The association between BCG treatment in patients with bladder cancer and subsequent risk of developing Alzheimer and other dementia.—A Swedish nationwide cohort study from 1997 to 2019

Eugen Wang; Oskar Hagberg; Per-Uno Malmström

doi:10.1371/journal.pone.0292174

Peer Review History

Original SubmissionFebruary 21, 2023
8 May 2023 Decision Letter - Robert Jeenchen Chen, Editor Transfer Alert This paper was transferred from another journal. As a result, its full editorial history (including decision letters, peer reviews and author responses) may not be present. PONE-D-23-05113The association between BCG treatment in patients with bladder cancer and subsequent risk of developing Alzheimer and other dementia.PLOS ONE Dear Dr. Wang, 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. Please submit your revised manuscript by Jun 22 2023 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, Robert Jeenchen Chen, MD, MPH 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 https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf 2. We note that the grant information you provided in the ‘Funding Information’ and ‘Financial Disclosure’ sections do not match. When you resubmit, please ensure that you provide the correct grant numbers for the awards you received for your study in the ‘Funding Information’ section. 3. Thank you for stating the following financial disclosure: "This study was funded by Center for Clinical Research, Sörmland, Uppsala University and Schmekel funder for Urological research." 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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Upon re-submitting your revised manuscript, please upload your study’s minimal underlying data set as either Supporting Information files or to a stable, public repository and include the relevant URLs, DOIs, or accession numbers within your revised cover letter. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. Any potentially identifying patient information must be fully anonymized. Important: If there are ethical or legal restrictions to sharing your data publicly, please explain these restrictions in detail. Please see our guidelines for more information on what we consider unacceptable restrictions to publicly sharing data: http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. Note that it is not acceptable for the authors to be the sole named individuals responsible for ensuring data access. We will update your Data Availability statement to reflect the information you provide in your cover letter. 5. We note that you have stated that you will provide repository information for your data at acceptance. Should your manuscript be accepted for publication, we will hold it until you provide the relevant accession numbers or DOIs necessary to access your data. If you wish to make changes to your Data Availability statement, please describe these changes in your cover letter and we will update your Data Availability statement to reflect the information you provide. 6. Please amend either the title on the online submission form (via Edit Submission) or the title in the manuscript so that they are identical. 7. Please upload a copy of Supporting Information Table S1 which you refer to in your text on pages 13 and 21. Additional Editor Comments: Please revise. [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: Yes 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 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 ****** 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 ****** 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: Dear Editor The authors compared Alzheimer and other dementia development among 39,934 bladder patients, 6,496 of them received BCG and control patients. They found that BCG lowers the risk of developing dementia significantly but marginally. The manuscript is well written but there are drawbacks that should be acknowledged. Comments: 1. Median follow-up was 4.6 years, as compared to 8 years in a previous study (ref#7). Since the median patient’s age was 72 years in this study, there was probably not enough time to develop dementia and to make the difference apparent (median age at diagnosis of Alzheimer’s diseases in ref#7 was 84 years). The authors may study a subgroup of their patients in which follow-up is longer. 2. 6.1% of the study group developed dementia but only 1.5% Alzheimer’s disease. Alzheimer’s disease is responsible for 60-70% of all dementia cases. How can this be explained? 3. Page 15, second paragraph, third line should be ref#7. Reviewer #2: In their manuscript PONE-D-23-05113, the authors studied the potential effect of BCG instillations and the risk of later developing AD or dementia in a Swedish population-based prospective cohort of patients with non-muscle invasive bladder cancer (NMIBC). The manuscript is organized, well written, and may be suitable for publication. Although this work is very interesting, please see below my comments and questions: 1- Please provide a list of abbreviations, because some abbreviations are mentioned without their full names. 2- It has been shown that adult vaccination against several infections has reduced the risk of developing Alzheimer (AD); how is the difference in BCG vaccine instillations in patients with NMIBC? 3- Accumulating data argue for the beneficial role of BCG to reduce the risk for developing AD. BCG vaccines are manufactured under different conditions across the globe generating divergent formulations, contributing to differences in the ability of these diverse formulations to induce specific and heterologous protection. Could this strains variation explain your results and conclusions that the BCG treatment is not associated with a significant decreased risk of developing Alzheimer but a marginally lower risk for all dementia diseases? 4- In the perspective of this study would it be possible to evaluate if there is any difference in doses exposure to BCG and risk of developing AD or Dementia? ****** 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 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.] 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. https://doi.org/10.1371/journal.pone.0292174.r001
