Peer review report

Title: Publication Patterns and Perceptions of Open Science in Indian Scholarly Community: Insights from a Survey

version: 2

Referee: Moumita Koley

Institution: Indian Institute of Science, Bangalore, India

email: moumitakoley@iisc.ac.in

ORCID iD: 0000-0003-2394-0663

General assessment

The author of the article provides a limited perspective on Publication Patterns and Perceptions of Open Science in the Indian Scholarly Community. This article sheds some light on open science practices, considering the scarcity of data on this topic. The main drawbacks, the survey conducted in the article is the only methodology used, and it is limited to a small group of researchers. Understanding publication patterns (Open Access publication and use of preprints) should be made using bibliometric studies. Another drawback of the article is that it primarily focuses on researchers from the agriculture field, which is over-represented and makes it misleading to claim that the study represents the entire Indian scholarly community. This is particularly problematic since the physical and chemical sciences dominate the Indian research community, and data from these fields are entirely absent in the article.

Essential revisions that are required to verify the manuscript

This study is at an early stage; more data points and representations of various fields are necessary to claim validity. Moreover, a mixed-method approach is more suitable.

Other suggestions to improve the manuscript

The introduction section mentions several preprint servers, but some are not operational. For example, ArabiXiv is not accepting new submissions, and IndiaRxiv has few submissions. Since there are limited responses from other South Asian countries, the author has chosen to focus on India. However, it is unclear if the percentages of career levels of professionals are representative of India alone.

One drawback of this article is the over-representation of researchers from the agriculture field. In the Indian ecosystem, agricultural research institutes are separate from the general university system and governed by different funding and governance systems. Therefore, the norms and practices can vary significantly.

In the STEM subjects, Chemical Sciences contributed the most publications in India from 2015-2019, followed by Physical Sciences. Biological Sciences had fewer publications during this period(the method used for this statement: a quick search in the Web of Science). However, this data does not represent the publication behaviour of the major constituents (Physical and Chemical Science) of the Indian academic community. Therefore, it is suggested to shift the narrative towards agricultural science.

The statement "patent and scholarly data website, India has produced 19,76,966 scholarly works till date" lacks a timeframe.

The APC section statements are unclear. As far as current knowledge goes, no study has shown a correlation between JIF and APC. The statement "Was it because of JIFs they must publish in Open Access when there is Green Route to Open Access (depositing in subject or institutional repositories)" is unclear. Moreover, while Indian national funding agencies have green OA mandates, they have not been enforced. Several studies indicate that Indian researchers' adoption of green OA is low, so authors have no obligation to publish OA.

The article concludes that advocacy is needed, but it is essential to understand the research assessment frameworks of Indian academia and funding agencies. Without recognition in assessment, researchers are unlikely to adopt Preprints. Preprint submission is becoming the norm in some disciplines, which may improve the situation.

Decision

Requires revisions: The manuscript contains objective errors or fundamental flaws that must be addressed and/or major revisions are suggested.

Peer review report

Title: Maintained imbalance of triglycerides, apolipoproteins, energy metabolites and cytokines in long-term COVID-19 syndrome (LTCS) patients

version: 1

Referee: Paola Turano

Institution: University of Florence

email: turano@cerm.unifi.it

ORCID iD: 0000-0002-7683-8614

General assessment

This is an integrated study reporting NMR-based metabolomics data and flow cytometry-based cytokine in the blood of 125 individuals (healthy controls (HC; n=73), COVID-19-recovered (n=12), COVID-19 acute (n=7) and LTCS (n=33)).

The main goal appears to be that of demonstrating alterations in the metabolome and immune markers of patients with long COVID. This condition is defined as the continuation or development of new symptoms 3 months after the initial SARS-CoV-2 infection, with these symptoms lasting for at least 2 months with no other explanation.

As admitted by the authors, the 4 groups are very unbalanced in terms of numbers of enrolled subjects; moreover, all numbers are low but those in the recovered groups and even more in the acute phase are extremely low. Therefore, the only reliable comparison appears to be that between HC and LTCS. And this is a pity because the most important comparison to define the signature associated with long-COVID symptoms would have been the one between recovered and LTCS subjects.

Another problem is that there is no information on the status of the LTCS before infection nor during the acute phase. This, combined with the low number of individuals, does not allow to draw a real trajectory of the alterations during the observed time line. It is therefore difficult to be 100% sure that alterations in certain metabolites of lipoproteins are a consequence of LTCS or instead intrinsic characteristics of a group of individual that make them more prone to develop LTCS.

These critical aspects have nothing to do with the experimental approach, which is powerful and carefully performed. Unfortunately, the available cohort is not the best to achieve the goal of a molecular characterization of LTCS.

In any case the present manuscript provides useful hints to be further investigated in future studies and therefore might deserve publication.

Essential revisions that are required to verify the manuscript

If it were possible to enlarge the cohort of patients, confirming the observed trends, this would lead to a significant improvement in the impact of the work. But I understand the practical difficulties in achieving this goal.

Decision

Verified with reservations: The content is academically sound but has shortcomings that could be improved by further studies and/or minor revisions.

Peer review report

Title: Maintained imbalance of triglycerides, apolipoproteins, energy metabolites and cytokines in long-term COVID-19 syndrome (LTCS) patients

version: 1

Referee: Christopher Gerner

Institution: University of Vienna

email: Christopher.gerner@univie.ac.at

ORCID iD: 0000-0003-4964-0642

General assessment

The manuscript of Berezhnoy et al. is a well written report regarding metabolomics and cytokines in long term COVID-19 syndrome patients. The applied methodology is of some interest and I cannot detect methodological errors. However, I have some concerns which need to be addressed before the manuscript should sent for journal publication.

Most importantly, the manuscript did not adhere to good scientific practice regarding literature research. There are papers about LTCS patients published more than a year ago following highly similar research strategies with quite similar results. It is not sufficient to cite them in subordinate clauses in the Discussion, they need to be cited in the Introduction accordingly, as well when discussing the results. Indeed, relevant similarities in the results would deserve some discussion, such as the dysregulation of cytokines in LTCS.

Another weakness is the structure of data interpretation. It is mentioned in the Introduction that several cell types were reported to show altered metabolism after a COVID-19 infection. I cannot see how plasma analysis should allow to verify such observations as it represents a mixture of all cell types in the body. This obvious challenge regarding data interpretation should be addressed.

This is in line with another weak aspect. The numerous findings a reported without a clear structure regarding potential pathomechanisms. As such, the manuscript is sometimes not easy to read.

To sum up, the manuscript reports interesting analysis results largely corroborating previous results, which deserved publication after some essential improvements.

Essential revisions that are required to verify the manuscript

An improved appreciation of existing literature is essential, as well as an improved data interpretation.

Other suggestions to improve the manuscript

A discussion of the pros and cons of NMR-based metabolomics in contrast to other techniques would be helpful.

Decision

Verified with reservations: The content is academically sound but has shortcomings that could be improved by further studies and/or minor revisions.

Peer review report

Title: If it’s there, could it be a bear?

version: 2

Referee: Rahul Raveendran

Institution: Biodiversity Institute, University of Kansas

email: rahulravi777@gmail.com

General assessment

The manuscript needs to be revised thoroughly.

Essential revisions that are required to verify the manuscript

I feel that the introduction can be a little more elaborative. My suggestions are as follows:

• In the first paragraph, the author can give more details about ‘hominology’ by citing the works of Dmitry Bayanov. This is to give a historical account of ‘hominid research’ to the readers who are unfamiliar to this topic.

• Second paragraph has information related to the ‘misdeeds’ of the ‘proponents of hominology’. According to me, there must be continuous flow of information from paragraph to paragraph. Currently, I do not see a proper chronological flow of details in 1st and 2nd paragraph. I request the learned author to check this in such a way that 1st para must provide details about ‘hominids’, ‘hominology’, and the 2nd para must give the scientific explanation about these ‘controversial findings’.

• Line numbers 43-44: This paragraph must be expanded, and possibly include more information about ‘American black bear’ being misrecognized as ‘bigfoot sightings’ with references. If available, provide details regarding the molecular/clinical test results (i.e., references).

• A separate paragraph has to be incorporated to detail the methods adopted by scientists/researchers to link the population density of American black bear and bigfoot sightings.

• Line numbers 49-51: The sentence “No positive correlation between……a small proportion of all sightings” has to be re-written as I think that it does not convey its meaning properly.

• Provide the fundamentals of ecological niche modeling. How such a concept can be adopted in this sort of a study with a strong emphasis on the results of Lozier et al. (2009) would be helpful for the readers.

• In the last paragraph of the introduction, although not in detail, the author should state clearly the approach that was taken to execute the study. For example, details related to the chosen statistical methods with references. And state your hypothesis clearly.

Materials and Methods

• Line numbers 67-77: Please make these sentences more lucid. I feel that this paragraph lacks coherence.

• Line numbers 90-94: Please make these sentences more understandable.

• Line numbers 113-116: Please re-write these sentences to make them more understandable. Results

• Line numbers 121-123: The article states that both the sasquatch sighting and black bear population maps are strongly coloured in the Pacific Northwest area……”. BUT, in PNW, I do not think that bigfoot sightings in British Columbia are proportional to the black bear population.

• Presentation of results is a bit confusing for me. I would suggest to rewrite the results with a view to make everyone who reads this article understands the results properly.

Discussion

• Discussion must be vastly improved

a) It is difficult to understand the very first sentence of the discussion that starts with “The present study regressed ………………..”. Please re-write it.

b) Results of the present study should be discussed in detail, linking previous published reports.

c) The models employed must be discussed in detail with the support of previous reports to substantiate the conceptual correctness of the methodological framework.

Decision

Requires revisions: Major revisions are suggested.

Peer review report

Title: If it’s there, could it be a bear?

version: 2

Referee: Julie Sheldon

Institution: University of Tennessee

email: jsheldo3@tennessee.edu

ORCID iD: https://orcid.org/0000-0003-2813-3027

General assessment

This manuscript is a collection of statistical analyses attempting to show that sasquatch sightings correlate with black bear populations, and humans may be mistaking black bears for sasquatch.

The author effectively introduces the topic, provides adequate background on sasquatch, but does not provide much on black bear populations, natural history, or human-bear interactions.

The author performs several statistical tests to support the findings. I am not a statistician, but the tests seem valid. The data used for the statistical analyses, however, are not ideal. The resource (Hristienko and McDonald) provided for obtaining black bear populations was published in 2007 and the data was from 2001 via “subjective extrapolations” and “expert opinions”. Thus, this resource is outdated and suboptimal as black bear populations have changed over time. A more updated resource with more scientific methods in data collection would improve this manuscript since having as accurate as possible bear population estimates is very important for the goal of this study. The author notes this briefly in the limitations. If the human population and sasquatch sighting data matched up with the dates of bear population estimates, it would be more valid (just outdated), but there are no date ranges of human or sasquatch data provided in the manuscript.

In the results, the maps of bigfoot sightings and black bear population do not appear to correlate visually, which downplays the value of the statistical analysis. The stats should support the visual data and vice versa if the study is sound. Perhaps more updated bear population data will improve this.

The discussion is short and briefly brings up important points that can invalidate the study without much discussion or argument supporting the findings of this study.

Essential revisions that are required to verify the manuscript

I recommend the following to improve the manuscript enough to consider it valid:

Date-match the bear population, human population, and bigfoot sightings to improve the validity of the data analysis. One way to do this is to use data from the same 10-year period only.

Improve the sources of bear population information.

Expand the discussion to include reasons and ideas the maps don’t line up like the statistical analyses do – ie bears in Florida and the southeast.

Other suggestions to improve the manuscript

I recommend provide some information on black bear population/natural history in the introduction – ie what sort of habitats do black bears live in. Consider the possibility that sasquatch sightings may correlate with a type of habitat (ie forest), which happen to also correlate with black bear habitat. This may support the idea that sasquatch sightings are bears, or that sasquatch also likes to live in similar habitats as bears.

The author reports that black bears are not prominent in Florida; however, there are > 4,000 black bears bears in Florida, that are reportedly large, and it may be worth considering this as a reason for the concentration of sasquatch sightings in Florida as seen on the map. More accurate black bear data as discussed above may help improve this aspect. Experientially, there is also a high concentration of black bears in the southeastern US, where there is also a high concentration of humans and human-bear encounters. The author does not discuss this along with the number of sasquatch sightings in this region as seen on the map.

Decision

Verified with reservations: The content is academically sound but has shortcomings that could be improved by further studies and/or minor revisions.

Peer review report

Title: Types of Arrhythmias and the risk of sudden cardiac death in dialysis patients: A Systematic Review and Meta-analysis

version: 1

Referee: Milaras Nikias

Institution: National and Kapodistrian University of Athens- Ippokrateion Hospital

email: nikiasmil@med.uoa.gr

ORCID iD: 0000-0001-7312-0976

General assessment

It is now well known that high cardiovascular mortality in ESRD patients is only partly due to atherothrombotic events. Ventricular tachyarrhythmias and electromechanical dissociation account for a significant amount of those deaths as was reported in landmark trials such as the MADIT II. VT or VF might be the mode of death in only a minority of those patients and this is extrapolated from the fact that ICD implantation in this population does not extend survival, whether due to high competing comorbidities or due to electromechanical dissociation being the cause of death. It is true that ESRD patients are underrepresented in such studies due to the high competing factor for non-cardiac death and no safe conclusion can yet be drawn. It remains yet to be seen whether a better risk stratification algorithm through Holter monitoring or programmed ventricular stimulation can unveil those truly at high risk for SCD.

This meta-analysis tries to unveil the mode of death and the high cardiovascular mortality in renal failure through a thorough literature search that included 11 studies. This systematic review/meta-analysis follows current writing and reporting guidelines.

The English used is adequate although some parts of the manuscript could be refined (eg 3rd paragraph in Introduction)

Essential revisions that are required to verify the manuscript

ESRD and ESKD are both discussed in the manuscript. I would personally prefer that the authors devoted more effort in commenting on the meta-analysis results and its implications. The included studies are not adequately annotated in the text, making reading difficult for the statistically unschooled reader who must understand the plots provided.

Decision

Verified with reservations: The content is academically sound but has shortcomings that must be improved.

Peer review report

Title: If it’s real, could it be an eel?

version: 2

Referee: Dr Don Jellyman

Institution: National Institute of Water and Atmosphere (New Zealand)

email: don.jellyman@niwa.co.nz

ORCID iD: 0000-0002-6941-2703

General assessment

An interesting assessment that verifies the obvious – that any monster of ~ 6 m cannot be an eel (Anguilla anguilla), although there is a reasonable likelihood that eels of ~ 1 m could account for some of the “sightings” of elongate animals in the loch. However, even though the outcome is unsurprising, the author approaches the subject in a rigorous and systematic way. As such, the manuscript is of value in eliminating eels as possible candidate species for the mythical monster.

The manuscript is well written and referenced.

Essential revisions that are required to verify the manuscript

Nil

Other suggestions to improve the manuscript

Nil

Decision

Verified: The content is academically sound, only minor amendments (if any) are suggested.

Peer review report

Title: An Improved Peer-Review System to Compensate for Scientific Misconduct in Health-Sensitive Topics

version: 7

Referee: Cristina Candal-Pedreira

Institution: University of Santiago de Compostela

email: cristina.candal.pedreira@rai.usc.es

ORCID iD: 0000-0002-1703- 3592

General assessment

In this letter, the authors propose a series of actions that the main actors responsible for scientific integrity (researchers, scientific journals, academic institutions, and funding entities) could (and should) implement to prevent and/or detect cases of scientific misconduct. Although the authors refer primarily to high-sensitive publications, in my opinion, many (if not all) of the provided proposals can be applied to any type of publication. Examples of scientific misconduct are commonplace, and the policies implemented so far do not seem to be strong enough to prevent the publication of fraudulent articles. I believe that this article is necessary and very relevant.

Essential revisions that are required to verify the manuscript

In my opinion, this letter presents a very comprehensive list of potential strategies that different stakeholders can undertake to reduce the burden of research misconduct. Of course, there are many other actions that could be implemented, such as promoting post- publication review, imposing sanctions, or auditing research funding from an ethical point of view, among others. However, I consider all the strategies developed by the authors to be important and necessary, so I have no essential revisions to this manuscript.

Other suggestions to improve the manuscript

The text is well written, very clear and easy to follow.

Some comments/suggestions/reflections:

I would suggest introducing the definition of “high sensitivity topic” in the first part of the manuscript. Also, in the title another term is used (health-sensitivity topic), I would homogenize terms.

J2. In addition to solving the problem of coercive citations, open peer review can make the peer review process more transparent by making public how many rounds of review have been done and how the conclusion was reached to publish or reject the article. In addition, reviewers, because they are not anonymous, can take the review more seriously.

R1-R2-R3. Regarding regulatory agencies, funders and institutions, it could also be helpful for them to perform audits of the projects, not only justification of where the money was spent, but also whether the research is being done ethically, including during the phase of dissemination of results.

Decision

Verified: The content is academically sound, only minor amendments (if any) are suggested.

Peer review report

Title: Crossref as a source of open bibliographic metadata

version: 2

Referee: Silvio Peroni

Institution: University of Bologna

email: silvio.peroni@unibo.it

ORCID iD: 0000-0003-0530-4305

General assessment

This article describes an analysis of the Crossref dataset to assess if it can be a rich and reliable source for open bibliographic metadata, considering its central role as a primary source of several Open Science infrastructures such as OpenCitations and OpenAlex. The article is very well-written and addresses an important topic for the community. The analysis focuses mainly on the availability of some metadata, namely reference lists, abstracts, ORCIDs, author affiliations, funding information, and license information. Both data and interactive versions of the figures in the article are openly available online, shared in open formats and appropriately cited, supporting well the reproducibility of the analysis. However, it would be crucial to clarify a few aspects, listed in the section below.

Essential revisions that are required to verify the manuscript

Only a few aspects may need to be clarified in the paper.

1. In Section 3.2, there is a link between the fact that large publishers support I4OC and the fact that we have reached a tipping point of one billion open citations available. However, in the cited paper by Hutchins (2021), while there is a strict reference to I4OC, the reaching of the tipping point was not computed directly using Crossref (which is the dataset discussed in the present article) but by combining the data contained OpenCitations’ COCI (derived from Crossref data) and the NIH Open Citation Collection (derived from PubMed data). Thus, while indeed this result has been reached thanks to the enormous contribution of Crossref data, it was necessary to involve other open collections that do not necessarily involve the same publishers participating in I4OC and releasing their bibliographic references via Crossref.

