter blue?

Supplemental Figure 11: All I see is a black box with squares and a yellow “L” line. Should there be labels somewhere? Are the points corresponding to the red and yellow sequences from 10a? Again, keeping consistent color coding would be really helpful.

Figure 4: Please offset the node numbers and bars so that it’s easier to read. Move the node numbers off of the node labels. Also provide a label for the time scale and increase the font size of the scale numbers. Define violet arrow in legend.

Supplemental Figure 20: I don’t think this figure is necessary or provides any information beyond the text. What’s written in the legend is all the info that is needed.

Figure 6: what do the colors other than blue represent?

Figure 7: define "pI"

Overall comment: My list of figure corrections is probably not exhaustive, I would suggest going back through everything to find other missing information, mismatched colors, labels that need definitions, etc.
Experimental design: See comments on conclusions that may relate to experimental design.
Validity of the findings: Comments on interpretation/conclusions:

I admit that I am only partly familiar with some of the techniques used in the manuscript. An over-arching question that I have is, How are your results/interpretations influenced by the fact that you are comparing DmdA vs a potentially “mixed bag” of other proteins (i.e. DmgdH + DmdA-like paralogs) that 1) may have multiple different functions and 2) represent different taxonomic groups?
For example, how is your comparison of purifying selection in DmdA versus non-DmdA clades (Lns 491-504) influenced by analysis of so many different taxa/potential functions?

Lns 407-408: If I understand correctly, by ‘second cluster’ this is the one in green (please clarify this in the text). You conclude that the number of paralogous genes is greater for Roseobacters versus SAR11. Does having greater representation of Roseobacter sequences on the tree influence this? What about the greater phylogenetic distance among members in the Roseobacters? I may be confused because I was under the impression that the green block included DmdA orthologs only.

Ln 546-548: I’m not sure I understand/agree with this conclusion. The authors say that this phenomenon would be rare, but could your interpretation potentially be wrong?
Firstly, is it true that both the dmdA_1 and dmdA_2 clades on the tree are all true DmdA sequences? (You reference a paper, Gonzalez, 2019, but this is based purely on computational analysis, not experimental verification of function) which gives me concern. For the tertiary structure analysis, you are feeding in known structures of DmdA and DmgdH, but you don’t have an accurate structure of whatever makes up the dmdA_1 and dmdA_2 clades. Could it be that you are seeing an effect of not having a good predicted model for dmdA_1/2, and those sequences are just matching up with the best hit, which is the "true" DmdA model? This goes back to my concerns about interpreting the results when you have these ‘mixed bags’ of protein sequences that could represent multiple, different functions. Alternatively, what if the ancestor of the protein famil looked more like DmdA; you are only two yellow nodes away from a different conclusion (Fig 7)?
Additional comments: The authors use a suite of phylogenetic and computational approaches to reconstruct the evolutionary timeline and history of DmdA in marine bacteria. The topic is timely and interesting overall, and there has been recent literature that questions when/how DMSP degradation genes evolved (with some controversy). So, I applaud the authors for tackling this question. My main issue with the manuscript has to do with clarity. Many figures need better descriptions/definitions in the legends; at times, it was challenging as the reader to interpret results because of this. There are also many figures and tables, and the paper would benefit from more consistency in colors/labels and possibly removing/consolidating some figures. I also question some of the conclusions that the authors draw, but these concerns may be addressed through clearer language and explanation in the text. My specific comments are listed herein.


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: CONSISTENT ADMINISTRATION OF CETUXIMAB IS ASSOCIATED WITH FAVORABLE OUTCOMES IN RECURRENT/METASTATIC HEAD AND NECK SQUAMOUS CELL CARCINOMA IN AN ENDEMIC CARCINOGEN EXPOSURE AREA: A RETROSPECTIVE OBSERVATIONAL STUDY
Review round: 1
Reviewer: 1

Output:
Basic reporting: No comment
Experimental design: No comment
Validity of the findings: No comment
Additional comments: Overall, this is a well written article that clearly explains the important real-world data of cetuximab-containing treatment in RM HNSCC. Authors should consider providing high resolution images for all figures.


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: CONSISTENT ADMINISTRATION OF CETUXIMAB IS ASSOCIATED WITH FAVORABLE OUTCOMES IN RECURRENT/METASTATIC HEAD AND NECK SQUAMOUS CELL CARCINOMA IN AN ENDEMIC CARCINOGEN EXPOSURE AREA: A RETROSPECTIVE OBSERVATIONAL STUDY
Review round: 1
Reviewer: 2

Output:
Basic reporting: In their manuscript the authors retrospectively analyze the efficacy of cetuximab based therapy in 106 Taiwanese patients suffering from R/M HNSCC in a real-world setting. Since the outcome parameters were comparable to what has been published in the literature, the authors conclude that cetuximab is effective in this population as well.
Although it is a strength of this manuscript provide real-world data in a population with a high percentage of carcinogen exposure, a couple of questions arose, when reviewing the manuscript:
-	The introduction section states that “oropharyngeal SCC accounts for the largest group of head and neck cancers related to HPV” (line 72) and that the most predominant site in Taiwan is OPC.  However, it has to be noted that the most predominant HNSCC in western countries is OPC as well, which is usually HPV negative (see Cramer et al. Nature Rev.Cancer or for epidemiology data extraction from https://gco.iarc.fr/; or Gatta et al. EJC 2015 for Europe). Only a minority of the patients in the EXTREME trial were HPV positive (Vermorken, Annals of Oncology 2014). Thus, the introduction should be revised accordingly.
-	The inclusion/exclusion criteria are poorly defined in the method section: Were patients included, which were platinum resistant? This seems to be likely, since patients resistant to CRT were included. Why were those patients not excluded? The EXTREME or TPEX trials excluded those patients. Why were patients included, who did not receive platinum based first line therapy such as MTX (line 145). This decision results in a heterogeneous population and a potential bias. The results are hardly comparable to the Extreme trial or the trials listed in table 5. All of them including the European real-world trial evaluated a well-defined homogenous population.
-	Likewise the ORR is considerably lower in this study compared to the aforementioned trials and especially to the Japanese trial. This should be stated and discussed accordingly.
-	It stated in the manuscript that cetuximab exposure <11 cycles is an independent risk factor for progression. However the reason for cetuximab discontinuation is not given. It is very likely that cetuximab was stopped because of disease progression. Therefore, disease progression might be the reason for cetuximab exposure <11 cycles or at least the very same endpoint and not the other way round?? What would figure 2A look like, when plotting the PFS curve in patients with at least SD vs. patients with PD?
-	The adverse event rate should be included in a real-world report and compared to the literature. There are studies in HNSCC that show that cetuximab can cause severe lung injuries in Asian patients (Nakano et al, Head and neck 2019). Was ILD observed in this population?
-	Additional ref. should be included and discussed such as Guo et al. Head and Neck 2014, who performed a cetuximab/platinum R/M HNSCC first line trial in a Chinese population.
-	Revision with respect to English grammar is advised (i.e. line 322-324 is hardly comprehensible)
Experimental design: See above
Validity of the findings: See above
Additional comments: See 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: CONSISTENT ADMINISTRATION OF CETUXIMAB IS ASSOCIATED WITH FAVORABLE OUTCOMES IN RECURRENT/METASTATIC HEAD AND NECK SQUAMOUS CELL CARCINOMA IN AN ENDEMIC CARCINOGEN EXPOSURE AREA: A RETROSPECTIVE OBSERVATIONAL STUDY
Review round: 1
Reviewer: 3

Output:
Basic reporting: The first sentence of the ‘results’ section in the abstract does not add much value. It would rather be more interesting for the reader to get a sense of what proportion of total HNSCC patients developed recurrent or metastatic disease within the timeframe of the study.

