Feasibility and acceptability of GeneXpert MTB/XDR implementation among healthcare workers in three low-middle income African countries

Sara Keller; Kogieleum Naidoo; Medhane Zekarias; Sussan Israel-Isah; Mohammed Shaka; Gcinile Gule; Anushka Naidoo; Miriam Bathnna; Judith Nomthandazo Dlamini-Miti; Kalkidan Yae; Evaezi Okpokoro; Alash’le Abimiku; Ahmed Bedru; Edine W. Tiemersma; on behalf of the TRiAD Study Consortium

doi:10.1371/journal.pone.0326342

Peer Review History

Original SubmissionJanuary 24, 2025
24 Jan 2025 Author Response https://doi.org/10.1371/journal.pone.0326342.r001
Decision Letter - Padmapriya Banada, Editor PONE-D-24-58843Feasibility and acceptability of GeneXpert MTB/XDR workflow implementation among healthcare workers in three low-middle income African countriesPLOS ONE Dear Dr. Tiemersma, 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 see below the reviewers comments and I hope you find it helpful to further improve your manuscript. Please address the reviewers concerns carefully and I encourage you to please include that in your manuscript, not just write an answer in your response to reviewers. Especially, please consider reviewer 1 recommendation on the title. ============================== Please submit your revised manuscript by Apr 03 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. 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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. Additional Editor Comments: Please see below the reviewers comments and I hope you find it helpful to further improve your manuscript. Please address the reviewers concerns carefully and I encourage you to please include that in your manuscript, not just write an answer in your response to reviewers. Especially, please consider reviewer 1 recommendation on modifying the title. [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: N/A ****** 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: 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: I have reviewed the manuscript by Keller et al. The manuscript is addressing a relevant aspect of the diagnosis of drug resistant TB using the GeneXpert XDR test. It is reporting the Feasibility and acceptability of the test workflow. I have raised comments to be addressed below: Major comment 1) The manuscript is about workflow, how ever the content is mainly about acceptability of the test and less of the workflow. The authors should have looked into the proposed workflow of the GeneXpert XDR and conduct a study looking into the feasibility and acceptability of such steps towards GeneXpert XDR testing. For examples, the feasibility and acceptability of testing the same sample as GeneXpert Ultra Vs collecting another sample, on the same day versus on a different day. looking into both lab, clinic and patient workflow. This could be still looked at through the same study population, Lab, clinician and PWTB. If this is not the case, then, word "Workflow" should be removed from the title and the entire writeup of the manuscript revised to concentrate on the "Feasibility and Acceptability of the test only. Minor comments 1) abstract: L38: the why "especially laboratories" yet the manuscript is about lab personnel, clinician patients 2) The study happened in only 4-months, was this nested in another already existing study or it was the main and primary study? this seems to be a very short time for a multi-country study. 3) There is less literature about the concepts of the study under L108-112 4) L132-133: were these numbers considered adequate? Usually IDs consider a sample size of 9-17 participants to reach saturation. 5) L143: Very difficult to find interviewers who can speak all languages the participant feels comfortable! may be the language the can understand. 6) L146: The interviewers varied in different strength, BUT the study had only 5 interviewers 7) Results section: The number of people interviewed are higher than those intended as per L132: Did the REC approve the additional numbers of interviewees than those intended for? 8) L188-190: Is this section for methods or these are results? 9) L209: This should have a sub section i.e "Factors contributed to Acceptability" and avoid repeating "acceptability or Feasibility going forward. 10) L290: "Lower sensitivity for TB detection". Since this study was not a diagnostic accuracy study, there is possibility of this assumption not being true. There are several factors such as sample collection, bacterial load in the sample and processing as you indicate in table 2 that may affect the outcome of the test. I suggest you change to "discordant results" and not lower sensitivity. Reviewer #2: The manuscript is well-written. The authors have stated that the data cannot be publicly shared as it consists of individual opinions provided under the condition of deidentification and restricted access to the research team. However, they could consider sharing a checklist of interview questions along with the aggregated qualitative responses in numerical or percentage form. The GeneXpert MTB/XDR assay is unable to detect resistance to key drugs such as linezolid, bedaquiline (Group A drugs under the new WHO guidelines), pyrazinamide (PZA), and other repurposed second-line drugs. Furthermore, targeted NGS from clinical specimens is not yet feasible in many low- and middle-income countries (LMICs) with a high burden of DR-TB, making phenotypic DST (pDST) or molecular PCR assays essential for detecting susceptibility or resistance to these drugs. Therefore, it is crucial to assess the turnaround time and cost-effectiveness of using GeneXpert MTB/XDR in combination with pDST or additional molecular PCR assays for drugs like PZA, bedaquiline, and linezolid in XDR-TB patients. ****** 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: Yes: Willy Ssengooba 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.0326342.r002