2. In the case of ORCIDs (page 9), it would be good to clarify whether the availability of such identifiers (and other metadata) in Crossref is full responsibility of the publisher or Crossref makes some inference (e.g. using specific tools and/or external sources) either to fill in fields that are not specified or to validate them (at least at a first syntactic level, e.g. by seeing if the check digit of the ORCID identifier is correct or not).

Other suggestions to improve the manuscript

There are two aspects that, if included, would make the analysis even more robust.

First, the authors explicitly tell us that IEEE references have yet to be considered in the analysis since the Crossref dump they have used precedes the release of IEEE bibliographic references in Crossref. It would be great to re-run everything with a newer dump to address this lack, if feasible, considering the publisher's importance and dimension in terms of publications.

Second, it is clear that the authors have developed some tools (e.g. scripts, software, queries) they used to parse the Crossref dump and extract the relevant information from it. However, there is no mention of such tools in the paper. Having them available as open-source material would be ideal since they implement the methods that have been used for processing data and gathering the statistics introduced in the article. Indeed, such a code's availability would increase the analysis's reproducibility. Therefore, even if it is not mandatory for the narrative of the article, I would suggest (if feasible and legally allowed) publishing such sources with a readme file that explains how to run them, providing them with a persistent identifier (either Software Heritage or GitHub+Zenodo can be used for it), and to cite them properly in the article.

Decision

Verified: The content is scientifically sound, only minor amendments (if any) are suggested.

Peer review report

Title: Burden of HCoV infection in children hospitalized with lower respiratory infection in Cape Town, South Africa

version: 1

Referee: Jessica Price

institution: University of Witwatersrand

email: Jessica.Price@wits.ac.za

ORCID iD: 0000-0002-4020-6850

General assessment

This manuscript it well written, with a clear description of the methods, results and discussion of findings. I think that with minor corrections it would be ready for publication.

Essential revisions that are required to verify the manuscript

Methods:

Study procedure:

1) Please add a reference to the parent study which details the full methods of the parent study.

2) In the third paragraph of this section the authors refer to children young than 18 months with a positive HIV Elisa as being confirmed to have HIV infection. Please double check this - I think it is supposed to be that these children were categorised as HIV- exposed with a confirmatory HIV PCR preformed to determine HIV infection.

Results:

3) The current phrasing of the results suggests that there were no refusals amongst those eligible to participate. Is that accurate?

4) In table 1: HIV status “exposed by negative” – is that children under 18 months or under 6 months? If only those less than 6 months please explained where children between 6-18 months are categorised.

Discussion:

5) 16 patients were found to have different human coronaviruses on the IS and NP samples. Please discuss the implications of this finding. Which would you act on? Does this bring into question the validity of the two methods if they are detecting different viruses in the same patient. I would understand if one method detected additional viruses but to have completely different viruses across the two specimens on the same patient is potentially problematic.

6) The authors note that the study group only incudes hospitalised patients and therefore cannot comment on community transmission/burden. However there have been many community-based surveillance programmes to track respiratory virus burdens and transmission patterns in SA (including work by Sharon Cohen, NICD) – it would be helpful to the readers if the authors could review some of these publications and comment on relevant similarities or differences. (most recent of these publications can be found here: https://crdm.nicd.ac.za/projects/phirst-c/)

7) Please review and redraft this paragraph 5 in the discussion – starting “compared to RSV and other respiratory viruses…”. I could not follow what the authors are trying to say in this paragraph.

8) Please add in a limitations/recommendations section.

Conclusion:

9) The final paragraph of the conclusion raises some interesting questions but does not fit as part of the conclusion. I suggest moving this to be included as part of the discussion, and more fully discussing the questions raised regarding the value of testing for disease if they do not cause severe disease, nor change treatment strategies.

Other suggestions to improve the manuscript

• Stylistic preferences in the introduction: avoid using “for example” when describing work referenced. Either just add the reference number, or use phrasing such as “as shown by (author name) who found …” etc.

• Methods - Statistics: Typo in the last paragraph – please confirm if Stata 13 or stata 16, and add in the necessary stata package reference.

Decision

Requires revisions: The manuscript contains objective errors or fundamental flaws that must be addressed and/or major revisions are suggested.

Peer review report

Title: Angiotensin converting enzyme (ACE) 1 expression in leukocytes of adults from 64 to 67 years old

version: 2

Referee: Calogero Caruso MD

Institution: Professor Emeritus, University of Palermo

email: Calogero.caruso@unipa.it

ORCID iD: 0000-0001-8004-2363

General assessment

The paper is essentially anecdotal because it studies the cells of 6 subjects without any comparison with other age groups. There is also a serious limitation because beyond the age and sex there is no information on the donors (how and why they were recruited, what drugs they took, etc.). To infer that chronological and biological ages do not match is inappropriate in the absence of the above information.

However, the paper is of some interest because there are few studies on the topic.

Essential revisions that are required to verify the manuscript

1) Although we do not have data on donors, placing an age and gender column in all tables adds a minimum of useful information for the reader.

2) Inflamm-ageing means low grade of inflammation. The value of CRP 23.1 suggests acute inflammation (also because albumin has high values, while in chronic inflammation its values decrease). Therefore the Ly averages do not have to take this subject into account.

Other suggestions to improve the manuscript

The authors write that their findings suggest that ACE1 could play a role in several processes linked to aging including the generation and activation of autoimmune cells, due to the experimental evidence that inhibitors of ACE suppress the autoimmune process in a number of autoimmune diseases such as EAE, arthritis, autoimmune myocarditis. [49] They do not appear to have these findings in their paper. So, it needs to change the sentence.

Decision

Requires revisions: The manuscript contains objective errors or fundamental flaws that must be addressed and/or major revisions are suggested.

Decision changed:

Verified manuscript: The content is scientifically sound, only minor amendments (if any) are suggested.

Peer review report

Title: Abnormalities in migration of neural precursor cells in familial bipolar disorder

version: 6

Referee: Shani Stern

Institution: University of Haifa

email: sstern@univ.haifa.ac.il

ORCID iD: 0000-0002-2644-7068

General assessment

I have read the study by Sukumaran et al. The authors describe that NPCs derived from bipolar disorder patients using induced pluripotent stem cells show abnormal migration and that transcriptionally there is a dysregulation of a network of genes that relate to on EGF/ERBB proteins. Overall, the study is interesting. However, some points should be addressed. See below.

The following points are important to take into consideration:

1. Some English edits are required. Also, some acronyms appear before their definition (for example MSD).

2. In the introduction, some important studies that describe transcriptomics of BD patients should be described such as Santos et al 2021 and also neuronal phenotypes such as hyperexcitability and physiological instabilities.

3. The transcriptomics is performed only for one of the control lines although there are 3 controls. More control samples should be taken for the gene expression analysis.

4. The figures are not in the correct order.

5. The damaging variants of the patients are not described. Although there are references to previous publications, since this may be central it is good to add a table describing these variants in the patients and in the controls.

6. The differentiation to which type of neurons should be briefly described (although there is a reference to previous publications, but this should be mentioned).

7. The statistical analysis is not very clear. Moreover, the images of the migration assays are not convincing enough that indeed there is a significant difference. How many times was this performed? This should be repeated with several cultures, especially since the number of patients and controls is small. It would be more convincing if this is reproducible over several repetitions.

8. It would be good to also include representative videos in the supplementary.

Decision

Requires revisions: The manuscript contains objective errors or fundamental flaws that must be addressed and/or major revisions are suggested.

Peer review report

Title: Crossref as a source of open bibliographic metadata

version: 2

Referee: Simon Porter

Institution: Digital Science

email: s.porter@digital-science.com

ORCID iD: https://orcid.org/0000-0002-6151-8423

General assessment

This is a clear paper that outlines a motivation (assess the metadata completeness of the Crossref record for the purposes of scientometric analysis,) along with providing a set of useful metrics to assess the completeness of each metadata field.

Essential revisions that are required to verify the manuscript

No essential revisions identified

Other suggestions to improve the manuscript

Minor suggestions: Figures in the interactive version of the preprint do not have headings or captions, or a link back to the paper.

On data availability, In the context of the paper, making the code used to process the Crossref’s XML Metadata Plus Snapshot would be a useful contribution enabling scientometric analysis of the Crossref dataset.

The following are offered as suggestions that could be added to the paper at the authors discression, but do not effect the content or the conclusions of the peer review

The authors have chosen to frame metadata completeness of Crossref records as a ‘good in itself,’ leaning on Waltman, L. (2020b) to do the work of setting this up.

Within this framework, the analysis is offered as a set of observations to help publishers understand where they need to do better. It might be the case that Publishers do not intrinsically understand why making certain metadata types available is valuable to the community.

On the question of how Crossref can be used in scientometric analysis, readers are left to make up their own minds on what Crossref can be used for today, vs what it might be capable of providing in the future based on the evidence presented. It would be a stronger conclusion to highlight the types of scientometric analysis that are now possible with Crossref, (for instance bibliometric coupling,) and those that require limits or caveats (analysis by affiliation, abstract.) As this analysis lends itself to being rerun in the future, it would be useful to trace advances (hopefully!) not just in terms of the number of things, but also in terms of how sceintometric analysis capability is progressing because of it.

Decision

Verified manuscript: The content is scientifically sound, only minor amendments (if any) are suggested.

Peer review report

Title: A single measurement of fecal hemoglobin concentration outperforms polygenic risk score in colorectal cancer risk assessment

version: 1

Referee: Andrea Buron

Institution: Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain

email: aburon@psmar.cat

ORCID iD: E-5705-2016

General assessment

This is a well-written paper describing the compared utility of FIT and PRS as risk assessment tools, and as means of colorectal cancer screening. The results are very informative given that many screening programmes are currently using FIT and the evidence of using PRS as additional or alternative test in this context is scarce.

One of the main strengths of this study is its population, a cohort of participants in screening colonoscopy program which means that for all participants we have the colonoscopy result as well as the PRS and FIT result.

Essential revisions that are required to verify the manuscript

Some issues need some consideration:

1. The context and the study population is not sufficiently described: how does the German screening colonoscopy program work (exclusion and inclusion criteria, invitation methods, funding and cost to the participant), also main results especially in terms of uptake rates and how any differences by age, sex, etc.

2. Include at least in the discussion possible issues that might affect representability of the study population compared to the general population, and whether this might potentially alter the study results. Ideally, a (annex o supplementary) table describing the characteristics of non-participants in the program as well as non-participants in the study would be very informative in this regard.

Other suggestions to improve the manuscript

1. Authors say that “FIT-based risk assessment is restricted to CRC risk” – there is evidence that FIT tests are useful to predict not only CRC but also pre-neoplasic disease. Also, to a less extent, it has been found to correlate and act as a potential risk marker of other non-digestive diseases.

2. As part of the discussion, authors do not comment on the possibility of using FIT and PRS concomitantly. It would be very interesting to know if their results they could further inform in this direction, on whether adding a PRS test to FIT could improve the prediction and hence better select the population in which to recommend colonoscopy.

Decision

Verified with reservations: The content is scientifically sound but has shortcomings that could be improved by further studies and/or minor revisions.

Peer review report

Title: Post-traumatic Stress Disorder symptom sub-cluster severity predicts gray matter volume changes better than overall symptom severity

version: 1

Referee: Wencai Zhang

Institution: Institute of psychology, Chinese Academy of Sciences

email: Zhangwc@psych.ac.cn

General assessment

The current results provide very limited explanations.

Because there was no comparison of healthy controls, it cannot be concluded that the relationship between symptoms and brain structure is PTSD specific, nor is there a entire-population measure to capture the relationship between symptom severity and gray matter volume.

A total of 12 people, the sample size is too small. The correlation between symptom cluster severity and brain gray matter volume is certainly worth investigating, but a sufficient sample size is needed to obtain reliable results. Because of individual differences, such a small sample is not representative of the population from which the sample came. In this case, it is not reliable for the correlation analysis between the total score and brain gray matter volume. This question is more serious when conducting the correlation analysis between four symptom clusters and brain gray matter volume, the problem of insufficient representation of sample is particularly prominent.

Essential revisions that are required to verify the manuscript

This paper presented a small amount of correlation analysis results between total score and brain gray matter volume and a large number of positive correlation or negative correlation results between symptom clusters and brain gray matter volume. They two are not consistent with each other. The problem here is that, because the results from the total score and symptom clusters can hardly support each other, I think the author needs to discuss, explain or integrate these complex results. If the brain regions associated with the total score and the brain regions associated with the symptom cluster are interpreted separately without integration, it is contradictory to the general view that the PTSD total score means the overall symptom severity.

The authors only discussed and interpreted the results in some brain regions, but not in others. Some explanations are too simple and do not integrate the associations between various brain regions. At present, it is not possible to obtain from these discussions which brain region abnormalities are more valuable for understanding PTSD.

This paper has shortcomings in both sample size, which should be expanded and limitations discussion should be added.

Decision

Requires revisions: The manuscript contains objective errors or fundamental flaws that must be addressed and/or major revisions are suggested.

Peer review report

Title: Burden of HCoV infection in children hospitalized with lower respiratory infection in Cape Town, South Africa

version: 1

Referee: SOCORRO P. LUPISAN, MD MSc

email: socorrolupisan@yahoo.com

ORCID iD: 0000-0002-8916-4380

General assessment

This study reports interesting results, but the description of the methodology needs to be improved.

Essential revisions that are required to verify the manuscript

I provide below some comments/queries to strengthen the methodology, and to increase the clarity in the interpretation of the results.

1. The parent study was not described in the Methods Section. The parent study was disclosed only in the Conclusion: “While this study which is a sub-study restricted itself to the burden of human coronaviruses in children, the main respiratory pathogen under review in the parent study was Bordetella pertussis which only assessed similar risk factors in the same cohort of children. “

2. This sub study is also prospective in nature.

3. Was the Informed Consent Form prepared for the parent study only? Did the sub study investigator get a signed Informed Consent Form for the collection and laboratory analysis of samples for this HCoV study?

4. Study Population: In order for the study to reflect the whole season, recruitment was limited to a maximum of four qualifying participants per day. Did you do stratified and systematic sampling? Please describe your sampling procedures as you have done.

5. In the Discussion it was written: Although the study was sufficiently powered, it had low precision and could not demonstrate statistically significant associations. How did you calculate sample size?

Other suggestions to improve the manuscript

I also have some clarifications which need to be addressed:

1. Would you know the other viruses detected? If yes, include in the results as this will enrich you results.

2. Was ceftriaxone really given prior to admission? At home, as injection?

3. What were the clinical diagnosis of cases with HCoV and no HCoV?

Decision

Requires revisions: The manuscript contains objective errors or fundamental flaws that must be addressed and/or major revisions are suggested.

Peer review report

Title: Angiotensin converting enzyme (ACE) expression in leukocytes of older adults

version: 1

Reviewer: Heikki Vapaatalo, MD, PhD, Emeritus professor of Pharmacology

Institution: Department of Pharmacology, Medical Faculty,University of Helsinki, Finland

email: heikki.vapaatalo@helsinki.fi

General assessment

The study is interesting and the title promises for me more than the MS finally contains.

The background, question and the aim are relevant as explained in the introduction.

The major criticism concerns the small size of the material (subjects, n=6), the small age difference (64-67 years) and the lack of younger controls.

In the following minor notes:

Title: ACE > better ACE1, or does the sophistic, elegant method include both ACE:s? The same should be explained and taken into consideration throughout the text.

Introduction: The last chapter, the Author should explain in more detail, how references 11-14 suggest that “ACE play an important role in the aging process”. ACE plays. Does this mean, that ACE is somehow regulating the aging process or in increasing age ACE -levels are changed?

Material and Methods: The N-value of the subjects should be mentioned here, as well the relation of females/males. Do the Authors really regard 64-67 “older age” nowadays? Lack of younger controls! Why first many years later the assays have been done in comparison to the collection of the blood? Are the samples still useable, not destroyed? Did the subjects have some diseases and/or drugs because the possibly were from hospital sample bank? Express the company details similarly than Amersham, cities and countries.

Results: “Table 1 shows that older adults…..” The comparison between the present data and historical studies belongs to the Discussion. Give also individual ages and gender of the subjects in the table 1. What means p-values here? Compared with which or interindividual differences in the particular variable? Should be explained The numbering of tables and the text seems to me confusing. Only three tables, but in the text mentioned four. Number 4 does not exist. It would be good to have a list of abbreviations used in the description of the cell types for an unfamiliar reader.

Discussion: A major part of the discussion deals with previous publications and not meaning or clinical significance of the present findings and comparison between the present and earlier studies. In those previous studies, also ACE2 has been reported, why not studied here? In the limitations, the Authors fairly mention the real problem: The small sample size, and I would like to say lack of younger subjects. The COVID-19 point even tempting to-day, is too far from this study and unnecessary. Linguistic checking would improve the MS.

As a summary: I recommend the acceptance of the MS for publication after the Authors careful rethinking of the message of the results and correction of the minor comments. I hope that in the future the possible age -related correlations to old age up to >80 years would be possible.

Decision

Verified with reservations: The content is scientifically sound but has shortcomings that could be improved by further studies and/or minor revisions.

Decision changed:

Verified manuscript: The content is scientifically sound, only minor amendments (if any) are suggested.

Peer review report

Title: A single measurement of fecal hemoglobin concentration outperforms polygenic risk score in colorectal cancer risk assessment

version: 1

Referee: Iris Lansdorp-Vogelaar

Institution: Erasmus MC, Rotterdam, the Netherlands

email: i.vogelaar@erasmusmc.nl

ORCID iD: 0000-0002-9438-2753

General assessment

This is a well conducted study, clearly written study. The main strengths of the study include the novelty of the topic, its large sample size and that physicians and lab analysts were blinded to each other’s outcomes. There are few weaknesses. First, FIT and SNPs in essence service different purposes. Although I agree with the authors that FIT can be used both ways, this deserves more explicit explanation in the discussion section. Second, I disagree with the exclusion of non-advanced adenomas as relevant findings. Given that the authors suggest using FIT/SNPs for risk prediction at younger ages, non-advanced adenomas are also relevant because with time they could develop into colorectal cancer.

Essential revisions that are required to verify the manuscript

1. There is an essential difference between SNPs and FIT: SNPs predict risk of developing colorectal lesions, whereas FIT signals presence of colorectal lesions. In the current manuscript, SNPs are essentially compared on their performance to detect advanced neoplasms, which is not their intention. Yet, I agree with the authors that in order to predict development of colorectal cancer, one would expect the presence of precursor lesions >10 years prior and thus the performance can be compared that way. However, this is not immediately obvious. I therefore feel very strongly that this difference in initial purpose should be more explicitly explained in the discussion section, and also the argument why this comparison is reasonable nevertheless.

