The mortality impact of pulse oximetry use during infant and childhood pneumonia management at the primary healthcare level in low-income countries is unknown. We sought to determine mortality outcomes of infants and children diagnosed and referred using clinical guidelines with or without pulse oximetry in Malawi.2) thresholds and World Health Organization (WHO) and Malawi clinical guidelines for referral. We used unadjusted and adjusted  regression to account for interaction between SpO2 threshold (pulse oximetry) and clinical guidelines, clustering by child, and CHW or HC catchment area. We matched CHW and HC outpatient data to hospital inpatient records to explore roles of pulse oximetry and clinical guidelines on hospital attendance after referral. From 7,358 CHW and 6,546 HC pneumonia episodes, we linked 417 CHW and 695 HC pneumonia episodes to 30-day mortality outcomes: 16 (3.8%) CHW and 13 (1.9%) HC patients died. SpO2 thresholds of <90% and <93% identified 1 (6%) of the 16 CHW deaths that were unidentified by integrated community case management (iCCM) WHO referral protocol and 3 (23%) and 4 (31%) of the 13 HC deaths, respectively, that were unidentified by the integrated management of childhood illness (IMCI) WHO protocol. Malawi IMCI referral protocol, which differs from WHO protocol at the HC level and includes chest indrawing, identified all but one of these deaths. SpO2 < 90% predicted death independently of WHO danger signs compared with SpO2 ≥ 90%: HC Risk Ratio (RR), 9.37 ; CHW RR, 6.85 . SpO2 < 93% was also predictive versus SpO2 ≥ 93% at HC level: RR, 6.68 . Hospital referrals and outpatient episodes with referral decision indications were associated with mortality. A substantial proportion of those referred were not found admitted in the inpatients within 7 days of referral advice. All 12 deaths in 73 hospitalised children occurred within 24 hours of arrival in the hospital, which highlights delay in appropriate care seeking. The main limitation of our study was our ability to only match 6% of CHW episodes and 11% of HC episodes to mortality outcome data.We conducted a data linkage study of prospective health facility and community case and mortality data. We matched prospectively collected community health worker (CHW) and health centre (HC) outpatient data to prospectively collected hospital and community-based mortality surveillance outcome data, including episodes followed up to and deaths within 30 days of pneumonia diagnosis amongst children 0–59 months old. All data were collected in Lilongwe and Mchinji districts, Malawi, from January 2012 to June 2014. We determined differences in mortality rates using <90% and <93% oxygen saturation  identified 6% of deaths at community health worker level (1/16) and 23% of deaths at health centre level (3/13) not identified by clinical signs.Pulse oximetry readings of less than 90% oxygen saturation  not identified by clinical signs at the health centre level only.Increasing the threshold to less than 93% SpOAll of the health centre deaths identified by pulse oximetry except one were also identified by chest indrawing in this high-mortality setting.Our findings suggest that pulse oximetry could be beneficial in supplementing clinical signs to identify children with pneumonia at high risk of mortality in the outpatient setting in health centres for referral to a hospital for appropriate management.In high-mortality settings in low- and middle-income countries, in the absence of pulse oximetry, presence of chest indrawing could potentially be explored as a referral sign to a hospital but needs further research in routine settings. Pneumonia remains a leading cause of death in children under 5, especially in low-income and middle-income countries (LMICs), with around 800,000 pneumonia-related deaths a year globally . IncidenEarly identification and action is required to prevent more pneumonia-related deaths that currently occur in hospital, often because of late presentation , and at 2) measurement by pulse oximeters at outpatient primary care and first level health facilities has a potential role to aid early recognition and referral of severe pneumonia episodes for oxygen and injectable antibiotic treatment ..6].2 measurements were taken using the Lifebox device , with a universal adult clip probe applied to the child’s big toe if less than 2 years of age or below 10 kg. Otherwise, for older or heavier children, providers were instructed to use either the big toe or an appropriately sized finger. A paediatric probe was not available during this time period. CHW and HC workers were trained and retrained in the use of pulse oximetry by a paediatric pulmonologist (EDM) as described by McCollum and colleagues ) and <93% (RR: 6.68 [95% CI: 1.52–29.4]) thresholds are significantly associated with mortality in both the Malawi and WHO IMCI guideline models  of the 417 episodes had outpatient referral decisions, and these were more common in patients who were clinically or SpO2 eligible (33.3%–100%) than those who were not (3.6%–7.0%). Only 0.7% (3) of the CHW episodes were found to be hospital inpatients within 7 days of outpatient diagnosis , healthcare workers referred 90.6% who were eligible by both criteria, 62.3% who were clinically eligible only, and only 20.0% of those eligible because of SpO2 < 90% only. Seventy (10.1%) of the 695 HC episodes were hospital inpatients within 7 days; 60 of these followed an outpatient referral decision .iagnosis , precludiagnosis , 30.4%  nor iCCM clinical signs alone (DOR: 1.33 [95% CI: 0.29–6.05]) accurately identified those who died. At the HC level, pulse oximetry was able to accurately identify those who die with both Malawi  and WHO  IMCI clinical signs. Although the point estimates for these DORs are higher than those for when Malawi and WHO IMCI clinical signs alone are used without pulse oximetry , WHO: DOR 3.43 [95% CI: 1.10–10.7]), the confidence intervals are wide and overlapping, indicating these differences are not statistically significant.2 is less than 90%; however, pulse oximetry is not frequently available at the outpatient level. With low-cost portable pulse oximeters becoming much more available compared to 2014, especially in the context of the ongoing COVID pandemic In light of these reviews, I am afraid that we will not be able to accept the manuscript for publication in the journal in its current form, but we would like to consider a revised version that addresses the reviewers' and editors' comments. Obviously we cannot make any decision about publication until we have seen the revised manuscript and your response, and we plan to seek re-review by one or more of the reviewers. http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments, the changes you have made in the manuscript, and include either an excerpt of the revised text or the location (eg: page and line number) where each change can be found. 