Revision 1
11 Apr 2025 Author Response Review Comments to the Author Reviewer #1: I have reviewed the manuscript by Keller et al. The manuscript is addressing a relevant aspect of the diagnosis of drug resistant TB using the GeneXpert XDR test. It is reporting the Feasibility and acceptability of the test workflow. I have raised comments to be addressed below: Major comment 1) The manuscript is about workflow, how ever the content is mainly about acceptability of the test and less of the workflow. The authors should have looked into the proposed workflow of the GeneXpert XDR and conduct a study looking into the feasibility and acceptability of such steps towards GeneXpert XDR testing. For examples, the feasibility and acceptability of testing the same sample as GeneXpert Ultra Vs collecting another sample, on the same day versus on a different day. looking into both lab, clinic and patient workflow. This could be still looked at through the same study population, Lab, clinician and PWTB. If this is not the case, then, word "Workflow" should be removed from the title and the entire writeup of the manuscript revised to concentrate on the "Feasibility and Acceptability of the test only. Reply: We thank the reviewer for this comment and agree that this paper is about the overall implementation of Xpert MTB/XDR and the impact of adding this new test on the work of health care workers. While we, indeed, did not look specifically and separately at each step in the workflow, we did intend to broadly examine clinic workflow. To address the reviewer’s comment, we have removed the word ‘workflow’ from the title and at places in the manuscript where we felt that the term was not necessary to keep the meaning of the sentence. However, where discussing the overall broader impact of the new workflow, we left the term in. Minor comments 1) abstract: L38: the why "especially laboratories" yet the manuscript is about lab personnel, clinician patients Reply: This line concerns background information, and we believe that introduction of the Xpert MTB/XDR test will especially change the workflow in those laboratories that previously did not conduct Xpert testing, as this means a new test being introduced with an additional follow-on (reflex) test that needs to be done and interpreted, and additional results to be shared with clinicians, whereas previously, another sample might have been collected for submission to a reference laboratory. 2) The study happened in only 4-months, was this nested in another already existing study or it was the main and primary study? this seems to be a very short time for a multi-country study. Reply: This study was indeed nested into a larger study, as is briefly explained in the abstract (lines 43-44) and in more detail in lines 108-110. The data collection could be done in just 4 months as data were concurrently collected by different teams in each country (2 interviewers per team). 3) There is less literature about the concepts of the study under L108-112 Reply: Indeed, this paragraph does not contain any references to literature as it pertains to the study itself, explaining the aims of our study. Therefore, no references were added. 4) L132-133: were these numbers considered adequate? Usually IDs consider a sample size of 9-17 participants to reach saturation. Reply: The main population of our study were health care workers. Interviews with patients and policy makers were added to enrich our data. We admit that this may not have become very clear from the manuscript. Therefore, we changed lines 132-136 as follows: “...our aim was to reach thematic saturation in interviews with healthcare workers (clinicians, nurses, laboratory staff). In addition, we interviewed PWTB and policy makers to provide additional insight into the impact of the introduction of Xpert-XDR. The intent here was supplemental and not to reach thematic saturation.” 5) L143: Very difficult to find interviewers who can speak all languages the participant feels comfortable! may be the language the can understand. Reply: Interviewers were hired on the basis that they could speak the languages of the interviewees. So indeed, they did feel comfortable in the languages used during the interview. 6) L146: The interviewers varied in different strength, BUT the study had only 5 interviewers Reply: As explained in lines 141-142, there were six persons conducting the interviews (five interviewers and one data collector). As explained in the next paragraph, all these were trained both in TB and in qualitative data collection skills. During the training, trainees with less experience in TB but strong qualitative interviewing skills were paired with trainees with more experience in TB but less experience in conducting qualitative interviews. 7) Results section: The number of people interviewed are higher than those intended as per L132: Did the REC approve the additional numbers of interviewees than those intended for? Reply: In response to comment #4 of this reviewer, the number of intended interviewees has been removed from the methods section as numbers of interviews planned concerned the maximum number of interviews considered to be needed to reach thematic situation, and are thus not essential. The total number of interviews was lower than this maximum in all countries (25 health care workers, 4 persons with TB and 3 policy makers per country): 20, 20 and 21 health care workers, 3 ,4 and 4 PWTB, and 3, 3 and 3 policy makers were interviewed respectively in South Africa, Nigeria and Ethiopia. Final numbers of interviews conducted are listed in Table 2 in the Results section. In direct response to the comment of going above numbers - there was no need for approval as in qualitative research there is not a strict number of interviews required, but rather the aim of reaching thematic saturation. See also our response to comment #4. 