Revision 1
28 Jun 2023 Author Response Here is a point-by-point response to the reviewers’ comments and concerns. Reviewers comments and concerns our responses and changes Editor General comments 1. Please ensure that your manuscript meets PLOS ONE's style requirements OK 2. We note that the grant information you provided in the ‘Funding Information’ and ‘Financial Disclosure’ sections do not match. OK, we will mention our financial disclosures as following: "This study was funded by Center for Clinical Research, Sörmland, Uppsala University and Schmekel funder for Urological research." 3. Thank you for stating the following financial disclosure: "This study was funded by Center for Clinical Research, Sörmland, Uppsala University and Schmekel funder for Urological research." 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." If this statement is not correct you must amend it as needed. Please include this amended Role of Funder statement in your cover letter; The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript 4. In your Data Availability statement, you have not specified where the minimal data set underlying the results described in your manuscript can be found. PLOS defines a study's minimal data set as the underlying data used to reach the conclusions drawn in the manuscript and any additional data required to replicate the reported study findings in their entirety. All PLOS journals require that the minimal data set be made fully available. For more information about our data policy, please see 5. We note that you have stated that you will provide repository information for your data at acceptance. Should your manuscript be accepted for publication, we will hold it until you provide the relevant accession numbers or DOIs necessary to access your data. If you wish to make changes to your Data Availability statement, please describe these changes in your cover letter and we will update your Data Availability statement to reflect the information you provide. Data used in the present study was extracted from the research database BladderBaSe, which is based on the Swedish National Registry of Urinary Bladder Cancer (SNRUBC) and linkage to several national health-data registers. The data cannot be shared publicly because the individual-level data contain potentially identifying and sensitive patient information and cannot be published due to legislation and ethical review restrictions (https://etikprovningsmyndigheten.se). Use of the data from national health-data registers is further restricted by the Swedish Board of Health and Welfare (https://www.socialstyrelsen.se/en/) and Statistics Sweden (https://www.scb.se/en/) which are Government Agencies providing access to the linked healthcare registers. The data in in BladderBaSe is partly available in annual reports from the Swedish National Registry of Urinary Bladder Cancer (SNRUBC) and are also accessible online at https://statistik.incanet.se/urinblasecancer/. Researchers can propose and apply for data and studies in BladderBaSe or SNRUBC using a standardized form. After approved application, the project data administrators can upload study-specific files with selected variables to a server for statistical analysis through remote access. De-identified data can be available to researchers after application to the BladderBaSe Steering Committee. 6. Please amend either the title on the online submission form (via Edit Submission) or the title in the manuscript so that they are identical. OK 7. Please upload a copy of Supporting Information Table S1 which you refer to in your text on pages 13 and 21. OK Additional Editor Comments: Reviewer #1: 1. Median follow-up was 4.6 years, as compared to 8 years in a previous study (ref#7). Since the median patient’s age was 72 years in this study, there was probably not enough time to develop dementia and to make the difference apparent (median age at diagnosis of Alzheimer’s diseases in ref#7 was 84 years). The authors may study a subgroup of their patients in which follow-up is longer. It is correct that we had a shorter follow-up but the mean age was three years more in our study group. To analyse if the shorter follow-up had an impact we established one subgroup who were 85 years or older at follow-up. As far as we can see, our conclusions will not be changed even in this subgroup. This information is now added in the results. 2. 6.1% of the study group developed dementia but only 1.5% Alzheimer’s disease. Alzheimer’s disease is responsible for 60-70% of all dementia cases. How can this be explained? Our data from register was like as we presented, which may be because doctors (especially general practitioners from Health center) did not give detail diagnosis with Alzheimers, but only generally diagnosis with dementia. In discussion, we mentioned: The diagnosis in Sweden is often made by the GP ( general practitioners) and misclassification between dementia subtypes is quite common according to a validation study of the Swedish registry. 