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 FUNCTIONAL MAGNETIC RESONANCE IMAGING INVESTIGATION OF THE AUTONOMOUS SENSORY MERIDIAN RESPONSE
Review round: 2
Reviewer: 1

Output:
Basic reporting: This is clear.
Experimental design: This seems to be done to a good standard though I am not an expert in fMRI.
Validity of the findings: The analyses seem robust and statistically sound; the conclusions are based on the data and any speculation is clearly identified as such.
Additional comments: I think the authors have done a good job of revising the manuscript. Thank you for taking on board my 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 FUNCTIONAL MAGNETIC RESONANCE IMAGING INVESTIGATION OF THE AUTONOMOUS SENSORY MERIDIAN RESPONSE
Review round: 2
Reviewer: 2

Output:
Basic reporting: no comment
Experimental design: no comment
Validity of the findings: no comment
Additional comments: The authors have adequately addressed my comments and I appreciate they have added additional figures showing the interaction effect and the beta values of individual participants.

A minor point is that the labels 'ASMR Group' and 'Ctl Group' are not entirely visible in Fig. 3.


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: MOLECULAR MECHANISMS LINKING PERI-IMPLANTITIS AND TYPE 2 DIABETES MELLITUS REVEALED BY TRANSCRIPTOMIC ANALYSIS
Review round: 1
Reviewer: 1

Output:
Basic reporting: -The language is professional and clear.
- The research question is clearly stated and no outlandish conclusions are drawn
Experimental design: - How many datasets were available in GEO for this study? What were the criteria for choosing these two datasets?

- Please rephrase line 25-26

- Please explain more clearly what 'experimentally validated genes from T2DM' means. Where was this differential expression observed? In blood, or tissue or some other particular sub-condition? It is important to know in what context these genes are associated with T2DM
Validity of the findings: Results

-line 132-133: What explains the 4-fold difference in DEGs between the two selected datasets?

- T2DM is the pre-existing condition, so discussion of results should be ordered with T2DM first then followed by peri-implantitis, which presents a clearer picture.

- Comparison of peri-implantitis in normal vs T2DM patients will give a more complete picture of the differential mechanisms
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: MOLECULAR MECHANISMS LINKING PERI-IMPLANTITIS AND TYPE 2 DIABETES MELLITUS REVEALED BY TRANSCRIPTOMIC ANALYSIS
Review round: 1
Reviewer: 2

Output:
Basic reporting: no comment
Experimental design: no comment
Validity of the findings: no comment
Additional comments: Yu et al in their manuscript entitled “Molecular mechanisms linking peri-implantitis and type II diabetes mellitus revealed by transcriptomic analysis” performed a bioinformatic study of existing experimental datasets, aimed to determine putative molecular links between peri-implantitis and T2DM by identifying cross-talk genes, biological processes and signaling pathways involved in both diseases.
The results concluded that 3 hub genes IL-6, NFKB1, and PIK3CG expression along with the IL-17 signaling pathway were the top candidate molecular linkage mechanisms between peri-implantitis and T2DM.

In general, as was mentioned a limitation, this study arose from bioinformatic data mining of experimental transcriptomes, and lack of experimental validation in clinical or in-vitro studies. Thus the results could only be regarded as hypotheses-driven data.

Major point:
A table is needed for briefly describing the functions of the 3 hub genes (IL-6, NFKB1, and PIK3CG), 3 cross-talk genes (PSMD10, SOS1, and WASF3) and 8 cross-talk genes (PSMD10, PSMD6, EIF2S1, GSTP1, DNAJC3, SEC61A1, MAPT, and NME1).

Minor points
1.	Type 2 diabetes, instead of type II diabetes (title, line 104, and Fig 1 legend)
2.	line 126, using a (redundant repeat)
3.	line 193, “Three” common leader genes; instead of “3” common leader genes


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: MOLECULAR MECHANISMS LINKING PERI-IMPLANTITIS AND TYPE 2 DIABETES MELLITUS REVEALED BY TRANSCRIPTOMIC ANALYSIS
Review round: 1
Reviewer: 3

Output:
Basic reporting: The review is very well written piece of scientific work. It is clear what the study wanted to achieve, how it was done and the results/discussion of the article is clear.
Experimental design: They used the most appropriate software available in this bioinformatic analysis. The research methods were well executed, rigorous using multiprong analysis from genes to the protein interaction to establish co-relation between the two disease. Also with the existence of only a handful of literature or studies that correlates T2DM with peri-implantitis, this study stands out to be a needed one to fulfill the present gap.
Validity of the findings: The results/discussion and conclusion section of the study were well described overall. Whenever applicable proper statistical methods were applied to discern the significance of the study. The study at the end lists the limitation and suggests potential in-vitro experiments needed to be conducted to verify the current findings.
Additional comments: Nice and scientifically stimulating work.


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: MOLECULAR MECHANISMS LINKING PERI-IMPLANTITIS AND TYPE 2 DIABETES MELLITUS REVEALED BY TRANSCRIPTOMIC ANALYSIS
Review round: 1
Reviewer: 4

Output:
Basic reporting: Basically, this article is clear and well-organized. However, the rationals to do this experiment to investigate the possible linking between T2DM and peri-implantitis are relative weak and vague. I hope the author should emphasize why this study was initiated and why?
Experimental design: The experimental design is fine. But the author should explain a little bit more about why the author choose this kind of software, such as network analysis and...etc. because current there is many software available.
Validity of the findings: The novelty is fine and this approaches should be an alternative method to explain the link between T2DM and peri-implantitis.
Additional comments: This rationale of this study, and clinical relevant of  this study should be emphasized and re-organized.


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: INITIAL DECOMPOSITION OF FLOATING LEAF BLADES OF WATERLILIES: CAUSES, DAMAGE TYPES AND IMPACTS
Review round: 1
Reviewer: 1

Output:
Basic reporting: 1.The language can be improved, as suggested in several notes on the attached manuscript. Many explanations through the text are given in parentheses. The manuscript would benefit with the removal of the parentheses; e.g. line 57: «…of agriculture, horticulture and forestry (for which phytopathology is a main discipline),…» replaced by «…of agriculture, horticulture and forestry, for which phytopathology is a main discipline,…»
2.The introduction has enough background to show the context of the study. However, the contents of the sub-section «Initial decomposition and causes» in Materials and Methods also belong to Introduction, after the explanation of the phases of decomposition.
3.The literature is well referenced and relevant. However, most of the references are from the 1070s-1990s, maybe due to the fact that the data was collected in 1977 and 1988. Also, there are too many references for the same subject in some parts of the text as in lines 109-112.
4.The structure of the manuscript conforms to PeerJ standards, but the contents of some sections must be reorganized. The sub-section «Initial decomposition and causes» in Materials and Methods belong to Introduction. While reporting the results, the authors discuss the results and cite other authors and during the Discussion, only one author is cited. In the conclusions, the authors continue the discussion. To conform to the PeersJ standars, all discussion should be allocated to the Discussion section, the contents of lines 378-383 (Discussion) are an introductory synthesis of the results and should be in fact the beginning of the results section. In order to fully understand that the work was carried out during 1977 and 1988, this should be referenced in the beginning of the Materials and Methods, before using, for instance, (HW, 1977).
5.Figures and tables: table 1 must be improved in the information provided, namely: is depth an average? If so, a range or at least maximum depth should also be provided. Still in table 1, the values of the physical characteristics are not uniform: there is no range for the first two data points, and the number of measurement should also be provided Table 2 is not necessary since its contents are already in text. Figure 4 is not necessary since it does not illustrate any result. Legend of figure 14 does not match its contents and figure 14 not necessary in the manuscript. Regarding the rest of the figures, they are mostly photographs and drawings which, in some cases, would benefit from better quality if they are to be used as a guide by other authors.
6.Raw data is supplied as an Excel file, it opens, but as far as I understand, only data for one of the species in one of the years is provided. Also, it is not clear what the numbers 3-21 mean
Experimental design: No comment
Validity of the findings: No comment
Additional comments: This is a descriptive manuscript reporting the causes and effects of initial leaf decomposition in floating leaves of 3 species in 3 lakes. Data is old and was collected in different occasions (with a difference of eleven years) in the 3 lakes, and the sampled species are not the same in the 3 lakes. The lakes differ in their abiotic variables, sampling dates are not uniform and there is no true replication, and it is clear that the manuscript reports the results of two different studies, one performed in 1977 and the other in 1988. However, given the descriptive characteristics of the study and given that the study does not compare either the lakes or the plant species –although in the discussion, you address the effects of some environmental variables on the results, the timing of sampling and the sampled species are not truly important. In fact, other investigators may use the descriptive nature of the results of the study as a kind of key for identification of the causes of initial decomposition in floating leaves. However, to fulfil this objective the manuscript has to be greatly improved.


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: INITIAL DECOMPOSITION OF FLOATING LEAF BLADES OF WATERLILIES: CAUSES, DAMAGE TYPES AND IMPACTS
Review round: 1
Reviewer: 2

Output:
Basic reporting: See General comments to authors below.
Experimental design: The study is original and within the aims and scope of the journal. Overall experimental design seems sound and will fill a gap in knowledge concerning floating leaf macrophyte damage and decomposition.  However, as stated in the general comments to authors below, I feel the manuscript is in need of editing to provide greater clarity
Validity of the findings: See General comments to authors below.
Additional comments: “Initial decomposition of floating leaf blades of waterlilies: causes, damage types and their impact” by Klok and van der Velde.

