Adults with chronic kidney disease (CKD) are hospitalized more frequently than those without CKD, but the magnitude of this excess morbidity and the factors associated with hospitalizations are not well known.2. CRIC participants had an unadjusted overall hospitalization rate of 35.0 per 100 person-years (PY) [95% CI: 34.3 to 35.6] and 11.1 per 100 PY [95% CI: 10.8 to 11.5] for cardiovascular-related causes. All-cause, non-cardiovascular, and cardiovascular hospitalizations were associated with older age (≥65 versus 45 to 64 years), more proteinuria (≥150 to <500 versus <150 mg/g), higher systolic blood pressure (≥140 versus 120 to <130 mmHg), diabetes (versus no diabetes), and lower eGFR (<60 versus ≥60 ml/min/1.73m2). Non-Hispanic black (versus non-Hispanic white) race/ethnicity was associated with higher risk for cardiovascular hospitalization , while risk among females was lower . Rates of cardiovascular hospitalizations were higher among those with ≥500 mg/g of proteinuria irrespective of eGFR. The most common causes of hospitalization were related to cardiovascular (31.8%), genitourinary (8.7%), digestive (8.3%), endocrine, nutritional or metabolic (8.3%), and respiratory (6.7%) causes. Hospitalization rates were higher in CRIC than the NIS, except for non-cardiovascular hospitalizations among individuals aged >65 years. Limitations of the study include possible misclassification by diagnostic codes, residual confounding, and potential bias from healthy volunteer effect due to its observational nature.Data from 3,939 participants enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study between 2003 and 2008 at 7 clinical centers in the United States were used to estimate primary causes of hospitalizations, hospitalization rates, and baseline participant factors associated with all-cause, cardiovascular, and non-cardiovascular hospitalizations during a median follow up of 9.6 years. Multivariable-adjusted Poisson regression was used to identify factors associated with hospitalization rates, including demographics, blood pressure, estimated glomerular filtration rate (eGFR), and proteinuria. Hospitalization rates in CRIC were compared with rates in the Nationwide Inpatient Sample (NIS) from 2012. Of the 3,939 CRIC participants, 45.1% were female, and 41.9% identified as non-Hispanic black, with a mean age of 57.7 years, and the mean eGFR is 44.9 ml/min/1.73mIn this study, we observed that adults with CKD had a higher hospitalization rate than the general population that is hospitalized, and even moderate reductions in kidney function were associated with elevated rates of hospitalization. Causes of hospitalization were predominantly related to cardiovascular disease, but other causes contributed, particularly, genitourinary, digestive, and endocrine, nutritional, and metabolic illnesses. High levels of proteinuria were observed to have the largest association with hospitalizations across a wide range of kidney function levels. Hsiang-Yu Chen and colleagues report the factors associated with hospitalization in patients with Chronic Kidney Disease. Chronic kidney disease (CKD)  is increasingly common globally, and individuals with CKD have a high risk of health complications, including hospitalizations.Many of the hospitalizations experienced by those with CKD are thought to be due to cardiovascular disease, but little else is known about the other causes for hospitalization or why people with kidney disease are at higher risk of hospitalizations.Learning more about causes of hospitalization and risk factors for hospitalizations can guide outpatient management.Research to date on hospitalizations in kidney disease has mainly focused on those with dialysis-dependent kidney disease.We looked at hospitalization data from adults with CKD who were followed for nearly 10 years.We classified hospitalizations by the primary discharge code and found that non-cardiovascular causes, such as genitourinary-, digestive-, and endocrine-related causes, comprised the majority of hospitalizations and that the largest single contributor to hospitalizations was due to cardiovascular reasons.We modeled the risk of hospitalizations with patient characteristics, such as age and sex, and clinical factors, such as level of kidney function, blood pressure, and proteinuria, and found that high levels of proteinuria were found to have a high risk of hospitalization regardless of kidney function level, and the risk of hospitalizations occurred even at moderate levels of kidney function.We also compared the hospitalization data from individuals with known CKD to a sample of the general hospitalized population in the United States and found that adults with CKD have higher hospitalization rates than this general sample.These findings highlight the need for developing better approaches to identifying patients at risk for severe complications of CKD and to guiding outpatient management strategies to improve outcomes in CKD.The findings may be particularly relevant to health care providers in general medicine since the increased risk of hospitalization occurred with even moderate reductions in kidney function, which do not typically correspond to being under the care of a kidney disease expert.Our study’s findings might not be applicable to other CKD populations since the study enrolled volunteers, who might be healthier than other populations. The prevalence of chronic kidney disease (CKD) is high, affecting up to 15% to 20% of the adult population in the United States (US) . NumerouCardiovascular disease has been identified as a major cause of