Lines 85 – 87: It is misleading to suggest that Cetuximab is first-line therapy for RM HNSS across the board. The authors should clarify the rationale for choosing Cetuximab therapy when CPS <0

Line 99-102: Please fix grammar

Line 171 – multivariable

Line 197-198 – Please add percentage

Line 214: Table 2 does not summarize ORR. Have the authors missed including a table

Line 222: The ‘median’ PFS was calculated as 6 months. This has been overlooked in multiple places

Line 300: Not sure how the conclusion of more frequent visits can be drawn from this dataset
Experimental design: 1)	Line 124: Were interviews conducted in all patients in the cohort? If not, this could lead to information bias, and preferentially higher recall in these patients compared to those who were recruited on the basis of EMR alone.
2)	Besides OS, and PFS, methods to assess categorical responses (CR, PR ,SD,PD) have not been detailed in the methods. Why was the RECIST methodology not used (PMC2785927, PMC5373019)? Additionally, was response determined at the time of first restaging or was this best objective response?
3)	Line 160: Unclear to the reviewer which patients represent the control group? Please refrain from using ambiguous terminology - this is a retrospective cohort study
4)	What was the median time interval between time of start of treatment and determination of response in all patients? What was the median number of cycles in all patients after which response was determined?
5)	Line 169-170. Unclear what the rationale is for excluding patients who were alive and without disease progression at the time of last follow-up – this is not a typical censoring strategy. In fact, it would lead to overestimation of the true hazard ratio
6)	Model building strategy is confusing. How were variables selected for inclusion in the final models? Additionally, multivariable models for both PFS and OS seem to be overfit, as there are likely more variables in the model than the number of events would allow. This reviewer recommends a best subsets or stepwise regression for more prudent model building
Validity of the findings: 7)	The results section is poorly written and is merely a line-by-line recapitulation of thee tables themselves. As such, the leader struggles with a lack of perspective. Along the same lines Tables 1 and 2 are largely uninformative. Since the authors seem to pivot around number of cycles of cetuximab CRT refraction, it would be interesting to see for instance what the distribution is of demographic characteristics is between >11 and <11 treatment cycles.
8)	The use of a binary variable for CRT use, as well as a separate variable for CRT refraction seems redundant. This reviewer recommends using CRT refraction only. Additionally, a large majority of patients were Stage IV at initial diagnosis. Were the response rates better in patients with stage I – III at initial diagnosis? Why were earlier stage patients included in the analysis?
Additional comments: In their work entitled, ‘ Consistent administration of cetuximab is associated with favorable outcomes in recurrent/metastatic head and neck squamous cell carcinoma at endemic carcinogen exposure area: a retrospective observational study’, Wang et al. have studied factors associated with survival in a cohort of RM HNSCC patients treated with Cetuximab in a region of high endemic carcinogen exposure. The authors have specifically reported an association between CRT-refraction and number of Cetuximab cycles on treatment response. While the analysis itself is not novel, the choice of study population with endemic carcinogenic habits, and lack of drug accessibility is potentially interesting. That being said none of the endemic factors seem to impact survival in the cohort – in fact smoking seems to have a protective effect which is odd. Furthermore, several issues exist as have been detailed


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: CONSISTENT ADMINISTRATION OF CETUXIMAB IS ASSOCIATED WITH FAVORABLE OUTCOMES IN RECURRENT/METASTATIC HEAD AND NECK SQUAMOUS CELL CARCINOMA IN AN ENDEMIC CARCINOGEN EXPOSURE AREA: A RETROSPECTIVE OBSERVATIONAL STUDY
Review round: 2
Reviewer: 1

Output:
Basic reporting: Although the authors addressed the majority of the issues stated, there are still a few issues pending:
-Abstract: A “conclusion section” is missing.
- it is still incorrect that “In western countries, oropharyngeal SCC accounts for the largest group of HNSCC”, since oral cavity is the largest group.
- Revision with respect to English grammar is still advised for the whole manuscript.
Experimental design: See above
Validity of the findings: See above
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: CONSISTENT ADMINISTRATION OF CETUXIMAB IS ASSOCIATED WITH FAVORABLE OUTCOMES IN RECURRENT/METASTATIC HEAD AND NECK SQUAMOUS CELL CARCINOMA IN AN ENDEMIC CARCINOGEN EXPOSURE AREA: A RETROSPECTIVE OBSERVATIONAL STUDY
Review round: 2
Reviewer: 2

Output:
Basic reporting: Please see comments to author
Experimental design: Please see comments to author
Validity of the findings: Please see comments to author
Additional comments: This reviewer appreciates the authors rebuttal and most issues that were raised have been adequately addressed. The flow of the manuscript is also much better. A few outstanding issues still remain that requires their attention, though missing line numbers made it difficult to recommend specific changes.

•	Several grammatical errors still exist, and a thorough proof-read is imminently warranted
•	Please replace multivariate with multivariable throughout the manuscript. The difference is key. Multivariate refers to multiple outcome which is not the case for this analysis
•	Per the letter – line 99-102 is still grossly incorrect – “Different from clinical trials…”. Please fix
•	Median time to determination of response should be included in the manuscript
•	Regarding the impact of endemic habits, what is the impact of OS in patients who have more than 1 endemic habit compared to those who have multiple endemic habits? For ex: smoking alone vs smoke + alcohol use?
•	Along the same line, the authors belief in the novelty of this work lies in the population being ‘endemic’. Perhaps a paragraph is warranted in the discussion section to go over how they are impacting treatment responses.
•	Study design: It would be important to clarify that the primary endpoint was assessed after treatment with cetuximab
•	Table 2:
Were SD patients also included in the calculation of ORR? If yes, how long were they classified as SD
What was the median time to disease progression?
Since 99.1% of patients progressed, how was DCR defined? No description of this estimation has been provided in the methods
•	Interesting that there are no differences in concurrent chemotherapy use between patients who received <11 vs >11 cycles. This would be an important fact to highlight
•	Please refrain from using the word ‘favorite’ in describing the predictor variable after multivariable adjustment
•	Table 3: Why suddenly change the annotation from ‘Cetuximab’ to ‘Erbitux’. Please be consistent


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 SURVEY OF RNA SECONDARY STRUCTURAL PROPENSITY ENCODED WITHIN HUMAN HERPESVIRUS GENOMES: GLOBAL COMPARISONS AND LOCAL MOTIFS
Review round: 1
Reviewer: 1

Output:
Basic reporting: It is well established that virus genomes can harbor vast amounts of sometimes overlapping information: binding sites for transcription regulators, ORFs, polyA signals, and more.  Virally-encoded RNAs can do much more than direct translation of proteins, including microRNAs and other forms of non-coding RNA.  This submission relates to tools the authors have developed for genome-wide discovery of RNA structures of potential biological significance.