This manuscript presents an overview of a series of field studies that investigated the biotic and abiotic factors involved in the initial decomposition of floating leaf blades of Nuphar lutea, Nymphaea alba, and Nymphaea candida. Here, floating leaf blades of N. lutea, N. alba, and N. candida were examined at three freshwater sites that differed in environmental conditions (trophic status, pH and alkalinity. Floating leaf blades were tagged/numbered within replicate plots and leaf length, percentages and types of damage to, and decay of, each leaf was measured and estimated weekly for all plots during the growing season. The manuscripts proceeds to describe the initial decomposition stages of leaves and the various causes (biotic and abiotic) that are chiefly responsible.

Overall Comment
Overall, I found that this manuscript is interesting and contains meticulous data on the types of damage to, and decay of, the leaf blades of water lilies. However, I must admit from the outset that there is a lot going on in the manuscript that makes any full evaluation quite difficult. In my opinion, this manuscript is not yet ready for publication in its present form. I believe the underlying premise of the study is sound and interesting, and will add to our understanding of decay patterns (and causes) in water lilies. My main concern with this paper is with the overall writing and logical flow of the manuscript. In my opinion, this manuscript is just not ready for publication and will require a very careful, lengthy revision. A large part of the writing within the manuscript is in need of editing. There are several confusing words, sentences and passages throughout the manuscript that are not well written or connected. As a consequence, the manuscript lacks clarity and overall flow of thought in many areas.  Hence important information and its significance are lost or obscured. I would have so many specific comments concerning the text that it would be just pointless to list them all.

I will give just a few examples in my specific comments below:

Abstract – In my opinion the abstract needs to be restructured.  I am ok with the first paragraph, with some editing se below.  However, the second paragraph needs to be entirely rewritten for the following reason:

The authors state - “Initial decomposition and its various causes are depicted and described. Also leaf damage with respect to the potential leaf area per species per plot, contributions to leaf damage by external causes, leaf loss in time and succession of damage causes are presented.”
Please do not tell me in the abstract of the manuscript that data will be depicted, described or presented within the manuscript.  Please depict, describe or present a synopsis of the actual data in the manuscript within the abstract.

Abstract – first paragraph. How about - Initial decomposition (i.e. leaf damage and loss) of large floating leaved macrophytes, such as waterlilies, can be studied well: the turnover of floating leaf blades is low and leaves can persist for a relatively long time. In the present study, the initial decomposition patterns of floating leaf blades of Nuphar lutea (L.) Sm., Nymphaea alba L. and Nymphaea candida Presl, were examined at three freshwater sites differing in water quality, such as nutrient status, pH and alkalinity. Floating leaf blades of each species were tagged and numbered within established replicate plots and the leaf length, percentages and types of damage to and decay of leaves measured and estimated weekly throughout the growing season.

Abstract – second paragraph. Here is an example of what I mean when a passage is not very well connected in terms of flow of thought.  Below I list the sentences in the second paragraph in order. Each addresses a quite separate topic, giving the reader an impression that the paragraph just jumps around and is a random collection of statements. It would be much better to restructure this paragraph for clarity (particularly the 4th sentence which is quite long).  Also, the authors state (4th sentence)  “…followed by cellulolytic bacteria, or fungi…followed by microbial decay”. Cellulolytic bacteria or fungal decay is microbial decay, so I do not have any idea what the authors are trying to convey here.

“Only a few damage causes had a significant impact on leaf damage and leaf loss: autolysis, fungi, snails and mechanical damage.

The floating leaves offer food for a series of specialized insects consuming leaf area from below the water surface, from the upper surface or by mining the leaf tissue.

Waterfowl (e.g. Rallidae) consume leaf parts and walk on the leaves scratching the upper surface.

Several forms of succession of damage can be distinguished such as erosion of the wax layer, followed by cellulolytic bacteria, or fungi, followed by snails, or mechanically damaged leaves (by wind and wave action, desiccation and hail stones), followed by biotic causes and decay, or autolysis, followed by microbial decay, followed by tissue removal by snails, followed by breaking up of leaves.

In alkaline waters the seasonal patterns of initial decomposition differed between Nymphaea and Nuphar.”

Introduction- first paragraph

“Already during their development plant leaves are exposed to abiotic factors (such as weather conditions, causing physical damage, fragmentation and drying out) as well as biotic factors (such as infection by fungi and viruses, herbivores, and animals using these parts of the plant in various ways). This exposure is well-known for crops and ornamental plants as it causes economic damage. Plant resistance depends on age and plant injuries (Kennedy & Barbour, 1992). Initial causes of decomposition (when the leaves are still connected to the plant) precede the process of leaf material entering the decomposition cycle on the soil. In ecological studies much attention is paid to the latter because these soil processes are important for the biogeochemical cycles. However, with the exception of agriculture, horticulture and forestry (for which phytopathology is a main discipline), much less attention is paid to the first process, in particular for aquatic macrophytes.”

I find the sentences in this paragraph (particularly the first three) to be a rather awkward transition between each other.  I am just what the authors want to convey here?  The first sentence sets the idea of leaf damage in terms of biotic and abiotic factors (which I get), but following sentences confuse me and don’t seem to fit the idea being proposed, particularly “Plant resistance depends on age and plant injuries (Kennedy & Barbour, 1992).” This sentence is just kind-of stuck in there with no logical transition or flow of thought.

These are just two examples, but there are several more scattered throughout the manuscript.

There are also some usage of words that seem odd to me…like “vital”, “sapropelium”, and “ “percentual”.  Why not just use living, organic matter (or detritus) and percent (or percentage).  These words are better suited for the manuscript as they are more widely accepted, in my opinion.

Results – Causes of initial decomposition and their impact.

In my opinion, a lot of this material could be consolidated and summarized better.  Perhaphs having a section labeled biotic and abiotic, where the influence of such factors are described. Right now, I feel it is too long and is hard to get through and pick out the important information.  This section should be restructured.

Discussion and Conclusion – In comparison to other sections in the manuscript.  I feel that this section is under-developed. In addition, some of this information in the results could be moved here and put in to the context of other studies.

Figures and Tables – 23 Figures and 5 Tables.  Seems like a lot, but in general I am ok with many of them.  I think some can be consolidated and some are not really necessary (Figure 19-20).  Also, I am not sure what is going on with Figure 14. Is this in error?  This figure legend does not match the presented figure in what I downloaded.

Another question I have is in relation to Figure 2.  If the authors have data concerning the leaf loss in time per plot, could they potentially calculate a leaf decay rate (k). This would be useful for comparing to other macrophyte leaf species in aquatic habitats.

In conclusion, the authors have some interesting data on biotic and abiotic factors leading to damage and decay of floating leaved macrophytes. I feel this study was a lot of work for the authors and that it can contribute positively to our understanding of floating leaf macrophyte decay.  However, this manuscript needs a serious and comprehensive editing before it can be adequately evaluated.


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: INITIAL DECOMPOSITION OF FLOATING LEAF BLADES OF WATERLILIES: CAUSES, DAMAGE TYPES AND IMPACTS
Review round: 2
Reviewer: 1

Output:
Basic reporting: 1.It is a little bit odd to have the explanation of the several marks found on the leaves in section Results. Typically, Results is a very straight forward section where no discussion or explanations are given; explanations, and the references used to support the explanations, would fit better the discussion than the results section;
2.Because some of the contents of the Discussion are in the Results, the Discussion -although greatly improved – still needs a little bit more work. In fact, there are only two references in the Discussion, which still is more a synthesis of the results than a discussion.
3.The discussion would also benefit from a reorganization of subjects. As it is, it goes back and forth from one issue to another, and it is difficult to follow by the reader.
Experimental design: no comment
Validity of the findings: no comment
Additional comments: The manuscript was greatly improved during the revision made by the authors: the written language was improved (I have some minor corrections/suggestions on the attached document); the text was rearranged, removing from materials and methods the sentences that clearly belonged to introduction; the reference list was shortened; the discussion was improved; the number of figures was reduced, and the raw data is now complete.
However, some of the problems reported by both reviewers still persist and thus the manuscript needs to suffer another round of revision before being accepted for publication in PeerJ.


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: INITIAL DECOMPOSITION OF FLOATING LEAF BLADES OF WATERLILIES: CAUSES, DAMAGE TYPES AND IMPACTS
Review round: 2
Reviewer: 2

Output:
Basic reporting: See General comments to authors below.
Experimental design: As I stated before - The study is original and within the aims and scope of the journal. Overall experimental design seems sound and will fill a gap in knowledge concerning floating leaf macrophyte damage and decomposition. However, as stated in the general comments to authors below, I feel the manuscript is in need of editing to provide greater clarity
Validity of the findings: See General comments to authors below.
Additional comments: “Initial decomposition of floating leaf blades of waterlilies: causes, damage types and their impact” by Klok and van der Velde.