8) L188-190: Is this section for methods or these are results? Reply: The sentences “The laboratory staff provided insights into the feasibility and acceptability of the GeneXpert instrument and of conducting the Xpert-XDR assay. The clinicians and nurses provided feedback about the acceptability and feasibility of the new workflow” rather describe the type of information to be collected in the interviews than the precise information that was obtained. We have now changed the sentences slightly and moved them to the methods section (lines 154-156) as proposed by the reviewer. 9) L209: This should have a sub section i.e "Factors contributed to Acceptability" and avoid repeating "acceptability or Feasibility going forward. Reply: Subheadings have been adapted to reflect this comment of the reviewer. 10) L290: "Lower sensitivity for TB detection". Since this study was not a diagnostic accuracy study, there is possibility of this assumption not being true. There are several factors such as sample collection, bacterial load in the sample and processing as you indicate in table 2 that may affect the outcome of the test. I suggest you change to "discordant results" and not lower sensitivity. Reply: While we agree with the reviewer that this is not necessarily true, the text describes results directly associated with the responses from the participants, and not our assumptions. Thus, we feel that leaving the wording as is, is most true to the results. Reviewer #2: The manuscript is well-written. The authors have stated that the data cannot be publicly shared as it consists of individual opinions provided under the condition of deidentification and restricted access to the research team. However, they could consider sharing a checklist of interview questions along with the aggregated qualitative responses in numerical or percentage form. Reply: While the reviewer provides an interesting suggestion which we will consider if the editor thinks this is needed, we considered this not feasible as the first author has left KNCV and no longer has direct access to the database. Instead, we have added all interview guides to the manuscript as a supplemental file (see reference to this in line 160). The GeneXpert MTB/XDR assay is unable to detect resistance to key drugs such as linezolid, bedaquiline (Group A drugs under the new WHO guidelines), pyrazinamide (PZA), and other repurposed second-line drugs. Furthermore, targeted NGS from clinical specimens is not yet feasible in many low- and middle-income countries (LMICs) with a high burden of DR-TB, making phenotypic DST (pDST) or molecular PCR assays essential for detecting susceptibility or resistance to these drugs. Therefore, it is crucial to assess the turnaround time and cost-effectiveness of using GeneXpert MTB/XDR in combination with pDST or additional molecular PCR assays for drugs like PZA, bedaquiline, and linezolid in XDR-TB patients. Reply: We agree with the reviewer that this is a major limitation of the Xpert-XDR assay, although it was not raised as a limitation by the interviewees. We therefore included this as a limitation in the Discussion section (lines 398-407). To strengthen the manuscript, we now added to the concluding section (lines 443-447): “Finally, it should be noted that additional tests, such as pDST or (targeted) genome sequencing are needed to detect resistance to key drugs as bedaquiline and linezolid. Therefore, it is crucial to assess turnaround times and cost-effectiveness of combining Xpert-XDR which such tests, especially for pre-XDR-TB patients.” Attachments Attachment Submitted filename: reply_reviewers_250319.docx https://doi.org/10.1371/journal.pone.0326342.r003
Decision Letter - Padmapriya Banada, Editor PONE-D-24-58843R1Feasibility and acceptability of GeneXpert MTB/XDR implementation among healthcare workers in three low-middle income African countriesPLOS ONE Dear Dr. Tiemersma, 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. ============================== Thank you for submitting your revised manuscript and considering the reviewers comments. Although I accept most of your rebuttal, some remain unanswered. for Reviewer 1 question 3 about the reference, I believe the reviewer is intending to ask if your proposed workflow is supported by any other published literature? and if so, please give a reference although we understand this is your protocol. however, if this protocol is completely novel to this study, you will have to explain the need for deviation from similar published studies. As for the reviewer 2's concern about the data sharing, please note that PLOS journals require authors to make all data underlying the findings described in their manuscript fully available without restriction when at all possible. The data should be part of the institution not the author who has left. Please make every effort to make all data available ============================== Please submit your revised manuscript by Jun 26 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols . We look forward to receiving your revised manuscript. Kind regards, Padmapriya P Banada, PhD 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. Additional Editor Comments : Dear authors, Thank you for submitting your revised manuscript and considering the reviewers comments. Although I accept most of your rebuttal, some remain unanswered. for Reviewer 1 question 3 about the reference, I believe the reviewer is intending to ask if your proposed workflow is supported by any other published literature? and if so, please give a reference although we understand this is your protocol. however, if this protocol is completely novel to this study, you will have to explain the need for deviation from similar published studies. As for the reviewer 2's concern about the data sharing, please note that PLOS journals require authors to make all data underlying the findings described in their manuscript fully available without restriction when at all possible. The data should be part of the institution not the author who has left. Please make every effort to make all data available. [Note: HTML markup is below. Please do not edit.] [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.0326342.r004