The authors applied their algorithm to all nine human herpesviruses.  Most of the detailed descriptions relate to EBV, with one example from KSHV.  The analyses for all nine viruses are available for inspection and further analysis at a publicly-accessible website hosted by the Moss lab.

It seems clear that much of value can be learned from study of non-coding functions of virally-encoded RNA.  This work constitutes a significant advancement in development of tools for identifying candidates for experimental evaluation.  Making a database of a set of comprehensive analyses spanning all nine human herpesviruses greatly lowers the threshold for others to engage in this line of work.

As detailed below, there are numerous issues related to details of how figures were prepared that get in the way of understanding the results.
Experimental design: I had no major issues with the experimental design.

It is good that the authors ran their analysis on genomes of all nine human herpesviruses.

A brief summary of interesting features from each virus would increase the likelihood of the information being used.
Validity of the findings: The new tools were able to independently predict previously-identified bioactive ncRNAs of EBV, plus additional EBV species that seem worthy of experimental investigation.  One of the new predictions was experimentally validated.
Additional comments: 1.  While the work seems interesting, more needs to be done to make the work accessible and useful to people who might be able to make use of it.
a.  Every type of graphical element in figures needs to be explained, and repeated in other such figures, so the reader does not need to spend a day chasing down explanatory factoids needed to understand what was done.
b.  The purpose of every Supplementary table needs to be explained.
c.  Every column in Supplementary tables needs to be explained.
d.  Each of the Word files that contain collections of FASTA-formatted sequences needs an understanding-enabling explanation of what was included and why.
e.  In the figures, sequence coordinates need to be legible without magnification; if the numbers come out of some software that uses characters too small to be read, they need to be replaced with legible numerals in the version intended for publication.

2.  Fig. 4a includes several horizontal lines above “EBER2”.  What do they mean?  How is the reader supposed to decipher intent vs. irrelevant graphical residue.  Similar questions about Figs. 5 and 8.

3.  In Fig. 7, the colors used in the upper and second panel are described as being the same for the representations of the F/Q and U exons, but the colors don’t actually match, which places an unnecessary burden on the reader to decipher the intended meaning.  Few readers will persist.

4.  Table 1 mentions large numbers of “total bp” for each virus.  It is not clear how the numbers connect to the statement in the legend that “Total base pairs gives the number of stable pairs predicted in each genome”.  For HCMV, how do you go from a 236 kb genome to 1.13 million total bp?  Similar question for the others.

5.  The Supplemental Fig. 2 legend mentions red and blue bars for Z-values, but the entire plot is blue.  The graph says the scale ranges from -8.380 to 3.87, but that does not make sense relative to the graph that is shown (small y-values).

6.  In figures and at the website, I would like to see the folding information presented in the context of major well-understood genomic features, such as ORFs, polyA signals, etc. Including two or three tracks for display of such information as available in Genbank features tables would be helpful to many users.

7.  It is good that the authors ran their analysis on genomes of all nine human herpesviruses.  A brief summary of interesting features from each would increase the likelihood of the information being used.

8.  Is information available from RNAseq data that might provide additional validity for the presence of some of the predicted ncRNAs?

Suggested edits:
Abstract:  EBV is not the only herpesvirus with very high prevalence.  VZV, HHV-6B, and HHV-7 are in the same ballpark as described in the abstract for EBV.  A friend once screened >1500 specimens for antibodies against HHV-6 and found only one clear negative.

Abstract:  I am not sure what is meant by “transcriptome-wide”.  It seems like your analysis is based on examination of genome sequences, not on products of RNAseq.

Line 63 and 167:  In general, “herpesvirus” is better as one word.  Being consistent in usage is good, too.

Line 70:  Order Herpesvirales, Family Herpesviridae, Subfamily Gammaherpesvirus, Genus Lymphocryptovirus.  Italicize the Latinized taxon names.

Line 74.  “herpes simplex viruses 1 and 2”

Line 104.  It was not clear how the closely related lymphocryptovirus was used.

Line 206.  Something is missing after “in”.

Line 238.  “Whole cell RNA”


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 SURVEY OF RNA SECONDARY STRUCTURAL PROPENSITY ENCODED WITHIN HUMAN HERPESVIRUS GENOMES: GLOBAL COMPARISONS AND LOCAL MOTIFS
Review round: 1
Reviewer: 2

Output:
Basic reporting: This is a clearly written new comprehensive study of folding predictions for all member of herpesviruses known to infect humans. The background and introduction set the stage perfectly for the study although the sentence beginning at line 102 (“Here the ncRNA…”) seems to fit better within the last paragraph of the introduction (the text that follows the current positioning refers to previous studies, whereas this sentence implies a reference to the current study). The figures are all of high quality and are state of the art for presenting this type of data. Further, they clearly illustrate the points being addressed. All aspects of experimental design are well laid out and derived from previous groundwork.
Experimental design: All experiments are well designed that are well laid out and presented in a fashion that will allow for reproducibility
Validity of the findings: The findings are presented in an appropriate scientific manner and outline the strengths and limitations for the results.
Additional comments: Overall, this is a nice comprehensive study of folding predictions across the human herpesvirus clades. It is refreshing that a validation experiment is provided which suggests functional relevance of sequences within the BFRF1 3’ UTR that are predicted to form hairpins. The reporter system certainly appears to demonstrate different impacts on RNA stability and translation efficiency although it would have been nice if the authors had included mutational studies to formally demonstrate that the predicted structures (rather than the sequences themselves) are functional.

Overall, this is a well presented comprehensive analysis of predicted human herpesvirus structures and lays important groundwork for future functional studies.


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: EVALUATION OF DIFFERENT CULTURE MEDIA TO SUPPORT IN VITRO GROWTH AND BIOFILM FORMATION OF BACTERIAL VAGINOSIS-ASSOCIATED ANAEROBES
Review round: 1
Reviewer: 1

Output:
Basic reporting: The authors of the manuscript have long been working in the field of bacterial biofilms and reveal their significance in developing vaginal dysbiosis using in vitro models. In this manuscript, the authors test various culture media to analyze the ability of vaginal bacteria to grow in vitro. The selection of appropriate medium/a to generate suitable models would allow measuring the impact of other vaginal bacterial species earlier not tested. Evaluation of medium/a suitable for a generation multi-species biofilms allows modeling the strategies for the management and eradication of biofilms.
The aim of the manuscript is clear and unambiguous; the background has written very clear, and with deep knowledge in the field. The structure of the article is clear with sufficient tables and figures provided; raw data are included.
Experimental design: The experimental methods are well described, data from the technical replicates and independent assays are generated.
Validity of the findings: The data provided are well-grounded and statistically relevant. Conclusions are well-stated.