This revised manuscript version presents an overview of a series of field studies that investigated the biotic and abiotic factors involved in the initial decomposition of floating leaf blades of Nuphar lutea, Nymphaea alba, and Nymphaea candida. Here, floating leaf blades of N. lutea, N. alba, and N. candida were examined at three freshwater sites that differed in environmental conditions (trophic status, pH and alkalinity). Floating leaf blades were tagged/numbered within replicate plots and leaf length, percentages and types of damage to, and decay of, each leaf was measured and estimated weekly for all plots during the growing season. The manuscript describes the initial decomposition stages of leaves and the various causes (biotic and abiotic) that are chiefly responsible.

Overall Comment
As I stated in my prior review, I found that this manuscript to be interesting. It contains meticulous data on the types of damage to, and decay of, the leaf blades of water lilies, which the authors are well known for studying.  It is a large data set that they have compiled and I applaud them for their efforts. Having that said, I admit that am rather disappointed in the present revision. In my prior review I stated… “My main concern with this paper is with the overall writing and logical flow of the manuscript. In my opinion, this manuscript is just not ready for publication and will require a very careful, lengthy revision.”

I still have this same opinion after reading this revised version. A large part of the writing within this manuscript needs editing for both clarity and flow. There are several confusing sentences and passages throughout the manuscript that are not well written or connected.  As I mentioned in my prior review…“I would have so many specific comments concerning the text that it would be just pointless to list them all.”

In my prior review, I tried to specifically illustrate some examples of passages that were, in my opinion, symptomatic of the manuscript.  While the authors specifically addressed these examples, they failed to realize or ignored that these were just some examples of many passages I encountered throughout the manuscript. It appears that they did just a casual editing (addressing what I only specifically listed), rather than engage in a serious polishing of the manuscript text.

Again, I will give just a FEW EXAMPLES in my specific comments below:

Abstract – Again, in my opinion the abstract needs to be restructured.  I am ok with the first paragraph.  However, the second paragraph needs to be entirely rewritten for the following reason:

The authors state - “Initial decomposition and its various causes are depicted and described. Also leaf damage with respect to the potential leaf area per species per plot, contributions to leaf damage by external causes, leaf loss in time and succession of damage causes are presented.”
Please do not tell me in the abstract of the manuscript that data will be depicted, described or presented within the manuscript.  Please present a synopsis of the actual data in the manuscript within the abstract.  In addition, the second paragraph of the abstract is an example of what I mean when a passage is not very well connected in terms of flow of thought.  In my opinion, it reads like a collection of sentences thrown together.  Please think about the overall importance of the study and the results (i.e., the take-home message) and fashion an appropriate abstract.

Introduction- first paragraph

Original - “Already during their development plant leaves are exposed to abiotic factors (such as weather conditions, causing physical damage, fragmentation and drying out) as well as biotic factors (such as infection by fungi and viruses, herbivores, and animals using these parts of the plant in various ways). This exposure is well-known for crops and ornamental plants as it causes economic damage.”

Revised – “Plant leaves are, already during their development exposed to abiotic factors such as
weather conditions, as well as biotic factors such as infection by fungi and viruses, herbivores, and animals using these leaves in various ways. This exposure is well-known for crops and ornamental plants as it causes economic damage.”

In my opinion, I find that instead thinking about and revising the first paragraph, the authors are simply involved in an exercise of moving words around.  The new revised sentence above is even more awkward than the former.

These are just two examples, but there are several more scattered throughout the manuscript.

For example,

Line 76-79. These phases of initial decomposition can be studied well in the leaf blades (laminae) of large leaved plants such as waterlilies in which the turnover of floating leaf blades, further indicated in this paper as floating leaves or leaves, is low (P/Bmax 1.35-2.25) and the leaves exist for a relatively long time, on average 38-48 days (Klok & Van der Velde, 2017).

I really don know what the authors are trying to convey here?

Line 168-170.  Is this passage really needed?

Line 184.  Is Ci a correlation coefficient or a regression coefficient from the quadratic regression equation modeling leaf area from leaf length.  Note the difference between correlation and regression.  Please provide more details on this equation.

Line 216-217. “Initial decomposition tends to increase in time during the vegetation season with the exception of the acid Voorste Goorven (with Nuphar lutea and Nymphaea alba).”  I have no idea what this sentence is trying to convey.  To me, of course initial decomposition of leaves tends to increase with time as leaves grow, senesce and decay throughout vegetation season.  In regards to Voorste Goorven, do the authors suggest here that initial decomposition does not proceed until the end of the growing season?

Line 217- 219 In the alkaline waters (Oude Waal and Haarsteegse Wiel) leaf damage for Nuphar lutea was less than 20% related to the total potential leaf area in the plot until half September…”
Half Semtember?  How about mid-September.

Line 240-243. “Autolysis starts shortly after the first leaves are fully grown and continues the
whole floating leaf vegetation period. The leaf turns from green to yellow, which leads at
the end of the existence of the floating leaf to total microbial decay, the leaf turning brown.”

What do these two sentences mean?  In addition, this passage is a good example of what I mean by a confusing and not well written/connected passage.  The passage (Autolysis) starts out with… “The newly unrolled floating leaves are green and hydrophobic by an epicuticular wax layer (Fig. 4). During senescence this wax layer erodes by colonization of bacteria and fungi. In this stage the leaf tissue can be attacked by cellulolytic bacteria (Howard-Williams et al., 1978; Robb et al., 1979; Rogers & Breen, 1981; Barnabas, 1992).”  What do the first two sentences have to do with autolysis?  The authors don’t even begin to address autolysis until the third sentence?  Are the above processes a result of autolysis?

“Autolysis is controlled by the plant itself by hormones (e.g. Osborne, 1963)”? What?

Line 245-248. “In October the percentage of affected leaves rose to 100%, however, the surface
area affected was quite stable and generally around 10%. For separate leaves the area affected by autolysis may decrease in time, since microbial decay will take over part of the area (Fig. 5).”  I really have no idea what this sentence is trying to convey to the reader?

Line 255-257. “Due to hard wind floating leaves are lifted from the water, flip over and
subsequently air exposed parts (in particular the leaf margin) dry out (Fig. 8). The effect
on leaf surface area was generally less than 5%”.  Lets use some commas – a example.

How about…Due to hard wind, floating leaves are often lifted from the water and flip over.  Subsequently, leaves are exposed to air (in particular the leaf margin), leading to leaf dessication (Fig. 8). Overall, the effect of dessication stress on leaf surface area was generally less than 5%.

Line 259-261. The percentage of affected leaves was quite high during the whole data taking period for plots (Nuphar lutea, HW), (Nymphaea alba, OW) and (Nymphaea candida, HW), ranging about 60-80%. Awkward phrasing

Line 273- 275. Damage by consumption of leaf tissue by the Coot (Fulica atra) can be recognized by omissions in the form of triangular areas at the edge of a leaf.  Omissions?  What does this mean in relation to this sentence? Again, awkward sentence phrasing.

Line 290-292.  “The imagines live on the floating leaf upper side where they feed on leaf tissue (upper epidermis, parenchym till the under epidermis).”  Imagines?  That one is new to me.  I had to look it up.  Although correct, it is a confusing term that most readers will find awkward, like “vital”, “sapropelium”, and “percentual”.  Why not just state here and elsewhere “adults”, like “The adults live on the floating leaf upper side where they feed on leaf tissue (upper epidermis, parenchym till the under epidermis).”

Line 343-344. “With translucent light it appeared that the real damage was higher due to leakage, etc. What?  This sentence is just sort of thrown in at the end of this paragraph with no context to the preceeding sentences.

The discussion, in my opinion, is in need of serious editing.  This is yet another example of several paragraphs that read like a collection of random sentences (thoughts), that are not very well connected in terms of flow of thought.  In addition, some of what is presented in the discussion is just a reiteration of what is in the results and thus is rather redundant.  Dido for the conclusion.

In conclusion, the authors have some interesting data on biotic and abiotic factors leading to damage and decay of floating leaved macrophytes. I feel this study was a lot of work for the authors and that it can contribute positively to our understanding of floating leaf macrophyte decay.  However, this manuscript needs a serious and comprehensive editing.  I just cannot go through this manuscript and provide a specific example and justification for everything.  I would literally be going sentence by sentence throughout the entire manuscript.  I hate to be so negative about this revision.  I was hoping the authors would make a diligent attempt at comprehensive revision, as I felt, and still feel that the data presented in this manuscript is interesting and beneficial to the scientific community.  I now urge the authors to spend more time editing this manuscript.  Ultimately the authors greatly diminish this work and its potential impact by the present manuscript text.