2. Given the above point, I feel that non-advanced adenomas should be included as relevant findings. The purpose of SNPs/FIT in this paper is to predict colorectal cancer risk for stratified screening approaches. In that case, non-advanced adenomas are relevant for future cancer risk in 10+ years. Omitting these basically makes the tests focused on early detection rather than risk prediction and stratification.

Other suggestions to improve the manuscript

1. Genotyping was done on a random age- and sex- matched sample of participants without advanced neoplasms before applying exclusion criteria. As a consequence, there actually was an age- and sex-difference between participants with and without advanced neoplasms in the study. Would it not have been better to age- and sex- match after exclusion criteria were applied.

2. Provide statistical tests for difference in baseline characteristics between participants with and without advanced neoplasms in Table 1.

3. Have the authors evaluated a combined approach of FIT and SNPs to see if that improves risk prediction and outperforms use of either one separately.

Decision

Requires revisions: The manuscript contains objective errors or fundamental flaws that must be addressed and/or major revisions are suggested.

Peer review report

Title: Patients’ satisfaction and quality of clinical laboratory services provision at public health facilities in northeast Ethiopia

version: 1

Reviewer: I wish for this review to remain anonymous. While certainly imperfect, I believe that well- conducted reviews anonymous are preferable to signed reviews and free of the bias that may affect reviewers in a relatively small field.

General assessment

The authors report on an ambitious study that sought to rigorously assess the level of patient satisfaction with a representative sample of laboratory service facilities in the Amhara region of Ethiopia. The relevance of this topic is clearly explained and the role of patient satisfaction in the assessment and life cycle of laboratory services is likely underappreciated – particularly in low-resource settings. The manuscript is reasonably well written but would benefit from some English-language copyediting, as well as editing for length as the manuscript contains several redundant passages.

Overall, the assessment of customer satisfaction as a metric of lab quality is potentially important, and not easily captured by accreditation processes such as SLIPTA or ISO. As such this is a valuable endeavour that will stimulate the field in my view.

In the present study, the authors directly address the fact that patients experience may not reflect the quality or safety of a diagnostic laboratory. They did so by conducting their own measures of laboratory quality assessment, with the aim of establishing whether patient satisfaction is associated with such measures.

Given that this aspects is in my view the core of the study, it is important that the methods used for the quality assessments be better explained and expanded. It is laudable that the authors undertook what appears to be an external quality assurance audit of malaria and TB slides examined in the last 3 months. It is important to understand exactly who performed this examination and what their qualifications were. Moreover, other details on the methods are important such as whether the slides were re-stained at the time of the audit.

Similarly, the section on facility assessment (line 177) suggests that the investigators performed a full SLIPTA audit on participating centres. This would require a huge amount of work from both auditors and the facilities in order to be a valid account. This should be described in much more detail. I was surprised to find few references detailing Ethiopian laboratory implementation or strengthening experiences (of which there are a few instructive published examples).

Finally, the finding that satisfaction is most strongly associated with objective measures of quality – such as use of fresh gloves (pre-analytical quality), EQA results of microscopy (analytical quality) and TAT (post-analytical quality) is interesting and supports the idea that quality is not a compartmental issue, but rather a local culture that permeates all laboratory activities. This is a finding that deserves to be highlighted, even if it is unclear that patient satisfaction should be used as a surrogate for more direct measures of lab quality. The emphasis on the lack association with the SLIPTA score is overstated in my view because there wasn’t sufficient variation in these scores – i.e. they were all rather poor - to yield an association.

Decision

Verified with reservations: The content is scientifically sound but has shortcomings that could be improved by further studies and/or minor revisions.

Peer review report

Reviewer: Richmond Dzekoe

Institution: Iowa State University

email: rsdzekoe@iastate.edu

General assessment

This study explores and addresses an important issue of how to identify linguistic Markers of Intercultural Competence in students’ writing. The study sheds some important light on the potential of “I-words,” “In-sight words,” and “quantifiers” to indicate ICC in students’ writing. However, some significant issues need to be addressed to justify the conclusions drawn in this study. The study, therefore, requires a Major Revision. Please see my specific suggestions for revision.

Essential revisions that are required to verify the manuscript

Theoretical Background and Literature review

1. These sections need a major revision. Move the discussion on studies on the importance of reflection to the literature review section and provide more current references. These sections also read more like annotations. It will be better to focus on particular insights from the studies you cited and the implications of those insights for framing your current study.

2. You mention Byram’s (1997) intercultural speaker model and go on to say, “Like most of the current ICC frameworks, Byram’s model offers a holistic approach.” What are some of the current ICC frameworks you are referring to? Giving some examples here will be helpful for your readers.

3. The information in Table 2 should be added to your description of the Corpus.

In order to support the claim that the use of many “I-words” indicates a more open, curious, and involved stance, it is important to explain more clearly how you differentiate the “I- words” which are descriptive from “I-words” that are reflective in your analysis.

Methods, Results, Discussion

1. Explain the strengths and limitations of the integrated approach you are using. What does each model add to your integrated framework, and why is this integrated approach the best way to frame your study?

2. In describing the use of the rubrics to score the blogs, you mention calculating inter- rater reliability. How was this reliability calculated, and what was it?

3. The strong evidence of intercultural competence comes from your analysis of the “Insight words.” There is, however, a problem with the analysis of “I-words.” As you explain the use of “I-words” as indicators of reflective writing, it will be good to explain more clearly how you differentiate the reflective and descriptive functions of “I-words” in your analysis.

4. The discussion is weak. Besides a list of limitations, the discussion lacks an insightful engagement with conclusions drawn by previous research. Contextualizing the discussion within already reported insights on this topic from studies such as Belz (2003), Byram (1997), Chen, Wong, & Luo (2020), Deardorff (2006), Elola & Oskoz (2008), Hoefnagels & Schoenmakers (2018) will help you address the main aim of your study which is identifying linguistic markers of ICC in order to provide teachers and other supervisors with tangible cues to help students develop ICC.

Other suggestions to improve the manuscript

1. In the abstract, it might be a good idea to mention how many students were involved in the study and their level of linguistic proficiency in English.

2. You used the expression “a more analytical approach.” Please be more specific and mention that approach by name and what makes it more analytical. Introduction

3. In the introduction, please provide more substantial evidence from the literature to support the claim that a “successful career path increasingly depends on ICC.” One example from Linked in is not enough.

4. Please provide a clearer definition of ICC. Besides the mention of Deardorff’s (2006) definition, the reader is lost as to what ICC really means in this study and how that definition informs the framing and findings of the study.

5. There seems to be a jump from a discussion on “reflective writing” to the “role of language as a source if information for students learning” and a justification of the use of the “Linguistic Inquiry and Word Count framework” to study the use of “I-words” by President Nixon during the Watergate scandal. This structure makes the introduction a bit confusing. Please revise the introduction. Explaining the use of LIWC in other corpus analysis studies for Word Counts might help you provide a stronger justification for using this framework than the Watergate research you cited in the introduction. For current studies that use LIWC please see (Dud ̆au DP and Sava FA (2021). Performing Multilingual Analysis With Linguistic Inquiry and Word Count2015 (LIWC2015).

6. Beginning the Literature review with the sub-section “Language in relation to ICC” might provide a better flow of ideas in your lit. review.

7. The information in Table 2 should be added to your description of the Corpus. In order to support the claim that the use of many “I-words” indicates a more open, curious, and involved stance, it is important to explain more clearly how you differentiate the “I-words” which are descriptive from “I-words” that are reflective in your analysis.

Decision

Requires revisions: The manuscript contains objective errors or fundamental flaws that must be addressed and/or major revisions are suggested.

Peer review report

Reviewer: Dr. Kilani Hajer,

Institution: Tunisian Institute of Veterinary Research

email: hajerkilani@yahoo.fr

General assessment

The article is scientifically correct, the English language is acceptable; discussion is rich and linked to their results. The article can be accepted after minor revision.

Essential revisions that are required to verify the manuscript

1- Abstract, you said that you found ‘Twelve E. coli’, then you wrote ‘Phylogroup B1 of environment origin was the most predominant (58%, n=12) among the isolates, followed by commensal phylogroup A (16%), phylogroup C (8%), D (8%), and E (8%)’. The number of these phylogroups do not correspond to the total isolates that you collected (n=12)?? Please verify. I realized that you mean by percentage among 12 isolates, therefore it is better for example to write ‘most predominant (n=7; 58%), also for the other phylogroups

2- If the number of studied isolates is 12, please never use percentages, since it is not appropriate for number under at least 30.

3- In the abstract as well in the manuscript, the occurrence of integrons do not means that these integrons contains gene cassettes that encode antimicrobial resistance. Many studies reported the occurrence of class 1 integrons with empty variable regions. Therefore, please take this in mind and modify your discussion.

4- Introduction, you wrote ‘..are typically comprised of phylogenetic groups A, B, and D’. I believe you mean B1 phylogroup, correct this.

5- You wrote ‘..prepared, as Mandal et al. (2014) said’. PLEASE delete the word ‘said’

6- Write ‘Purified 16S rRNA amplicons (Figure 2) were digested with three different restriction enzymes’ correct this also in Figure 2.

7- You wrote ‘In this research, E. coli was isolated at a rate of 8%’. Please, you investigate 60 samples and you find 12 isolates, so 12/60 X100 = 20%. So how you speak about 8%?

8- As I mentioned above since you find only 12 isolates, please avoid to provide percentage, please provide the number of isolates when appropriate and especially in the section ‘Distribution of phylogroups of E. coli in street foods’

9- You provide figure 4, but it is not indicated in your manuscript. If it is not necessary, you can delete it.

10- You wrote ‘..Genes carried by integrons usually express multiple resistance mechanisms, such as resistance to beta-lactams…’ in reality beta-lactamase genes are not part of integrons, they are not gene cassette, they can be near integrons but not as gene casette.

Other suggestions to improve the manuscript

Try to avoid unnecessary figures, and shorten the discussion if possible

Decision

Verified with reservations: The content is scientifically sound but has shortcomings that could be improved by further studies and/or minor revisions.

Peer review report

Reviewer: Suleyman Sedar Koca

ORCID: 0000-0003-4995-430X

email: kocassk@yahoo.com

General assessment

The latest version (bioRxiv V3) of the manuscript is acceptable/publishable as it stands.

Essential revisions that are required to verify the manuscript

There are no suggestions for revisions

Decision

Verified manuscript: The content is scientifically sound, only minor amendments (if any) are suggested.

Peer review report

Reviewer: Božena Horváthová

Institution: University of Constantine the Philosopher in Nitra

email: bhorvathova@ukf.sk

ORCID: 0000-0002-0611-2623

General comments

The manuscript is well written and follows the standards of academic writing, the research is thorough and the conclusions are comprehensive.

Serious concerns

• Do you have any serious concerns about the manuscript such as fraud, plagiarism, unethical practices? No

• Have authors’ provided the necessary ethics approval (from authors’ institution or an ethics committee)? Yes

Language quality

• How would you rate the English language quality? High quality

validity and reproducibility

• Does the manuscript contain any objective errors, fundamental flaws, or is key information missing? No

Suggestions

• Do you have any other suggestions, feedback, or comments on how the study could be improved? No

Decision

Verified manuscript: The content is scientifically sound, only minor amendments (if any) are suggested.

Peer review report

Reviewer: Yulia Karmanova

Institution: Research Centre Kairos

email: yulia.karmanova@gmail.com

General assessment

In my honest opinion the topic of intercultural competence (ICC) should be of great interest not only to researchers involved in linguistics and pedagogics but to a general reader as well. By developing ICC, that represents a set of skills needed when encountering people from various backgrounds, one can learn valuable communication skills, flexibility in behaviour and become more aware of a lack of one’s tact and tolerance.

The manuscript is well written in an engaging and lively style, it provides excellent context about linguistic cues of ICC that will help educators steer and stimulate the ICC development of their students.

The manuscript cites relevant and sufficient literature that provides a very useful resource for current practitioners.

I do not identify fundamental flaws in the manuscript, there is nothing illogical or irrational, although I have a few suggestions for minor improvements. Please see my comments below for further details.

Essential revisions that are required to verify the manuscript

No essential revisions. The manuscript clearly describes the research methods of data collection and analysis as well as other meaningful parameters. Section number 3 (Research Method and Results) is recipe-like, the study can be reproduced.

The data collected for the research is impressive: 1,635 blogs (on average 400 words each) written by 672 students majoring in Hotel Management.

The data and analysis provided in the manuscript are not deprived of clarity and logic. No additional experiments are needed to validate the results presented in the manuscript.

Discussion and conclusion section aligns with objectives stated in the first section.

The authors of the manuscript made a valuable contribution by identifying linguistic markers for ICC in the language use of students blogging about intercultural experiences: I-perspective lexemes, insight verbs and quantifiers. These language cues make ICC more «tangible» and as a result provide teachers with concrete tools for giving students more targeted ICC assessments in their reflective writing tasks. By giving certain linguistic prompts to students, educators may form a more thoughtful and personalised approach in describing their intercultural experience.

Other suggestions to improve the manuscript

The content of the manuscript is scientifically sound but has minor shortcomings that could be improved by further revisions.

I do agree with the limitations of the research mentioned by the authors, especially with the lack of the explanatory value of a significant difference in frequency of use of the linguistic markers which I think can be resolved in future studies of this topic.

I suggest that the authors should involve more assessors in their future research. Two lecturer-researchers and three senior students were involved in the process which I assume is not enough for such large-scale research like this. A bigger team of professional assessors could make valuable contribution when analysing the data and resolving emerging research questions.

I would also recommend providing the manuscript with brief comments on the meanings of the parameters in column 4 (Table 3, 4, 5, 6) for readers’ clarity. What do t, p and n.s. stand for?

I believe that the manuscript would benefit from correcting minor inaccuracies. I would recommend to:
 replace «his» with gender neutral «their», page 6: In these blogs, the language use of students serves as a vehicle of information on the students’ development of ICC, offering the reader concrete cues – henceforth referred to as linguistic markers – of his reflective learning process.

• add a space between that and are, page 19: In order to bring more focus to our research, we initially focused on word categories thatare characteristic of properties that can be linked to ICC and cultural sensitivity, such as openness, self- relativity, curiosity and reflection or analytical thinking.

• add missing parentheses, page 22; Deardorff, D. 2006. Identification and Assessment of Intercultural Competence as a Student Outcome of Internationalisation. Journal of Studies in International Education, 10 (3), 241-266.

All in all, I find the topic of the manuscript fascinating and the research question relevant and essential to the field.

Decision

Verified manuscript: The content is scientifically sound, only minor amendments (if any) are suggested.

Peer review report

Reviewer: Ludo Waltman

Institution: Leiden University

email: waltmanlr@cwts.leidenuniv.nl

ORCID: https://orcid.org/0000-0001-8249-1752

I would like to note that I am an expert in the field of bibliometrics and that my review therefore focuses on the bibliometric aspects of this paper. I am not an expert on scoping reviews or on curcumin. I hope that other reviewers have expertise on these aspects of the paper.

I am one of the developers of the VOSviewer software, which may perhaps be seen as a competing interest.

General comments

Please find below my detailed comments on the paper, including suggestions for improvements.

“A study by Loannidis et al.”: ‘Loannidis’ should be ‘Ioannidis’.

The author uses the Web of Science Core Collection. This database consists of a number of citation indexes (e.g., Science Citation Index, Social Sciences Citation Index, etc.). Depending on their subscription, different Web of Science users have access to different citation indexes. Please mention which citation indexes were used.

The description of the search query in Section 2 is unclear, because the search query doesn’t seem to be restricted to COVID-19 research. The full search query should be reported in the main text of the paper (not only in Appendix 1).

The VOSviewer visualizations presented in the paper are hard to read (especially Figures 1 and 2). The font size used in the visualizations needs to be increased. This can be done using the ‘Scale’ slider in VOSviewer. The author may also consider making interactive versions of the visualizations available online, so that readers can explore these visualizations in their web browser. A visualization can be made available online using the ‘Share’ button on the ‘File’ tab in VOSviewer.

I found Section 3.2 to be quite confusing. This section is presented as a ‘bibliometric analysis of citations’. However, it is not clear to me whether Figures 1 and 2 show visualizations of citation networks or visualizations of co-authorship networks. Also, the results presented in Section 3.2 rely strongly on the total link strength attribute in VOSviewer. If the author wants to use this attribute, it needs to be explained to the reader how the total link strength is defined and how it can be interpreted. However, I think it is better not to use the total link strength. Presenting statistics based on publication and citation counts is more useful, since these statistics are easier to interpret.

“Regarding keyword analysis, VOSviewer software features two options, one for keywords provided by the authors and the second for keywords provided by authors in addition to others extracted from title and abstract”: This is not correct. VOSviewer users need to choose between analyzing keywords (keywords provided by authors and/or keywords assigned algorithmically by Web of Science) and analyzing terms extracted from titles and/or abstracts. Combining these two analyses is not possible in VOSviewer. Also, while the author mentions a number of frequently occuring keywords, a visualization of the keyword co-occurrence network seems to be missing.

To reduce the number of clusters in a VOSviewer visualization, the author increased the minimum cluster size. Instead of (or in addition to) increasing the minimum cluster size, my advice is to reduce the value of the resolution parameter. This can be done on the ‘Analysis’ tab in VOSviewer.

The discussion section needs major improvements. This section provides a lot information that could better be presented in the introduction or methods sections.

The conclusion section is very brief. The section needs to be extended and improved. The conclusion that the “VOSviewer software is very successful” doesn’t seem relevant, since the paper is not about evaluating the VOSviewer software.

There is room for improving the writing style of the paper. In particular, my suggestion is to avoid the use of exclamation marks and the unnecessary use of capitals in the middle of a sentence (e.g., “found that Till 1 August 2021” should be “found that till 1 August 2021”). Also, there should be no colon at the end of a section heading.

According to the data availability statement, “all data produced in the present study are available upon reasonable request to the authors”. Making data available upon request is poor practice. It is preferable to make data openly available in a data repository (e.g., Zenodo). However, the author should check whether data sharing is allowed in the case of Web of Science data. It probably violates the terms of use of Web of Science. If data sharing is not allowed, this needs to be reported in the data availability statement.

According to the copyright statement, reuse is not allowed without permission. It is good practice to allow preprints to be reused provided that authors are properly acknowledged. I therefore recommend to attach a CC-BY license to the paper.