There is an issue to be addressed:
Table 1, footnote 2: for clarity, please, explain how do you know that strain UM241 “belongs to the cluster containing genomic species 1 to 4 as depicted in Figure 1 of Vaneechoutte et al., 2019, hence, likely genomic species 2 or 3”. Could you please provide any evidence for this statement in the article? UM241 strain does not belong to G. vaginalis, G. piotii, G. leopoldii, and G. swidsinskii as stated in Castro et al., 2020.

My suggestion:
Table 2: it is not clear what is the difference between medium sBHI and sBHI.Aa, BHV/ BHV.Aa etc. Could you please provide an explanation of Aa in e.g. a footnote? In the Methods section (subsection Bacterial species and growth conditions, line 105) designation of Aa is lost among the recipes of culture media.
Additional comments: The article is well written and it is of high importance for the generation of in vitro models analyzing microbial species interaction in vaginal.
There is an issue to be addressed:
Table 1, footnote 2: for clarity, please, explain how do you know that strain UM241 “belongs to the cluster containing genomic species 1 to 4 as depicted in Figure 1 of Vaneechoutte et al., 2019, hence, likely genomic species 2 or 3”. Could you please provide any evidence for this statement in the article? UM241 strain does not belong to G. vaginalis, G. piotii, G. leopoldii, and G. swidsinskii as stated in Castro et al., 2020.
My suggestion:
Table 2: it is not clear what is the difference between medium sBHI and sBHI.Aa, BHV/ BHV.Aa etc. Could you please provide an explanation of Aa in e.g. a footnote? In the Methods section (subsection Bacterial species and growth conditions, line 105) designation of Aa is lost among the recipes of culture media.


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: EVALUATION OF DIFFERENT CULTURE MEDIA TO SUPPORT IN VITRO GROWTH AND BIOFILM FORMATION OF BACTERIAL VAGINOSIS-ASSOCIATED ANAEROBES
Review round: 1
Reviewer: 2

Output:
Basic reporting: Evaluation of different culture media to support in vitro growth and biofilm formation of bacterial vaginosis-associated anaerobes

The author(s) tried to grow BV-associated anaerobes in different culture media. However, the selection criteria for the anaerobes was not clear. Using only PubMed as the only search engine will exclude other BV-associated microbes. The frequency level was not quantified. Stating very frequent or frequent is misleading as there other BV microbes more prevalent in certain populations.

I wonder why the author(s) did not reference the original source for the
Chemically defined medium simulating genital tract secretions (Stingley et al., 2014). Stingley et al are not the original developers of the medium but may have modified it by adding proteose peptone and ascorbic acid which have been documented by several authors.
These authors should be the right reference.
Geshnizgani AM, Onderdonk AB. Deﬁned medium simulating genital tract secretions for growth of vaginal microﬂora. J Clin Microbiol 1992;13236
Experimental design: The inclusion of Lactobacillus iners as a BV-associated microbes is still under debate as the microbes is very much found in all healthy women without symptoms.

The experimental design should have included vaginal secretion from BV subjects to see whether these microbes could be isolated from the various media used in this experimental study.

On the biofilm assay, the author(s) should explain why they did not use confocal microscopy to visualize the biofilm formed. Using the crystal violet has low sensitivity.
Validity of the findings: This statement "A particularity of NYC medium, compared to the other tested media, is the presence of proteose peptone no. 3, which has been described by the manufacturer as offering high nutritional benefits to fastidious anaerobic species by providing the necessary amount of nitrogen, carbon, amino acids, and essential growth factors" is also misleading as this factor was not determined.

This may not the only reason as proteose peptone is present in other Vaginally deﬁned medium 0.5% proteose peptone (VDMP).
Additional comments: In real clinical setting, how can the author(s) defend this statement?
"NYC medium revealed to be an ideal candidate for future studies addressing multi-species biofilm formation since this growth medium allowed significant levels of single-species biofilm formation" In reality, BV forms polymicrobial biofilms. There is no single-species associated with BV condition.


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: EVALUATION OF DIFFERENT CULTURE MEDIA TO SUPPORT IN VITRO GROWTH AND BIOFILM FORMATION OF BACTERIAL VAGINOSIS-ASSOCIATED ANAEROBES
Review round: 1
Reviewer: 3

Output:
Basic reporting: 1.	The authors reference Diop et al., 2019 (line 85) and list the bacteria in Table 1 as the rationale for selecting bacteria tested in this manuscript. Additional reasoning on why these bacteria were selected is needed. For example, why was Lactobacillus iners selected? Most readers outside the immediate field consider lactobacilli as being associated with health. It would be important to highlight that L. iners is present in high relative abundance and concentrations in women with and without BV and include appropriate references that discuss this point specifically (Petrova et al. 2017; Srinivasan et al., 2012). Likewise, given that Gardnerella vaginalis have now been classified as at least four different species, why was only one Gardnerella species selected for these studies? There is limited information as to which Gardnerella species may be important in BV, and hence it would be important to present data for all four Gardnerella species.  It is also unclear what search strings were used in Pub Med to result in the frequency of articles that were listed in Table 1 and they need to be clarified.

7.	There are areas where language can be clarified, improved or made concise. Examples below.
-	Line 119-120: Combine both sentences to make concise
-	Line 147: No need to emphasize that “our results demonstrated” that the different BV anaerobes had different nutritional requirements for optimal growth – this is to be expected and can be stated as such.
-	Line 168: similar, not similarly
-	Line 201: rephrase
Experimental design: 2.	Growth was assessed using optical density measurements and reported as a ratio of OD of the culture media relative to values at time 0. In many instances, the value was close to 1 (0.8 to 1.5). This would represent an OD of 0.1 at time 0 and 0.1 after the incubation period (can go up to 0.15) which really does not represent any growth. For example, an OD ratio of 1.4 (change in OD from 0.1 to 0.14) for Mobiluncus curtisii in NYC does not seem like growth. Measuring CFU/mL using colony counts would have been a better approach to evaluate growth and viability. I would recommend showing these data for at least the medium that the authors are proposing as optimal for growth (NYC).
3.	The authors nicely show that ascorbic acid may inhibit growth as is the case with Prevotella bivia in SB and SB.Aa medium. Practically no growth was observed for any bacterium in mGTS medium. Did the authors consider preparing mGTS medium without ascorbic acid to determine if the primary reason for lack of growth was the presence of ascorbic acid in mGTS medium?
4.	Table 3 shows growth and p-values represented in the form of letters to show comparisons between different referent groups. It would be easier if only one referent group was shown in this table and another table showed the different comparisons as a heatmap with actual p-values.
5.	Lines 241-245: The authors propose that ascorbic acid may play a role in recolonization of the vaginal environment with lactic acid-producing bacteria. Did the authors consider testing the growth of Lactobacillus crispatus or L. jensenii (lactic acid producers)  in media with ascorbic acid to test this hypothesis?
6.	How many times were bacterial cells passaged before a new stock was obtained from the freezer?
Validity of the findings: No comment
Additional comments: The manuscript by Rosca et al. evaluates 5 different culture media with and without supplementation with ascorbic acid for growth of 6 bacterial species that have been associated with the common dysbiotic condition, bacterial vaginosis. One goal was to identify a cultivation medium that can support in vitro biofilm formation for all bacterial strains tested such that future co-culture experiments evaluating multi-species interactions can use a single cultivation medium in experiments. While the data presented will be of value for investigators interested in conducting in vitro mechanistic studies of BV-associated anaerobes, I have some questions regarding the study which are listed in the sections 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: EVALUATION OF DIFFERENT CULTURE MEDIA TO SUPPORT IN VITRO GROWTH AND BIOFILM FORMATION OF BACTERIAL VAGINOSIS-ASSOCIATED ANAEROBES
Review round: 2
Reviewer: 1