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

Input:
Title: INITIAL DECOMPOSITION OF FLOATING LEAF BLADES OF WATERLILIES: CAUSES, DAMAGE TYPES AND IMPACTS
Review round: 3
Reviewer: 1

Output:
Basic reporting: The manuscript was greatly improved during the second revision made by the authors, which tried to follow all suggestions made by both referees. There are still a few minor language problems which I tried to fix in the attached annotated manuscript. But at least two sentences have to be completely re-written in order to make them understandable for the reader. I rephrased them in order to help the authors, but since they were difficult to understand I am not sure if the meaning I gave them was the meaning intended by the authors.
Some of the  aspects needing attention include:
Lines 190-194 & 292-293: Delete the sentence marked in blue. In the first sentence you state that the results of translucent light were not going to be reported. If they are not being reported than you don’t explain the method. In the second sentence you report a result with translucent light, which in fact is not necessary.
Lines 336-338: Very difficult to follow. I suggest rephrasing for something like “Leaves can grow during 53 to 73% of the vegetation period (citations). In the present study the development of new leaves and the dying of old ones continued for as long as... (state a period instead of saying "a long period")
Lines 369-372: rephrase sentence marked in blue. Maybe “Cricotopus trifasciatus, which causes damage to the floating leaves of Nymphoides peltata (Gmel.) O. Kuntze (Lammens & Van der Velde, 1978) was also observed to cause damage on waterlily leaves (Van der Velde & Hiddink, 1987).” Although is still confusing because of the general term “waterlily”. Maybe state the species instead of using the word waterlilies?
Lines 390-394. Very confusing sentence. Rephrase. Maybe “"Nymphaea candida (HW) showed an increase in nail scratches towards the end of June, which may be the influence of young coots. In fact, high densities of waterfowl lead to higher damage of the leaves, and the meadows surrounding OW and HW important for coot to survive winter time by grazing grass in groups. “
Lines 398-404: This was really difficult to follow. If I understood correctly, maybe the sentence could be re-written as “The inhibition of cell wall degradation slows leaf fragmentation and leads to increased storage of phenolics, decreasing fragmentation and preventing the softening of the tissue. Thus the plant tissue constitutes a low quality resource for detritivores (Kok, 1993) which are also inhibited by high Al concentrations and low pH.” (and the next sentence which is on other subject should be in the beginning of the next paragraph)
Experimental design: Not applicable on this round of revision
Validity of the findings: Not applicable on this round of revision
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: INITIAL DECOMPOSITION OF FLOATING LEAF BLADES OF WATERLILIES: CAUSES, DAMAGE TYPES AND IMPACTS
Review round: 3
Reviewer: 2

Output:
Basic reporting: See General comments to authors below.
Experimental design: The study is original and within the aims and scope of the journal. Overall experimental design seems sound and will fill a gap in knowledge concerning floating leaf macrophyte damage and decomposition. However, as stated in the general comments to the editor and authors (see below), I feel the manuscript is still in need of editing to provide greater
clarity.
Validity of the findings: See General comments to authors below.
Additional comments: “Initial decomposition of floating leaf blades of waterlilies: causes, damage types and their impact” by Klok and van der Velde.

This revised manuscript (2nd) version presents an overview of a series of field studies that investigated the biotic and abiotic factors involved in the initial decomposition of floating leaf blades of Nuphar lutea, Nymphaea alba, and Nymphaea candida. Here, floating leaf blades of N. lutea, N. alba, and N. candida were examined at three freshwater sites that differed in environmental conditions (trophic status, pH and alkalinity). Floating leaf blades were tagged/numbered within replicate plots and leaf length, percentages and types of damage to, and decay of, each leaf was measured and estimated weekly for all plots during the growing season. The manuscript describes the initial decomposition stages of leaves and the various causes (biotic and abiotic) that are chiefly responsible.

Overall Comment
As stated in my two prior reviews, I find this manuscript to be interesting. It contains meticulous data on the types of damage to, and decay of, the leaf blades of water lilies, which the authors are well known for studying. It is a large data set that they have compiled and I applaud them for their efforts. The present version has certainly improved from the first submission. However, I must admit that I do not see any systematic attempt by the authors to edit and polish the textual presentation of this manuscript. In my opinion, the present manuscript is only marginally ready. This is unfortunate as I believe the current presentation diminishes this work and its potential scientific impact.

At present, I am not sure what more I can add to this discussion apart from what I have tried to communicate in my two prior reviews. I really hate to be so negative about this manuscript.  The authors have some interesting data and it can contribute greatly to our understanding. Unfortunately, I feel that the textual presentation is still in need of some restructuring for clarity and flow.


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

Input:
Title: CLINICAL OUTCOMES AND RISK FACTORS OF SECONDARY EXTRAINTESTINAL MANIFESTATION IN ULCERATIVE COLITIS: RESULTS OF A MULTICENTER AND LONG-TERM FOLLOW-UP RETROSPECTIVE STUDY
Review round: 1
Reviewer: 1

Output:
Basic reporting: The overall English language is acceptable. However, there are some inappropriately placed terms, e.g.: line 205 accompanied by should be (associated with), line 209:associated with disease activity, should be (a flare)

Literature references ,sufficient felid background/ context were provided. However, two of the main references they used for discussion were not open access articles and were difficult to obtain

Professional article structure, raw data shared. However, table 4 had a missing p value for the variable surgery, the flow chart  could be simplified

Self contained with relevant results to hypothesis was described
Experimental design: It is an original article within the aims and scopes of the journal.

Research question was not similarly defined in abstract and introduction. However, it could be understood from the sequence. Additionally, lines 60,61  were little difficult to understand, They didn't assess the severity of EIM but they did check the clinical outcomes according to EIM or non EIM.

The knowledge gap was well stated and they designed their study to cover this gap

investigations performed to ethical standards

methods: were described but there are some issues:
(lines 87):They used the Montreal classification system then they described all types of symptoms manifested by the patients. It would be easier, probably more valid and statistically significant, if they calculated the S1,S2 and S3 and include it in the analyses

(lines 95,96 They defined weight loss as losing more than 5 kg over study period (mean 13 years of follow up)

(Line 99) is the should not refer to statistics in other paper, instead write it.

( line 139) should be moved to the method. We suddenly find in the results that they compared the groups with no prior explanation in the methods

(line  104) they didn't describe in statistics the univarite analysis used

I expected to find a definition for anemia grades in methods not in the line 220 in the discussion

Table 1 family history of other cancers were analysed for but it was not included in the methods
Validity of the findings: Repetition of results both in text(in the results and discussion) and tables except for table 5 and table 6 is noted. Even tables 1 and 5 include repeats, instead keep table 5 with the p values

Table 5 it seems that the statistical method used was chi square and student t test. I don't believe they are univariate analyses. It is better to state which statistic test used under each table.

conclusions are stated ,linked to original research question and supporting results.However, it includes a term in line 244(early appropriate and effective comprehensive) it sounds over structured
Additional comments: Thank you for submitting your research, I can see that you made an big effort to collect and analyze your data. I would also thank you for providing your raw data. However, I suggest you organize your paper a little bit:
1- clearly state your aim.
2-clearly describe your methods and get it more organized, don't under-write in statistics part. It is important that the readers understand how you did your research.
-I have a question in line 90 ,why did you choose to exclude primary EIM? in such case how many patients were they and why they were not described on the figure1? on table 1 are the single EIM (single secondary EIM)

3-When you report your results avoid unnecessary repletion: I would suggest cleaning the figure 1 ,keep tables 5 and 6 and state which type of statistical test you have used, if you wish to keep table 4 add the p value on surgery and don't repeat it in the text.
- It is better to mention the sites for single or multiple EIM.
Table 3 why did you include CD patient in the analysis, if he was a UC then moved into CD this should be excluded.
-Keep the( medical refractory disease) standardized allover the manuscript don't use the alternate or continuous disease activity in table 4 don't us
- In line 124, why did you consider PSC as an EIM?
line 134 did you mean colon or rectal stricture? How severe was the gastro-intestinal bleeding? was it endoscopically diagnosed or a clinically manifested bleeding?

4-limitation of the study: you did report some study limitations on the lines 232-235. You didn't not comment on missing data and how to handle it, was there any miss recording.

5- I suggest more thorough revision of English language


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

Input:
Title: CLINICAL OUTCOMES AND RISK FACTORS OF SECONDARY EXTRAINTESTINAL MANIFESTATION IN ULCERATIVE COLITIS: RESULTS OF A MULTICENTER AND LONG-TERM FOLLOW-UP RETROSPECTIVE STUDY
Review round: 1
Reviewer: 2

Output:
Basic reporting: The paper is relatively easy to follow with clear and unambiguous English used throughout. References seem to be outdated with not so many most recent  and relevant papers cited. The article is structered in professional way.
Experimental design: Original primary research is within Aims and Scope of the journal. The methodology has several drawbacks. Methods are described with insufficient details. Some important data are lacking (e.g. reporting of disease activity index, endoscopic disease activity index, C-reactive protein)
Validity of the findings: The study population consisted of UC patients who were identified from a prospectively maintained, institutional review board-approved database at Authors institutes from
June 1986 to December 2018 and 271 ulcerative colitis patients were included into the study. It is difficult to extrapolate these results to the whole population of Shanghai, eastern China as authors state in conclusion: “In Shanghai, eastern China, approximately 11.4% UC patients go on to develop at least one EIM”. It is not clear from the paper what was the baseline population of patients. Were these patients admitted to surgery word due to ongoing complications (e.g. severe bleeding ?). Where these patients admitted with suspicion of ulcerative colitis or signs of bleeding ? Where the study group outpatients ?
Additional comments: Other comments:

The demographic and clinical characteristics of the study participants were analyzed, but there is no information of disease activity index or endoscopic disease activity index. There is no information on C-reactive protein (CRP) or any other inflammatory indicators. The clinical remission (> stools per day plus other symptoms such as bloody diarrhea) was the only measure to evaluate whether patients were in remission or not. It seems that significant number of patients might have been qualified as in remission in fact without remission.

Mean age of diagnosis is relatively high 42.0 (29.0–53.3). Where are the younger patients ? Were they managed by other units ? Outpatient clinics ?

