Infectious diseases, comorbidities and outcomes in hospitalized people who inject drugs (PWID)

Jacqueline Lim; Sureka Pavalagantharajah; Chris P Verschoor; Eric Lentz; Mark Loeb; Mitchell Levine; Marek Smieja; Lawrence Mbuagbaw; Dale Kalina; Jean-Eric Tarride; Tim O’Shea; Anna Cvetkovic; Sarah van Gaalen; Aidan Reid Findlater; Robin Lennox; Carol Bassim; Cynthia Lokker; Elizabeth Alvarez

doi:10.1371/journal.pone.0266663

Peer Review History

Original SubmissionApril 5, 2021
9 Jul 2021 Decision Letter - Judith I Tsui, Editor PONE-D-21-11155 Infectious diseases, comorbidities and outcomes in hospitalized people who inject drugs (PWID) PLOS ONE Dear Dr. Alvarez, 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 Aug 23 2021 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: http://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, Judith I Tsui 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. Please include in your Methods section (or in Supplementary Information files) the participating hospitals/institutions. 3. In ethics statement in the manuscript and in the online submission form, please provide additional information about the patient records/samples used in your retrospective study. Specifically, please ensure that you have discussed whether all data/samples were fully anonymized before you accessed them and/or whether the IRB or ethics committee waived the requirement for informed consent. If patients provided informed written consent to have data/samples from their medical records used in research, please include this information. 4. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. In your revised cover letter, please address the following prompts: a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent. b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. We will update your Data Availability statement on your behalf to reflect the information you provide. [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: Partly ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: No ****** 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: No Reviewer #2: No ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in 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: Summary: This manuscript used hospital charts/records to abstract data from people who inject drugs and hospital diagnoses and outcomes. 240 individuals were included in the analysis from two hospitals in Hamilton, Ontario. One third were admitted to the ICU, 36% had surgery, 9% died and 12% left AMA. Bacteremia was the most common diagnosis. Many of those who left AMA were seen in the ER or re-admitted within 30 days. In general, the topic of health outcomes in PWID is important to try and improve hospital care. However, the paper lacks details in some areas to help conceptualize the findings. Major comments: 1. A better understanding of the hospitals included in this manuscript would be helpful—all hospitals in Hamilton? What kind of hospitals, etc. it sounds like these are urban? Those who aren’t familiar with Hamilton and/or Ontaria would benefit from a better understanding of this. 2. Could you please describe the data audit in more detail? What happened if discrepancies were found? Who conducted the audit? 3. In general, there are many areas that I would recommend adding more detail either in the body of the text or in a supplement. What criteria were used to abstract patient data including: HIV status (based on labs, meds, diagnosis codes’]?); Hep C status (labs? Treated/untreated?); comorbid conditions? Were these included if documented in a note or need ICD9/10? A line in the discussion describes missing HIV or Hep C diagnoses if they were tested during the index admission—so was this the only way these diagnoses were captured? The index admission was used but where chart records examined prior to index admission? 4. The use of two reviewers, a third as a tie-breaker, and an audit adds rigor to the study. Minor comments: 1. Could you clarify that those charts who were excluded in paragraph 1 of the results were because they didn’t mean eligibility criteria upon further inspection? 2. Substances used: is this inpatient? Or prior to admission? Hydromorphone is a prescription drug but is it being misused/abused/bought in these settings? Reviewer #2: This manuscript is a descriptive, retrospective chart review study of PWID admitted to two hospitals with infections in a Hamilton, Ontario between 2013 and 2018. The authors report demographics, diagnoses, as well as healthcare utilization for this cohort and provide stratified results by patient-initiated and death-status. While the study nicely describes PWID/ID hospital care utilization, the manuscript lacks focus and the principal conclusions that patient directed discharges and readmissions are common have been demonstrated previously in national datasets. I think the introduction and discussion could better frame the primary hypotheses and contextualize the limited analyses performed. Additionally, the authors frame the manuscript as an initial baseline study to address longer term trajectories and improve care for PWID but do not describe any addiction interventions or withdrawal management approaches in the hospital which is essential and could be one of the strengths of retrospective chart review study like this (similar studies using publicly available databases lack detailed inpatient medication administration records or other interventions). Overall, the authors have done considerable work to gather this data yet lacks key information and requires additional focus. Below are several additional suggestions to strengthen the manuscript. Major comments: 1. Abstract: “little is known about outcomes” – The manuscript would be better framed with more specific identification of the gap and the goals. Which outcomes? There’s a fairly robust literature on outcomes related to specific infectious diseases (HIV, HCV, endocarditis) though less about this larger collection of diagnoses. 