PONE-D-24-34897Protocol the Evolution of CROSSWORD Study: Implementing an interoperable web-based platform to support health surveillance against latent tuberculosis infection in health care workers and students to define prevention strategies and interventionsPLOS ONE

Dear Dr. Inchingolo,

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.

==============================

ACADEMIC EDITOR:

Dear Authors, 

  the manuscript is interesting, but it needs some changes. Both reviewers suggested some changes to be made that I think are appropriate. Finally, I suggest providing more details in the sample size section, describing how the percentages were identified, and the sample size formula used.

Best regards,

Nicola, Serra

==============================

Please submit your revised manuscript by Nov 13 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're 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.

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). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols .

We look forward to receiving your revised manuscript.

Kind regards,

Nicola Serra

Academic Editor

PLOS ONE

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2. We note that you have selected “Clinical Trial” as your article type. PLOS ONE requires that all clinical trials are registered in an appropriate registry (the WHO list of approved registries is at      https://www.who.int/clinical-trials-registry-platform/network/primary-registries" https://www.who.int/clinical-trials-registry-platform/network/primary-registries and more information on trial registration is at http://www.icmje.org/about-icmje/faqs/clinical-trials-registration/ ).  

Please state the name of the registry and the registration number (e.g. ISRCTN or ClinicalTrials.gov) in the submission data and on the title page of your manuscript.

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“This research was co-funded by the Italian Complementary National Plan PNC-I.1 "Research initiatives for innovative technologies and pathways in the health and welfare sector” D.D. 931 of 06/06/2022, "DARE - DigitAl lifelong pRevEntion" initiative, code PNC0000002.”

Please state what role the funders took in the study.  If the funders had no role, please state: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."

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We will update your Data Availability statement on your behalf to reflect the information you provide.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

Reviewer #2: Yes

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2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Yes

Reviewer #2: Partly

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3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #1: No

Reviewer #2: Yes

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4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. The data should be provided as part of the manuscript or its supporting information, or deposited to 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.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: No

**********

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 submitted 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 #1: Yes

Reviewer #2: No

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The protocol titled "Protocol the Evolution of CROSSWORD Study: Implementing an interoperable web-based platform to support health surveillance against latent tuberculosis infection in healthcare workers and students to define prevention strategies and interventions" is well-structured and addresses a crucial area in tuberculosis (TB) prevention. This study has the potential to make a significant impact on the development of TB preventive strategies in low-TB-burden countries, especially for healthcare workers (HCWs) and students. However, some aspects need clarification and further elaboration:

1. Methods for LTBI Detection Tests:

o The manuscript did not clearly define the methods for latent tuberculosis infection (LTBI) detection tests. Both Interferon-Gamma Release Assay (IGRA) and Tuberculin Skin Test (TST) were mentioned in determining the primary endpoint. It is essential to specify whether the IGRA or TST will be used. Since the study involves the conversion of TST, multiple tests are assumed to be done. Information on how often follow-up testing will occur is needed to provide a comprehensive understanding of the testing process.

2. Interaction with the Developed Web-Based Framework:

o The article mentions the development of a web-based interactive platform but does not elaborate on how this framework will engage in the prediction and detection of LTBI. It would be helpful to describe how the platform will interact with collected data, monitor participants, or offer decision support for LTBI prediction.

3. Rationale for the Estimated Prevalence:

o The protocol estimates an LTBI prevalence of 1% in the participating institutes. However, the rationale behind this estimate is not sufficiently explained. Is it derived from the ongoing CROSSWORD study? Clarifying how this estimate was derived, considering factors such as the previous prevalence rates in similar settings or literature, would strengthen the study's methodology.

4. Consideration of Changes in Participants’ Roles Over Time:

o Since the study involves a potentially prolonged follow-up period, there is a high likelihood that participants’ roles and exposure risks may change (e.g., from students to practicing HCWs). This factor should be taken into account when identifying risk factors and analyzing LTBI risk. Clarifying how these changes will be tracked and integrated into the analysis is crucial for ensuring accurate risk assessment.