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Manuscripts submitted to PLOS should not contain research participants personally-identifying information. In rare exceptions where this is unavoidable and a manuscript does contain PII, the authors should be willing and able to provide PLOS with confirmation of GDPR compliance upon request.Map of Malawi- you may consider adding this into the main text as it gives an immediate visualisation of where the data were collected fromComments from the reviewers:Reviewer #1: This is a very important piece of work that merits consideration by the journal as it tries to assess the "… mortality outcomes of infants and children diagnosed and referred using clinical guidelines with or without pulse oximetry in Malawi". Recent advances in the wider scale up and implementation of pulseoximetry need to go hand in hand with data like the one presented in this manuscript, which are clear-cut. Pulseoximetry helps identify children at risk of dying. Authors conclude that "Pulse oximetry identified fatal pneumonia episodes at HCs in Malawi that would otherwise have been missed by WHO referral guidelines alone", which is a statement with which I do agree. I believe the journal should consider  the inclusion of a comment to go hand in hand with the manuscript. I only have a few minor comments to add:* The word data should be used in plural* Current global estimates for Pneumonia mortality are closer to 800,000 than to 900,000/year* The fact that mortality as an endpoint was assessed at day 7 but also at day 30 means that many of these deaths may not (or may indeed) be related to the initial episode that took the patient to the health system (particularly for those at day 30). This should be further discussed, but it doesn't eliminate the validity of the association and therefore of the use of oxygen saturation as a risk stratification tool* In this respect, is there any information  regarding the potential underlying causes of those deaths? It would be very helpful to be able to state that an elevated proportion of those deaths were secondary to respiratory problems* I understand vaccination data were also collected. Was there any association between mortality and lack of adequate vaccination against Hib or pneumococcus?* The findings that association with mortality is maintained with threshold 93% is also very important but has the risk to overload the  system if all patients fulfilling this criterion are recommended for a transfer. Have you been able to conduct any economic modeling of costs associated with the two scenarios . This would be super helpful, as I predict that costs to the system would be massively increased (and be unassumable). Were there other specific variables associated to mortality within the specific group with saturations between 90-93% which were also associated with mortality? Could the recommendation include a need to fulfil at least two of the risk factors, rather than one?* Noting is mentioned on the absence/availability of emergency oxygen/systems for transfers. Recognizing this is a major deficit in the health systems of LMICS, it may be worth stating it as an important consideration for the future. There is an ethical dilemma of measuring oxygen saturation but not being able to provide life-saving oxygen, at least for the transport. This is perhaps the most neglected field in pneumonia research, how to ensure cheap and durable availability of oxygen for emergency transport* Pulseoximter readings are very variable and often can produce false positive results of hypoxemia values which are not real. I understand that there was a specific training conduted, but perhaps it may be useful to add in the methods section how values obtained in the peripheral health system were considered "reliable" and robust . This is particularly important with one of your conclusions in relation to the association with mortality: "the failure to obtain an SpO2 measure using pulse oximeters in identifying otherwise unrecognized fatal childhood pneumonia cases accessing primary care". Could some of those cases be failures of the measurement technique? Of the devices used? It may seem very obvious, but this appears important to me.Reviewer #2: PLOS Medicine Colbourn SpO2 Malawi reviewThe lowest denomination of low-cost factors to determine poor outcome is required. Oxygen saturation monitors will be increasingly available for use in developing health and an assessment of their impact is required. This first report is very useful for informing this field and provides structure to the reporting of future studies. CommentsMethodsDescribe the process for patients to access and move through the HC system . ResultsP10 L227. This manuscript would be helped by a figure or initial text in the results that provide cascade detail to the patients, matching and deaths to provide better context to what is reported.i.e. N = 13814 pneumonia episodes, 6941 CHW + 5761 HC in which SpO2 <90% found in 86/6941 (1.2%) and 608/5761 (10.5%) respectively. There was matching of pneumonia episodes to mortality cohort in N=1112, 417/6941 CHW and 695/5761 HC. of which there were 29 deaths representing 2.6% of the matched episodes (16/417 CHW and 13/608).P10 L252 The case for chest indrawing is well made. Page 11 L259In light of the finding of a discrepancy in the SpO2 <90% and deaths in CHW cohort (missing 75% of deaths), please provide discussion on the use of an adult probe in a paediatric community setting and the potential for error from extraneous light and the difficulty in positioning. Please also consider discussion that Table 1 The results identify that an SpO2 threshold of 93% would result in a 6 times higher referral rate by CHW and double referral rate by HC. Please discuss the potential impact of this on the ability to deliver safe and effective care to children with pneumonia with increased sensitivity to identify severe disease, but the potential impact of reduced sensitivity having an economic and hospital bed impact that could reduce the ability to priortise services for those with severe disease. DiscussionKey finding is that study identifies that clinical criteria including chest indrawing together with SpO2 <90% fail to identify 75% of deaths from pneumonia in children. It is difficult to understand that 75% of deaths occurred in children whose parents were concerned enough to attended services so early that they had no severe signs and no desaturation, but then did not re-attend when things got worse. As this represents such a large proportion of 'inaccessible pneumonia deaths' it would be useful to consider how this may be resolved in a future study, i.e red flag information. Please discuss that health seeking behaviours are orientated to younger children and it is older children that do not attend out patient services after referral. Whilst this is regrettable, parents so appear to understand that younger children are at greater risk. Overall the study is of value for providing an indication of the potential value of pulse oximetry in childhood pneumonia - but large missing data and relatively few deaths limit the strength of conclusions despite rigorous analysis. The conclusions could be more circumspect. Line 300 - This evidence 'could' support… The evidence in itself is not strong enough to support the inclusion at this time. Line 420 'should' is inappropriate based on this evidence alone. Reviewer #3: Alex McConnachie, Statistical ReviewColbourn et al consider the potential for the use of pulse oximetry for identifying children likely to die from pneumonia in Malawi. This review looks at the use of statistics in the paper.Unfortunately, I have a number of concerns.A major problem is the very poor linkage rate, which casts doubt on the validity of the results. The authors comment that there were some differences between those matched and not matched, with reference to the tables and appendix, but should perhaps expand on what these differences were in the main text.My main concern with the analysis is the regression modelling. There were problems with convergence, and the models that it had been intended to fit  were not possible. There were generally few events, and the models that were fitted produced estimates with very wide confidence intervals. Some models reported in the supplement only worked using a logit link. All of these factors