2. Intro: Little is known about “health trajectory of this population.” I would define this term as it is important theoretically to the framing (over what time period, what outcomes). 3. Intro: P 4, line 85: The authors argue that by including all infections among PWID together this manuscript fills a gap in the literature. Each of these infections has distinct presentations and clinical courses, I think the manuscript would be stronger with a theoretical argument about why it is crucial to group these infections together. 4. P5 line 98: “This project will set the stage to further study healthcare trajectories of PWID with infections.” I’m not clear where this is going or what this means. I would suggest using this space in the manuscript instead to set up the analyses you are doing in this paper. 5. P5 Line 99: “The overall aim…” – I would delete or make this sentence much more focused. Based on the analyses later in the manuscript, it seems the goal of this manuscript is to understand characteristics of people who do and do not have patient initiated discharges but the introduction doesn’t really set this up. 6. P5, Line 107 --- This is pretty well documented in the literature in addition to clinical experience. 7. Methods: I would encourage the authors to describe a bit more about how injection drug use in the last 6 months determined/verified. 8. If patient-initiated discharges are indeed the focus of this paper, it would be valuable to report on medication for opioid use disorder provision in the hospital and/or withdrawal management strategy which has been shown to be linked with discharge. The authors report on medication for opioid use disorder provision prior to the hospitalization but not how the hospital approaches addiction treatment. 9. Additional analyses to consider: do people with serious deeper infections leave later in the hospitalization than people with less serious infections (cellulitis, abscesses vs endocarditis, bacteremia, etc). 10. Are the comorbidities baseline or identified during the hospitalization? 11. Page 17 Line 293-94 – would move sentence about HIV/HCV diagnosis to the limitations section. 12. It is interesting that 55% of the population was injected unspecified opioids or hydromorphone. Can the authors provide additional information about the local context? 13. Limitations: This is descriptive data with bivariate analyses and does not adjust for co-variates. The authors could consider a basic, simple logistic regression model looking at factors associated with patient initiated discharge or mortality, but will be limited in the number of covariates that can be included. Regardless, the limitations section should acknowledge the limitations of this kind of analysis. ****** 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.0266663.r001
Revision 1
7 Oct 2021 Author Response 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 Response: Thank you for outlining formatting requirements. We have reviewed the samples provided. Our title page and main manuscript have been revised to ensure compliance with formatting requirements as noted in the templates provided above. 2. Please include in your Methods section (or in Supplementary Information files) the participating hospitals/institutions. Response: Thank you. As Reviewer #1 indicated the same suggestion, our methods section has been expanded to include a brief description of the two participating hospitals. 3. In ethics statement in the manuscript and in the online submission form, please provide additional information about the patient records/samples used in your retrospective study. Specifically, please ensure that you have discussed whether all data/samples were fully anonymized before you accessed them and/or whether the IRB or ethics committee waived the requirement for informed consent. If patients provided informed written consent to have data/samples from their medical records used in research, please include this information. Response: Thank you for outlining these instructions. We have elaborated on the patient records used under our Methods section in our manuscript. We also specified that we used patient names and insurance numbers to prevent duplicate data entries. We anonymized the data set prior to statistical analyses. 4. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. In your revised cover letter, please address the following prompts: a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent. b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. We will update your Data Availability statement on your behalf to reflect the information you provide. Response: Thank you for outlining these instructions. The team has agreed that we wish to preserve patient privacy where possible, as our data contains potentially identifying information (such as hospital sites and diagnoses) and considering the sensitivity and stigma surrounding injection drug use. Our protocol was approved by the Hamilton integrated Research Ethics Board. We have briefly summarized these sentiments and included contact information for the ethics board in our cover letter. Comments to the Author Reviewer #1: Summary: This manuscript used hospital charts/records to abstract data from people who inject drugs and hospital diagnoses and outcomes. 