Overall Recommendations:

• The study protocol is valuable and has the potential to contribute significantly to TB prevention efforts. Addressing these points will enhance the clarity and comprehensiveness of the study. The authors are encouraged to provide detailed explanations regarding the LTBI detection protocols, web-based framework interaction, rationale for prevalence estimation, and adjustments for role changes during the study follow-up.

Reviewer #2: The authors describe the protocol of a longitudinal study (retrospective and prospective), aimed at providing a large amount of data on the incidence and prevalence of latent tuberculosis infection, on the incidence of tuberculosis and on the results of screening tests among health workers and students enrolled in 3 university hospitals in Central and Southern Italy. The objective would be achieved through the digital registration of some selected variables reported in a self-administered questionnaire. The objective is ambitious and the study protocol could validly contribute to scientific progress on a pathology present throughout the world, slightly increasing after the pandemic and with a significant socioeconomic burden even in low-incidence countries, such as Italy. Moreover, university students, an undestudied population strata, are included.

However, I think that the submitted description of the protocol should be enriched with details and few methodological aspects should be further clarify. I recommend substantial revisions that take into account the considerations reported below.

First of all, it's necessary to know how many employees and students are in the 3 hospitals considered, this to have information on the feasibility of reaching the sample size in the expected period. It might be useful to know how many people are divided into different age groups, how many students, whether only medical courses or other types of courses, such as engineering, are included, how many men and how many women. It might also be useful to know what is the incidence of tuberculosis in the reference population of the 3 hospitals considered and what is the estimated incidence of active or latent tuberculosis in previous periods among the healthcare workers and students. As regards the feasibility, add information on the progress of the Crossword study, which represents the retrospective phase of the study protocol. Moreover, it's necessary to provide more details on which aspects of the Periskope-TB study were captured in the described protocol, to better support the choice of selected variables.

The DARE project is mentioned but its contribution to this protocol is unclear. More information on the Dare study (blibliographic citation, if available) could clarify how the predictive algorithms adopted in this protocol were digitized and created.

It's necessary to stratify the sample size calculation by workers and students, sex and age groups, considering that the enrolled population includes workers and students probably in a wide age range.

Since workers and students are subjected to annual health surveillance, it is not clear whether they will answer only once or multiple times (and how many?) to the proposed questionnaire.

Authors should consider adding to the exclusion criteria, having had tuberculosis or having already undergone chemoprophylaxis .

About the primary outcomes, consider to add a symptom questionnaire. It should also be clarified how to consider the possible movement between working units.

Among the secondary outcomes, it would be better to add a definition of exposure to TB-infected patients, to avoid different descriptions

I would like the authors to explain the reasons why they collect health information through a self-administered questionnaire and not through medical records, which would avoid recall bias and inaccuracies. For question 4 I would put an indicative time (1 month or 3 months of stay).

Consider to add a table or a figure to list the recorded variables . Line 243: it's not clear if the items listed will be recorded.

Furthermore, authors should reread the text to make the English grammar more fluent. Few typos should be corrected: uniform the acronym TB or TBC, replace the word tuberculosis with the somewhat long acronym in the text; add title and description of figure 2 and 3.

I would encourage the authors to consider making the dataset public, possibly removing variables that could identify the respondent (e.g. department, course of study, etc.).

Authors should check bibliography according to the journal's instructions, in particular citations 1, 5, 6, 7, 9, 19, 20.

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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 anonymous but 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 attachment files.]

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PONE-D-24-34897R1Protocol the Evolution of CROSSWORD Study: Implementing an interoperable web-based platform to support health surveillance against latent tuberculosis infection in health care workers and students to define prevention strategies and interventionsPLOS ONE

Dear Dr. Inchingolo,

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.

==============================Dear Authors, your manuscript has been greatly improved and both reviewers agree on minor revisions. Please submit the revision by the deadline and also provide a general check of the English language. Best regards==============================

Please submit your revised manuscript by Feb 19 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're 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.

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). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols .

We look forward to receiving your revised manuscript.