3. Page 15, second paragraph, third line should be ref#7. Ok Reviewer #2: 1- Please provide a list of abbreviations, because some abbreviations are mentioned without their full names. List of abbreviations: AD – Alzheimer´s disease BCG - Bacillus Calmette-Guerin BladderBaSe - Bladder Cancer Data Base Sweden CI – confidence interval G1/LMP: Bladder cancer Grade 1 or Low Malignant Potential GP - general practitioner HR – hazard ratio ICD – International classification of diseases NMIBC - non-muscle invasive bladder cancer Q1-Q3; Inter quartile range, the range between the first quartile (Q1) and the third (Q3) SNRUBC – Swedish national register of urinary bladder cancer 2- It has been shown that adult vaccination against several infections has reduced the risk of developing Alzheimer (AD); how is the difference in BCG vaccine instillations in patients with NMIBC? We do not fully understand this question but it is clear that BCG bladder instillations leads to a systemic immune response with for example fever in some patients and getting a positive PPD skin test. 3- Accumulating data argue for the beneficial role of BCG to reduce the risk for developing AD. BCG vaccines are manufactured under different conditions across the globe generating divergent formulations, contributing to differences in the ability of these diverse formulations to induce specific and heterologous protection. Could this strains variation explain your results and conclusions that the BCG treatment is not associated with a significant decreased risk of developing Alzheimer but a marginally lower risk for all dementia diseases? Yes, using different BCG strains could be one of many factors to influence our results, which we will mention in our discussion. 4- In the perspective of this study would it be possible to evaluate if there is any difference in doses exposure to BCG and risk of developing AD or Dementia? In discussion we wrote that one limitation was that dose and duration of the treatment, was data we did not have available. 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. OK. Attachments Attachment Submitted filename: A rebuttal letter to PLOS ONE.docx https://doi.org/10.1371/journal.pone.0292174.r002
24 Jul 2023 Decision Letter - Robert Jeenchen Chen, Editor PONE-D-23-05113R1The association between BCG treatment in patients with bladder cancer and subsequent risk of developing Alzheimer and other dementia. - A Swedish nationwide cohort study from 1997 to 2019.PLOS ONE Dear Dr. Wang, 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. Please revise. Please submit your revised manuscript by Sep 07 2023 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, Robert Jeenchen Chen, MD, MPH 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. 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: 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 #1: No Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes 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 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 ****** 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: 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. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: Dear Editor Thank you for your letter and for the response of the authors. Previous studies with long follow-up showed significant decrease in the risk of Alzheimer's disease in BCG treated patients. The current study with a short follow-up found only a marginal decrease. One may figure that with longer follow-up the marginal benefit will be more pronounced. The explanation why only 1.5% patient were diagnosed with Alzheimer's disease (out of 6.1% patients with dementia), due to the poor capacity of the doctors, cast shadow on all their diagnoses. Reviewer #2: In the present revised manuscript PONE-D-23-05113R1, the authors have addressed answers to questions and they have incorporate changes to reflect most of the suggestions. Their article may be suitable for publication in the PLOS journal. ****** 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.] 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. https://doi.org/10.1371/journal.pone.0292174.r003
Revision 2
1 Aug 2023 Author Response Following is our answer for comment from reviewer 1: Reviewers comments and concerns: Previous studies with long follow-up showed significant decrease in the risk of Alzheimer's disease in BCG treated patients. The current study with a short follow-up found only a marginal decrease. One may figure that with longer follow-up the marginal benefit will be more pronounced. Our answer: The median follow-up was 8 years in one study (ref 7) and about 3 years in the other previous studies (ref 5 and 6) compared to 4.6 years in our study. Both these later studies showed a substantial decrease in risk as opposed to our marginal decrease despite similar follow-up length. To further address the reviewers concern regarding the follow-up time we conducted a subgroup analysis with subjects followed until using the number of years from year of diagnosis to 2019. If this number plus the age of the patient is at least 85, the patients are kept in the analysis. I.e., only patients who could be under risk at age 85 or older are kept in the analysis. Then 12798 patients with a mean age of 79.8 at diagnosis remain with a median follow-up time of about 5 years. The HR was then 0.87 and 0.81 for AD and dementia respectively. This was in the same range as for the whole study group (0.89 and 0.88) with shorter follow up. As more details to explain this point, we will add one more table (Table S2) in support information. Reviewers comments and concerns: The explanation why only 1.5% patient were diagnosed with Alzheimer's disease (out of 6.1% patients with dementia), due to the poor capacity of the doctors, cast shadow on all their diagnoses. Our Answer: The first referred study (ref 5) presented results separately for AD and other dementia. The AD represented 24% of all dementias as opposed to 25 % in our study. The second referred study (ref 6) reported 6 % with AD as sole diagnosis and 36 % with AD coupled to other types of dementia. The third study (ref 7) did not analyse other dementia than AD. Reviewer 2 had no comments. Attachments Attachment Submitted filename: rebuttal letter to PLOS ONE (2) (002).docx https://doi.org/10.1371/journal.pone.0292174.r004