The study included secondary EIM in UC patients and follow-up, while primary EIM was excluded. Please explain what are primary and secondary EIM as it is not clear in the draft.
(For example: This study focused on secondary EIM in UC disease course and follow-up, while primary EIM was excluded) The diagnosis of EIM was based on clinical, radiological, endoscopic, and immunologic examination and histological findings. No information and data are provided as for these diagnostic tests used (how many or which patients had which test performed)

All complications were diagnosed based on clinical manifestations, laboratory results, and endoscopic and imaging findings – for example bleeding is reported by authors as complication (10.3% experienced gastrointestinal bleeding – upper or lower GI ?), but bleeding is also reported as necessary clinical symptom of no remission. It is impossible to find out from the study whether bleeding was a complication or natural course of disease in non-remission. There is lack of information on the history of mesalamine use. It would be useful to add information on other treatments including biologic therapy.

As shown in Table 4, remission was more common in the non-EIM group (n = 127, 52.9%) than in the EIM group (n = 8, 25.8%) (p = 0.004). From the study it is difficult to verify, which patients were in remission. It is also not known if lack of adherence or therapy non-complience wast the risk factor for EIM.


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

Input:
Title: CLINICAL OUTCOMES AND RISK FACTORS OF SECONDARY EXTRAINTESTINAL MANIFESTATION IN ULCERATIVE COLITIS: RESULTS OF A MULTICENTER AND LONG-TERM FOLLOW-UP RETROSPECTIVE STUDY
Review round: 1
Reviewer: 3

Output:
Basic reporting: The language is, for the most part, fine, but here and there you find are surprising linguistic mistakes.

The literature references are fine, and sufficient background is provided.

The article structure, figures, and tables are fine.

The manuscript is self-contained.
Experimental design: The study represents primary research within the Aims and Scope of the journal.

The research question is fairly well defined, however, it consists of a combination of questions, including 1) to report the prevalence and type of EIMs in China; 2) examining the degree of association between EIM and clinical outcomes; and 3) determining risk factors associated with EIMs. These questions have been addressed in the literature previously, but not well enough for the Chinese population.

There are some caveats with regards to the methodological work (see comments below).

Methods description lacks enough detail in some parts.
Validity of the findings: The study as such and reporting the data it has generated are both justified.

Data is statistically sound, but I would not say robust.

Conclusions need to be adjusted.
Additional comments: This is a well written manuscript examining the prevalence of extraintestinal manifestations (EIMs) of ulcerative colitis (UC) in 271 patients in Shanghai, followed for a median of 13 years. In addition, EIM-associated features of UC are presented, as well as clinical outcomes for UC in patients with, as compared to without, EIMs. Inflammatory bowel disease (IBD), including ulcerative colitis, is on the rise in China, and it is interesting to report on a number of aspects of IBD in this population, including EIM, albeit that numerous similar reports have been published previously from other parts of the world.

The statistical work seems to be correct, but there are other methodological caveats that are problematic (see below).

Major comments:

1. The authors discuss EIM-associated features as if there is a direct causal relationship between them. For example, their data show that anemia is associated with EIMs, and they conclude that anemia should be treated in order to prevent the development of EIM and improve disease prognosis. A more likely relationship is that a high level of colonic inflammation increases the risk for EIMs as well as for anemia, but treating the anemia as such will probably have little impact on the EIMs. One could be very speculative and suggest that relative systemic hypoxia could increase the risk for EIMs, but this is quite far-fetched. Thus, my suggestion is that the authors modify the text so that the various features that are shown to be more common in patients with EIMs or the other way around are described as "associated", but not "contributing" or that there is an "interaction [between anemia and EIM] responsible for the development of EIM".

2. The same goes for the relationship between EIMs and clinical outcomes, i.e. write "associated with" rather than "EIMs having an impact on clinical outcomes" or "EIM can increase the risk of poor clinical outcomes, such as lower remission rates..".

3. The criteria or definitions of EIMs are not well described. Please describe in greater detail how the different EIMs were defined and diagnosed.

4. The patients were followed for a median of 13 years. Table 1 presents the frequency for a number of features including number of EIMs, history of surgery, weight loss, steroid-treatment, treatment with "immunomodulators", etc. The Table-heading says that these are "Baseline characteristics" but nevertheless the table includes data for history of surgery. It is unclear what timepoint these data refer to: First presentation, at the time-point when the medical records were reviewed, or end of follow-up? Are the numbers cumulative or cross-sectional? Are the data for EIMs before, during or after the stated treatment? Do the treatment-numbers refer to "current" treatment or "ever treated with". For the uni- and multivariate association analyses (Table-title reads "univariable" analysis), were the tested factors aligned in time with the EIMs or are they registered as "ever"? Please clarify.

Minor comments:

The Discussion is too wordy, may be shortened.

Row (R) 79-80: How was "poor compliance" defined and why were these patients excluded? What does "underlying disease" mean in this context, and why were these patients excluded? What does "impaired general health" mean in this context, and why were these patients excluded?

R89: Hb and Alb were collected. Why not CRP?

R90: Define what secondary and primary EIMs are.

R93: How was "remission" defined? If "refractory clinical symptoms" includes more than 5 stools per day, it gives the impression that 5 stools/day or less is considered as remission. Is this the case?

R94: In Table 1 the % of patients on "immunomodulators" was 12.5%. In the text the authors discuss "immunosuppressive agents" and "biologics". Clarify what is meant by these terms. How many patients were/had been treated with 5-ASA and biologics, respectively?

R96: The authors define moderate anemia as <90 g/L. Present the cut-offs you used for mild and severe anemia too. Same cut-offs for males and females?

R118: Pancolitis is a subtype of extensive colitis which is the correct term for E3.

R122: How was "rash" defined? A rash can be non-related to UC; caused by medication, or potentially related to UC. Did not any patients present with erythema nodosum or pyoderma gangrenosum?

R123: Arthritis should be divided into Type I and II if possible.

R125: 1/271 is 0.4% (correct in Table 2 but not the text).

R140: "Cure" as a clinical outcome of UC I would suggest to avoid.

R141: "Bleeding" is one of the most common manifestations of UC, thus, defining it as a "serious complication" is not adequate. Crohn's disease should not be defined as a complication of UC (Table 3). "Iris" should be "iritis" and included in the text in addition to the table.

R181: Swiss -> Switzerland

Table 5 and 6: Explain how data were collected - were these factors present at the time of an EIM, or are they not connected in time?


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

Input:
Title: CLINICAL OUTCOMES AND RISK FACTORS OF SECONDARY EXTRAINTESTINAL MANIFESTATION IN ULCERATIVE COLITIS: RESULTS OF A MULTICENTER AND LONG-TERM FOLLOW-UP RETROSPECTIVE STUDY
Review round: 1
Reviewer: 4

Output:
Basic reporting: Clear and easy understood.
Experimental design: Retrospective cohot study.
Validity of the findings: no comment
Additional comments: 1. The title may have been over-stated, because 1) UC patients from two large general hospitals in Shanghai only, 2) this is a two-center study, and 3) the sample size is relatively small. It would be difficult to generalize the findings to UC patients of eastern China.
2. This is a follow-up study on secondary EIM occurrence in UC patients. So please specify secondary EIM in the title. Prevalence is not appropriate here, it should be cumulative incidence rate. The authors may need to consult an epidemiologist.
3. It would be helpful to specify how UC and EIM are diagnosed, because details are unclear in the paper.
4. In follow up studies, time to event (secondary EIM) is also import. I am confused that why the authors did not provide data on this variable. And survival and cox regression analyses are appropriate in this paper. Statistical methods used are not detailed enough, for example, line 102-104, t-test was used to compare the difference between ?. Methods for selecting significant predictors in multiple analyses are not described. I feel it is unnecessary to mention the statistical methods used in this paper are similar to one previous study.
5. The sample size is too small, particularly those with secondary EIM. Please consider its impact on multiple analysis.


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

Input:
Title: CLINICAL OUTCOMES AND RISK FACTORS OF SECONDARY EXTRAINTESTINAL MANIFESTATION IN ULCERATIVE COLITIS: RESULTS OF A MULTICENTER AND LONG-TERM FOLLOW-UP RETROSPECTIVE STUDY
Review round: 2
Reviewer: 1

Output:
Basic reporting: Thank you for the thorough and clear revision of the manuscript. The introduction is relevant to the study and the hypothesis is clearly stated. The results are also relevant to the hypothesis

However, I have two comments on the introduction:
-is it possible to describe the Primary and secondary EIM in the introduction?
- in the hypothesis can you state that you are investigating the secondary EIM for Ulcerative colitis?
Additionally, the incidence here is not a cumulative incidence. It can be just that incidence of secondary EIM in Ulcerative colitis patients ....and complete the hypothesis.
Experimental design: The aim is clearly stated thank you and the research question is well defined . Methods are clearly stated and well-detailed. Thank you for providing definitions for each criteria.

line 80 :Just a comment on the exclusion criteria: why do you exclude FAP if you have decided from the beginning to study UC patients. You can exclude UC patients who later had an indeterminate colitis diagnosis. you can also say that you have excluded primary EIM.

