PONE-D-19-18899

The N125S polymorphism in the G gene is associated with susceptibility to<gwmw class="ginger-module-highlighter-mistake-type-3" id="gwmw-15664826668904541061438"> .</gwmw>

PLOS ONE

Dear Dr. Asensi,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

We would appreciate receiving your revised manuscript by Oct 07 2019 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For<gwmw class="ginger-module-highlighter-mistake-type-3" id="gwmw-15664826752933044759050"> :</gwmw> http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as and labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as and labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without changes. This file should be uploaded as and labeled 'Manuscript'.

<gwmw class="ginger-module-highlighter-mistake-type-2" id="gwmw-15664826912533761596689">Please</gwmw> forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

We look forward to receiving your revised manuscript.

Kind regards,

Manal S. <gwmw class="ginger-module-highlighter-mistake-type-1" id="gwmw-15664832293081786252396">Fawzy</gwmw>, Ph.D., M.D.

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

http://www.journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and http://www.journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. Please provide additional details regarding participant consent. In the ethics statement in the Methods and online submission information, please ensure that you have specified whether consent was written or verbal/oral. If consent was verbal/oral, please specify: a) whether the ethics committee approved the verbal/oral consent procedure, b) why written consent could not be obtained, and c) how verbal/oral consent was recorded. If your study included minors, please state whether you obtained consent from parents or guardians in these cases. If the need for consent was waived by the ethics committee, please include this information.

3. Please note that all PLOS journals ask authors to adhere to our policies for sharing of data and materials: https://journals.plos.org/plosone/s/data-availability. According to PLOS ONE’s Data Availability policy, we require that the minimal dataset underlying results reported in the submission must be made immediately and freely available at the time of publication. As such, please remove any instances of 'unpublished data' or 'data not shown' in your manuscript and replace these with either the relevant data (in the form of additional figures, tables or descriptive text, as appropriate), a citation to where the data can be found, or remove altogether any statements supported by data not presented in the manuscript."

4. We noticed you have some minor occurrence(s) of overlapping text with the following previous publication(s), which needs to be addressed:

https://en.wikipedia.org/wiki/Cathepsin_G

https://doi.org/10.1093/infdis/jit158

https://doi.org/10.1097/GIM.0b013e318039b23d

https://doi.org/10.1016/j.molimm.2007.10.013

In your revision ensure you cite all your sources (including your own works), and quote or rephrase any duplicated text outside the Methods section. Further consideration is dependent on these concerns being addressed.

5. Thank you for including your ethics statement:

"Each participant gave informed consent for the study, which was approved by the Ethics Committee of the HUCA.".

i) Please amend your current ethics statement to include the full name of the ethics committee/institutional review board(s) that approved your specific study.

ii) Once you have amended this/these statement(s) in the Methods section of the manuscript, please add the same text to the “Ethics Statement” field of the submission form (via “Edit Submission”).

For additional information about PLOS ONE ethical requirements for human subjects research, please refer to http://journals.plos.org/plosone/s/submission-guidelines#loc-human-subjects-research.

6. Thank you for stating in your Funding Statement:

"Partially funded by a Fondo de Investigaciones Sanitarias (FIS) grant PI16/01999 given

to VA.

The funders had no role in study design, data collection and analysis, decision to

publish, or preparation of the manuscript".

Please provide an amended statement that declares *all* the funding or sources of support (whether external or internal to your organization) received during this study, as detailed online in our guide for authors at http://journals.plos.org/plosone/s/submit-now.  Please also include the statement “There was no additional external funding received for this study.” in your updated Funding Statement.

Please include your amended Funding Statement within your cover letter. We will change the online submission form on your behalf.

7. We note that you have included the phrase “data not shown” in your manuscript. Unfortunately, this does not meet our data sharing requirements. PLOS does not permit references to inaccessible data. We require that authors provide all relevant data within the paper, Supporting Information files, or in an acceptable, public repository. Please add a citation to support this phrase or upload the data that corresponds with these findings to a stable repository (such as Figshare or Dryad) and provide and URLs, DOIs, or accession numbers that may be used to access these data. Or, if the data are not a core part of the research being presented in your study, we ask that you remove the phrase that refers to these data.

Additional Editor Comments:

1- The authors should use a language-editing service to refine the use of English in their manuscript and submit an "Editing Certificate" with the revised version of the manuscript.

2- Abbreviations must be spelled out on first mention particularly in the abstract.

3- Authors are advised to revise all the manuscript to ensure that all gene names are written in italic font.

4- Authors should pay attention to the use of "Gender" terminology and substitute by the "sex" terminology as it appears from the results they mean the normal biological differences between males and females.

5- Thanks to the authors for providing the PCR primer sequences. Are these primers -designed or derived from other published work? If the former, please provide the name of the program you applied in its formal citation in the text, or provide the citations you follow if they were derived from other publications.

6- The PCR results need more elaboration and clarification (recommended for acceptance). The authors wrote that "PCR products were incubated overnight at 37º C with the restriction enzyme<gwmw class="ginger-module-highlighter-mistake-type-3" id="gwmw-15664829754791295809559">.</gwmw> Results were determined by using the Peak ScannerTM Software v10". The authors should send a photo related to the original scanner and an edited one for publication (in which all the details of band size for each genotype are written clearly) to facilitate replication of the work by future readers.