suggest that these models are unstable, and I would not trust these results.Note that the description of the model is not entirely correct. On line 184, mu.i is not death for subject i, it is the probability of death; Yi is not the log risk of death, it is the outcome, death, for subject i.Nevertheless, there may be valuable data here, but the tables as presented are quite complex, and are not easy to follow. A simpler approach might be to report more standard measures of diagnostic performance, i.e. sensitivity, specificity, PPV, NPV. That might show, in terms that are easily understood, which combinations of screening criteria  worked best. I doubt that the sample size is enough to test say whether any differences are statistically significant, but might make the case for additional research.Overall, the conclusions of the paper, that SpO2 measurements (or lack of), and chest-indrawing should be included in screening criteria, seems premature given these data.Minor points on Table 1: p values of "0.000" should be reported as "<0.001", and there is no need to add asterisks - the actual p-values are reported.Table 2 is confusing - some percentages are in columns, some in rows, but as stated above, if the focus were changed to measures of diagnostic performance, that might help/Tables 3 and 5 mix up risks and odds, with the constant term referred to as baseline odds.I note that individual consent was not obtained for this study, but individual patient data is reported in the supplement, which could potentially identify individuals.Reviewer #4: page 6 the phrase chest in drawing might likely is the same as retractions, a term more familiar to north american. Please addpage 7 it is customary to add the name and address and even model number of a device used in research. Please addAlso, please detail why an adult universal probe was used in young children. did it work better than pediatric one or thats all there was? Thank you.Page 10. Please define what SpO2 eligible meansPage 13. Please expand the discussion about specific limitation with SpO2 measure in your specific setting. It's what people would likely want to read in the paper.Any attachments provided with reviews can be seen via the following link:[LINK] 29 May 2020AttachmentResponse_to_reviewers_Outpatient pulse oximetry mortality.docxSubmitted filename: Click here for additional data file. 17 Jul 2020Dear Dr. Colbourn,Thank you very much for submitting your manuscript "Predictive value of pulse oximetry for mortality in infants and children presenting to primary care with clinical pneumonia in rural Malawi: a data linkage study" (PMEDICINE-D-20-00470R2) for consideration at PLOS Medicine. Your paper was evaluated by a senior editor and discussed among all the editors here. It was also discussed with an academic editor with relevant expertise, and sent to independent reviewers, including a statistical reviewer. The reviews are appended at the bottom of this email and any accompanying reviewer attachments can be seen via the link below:[LINK]In light of these reviews, I am afraid that we will not be able to accept the manuscript for publication in the journal in its current form, but we would like to consider a revised version that addresses the reviewers' and editors' comments. Obviously we cannot make any decision about publication until we have seen the revised manuscript and your response, and we plan to seek re-review by one or more of the reviewers. http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments, the changes you have made in the manuscript, and include either an excerpt of the revised text or the location (eg: page and line number) where each change can be found. 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If you encounter any issues or have any questions when using PACE, please email us at PLOSMedicine@plos.org.In addition, we request that you upload any figures associated with your paper as individual TIF or EPS files with 300dpi resolution at resubmission; please read our figure guidelines for more information on our requirements: plosmedicine@plos.org) if you have any questions or concerns.We expect to receive your revised manuscript by Jul 27 2020 11:59PM. Please email us  and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***http://journals.plos.org/plosmedicine/s/competing-interests.We ask every co-author listed on the manuscript to fill in a contributing author statement, making sure to declare all competing interests. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. If new competing interests are declared later in the revision process, this may also hold up the submission. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT. You can see our competing interests policy here: Please use the following link to submit the revised manuscript: https://www.editorialmanager.com/pmedicine/Your article can be found in the "Submissions Needing Revision" folder. http://journals.plos.org/plosmedicine/s/submission-guidelines#loc-methods.To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it. Please ensure that the paper adheres to the PLOS Data Availability Policy . Ref 3 is our statistician and we see these points as important. I realise in some instances toning down will be a compromise. Comments from the reviewers:Reviewer #1: all my comments have been addressed, and I'm pleased how authors have rewritten the manuscript. I'm also happy how they have dealt with other reviewer's comments. I still think, however, that this manuscript would benefit from an accompanying commentary.Reviewer #2: Thank you for responding to the primary review. The responses were very helpful and provide clarity.I have one remaining comment. Whilst I note that the authors have provided detail on the training for CHW in pulse oximetry, that '12 (75% of the 16 deaths) 'CHW may have missed danger signs, meaning further support for training...' could be inferred that CHW may somehow be considered responsible for these omissions as the children were not 'hypoxemic'. I would ask that the authors also acknowledge within their limitations, that the use of adult probes on pulse oximeters was a limitation and some of these children may have been hypoxemic at the time of review - we would not use adult probes where a paediatric probe is available - as is increasingly the case globally. The use of adult probes for young children have documented limitations. This potential technological failure to detect hypoxemia does not detract from their core message - but to me adds to it - as it implies that the use of age appropriate sensors may likely provide even greater sensitivity to detect children who may die from lower respiratory tract infection. Reviewer #3: Alex McConnachie, Statistical ReviewI thank Colbourn and colleagues for their responses to my original comments. Seeing Table 6 (sensitivity etc.) helps me to understand the data a little better. Pulse oximetry adds sensitivity, at the expense of a loss of specificity. The results section of the paper concentrates on sensitivity, but the loss of specificity it is touched on in the discussion. No confidence intervals are provided for any of the diagnostic measures, but the authors do note that none of the differences are statistically significant.The diagnostic odds ratios in table 6 are:A1: 1.26, A2: 1.17, A3: 1.32B1: 7.13, B2: 6.19, B3: 5.24B4: 6.57, B5: 6.82, B6: 3.43This suggests that pulse oximetry may be of no real value in the community setting, but might be in a HC setting, particularly when added to the WHO clinical criteria. It also suggests that the Malawi danger signs may perform better than the WHO danger signs on their own.These