240 individuals were included in the analysis from two hospitals in Hamilton, Ontario. One third were admitted to the ICU, 36% had surgery, 9% died and 12% left AMA. Bacteremia was the most common diagnosis. Many of those who left AMA were seen in the ER or re-admitted within 30 days. In general, the topic of health outcomes in PWID is important to try and improve hospital care. However, the paper lacks details in some areas to help conceptualize the findings. Response: Thank you for taking the time to review our manuscript, we appreciate your consideration and thoughtful feedback. We have addressed each comment to ensure our paper includes the details as suggested. Major comments: 1. A better understanding of the hospitals included in this manuscript would be helpful—all hospitals in Hamilton? What kind of hospitals, etc. it sounds like these are urban? Those who aren’t familiar with Hamilton and/or Ontaria would benefit from a better understanding of this. Response: Thank you for this suggestion, we agree that further detail on the participating hospitals would benefit readers outside of Ontario. We have therefore listed the participating hospitals and included a brief description of them in our methods section. 2. Could you please describe the data audit in more detail? What happened if discrepancies were found? Who conducted the audit? Response: Thank you for your comment, we see that more explanation of the audit process is warranted to fully capture our team’s commitment to accuracy in data collection. A more thorough explanation of the data audit has been added to the methods section accordingly. 3. In general, there are many areas that I would recommend adding more detail either in the body of the text or in a supplement. What criteria were used to abstract patient data including: HIV status (based on labs, meds, diagnosis codes’]?); Hep C status (labs? Treated/untreated?); comorbid conditions? Were these included if documented in a note or need ICD9/10? A line in the discussion describes missing HIV or Hep C diagnoses if they were tested during the index admission—so was this the only way these diagnoses were captured? The index admission was used but where chart records examined prior to index admission? Response: Thank you for your suggestion, we agree that the additional detail to our data extraction and collection process is needed, as the criteria for abstraction was not clear. We have elaborated upon this step in our methods section to indicate how and where data was extracted from in Meditech. 4. The use of two reviewers, a third as a tie-breaker, and an audit adds rigor to the study. Response: Thank you, we appreciate this feedback. We have further expanded on our data audit process to ensure this rigor. Minor comments: 1. Could you clarify that those charts who were excluded in paragraph 1 of the results were because they didn’t mean eligibility criteria upon further inspection? Response: Thank you for suggesting this clarification, we agree this suggestion will improve the cohesiveness of our paper. We have thus restated our exclusion criteria in the first paragraph of the results section. 2. Substances used: is this inpatient? Or prior to admission? Hydromorphone is a prescription drug but is it being misused/abused/bought in these settings? Response: Thank you for your comment, we agree this was unclear in our original submission. We have included a more detailed explanation of how information regarding used substances was obtained from the charts. Reviewer #2: This manuscript is a descriptive, retrospective chart review study of PWID admitted to two hospitals with infections in a Hamilton, Ontario between 2013 and 2018. The authors report demographics, diagnoses, as well as healthcare utilization for this cohort and provide stratified results by patient-initiated and death-status. While the study nicely describes PWID/ID hospital care utilization, the manuscript lacks focus and the principal conclusions that patient directed discharges and readmissions are common have been demonstrated previously in national datasets. I think the introduction and discussion could better frame the primary hypotheses and contextualize the limited analyses performed. Additionally, the authors frame the manuscript as an initial baseline study to address longer term trajectories and improve care for PWID but do not describe any addiction interventions or withdrawal management approaches in the hospital which is essential and could be one of the strengths of retrospective chart review study like this (similar studies using publicly available databases lack detailed inpatient medication administration records or other interventions). Overall, the authors have done considerable work to gather this data yet lacks key information and requires additional focus. Below are several additional suggestions to strengthen the manuscript. Response: Thank you for taking the time to review our manuscript. We greatly appreciate your insightful feedback for our paper. We would like to clarify that our goal with this chart review was the establish the feasibility of studying injection drug use in Hamilton. Studies in the past have described general statistics of people who inject drugs, but have not yet considered the nature of hospital admissions for this group. This investigation is a first step to develop a better understanding this population for future studies to be conducted surrounding trajectories and interventions. Major comments: 1. Abstract: “little is known about outcomes” – The manuscript would be better framed with more specific identification of the gap and the goals. Which outcomes? There’s a fairly robust literature on outcomes related to specific infectious diseases (HIV, HCV, endocarditis) though less about this larger collection of diagnoses. Response: Thank you for your comment, we have clarified this point in our abstract. 2. Intro: Little is known about “health trajectory of this population.” I would define this term as it is important theoretically to the framing (over what time period, what outcomes). Response: Thank you for your comment, we have clarified this point in our introduction. We agree that the term “health trajectories” may not be intuitive and warrants clarification. 