Serious concerns

• Do you have any serious concerns about the manuscript such as fraud, plagiarism, unethical or unsafe practices? No

• Have authors’ provided the necessary ethics approval (from authors’ institution or an ethics committee)? not applicable

Language quality

• How would you rate the English language quality? Low to medium quality, but I understand the content

validity and reproducibility

• Is the rationale for, and objectives of, the scoping review clearly stated? Yes

• Are the methods documented and analysis provided so that replication can be conducted? No

• Is the statistical analysis and its interpretation appropriate? Not applicable

• Are quality of the figures and tables satisfactory? No

• Are the conclusions adequately supported by the results presented in the review? Not applicable, since the conclusion section is extremely short

• Are there any fundamental flaws or errors that make the scoping review invalid?

Please see my comments above.

Decision

Requires revisions: The manuscript contains objective errors or fundamental flaws that must be addressed and/or major revisions are suggested.

Peer review report

Reviewer: Daniel Griffin, MD PhD, <br /> Institution: Columbia University ORCID: 0000-0001-5853-6906 email: danielgriffinmd@gmail.com, dgriffin@cumc.columbia.edu

Please describe your research in a sentence or a few key words

COIVD-19, general infectious disease, immunology, virology

General comments

The authors lay out a reasonable protocol for this type of investigation.

Section 1 – Serious concerns

• Do you have any serious concerns about the manuscript such as fraud, plagiarism, unethical or unsafe practices? No
• Have authors’ provided the necessary ethics approval (from authors’ institution or an ethics committee)? Yes

Section 2 – Language quality

• How would you rate the English language quality? High quality

Section 3 – validity and reproducibility

• Is the reasons for conducting the study and its objectives clearly explained? Yes

• Is the study design appropriate? Yes

• Are sufficient details provided so that the method can be replicated? Yes

• Are datasets available so that others could use them? not applicable

Section 4 – Suggestions

• Based on your answers in section 3 how could the author improve the protocol? Fine as is.

• Do you have any other feedback or comments for the Author?

The authors lay out a reasonable protocol for this type of investigation that is based on a fairly standard approach with the standard GRADE grading.

Section 5 – Decision

Verified manuscript: The content is scientifically sound, only minor amendments (if any) are suggested.

Peer review report

Reviewer: Richard L. Guerrant Institution: University of Virginia email: guerrant@vrginia.edu

Section 1 – Serious concerns

• Do you have any serious concerns about the manuscript such as fraud, plagiarism, unethical or unsafe practices? No

• Have authors’ provided the necessary ethics approval (from authors’ institution or an ethics committee)? not applicable

Section 2 – Language quality

• How would you rate the English language quality? Low to medium quality, but I understand the content

Section 3 – validity and reproducibility

• Does the work cite relevant and sufficient literature? Yes
• Is the study design appropriate and are the methods used valid? No — See comments
• Are the methods documented and analysis provided so that the study can be replicated? No — See comments
• Is the source data that underlies the result available so that the study can be replicated? not applicable
• Is the statistical analysis and its interpretation appropriate? Yes
• Is quality of the figures and tables satisfactory? Yes
• Are the conclusions adequately supported by the results? No — See comments
• Are there any objective errors or fundamental flaws that make the research invalid? Yes, see comments below

Section 4 – Suggestions

• Based on your answers in section 3 how could the author improve the study?

Major concerns include:

1. Quantification of coliforms is key; if done as suggested by MPN method, actual projected counts should be put into a table and discussed by food type, pathogenic potential.

2. Were any actual pathogens detected? (ex ETEC, EPEC, EAEC, EHEC); probes are not those typically used for that. Were any Shigella, Salmonella? Are other pathogens detected? If not, why not?

3. Many statements are expressed as causal facts, but this is far from proven. Examples include ‘foodborne infections …have accelerated … resistance’ on page 1; ‘infections … are due to fast food ingredients;’ on page 2; these points require citation of documented data.

4. At the bottom of page 2, the objective of ‘determining the origin’ is not addressed.

5. Do you have any other feedback or comments for the Author? No

Tighten statements, like the opening line of abstract to say more directly, ‘burden…compromises health.’

Section 5 – Decision

Requires revisions: The manuscript contains objective errors or fundamental flaws that must be addressed and/or major revisions are suggested.

Peer review report

Reviewer: Samuel Mayeden Institution: Ghana Health Service email: csmayeden@gmail.com

Section 1 – Serious concerns

• Do you have any serious concerns about the manuscript such as fraud, plagiarism, unethical or unsafe practices? No
• Have authors’ provided the necessary ethics approval (from authors’ institution or an ethics committee)? Yes

Section 2 – Language quality

• How would you rate the English language quality? High quality

Section 3 – validity and reproducibility

• Does the work cite relevant and sufficient literature? Yes
• Is the study design appropriate and are the methods used valid? Yes
• Are the methods documented and analysis provided so that the study can be replicated? Yes
• Is the source data that underlies the result available so that the study can be replicated? Yes
• Is the statistical analysis and its interpretation appropriate? Yes
• Is quality of the figures and tables satisfactory? Yes
• Are the conclusions adequately supported by the results? Yes
• Are there any objective errors or fundamental flaws that make the research invalid? No

Section 4 – Suggestions

• Do you have any other feedback or comments for the Author?

• Line 35, 36 and 37: Authors should be consistent in using odds ratios and/or p values to indicate associations.

• Line 37 (Conclusion): Should align with objectives and results stated in abstract

• 42: Keywords should emerge from the text of the abstract. Kindly review the keywords to align with the body of the abstract

• Introduction: Has no concrete global, regional or local level statistics on the subject. It will be good to indicate some statistics of existing work to appropriately conceptualize your work.

• The introduction is too long. It will be good to keep it within 2 pages

• Line 73: It helps to move citation to the end of the sentence

• Line 132: Indicate from which department(s) of the health facilities the participants were recruited

• Methods: Needs lots of clarification. Authors have to indicate the process of sampling more clearly

• What influenced the selection of the 32 facilities out of the 252

• You indicated 15 clients from health centres and 22 clients from hospitals. Are these the authors’ assumptions? Was this calculated from the facility registers? If so what amount of data from which period was used to make the estimates

• Line 154: Did each facility have a sampling frame? What was k?

• Line 172: Which department were patient exiting from. Was it outpatients or laboratory only cases, or inpatients as well.

• Line 174: Was scale adapted or developed by authors

• Line 183-185: how many slides were reviewed. Why did you choose only malaria and TB.

• Line 196: Is the score decided by researchers or it has been adopted or adapted

• Line 205: Reference star grading system

• Line 256: state p value as p<0.001

Section 5 – Decision

Verified manuscript: The content is scientifically sound, only minor amendments (if any) are suggested.

Peer review report

Reviewer: Wei Zhang Institution: The First Affiliated Hospital of Hebei North University, Hebei Province, China. email: 15369318318@163.com

Section 1 – Serious concerns

• Do you have any serious concerns about the manuscript such as fraud, plagiarism, unethical or unsafe practices? No
• Have authors’ provided the necessary ethics approval (from authors’ institution or an ethics committee)? *Yes

Section 2 – Language quality

• How would you rate the English language quality? High quality

Section 3 – validity and reproducibility

• Does the work cite relevant and sufficient literature? Yes
• Is the study design appropriate and are the methods used valid? Yes
• Are the methods documented and analysis provided so that the study can be replicated? Yes
• Is the source data that underlies the result available so that the study can be replicated? not applicable
• Is the statistical analysis and its interpretation appropriate? Yes
• Is quality of the figures and tables satisfactory? No
• Are the conclusions adequately supported by the results? not applicable
• Are there any objective errors or fundamental flaws that make the research invalid?

Table 1 - The number of people in the gender section is wrong.

Section 4 – Suggestions

• Based on your answers in section 3 how could the author improve the study?

（1）There is no "conclusion" in the abstract.

（2）In order to make the study group comparable with the control group, should the patients in the control group be CSKP infected patients? Or the control group should at least be patients with bacterial infection.

（3）The font in Table 2 is inconsistent with the original text.

（4）The table format should be "three line table".

（5）The number "0" can be added before some decimal points in Table 2.

（6）The references are generally too old. It is suggested to increase the proportion of references published within 5 years.

（7）It is suggested to write more specific experimental methods for amplifying KPC gene, such as primers, PCR reaction conditions and reaction system of KPC gene.

（8）Have you done the drug sensitivity test of Klebsiella pneumoniae? If so, it is recommended to write the results in the article.

Section 5 – Decision

Verified with reservations: The content is scientifically sound but has shortcomings that could be improved by minor revisions.

Peer review report

Reviewer: Adam Marcus, co-founder Retraction Watch & Alison Abritis, PhD, researcher at Retraction Watch

General comments

Major Problems: I found serious deficits in both for this article, and thus I have serious concerns as to the usefulness of this article. Therefore, I have not proceeded in a line-by-line, as I consider the overall problems to be grave enough to require attention and revision before getting to lesser items of clarity.

I would like to point out that the authors show a marvelous attention to their work, and they have much to contribute to the field of retraction studies, and I do honestly look forward to their future work. However, in order for the field to move ahead with accuracy and validity, we must no longer just rely on superficial number crunching, and must start including the complexities of publishing in our analyses, as difficult and labor-intensive as it might be.

1) The authors stated that they used the search protocol (and therefore presumably the same dataset) as described in Toma & Padureanu, 2021, and do not indicate any process to compensate for its weaknesses. In the referenced study, the authors (same as for this article) utilized a PubMed search using only “Retracted Publication” in Publication Type. This search method is immediately insufficient, as some retracted articles are not bannered or indexed as retracted in PubMed. This issue is well-understood among scholars who search databases for retractions, and by now one would expect that these searches would strive to be more comprehensive.

A better method, if one insists on restricting the search to PubMed, would have been to use Publication Type to search for “retracted publication,” and then to search for “retraction of publication,” and to compare the output to eliminate duplications. There are even more comprehensive ways to search PubMed, especially since some articles are retitled as “Withdrawn” – Elsevier, for example, uses the term instead of “Retracted” for papers removed within a year of their publication date – but do not come in searches for either publication type. Even better would have been to use databases with more comprehensive indexing of retractions.

2) The authors are using the time from publication to retraction based on the notice dates and using them to indicate efficacy of oversight by publishers. However, this approach is seriously problematic. It takes no notice of when the publisher was first informed that the article was potentially compromised. Publishers who respond rapidly to information that affects years/decades old publications will inevitably show worse scores than those who are advised upon an article’s faults immediately upon its publication, but who drag their heels a few months in dealing with the problem.

Second, there is little consistency in dealing with retractions between publishers, within the same publishers or even within the same journal. Under the same publisher, one journal editor may be highly responsive during their term, while the next editor may not be. Most problems with articles quite often are first addressed by contacting the authors and/or journal editors, and publishers – especially those with hundreds of journals – may not have any idea of the ensuing problem for weeks or months, if at all. Therefore, the larger publishers would be far more likely to show worse scores than publishers with few journals to manage oversight.

Third, the dates on retraction notices are not always representative of when an article was watermarked or otherwise indicated as retracted. Elsevier journals often overwrite the html page of the original article with the retraction notice, leaving the original article’s date of publication alone. A separate retraction notice may not be published until days, weeks or even years after the article has been retracted. Springer and Sage have done this as well, as have other publishers – though not to the same extent (yet).

Historically, The Journal of Biological Chemistry would publish a retraction notice and link it immediately to the original article, but a check of the article’s PDF would show it having been retracted days to weeks earlier. They have recently been acquired by Elsevier, so it is unknown how this trend will play out. And keep in mind, in some ways this is in itself not a bad thing – as it gives the user quicker notice that an article is unsuitable for citation, even while the notice itself is still undergoing revisions. It just makes tracking the time of publication to retraction especially difficult.

3) As best as can be determined, the authors are taking the notices at face value, and that has been repeatedly shown to be flawed. Many notices are written as a cooperative effort between the authors and journal, regardless of who initiated the retraction and under the looming specter of potential litigation.

Trying to establish who initiated a retraction process strictly by analyzing the notice language is destined to produce faulty conclusions. Looking just at PubPeer comments, questions about the data quality may be raised days/month/years before a retraction, with indications of having contacted the journal or publisher. And yet, an ensuing notice may be that the authors requested the retraction because of concerns about the data/image – where the backstory clearly shows that impetus for the retraction was prompted by a journal’s investigation of outside complaints. As an example, the recent glut of retractions of papers coming from paper mills often suggest the authors are requesting the retraction. This interpretation would be false, however, as those familiar with the backstory are aware that the driving force for many of these retractions were independent investigators contacting the journals/publishers for retraction of these manuscripts.

Assigning the reason for retraction from only the text of the notice will absolutely skew results. As already stated, in many cases, journal editors and authors work together to produce the language. Thus, the notice may convey an innocuous but unquestionable cause (e.g., results not reproducible) because the fundamental reason (e.g., data/image was fabricated or falsified) is too difficult to prove to a reasonable degree. Even the use of the word “plagiarism” is triggering for authors’ reputations – and notices have been crafted to avoid any suggestion of such, with euphemisms that steer well clear of the “p” word. Furthermore, it has been well-documented that some retractions required by institutional findings of misconduct have used language in the notice indicating simple error or other innocuous reasons as the definitive cause.

The authors also discuss changes in the quality of notices increasing or decreasing in publishers – but without knowing the backstory. Having more words in a notice or giving one or two specific causes cannot in itself be an indicator of the quality (i.e., accuracy) of said notice.

4) The authors tend to infer that the lack of a retraction in a journal implies a degree of superiority over journals with retractions. Although they qualify it a bit ( “Are over 90% of journals without a retracted article perfect? It is a question that is quite difficult to answer at this time, but we believe that the opinion that, in reality, there are many more articles that should be retracted (Oransky et al. 2021) is justified and covered by the actual figures.”), the inference is naive. First, they have not looked at the number of corrections within these journals. Even ignoring that these corrections may be disproportionate within different journals and require responsive editorial staff, some journals have gone through what can only be called great contortions to issue corrections rather than retractions.

Second, the lack of retractions in a journal speaks nothing to the quality of the articles therein. Predatory journals generally avoid issuing retractions, even when presented with outright proof of data fabrication or plagiarism. Meanwhile, high-quality journals are likely to have more, and possibly more astute, readers, who could be more adept at spotting errors that require retraction.

Third, smaller publishers/journals may not have the fiscal resources to deal with the issues that come with a retraction. As an example, even though there was an institutional investigation finding data fabrication, at least one journal declined to issue a retraction for an article by Joachim Boldt (who has more than 160 retractions for misconduct) after his attorneys made threats of litigation.

Simply put, the presence or lack of a retraction in a journal is no longer a reasonable speculation about the quality of the manuscripts or the efficiency of the editorial process.

5) I am concerned that the authors appear to have made significant errors in their analysis of publishers. For example, they claim that neither PLOS nor Elsevier retracted papers in 2020 for problematic images. That assertion is demonstrably false.

Decision

Requires revisions: The manuscript contains objective errors or fundamental flaws that must be addressed and/or major revisions are suggested.

Peer review report

Reviewer: Yin Qianlan Institution: Navy Medical University email: yinqianlan@smmu.edu.cn

Section 1 – Serious concerns

• Do you have any serious concerns about the manuscript such as fraud, plagiarism, unethical or unsafe practices? No
• Have authors’ provided the necessary ethics approval (from authors’ institution or an ethics committee)? Yes

Section 2 – Language quality

• How would you rate the English language quality? High quality

Section 3 – validity and reproducibility

• Is the reasons for conducting the study and its objectives clearly explained? No

• Is the study design appropriate? Yes

• Are sufficient details provided so that the method can be replicated? Yes

• Are datasets available so that others could use them? not applicable

Section 4 – Suggestions

• Based on your answers in section 3 how could the author improve the protocol?

As an important part of a review is the declaration of the purpose, the introduction should be the core of the article. However, after reading the beginning of the paper, I could realize the seriousness of COVID-19, but I cannot see the key point of the research. There is a lot of data to emphasize the worse results, but I don’t know how this data contributed to the relationship between the major topic of Post-acute sequelae of COVID-19 and adverse psychiatric outcomes, for example, the introduction about the effect of therapies. Hence, more organized structure for the introduction of could be more concise and easier for readers.

Section 5 – Decision

Requires revisions: The manuscript contains objective errors or fundamental flaws that must be addressed and/or major revisions are suggested.

Peer review report

Reviewer: Argentina Felisbela Muianga,<br /> Institution: Instituto Nacional de Saúde-Maputo-Mozambique email: valiosa.muianga@gmail.com, Argentina.muianga@ins.gov.mz

General comments

The manuscript addresses a relevant subject that is still, in a way, little prioritized, therefore little developed and therefore raises the need for further in-depth studies to develop a good RDT that can detect infection in the most important phase of infection and ensure a better real-time response.

Section 1 – Serious concerns

• Do you have any serious concerns about the manuscript such as fraud, plagiarism, unethical or unsafe practices? No
• Have authors’ provided the necessary ethics approval (from authors’ institution or an ethics committee)? No, I did not see any approach on ethical aspects of the study. This should updated.

Section 2 – Language quality

• How would you rate the English language quality? High quality

Section 3 – validity and reproducibility

• Is the rationale for, and objectives of, the scoping review clearly stated? Yes

• Are the methods documented and analysis provided so that replication can be conducted? Yes

• Is the statistical analysis and its interpretation appropriate? Yes

• Are quality of the figures and tables satisfactory? Yes

• Are the conclusions adequately supported by the results presented in the review? Yes

• Are there any fundamental flaws or errors that make the scoping review invalid? No

Section 4 – Suggestions

• Based on your answers in section 3 how could the author improve the study?

I did not see information regarding to the type of sample used on the different platforms, since for the RDT the type of samples influences accessibility.

How was the prototype evaluated, in terms of type of samples and environmental conditions?

• Do you have any other feedback or comments for the Author?

No

Section 5 – Decision

Verified manuscript: The content is scientifically sound, only minor amendments (if any) are suggested.

Peer review report

Reviewer: Sadia Ali Pereira,<br /> Institution: Instituto Nacional de Saúde, Mozambique email: Sadia.abdul.ali@gmail.com / sadia.pereira@ins.gov.mz

Section 1 – Serious concerns

• Do you have any serious concerns about the manuscript such as fraud, plagiarism, unethical or unsafe practices? No
• Have authors’ provided the necessary ethics approval (from authors’ institution or an ethics committee)? not applicable

Section 2 – Language quality

• How would you rate the English language quality? High quality

Section 3 – validity and reproducibility

• Is the rationale for, and objectives of, the scoping review clearly stated? Yes

• Are the methods documented and analysis provided so that replication can be conducted? No

• Is the statistical analysis and its interpretation appropriate? Yes

• Are quality of the figures and tables satisfactory? No

It is difficult to read figure 4, on page 29 there is no legend of the figure, in figure 1 the pallet colours could have greater variation.