data are limited though, because they are derived from real world data in which children are being assessed and treated. The aim of the assessments and subsequent treatment and referrals will be aiming to prevent adverse outcomes. It cannot be known how many of these children might have died in the absence of treatment. So, the actual number of true positives will be higher, and the number of false negatives lower, than suggested by simply looking at death as the outcome. Using referral and hospitalisation data as in Tables 4 and 5 does not really help, because these decisions are being made in the light of the assessments being done; in this study, there is no "gold standard" against which to assess the alternative screening criteria.I still feel the logistic regression models are pushing the data too far. For death as the outcome, there are only 13 or 16 events being analysed, depending on the dataset, and models are being fitted (or are being attempted) with a total of 6 parameters , clinical danger signs, interaction (2 df)), so the events-per-variable ratio is very low. Some of the interaction terms are not estimable due to the lack of events in some subgroups. When looking at referral and hospitalisation as the outcome, there are more events, but still very few in some subgroups. The text of the paper mentions associations with low SpO2 and with clinical assessments, but these are the main effects, and each applies only in the absence of the other. The interaction terms are not taken into account, and these are generally below 1. I think these data are interesting, and suggest that chest in-drawing and SpO2 measurements may be of value in some settings, but it is quite messy data, which was not collected with this analysis in mind.The linkage may be highly novel, but the success rate was very low, with many differences between those linked and not linked.Any attachments provided with reviews can be seen via the following link:[LINK] 27 Jul 2020AttachmentPMEDICINE-D-20-00470R2 Response to review.docxSubmitted filename: Click here for additional data file. 11 Aug 2020Dear Dr. Colbourn,Thank you very much for re-submitting your manuscript "Predictive value of pulse oximetry for mortality in infants and children presenting to primary care with clinical pneumonia in rural Malawi: a data linkage study" (PMEDICINE-D-20-00470R3) for review by PLOS Medicine.I have discussed the paper with my colleagues and the academic editor. 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Please let us know if this is acceptable.”Comments from Reviewers:Any attachments provided with reviews can be seen via the following link:[LINK] 1 Sep 2020Attachmentresponse to editorial and production requirements.docxSubmitted filename: Click here for additional data file. 11 Sep 2020Dear Dr. Colbourn, On behalf of my colleagues and the academic editor, Dr. Quique Bassat, I am delighted to inform you that your manuscript entitled "Predictive value of pulse oximetry for mortality in infants and children presenting to primary care with clinical pneumonia in rural Malawi: a data linkage study" (PMEDICINE-D-20-00470R4) has been accepted for publication in PLOS Medicine. PRODUCTION PROCESSBefore publication you will see the copyedited word document (in around 1-2 weeks from now) and a PDF galley proof shortly after that. The copyeditor will be in touch shortly before sending you the copyedited Word document. 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Chronic use of proton-pump inhibitors (PPIs) is common in kidney transplant recipients (KTRs). However, concerns are emerging about the potential long-term complications of PPI therapy. We aimed to investigate whether PPI use is associated with excess mortality risk in KTRs.P < 0.001) compared with no use. After adjustment for potential confounders, PPI use remained independently associated with mortality . Moreover, the HR for mortality risk in KTRs taking a high PPI dose  compared with patients taking no PPIs  was higher than in KTRs taking a low PPI dose . These findings were replicated in the Leuven Renal Transplant Cohort. The main limitation of this study is its observational design, which precludes conclusions about causation.We investigated the association of PPI use with mortality risk using multivariable Cox proportional hazard regression analyses in a single-center prospective cohort of 703 stable outpatient KTRs, who visited the outpatient clinic of the University Medical Center Groningen (UMCG) between November 2008 and March 2011 . Independent replication of the results was performed in a prospective cohort of 656 KTRs from the University Hospitals Leuven (NCT01331668). Mean age was 53 ± 13 years, 57% were male, and 56.6% used PPIs. During median follow-up of 8.2 (4.7–9.0) years, 194 KTRs died. In univariable Cox regression analyses, PPI use was associated with an almost 2 times higher mortality risk  are commonly prescribed to prevent gastrointestinal side effects of immunosuppressive medication after kidney transplantation, and there is little incentive to discontinue use of PPIs in the long term.Several observational studies among individuals from the general population and among patients on hemodialysis have found that PPI use is associated with a higher mortality risk.Long-term mortality rates in kidney transplant recipients (KTRs) are high. Therefore, we aimed to investigate whether PPI use is associated with increased mortality risk in KTRs.We performed a post hoc analysis using data from the TransplantLines Food and Nutrition Biobank and Cohort Study, a prospective cohort study in 703 KTRs, with baseline assessments performed between November 2008 and March 2011. Follow-up was performed for a median of 8.2 years.We found that PPI users had an almost 2-fold increased mortality risk compared with nonusers. When we looked at the cause of death, we found that PPI use was particularly associated with mortality due to cardiovascular diseases and infectious diseases. We also demonstrated that mortality risk is highest among KTRs taking high PPI dosages .These findings were replicated in an independent cohort of 656 KTRs from the University Hospitals Leuven, which strengthens the evidence for an association between PPI use and mortality risk in KTRs.Results of this study suggest that PPI use is associated with mortality risk in KTRs, independent of potential confounders.The current study highlights the importance of an evidence-based indication for PPI treatment and provides a rationale to perform a randomized controlled trial on chronic PPI therapy in KTRs. Renal transplantation is considered the preferred treatment for patients with end-stage renal disease, providing improved prognosis and quality of life at lower cost compared with dialysis treatment –3. AlthoClostridium difficile infections In light of these reviews, I am afraid that we will not be able to accept the manuscript for publication in the journal in its current form, but we would like to consider a revised version that addresses the reviewers' and editors' comments. Obviously we cannot make any decision about publication until we have seen the revised manuscript and your response, and we plan to seek re-review by one or more of the reviewers. http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. 