3. Intro: P 4, line 85: The authors argue that by including all infections among PWID together this manuscript fills a gap in the literature. Each of these infections has distinct presentations and clinical courses, I think the manuscript would be stronger with a theoretical argument about why it is crucial to group these infections together. Response: Thank you for this consideration to help strengthen our paper. We have clarified the importance of considering all drug-related infections for this population accordingly. 4. P5 line 98: “This project will set the stage to further study healthcare trajectories of PWID with infections.” I’m not clear where this is going or what this means. I would suggest using this space in the manuscript instead to set up the analyses you are doing in this paper. Response: Thank you for your comment, we understand our original wording may not have been clear. We have clarified our aims for our study and ensured it flows with our analysis. 5. P5 Line 99: “The overall aim…” – I would delete or make this sentence much more focused. Based on the analyses later in the manuscript, it seems the goal of this manuscript is to understand characteristics of people who do and do not have patient initiated discharges but the introduction doesn’t really set this up. Response: Thank you for your suggestion, we acknowledge that this sentence is rather broad. We have modified the sentence for more specificity and incorporated the suggestion from the last comment to ensure our aims are clearer and more reflective of our work. 6. P5, Line 107 --- This is pretty well documented in the literature in addition to clinical experience. Response: Thank you for your comment. We have changed this sentence to reflect this. 7. Methods: I would encourage the authors to describe a bit more about how injection drug use in the last 6 months determined/verified. Response: Thank you for this excellent suggestion. Reviewer #1 expressed a similar sentiment above. As such, we have added more detail to explain our data extraction process by including how each survey query was answered and which parts of the patient chart were referenced for each query. 8. If patient-initiated discharges are indeed the focus of this paper, it would be valuable to report on medication for opioid use disorder provision in the hospital and/or withdrawal management strategy which has been shown to be linked with discharge. The authors report on medication for opioid use disorder provision prior to the hospitalization but not how the hospital approaches addiction treatment. Response: Thank you for your comments. We would like to clarify that patient-initiated discharges represent one of the multiple outcomes we focused on in our investigation. Unfortunately, there is little available on how the participating hospitals respond to and address addictions treatment, aside from what was found in consult notes surrounding opioid substitution therapy. We agree that linking substitution or withdrawal management with discharge data would be an excellent addition. We hope that our study, as a first step into investigating outcomes of PWID, will be conducive to such analysis in the near future. 9. Additional analyses to consider: do people with serious deeper infections leave later in the hospitalization than people with less serious infections (cellulitis, abscesses vs endocarditis, bacteremia, etc). Response: Thank you for these excellent suggestions. We agree that such analyses would yield important and insightful considerations in developing strategies to better care for this population. As mentioned above, we hope our study will allow further analyses to be carried out among this population to better understand the impact of infections of varying severities. 10. Are the comorbidities baseline or identified during the hospitalization? Response: Thank you for this question. We have clarified that information on comorbidities included those at baseline (made available in the electronic records system) as well as those identified during the hospitalization. 11. Page 17 Line 293-94 – would move sentence about HIV/HCV diagnosis to the limitations section. Response: Thank you for this suggestion, we agree that this makes more sense in structuring our paper. This portion originally in the fit within literature subsection has been moved above to the limitations subsection as suggested. 12. It is interesting that 55% of the population was injected unspecified opioids or hydromorphone. Can the authors provide additional information about the local context? Response: Thank you for suggesting this addition. We agree that providing additional information with local data would fortify the clinical picture. We have included local data from a needs assessment and feasibility study for the Hamilton supervised injection site to help contextualize our findings. This addition was written into our discussion section, under the fit within literature subsection. 13. Limitations: This is descriptive data with bivariate analyses and does not adjust for co-variates. The authors could consider a basic, simple logistic regression model looking at factors associated with patient initiated discharge or mortality, but will be limited in the number of covariates that can be included. Regardless, the limitations section should acknowledge the limitations of this kind of analysis. Response: Thank you for your comment. We agree that limitations in our statistical analyses should be recognized. We have addressed this issue in our limitations subsection. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0266663.r002