• Are the conclusions adequately supported by the results presented in the review? No

• Are there any fundamental flaws or errors that make the scoping review invalid? Not any major errors detected

Section 4 – Suggestions

• Based on your answers in section 3 how could the author improve the study?

I would suggest improving the methodology and the criteria for articles selection/inclusion

• Do you have any other feedback or comments for the Author?

Will be helpful if the authors could better discussion the risk bias and applicability. Why select studies with patients with signs for CHIKV? What about asymptomatic? Not proper discussed the possibility of cross reactivity between other alphaviruses.

Section 5 – Decision

Verified with reservations: The content is scientifically sound but has shortcomings that could be improved by further studies and/or minor revisions.

Peer review report

Reviewer: Veena Nair Institution: UW Madison email: vnair@uwhealth.org

Section 1 – Serious concerns

• Do you have any serious concerns about the manuscript such as fraud, plagiarism, unethical or unsafe practices? No
• Have authors’ provided the necessary ethics approval (from authors’ institution or an ethics committee)? Yes

Section 2 – Language quality

• How would you rate the English language quality? High quality

Section 3 – validity and reproducibility

• Does the work cite relevant and sufficient literature? Yes
• Is the study design appropriate and are the methods used valid? Yes
• Are the methods documented and analysis provided so that the study can be replicated?

See comments below at the end of Section 3; some more methodological details could be provided.

• Is the statistical analysis and its interpretation appropriate? Yes
• Is quality of the figures and tables satisfactory? No

In the demographics table, could you please add number of left versus right stroke patients, distribution of stroke location too. Thank you.

In figure 1 I don’t see a L for left; perhaps missing in the pdf I have.

• Are there any objective errors or fundamental flaws that make the research invalid? How could the author improve the study?

It would be helpful to see the demographic characteristics of the normative database. Do the subjects in that database have a similar distribution of age and sex.

Scanner variance is a known confound that studies must deal with; should we be concerned that the normative database was collected on a 7T whereas the current study’s data were all collected on a 3T? are there ways to do some kind of harmonization? Likewise, the multimodal Glasser atlas is based off of 21-35 old young healthy adults; but the variability in the current study population is large.

In the Disconnectome map, what does each ‘map’ represent? Is it a structural connectivity map? What do the connections represent (fiber cross-sectional area, number of fibers etc.?). More details would be helpful.

Based on Figure 4, prediction accuracy on the test set is low, at 22%; can this be improved by improvements in normalization? Perhaps by using a more age-appropriate template than the MNI152? [see for e.g., Mayo clinic template for older adults].

Section 4 – Suggestions

• Do you have any other feedback or comments for the Author?

This is a very interesting study and the research question is an important one and very relevant to the field. Thank you.

Section 5 – Decision

Verified with reservations:The content is scientifically sound but has shortcomings that could be improved by further studies and/or minor revisions.

Peer review report

Reviewer: Dacre Knight, MD Institution: Mayo Clinic email: Knight.dacre@mayo.edu

Section 1 – Serious concerns

• Do you have any serious concerns about the manuscript such as fraud, plagiarism, unethical or unsafe practices? No
• Have authors’ provided the necessary ethics approval (from authors’ institution or an ethics committee)? not applicable

Section 2 – Language quality

• How would you rate the English language quality? High quality

Section 3 – validity and reproducibility

• Is the reasons for conducting the study and its objectives clearly explained? Yes

• Is the study design appropriate? Yes

• Are sufficient details provided so that the method can be replicated? Yes

• Are datasets available so that others could use them? not applicable

Section 4 – Suggestions

• Based on your answers in section 3 how could the author improve the protocol?

There is a more specific definition of PASC that should be included (with reference). Need to list specific medical databases to search, not just “various”. PECO criteria needs to be listed, not only implied that it will be used.

• Do you have any other suggestions, feedback, or comments for the Author?

GRADE approach will be useful, as is mentioned along with narrative synthesis if needed. Strengths and limits seem accurate, good to list.

Section 5 – Decision

Verified with reservations: The content is scientifically sound but has shortcomings that could be improved by further studies and/or minor revisions.

Peer review report

Reviewer: Bertrand Fournier Institution: Potsdam University email: bfourni@gmail.com

General comments

This paper investigates context-dependencies in metacommunities using a modelling approach. The authors present a new metacommunity model (the Unified Metacommunity Model) that includes habitat heterogeneity, dispersal, specialization, and species interactions. The authors use this model to illustrate two forms of context-dependency: directional and reciprocal context-dependency. They present several simulations that illustrate these two aspects. The authors also discussed the implications of their results for future research in metacommunity dynamics. I overall enjoyed reading this manuscript which I consider as an interesting contribution to the field of metacommunity ecology. I think that it has a clear structure and is well-written. The data, illustrations, and tables are of good quality. The cited literature is appropriate. Overall, the work and methods meet the expected scientific standards, but several precisions are needed to allow the replication of the study. The model created in this study presents interesting adaptations of existing concepts and is one of the main strength of this study. Another strength of this work is that it investigates a known weakness of metacommunity ecology (context-dependency) and ecology in general and discuss potential ways to tackle this problem. Overall, I think that the paper is of direct interest to scientists working in the field of metacommunity ecology and can be interesting for a broader audience in various fields of ecology including community assembly, biodiversity, and metapopulation. I did not identify major flaws, but I have a few suggestion for minor improvements. I think that addressing these concerns can further improve this work. See my comments below for further details.

Section 1 – Serious concerns

• Do you have any serious concerns about the manuscript such as fraud, plagiarism, unethical or unsafe practices? No

• Have authors’ provided the necessary ethics approval (from authors’ institution or an ethics committee)? Yes

Section 2 – Language quality

• How would you rate the English language quality? High quality

Section 3 – validity and reproducibility

• Does the work cite relevant and sufficient literature? Yes
• Is the study design appropriate and are the methods used valid? Yes
• Are the methods documented and analysis provided so that the study can be replicated? No
• Is the source data that underlies the result available so that the study can be replicated? not applicable
• Is the statistical analysis and its interpretation appropriate? Yes
• Is quality of the figures and tables satisfactory? Yes
• Are the conclusions adequately supported by the results? Yes
• Are there any objective errors or fundamental flaws that make the research invalid? Please describe these thoroughly. No

Section 4 – Suggestions

• Do you have any feedback or comments for the Author?

Abstract:

The use of abbreviation in the abstract is to me unnecessary and I encourage the authors to remove them (i.e. C-D). The mention of macro-variables got me confused. While it becomes clearer what those are later in the ms, I would suggest explicitly mentioning the four dimensions of the model (habitat heterogeneity, dispersal, specialization, and species interactions) in the abstract.

Context-dependency in metacommunities:

This section is nicely written. Please, consider providing a definition of directional and reciprocal context-dependency earlier in the text.

Context-dependency in a model:

This section clearly explains the functioning of the model and how it allows interactions among “macro-variables”. However, I would like to see more technical information because I don’t think that I would be able to replicate the same model with the information provided (either here or in the SupMat). I encourage the authors to add more detailed information about the functioning of the model (maybe as an additional document published at the same time as the models itself ...)

Directional and reciprocal C-D:

Nice section. I like the chosen examples for the two types of context-dependency.

C-D in future metacommunity research:

Also nicely written. Consider adding a few words about the implications of this work beyond the metacommunity framework.

Fig. 3: Even with the explanation provided, I still struggle to understand the abbreviations (panels A-D).

Fig. 4: Consider replacing the vector image by a raster image (png, jpeg...). While the quality is nice, it slows down the whole document.

Fig. 4B: There is no legends for the R2 values (which values correspond to which line).

Section 5 – Decision

Verified with reservations: The content is scientifically sound, but has shortcomings that could be improved by further studies and/or minor revisions.

Peer review report

Reviewer: Cristian Malavert Institution: University of Buenos Aires, Argentina email: malavert@agro.uba.ar

General comments

Overall, the manuscript is very good. There are some things to improve and revise that will help to make the manuscript clearer.

Section 1 – Serious concerns

• Do you have any serious concerns about the manuscript such as fraud, plagiarism, unethical or unsafe practices? No

• Have authors’ provided the necessary ethics approval (from authors’ institution or an ethics committee)?

Not applicable

Section 2 – Language quality

• How would you rate the English language quality? Low to medium quality, but I understand the content

Section 3 – validity and reproducibility

• Does the work cite relevant and sufficient literature? Yes
• Is the study design appropriate and are the methods used valid? Yes
• Are the methods documented and analysis provided so that the study can be replicated? Yes
• Is the source data that underlies the result available so that the study can be replicated? No
• Is the statistical analysis and its interpretation appropriate? Yes
• Is quality of the figures and tables satisfactory? No
• Are the conclusions adequately supported by the results? Yes
• Are there any objective errors or fundamental flaws that make the research invalid? No

Section 4 – Suggestions

- Based on your answers in section 3 how could the author improve the study?

The authors could improve the work by redesigning the figures, many of the symbols are not understood. Organizing tables and explaining abbreviations only once, perhaps making a list of abbreviations used throughout the manuscript. Equations, many do not describe what the components correspond to, are not listed.

Suggested edits and comments have been added to the manuscript. Comments taken from manuscript below:

Materials and methods

add location coordinates

How many samples were used?

Soil Physiochemical Parameter: can you explain briefly what the APHA method consists of?

Experimental Procedures: How many replications were used??

Root and Shoot growth: Where is the germination test?? what does the germination test consist of?

Median germination time: Explain how T(50) is calculated?

The GRI equation is not explained

the SAG equation is not explained

Please explain component of the equations: Corrected germination rate index, Timson’s Index, Modified Timson’s Index

Figure 1: are they plants or seeds? also germination of which species?

Section 5 – Decision

Verified with reservations: The content is scientifically sound but has shortcomings that could be improved by further studies or minor revisions.

The content has many errors, which I marked throughout the manuscript. Once these errors are corrected, the manuscript will look great

Peer review report

Reviewer: Dr.Debojyoti Moulick Institution: University of Kalyani

Section 1 – Serious concerns

• Do you have any serious concerns about the manuscript such as fraud, plagiarism, unethical or unsafe practices? No
• Have authors’ provided the necessary ethics approval (from authors’ institution or an ethics committee)? No, there is no Institutional affiliation, approval from ethical committee, and other disclosures (like details of chemicals) are missing.

Section 2 – Language quality

• How would you rate the English language quality? - low quality, the content is difficult to understand

Section 3 – validity and reproducibility

• Does the work cite relevant and sufficient literature? No
• Is the study design appropriate and are the methods used valid? No
• Are the methods documented and analysis provided so that the study can be replicated? No
• Is the source data that underlies the result available so that the study can be replicated? No
• Is the statistical analysis and its interpretation appropriate? No, Statistical data should be incorporated, contrast and quality can be increased.
• Is quality of the figures and tables satisfactory? No
• Are the conclusions adequately supported by the results? No. The research should consider recent literature in this area. The conclusion should contain the vision for the research with honest self-criticism.
• Are there any objective errors or fundamental flaws that make the research invalid?

The study does not satisfy ISTA rule. Methods should have references.

https://www.seedtest.org/en/international-rules-for-seed-testing-_content---1--1083.html

Section 4 – Suggestions

• In your opinion how could the author improve the study?

Introduction:

“ Soil heavy metal concentrations may not however be totally due to industrial activities as some soils are originally ferruginous and therefore have increasingly high quantities of iron yet some others have increased levels of aluminium which predisposes such soils to more soil acidity (Ikhajiagbe,2016).”

What about geogenic sources of Fe, Al? Please explain this.

“Many studies have shown that application of growth regulators enhance plant growth and crop yield (Hernandel, 1997).”

States many studies, yet there is only one reference which is a decade old. Please provide additional references.

The introduction should describe the need for selecting Fe stress, role seed priming in synchronizing germination, stress tolerances. The section should also contain the level of Fe toxicity in “Local-Regional-Global” perspective.

The aim of the study should be clearly presented.

Materials and methods

Please describe the selected variety

“Sand and Iron (Fe) were determined…” The authors are required to disclose the comparison carried out among the obtained result (Fe content) and Fe content of SRMs/CRMs.

Soil Priming Material

Which is applicable, Soil or Seed priming?

Why are only 3 doses selected?

The number of treatment combinations should be included.

Which seed priming method did the authors follow?

Details of chemicals should be included.

Which chlorophyll meter is used? please disclose with details.

How many seedlings were considered for taking weight?

Statistics are not adequate. Factors (GA, AA,IA and Fe stress) 4 factors and their respective interaction and individual effects can be understand if 2-WAY-ANOVA can be used.

• Do you have any other feedback or comments for the Author?

Title could be brief, short and attractive.

Abstract: Punctuation should be improved.

For Fe, the term ‘essential nutrient’ can be used rather than ‘micronutrient’ Keywords could be expanded

Section 5 – Decision

Requires revisions: The manuscript contains objective errors that must be addressed.

Peer review report

Reviewer: Wade H. Morris Institution: Georgia State University email: morriswh@gmail.com

General comments

The authors dove headfirst into Dalhousie’s archives, unpacking the subtle shifts in grading policy. Their work seems to be comparable to archaeologists, digging deep beneath mountains of primary sources to find nuggets of clues into Dalhousie’s grading evolution. I particularly liked when the authors were able to link these changes to student voices, as seen in moments when they referenced student publications.

Ultimately, I kept coming back to one main comment that I wrote in the margins: “So what?” I would humbly suggest that the authors reflect on why this history matters to them. Granted, they do this in the conclusion, where they touch on Schneider & Hutt’s argument that grades evolved to increasingly be a form of external communication with audiences beyond school communities. Sure. But I want more. I wanted to see a new insight that this microhistory of Dalhousie significant to the history of Canada or the history of education more generally.

If the authors are so inclined, there might be several approaches to transform this manuscript. I would suggest the following. First, instead of tracing the entire history of grading at the institution, choose one moment of change that you think is the most important. Perhaps in the 1920s and the lack of transparency in grading, or the post-war shift toward American grading. Second, show me – don’t tell me – what Dalhousie was like at this moment. Paint a picture of the institution with details about student demographics, curriculum, educational goals, the broader town, etc. Make the community come alive. Show me what makes Dalhousie unique from other institutions of higher ed. Once you establish that picture, perhaps you could link the change in grading practices to subtle changes at the university community, thereby establishing a before and after snapshot.

This will require considerable amounts of work, and the skills of a historian. You will have to find primary and secondary sources that go far beyond what you’ve relied on thus far.

In the end, I found myself wanting the authors to humanize this manuscript, meaning I wanted them to show me that changes in grading practices have tangible effects on real-life human beings. A humanization of their research would mean going narrower and deeper; or, in other words, eliminating much of what they have documented.

However, if that is too tall of an order, I would ask that the authors clarify for themselves who this manuscript is for. Is this a chronicling of facts for an internal audience at Dalhousie’s faculty, alumni, and students? Fine. But my guess is that even members of the Dalhousie community want to read something relatable.

Section 1 – Serious concerns

• Do you have any serious concerns about the manuscript such as fraud, plagiarism, unethical or unsafe practices? No

• Have authors’ provided the necessary ethics approval (from authors’ institution or an ethics committee)? not applicable

Section 2 – Language quality

• How would you rate the English language quality? There are a few nagging stylistic quirks. Most obvious to me, the authors switch into and out of present tense. Stick with past tense. Also, I would suggest that they remove the first person.

Section 3 – validity and reproducibility

• Does the manuscript contain any objective errors, fundamental flaws, or is key information missing?

Not that I am aware.

Section 4 – Decision

Requires revisions: The manuscript contains objective errors or fundamental flaws that must be addressed and/or major revisions are suggested.

I am suggesting revisions, although not because of objective errors. History is more of an art, in my opinion. With that in mind, I would suggest that the authors paint a more vivid picture (metaphorically) of Dalhousie, showing me how changes one moment of change in grading practices impacted the lives of human beings.

Peer review report

Reviewer: GE Rainger Institution: University of Birmingham, UK email: g.e.rainger@bham.ac.uk

General comments

The English is generally acceptable, but there are serious lapses of syntax throughout the manuscript that require revision.

Some sections, e.g. the introduction revert to a bullet pointed format for conveying information from specific citations. If the authors choose to submit to a journal, this is not acceptable in many journal formats.

Figures are not publication quality and do not conform to a standard format. They often show images of single cells or sections as evidence of complex biology which needs formalising into graphs which show outcomes of the analysis of multiple experiments.

As far as I can see there is no statistical analysis of any of the data (at least as presented in the figures), it is unclear what statistical analysis has been conducted when the text states that significant effects have been observed.

It is not clear how reproducible assays such as the in vitro EC injury model are and this sort of concern would need addressing.

The discussion is unfocused. Having read the full manuscript I am not informed about what SAMD1 is, how it achieves extracellular distribution, how it functions in the localisation of LDL and formation of foam cells etc. There are many broad brush strokes here, but there is not enough mechanistic detail to provide convincing arguments for its functions as extrapolated by the authors.

Section 1 – Serious concerns

• Do you have any serious concerns about the manuscript such as fraud, plagiarism, unethical or unsafe practices? No

• Have authors’ provided the necessary ethics approval (from authors’ institution or an ethics committee)? No

Requires revisions: No details of ethics and the manuscript contains objective errors that must be addressed

Peer review report

Reviewer: Yaw Asare Institution: ISD LMU email: yaw.asare@med.uni-muenchen.de

General comments

The current manuscript is very diffuse with many figures that should be merged to one main figure with a clear message. The reader is easily lost going through multiple figure panels conveying pieces of information. The manuscript will further benefit from reducing the length of the discussion.

Section 1 – Serious concerns

• Do you have any serious concerns about the manuscript such as fraud, plagiarism, unethical or unsafe practices? No
• Have authors’ provided the necessary ethics approval (from authors’ institution or an ethics committee)? not applicable

Section 2 – Language quality

• How would you rate the English language quality? High quality

Section 3 – validity and reproducibility

• Does the work cite relevant and sufficient literature? Yes
• Is the study design appropriate and are the methods used valid? Yes
• Are the methods documented and analysis provided so that the study can be replicated? Yes
• Is the source data that underlies the result available so that the study can be replicated? Yes
• Is the statistical analysis and its interpretation appropriate? Yes
• Is quality of the figures and tables satisfactory? No
• Are the conclusions adequately supported by the results? No

Section 4 – Suggestions

• In your opinion how could the author improve the study?