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For instructions see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it. Please ensure that the paper adheres to the PLOS Data Availability Policy  early in the Methods section.a) If a prospective analysis plan  was used in designing the study, please include the relevant prospectively written document with your revised manuscript as a Supporting Information file to be published alongside your study, and cite it in the Methods section. A legend for this file should be included at the end of your manuscript. b) If no such document exists, please make sure that the Methods section transparently describes when analyses were planned, and when/why any data-driven changes to analyses took place. c) In either case, changes in the analysis—including those made in response to peer review comments—should be identified as such in the Methods section of the paper, with rationale.Please ensure that the study is reported according to the STROBE guideline, and include the completed checklist as Supporting Information. When completing the checklist, please use section and paragraph numbers, rather than page numbers. Please add the following statement, or similar, to the Methods: "This study is reported as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline (S1 Checklist)."http://www.equator-network.org/Please report your study according to the relevant guideline, which can be found here: --> transparent reporting of a multivariable prediction model for individual prognosis or diagnosis (TRIPOD) guideline (S1 Checklist).Comments from the reviewers:Reviewer #1: I liked this paper. Very well thought out . well controlled for distracting variables. We wrote on this.... "Concomitant Proton Pump Inhibitors with Mycophenolate Mofetil and the Risk of Rejection in Kidney Transplant Recipients. J. Knorr, M. Sjeime, L. Braitman, P. Jawa, R. Zaki, J. Ortiz. Transplantation March 15 2014. Vol 97 issue 5". Your team did not use.I like it. well written. good conclusion.Reviewer #2: The investigators conducted this study to evaluate whether PPI use is associated with mortality risk in kidney transplant recipients.While this is important study, the findings of this study alone to evaluate mortality outcome might not adequately worth publishing in this high impact journal without significant modifications/revisions. There are many factors that can affect mortality risk in kidney transplant patients, such as cardiovascular, infection, rejection, allograft outcomes. However, the investigators barely look into this.It is possible that the investigators plan to separate these outcomes to several publications, since the investigators have published their works by using this cohort to evaluate several outcomes e.g. hypomagnesemia (PMID: 31817776) and iron status (PMID: 31484461)Without knowing the causes of mortality and lack of granularity , this finding of this study does not add much into the field of transplantation.Reviewer #3: I applaud the authors on this significant work. This is an important study as it adds to the growing literature supporting an association between PPI and increased mortality, specifically involving kidney transplant recipients. The authors have provided two different cohorts demonstrating an association between PPI use and increased mortality. Based on current knowledge, I would not be surprised to find that such a positive correlation does exist between PPI and mortality. However, I question whether the reported risk is as great as presented as noted below.Page 7, line 107. Looking at their prior described cohort (reference 28), this study appears to be a retrospective rather than prospective study as the prior cohort was established with an aim that would not have accrued the same information as presented in this study. If the authors can confirm this is accurate, the manuscript should be adjusted accordingly. Page 7, line 112. What other KTR patients were excluded as noted for "concurrent systemic illnesses" aside from the named malignancies other than cured skin cancer, opportunistic infections, and overt congestive heart failure? It should be noted that this study may not be generalizable to KTR patients who had these systemic illnesses. As opportunistic infections can be an acute process rather than chronic, it would have been helpful to include these patients. In addition, it would be interesting to know the results from patients with overt CHF as these patients may have an increased atherosclerotic burden compared to non-CHF patients. As such, these patients The patients in the non-PPI group had a significantly increased time since transplantation compared to the PPI group. This would seem to cause a significant survival selection bias. This may be due to the retrospective nature (see above regarding question of retrospective vs prospective) of this study. If this was a prospective study as the authors stated, then performing a study where patients were at the same timepoint after kidney transplant with or without PPI would have helped avoid this significant survival bias . I appreciate that the authors adjusted for this factor, but as we know, there are many unknown confounders that may be present in an individual who has survived with a functional graft already for 9 years vs an individual for 4 years.Table 1: It would have been interesting to include antiplatelet use. Previously, there was some concern that PPI's may interfere with clopidogrel efficacy, and KTR are at high risk for CV complications and mortality. Furthermore, since patients on dual antiplatelet medications for coronary atherosclerosis either before or after stenting tend to also be on PPI's, these patients are likely at higher risk for CV complications and mortality. The omission of patients with overt heart failure and not adjusting for antiplatelet agents may influence the results of this study.Page 11, line 220. What percentage of patients from the PPI vs non-PPI group developed graft failure? Along this line, was the eGFR was only determined at the initial baseline measurement or was it determined closer to patient death? Since tubulointerstitial nephritis (acute or chronic) is associated with PPI's, it would have been useful to see if PPI patients also had a decreased eGFR at time of death. Since renal function is associated with mortality, this would be another important covariate to control for  combined? What was this result?I appreciate the authors providing several mechanisms for PPI use and increased mortality. Minor english revisions recommended to help improve readability.Reviewer #4: The authors have attempted to investigate the effect of PPI therapy on mortality in a large single center cohort of stable outpatient KTR, and performed independent replication of the results in a second cohort. Cohort demographics and characteristics - is the sample representative of wider population? It is noted from the discussion on limitations that subjects were predominantly Caucasian - what other comparisons can be made to better understand generalisability of the results? It is also noted that the data used is from a previously described cohort, but a brief overview or summary within this manuscript would be helpful to the reader in their assessment of how robust the findings and conclusions are. Confounding has been accounted for adequately, given the limitations of the data, and the description, production and presentation of all 6 models is very useful. Under methods:"Follow-up was recorded until September 2015. "Can follow-up now be extended? The current data has median follow-up of 5.3 [4.5-6.0] years, which could almost be doubled in length adding great value to the longitudinal aspects of this study.The statistical techniques appear to be appropriate for the data and the research question in hand.It is also good to see that a sensitivity analysis of missing data has been performed, by comparing mulitple imputation results to no imputation.Did the authors undertake any sub-group anaylses ? Was there an association between outcome and age, for instance, as suggested by the literature [23-25]?The conclusions are fair given the study design undertaken, and the manuscript as a whole is well written, clear and concise.The Tables and Figures are also clear and informative.Any attachments provided with reviews can be seen via the following link:[LINK] 17 Mar 2020AttachmentResponse to the reviewers_final.docxSubmitted filename: Click here for additional data file. 22 Apr 2020Dear Dr. Douwes,Thank you very much for re-submitting your manuscript "The Association between Use of Proton-Pump Inhibitors and Excess Mortality after Kidney Transplantation: A Prospective Cohort Study." (PMEDICINE-D-20-00132R2) for review by PLOS Medicine.I have discussed the paper with my colleagues and the academic editor and it was also seen again by xxx reviewers. 