Output:
Basic reporting: No comment
Experimental design: No comment
Validity of the findings: No comment
Additional comments: I have read the rebuttal letter and the revised manuscript.  All my comments are addressed in the revised manuscript.


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: EVALUATION OF DIFFERENT CULTURE MEDIA TO SUPPORT IN VITRO GROWTH AND BIOFILM FORMATION OF BACTERIAL VAGINOSIS-ASSOCIATED ANAEROBES
Review round: 2
Reviewer: 2

Output:
Basic reporting: No comment
Experimental design: The authors have made and supported their case
Validity of the findings: The authors have provided extra points including references to prove their findings.
Additional comments: In my opinion, authors did go extra mile to provide answers to the queries. Good job!!!


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: EVALUATION OF DIFFERENT CULTURE MEDIA TO SUPPORT IN VITRO GROWTH AND BIOFILM FORMATION OF BACTERIAL VAGINOSIS-ASSOCIATED ANAEROBES
Review round: 2
Reviewer: 3

Output:
Basic reporting: The edits made to improve clarity is appreciated.

One quibble is on line 90. L. iners does not necessarily play a controversial role, just we have a poor understanding of the role of L. iners in bacterial vaginosis as it is present both in women with and without BV.

Perhaps re-state along the lines of: L. iners was also included in the study as this bacterium is present in women with and without BV and its role in the vaginal microenvironment is poorly understood.

Also Line 246: I believe the word here should be "recipe" not "receipt."
Experimental design: I applaud the authors on being responsive to the comments made by the authors including performing additional experiments

1. to evaluate whether there were any differences in biofilm mass due to specialized components in NYC with proteose peptone no. 3 compared with NYC with peptone from meat

2. to evaluate differences if any in biofilm formation by the validly named Gardnerella species including G. piotii, G. leopoldii, G. vaginalis, and G. swidsinkii
Validity of the findings: No additional comments
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 MULTI-CLASS CLASSIFICATION MODEL FOR SUPPORTING THE DIAGNOSIS OF TYPE II DIABETES MELLITUS
Review round: 1
Reviewer: 1

Output:
Basic reporting: Clear and unambiguous, professional English used throughout?
The manuscript is well written and easy to read for the most part.

Literature references, sufficient field background/context provided?
Yes, the related work section is okay.

Structure conforms to PeerJ standards, discipline norm, or improved for clarity?
Yes, it meets the requirements.
Experimental design: Original primary research within Aims and Scope of the journal?
Can be improved.

Research question well defined, relevant & meaningful. It is stated how research fills an identified knowledge gap?
Yes.

Rigorous investigation performed to a high technical & ethical standard?
Can be improved.
Why this paper only compares tree based algorithms? As far as I know, there are many other advanced machine learning algorithms can be used to make predictions, such like neural networks, SVM, etc. Will bagging and boosting be better than these algorithms?

Methods described with sufficient detail & information to replicate?
Yes, methods can be replicated.
Validity of the findings: There are few explanations for the selected features, and there is little discussions how the features selected in this study different from other studies.
Additional comments: The authors built an appropriate model for predicting ICD-10-CM code by utilizing bagging and boosting ensemble techniques for Asian T2DM patients. This is a small innovations but it’s interesting.


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 MULTI-CLASS CLASSIFICATION MODEL FOR SUPPORTING THE DIAGNOSIS OF TYPE II DIABETES MELLITUS
Review round: 1
Reviewer: 2

Output:
Basic reporting: The paper is technically  and logically sound and will contribute the scientific knowledge.
The introduction and literature,methodology, references are presented in systematic way.
The English proof reading is recommended for further improvement.
The figures are not suitable for publication and need proper modification.
Experimental design: The authors performed enough experiments for proposed method.
Validity of the findings: The experimental results are significants
Additional comments: The authors in this study design a multi-class classification model for supporting the diagnosis
of type II diabetes mellitus. To me the paper is well presented and suitable for publication in journal. Furthermore, 1 recommend to authors to incorporate the following changes for further improvement of the paper.
1.	Remove all abbreviation from abstract and define in remaining parts of the paper such as F1, C5.0 etc.
2.	Clearly mention your contribution in introduction section.
3.	In last paragraph of introduction mention the paper organization
4.	The literature need systematic way to write that present the existing methods issues and the important of proposed method.
5.	This data set is linear or nonlinear.
6.	The theoretical and mathematical back ground of the ML classifiers are necessary.

7.	Authors only used machine learning algorithms for classification, I recommend to use Deep learning model for classification also and compared the prediction performance of both.
8.	The authors also need to use LOSO, Hold out CV.
9.	Used other performance evaluation metrics such, MCC, AUC ROC processing time of the model.
10.	Why Random Forest algorithm performance high as compared to other models.
11.	Statistically compare the ML models performance using McNamara’s test.
12.	The figures and tables are not adjusted properly, all the figures  X-axis and Y- axis titles are missing. Further the figures are not suitable for publication.
13.	Compare you work with state of the art works
14.	The conclusion is not clear
15.	please use proper journal reference format all references are not properly used.


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 MULTI-CLASS CLASSIFICATION MODEL FOR SUPPORTING THE DIAGNOSIS OF TYPE II DIABETES MELLITUS
Review round: 2
Reviewer: 1

Output:
Basic reporting: no comment
Experimental design: no comment
Validity of the findings: no comment
Additional comments: This manuscript has been greatly improved, but a couple of minor corrections should be incorporated:
1.Is it Matthew correlation coefficient or Mathew correlation coefficient?
2.The keywords should be modified. I think Bagging and Boosting can not represent the entire article.
3.Line 105-241: Can be simplified


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 MULTI-CLASS CLASSIFICATION MODEL FOR SUPPORTING THE DIAGNOSIS OF TYPE II DIABETES MELLITUS
Review round: 3
Reviewer: 1

Output:
Basic reporting: no comment
Experimental design: no comment
Validity of the findings: no comment
Additional comments: The authors have addressed all my concerns I  had with the previous submission.  I recommend an accept of this paper.