The manuscript will further benefit from the following experiments:

1) Assessing the effect of targeting SAMD1/LDL axis in neointima formation following arterial injury given the reduced LDL retention in injured carotids.

2) Analyzing effects of PEG-fab inhibitors in early lesions induced by atherogenic diet.

3) Describing the role of SAMD1 in VSMC foam cell formation.

Section 5 – Decision

Requires revisions: The manuscript contains objective errors that must be addressed

Peer review report

Reviewer: Barbara Ruaro Institution: University of Trieste email: barbara.ruaro@yahoo.it

Section 1 – Serious concerns

• Do you have any serious concerns about the manuscript such as fraud, plagiarism, unethical or unsafe practices? No
• Have authors’ provided the necessary ethics approval (from authors’ institution or an ethics committee)? Yes

Section 2 – Language quality

• How would you rate the English language quality?

Low to medium quality, but I understand the content (e.g. Our study is the first clinical study in which Netrin-1 elevation was demonstrated in SSc patients. It is better “studied” than “demonstrated”

Section 3 – validity and reproducibility

• Does the work cite relevant and sufficient literature? No
• Is the study design appropriate and are the methods used valid? Yes
• Are the methods documented and analysis provided so that the study can be replicated? Yes
• Is the source data that underlies the result available so that the study can be replicated? Yes
• Is the statistical analysis and its interpretation appropriate? No
• Is quality of the figures and tables satisfactory? No
• Are the conclusions adequately supported by the results? No
• Are there any objective errors or fundamental flaws that make the research invalid? No

Section 4 – Suggestions

• In your opinion how could the author improve the study?

1) Abstract. Results There was no significant correlation between netrin-1 level, organ involvement in SSc, and MRS (p>0.05). Please clarify MRS acronym. Is it mRSS (modified Rodnan Skin Score)?

2) Abstract. Conclusion: In this study, we found that there is a significant relationship between Netrin-1 levels and SSc disease. Our study is the first clinical study in which Netrin-1 elevation was demonstrated in SSc patients. Please in the last sentence use “elevation was shown”

3) Systemic sclerosis (SSc), often called scleroderma, is an autoimmune, destructive systemic connective tissue disease characterized by organ fibrosis and vasculopathy. Pathophysiological mechanisms that may play a role in disease development include platelet activation, fibroblast proliferation, endothelial disruption, fetal microchimerism, and increased transforming growth factor-β. In addition, VEGF is an important signaling factor contributing to the pathogenesis of SSc, even in the earliest clinically detectable stages of the disease.[1] Please add some references.

4) Introduction. In this study, we aimed to evaluate the levels of Netrin1 between SSc and healthy controls and to emphasize the role of the known effects of Netrin-1 in the pathophysiology of SSc, which increases VEGF and supports the fibrotic process. Please change “to evaluate the levels of Netrin1 between SSc and healthy controls” and write” to compare the levels of Netrin1 in SSc patients and healthy controls”

5) Methods. Modified Rodnan scoring (MRS) was used for skin thickness scoring in SSc patients. For MRS, 17 body areas were evaluated and scored in the range of 0-51 points. Please use the acronym mRSS.

6)Results. Please underline the statistical values to support the conclusions. 7) DISCUSSION SSc is a progressive disease that pathophysiologically starts with microvascular damage and then develops widespread fibrosis due to increased autoimmune response and inflammation.[18]. Please summarise and underlie here the most important data of the study.

Section 5 – Decision

Verified with reservations: The content is scientifically sound but has shortcomings that could be improved by further studies and/or minor revisions.

Peer review report

Reviewer: : Charlotte Martial Institution: University of Liège email: cmartial@uliege.be

Section 1 – Serious concerns

• Do you have any serious concerns about the manuscript such as fraud, plagiarism, unethical or unsafe practices? No
• Have authors’ provided the necessary ethics approval (from authors’ institution or an ethics committee)? Yes

Section 2 – Language quality

• How would you rate the English language quality? High quality (but English typos)

Section 3 – validity and reproducibility

• Does the work cite relevant and sufficient literature? No
• Is the study design appropriate and are the methods used valid? Yes
• Are the methods documented and analysis provided so that the study can be replicated? Yes
• Is the source data that underlies the result available so that the study can be replicated? Yes
• Is the statistical analysis and its interpretation appropriate? No
• Is quality of the figures and tables satisfactory? No
• Are the conclusions adequately supported by the results? No
• Are there any objective errors or fundamental flaws that make the research invalid? No*

Section 4 – Suggestions

• In your opinion how could the author improve the study?

I read with great interest this manuscript, studying a fascinating topic. Although this study is highly interesting and intriguing, I think that some major improvements could be made. Notably:

The work does not cite relevant and sufficient literature. For instance, the authors do not cite a recent publication which aimed to induce OBE using hypnosis (Martial et al., Scientific Reports, 2019). Another example: The authors could have at least briefly discussed Parnia’s AWARE prospective study reporting OBE in NDE experiencers (Parnia et al., 2014). Besides, they sometimes cite some inappropriate references; I would like to invite the authors to cite rigorous and serious articles in the field. For example, they used Jourdan (2011) reference to draw a parallel with NDEs, however, Jourdan (2011) is not a reference article in the field…

Importantly, it is worth mentioning that, so far, no rigorous empirical scientific study has shown evidence of veridical perceptions during OBE; according to me, it is not clear in the manuscript.

Some limitations of the study are not mentioned in the discussion section.

Some details of the study are missing. Notably, the description of the Table 6 is incomplete: what do the bold numbers mean? Another example: how did they recruit the participants –who are co-authors of the paper? Are they researchers?

The conclusions they draw in the discussion are not based on the present findings; they extrapolate.

• Do you have any other feedback or comments for the Author?

page13: what do they mean by “general consensus”? This is not clear to me

I would like to invite the authors to correct English typo and spelling errors (example: “We also thankS”)

Section 5 – Decision

Requires revisions: The manuscript contains objective errors that must be addressed

Peer review report

Reviewer: : Aminata Bicego Institution: University of Liège email: abicego@uliege.be

Section 1 – Serious concerns

• Do you have any serious concerns about the manuscript such as fraud, plagiarism, unethical or unsafe practices? No
• Have authors’ provided the necessary ethics approval (from authors’ institution or an ethics committee)? Yes

Section 2 – Language quality

• How would you rate the English language quality? - Low to medium quality, but I understand the content

Section 3 – validity and reproducibility

• Does the work cite relevant and sufficient literature? No
• Is the study design appropriate and are the methods used valid? Yes
• Are the methods documented and analysis provided so that the study can be replicated? no
• Is the source data that underlies the result available so that the study can be replicated? Yes
• Is the statistical analysis and its interpretation appropriate? Yes
• Is quality of the figures and tables satisfactory? No
• Are the conclusions adequately supported by the results? Yes
• Are there any objective errors or fundamental flaws that make the research invalid? No*

Section 4 – Suggestions

• In your opinion how could the author improve the study?

Abstract :

L13 : what do the authors mean by “hypnotic induction”, is it hypnotic experience ? During a hypnosis session, the therapist starts by an induction and then makes some suggestions according to the goal that has been decided. It is not clear to what the “hypnosis induction” refers to.

L16 : “under hypnosis” should be changed as it suggests that the individual who is in hypnosis is passive. I would suggest “in hypnosis”.

Introduction:

L 54-56 : there has been some recent literature on hypnosis and OBEs or NDEs. It would be interesting to add newer literature on that topic.

L75 : if the study’s aim is to confirm Tressoldi and Del Prete (2007), then this study should be explicitly explained in detail. That way the reader understands better the present study.

L76 : could the authors specify the suggestion used.

L78 : the induction is not the only and principal part of the hypnotic sessions that impacts an individual perceptions but rather the suggestion that is used. This paragraph could be clearer in terms of methodology

L79 to L95 : this should be in methods.

Materials and Methods :

L110 : can the authors define and detail “clinical level of medical or psychiatric disease”.

L111 : took, should be written “take”. Throughout the manuscript there are language mistakes that have to be checked.

L111 : can the authors be more specific on the “personal experience with hypnosis” ? What do you mean by experience ?

Procedure :

in general the procedure is not very clear. Some results appear in the section when they should be in the result section

L125 : Can the authors explain why some participants had one or two sessions ?

L127 : Can the supplementary Material be numbered.

L129 to 132 : Have all participants been seen in real life? Were all of them called? If not, was it always the same people in person or on the phone? This part should be more specific.

L130 : hypnotized should not be used. Same comment as comment L16.

L140 : was the order of the picture position randomized ? If so it should be mentioned here.

L164: Who did the authors know that the participants where in an OBE state ? What were the criteria ? Especially on the phone ?

L174 : did the authors create the questions ? Do they come from a questionnaire ? This should be specified.

L188 : this should be in results

L191 : “... and give suggestion...” : It is confusing to use that word, comments, mught be more appropriate.

L198: what are the eleven questions ?

L208 : all the questionnaires used should also be described in material. The reader has no information on the minimal phenomenal selfhood, nor has he information about the “characteristics of spatial and temporal perception reported in NDEs”.

L221 : how did the 3 decoys were selected ?

L225 : I only see 2 authors, not three.

L234 : a section with the statistical analyses should be written before the results.

L241 : 52.4 % is not metionned in the table, this is confusing.

L245 : this should be in the statistical analyses part, it is not a result per se.

L260 : the table 3 should be more specific: define ES + formula, CI, BF, H1, H0. A table should be able to be read by itself.

L277 : This part merits some clarifications : - Did the approval from the Ethical committee approved this part ? If so, did the participants signed an informed consent ? - What should they refer to when they answered the questions ? Did the ones that had an OBE had to refere to that episode ? And those who did not life an OBE ? What was the experience of reference ? - It there is no reference for the controls without an OBE expereince then is seems logical that they do not answer like the others.

L304 : the % is not correct, is should be 46.6%

L338 : With what material was the comparison made ? With the material from Jourdan (2011) or the participants that were contacted after the study ? This part should be clearer If the cmparison is made with Jourdan, then a table with the similaritie and differences could be added.

L382 : “but his aim was not to confirm his knowledge, but to compare it with the participants’ experience” : this was not mentionned before. It is hard to understand as we have no information in the hypnostist knowledge or the comparison that is mentionned. Could the authors clarify ?

L387 : Another limitation it the response expectancy during hypnosis. There is a large literature on the subject this should be discused in the limites. More so because all the subject had good knowledge about OBEs

L412 : Is it acceptable to disclose the participants identity ?

Page 5 : The authors mention in a foot note that some other informatio will be avaiable in a future publication but the publication has since been published. Furthermore, that publication is cited in the bibliography this is confusing.

Table S1 : it is hard for the reader to understand to what the table refers to. GAPED has to be explained.

Section 5 – Decision

Verified with reservations: The content is scientifically sound, but has shortcomings that could be improved by further studies and/or minor revisions.

Peer review report

Reviewer: Nidia Bañuelos Institution: University of Wisconsin-Madison email: nbanuelos@wisc.edu

General comments

Questions of how and why grading practices change over time, how students, faculty, and administrators respond to grades, and the external pressures on grading practices (e.g. war, graduate school requirements) are inherently interesting! The authors have clearly done a careful job of tracking these – often minute, and likely, difficult to follow – changes at Dalhousie University. The manuscript is well-written and relatively easy to follow.

My biggest concern, reflected in the more detailed comments below, is that the authors could do a better job of explaining to the reader why these changes are interesting, important, and relevant to historians of higher education more broadly – even those who aren’t at Dalhousie. They do some of this at the very end of the paper and, indeed, this summing up of their findings and explanation of their relevance was my favorite part of the manuscript. I would suggest reorganizing the paper so that these bigger takeaways appear in the introduction and so that the reader is reminded of them at each major section break of the paper. For example, when the authors present a quote from a student who is concerned that grades have little to do with learning outcomes, they might remind us that one of their main arguments is that “decisions about university grading schemes had very little to do with actual pedagogy” (p. 15).

As it is written, the manuscript sometimes reads like a list of facts about grading changes. But, I think a reframing that focuses on the general importance of these changes could make the entire piece more engaging. More on this below…

Section 1 – Serious concerns

• Do you have any serious concerns about the manuscript such as fraud, plagiarism, unethical or unsafe practices? No

• Have authors’ provided the necessary ethics approval (from authors’ institution or an ethics committee)? not applicable

Section 2 – Language quality

• How would you rate the English language quality? High quality

Section 3 – validity and reproducibility

• Does the manuscript contain any objective errors, fundamental flaws, or is key information missing?

While I don’t notice any “objective errors”, I do think the paper has a major flaw (i.e. little explanation of the broader significance of this case study) and could benefit from additional information about the institutional context, the archival material, and external influences on grading trends. (Please see below.)

Section 4 – Suggestions

• Based on your answer in section 3 how could the author improve the study?

I. Most importantly, I would like to see an introduction that explains the authors’ general arguments about grading changes – including the trajectory of these changes at Dalhousie and why this arc contributes to our knowledge of the history of higher education more broadly. Then, the authors might continually remind us of the arc they present at the outset of their paper – especially when they are highlighting a piece of evidence that illustrates their central argument. To me, the quotes from students and faculty responding to grading changes are among the most interesting parts of the paper and placing these in additional context should make them shine even more brightly!

II. I’d like to read a little more about Dalhousie itself – why it is either a remarkable or unremarkable place to study changes in grading policies. Is it representative of most Canadian universities and thus, a good example of how grading changes work in this national context? Is it unlike any other institution of higher education and thus, tells us something important about grades that we could not learn from other case studies? I don’t think this kind of description needs to be particularly long, but it should be a little more involved than the brief sentences the authors currently include (p.3, paragraph 1) and should explain the choice of this case.

III. I’d also like to know more about the archival materials the authors used. The authors mention that they drew from “Senate minutes, university calendars, and student newspapers” (p. 3), but what kinds of conversations about grades did these materials include? At various points, the authors engage in “speculation” (e.g. p.4) about why a particular change occurred. This is just fine and, in fact, it’s good of the authors to remind us that they are not really sure why some of these shifts happened. But, they might go one step further and tell us why they have to speculate. Were explicit discussions of grading changes – including in inter- and intradepartmental letters and memo, reports, and other documents – not available in these archives? Why are these important discussions absent from the historical record?

IV. At various points, the authors make references to the outside world – for example, WWII (p. 5), the Veteran’s Rehabilitation Act (pp. 6-7), and British versus American grading schemas (p. 6). But, these references are brief and seem almost off-handed. I know space is limited, but putting these grading changes in their broader context might help make the case for why this study is interesting and important. Are the changes in the 1940s, for example, related to the ascendance of one national graduate education model over another (e.g. American versus British)? Are there any data on how many Canadian undergraduates enrolled in British versus American graduate programs over time? If so, I would share any information you might have on these broader trends.

Similarly, the authors make brief mention of the internal reaction to grade changes – quoting students or faculty minutes. But, it would be wonderful (space permitting) to have even more information the internal impact of these changes. Did they change faculty instructional practices? Did they seem to have any effect on students’ orientation to their learning? Did standardization reflect an increasing interdependence of departments, or did it contribute to their lessening autonomy? If the archival record doesn’t permit us to know these things, then this might be a limitation the authors note at the end of the manuscript. I noticed that the authors reference a secondary source on Dalhousie student experiences repeatedly (Waite, 1998). Even a little more from this text or another secondary source like it could help the reader better understand the impact of grade changes.

• Do you have any other suggestions, feedback, or comments for the Author?

This is a very nitpicky concern that doesn’t fit well elsewhere, so please take it with a grain of salt. I was surprised at the length of the reference list – it seemed quite short for a historical piece! I wonder, again, if more description of the archival material - including why you looked at these sources, in particular, and what was missing from the record – would help explain this and further convince the reader that you have all your bases covered.

Section 5 – Decision

Requires revisions: The manuscript contains objective errors or fundamental flaws that must be addressed and/or major revisions are suggested.

Peer review report

Reviewer: Champion Deivanayagam

Institution: University of Alabama at Birmingham

email: champy@uab.edu

General comments

Summary of the study: The authors begin the manuscript describing an effort to understand the various sizes of DMBT1 protein, namely variations in the copy numbers of SRCR repeats based on its DNA sequence variations among various groups. In this effort they have identified/chosen three major groups namely European (states in Figure 1of the manuscript they are European-Americans in Utah), African (Yoruba of Ibadan, Nigeria) and Asian (Chinese from Beijing). The observed high D value shown in Figure 1, they contend is the evidence for balancing selection (which this Reviewer has no expertise on). Based on this Tajima scores, they were able to identify two haplotypes, and this led to them arriving at SNP (rs11523871).

Now comes the interesting part of parsing the copy number variations of DMBT1’s SRCR domains within these two haplotype clades, where they conclude that the SRCR copy numbers are population specific. Then looking at tissue specific expression of DMBT1, where they observe higher expression levels in some tissues such as lung, small intestine, colon, and minor salivary gland. More interestingly they observe that there exists no linear relationship that exists among the alleles and concluding that there is no plausible explanation for protein expression, but the selection locus rs11523861 somehow is related at balancing selection.

In an attempt to determine the copy number variations, a small set of samples (8) were collected from saliva and analysed. In table 1 they summarize these findings, where they observe four different isoforms. They report that there is a strong linear relationship, but do not present a figure or other details, except statistical parameters to convince the reader. From here, they step into establishing alternative splicing as a possibility, where they use the H292 lung cell line model, and report in past tense that the H292 cell line was homozygous for the 11/10 SRCR domain repeats (Figure 4). While they could not conclude, it mentions that alternative splicing may play a minor role.

Finally, this study attempts to use the results from the classic Stromberg lab study published in 2007, which enumerated various properties of Gp340, and classified them into 4 groups, and enumerated their affinities for various carbohydrates, Lewis antigens and compared the oral and lung Gp340. The authors here use western blots to determine if the short allele is different from the normal one. They use two knock-outs of surface components on S. mutans, SpaP and Cnm to show that the shorter alleles display no binding. In the same set of experiments, they also show that S. mutans adheres to mono and dimeric amylase.

Finally, they conclude that some of the variations in adherence may be due to the carbohydrates present on the different DMBT1.