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When you receive this version you should check and revise it very carefully, including figures, tables, references, and supporting information, because corrections at the next stage (proofs) will be strictly limited to (1) errors in author names or affiliations, (2) errors of scientific fact that would cause misunderstandings to readers, and (3) printer's (introduced) errors.If you are likely to be away when either this document or the proof is sent, please ensure we have contact information of a second person, as we will need you to respond quickly at each point.PRESSA selection of our articles each week are press released by the journal. You will be contacted nearer the time if we are press releasing your article in order to approve the content and check the contact information for journalists is correct. If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. 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P < 0.05). At the last follow-up, the limb length difference in the modular group (2.3 ± 2.7 mm) was significantly lower than that in the nonmodular group , and the postoperative prosthesis subsidence in the modular group  was significantly less than that in the nonmodular group . Both modular and nonmodular tapered fluted titanium stems can achieve satisfactory mid-term clinical and imaging results in patients who underwent femoral revision. The modular stems have good control of lower limb length and low incidence of prosthesis subsidence.Both modular and nonmodular tapered fluted titanium stems are commonly used in revision total hip arthroplasty (THA). However, which type of femoral stem is superior remains controversial. The purpose of this study was to assess the clinical and radiographic outcomes of modular and nonmodular tapered fluted titanium. The clinical data of patients undergoing primary revision THA from January 2009 to January 2013 in two institutions were retrospectively analyzed. According to the type of prosthesis used on the femoral side, the patients were divided into the modular group  and nonmodular group . The operative time, hospital stay, blood loss, blood transfusion volume, hip function, hip pain, limb length discrepancy, imaging data, and complications were compared between the two groups.A total of 218 patients were followed up for 78–124 months, with an average of 101.5 months. The incidence of intraoperative fracture in the modular group (16.7%) was significantly higher than that in the nonmodular group (4.5%; ( In the UK, the hip revision rate has exceeded 10% in 2015 and is expected to increase by 31% by 20302. With the development of materials science, prosthesis design, and surgical techniques, the initial THA has been increased year by year around the world. Unfortunately, patients were found to be younger. Therefore, the revision surgery is also increasing yearly. In hip revision, 40% of patients require only acetabular revision, and 60% require femoral revision3.Total hip arthroplasty (THA) is an effective treatment for end-stage hip disease. It not only relieves pain caused by hip disease but also improves hip function. In 2005, a total of 40,800 patients underwent hip revision surgery in the United States. These cases account for approximately 17.5% of all hip arthroplasty, and this number is expected to increase by 137% by 20303. The loosening rate of cement prosthesis after revision is high5. In view of the high loosening rate after revision of the cemented prosthesis, some scholars proposed the use of a biological long-handle revision prosthesis of the femoral side in revision6. In North America, extensively coated cylindrical stems have been widely used for many years. However, concerns regarding severe postoperative thigh pain (8–9%), severe stress shielding of the proximal femur (6–7.6%), and high failure rate of patients with Paprosky type III femoral defects remain9. Many scholars10 believe that the tapered stem with ridge is more suitable when bone defects affect the rubbing requirements than cylindrical stems. During femoral revision, tapered stems can deal well with various bone defects.The cement prosthesis will lead to a decrease in the cement–bone interface bonding strength. This reduction can affect the stability of the prosthesis, thereby influencing the long-term efficacy. Studies have shown that the cement–bone interface’s bonding strength is only 20.6% of the initial replacement. If the hip joint is subjected to re-revision, the intensity is only 6.8% of the initial replacement13. They also have some disadvantages such as high incidence of intraoperative fracture, corrosion, and fracture at the proximal and distal parts of the prosthesis15. Some scholars suggested the use of nonmodular tapered fluted titanium stems in femoral revision. They believe that the implantation of nonmodular tapered fluted titanium stems is simple, and the prosthesis does not have the disadvantages of corrosion and fracture. However, nonmodular tapered fluted titanium stems have the disadvantages of postoperative dislocation and high incidence of prosthesis sinking16.Previous studies have shown that modular tapered fluted titanium stems have the advantages of easy adjustment of lower limb length, forward inclination, and eccentricity18 only explored the different early clinical effects of the two stems. The mid- and long-term efficacy of modular and nonmodular tapered fluted titanium remains uncertain. The purpose of this study was to assess the clinical and radiographic outcomes of modular and nonmodular tapered fluted titanium.At present, distal fixation femoral prostheses are mainly divided into modular and nonmodular tapered fluted titanium stems, and both types have been widely used. There is no consensus in the academic community on which prosthetic design is presently appropriate for femoral revision. However, in revision, there is no theoretical basis in choosing modular or nonmodular tapered fluted titanium stems. The criteria for clinical selection of modular or nonmodular tapered fluted titanium stems are often based on the preferences and experience of the operators. The selection of a suitable prosthesis can not only improve the success rate of revision surgery but also improve the prognosis of patients. Thus, the design characteristics, clinical efficacy, and radiographic results of the two kinds of prostheses should be compared to provide a basis for the clinical selection of revision prosthesis. Previous studiesPatients who underwent revision THA with modular or nonmodular tapered fluted titanium stems in the Affiliated Hospital of Xuzhou Medical University and Hyogo College of Medicine Hospital from January 2009 to January 2013 were reviewed. This retrospective