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: EFFECT OF NEST AGE AND HABITAT VARIABLES ON NEST SURVIVAL IN MARSH HARRIER (CIRCUS AERUGINOSUS) IN A FISHPOND HABITAT
Review round: 1
Reviewer: 1

Output:
Basic reporting: The manuscript reports the daily survival rates of Marsh Harrier (Circus aeruginosus) nests in relation to different environmental and temporal variables. It is a novel and well written contribution, although I find some problems in the general structure that concern me. I make numerous comments throughout the ms, among the most important ones I highlight that in the Introduction section, the background is not well ordered and does not allow asking clear questions about the objectives of the study. Also in Discussion I find some problems that deserve to be addressed.
Since English is not my native language, I have made only a few comments regarding writing.
The literature cited also worries me, since it is too broad and linked to birds with very different life stories. In this sense, I suggest adjusting Introduction and Discussion to raptors, preferably those that nest in the ground.
Experimental design: As I mentioned above, the background does not clearly link to the question in this study. Methods are well developed, I only make a few small observations. The results are clearly presented, I only make suggestions about the figures.
Validity of the findings: Discussion and Conclusions need to be revised (see comments in the text).
Additional comments: I believe the manuscript is potentially publishable after major changes in the Introduction and Discussion sections. Most of the comments are represented in the previous items.


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: EFFECT OF NEST AGE AND HABITAT VARIABLES ON NEST SURVIVAL IN MARSH HARRIER (CIRCUS AERUGINOSUS) IN A FISHPOND HABITAT
Review round: 1
Reviewer: 2

Output:
Basic reporting: Zaremba et al. analyses potential factors affecting daily survival rates of marsh harriers at nest in relation to predation. They focus in three types of factors: microhabitat characteristics of the nesting place, time of breeding and nest age. For this, they surveyed a total of 82 marsh harrier nests in four fish ponds in Poland in years 2008, 2009, 2011, 2018 and 2019. The paper is clear and well written and the scope is valuable, as information on nesting predation and its main drivers has been largely unexplored for the marsh harrier. However, I have some concerns about the data and statistical analyses.
Experimental design: My main concern is related to potential effects of non-independence of the data used for analyses. Non-independence might be occurring at different levels in this study (repeated years, repeated breeding locations (and maybe breeders in those locations) among years, repeated sampling in the four fishpond complexes considered and non-independence related to spatial autocorrelation of neighbouring nests). This is important as, if for example, predation is mainly concentrated in a few locations (with similar habitat characteristics given their non-independence), you might find a significant relationship with such characteristics even if they are not the ultimate reason of differences in DSR. To deal with this, authors should account for non-independence better. There are different ways to account for this: e.g., include breeding sites, years or locations as variables (random terms if possible) in models, include the X and Y coordinates, and all of their interactions terms up to the third order (Legendre & Legendre, 1998) in models, or apply Moran I test statistics to analyses non-independence in model residuals. Authors could also provide a better description of the distribution of nests depredated across fishponds, years or locations.

Second, the authors find an effect of time and nest age on DSR. However, detection probability of nests seems to be in turn affected by time. As authors stated, “a total of 82 nests were discovered in the study areas – 27 during the egg-laying phase, 53 during egg incubation and 2 during the early nestling period”. This suggests that higher DSR early in time, could be simply due to the fact that detection is lower early in the season, and as so nests depredated (i.e., early predations are not computed, because nests are simply not detected). To separate the effect of time on DSR from sampling biases, authors should account for detection differences across time in models.

Third, I have also concerns related to the variables used in analyses. Previous evidence (e.g., Cardador et al. 2011 Anim. Consev.) has shown that nesting site selection of marsh harriers is influenced by habitat characteristics at two scales (nesting site and foraging habitat). Both of these scales are, in turn, expected to affect predation risk at nests. Particularly, foraging habitat quality is expected to have a direct influence on time dedicated to parental care. Thus, considering broader scale variables might largely improve analyses.

Fourth, and related with the comment above, according to deviance information provided in table 2, authors’ final models do not fit very well the data (only 11% of deviance explained). This suggests that authors might be missing some relevant factors explaining DSR. Habitat at broader scale can be one of this. But other factors such as conspecific densities or individual quality could be also relevant. Authors should consider including some of such variables to improve model performance. At the very least, the low fit of models and its potential reasons should be better discussed.

More specific comments:

Line 99: Could you provide some more information on fishpond complexes? For e.g., potential differences in their surrounding habitat or in density of predators,…

Line 125-126. “A nest was considered to have been depredated when it was found empty before the predicted date of fledging, which is 35 days of age according to Witkowski (1989)”. What was the previous contact - 7 days earlier or more? This is important because, particularly in late stages, you might also be confounding predation with fledging. Apart from the nest empty, did you detect any other sign of predation? Also, for depredated nests, when was the late contact with breeders? Is it possible that for some predations, parents abandoned first and then the nest is depredated?

Lines 223-224: “The reason for this pattern could be that the earliest breeding birds are often older and more experienced than late nesters”. In Cardador et al. 2012 Plos one, we found evidence for this. Related to this, did you find differences in the phenotype of birds breeding earlier (i.e., grey vs. brown males)?

Figures: Providing raw data apart from model predictions might be more informative.
Validity of the findings: Results of the study are well presented and discussed, however they might be flawed by  some methodological issues commented above.
I hope my comments to improve it could be of help.
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: EFFECT OF NEST AGE AND HABITAT VARIABLES ON NEST SURVIVAL IN MARSH HARRIER (CIRCUS AERUGINOSUS) IN A FISHPOND HABITAT
Review round: 2
Reviewer: 1

Output:
Basic reporting: .
Experimental design: .
Validity of the findings: .
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 DESCRIPTIVE STUDY OF RANDOM FOREST ALGORITHM FOR PREDICTING COVID-19 PATIENTS OUTCOME
Review round: 1
Reviewer: 1

Output:
Basic reporting: The authors analysed many different clinical measures in 126 patients affected by COVID-19 from the Wuhan Fourth Hospital. They performed a descriptive study by identifying as the main predictors of the clinical outcomes LDH value higher than 500U/L and Myo value higher than 80ng/ml. They tried also to use very different features and a random forest classifier in order to predict the outcome of a specific patient affected by COVID-19 (alive/died). The manuscript is well articulated and written. I really appreciated also the supplementary material for reproducing the results of the paper and the idea to share all the important data for the fights against the virus.

In my opinion figure 1, 2, and 3 can be reviewed. The thickness of the lines is very small and the labels on the axis are not completely clear. The overall impression of the figures is that the resolution should be higher. The impression is the same for the two different equations in the methods section.