7- The quality control measurements the authors followed either in their PCR or other laboratory works, including ELISA, etc. <gwmw class="ginger-module-highlighter-mistake-type-1" id="gwmw-15664831811790536589857">should</gwmw> be written in details.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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

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

Reviewer #1: Partly

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or <gwmw class="ginger-module-highlighter-mistake-type-2" id="gwmw-15664829756224531275852">deposited a public</gwmw> repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—<gwmw class="ginger-module-highlighter-mistake-type-1" id="gwmw-15664829756322768885661">eg</gwmw>. <gwmw class="ginger-module-highlighter-mistake-type-1" id="gwmw-15664829756364873410917">privacy</gwmw> or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: No

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in <gwmw class="ginger-module-highlighter-mistake-type-3" id="gwmw-15664829757670599906198">articles</gwmw> must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Review Comments to the Author

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

Reviewer #1: The study concept is interesting and can be of clinical significance.

My main concern is that the authors recruited an accepted number of patients (329) and controls (415) for and when they made the correlation with the evaluated parameters, they included very small groups of individuals (10 to 27 per group). The validity of these results is an issue and the bias in the selection of these individuals could be another problem.

Other points include

The title should determine the polymorphism ID and the study ethnic group.

-<gwmw class="ginger-module-highlighter-mistake-type-1" id="gwmw-15664829758386099843190">value</gwmw> is sometimes mentioned as "equals" and other occasions as "less than". It should be consistent.

Page 4 last line. The authors mentioned that no similar association studies has been done so far. The reference dated 2006.

Page 5, last paragraph is a mixture of the hypothesis and information extracted from reference no.9. Please rewrite.

There are linguistic style and punctuation errors. The manuscript needs linguistic revision. For example a sentence is repeated page 7, parenthesis <gwmw class="ginger-module-highlighter-mistake-type-3" id="gwmw-15664829758768011961931">in</gwmw> page 19, the tense in discussion (mixture of present and past tenses), first line in the second paragraph p23, .....

The authors provided some data analysis based on the gender. It would be better to remove that as the female group is a minority.

Table 2 is confusing. Please separate into two tables (one for and the other for frequency)

The use of Yates correction is not preferred by some<gwmw class="ginger-module-highlighter-mistake-type-3" id="gwmw-15664829759029781080455"> .</gwmw> I am not sure if it is the best to use here.

Reviewer #2: The authors presented an interesting study evaluating the association between CTSG polymorphisms and the occurrence of and its clinical characteristics. The study is well-conducted, but I suggest the following edits:

* Abstract: The authors did not mention the objective of their study in the abstract.

* Introduction: the authors should present the different alleles, in their study.

* Methods: "We enrolled 329 adult patients with a diagnosis of bacterial between January 1998 and December 2018" Was this a part of a hospital database system or a one study effort that lasted 20 years?

- Also, was there a systematic sample size calculation?

- " <gwmw class="ginger-module-highlighter-mistake-type-1" id="gwmw-15664829759509741182248">was</gwmw> diagnosed using clinical and roentgenographic findings" Please clarify?

- The molecular techniques used in the current study are well-described.

* Results: The age and gender of control subjects and their comparisons to patients should be mentioned in the results' first paragraph. Because they are supposed to be matched, no significant difference should be noted.

- "No association of the CTSG N125S polymorphism with or type of bone infection (acute vs. ), source of infection or microorganism isolated was found" the authors should mention at least p for such associations!

* General: The manuscript needs a professional editing service because there are several grammatical errors across the entire manuscript.

- Data availability statement should be added to the manuscript after the conclusion explaining where the underlying data could be found.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no files to be viewed.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.

<gdiv></gdiv><gdiv></gdiv>

The N125S polymorphism in the <gwmw class="ginger-module-highlighter-mistake-type-1" id="gwmw-15703449758395636918275">cathepsin</gwmw> G gene (rs45567233) is associated with susceptibility to <gwmw class="ginger-module-highlighter-mistake-type-1" id="gwmw-15703449758393413330348">osteomyelitis</gwmw> in a Spanish population.

PONE-D-19-18899R1

Dear Dr. Asensi,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.

Shortly after the formal acceptance letter is sent, an invoice for payment will follow. To ensure an efficient production and billing process, please log <gwmw class="ginger-module-highlighter-mistake-type-1" id="gwmw-15703449930245554470188">into</gwmw> Editorial Manager at https://www.editorialmanager.com/pone/, click the "Update My Information" link at the top of the page, and update your user information. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

With kind regards,

Manal S. <gwmw class="ginger-module-highlighter-mistake-type-1" id="gwmw-15703450150231143822811">Fawzy</gwmw>, Ph.D., M.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

The authors have adequately addressed the concerns raised by the editor and the reviewers. Thank you

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

**********

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

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

Reviewer #2: Yes

**********

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

Reviewer #2: Yes

**********

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

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited <gwmw class="ginger-module-highlighter-mistake-type-3" id="gwmw-15703450284479521618669">to</gwmw> a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e<gwmw class="ginger-module-highlighter-mistake-type-3" id="gwmw-15703450313334784379329">.</gwmw>g. <gwmw class="ginger-module-highlighter-mistake-type-1" id="gwmw-15703450319090844961165">participant</gwmw> privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in <gwmw class="ginger-module-highlighter-mistake-type-3" id="gwmw-15703450342040199955324">submitted</gwmw> articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. <gwmw class="ginger-module-highlighter-mistake-type-3" id="gwmw-15703450378082981490053">(</gwmw>Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: All my comments were adequately addressed. I have no further comments on this manuscript and I recommend it for publication.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain <gwmw class="ginger-module-highlighter-mistake-type-3" id="gwmw-15703450417888275426159">anonymous but</gwmw> your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

<gdiv></gdiv>