study was approved by the local Ethical Committee . All methods were performed in accordance with the relevant guidelines and regulations. Informed consent was obtained from all patients.A total of 239 patients (239 hips) were initially identified. Twelve patients were lost to follow-up, and 9 patients died of causes unrelated to their operation. The remaining 218 hips (218 patients) were analyzed. On the basis of the type of prosthesis used on the femur side, the patients were divided into the modular group  and nonmodular group . The general information of the patients in the two groups is shown in Table There was no significant difference in gender, age, BMI, initial replacement to repair time, reasons for revision, type of bone defect, ASA classification, number of acetabular side revisions, preoperative Harris score, Visual Analogue Scale/Score (VAS) score, and limb length discrepancy (LLD) between the two groups.19. LLD was assessed via a subjective measurement method20.The patients were clinically evaluated on the basis of operation time, dominant blood loss (intraoperative blood loss + postoperative drainage volume), blood transfusion volume, hospitalization time, hip function, thigh pain, LLD, radiographic data , and complications . Hip function was assessed by the Harris hip score before surgery and during each visit. Thigh pain was assessed using the VAS scores21. Prosthetic subsidence was assessed by the criteria set forth by Callaghan et al.22. Stability of femoral prosthesis was assessed with the standard evaluation proposed by Engh et al.23. Heterotopic ossification was assessed using the Brooker24 standard.The degree of the femoral defect was evaluated from the preoperative X-ray according to the Paprosky classificationP < 0.05 was considered statistically significant.The analysis and production of data and charts were processed by IBM SPSS Statistics 19.0 statistical software  and GraphPad Prism6.0 . Continuous variables were analyzed using Wilcoxon rank-sum tests. Categorical variables were analyzed by the Pearson chi-square or Fisher exact tests. Kaplan–Meier survivorship analyses were conducted with the endpoint defined as any reoperation due to septic or aseptic complications and with the endpoint defined as any reoperation due to aseptic complications. Test level was set at both sides α = 0. 05, and 17. We estimated that 194 participants would be required to enable detection of significant difference at the 5% significance level with 85% power.Power of the original study. The observational cohort study was powered to detect a distance of postoperative prosthetic subsidence as the minimum mean difference of significance, and the standardized difference (0.39) was calculated using the standard deviation (0.98) based on an earlier report by Huang et al.P > 0.05). A comparison of intraoperative data between the two groups is shown in Table No significant differences were found between the two groups in terms of operation time, hospitalization time, blood loss, and blood transfusion (P < 0.05) and 40.1 ± 6.6 preoperatively to 85.5 ± 3.8 in the nonmodular group (P < 0.05). The final follow-up VAS score decreased from 7.6 ± 1.3 preoperatively to 1.9 ± 0.5 in the modular group (P < 0.05) and 7.5 ± 1.1 preoperatively to 1.8 ± 0.5 in the nonmodular group (P < 0.05). The leg length discrepancy of the modular group decreased from 18.7 ± 6.6 mm preoperatively to 2.3 ± 2.7 mm at the final follow-up (P < 0.05); the leg length discrepancy of the nonmodular group decreased from 20.3 ± 6.1 mm preoperatively to 5.6 ± 3.5 mm at the final follow-up (P < 0.05). At the final follow-up, the leg length discrepancy of the modular group was significantly lower than that of the nonmodular group (P < 0.05). A comparison of pain and hip function between the two group is shown in Table A total of 218 patients were followed-up for an average of 101.5 months. The modular and nonmodular groups did not significantly differ in the most recent postoperative Harris hip score and VAS scores. The most recent postoperative Harris hip score increased from 40.5 ± 6.1 preoperatively to 86.4 ± 3.9 in the modular group , which was significantly lower than that in the nonmodular group  and nonmodular groups . Among the 18 cases of fracture in the modular group, femoral trochanteric fracture occurred in 12 cases (with wire banding), femoral shaft fracture was noted in six cases (with wire banding), and all fractures had bone healing. In the nonmodular group, only five cases suffered from femoral shaft fracture (with wire binding) and also demonstrated bone healing.Intraoperative fractures occurred more frequently in the modular group  than in the nonmodular group . Patients with periprosthetic fractures were treated with open reduction and internal fixation.Two cases (1.9%) of periprosthetic fracture occurred in the modular group, and two cases (1.8%) of periprosthetic fracture were noted in the nonmodular group (P > 0.05). Three cases of frequent dislocation after closed reduction was treated with replacement of lining and femoral head size.No dislocation occurred in the modular group, and three cases (2.7%) of hip dislocation occurred in the nonmodular group (P > 0.05).Eighteen cases (16.7%) presented heterotopic ossification in the modular group (12 Brooker Degree I and 6 Degree II), whereas 20 cases (18.2%) demonstrated heterotopic ossification in the nonmodular group (16 Brooker Degree I and 4 Degree II). No significant differences were found in the two groups  and nonmodular (Wagner SL and AK-SL) stems are grit-blasted prostheses with a conical groove design, which can increase the contact area with diaphyseal cortex and achieve axial stability with the tapered geometry. Eight longitudinal ribs ensure rotational stability. Both stems have a titanium shaft with a circular cross section and a 2° taper. Titanium alloy can significantly reduce the elastic modulus in both kinds of prostheses to reduce the incidence of postoperative stress shielding and thigh pain. The design difference between the modular and nonmodular prostheses is the distal end of the modular prosthesis, which has a 3° tilt angle that matches the shape of the femur. However, this design was not found in Wagner SL and AK-SL. In addition, the significant difference between modular and nonmodular prostheses is a proximal design. Wagner SL and AK-SL femoral prostheses have an integrated design, and the modular femoral prosthesis adopts a neck component design made of multiple components. A length-adjusting washer in the proximal segment allows the length of the stem to be extended by 30 mm. Surgeons can select different components depending on the actual situation to achieve the desired leg length and facilitate the adjustment of anteversion and eccentricity.27 reported an average prosthetic subsidence of 1 mm in patients who underwent femoral revision with modular tapered fluted titanium stems. This finding was similar to the results of this study.This study showed that the LLD of the modular group was significantly smaller than that of the nonmodular group. This difference was mainly because modular tapered fluted titanium stems can be used to precisely adjust the length of the lower limb through the combination of proximal components during the operation. However, due to the integrated design of nonmodular tapered fluted titanium stems, the limb length cannot be adjusted again after the prosthesis is inserted. Therefore, the length of the lower limb with modular tapered fluted titanium stems demonstrates better control than that with nonmodular tapered fluted titanium stems. When the biological