In the text there are different typing errors:
Line 112 the authors wrote Pearce correlation: do the authors mean Pearsons correlation?
Line 163 "alvie" instead of, I suppose, alive.
Line 181 the authors wrote, “We divided the data into a training set and a test set at a ratio of 1: 4 (23：96）”. However, by opening the excel file of the training data (S3) there are 96 samples for the training set. In the text, it seems the opposite (23 for training and 96 for testing).
Experimental design: In the experimental design, in my opinion, there are two different points that should be revised:

1)	The binary classification task could be affected by the class imbalance problem (16 deaths / 103 no deaths). In this setting, the classifier will be able to identify the patients in the "no deaths" class becoming very specific. In order to overcome this problem, I recommend using an approach based on oversampling procedure (such as ADASYN) [1]-[2] before performing training and testing procedures. It is important to increase the number of observations in the "deaths" class to avoid the problem. Alternatively, it should be possible to reduce the number of observations in the no deaths class until 16. In this way, there are 32 observations. Then, using only two features (LDH and Myo) with a simpler classifier than RF like Linear Discriminant Analysis. This depends on the authors. In the latter case, the classification task becomes feasible. By selecting 90% for the training (28 observations) it is possible to estimate the only 2 weights (one for LDH and one for Myo).

2)	Another point is that the results are not presented after a cross-validation procedure. In this way, the results are biased depending on the training and testing set selected. If I try to perform the same analysis with different training and testing sets maybe the results will be different. I recommend performing also a cross-validation procedure. Training and Testing procedure repeated at least 5 times in order to generalize the results for the classification task. The authors should present the mean value of the AUC in the 5 different testing sets. This task is needed independently from the classifier used for the procedure.

References:

[1]-Sciaraffa, Nicolina, et al. "Double-Step Machine Learning-Based Procedure for HFOs Detection and Classification." Brain Sciences 10.4 (2020): 220.

[2]-He, H.; Bai, Y.; Garcia, E.A.; Li, S. ADASYN: Adaptive synthetic sampling approach for imbalanced learning. In Proceedings of the 2008 IEEE International Joint Conference on Neural Networks (IEEE World Congress on Computational Intelligence), Hong Kong, China, 1–8 June 2008; pp. 1322–1328.
Validity of the findings: The results analysis of the data is well explained and the data are the results of months of monitoring during a pandemic. The results could improve for sure the knowledge of the scientific community about the virus.

The statistical analysis presented in this work are strong and robust and gives an exhaustive overview of the effects of COVID-19 on the patients. Furthermore, all the analyses confirmed the fact that it is important to constantly monitor the clinical measures of the patients in order to predict the effects of COVID-19 on the specific patient.
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 DESCRIPTIVE STUDY OF RANDOM FOREST ALGORITHM FOR PREDICTING COVID-19 PATIENTS OUTCOME
Review round: 1
Reviewer: 2

Output:
Basic reporting: The English language should be improved throughout the manuscript to ensure the readers can understand the text. Some examples of English grammar mistakes include: line 26 (dead or deceased, not died), 27 (was contributed?), unnecessary articles (“the COVID-19”, line 50), lines 59-60, lines 69-71 (run-on sentence), lines 96-97 (incomplete sentence).
Experimental design: Introduction
Lines 63-65: Add further detail on why this is an important topic. What is the benefit of understanding which clinical characteristics predict disease outcome?

Methods:
How were patients selected? What was the study design?
Line 80-81: how was disagreement among the medical record collectors/coders handled? Was each record assessed by one researcher, two or three?
Data collection: what were the outcomes recorded? Discharged vs Dead? Or Alive (including still hospitalized) vs Dead?
Lines 85-88: Were you testing that each continuous variable was normally distributed vs not-normally distributed with t-tests? Or were you comparing the distribution of the continuous variable between the two outcome groups? As stated, it is unclear. Normality should be assessed prior to the application of the t-test. Also, how was the elevated type I error due to multiple comparisons addressed?
Lines 92-98: Please provide additional data on tree fitting, such as pruning and tree growth parameters, number of trees, and the size of the training vs testing sets. Some of this information is in lines 173-189 but should be moved from Results to Methods.

Results (many of these should be addressed by adding detail to Methods section):
Lines 134-135: What were the criteria for determining moderate, severe and critical illness?
Lines 136-137: How many were alive and discharged vs alive and hospitalized? If they were still hospitalized, then the final outcome is unknown.
Lines 140-151: When were laboratory values measured relative to admission? The time of measurement could confound the relationship between laboratory values and outcome. For example, if laboratory values improve during hospitalization for alive patients vs becoming worse for dead patients, then the time of measurement will impact the relationship between laboratory value and outcome.
Lines 196-197: How was the Pearson correlation coefficient incorporated into the trees to avoid over-fitting?
Lines 215-217: How were the 80ng/mL Myo and 500U/L LDH thresholds selected? The Myo threshold is the upper limit of the reference interval (Table 2) but the LDH threshold is much higher than the reference interval. For consistency, I suggest also using the upper limit of the LDH interval or a multiple of the upper limit as the threshold.
Lines 223-225: I don’t think the relationship between poor prognosis and elevated LDH levels is clear. Many patients that survived had levels of LDH outside the reference range (Figure 3B, Table 2).
Line 226: What was the threshold for Myo and LDH associated with these ROC values?
Table 1: Under clinical outcomes there is “Cure Death” and “Death”. Do you mean “Cure” and “Death”? Also, in the text patients are referred to as “Alive” and “Dead”. Which is the actual outcome measured, cure or alive?
Table 2, Headings are unclear: “Patient amount”, “Patient value of deviation”
Validity of the findings: Discussion:
Lines 231-239; 244-253: This seems more appropriate for the Results section
Lines 262-264: This sentence is unclear. What is meant by “high pressure”? High blood pressure?
Line 266-267, 276-277: Where is the partial correlation of the Myo and LDH values with survival? Figure 2 shows partial correlation among the independent variables only.
Please include a discussion of why this work is important and the impact it will have on the treatment of COVID-19 patients or public health response to COVID-19.
Additional comments: This manuscript addresses a timely problem, COVID-19, and could provide insight into patient risk factors for severe disease and death. Random forests are well-suited to this classification problem. However, I have two main concerns with the methodology: (1) censored outcomes, (2) unbalanced data. These concerns need to be addressed prior to publication. Additionally, further detail is required in the Methods section and the English grammar needs to be edited throughout for clarity.

Censoring of outcomes: It is unclear if the classification of alive vs dead represents the final status of each patient. Some patients that were alive on the date of the medical record examination may die at some later point. This can bias the conclusions of the classification algorithm. Therefore, the outcome criteria need to be more precise. Ideally the outcome is discharged alive vs died because this would include only patients that have progressed completely through the clinical disease. Alternatives could be alive vs died after a certain number of days following admission. The time-period following admission should be determined by considering the clinical course of the disease.

Unbalanced data: Algorithms that are trained on unbalanced data (unequal numbers of alive vs dead) can result in poor performance. Since the algorithms minimize the overall error rate, they tend to perform better on the majority class (in this case “alive”) rather than the minority class. In this data set, an algorithm can be correct 87% of the time by just guessing “alive” for every patient. The authors should address this issue. There are many ways to use random forests with unbalanced data, including over-sampling the minority group and under-sampling the majority group.