30 Aug 2023 Decision Letter - Robert Jeenchen Chen, Editor PONE-D-23-05113R2The association between BCG treatment in patients with bladder cancer and subsequent risk of developing Alzheimer and other dementia.- A Swedish nationwide cohort study from 1997 to 2019.PLOS ONE Dear Dr. Wang, 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. Please revise. Please submit your revised manuscript by Oct 14 2023 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, Robert Jeenchen Chen, MD, MPH 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. 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: 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 #1: Yes Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes 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 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 ****** 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: 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. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: None. Congratulations to the authors. They answered all the questions. Hope the production will be adequate to Reviewer #2: The reviewed manuscript entitled " The association between BCG treatment in patients with bladder cancer and subsequent risk of developing Alzheimer and other dementia.- A Swedish nationwide cohort study from 1997 to 2019",referenced under the number PONE-D-23-05113-R2, has been improved after implementing the reviewer’s suggestions, and may be acceptable for publication. Thank you for accurate response to suggestions. Minor remarks: The paper should be reviewed by an English native speaker. For example, the following sentences may need to be rewritten to avoid any ambiguity: -Results, Risk factors: “To further analyse age at follow-up had an impact we established…” - Discussion: the sentence starting by « One may argue that patients are to young to develop…” ****** 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.] 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. https://doi.org/10.1371/journal.pone.0292174.r005
Revision 3
2 Sep 2023 Author Response The paper has been now reviewed by an English native speaker, who made changes to a text without altering its meaning, according to the recommendation from reviewer #2. Attachments Attachment Submitted filename: A rebuttal letter to PLOS ONE (3).docx https://doi.org/10.1371/journal.pone.0292174.r006
14 Sep 2023 Decision Letter - Robert Jeenchen Chen, Editor The association between BCG treatment in patients with bladder cancer and subsequent risk of developing Alzheimer and other dementia.- A Swedish nationwide cohort study from 1997 to 2019. PONE-D-23-05113R3 Dear Dr. Wang, 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. An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. 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 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, Robert Jeenchen Chen, MD, MPH Academic Editor PLOS ONE Additional Editor Comments (optional): If possible, please revise the Title to make it more concise whereas informative. 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: 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 #1: Yes Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes 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 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 ****** 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: 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. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: The only issue left was the linguistic review which has been addressed. I hope that the manuscript will provide an important perspective to the growing interest in the association between the immune system and Alzheimer's disease. Reviewer #2: The reviewed manuscript referenced under the number PONE-D-23-05113-R3, has been improved after implementing the reviewer’s suggestions, and may be acceptable for publication. Thank you for accurate response to suggestions. ****** 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 ******** https://doi.org/10.1371/journal.pone.0292174.r007
Formally Accepted
6 Dec 2023 Acceptance Letter - Robert Jeenchen Chen, Editor PONE-D-23-05113R3 The association between BCG treatment in patients with bladder cancer and subsequent risk of developing Alzheimer and other dementia. - A Swedish nationwide cohort study from 1997 to 2019. Dear Dr. Wang: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. 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. If we can help with anything else, please email us at customercare@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Robert Jeenchen Chen Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0292174.r008

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