Section 1 – Serious concerns

• Do you have any serious concerns about the manuscript such as fraud, plagiarism, unethical or unsafe practices? No
• Have authors’ provided the necessary ethics approval (from authors’ institution or an ethics committee)? Yes

Section 2 – Language quality

• How would you rate the English language quality? Low to medium quality, but I understand the content

Section 3 – validity and reproducibility

• Does the work cite relevant and sufficient literature? Yes
• Is the study design appropriate and are the methods used valid? Yes
• Are the methods documented and analysis provided so that the study can be replicated? Yes
• Is the source data that underlies the result available so that the study can be replicated? Yes
• Is the statistical analysis and its interpretation appropriate? Yes to a large extent
• Is quality of the figures and tables satisfactory? No
• Are the conclusions adequately supported by the results? No
• Are there any objective errors or fundamental flaws that make the research invalid? Please describe these thoroughly. Yes

Section 4 – Suggestions

• In your opinion how could the author improve the study?

Additional experiments are needed to support the conclusions.

Major Concerns:

The research work presented here appears highly disjointed at times. While they begin this study to evaluate the need for copy numbers and how it could have been a part of selection process induced by a variety of factors, their analysis leads to Supplementary figure 1, where they identify two clades. From here they offer some evidence for the choice of rs11523861 to study the balancing selection. However, no concrete evidence is presented and/or discussed except peripherally. This Reviewer understands the effort, which is very interesting, however, without additional analysis the current form of results does not offer any new insights, and so the title is highly misleading.

At this point, they move into CNV’s, whereby their own admission have used a very small sampling of 8 individuals and extrapolate their results to be conclusive. Further sampling and additional studies are necessary to complete this section.

One solid set of results shown here are from the H292 lung cell line model, where they report different variations of the repeats. However, all analysis stops here, and conclusion is derived that alternative splicing is ruled out, but for a minimal role. Once again, the same pattern exists here to do an experiment, without further analysis and additional data, conclusions are drawn.

Finally, from sequence analysis the authors step into protein-based assays to expose the role of S. mutans adherence on the presence and absence of its surface proteins SpaP and Cnm. Their conclusion that Cnm is the major adherent protein is also out of one single experiment. More importantly, their analysis of I-IV alleles (without explaining them), an extension of a previous well cited article, results in a conclusion that smaller allelles (???) do not adhere to saliva. In Table 1, the molecular weights of these isoforms are in alignment with the 14 SRCR domains, but for their carbohydrate decorations, with one exceptions of sample 6. Also, this Reviewer is not sure if this table corresponds to the 8 samples, they have used for CNV analysis and/or for the smaller/larger alleles they allude to in the western blot study.

In summary this appears to be a manuscript that is not only disjointed, but also not detailed enough to warrant publication at this stage. If they could do additional analysis on each of the points raised, it would elevate the research and conclusions.

Minor concerns: The manuscript is extremely poorly written and needs major revamping in order to produce a more concrete publication.

Figure numbers and legends are often mixed up both in the text as well as in the legends. Figure 5 - Differential binding of S.mutans by DMBT1 isoforms in saliva: Overlay of individual saliva phenotypes with DMBT1 size isoforms I- IV with A) a biotinylated S. mutans SpaP A, Cnm strain and B) with DMBT1-specific antibodies. The positions of DMBT1, mono- and dimer amylase, and acidic PRP co-receptors are marked by arrows”. This bold line is not related to this figure but to the supplementary figure.

There is no marker in these figure 5A so indicate the specific molecular weights. The isoform IV on the last lane seems to lightup with the lower MW DMBT1 (allele?). However, the conclusions presented show that lower isoforms do not bind well is contrary to the results presented here.

Supplementary figure 2 should be in the main manuscript, even though this is not a new result, in combination with the other two, authors can summarize the results.

Abbreviations should be in the expanded form the first time.

Why do the authors use the SpaP A instead of SpaP?

What do they mean by a biotinylated S. mutans SpaP A, Cnm strain?

• Do you have any other feedback or comments for the Author?

These copy numbers have always been fascinating not only on DMBT1 but on other proteins, yet to date we don’t have a handle on the type of selection. If these authors could provide additional analysis on why and how balance selection could have played a role it would be very important and could be extended to numerous other proteins.

Section 5 – Decision

Requires revisions

Peer review report

Reviewer: Jinbao Liao Institution: Jiangxi Normal University. email: jinbaoliao@163.com

Section 1 – Serious concerns

• Do you have any serious concerns about the manuscript such as fraud, plagiarism, unethical or unsafe practices? No
• Have authors’ provided the necessary ethics approval (from authors’ institution or an ethics committee)? not applicable

Section 2 – Language quality

• How would you rate the English language quality? Low to medium quality. I understand the content

Section 3 – validity and reproducibility

• Does the work cite relevant and sufficient literature? Yes
• Is the study design appropriate and are the methods used valid? No
• Are the methods documented and analysis provided so that the study can be replicated? No
• Is the source data that underlies the result available so that the study can be replicated? Yes
• Is the statistical analysis and its interpretation appropriate? Yes
• Is quality of the figures and tables satisfactory? Yes
• Are the conclusions adequately supported by the results? Yes
• Are there any objective errors or fundamental flaws that make the research invalid? Please describe these thoroughly. No

Section 4 – Suggestions

• Do you have any feedback or comments for the Author?

Three basic models are used to study complex systems: dynamical system modelling, agent-based model, and complex networks. Dynamical system modelling uses top-down modelling ideas (modelling with macroscopic variables; based on mean-field ideas). The agent-based model uses bottom-up modelling ideas (modelling with micro variables; based on individual simulation ideas). Complex networks lie between dynamical system modelling and agent-based model (each individual interacts with each other, and the interactions are linked into edges to form a complex network). The paper 'Metacommunity research can benefit from including context-dependency' uses the agent-based model framework (NetLogo).

The agent-based model framework in this paper incorporates four dimensions: inter-habitat differences (heterogeneity), dispersal (dispersal rate on the probability of colonizing rather than general mobility), specialization (breadth of species response to collection of diverse habitats), species Interactions (competition, predation, mutualism, parasitism et al. mutualism, parasitism et al.), and these dimensions have been more or less extensively studied in the dynamical system framework and the complex network framework. Therefore, the authors should discuss in detail how agent-based model framework has advantages over the most common frameworks currently used for ecosystem modelling (dynamical systems, complex networks).

For example, for the dynamical system framework, recent studies suggest incorporating six modules (such as species interactions, dispersal, demography, evolution, environment and physiology) into the model to predict biodiversity (Norberg et al., 2012, Nature Climate Change; Urban et al., 2016, Science). For the complex network framework, early theoretical studies explored the effects of multiple relationship types or dispersal on complex networks (Holland & Hastings, 2008, Nature; Mougi & Kondoh, 2012, Science; Allesina & Tang, 2012, Nature).

Moreover, the idea of agent-based model is derived from the theory of complex adaptive systems (e.g., Kondoh, 2003, Science), and the core idea of this framework is that adaptability creates complexity. Many studies have focused on the evolution of dispersal strategies within single species (Cote et al., 2017, Ecography), while theoretical studies on the evolution of dispersal in meta-communities remain rare. For the dispersal dimension (a key dimension of this paper), do authors consider the evolution of dispersal strategies.

Finally, after reading this ms, it is really unclear what the model is and how to simulate the model. Maybe you should describe it in details following the ODD protocol for describing individual-based models (Grimm et al. 2006).

Section 5 – Decision

Requires revisions: The manuscript contains objective errors that must be addressed

Peer review report

Reviewer: Dr. Pradeep G Kumar Institution: Rajiv Gandhi Centre for Biotechnology email: kumarp@rgcb.res.in

Section 1 – Serious concerns

• Do you have any serious concerns about the manuscript such as fraud, plagiarism, unethical or unsafe practices? No
• Have authors’ provided the necessary ethics approval (from authors’ institution or an ethics committee)? not applicable

Section 2 – Language quality

• How would you rate the English language quality? High quality

Section 3 – validity and reproducibility

• Does the work cite relevant and sufficient literature? Yes
• Is the study design appropriate and are the methods used valid? Yes
• Are the methods documented and analysis provided so that the study can be replicated? Yes
• Is the source data that underlies the result available so that the study can be replicated? Yes
• Is the statistical analysis and its interpretation appropriate? Not applicable
• Is quality of the figures and tables satisfactory? Yes
• Are the conclusions adequately supported by the results? Yes
• Are there any objective errors or fundamental flaws that make the research invalid? No

Section 4 – Suggestions

• In your opinion how could the author improve the study?

• Do you have any other feedback or comments for the Author?

Text requires improvement at some places (citing them is difficult as pages and lines are not numbered). Some examples are given below:

.......was associated with molecular markers of the PGC...... (was associated with the expression of molecular???)

Primordial germ cells (PGCs), the developmentally first founder cells of the germline, are induced from epiblast cells on around embryonic day (E)6.25 by external signals,

Furthermore, it was shown for that male mouse ES cells cultured in serum that subjected to a chemical intervention, including a timed exposure to a combination of the a SIRT1 inhibitor Ex-527, the a DNA methyltransferase inhibitor RG-108 and the an electrophilic redox cycling compound tert-butylhydroquinone (tBHQ), was associated with induced the expression of molecular markers of the PGC

Section 5 – Decision

Verified manuscript

Peer review report

Reviewer: Takehiko Ogawa Institution: Yokohama City University email: ogawa@yokohama-cu.ac.jp

Section 1 – Serious concerns

• Do you have any serious concerns about the manuscript such as fraud, plagiarism, unethical or unsafe practices? No
• Have authors’ provided the necessary ethics approval (from authors’ institution or an ethics committee)? not applicable

Section 2 – Language quality

• How would you rate the English language quality? High quality

Section 3 – validity and reproducibility

• Does the work cite relevant and sufficient literature? Yes
• Is the study design appropriate and are the methods used valid? Almost Yes
• Are the methods documented and analysis provided so that the study can be replicated? Almost Yes
• Is the source data that underlies the result available so that the study can be replicated? I think, Yes
• Is the statistical analysis and its interpretation appropriate? Not applicable
• Is quality of the figures and tables satisfactory? Almost Yes
• Are the conclusions adequately supported by the results? No
• Are there any objective errors or fundamental flaws that make the research invalid? Please describe these thoroughly.

I would like to request authors to test the validity of cells with spermatogonia-like morphology (CSM) as spermatogenic stem cells. For this, transplantation of CSM into the seminiferous tubules in the testis of recipient mice is necessary. This may be an additional work, but authenticity of CSM as SSCs cannot be claimed without such experiment. They may claim that in case of ES cells most experiments do not perform blastocyst injection experiment to confirm the pluripotency of ES cells. However, culture system for ES cells has a long history and was established as robust method to maintain their pluripotency. It is actually the 2iL system as shown in this study as well. In case of SSCs or GS cells, the culture system is still fragile in my understanding, compared to the 2iL. The spermatogenic ability that SSCs and GS cells have could be lost during the cultivation in many cases. In particular, chemical intervention shown in this study could disturb cell’s intrinsic system, which could make almost anything happen. The enhanced expression of Lhx1 also could be an aberrant result of such turmoil in the cells. I do not insist that is the case, but intentionally taking a position to be extremely skeptical to the results. In order to dispel such doubts, it is necessary to do the transplantation experiments and prove that the CSM maintained the spermatogenic ability as SSCs.

Section 4 – Suggestions

• In your opinion how could the author improve the study?

Readers would wonder what the CSM is exactly. This naming means that CSM could be SSCs but possibly not, although they look like SSCs. It was honest naming but confusing in what the CSM really is. In order to start the experiment with CSM, authors should clear such ambiguous point. Thus, I recommend a transplantation experiment as stated above.

• Do you have any other feedback or comments for the Author?

In Page 6, it is described that medium change twice daily with a third of the volume at hour 8 and 16 was critical for the appearance of CSM. In case of the medium change with half of the volume every 12 hours, it was written that the CSM did not appeared at all. Authors argued that endogenously produced soluble factors might be the cause. I wonder what extent of difference could be there between the two method of culture medium change, regarding to the concentration of endogenously produced soluble factors. A simulation of the change in concentration of such hypothetical substances might help the speculation.

Section 5 – Decision

Requires revisions

Peer review report

Reviewer: Yuan Junpeng Institution: National Science Library, Chinese Academy of Sciences. email: yuanjp@mail.las.ac.cn

Section 1 – Serious concerns

• Do you have any serious concerns about the manuscript such as fraud, plagiarism, unethical or unsafe practices? No
• Have authors’ provided the necessary ethics approval (from authors’ institution or an ethics committee)? not applicable

Section 2 – Language quality

• How would you rate the English language quality? High quality

Section 3 – validity and reproducibility

• Does the work cite relevant and sufficient literature? Yes
• Is the study design appropriate and are the methods used valid? Yes
• Are the methods documented and analysis provided so that the study can be replicated? Yes
• Is the source data that underlies the result available so that the study can be replicated? Yes
• Is the statistical analysis and its interpretation appropriate? Yes
• Is quality of the figures and tables satisfactory? Yes
• Are the conclusions adequately supported by the results? Yes
• Are there any objective errors or fundamental flaws that make the research invalid?

The research question of this article is not clear enough, and this paper is more like a report than a research paper. Since a lot of research about retraction haven been published, many characteristics of retraction have been analysed. There seem not enough new messages comes from this article.

In addition, as ‘exploratory research’ defined by the title, the use of full data for analysis is more in line with the objectives of the title, instead of excluding other disciplines and restricting the analysis to human health. If the author’s goal is to analyse the characteristics of human health-related retractions, it is recommended to limit it in the title. The current topic is too general.

Section 4 – Suggestions

• In your opinion how could the author improve the study?

It is recommended that the author properly point out what have and haven’t been done in this topic, and their specific contribution to the existing knowledge, so as to show the innovation of the research.

It is recommended that the author clarify the research objectives and modify the title more in line with the content.

• Do you have any other feedback or comments for the Author? No

Section 5 – Decision

Requires revisions

Peer review report

Reviewer: Hurng-Yi Wang Institution: Institute of Ecology and Evolutionary Biology, National Taiwan University email: hurngyi@gmail.com

Section 1 – Serious concerns

• Do you have any serious concerns about the manuscript such as fraud, plagiarism, unethical or unsafe practices? No
• Have authors’ provided the necessary ethics approval (from authors’ institution or an ethics committee)? not applicable

Section 2 – Language quality

• How would you rate the English language quality? Medium quality

Section 3 – validity and reproducibility

• Does the work cite relevant and sufficient literature? No
• Is the study design appropriate and are the methods used valid? No
• Are the methods documented and analysis provided so that the study can be replicated? Yes
• Is the source data that underlies the result available so that the study can be replicated? Yes
• Is the statistical analysis and its interpretation appropriate? Yes
• Is quality of the figures and tables satisfactory? No
• Are the conclusions adequately supported by the results? No
• Are there any objective errors or fundamental flaws that make the research invalid?

Section 4 – Suggestions

• In your opinion how could the author improve the study?

• Do you have any other feedback or comments for the Author?

Agarwal and Parekh analyzed 685 SARS-CoV-2 isolates collected during 27th Jan - 27th May 2020 from India and described the distribution of virus strains and mutations across the country. While the information might be valuable to some local readers, the results are mainly descriptive and the data are a bit out of date. In addition, I have the following comments.

1. Some details of the methods are lacking. For example, the MUpro provides two methods, it is necessary to specify which method was used in the analysis. The confidence score of each prediction should also be provided. Besides, some results from I-Mutant and MUpro were conflicting, the authors may want to discuss the discrepancy.

1. The “Analysis of the Mutational Profile of Indian Isolates” should be moved to Materials and Methods.

1. The authors provided lengthy discussion about the effect of each mutation in some lineages, such as 20A and I/A3i. However, as these mutations are tightly linked, the effect of each individual mutation is difficult to access. It is possible that some of the mutations are just hitchhikers. They may want to address this alternative point.

1. Several figures are confusing and lack detail. The diversity plots of Figure 3 and Figure 8 are hard to be precisely compared to the mutations that occurred among different plots. Phylogenetic trees, as well as their figure legends, are confusing, especially Figure 9 and Figure 10. For Figure 9, it is impossible to tell which mutation site had changed from C to T. For Figure 10, spots depicted in yellow are both position 29827 A>T and position 29830 G>T, green spot only notes as G, but A29827 is not mentioned in the figure. Furthermore, the mutation position of blue spot C cannot be found.

1. Figure 9 and Figure 10 were not mentioned inside the text.

1. The Top 10 mutations in PCA analysis are the mutations in 20A and I/A3i. It is reasonable to observed a clear association of the clusters with the clades. It is not clear, however, how these distribution correlate with lockdown, contact tracing and quarantine measures.

Section 5 – Decision

Requires revisions

Peer review report

Reviewer: Dr. Jyotsnamayee Sabat Institution: Regional VRDL, RMRC(ICMR). email: jyotsnasabat@yahoo.com

Section 1 – Serious concerns

• Do you have any serious concerns about the manuscript such as fraud, plagiarism, unethical or unsafe practices? No
• Have authors’ provided the necessary ethics approval (from authors’ institution or an ethics committee)? not applicable

Section 2 – Language quality

• How would you rate the English language quality? Good quality

Section 3 – validity and reproducibility

• Does the work cite relevant and sufficient literature? Yes
• Is the study design appropriate and are the methods used valid? Yes
• Are the methods documented and analysis provided so that the study can be replicated? Yes
• Is the source data that underlies the result available so that the study can be replicated? Yes
• Is the statistical analysis and its interpretation appropriate? Yes
• Is quality of the figures and tables satisfactory? Yes
• Are the conclusions adequately supported by the results? Yes
• Are there any objective errors or fundamental flaws that make the research invalid?

No such application was observed.

Section 4 – Suggestions

• In your opinion how could the author improve the study?

They have analysed it in-depth and presented nicely.

• Do you have any other feedback or comments for the Author?

I want to know how the representative sequences were selected for different states. Is it based on no of sequences submitted or positivity rate of a particular region.

Section 5 – Decision

Verified manuscript

Peer review report

Reviewer: Parvin Abraham Institution: MIMS Research Foundation, Calicut, Kerala, India. email: parvinabraham@gmail.com

Section 1 – Serious concerns

• Do you have any serious concerns about the manuscript such as fraud, plagiarism, unethical or unsafe practices? No
• Have authors’ provided the necessary ethics approval (from authors’ institution or an ethics committee)? not applicable

Section 2 – Language quality

• How would you rate the English language quality? High quality

Section 3 – validity and reproducibility

• Does the work cite relevant and sufficient literature? Yes
• Is the study design appropriate and are the methods used valid? Yes
• Are the methods documented and analysis provided so that the study can be replicated? Yes
• Is the source data that underlies the result available so that the study can be replicated? Yes
• Is the statistical analysis and its interpretation appropriate? Yes
• Is quality of the figures and tables satisfactory? Yes
• Are the conclusions adequately supported by the results? Yes
• Are there any objective errors or fundamental flaws that make the research invalid? Please describe these thoroughly. No

Section 4 – Suggestions

• In your opinion how could the author improve the study?