6 Dec 2021 Decision Letter - Jianhong Zhou, Editor PONE-D-21-11155R1Infectious diseases, comorbidities and outcomes in hospitalized people who inject drugs (PWID)PLOS ONE Dear Dr. Alvarez, 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. Specifically, please address reviewers' remaining concerns, and particularly specify if data underlying the findings is fully available. Please submit your revised manuscript by Jan 17 2022 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, Jianhong Zhou Associate 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: 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: 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: Thank you for responding to the reviewer comments. I think this has strengthened the manuscript. This manuscript contributes to the literature of PWID and hospitalizations, patient-initiated discharges, and deaths. One minor comment--hydromorphone was the most commonly injected substance, though it is also a prescription pain medication. perhaps the first time that hydromorphone is introduced in the paper that it can be described as mis-used/illicit hydromorphone? I suspect that this is hydromorphone pills that are crushed and injected as opposed to the IV hydromorphone formulation but perhaps authors can comment on this? I think there may be differences in infection risk between these two formulations... Reviewer #2: The authors have largely addressed my comments but I think the methods section still feels a bit disjointed and does not set up the specific analyses performed. Perhaps the authors could move their discussion of sample size as it related to number of events to the statistical analysis section. The authors report detailed data collection strategy but could lay out more clearly which outcomes they will examine. The statistical analysis section can then more clearly state which comparison will be performed, etc. ****** 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.0266663.r003
Revision 2
20 Dec 2021 Author Response Please see below responses to reviewers’ comments: Specifically, please address reviewers' remaining concerns, and particularly specify if data underlying the findings is fully available. RESPONSE: A data sharing and availability section was added under methods 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. RESPONSE: A review of referenced articles has been completed. No articles were found to have been retracted. A couple of links have been updated. 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 RESPONSE: Thank you ________________________________________ 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: No Reviewer #2: No RESPONSE: A data sharing and availability section was added under methods ________________________________________ 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: Thank you for responding to the reviewer comments. I think this has strengthened the manuscript. This manuscript contributes to the literature of PWID and hospitalizations, patient-initiated discharges, and deaths. RESPONSE: Thank you! One minor comment--hydromorphone was the most commonly injected substance, though it is also a prescription pain medication. perhaps the first time that hydromorphone is introduced in the paper that it can be described as mis-used/illicit hydromorphone? I suspect that this is hydromorphone pills that are crushed and injected as opposed to the IV hydromorphone formulation but perhaps authors can comment on this? I think there may be differences in infection risk between these two formulations... RESPONSE: Thank you, this was clarified in the methods section under data collection. Reviewer #2: The authors have largely addressed my comments but I think the methods section still feels a bit disjointed and does not set up the specific analyses performed. Perhaps the authors could move their discussion of sample size as it related to number of events to the statistical analysis section. The authors report detailed data collection strategy but could lay out more clearly which outcomes they will examine. The statistical analysis section can then more clearly state which comparison will be performed, etc. RESPONSE: Clarifications were added throughout the methods section to address these points. ________________________________________ 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 Thank you again for your reviews. Attachments Attachment Submitted filename: Response to reviewers_2021Dec.docx https://doi.org/10.1371/journal.pone.0266663.r004
25 Mar 2022 Decision Letter - Yu Mon Saw, Editor Infectious diseases, comorbidities and outcomes in hospitalized people who inject drugs (PWID) PONE-D-21-11155R2 Dear Dr. Alvarez, 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, Yu Mon Saw Academic Editor PLOS ONE Additional Editor Comments (optional): 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 ******** 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 ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: 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: 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 ****** 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: Thank you for addressing my comment re: formulations of medications. This helps to clarify that substances can be regularly prescribed but in this case were used illicitly and injected in this way. ****** 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 https://doi.org/10.1371/journal.pone.0266663.r005
Formally Accepted
8 Apr 2022 Acceptance Letter - Yu Mon Saw, Editor PONE-D-21-11155R2 Infectious diseases, comorbidities and outcomes in hospitalized people who inject drugs (PWID) Dear Dr. Alvarez: 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 plosone@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. Yu Mon Saw Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0266663.r006

Open letter on the publication of peer review reports

PLOS recognizes the benefits of transparency in the peer review process. Therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. Reviewers remain anonymous, unless they choose to reveal their names.

We encourage other journals to join us in this initiative. We hope that our action inspires the community, including researchers, research funders, and research institutions, to recognize the benefits of published peer review reports for all parts of the research system.

Learn more at ASAPbio .