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 DESCRIPTIVE STUDY OF RANDOM FOREST ALGORITHM FOR PREDICTING COVID-19 PATIENTS OUTCOME
Review round: 1
Reviewer: 3

Output:
Basic reporting: The authors conducted a retrospective cohort analysis including 126 patients diagnosed with COVID-19 from Wuhan Fourth Hospital. They compared the clinical characteristics of patients between alive and deceased patients. They also conducted a random forest classification model, to find the optimal diagnostic predictors  for patients' clinical outcomes between those groups. They identified myo and LDH as the influential features.
1.	The English language and grammar should be improved throughout the text.
2.	Throughout the manuscript, there are a number of typing errors, such as:
Spaces before and after commas and parentheses;
Line 88 “spss” should be in capital letters;
Line 390 and Table 1: “condnition” must be condition;
Line 394 and Figure 2 caption: “Pearce” Correlation must be Pearson Correlation; etc.
3.	The quality of the figures should be improved
4.	In the title and conclusion parts, authors are talking about machine learning algorithms for predicting COVID-19 patients outcome, however the only method they use is Random Forest.
5.	References are not well-written.
Experimental design: 1.	The authors should give a clear description and contribution of their workflow, by mentioning their aim in each part.
2.	In line 134, they talk about moderate, severe and critical patients. Is there a measure to find the severity?
3.	In Figure 2 B, there is no need to show the AUC result for the training data.
4.	As shown in Fig 2.3, number of tree is chosen as 500; but they should discuss all other hyperparameters of Random Forest model; and the reasons to choose those parameters in their model.
5.	There are some independent variables whose correlations are high (in Figure 2A). Authors should mention whether they conducted an investigation to find the best subset (feature selection).
6.	The Random Forest algorithm can be affected by the class imbalance problem. Authors should mention how they handled this problem.
7.	In line 226 and Figure 3.C, they should give an information about the threshold for the variables (myo and LDH) associated with the ROC values.
Validity of the findings: 1.	The authors should mention whether they take the censoring observations into account. (alive/deceased)
2.	In lines 91-95 they talk about different R packages. Did they used a different package to build their model; and then another package for validation; it is unclear. For more consistent results, I recommend using a single package, like caret, which can handle all their workflow.
3.	They can also improve their results part, talking about the importance of their results, in order to give much deeper information to the readers.
Additional comments: In my opinion, the introduction part should be improved. The authors should talk more about the backgroud of their study, search for other similar studies in the literature; and they should mention about their motivation, and the contribution of this study.
They should address the problems or limitations of their study, such as censoring patients
English grammar needs to be edited throughout the manuscript.


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 DESCRIPTIVE STUDY OF RANDOM FOREST ALGORITHM FOR PREDICTING COVID-19 PATIENTS OUTCOME
Review round: 2
Reviewer: 1

Output:
Basic reporting: I would like to thank the authors for the great effort made.

The overall quality of the manuscript has been improved after the review. In particular, the manuscript now is very well articulated and explained. Also, fluency has been improved.
The description of the classification task in the method section is reasonably detailed and all the methodological steps are well explained
Experimental design: The computations have been performed using an oversampling procedure in order to avoid class imbalance problem. The classification results are showed for the training and test sets for avoiding overfitting issues.
Validity of the findings: the use of random forest classifier, with features derived from COVID-19 patients, such as LDH and Myo could allow predicting the prognoses at an early stage and provide scientific data for mortality reduction.

In my opinion, the study of classification accuracy using LDH and Myo as a feature is very important because it provides an objective measure of importance for a clinical measure which can help in identifying the stage of the disease.
Additional comments: Since all the requests made, have been addressed, I recommend this work for the publication.

I found some spelling mistakes that should be checked and I recommend a careful reading of the manuscript.


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 DESCRIPTIVE STUDY OF RANDOM FOREST ALGORITHM FOR PREDICTING COVID-19 PATIENTS OUTCOME
Review round: 2
Reviewer: 2

Output:
Basic reporting: The authors state they've implemented English editing, however the response letter is poorly written.
Experimental design: In my opinion, the authors try to address an important problem. However, it feels like they still lack necessary skills to conduct the machine learning pipeline for their valuable dataset.
Validity of the findings: The response they provided unfortunately does not satisfy my concerns. I think adding a new author did not improve the presentation of the results.
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: CORRELATION BETWEEN OBESITY AND CLINICOPATHOLOGICAL CHARACTERISTICS IN PATIENTS WITH PAPILLARY THYROID CANCER: A STUDY OF 1579 CASES: A RETROSPECTIVE STUDY
Review round: 1
Reviewer: 1

Output:
Basic reporting: This article is written well for the most part. Paragraphs and sentences needs to be split up as noted below. It has enough references.
Tables are fine but might be a bit too many. However, I think some additional analyses should be done.
Experimental design: This was done well.
Validity of the findings: Mostly ok but there are some issues with confidence intervals and data as noted below.
Additional comments: This article was written by a group from China about association of BMI with thyroid cancer aggressiveness. This is one of many studies of its kind but may be one of the largest single institution study.  Usually the benefit of single institution is that details that would have otherwise not been seen on large national databases can be seen.  I believe the study was done well but could use some improvements.

MAJOR revisions:
1.	Methods, line 77:  How was TNM stage calculated?  On presentation? I assume this is the case, but this should be mentioned.  Also how did you determine TNM stage IV?  via RAI scan 6 weeks postop?
2.	Methods line 82: Could the authors do analyses and split the obese from the morbidly obese categories? What are the BMI groups for those (since they differ in China)
3.	Line 102—why is menopause included in this article?  What is the evidence on how this affects thyroid cancer other than age?
4.	Lines 110-111, the details for this should be added (not just “there is a difference”)
5.	Line 116:  did you split this analysis by age?  I saw the atble with over 55, but truly the TNM/AJCC stages being used for all patients is confusing to assess since they differ by age. SO both above and below age 55 tables should be added.  Also, can you provide anaylsis also based on aggressive features rather than AJCC? i.e. nodal disease/metastatic disease, etc? that way age isn't as much of a factor?
6.	Line 134—I am not sure this is accurate data as written. These authors added both new cases and deaths—but it needs to be clearer. Does this mean that of everyone who died from thyroid cancer, 14% of the deaths occurred in China?
7.	The whole page of lines 147-161—is way too long. It needs to be split up into paragraphs. Very hard to read
8.	Lines 152-156—which study is “this” referring to? The one I am reviewing or the one you have referenced?
9.	Table 3—Lymph node metastases should be added to the text –this is important
10.	Table 6—the confidence intervals are not normal. Why is this and please correct.  I think some data was included that has skewed this and should be removed.
MINOR revisions:
1.	The authors’ degrees are not written so it is difficult for me to assess their level of competency. Please add those to the manuscript
2.	In the Abstract—the author’s should include the definitions of obesity that they used since it is different in China than other parts of the world. They should also detail all the different BMI groups here
3.	T stage should be listed in numeric form (3/4) and TNM should be listed in roman numerals (III/IV)—please change throughout manuscript
4.	The sentence in line 105 is too long—needs to be split up