In line 116 you can state it as a first,second or third degree relative in stead of immediate relative (according to what you have studied)

Again, thank you for a very clear writing for the methods used and adding the statistical test clearly.
Validity of the findings: Results section is clearly-written, fine-tuned based on statistically sound and controlled methods. The flow chart is

However, i have some comments:
lines 150-160: describes the studied EIM population. I suggest that you write all the data here and remove the table 2 to avoid repetition.

In lines 164-171: remove test from 164-166(it is more a methodology sentence.
keep text from 166 ,starting (in the entire cohort). then divide the complications according to EIM group or not and do the same in the table 3
then describe only the serious complications or the most common complications for the EIM only in the text. The study is eventually about EIM.
please don't forget to add the gastrointestinal bleeding in table 3 after modifying it.

Table 4 is very clear thank you. can you please add to the footnote what were the serious complications.

In results line 187: the age at diagnosis (can you add ≥ 50) and standardize the ≥ all over the text such as in line 210 and 278

table 5 and 6  please keep them. However, i wonder why you tested for relapse in table 6 while it was not significant as a risk factor in table 5

line 207 this is an incidence not a cumulative incidence as far as i know.Please standardize this all over the text starting from the abstract to conclusion.

line 235 don't state results again in the discussion.
line 251 how does it relate to the bowel disorder

line 272, this is not a strength of the study. You should write it in a better form.
Additional comments: Thank you for this nicely written manuscript. You were very through in following the comments and the text have evolved markedly.
Again thank you


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

Input:
Title: CLINICAL OUTCOMES AND RISK FACTORS OF SECONDARY EXTRAINTESTINAL MANIFESTATION IN ULCERATIVE COLITIS: RESULTS OF A MULTICENTER AND LONG-TERM FOLLOW-UP RETROSPECTIVE STUDY
Review round: 2
Reviewer: 2

Output:
Basic reporting: I would suggest one more English language spellcheck
Experimental design: No comment
Validity of the findings: It is a pitty that part of the databases were updated, which in consequence led to loss of some data. However it is worth presenting the results of the study to readers
Additional comments: I would recommend changing the term biologics to probiotics as it seems that none of the patients at that time were receiving immunobiologics such as anti-TNF monoclonal antibodies. Authors should perhaps mention this to clarify the terms and not to mislead the readers


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

Input:
Title: CLINICAL OUTCOMES AND RISK FACTORS OF SECONDARY EXTRAINTESTINAL MANIFESTATION IN ULCERATIVE COLITIS: RESULTS OF A MULTICENTER AND LONG-TERM FOLLOW-UP RETROSPECTIVE STUDY
Review round: 2
Reviewer: 3

Output:
Basic reporting: OK
Experimental design: OK
Validity of the findings: OK
Additional comments: Congratulations on addressing the comments thoroughly. Two remaining comments:

Reviewer 3:

Major 4: The title of the table cannot be "Baseline" if it refers to the most recent follow-up. Rename to "Patient characteristics at the most recent follow-up visit".

Minor 6: Probiotics should not be defined as Biologics although in a strict meaning they are. Name the "Probiotics" and use the term "Biologics" only for monoclonal antibody drugs.


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

Input:
Title: CLINICAL OUTCOMES AND RISK FACTORS OF SECONDARY EXTRAINTESTINAL MANIFESTATION IN ULCERATIVE COLITIS: RESULTS OF A MULTICENTER AND LONG-TERM FOLLOW-UP RETROSPECTIVE STUDY
Review round: 3
Reviewer: 1

Output:
Basic reporting: Thank you for editing your text. The hypothesis is well stated as well as the aim of the study. Raw data is shared and data is presented in tables/figure.
However, There is still some repetition of results both in tables and in text. I still suggest dropping table 2 or changing its format similar to table 3 (compare EIM and non EIM)

some English terms are inappropriately used : e.g. relationships (line 108) and contributing (lines 184 ,193) could be association
 now (line 99)  when writing the methods should define the date of the end of the study

May be provide a reference to the Montreal classification system( line 92)
Experimental design: research question is well defined and sufficient details are provided in the methods section
- I wonder what respectively in line 132 refers to?
-  loss of weight : I find it difficult to add loss of 5 kg during the course of UC a significant factor (which is according to your calculation can be 7 years)
Validity of the findings: The study aimed at evaluating the incidence of EIM in china but it didn't see this result reported in the results section, instead it gets reported in the discussion (line)

- line 145: the median age at diagnosis (is it for males or for all population)please make it clear.

- line 146: I wanted to see the demographics of the EIM patients: how many were males, their ages ,the disease duration (at the end this is the target population that the text addresses)

- I still find table 2 as a repetition of the text (lines 152-155). can you minimize the data here and refer to the table.

-Table 3 is very nice please keep it

- can you move line 167 to methods (the definition of serious complications)

-lines 168: add a little about the EIM patients complications ( this is your target population)

-lines 172-173: sounds like methods not results.

-table 4 : serious complications EIM (10 patients) ? where did that come from.When you count it from table 3 and read it in the text,they are only 4 patients!!!

-Table 4 : please mark which comparison used the chi square and which used the fisher's exact.

- Table 6: you mention in the text that you tested in table 5 for possible risk factors (univariate) then proceeded only with those significant into the multivariate analysis. Why did you test for relapse in the multi-variate analysis while it was not statistically significant in the univariate analysis

-the discussion contains a lot of repetition of results, this is not appropriate.

- the strengths of the study should be revised.
Additional comments: Thank you for the opportunity to re-revise your text. The text is getting better but it needs more careful revision in the light of the reviewers comments. I understand the difficulties with the English language but some terms are inappropriate.


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

Input:
Title: CLINICAL OUTCOMES AND RISK FACTORS OF SECONDARY EXTRAINTESTINAL MANIFESTATION IN ULCERATIVE COLITIS: RESULTS OF A MULTICENTER AND LONG-TERM FOLLOW-UP RETROSPECTIVE STUDY
Review round: 3
Reviewer: 2

Output:
Basic reporting: This study is now adequatly presented
Experimental design: No comment
Validity of the findings: No comment
Additional comments: Thank you for all amendments and revisions


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: ANTIOXIDANT ACTIVITY, Α-GLUCOSIDASE INHIBITION AND PHYTOCHEMICAL PROFILING OF HYOPHORBE LAGENICAULIS LEAF EXTRACTS
Review round: 1
Reviewer: 1

Output:
Basic reporting: This manuscript by James Williams and his co-authors examines the hypothesis that”Leaf extract of Hyophorbe lagenicaulis exerts antioxidant and α-glucosidase inhibitory potential”. To this aim, they determined in vitro antioxidant and anti-diabetic activity of the extract using α-glucosidase assay. The article needs corrections that are mentioned in the following:

ABSTRACT
1.	The abstract in not structured as background, methods, results and discussion rather it is presented in a single paragraph. The abstract should be structured as required by the journal.
2.	No evidence is given in support of the statement that the identified compounds in the extract exert strong anti-oxidant and enzymatic effects in synergistic mode.
3.	Spell mistakes are there in the abstract that should be reviewed carefully.

INTRODUCTION
1.	The introduction would be strengthened if the authors were to more clearly describe how free radicals are generated in the body as a result of diabetes (mechanism of action). At the moment, the description is quite brief. As well, given that the authors are proposing DMT-2 might be reduced by controlling oxidative stress, there should be a fuller description of studies showing that this approach shows promise.
2.	Three are so many grammatical mistakes in the introduction. Punctuations are not properly placed within the paragraphs. Should be revised carefully.

DISCUSSION
1.	The authors need to more thoroughly discuss their results.
2.	The presented results should be correlated with the management of DMT-2.
3.	No statement of significance is mentioned in the manuscript.

REFERENCES
Reference style at the end is not according to the journal requirements.
Experimental design: 1.	No information is given about the collection of the plant material, identification and authentication. Voucher details are also missing.
2.	Methodology is too brief to be understood by a common reader. Some more details are needed about the anti-oxidant activities protocols so that a common reader can get to know about the method.
3.	No information is given that at what nm, absorbance was noted.
4.	Α-amylase activity description is too brief. No information about the concentrations of the running solution.
Validity of the findings: RESULTS
1.	The results are presented well. Figures’ legends must be in some detail.
2.	Along with adopting a different approach to their analysis of statistical significance, the authors should also present a measure of practical significance; that is, they should report a standardized effect size (such as Cohen’s d value).
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: ANTIOXIDANT ACTIVITY, Α-GLUCOSIDASE INHIBITION AND PHYTOCHEMICAL PROFILING OF HYOPHORBE LAGENICAULIS LEAF EXTRACTS
Review round: 1
Reviewer: 2

Output:
Basic reporting: - The manuscript was written in a clear and concise manner.
- Bibliographical references were provided in an appropriate manner.
- Figures need to be standardized. In figures 1, 2 and 3 the ethanolic extract should be written in the same way in all figures. Captions of figures are incomplete. The letters corresponding to the statistical analysis should be provided. For figure 4, information about peaks should be provided in the captions.
- The results are promising for the purpose of the study. However, few analysis about pharmacological properties were performed.
Experimental design: - The research is original. Is in accordance with the objectives of the journal.
- The research is well defined, relevant e meaningful, since diabetes type 2 is a disease that affects many individuals worldwide.
- The results are very preliminary. It seems that the antidiabetic potential of the extract is the focus of the work.There are other parameters that could support the antidiabetic capacity of this extract, such as in vitro glucose uptake assay, glucose diffusion inhibitory study, in vitro α-amylase activity and nonenzymatic glycosylation of haemoglobin. In this way, one or more of these tests could be performed to increment the results.
- The methodology was written very briefly. More details should be provided. For example, with respect to enzyme α-glucosidase evaluation, information about incubation time and buffer were not provided. In the same way, in the evaluation of the antioxidant parameters, few information was provided.
Validity of the findings: - The findings are interesting, however more analyzes should be carried out to better validate the conclusion obtained. The data are superficial to support the conclusions of the study.
Additional comments: Abstract:
- Cite the parameters evaluated in the antioxidant evaluation.
- In the conclusion is cited the following sentence "The Hyophorbe lagenicaulis might be an appropriate choice to manage diabetes mellitus and to develop formulations with antidiabetic properties". The results are superficials to lead to this conclusion.
- Add diabetes mellitus in key words.