The dataset is only from 27th Jan – 27th May 2020. Maybe they can include more Numbers.

• Do you have any other feedback or comments for the Author? No

Section 5 – Decision

Verified manuscript

Peer review report

Reviewer: Dr. : Peter Dahlberg Institution: SLAC national laboratory email: pdahlb@slac.stanford.edu

Section 1 – Serious concerns

• Do you have any serious concerns about the manuscript such as fraud, plagiarism, unethical or unsafe practices? No
• Have authors’ provided the necessary ethics approval (from authors’ institution or an ethics committee)? not applicable

Section 2 – Language quality

• How would you rate the English language quality? Low to medium quality. I have added several comments to section 4 as suggested edits.

Section 3 – validity and reproducibility

• Is the reason for developing a new method explained? Yes
• Is the description of the method technically sound? Yes
• Are sufficient details provided so that the method can be replicated? No
• Is the source data that underlies the result available so that the study can be replicated? not applicable
• Is quality of the figures and tables satisfactory? Yes
• Are the conclusions adequately supported by the results? No
• Are there any objective errors or fundamental flaws that make the research invalid? Please describe these thoroughly. No

Section 4 – Suggestions

• In your opinion how could the author improve the method?

The manuscript describes the progressive refinement method for sparse recovery. This approach uses minimal RAM while producing a finely discretized output for high density 3d fluorescence localizations. Furthermore, the approach does not require the PSF to be translationally independent. This is an assumption that is often made that simplifies the computation, but does not account for field dependent aberrations. There are several comments that I believe would improve what is overall strong manuscript. The most serious of which is addressed in 1a below.

1. The two main claims of the manuscript are that the PRIS method requires less RAM than a brute force approach and that the algorithm functions for spatially varying PSFs. Neither of these claims are supported directly by the text or figures. a. Perhaps I missed it, but there were no field dependent aberrations in the simulations. If this is the case, how exactly has it been demonstrated that the approach works well for a spatially varying PSF? Because this is a central claim of the PRIS method, I think it is worth implementing. b. The authors describe a scenario of brute force solving of the inverse problem requiring 152.6 GB, while I have no doubt that the PRIS approach would require less RAM, the authors do not make it clear how much less. While I know that the reduction will depend on the exact implementation and the data at hand, a rough comparison of the RAM requirements would be helpful for the reader.

2. Following algorithm 1, the authors introduce the “shrink” operator. A one line description would be helpful of what this operator does. As I understand it, it is a threshold of the output to keep the data output sparse.

3. Following algorithm 1 and 2, the authors describe the use of “kicking.” They do a nice job of giving a brief description of what the “kicking” does (improve the convergence speed), but I am concerned because neither algorithm 1 or 2 shows kicking. The kicking is wrapped up in another conditional statement that is not shown in either algorithm. This is confusing for the reader. Perhaps a parenthetical should be added stating that the kicking is not shown in the algorithm.

4. The code for the PRIS method should be made available publicly, both so the results can be replicated and also so that others can use the approach.

• Do you have any other feedback or comments for the Author?

Additionally, I have some minor text/figure edits

1. In the title, the acronym PRIS is defined as “progressive refinement method on sparse recovery” however in the text it is “progressive refinement method for sparse recover” I think the wording in the text is correct.

2. 5th paragraph of the introduction: “In principal” should be “In principle”

3. Paragraph preceding section 3: “in case if a species” I think should read “in case a species”

4. Throughout the figures, dark red, dark green, and dark blue are used over black and this is very difficult to see. For example, dashed red line in figure 2 on the right hand side, the cy5 and cy3 labels in figure 7, the dark blue box in figure 8.

5. Throughout the figures there are also a lot of small symbols used. For example, Figure (a)-4 there are small (red?) marks on top of a red heat map. These are extremely difficult to see clearly.

6. Figure 6c, it is very challenging to see differences in the distributions of points. I think this data would be better represented if additional histograms were shown.

Section 5 – Decision

Requires minor revisions

Peer review report

Reviewer: Dr. Christopher H. Bohrer Institution: NIH/NCI email: bohrerch@nih.gov

Section 1 – Serious concerns

• Do you have any serious concerns about the manuscript such as fraud, plagiarism, unethical or unsafe practices? No
• Have authors’ provided the necessary ethics approval (from authors’ institution or an ethics committee)? not applicable

Section 2 – Language quality

• How would you rate the English language quality? High quality

Section 3 – validity and reproducibility

• Is the reason for developing a new method explained? Yes
• Is the description of the method technically sound? Yes
• Are sufficient details provided so that the method can be replicated? No
• Is the source data that underlies the result available so that the study can be replicated? No
• Is quality of the figures and tables satisfactory? Yes
• Are the conclusions adequately supported by the results? No
• Are there any objective errors or fundamental flaws that make the research invalid? Please describe these thoroughly. No

Section 4 – Suggestions

• In your opinion how could the author improve the method?

1. The approach is nice, but I really think they should highlight the advantage of their approach --- that is, perform a simulation with imperfect optics then apply the traditional methodologies as well as their own to show their superiority.

2. The comparison to previous methodologies is nice, but the fact that they are different simulations with different parameters is a major problem --- for example, the photons used in their simulations are higher than used in the previous studies. Therefore, if they are going to compare, it should only be done if the methodologies were applied to the same data.

3. A user guide with an example, walking through the specifics would aid this work greatly. For instance, it is unclear how one obtains the different matrices given their data --- though this is likely within the references. Additionally, if they want others to use the methodology, this is a must!

4. Finally, though I don’t think they necessarily need to do this, but utilizing real experimental data to validate their approach would be nice. For instance, investigate the structure of the nuclear pore complex with the different methodologies --- a standard within the field.

• Do you have any other feedback or comments for the Author? No

Section 5 – Decision

Requires revisions

Peer review report

Reviewer: Deyou Qiu Institution: Chinese Academy of Forestry. email: qiudy@caf.ac.cn

Section 1 – Serious concerns

• Do you have any serious concerns about the manuscript such as fraud, plagiarism, unethical or unsafe practices? No
• Have authors’ provided the necessary ethics approval (from authors’ institution or an ethics committee)? not applicable

Section 2 – Language quality

• How would you rate the English language quality? High quality

Section 3 – validity and reproducibility

• Does the work cite relevant and sufficient literature? Yes
• Is the study design appropriate and are the methods used valid? Yes
• Are the methods documented and analysis provided so that the study can be replicated? Yes
• Is the source data that underlies the result available so that the study can be replicated? Yes
• Is the statistical analysis and its interpretation appropriate? Yes
• Is quality of the figures and tables satisfactory? Yes
• Are the conclusions adequately supported by the results? Yes
• Are there any objective errors or fundamental flaws that make the research invalid? Please describe these thoroughly. No

Section 4 – Suggestions

• In your opinion how could the author improve the study? No

• Do you have any other feedback or comments for the Author?

The resolution of Fig 3 is not good, could you pls improve it?

Section 5 – Decision

Requires revisions

Peer review report

Reviewer: Max Shokhirev Institution: Salk Institute for Biological Studies email: maxshok@gmail.com

Section 1 – Serious concerns

• Do you have any serious concerns about the manuscript such as fraud, plagiarism, unethical or unsafe practices? No
• Have authors’ provided the necessary ethics approval (from authors’ institution or an ethics committee)? not applicable

Section 2 – Language quality

• How would you rate the English language quality? High quality

Section 3 – validity and reproducibility

• Does the work cite relevant and sufficient literature? Some, but seems to be very limited in terms of biological literature.
• Is the study design appropriate and are the methods used valid? Yes
• Are the methods documented and analysis provided so that the study can be replicated? not applicable
• Is the source data that underlies the result available so that the study can be replicated? Yes
• Is the statistical analysis and its interpretation appropriate? Yes
• Is quality of the figures and tables satisfactory? Yes
• Are the conclusions adequately supported by the results? Yes
• Are there any objective errors or fundamental flaws that make the research invalid? How could the author improve the study?

The author has laid out a theoretical argument for senescence as a tradeoff between information capacity between epigenetic and non-epigenetic content.“A constraints-based theory of senescence: imbalance of epigenetic and non-epigenetic information in histone crosstalk.” This work is interesting, but is based on a superficial understanding of the biology underlying senescence/aging, makes several dangerous oversimplifications and assumptions, and does not provide any data or analysis to support the theory. I’ve laid out my comments for each section below:

Sections 1.1-1.3

The author only mentions the Hayflick limit as a biological reference for senescence. There is a very rich body of literature on senescence and aging that is completely overlooked here. The author should include additional references to reviews for senescence and aging to orient the reader to the complexity of these biological processes (e.g. PMC8658264, PMC7846274). Please clarify what you mean by senescence vs aging for both cells and individuals. Senescence is a natural biological process that cells/organisms use to turn off cell replication due to damage (e.g. telomere shortening, double-stranded breaks, etc.). Other cells can also facilitate this process through signaling (e.g. immune cells or contact inhibition). Aging is typically thought of as an organismal phenomenon, which is still poorly understood but is theorized to include tradeoffs (as you describe in section 1.2). It is also accepted that aging is cell, tissue, and organism specific. Since you talk about senescence and aging across both biological scales, it is important to define exactly what your theory pertains to.

Section 1.4

The author posits that senescence is an imbalance in information contents of histone post-translational modifications around transcription start sites. This is just one level of regulation, albeit an important one. The author seems to completely overlook many other types of regulation (e.g. microRNA, lincRNAs, metabolic/energetic constraints, non-proximal regulation at enhancers, higher ordered structure of the chromatin, post-translational regulation of proteins, and etc.). How can all of these other important levels of regulation fit into this theory? All have been implicated in senescence/aging in some form or another. The author further suggests that histone crosstalk information content can be decomposed into two unrelated components: epigenetic and non-epigenetic. The non-epigenetic component is described as “hologenic information content,” which stems from a previously published work by the author. Non-epigenetic is confusing in this context since really this is information content that stems from the synergies of individual cells to form a whole, e.g. the emergent information content that comes from many cells working together (or at least this is how I understand the underlying theory). This information content is important for the general maintenance and survival of the organism. The author should clarify this point further, since this seems to be one of the fundamental assertions being made in the paper. For example, bringing in the descriptions used in section 2, can further clarify these central points. In addition, the author states: “ Moreover, the sum decomposition in Eq. 1 implies that the growth in magnitude (bits) of the hologenic (i.e., non-epigenetic) component must be accompanied by a decrease in magnitude of the epigenetic component.” This is not necessarily true, since signaling is a separate biological process from the regulation of gene expression. In other words, both can increase or decrease simultaneously. For example, a healthy non-senescent immune cell can upregulate very specific transcriptional programs that lead to very complex signaling and extra-cellular interactions. You can argue that both represent an increase in information content for both the epigenetic and non-epigenetic “hologenic” components. In addition, as cells naturally senesce they are programmed to turn off cell-cycling while upregulating autophagy and repair processes. They may not upregulate extracellular signaling at this time, which would seem to contradict the author’s theory/statement. In this case, the simplification that all cells are the same is dangerous because it overlooks the tradeoff of information contents between cells. It also ignores important repair pathways (senescence being one of them), to deal with cells that have dysregulated their natural processes over time. It also overlooks the important action of immune cells that work to get rid of cancer and poorly-functioning cells. Also, it seems crosstalk, correlation, capacity, and content, are used interchangeably. Please clarify that these are all the same, or use one of these terms to avoid confusion.

Section 1.5

The author provides a general approach for measuring the log of the ratio of epigenetic and non-epigenetic capacities for a particular histone modification at three positions (i,j,k), and for some measured abundance of mRNA Y. Since we typically measure abundance of a particular modification genome-wide, and the mRNA level for tens of thousands of genes, how would a realistic equation look like (i.e. one that has 10k mRNA levels, and 10k histone positions)? In addition, the author does not explain how to combine correlations across multiple histone modifications. Please expand this section to make it relevant for real-world genome-wide measurements since this will be important for falsifying the theory. Since public datasets are available (e.g. the aging atlas https://doi.org/10.1093/nar/gkaa894), the author should show an example of how a dataset might be used to falsify or demonstrate the theory in more detail.

Section 2.1

The author uses correlation of the log ratio of the epigenetic and non-epigenetic content with age as a readout of “reassignment” of crosstalk/contents, arguing that for cancer cells this correlation should be essentially zero. This seems like an oversimplification of the “reassignment” process since senescence may occur in phases across the age of a cell/organism, and since there might be both increases and decreases in the log ratio of contents due to natural biological processes and variability. Would it not be better to measure the sum of changes in the log ratio or the difference between the log ratios at different ages?

In addition, the biological age of a cell/tissue/organism can vary. For example, stem cells may have negligent aging, while other cells might age relatively quickly. Again, the author should clarify the context of age: are we measuring strictly chronological age correlation? Should we consider different correlations for each cell/tissue in the organism? What about tradeoffs in information content between cell types and tissues? In other words, it is unclear how the theory should be applied to biological systems.

Section 2.2

The author argues that senescence is an emergent property of the loss of information content for epigenetic histone crosstalk and an increase in information content of “hologenic” information content (e.g. cell signaling and anti-tumor signaling). I believe this premise does not stem from the reality of biological systems (see my comments for section 1.4). Also, this section seems to be contradicting the author’s conclusions and is very confusing. The author seems to argue that there is both more AND less constraint at the multi-cellular level (organismal)? Please clarify or remove this section.

Section 2.3

Senescence as transcriptional overregulation is vague. Here the author is arguing that as epigenetic constraint decreases, you have a decrease in precision (e.g. loss of regulation), but then you have a competing global or hologenic increase in constraints, which constrains the expression of genes for the overall benefit of the organism. A shift toward global constraint.

Section 2.4

This seems to be describing an illustrative real-world example? This section is incredibly specific and again only focuses on one possible mechanism and does not include any measured data or analysis. Please preface this section to explain that this is just one of many possible examples. Again, it will be good to provide other examples looking at other aspects of aging biology (not just histone modifications).

Section 2.5-2.9,3

This seems to be a general discussion. It would be easier to organize these sections into one discussion section for added clarity. Again, I would recommend not talking about sweeping statements like “Senesensce’s ultimate cause” and “Can senescence be stopped?” since this theory only addresses one small aspect of the biology underlying aging and senescence and does not address the heterogeneity of aging. These topics are controversial and should be addressed very carefully to avoid alienating the biological community.

Section 4 – Decision

Revisions required

Peer review report

Reviewer: Charles A. Schumpert Institution: University of South Carolina email: schumpca@email.sc.edu

Section 1 – Serious concerns

• Do you have any serious concerns about the manuscript such as fraud, plagiarism, unethical or unsafe practices? No
• Have authors’ provided the necessary ethics approval (from authors’ institution or an ethics committee)? not applicable

Section 2 – Language quality

• How would you rate the English language quality? High quality

Section 3 – validity and reproducibility

• Does the work cite relevant and sufficient literature? Yes
• Is the study design appropriate and are the methods used valid? Yes
• Are the methods documented and analysis provided so that the study can be replicated? not applicable
• Is the source data that underlies the result available so that the study can be replicated? Yes
• Is the statistical analysis and its interpretation appropriate? Yes
• Is quality of the figures and tables satisfactory? Yes
• Are the conclusions adequately supported by the results? Yes
• Are there any objective errors or fundamental flaws that make the research invalid? Please describe these thoroughly.

Overall the manuscript is written brilliantly and provides excellent context to the audience about a complex theoretical biological concept. No flaws can be found, although one could argue against a few of the points in the assumptions used to construct the theory, there’s nothing illogical or irrational.

Section 4 – Suggestions

• In your opinion how could the author improve the study?

The writing of the paper makes it easy to read, which can sometimes be a challenge with theoretical biology manuscripts. Potentially adding a bit more context on the various theories of aging may help demonstrate the marriage of the ideas into the theory he constructed.

• Do you have any other feedback or comments for the Author? No

Section 5 – Decision

Verified manuscript

Reuters. (2021, October 6). Sweden, Denmark pause Moderna COVID-19 vaccine for younger age groups. Reuters. https://www.reuters.com/business/healthcare-pharmaceuticals/sweden-pauses-use-moderna-covid-vaccine-cites-rare-side-effects-2021-10-06/

Soderberg, C. K., Errington, T., Schiavone, S. R., Bottesini, J. G., Thorn, F. S., Vazire, S., Esterling, K. M., & Nosek, B. A. (2020). Research Quality of Registered Reports Compared to the Traditional Publishing Model. MetaArXiv. https://doi.org/10.31222/osf.io/7x9vy

Max Primbs on Twitter. (n.d.). Twitter. Retrieved September 14, 2020, from https://twitter.com/MaxPrimbs/status/1304516869509066760

Brock. J. (2020). Rapid Registered Reports initiative aims to stop coronavirus researchers following false leads. Nature index

Sasaki, K., & Yamada, Y. (2020). The pandemic threatens the Registered Reports system as well as human lives [Preprint]. PsyArXiv. https://doi.org/10.31234/osf.io/6wdaz

Chris Chambers & David Mellor with the Center for Open Science - Registered Reports Q&A Video

ReconfigBehSci Post

Chambers, C. (2020 March 16). CALLING ALL SCIENTISTS: Rapid evaluation of COVID19-related Registered Reports at Royal Society Open Science

10 Updates*

New Media Consortium Horizon Report This page provides a link to the annual Horizon Report. The report becomes available late in the year. The report identifies emerging technologies that are likely to be influential and describes the timeline and prospective impact for each. Unlike the link to top learning tools that anyone can use, the technologies listed here may be beyond the ability of the average trainer to implement. While it is informative and perhaps a good idea to stay abreast of these listings, it is not necessarily something that the average instructional designer can apply. Rating: 3/5

This article has a Peer Review Report

This article has a Peer Review Report

This article has a Peer Review Report

This article has a Peer Review Report

This article has a Peer Review Report

This article has a Peer Review Report

This article has a Peer Review Report

This article has a Peer Review Report

This article has a Peer Review Report

This article has a Peer Review Report

This article has a Peer Review Report

This article has a Peer Review Report

This article has a Peer Review Report

This article has a Peer Review Report

This article has a Peer Review Report