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PONE-D-23-19885The association of Cobalturia with Cobaltism Symptoms

A prospective blinded study of 229 post-arthroplasty patientsPLOS ONE

Dear Dr. Tower,

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.

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Academic Editor

PLOS ONE

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2. Please amend your manuscript to include your abstract after the title page.

Additional Editor Comments:

Please perform all revisions required.

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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: Yes

Reviewer #2: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

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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 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 #2: Yes

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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 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: Yes

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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 paper need major revisions. Perform all the suggestions:

Here are some more detailed suggestions for improving each section:

Introduction:

- Provide 2-3 sentences explaining cobaltism - a clinical syndrome caused by cobalt exposure leading to neurological, cardiovascular, and other manifestations. cite PMID: 21066926.

- line 48, among differential diagnose other causes should be discussed leading to cognitive impairment, fatigue, sleepiness as obstructive apnea. Please cite doi:10.1007/s11325-021-02520-y

- Note that cobalt release from joint implants is a major cause today. Briefly explain mechanisms - corrosion, wear, release into blood/urine.

- State that relationship between symptoms, urine cobalt levels, and exposure time is not well studied.

Methods:

- In developing symptom questionnaire, describe process for choosing domains, consulting existing questionnaires, pilot testing questions.

- For urine cobalt testing, explain choice of 1 ppb cutoff based on prior studies showing associations with clinical effects at this level.

- Describe all statistical tests used - correlations, comparisons between groups, ROC analysis.

Results:

- Report demographics of cohort - age, gender, implant types.

- Present urine cobalt levels summary statistics before analyzing by cobaltism symptoms.

- Use tables/figures to clearly show symptom scores for each domain by cobalturic vs non-cobalturic groups.

Discussion:

- Note limitations including single-center cohort, selection bias, lack of universal cobaltism criteria.

- Compare associations found to prior studies linking urine cobalt to clinical effects.

- line 175, alternative causes of vertigo should be discussed as drugs or viral infections. please Cite doi: 10.1177/0960327111414280 and doi:10.3389/fmed.2021.790931

- Discuss need for multi-center studies to validate questionnaire, urine thresholds.

- Suggest future research on treatment effects tied to urine cobalt reductions.

- Avoid overstating the conclusions - cohort limitations preclude definitive conclusions.

Reviewer #2: I read with interest the manuscript by Tower et al. The paper is original and sound. However, there are some issues that need o be addressed with a revision:

- I could not find the abstract anywhere in the manuscript. Please provide it.

- Line 50-51. Authors should also cite hearing loss and delirium as possible adjunct misdiagnosis of cobaltism (doi: 10.1177/0960327111414280 - doi: 10.3390/jcm12020435). Please briefly discuss and add these 2 references.

- Line 58-64. These sentences summarize both methods and results, and should therefore be not included in the introduction section.

- Please provide ethical committee approval or waiver code and date of approval.

- How did authors retrieve data from patients with dementia? Were they excluded? Please specify.

- Please provide the main investigated outcome in the methods section.

- Lack of data on cardiovascular function of the patients enrolled should be highlighted as a further possible limitation of the study and direction of future research, as echocardiography is nowadays a feasible bedside tool to investigate systolic and diastolic function of hospitalized patients (doi: 10.2106/JBJS.16.00743- doi: 10.1007/s12630-022-02225-0 - doi: 10.1111/echo.15462). Please discuss and add these 3 references.

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Reviewer #1: No

Reviewer #2: No

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The association of Cobalturia with Cobaltism Symptoms

A prospective blinded study of 229 post-arthroplasty patients

PONE-D-23-19885R1

Dear Dr. Tower,

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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If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- 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.

Kind regards,

Antonino Maniaci

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

The paper is improved and can be accepted. Bests

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 #1: All comments have been addressed

Reviewer #2: (No Response)

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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 #1: Yes

Reviewer #2: (No Response)

**********

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

Reviewer #1: Yes

Reviewer #2: (No Response)

**********

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 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 #2: (No Response)

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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

Reviewer #2: (No Response)

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

Reviewer #1: All the suggestions required were addressed. I'm glad to hear that the revisions met our expectations. Best regards

Reviewer #2: The manuscript is well written and the authors assessed all the issues presented. I believe the paper is now ready for acceptance.

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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

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