Revision 2
14 May 2025 Author Response Response to editor’s comments: 1) For Reviewer 1 question 3 about the reference, I believe the reviewer is intending to ask if your proposed workflow is supported by any other published literature? and if so, please give a reference although we understand this is your protocol. however, if this protocol is completely novel to this study, you will have to explain the need for deviation from similar published studies. We apologize the comment of the reviewer. Re-reading the comment (“There is less literature about the concepts of the study under L108-112”) as well as the respective paragraph, we understand that the reviewer wants to know if there is any literature underlying the theoretical framework of acceptability and feasibility tha. The theoretical framework of feasibility and acceptability for this study was based on work published by Sekhon et al. (reference 14 in the original manuscript). With regards to the introduction of the Xpert MTB/XDR test in the laboratory workflow, this is based on recommendations by the manufacturer. This is further explained in a publication of the TRiAD study protocol (which was added to the original manuscript as reference 23). We have added references to both papers in lines 108-114 as follows: “The TriAD study aims to evaluate the effectiveness, feasibility, acceptability and cost-effectiveness of implementing a rapid triaging algorithm with the use of Xpert-XDR and selection of all-oral regimens for DR-TB in South Africa, Ethiopia, and Nigeria (13). To assess the programmatic and operational aspects of introducing this algorithm, we assessed its feasibility and acceptability, using the theoretical framework of acceptability of healthcare interventions developed by Sekhon et al. (14). We included barriers and facilitators from the perspective of healthcare workers, policy makers and PWTB in South Africa, Ethiopia, and Nigeria.” All references have been renumbered accordingly. 2) As for the reviewer 2's concern about the data sharing, please note that PLOS journals require authors to make all data underlying the findings described in their manuscript fully available without restriction when at all possible. The data should be part of the institution not the author who has left. Please make every effort to make all data available. We do apologize for our confusing answer; as we failed to update it in line with the text we added to the Data Availability Statement. Here, we do explain that the data is available on request and that it can be made available by addressing the respective ethical review boards: “The qualitative data collected for this study contains sensitive information that could lead to the identification of patients, staff and policy makers, despite the data having been de-identified. Data access requests can be made: • For South Africa, Caprisa sites, via the Biomedical Research Ethics Committee of the University of Kwazulu-Natal at the following e-mail address:BREC@ukzn.ac.za, citing protocol reference number BREC/00002654/2021; for the University of Witwatersrand via the Human Research Ethics Committee at the following email address: EthicsRegulatory@witshealth.co.za, citing protocol reference number 210805; • For Nigeria via the National Health Research Ethics Committee of Nigeria at the following email address: secretary@nhrec.net, citing NHREC approval number NHREC/01/01/2007-01/06/2023; • For Ethiopia via the Ethiopian Public Health Institute Institutional Review Board at the following email address: info@ephi.gov.et, citing the EPHI-IRB and protocol reference number EPHI-IRB-384-2021” Attachments Attachment Submitted filename: reply_editor_250514.docx https://doi.org/10.1371/journal.pone.0326342.r005
Decision Letter - Padmapriya Banada, Editor Feasibility and acceptability of GeneXpert MTB/XDR implementation among healthcare workers in three low-middle income African countries PONE-D-24-58843R2 Dear Dr. Tiemersma, 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 will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, 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, Padmapriya P Banada, PhD Academic Editor PLOS ONE Additional Editor Comments (optional): Thank you for revising the manuscript and responding to all the concerns. Reviewers' comments: https://doi.org/10.1371/journal.pone.0326342.r006
Formally Accepted
Acceptance Letter - Padmapriya Banada, Editor PONE-D-24-58843R2 PLOS ONE Dear Dr. Tiemersma, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset You will receive further instructions from the production team, including instructions on how to review your proof when it is ready. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few days to review your paper and let you know the next and final steps. Lastly, 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. Padmapriya P Banada Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0326342.r007

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