prostheses are used in revision, the prostheses will exhibit different degrees of subsidence, and most of them occur in the first year after surgery. The intraoperative prosthesis and the femoral medullary cavity are insufficiently fitted, and sinking can occur when the lower limb is loaded with weight. In this study, the modular stem and nonmodular stem also experienced different degrees of postoperative subsidence. At the last follow-up, the postoperative subsidence in the modular tapered fluted titanium stems was significantly lower than that in the nonmodular tapered fluted titanium stems. Park et al.29. In view of the high postoperative subsidence of the first- and second-generation Wagner SL stems, the modified third-generation Wagner SL stem is widely used in femoral revision. Although the postoperative subsidence is lower than the previous two generations, the subsidence was significantly greater compared with the modular tapered fluted titanium stems. The modular tapered fluted titanium stem is designed with a three-degree curvature to better match the femur, and the medullary cavity is better filled. The intraoperative prosthesis makes a good compression match with the femoral bone marrow cavity, while the nonmodular stem is designed without curvature. Therefore, an adequate match with the femoral bone marrow cavity may be difficult in nonmodular tapered fluted titanium stems. Second, surgeons need to consider the soft tissue tension of the hip joint when implanting nonmodular stems. Repeated tests are often performed to reduce both the risk of dislocation and the difficulty of reduction. Moreover, the distal part of the nonmodular stem is not fully fixed, and the immediate stability of the prosthesis cannot be guaranteed, which increases the risk of later prosthesis sinking or loosening. The distal part of the prosthesis can be firmly established when the modular stem is used. The femoral head and proximal component can be used to adjust the length, eccentricity, and forward inclination of the prosthesis, thereby reducing the length of limb discrepancy and the risk of prosthesis loosening and dislocation.In this study, the average postoperative subsidence of prosthesis in the nonmodular group was 2.20 ± 1.94 mm. The subsidence rate was found to be greater than 10 mm in 4% and 24% of first-generation and second-generation Wagner SL stems, respectively31. Stem subsidence may have drawbacks, such as limb shortening and altered hip biomechanics33. Tangsataporn et al.34 reported 13 hips (13.1%) with subsidence of at least 10 mm. In that group, five of the 13 (38.5%) stems required repeat femoral revision because of stem aseptic loosening. Moreover, no dislocation caused by subsidence was found. In our study, dislocation did not occur in the modular group, and three cases (2.7%) of hip dislocation occurred in the nonmodular group. Park et al.35 believed that the low dislocation rate of the modular stem may be related to its ability to make appropriate adjustments to the length of lower limbs, eccentricity, soft tissue tension around the hip joint, and anterior angle with the help of the special design of proximal components during the revision.Concerns regarding subsidence related to the dislocation risk persist in the field. In our study, most of the reasons for dislocation were due to the poor place of the prosthetic position, leading to early postoperative dislocation; no dislocation caused by subsidence was found. Stem subsidence was early after weight bearing, but all prosthetic subsidence stopped within 1 year after operation. The patient’s soft tissue adapts to subsidence and maintains good tension. Moreover, the hip joint can be stably maintained to a certain extent due to scar contracture. Previous studies have shown that notable tapered stem subsidence after surgery is uncommon; the majority of stems become stable when it does occur, rarely going on to aseptic loosening25 reported an incidence of intraoperative fracture of modular tapered fluted titanium stems of 16.9%, and this percentage was similar to the results obtained in this study. Previous studies have reported that the fracture rate of modular tapered fluted titanium stems during femoral revision can reach 16–32%37, and patients with bone defects of Paprosky type IIIB–IV are likely to have fractures during surgery25. Pattyn et al.37 reported that the incidence of intraoperative fracture is as high as 32% when modular tapered fluted titanium stems are used for femoral revision, which may be correlated with the intraoperative operation. We speculate that the high incidence of intraoperative fracture of modular tapered fluted titanium stems may be related to the design of the modular prosthesis and the operation experience of the operator. Compared with periprosthetic fractures, dislocation is one of the more common complications in revision. In this study, three cases of dislocation in the nonmodular group were due to extreme hip flexion, adduction, and internal rotation; the patient was treated with replacement of the inner liner and the femoral head. The advantage of modular tapered fluted titanium stems is that the anterior inclination, eccentricity, and length of the lower limb can be adjusted by changing the neck component, thereby reducing the incidence of dislocation.In this study, 18 cases (16.7%) presented intraoperative fracture in the modular group. Huang27. By contrast, the nonmodular tapered fluted titanium stems avoids the potential risk of modular fretting corrosion and joint dissociation.Some scholars believe that modular tapered fluted titanium stems are prone to fretting wear and corrosion fracture at the connection of proximal components. The proximal cervical junction is cylindrical and does not have a tapered design, allowing the stress concentration to increase. The proximal cervical component of the prosthesis is connected with the distal handle by a locking screw. If the locking screw fails, the teeth on both proximal and distal components will not bite each other, resulting in the proximal part to loosen, followed by mechanical separation. In the present study, the modular groups demonstrated two proximal segment dissociation, and the incidence of mechanical failure of the modular stem was similar to that in the study of Park et al.The present study has several limitations to acknowledge. First, the retrospective nature of the study makes it prone to selection bias. Although prospective randomized controlled studies can better control confounders and selective bias, they are difficult to be carried out in revision surgery. Second, the sample size was limited, and the selection of prosthesis was limited. Therefore, the results obtained were limited and could not be widely generalized to all modular and nonmodular tapered fluted titanium stems. Given the low incidence of subsidence, this study is underpowered, limiting our ability to correlate subsidence with the risk of dislocation. A large investigation with more patients experiencing subsidence of the stem would be necessary to provide greater statistically significant information on the subsidence related to the dislocation risk for this finding. Third, the attending surgeons who performed the revision came from two different institutions.In conclusion, both modular and nonmodular tapered fluted titanium stems can achieve satisfactory mid-term clinical and radiographic results in patients who undergo femoral revision. Furthermore, compared with nonmodular tapered fluted titanium stems, modular tapered fluted titanium stems have good control of lower limb length and low incidence of prosthetic subsidence.