Introduction:
- Write about the function of α-glucosidase. What carbohydrates are hydrolyzed for this enzyme?
- Remove this sentence "The UHPLC-Q-TOF-MS/MS was used to profile the metabolites in leaf extract of H. lagenicaulis.". This is metodology.

Results:
- In the method involving the reduction of molybdenum, the authors mention "This assay is widely used to evaluate the total antioxidant power of plant extracts and compounds (Prieto et al., 1999)." This is a very old reference. This method is currently used?
- Line 135: "Acarbose exhibited lowest IC-50 value (25.50 ± 0.45 μg/mL) being significantly higher than extracts.". IC-50 value of acarbose was lower than extract. The antioxidant activity was higher.

Discussion:
- The authors highlight the inhibitory activity of α-glucosidase by the extract. Some drugs are used in the treatment of DM and act by this mechanism, such as acarbose. These drugs commonly used in the treatment of DM present disadvantages and adverse effects? This should be mentioned since justifies the search for new drugs.
- What mechanism is associated with the antioxidant potential in the DPPH and molybdenum tests.

Conclusion:
- Experiments in vivo may be useful to suport this findings?


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

Input:
Title: ANTIOXIDANT ACTIVITY, Α-GLUCOSIDASE INHIBITION AND PHYTOCHEMICAL PROFILING OF HYOPHORBE LAGENICAULIS LEAF EXTRACTS
Review round: 2
Reviewer: 1

Output:
Basic reporting: no comments
Experimental design: no comments
Validity of the findings: The figure 5 & 6 are not visible ,  may be  there is some problem in the online software program. The author is suggested to redraw or upload once again for clear visibility to the reader.
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: ANTIOXIDANT ACTIVITY, Α-GLUCOSIDASE INHIBITION AND PHYTOCHEMICAL PROFILING OF HYOPHORBE LAGENICAULIS LEAF EXTRACTS
Review round: 2
Reviewer: 2

Output:
Basic reporting: Figures and legends have been corrected according to the suggestions.
The α-amylase inhibitor assay was added, which increased the pharmacological data.
Experimental design: The in vitro α-amylase activity has been added. More details about methodology has been added. The suggested changes were made.
Validity of the findings: The research is original. The research is well defined, relevant e meaningful, since diabetes type 2 is a disease that affects many individuals worldwide. The data provided by the manuscript are useful in this area of study
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: QUANTIFYING MORPHOLOGICAL VARIATION IN THE CASTILLEJA PILOSA SPECIES COMPLEX (OROBANCHACEAE)
Review round: 1
Reviewer: 1

Output:
Basic reporting: This study thoughtfully quantifies morphological variation in the Castilleja pilosa  species complex and considers the consequences of this variation for species delimitation and taxonomy. Integrating taxonomic and morphological data into species delimitation is extremely important and this is an excellent example of how these data can be collected and used. The manuscript is clearly written and methodologically sound, however there are places where I think the writing could be streamlined and places that need further clarification.

The manuscript is well written with an appropriate introduction and sufficient detail. The introduction and discussion should focus more on this specific complex rather than on Castilleja as a whole. For instance are these species annuals? Is there ploidy variation within the complex?

The only problem I encountered with the data is that the file “Jacobs.etal.raw.data.csv” is not readable by either excel or as a text file. I see only jibberish when I open it.
Experimental design: The research question is well defined and the statistical methods used seem reasonable. That said, I think that the authors should consider some of the issues addressed in the recent study of Cadena et al 2018 “Issues and persepctives in species delimitation using phenotypic data.” That paper brings up several topics that are relevant here:
Primary among these is that while PCA and similar reduction of dimensionality techniques find the axes of greatest variation, these are not necessarily the axes that are most useful for distinguishing clusters or species (Cadena et al. 2018). Since all of the axes from the PCoA are used in the subsequent analyses, this point will not change the results, but the authors should be careful in the way they discuss the results of the PCoA. For example lines 304-306 and 360-362 seem to imply that the axes of the greatest morphological distance among individuals are also the axes of greatest distinction among potential clusters.
The second issue that should be discussed is how fuzzy clustering will perform when quantitative traits within species are normally distributed. For example would samples on the tail ends of the trait distribution have lower assignment probabilities?

I am also somewhat concerned by the outlier points that were excluded. It would be helpful to have information in the supplemental material that describes these more thoroughly—perhaps a figure like Figure 7 or replicate analyses that include these outliers?

A summary definition for the silhouette coefficient would be helpful in the caption for Figure 6.

How much clinal variation is there across the ranges of these species? Are there consistent trends for these traits when plotted against latitude?

Line 299-302. How much variation do the first 3 PC axes account for?
Validity of the findings: The data is robust and the conclusions are reasonable.
Additional comments: The figures are very nice and easy to interpret.

Line 267—This assumption seems very questionable to me. Are there any traits that can be measured from the type specimens? Any data to confirm the hypothesized position of the type specimens in the morphospace would be helpful.

Line 65—While I agree that there can be taxonomic drift where the amount of variation ascribed to a certain species can change through time, I don’t agree that a type specimen ought to serve as a “central, anchoring point within the range of known variation for a species.” Type specimens are historical reference points and do not necessarily reflect the most common characteristics of a species. As single individuals sampled from a species, type specimens will necessarily represent only a portion of the variation that exists within the species.

Line 85—specify “young” here with “age”

Line 157—‘known’ is not the right word here because this is something that is being evaluated.

Line 161—what is “peak maturity”? I initially assumed it meant with fruit, but I suspect it means peak flower?

Line 415—I’m not sure that synonomizing is the problem. There do not appear to be morphological clusters within these groups—do you think that there are really clusters within them?

Figure 3. Kernel density plots like this one look really pretty but they also tend to obscure the data—particularly the sample sizes (it looks as though var. steenensis has the same number of individuals as var. longispica). This figure should be replaced with a plot that shows the data more clearly—perhaps a violin plot with points?


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

Input:
Title: QUANTIFYING MORPHOLOGICAL VARIATION IN THE CASTILLEJA PILOSA SPECIES COMPLEX (OROBANCHACEAE)
Review round: 1
Reviewer: 2

Output:
Basic reporting: see below
Experimental design: no comment
Validity of the findings: see below
Additional comments: Overall, this is a well done study of morphological variation in a small group of Castilleja species. The methods used are appropriate and I think that the conclusions are reasonable.

The main place that I would raise concerns is in the context and description of the nature of species and the meaning of types – basic ideas of taxonomy and nomenclature.  First, names have types, taxa (such as species) do not have types, so it is important to distinguish between the two things.  The taxonomic act is to delimit or circumscribe the species, while the nomenclatural act is to use types to determine what the correct names for those species are.  This paper seems to confuse the two aspects to some extent.

The typical approach to performing a study such as the one presented here is to analyze the variation and decide what patterns of variation are worth recognizing as species.  Then one uses types and their position in the variation pattern to decide what the names of the species should be.  While it is OK to evaluate previously named taxa in the way that its done here, focusing on the previous circumscriptions so much instead of just looking at the variation pattern (e,g, without colors to represent previous taxa as determined by how they key out in previous treatments) seems to miss the opportunity to evaluate the variation with a fresh and less biased view, asking the question “Are there distinct units within the pattern of variation that are worth recognizing?”

Specific points to raise are the following (and some are noted on the ms. itself):

32-33:  Species boundaries are not represented by type specimens – this does not make sense.  Circumscriptions are a taxonomic decision, whereas application of types is a nomenclatural act that just follows the rules.

39-40:  I don’t think that “Species delimitation relies on our ability to define boundaries between one population and the next.” Is an accurate statement.   Species delimitation has been practiced for decades-hundreds of years based on herbarium specimens – and often still is.  That does not require knowing anything about population boundaries.  Few current studies really deal with the limits of populations.

47-49:  this is true but the authors seem to take “species delimitation” as a newly discovered activity, when really that is what has been practiced all along.  If they mean “model-based molecular approaches” then it would be best to say that.

54-56:  This suggests a misunderstanding of what a type is.  Types are not necessarily central points around which the variation of a taxon sweeps.  There is no need for them to be central points in variation and certainly for most taxa they are not.  A type is just a specimen that fixes the name once a circumscription has been defined.  As long as it falls within that variation, the name (if oldest), is the correct one.

64-67:  This is partially true but again seems to misunderstand the nature of types (not central points).

104:  What does “herbage” mean here?  It is not a scientific term – in general use it means “plant stuff” – is that what is meant here – the whole plant?