Kind regards,

Nicola Serra

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

Reviewer #3: Yes

**********

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Yes

Reviewer #3: Yes

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #1: No

Reviewer #3: Yes

**********

4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. The data should be provided as part of the manuscript or its supporting information, or deposited to 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.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #3: 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 submitted 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 #1: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: 1. The author described the primary outcome as prevalence of LTBI. The LTBI was defined as positive TST plus positive QuantiFERON for participants with a baseline negative TST. Will participants with a baseline positive TST be excluded from the cohort? Base one such definition, the primary outcome seems to be the incidence of TB infection instead of prevalence of TB infection.

2. How many TST tests will be done for each participant? When will a follow-up TST test be done for a participant?

Reviewer #3: Management of latent tuberculosis infection (LTBI) is a key component of any TB elimination strategy, as people with LTBI represent a large "human reservoir" for the disease. In these purposes the European Centre for Disease Prevention and Control (ECDC), provides evidence-based guidance for the implementation of public health programmes for the management of LTBI in the European Union (EU) and the European Economic Area (EEA), which includes, beyond the prevalence of the LBT, the identification of risk groups. In this context, the present article fits well.

The authors made most of the changes requested by the reviewer 2; in the references the 7 must be corrected.

In addition, if possible, choose for pubblication a title more impactful, which is currently too long.

**********

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 anonymous but 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 #3: 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 attachment files.]

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 PLOS at figures@plos.org . Please note that Supporting Information files do not need this step.

PONE-D-24-34897R2An interoperable web-based platform to support health surveillance against latent tuberculosis infection in health care workers and students: the Evolution of CROSSWORD Study ProtocolPLOS ONE

Dear Dr. Inchingolo,

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.

==============================

ACADEMIC EDITOR:  Dear Authors,Please consider an important final suggestion from Reviewer 1 regarding the timing of the QuantiFERON-TB Gold (QFT) test. Best regards, Nicola Serra

==============================

Please submit your revised manuscript by Mar 14 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're 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.

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). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols .

We look forward to receiving your revised manuscript.

Kind regards,

Nicola Serra

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

Reviewer #3: Yes

**********

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Yes

Reviewer #3: Partly

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #1: Yes

Reviewer #3: Yes

**********

4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. The data should be provided as part of the manuscript or its supporting information, or deposited to 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.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #3: 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 submitted 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 #1: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The author addressed my concern. One minor suggestion:

I appreciate the comprehensive definition of LTBI used in the study; however, I would like to suggest a minor revision regarding the timing of the QuantiFERON-TB Gold (QFT) test. The current definition requires the QFT test to be performed on the same day as the positive TST result. In clinical practice, logistical challenges such as laboratory processing delays, sample collection issues, or the need for repeat blood draws may prevent same-day testing. This strict requirement could lead to unnecessary exclusions due to protocol deviations, even in cases where the QFT result is positive within a reasonable timeframe. To improve the feasibility of the study without compromising diagnostic accuracy, I recommend allowing a reasonable time window for QFT testing rather than requiring it strictly on the same day. This adjustment would better align with real-world clinical workflows and help avoid potential difficulties in data interpretation and patient classification.

Reviewer #3: The authors made the changes required and now I belive that the articol can be accepted.

**********

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 anonymous but 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 #3: 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 attachment files.]

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 PLOS at figures@plos.org . Please note that Supporting Information files do not need this step.

An interoperable web-based platform to support health surveillance against latent tuberculosis infection in health care workers and students: the Evolution of CROSSWORD Study Protocol

PONE-D-24-34897R3

Dear Dr. Inchingolo,

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

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Nicola Serra

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Dear Authors,

Congratulations for the great work done. Your article is now ready for publication

Best regards.

Nicola Serra

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

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2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Yes

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3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #1: Yes

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4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. The data should be provided as part of the manuscript or its supporting information, or deposited to 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.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

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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 submitted 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 #1: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Thanks to the authors for the revision. I have no further comments. I recommend accept the paper as current version.

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Reviewer #1: No

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