200:  By “nominal categorical” do the authors mean anything different that just “categorical” for characters?  I think that the latter is more commonly used.

264-267:  Why didn’t you just measure the features on the type specimen and use that instead of this rather indirect approach?  If you did this then you would not have to “hypothesize” the placement of the type (line 29), you could just determine it.

405:  Taxa or names (such as those given) are not the type specimens for anything.  They may be the basionyms if those epithets are the correct ones that are then used in a new combination.

426-427:  Again, this is a misunderstanding of what types are.


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: FISHING FOR VACCINES AGAINST VIBRIO CHOLERAE USING IN SILICO PAN-PROTEOMIC REVERSE VACCINOLOGY APPROACH
Review round: 1
Reviewer: 1

Output:
Basic reporting: Please convert the abstract to the structured version. The authors can refer to the Instructions for Authors (in PeerJ) or the similar published papers.

INTRODUCTION:
The presented evidence (lines 54-61) need to accompany with the relevant information regarding the efficacy/effectiveness of the mentioned interventions (anti-cholera oral formulation and genetically engineered V. Cholera O1 live attenuated Vaccine).
In the 3rd paragraph (lines: 63-70), the authors only indicated to the RV strengths. Authors should also consider the weaknesses of this approach. In addition, it is better to compare the effectiveness of this method with other similar methods or alternatives (traditional vaccine development methods or the others method).
Please consider the related literature on V cholera vaccines (different methods or technologies in according to efficacy, safety, …).
Experimental design: METHODS:
Although the method of this study has been published in one of the authors' previous articles (ref.no. 34), it is better to revise the method section of this article in greater detail in the investigation process.
Validity of the findings: RESULTS:
I think that it is appropriate.

DISCUSSION:
Unfortunately, the authors have not mentioned the limitations of this study and the directions for future research. It is better to consider the clinical implications based on the investigation findings.
Additional comments: Please convert the abstract to the structured version. The authors can refer to the Instructions for Authors (in PeerJ) or the similar published papers.


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: FISHING FOR VACCINES AGAINST VIBRIO CHOLERAE USING IN SILICO PAN-PROTEOMIC REVERSE VACCINOLOGY APPROACH
Review round: 1
Reviewer: 2

Output:
Basic reporting: In this paper, Rahid, Rehman and Andleeb use a multi-step computational approach to predict peptides that they propose would be useful as antigens for cholera vaccines. There may be some valuable information here, but the authors do not sufficiently contextualize their findings in light of other studies (e.g. see pt 7 below).

Major points

1.	Make clear in abstract (and title) that this is bioinformatics paper; i.e. that the screen was purely in silico. Usually, in reverse vaccinology approach, candidate polypeptides are tested for immunogenicity.
2.	There is an over-emphasis on the importance of antibiotic resistance; in general antibiotic therapy is an adjunct to re-hydration and not a key issue in cholera.
3.	It is not clear how/why the STRING analysis aides in predicting good antigens.
4.	The claim that NlpD, OmpU, AcfA and OmpW are “critically important virulence mechanisms in V. cholerae” (line 203-205) is not well-grounded. To the best of my knowledge ompU mutants are not attenuated and acfA mutants exhibit only a modest colonization defect.
5.	Additional details are necessary in the figure legends. For example, the legend for figure 2 should include a description of the yellow, blue, and red bars and the polar plot in the middle of each chromosome outline; the legend for figure 5 should list which of the protein structures are predictions and which are actual solved crystal structures, inclusion of any PDB accession codes used would also be helpful; in Figure 6 include a description of the different strains that are used in the multiple sequence alignment.
6.	The introduction and perhaps discussion requires a more thorough and up to date description of cholera vaccine research.
7.	Some references and discussion of prior studies of V. cholerae antigens; in particular the authors should include a comparison of their findings with those included in J Infect Dis. 2017 Jul 1;216(1):125-134. doi: 10.1093/infdis/jix253.
8.	The paper is in need of careful editing for typos and grammatical errors.

Minor points:
Line 36 Non-O1 non)139 serogroups can be choleragenic
Line 37 serotype should be serogroup
Experimental design: see comments above
Validity of the findings: see comments above
Additional comments: see comments above


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

Input:
Title: FISHING FOR VACCINES AGAINST VIBRIO CHOLERAE USING IN SILICO PAN-PROTEOMIC REVERSE VACCINOLOGY APPROACH
Review round: 2
Reviewer: 1

Output:
Basic reporting: It is acceptable. The authors appropriately revised the manuscript based on the reviewers' comments.
Experimental design: It is acceptable.
Validity of the findings: The findings are valid and robust.
Additional comments: The manuscript is appropriately prepared and revised based on the reviewer's 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: LINKED WITHIN-HOST AND BETWEEN-HOST MODELS AND DATA FOR INFECTIOUS DISEASES: A SYSTEMATIC REVIEW
Review round: 1
Reviewer: 1

Output:
Basic reporting: The manuscript is well written. However, there is no sufficient field background/context provided. The article does not include sufficient introduction to demonstrate how multiscale models which integrate within-host and between-host scale fit into the broader field of multiscale modelling of infectious disease systems. Infectious disease systems have many levels of organization apart from the host level. The authors should have a more general introduction that discusses multiscale modelling at the various levels of organization (cell level, tissue level, host level, etc.) and then indicate why they chose multiscale modelling at host level.
Experimental design: This is a review paper. The research objectives are well defined, relevant & meaningful. The paper is within the aims and scope of the journal. The study design is described in sufficient detail.
Validity of the findings: The findings of this study are clear. the conclusion are well stated, linked to original research question. However, the authors should justify the conclusion that host immunity can be considered as an alternative linking mechanism in multiscale modelling of infectious disease systems.
Additional comments: More general comments are in the pdf file attached.


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: LINKED WITHIN-HOST AND BETWEEN-HOST MODELS AND DATA FOR INFECTIOUS DISEASES: A SYSTEMATIC REVIEW
Review round: 1
Reviewer: 2

Output:
Basic reporting: see below
Experimental design: see below
Validity of the findings: see below
Additional comments: This is a nice review worth publishing, but I have several concerns that I think should be addressed.
My main concern is about the search strategy. I find it too narrow to be a convincing systematic review. First, it seems to me your search terms are not broad enough. For instance I have seen papers that use the term “in-host” instead of “within-host”. Similarly, there might be papers who have a population-level component but might not use the word “between-host”. With your search terms, you seem to be missing those. Further, systematic reviews generally search across multiple sources, it is unusual for systematic reviews to only search a single source (despite WoS being more than one database, I consider it essentially a single source). I recommend you re-do your search across multiple sources (e.g. include Scopus or others that you think might be complementary to WoS) and use somewhat more flexible search terms to ensure you get all relevant studies, not only those who explicitly use the term “within-host”. Such a broader search would make me more confident that this was truly systematic/broad.

My remaining comments are less substantial, listed in order of appearance:

Abstract: calling within-host the 1st scale is a bit arbitrary. One could equally say that within-cell/intracellular is the 1st scale. So I would re-word some to indicate that here you are looking at 2 of the – possibly many – ways one can define scales. Start of introduction is worded better.

Line 25: typo, should be holistic

Line 87: I’m unclear what ‘out of scope’ refers to. Can you clarify? It seems to me that if it’s not a multi-scale model and/or doesn’t contain data, it is flagged as ‘No’ for those categories. What other ‘out of scope’ evaluation did you perform? Where there some papers that were multi-scale models with data but you ignored them? If so why? Needs some more explanation.

Figure 3: since there are only 2 “other” in 3A and 1 in 3B, maybe explicitly state what this ‘other’ is. Especially for infection type, I’m wondering what it could be that’s not one of the listed categories.

Figure 4: I find that figure confusing since it looks as if these are mutually exclusive categories when they are not. IBM could be either deterministic (rare) or stochastic (common), any deterministic or stochastic model could be fit to data, which would make it ‘statistical’. The only clear mutually exclusive categories are deterministic vs stochastic. I think you need better terminology for this. I assume what you mean by deterministic is also a mechanistic, compartmental model (i.e. ODE), and stochastic is also a mechanistic compartmental model, while IBM is individual based (and maybe deterministic, maybe stochastic), and what you call statistical I assume by that you mean a non-mechanistic/process/system model?

Line 153 and following and 172 and following. I’m not clear how these paragraphs describe different things. And in the 1st paragraph, you say that one paper links between to within, while on line 175 you say that no paper linked between to within. That’s confusing, I can’t follow. Can you please clarify?

Line 191 and following. Could you be a bit more explicit about data use? The statement that one paper didn’t explain how they used data puzzles me. I was under the impression up to that point that all papers using data ‘used’ them in some statistical/fitting/inference way. Or do you also include papers that only parameterize their models based on data, without any statistical fitting? I would like a bit more explanation on this. Also, most of your analyses (i.e. up to this paragraph) could have been done on all papers, not just the ones with data. To justify excluding all those and focusing on the ones with data only, it seems to me you need to put some more focus on the data part, i.e. add further analysis/discussion of the connection between models and data. Maybe a version of figure 4S, together with more exploration on the model-data link, might be suitable for the main part of the paper?

Supplement:
•	You already include the flowchart in the main text, why include again?
•	Your pdf document of excluded papers also includes all the included papers.