hospitalization among those with advanced kidney disease, but little is known about the other causes contributing to the high burden of hospitalization among those with earlier stages of CKD ,6,19,20.In this manuscript, we characterize the burden of hospitalizations within a diverse study population with mild-to-moderate CKD enrolled in the multicenter observational Chronic Renal Insufficiency Cohort (CRIC) Study. We also explore associations of demographic and kidney-specific factors with rates of hospitalization, characterize the leading causes of hospitalization, and compare the rates of hospitalizations in this population with rates in a sample representative of nearly all hospitalizations in the US general population.This study is reported as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline .2 for individuals aged 21 to 44 years, 20 to 60 mL/min/1.73m2 for individuals aged 45 to 64 years, and 20 to 50 mL/min/1.73m2 for individuals aged 65 to 74 years. Major exclusion criteria included prior dialysis lasting more than 1 month, NYHA Class III/IV heart failure, polycystic kidney disease, or other primary renal diseases requiring active immunosuppression. Participants completed annual clinic visits at which data were obtained, and blood and urine specimens were collected.The CRIC Study enrolled a total of 3,939 men and women between 2003 and 2008 at 7 clinical centers  across the US. Eligibility criteria have been previously described ,26. Age-The National Inpatient Sample (NIS) was utilized as a representation of US nationwide hospitalizations from the year 2012. The NIS is the largest available all-payer inpatient database in the public domain that includes hospital discharge data, reflecting approximately 95% of all hospital discharges within the US . The yeaHospitalizations between 2003 and 2018 among CRIC participants were ascertained through self-report and hospital queries and confirmed after review of medical records by study personnel. Any hospitalization that occurred during the follow-up period was accounted for. The unit of observation in the NIS was an inpatient stay record, and after applying discharge weights, the amount of discharges in the US was estimated .The length of hospitalization was calculated as the date of discharge minus the date of admission, plus one. Hospitalizations that were longer than 1 calendar day are the primary focus of this paper; hospital stays with an admission and discharge on the same calendar day are classified as ≤1-day hospitalizations. To characterize the specific cause of each hospitalization, the primary ICD-9 or ICD-10 admission code was extracted from the hospitalization discharge record and classified into 1 of 18 categories using the CCS Software developed by the AHRQ . The cau2) 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. Please submit a clean version of the paper as the main article file; a version with changes marked should be uploaded as a marked up manuscript.In revising the manuscript for further consideration, your revisions should address the specific points made by each reviewer and the editors. Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/figures. 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Please see our author guidelines for more information: References- please use square brackets throughout and use Vancouver style for bibliography Methods- please briefly state where the participants were recruited in the USOn page 8- please remove the information regarding the funding source as this is pulled from the article meta-data onlyPlease provide 95% confidence intervals and p values throughout as needed. Please note we need exact p values unless p<0.001Please present and organize the Discussion as follows: a short, clear summary of the article's findings; what the study adds to existing research and where and why the results may differ from previous research; strengths and limitations of the study; implications and next steps for research, clinical practice, and/or public policy; one-paragraph conclusion.Did your study have a prospective protocol or analysis plan? Please state this (either way) 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.STROBE- please specify where individual items on the checklist can be found using paragraphs and sections. The Data Availability Statement (DAS) requires revision. For each data source used in your study: a) If the data are freely or publicly available, note this and state the location of the data: within the paper, in Supporting Information files, or in a public repository (include the DOI or accession number).b) If the data are owned by a third party but freely available upon request, please note this and state the owner of the data set and contact information for data requests (web or email address). Note that a study author cannot be the contact person for the data.c) If the data are not freely available, please describe briefly the ethical, legal, or contractual restriction that prevents you from sharing it. Please also include an appropriate contact (web or email address) for inquiries .Comments from the reviewers:Reviewer #1: I confine my remarks to statistical aspects of this paper. The general approach is fine but I have a couple issues to resolve before i can recommend publication.https://medium.com/@peterflom/what-happens-when-we-categorize-an-independent-variable-in-regression-77d4c5862b6c?source=friends_link&sk=1428cd15968e218268121dc507ce8025The biggest one is that continuous independent variables should not be categorized. In *Regression Modeling Strategies* Frank Harrell lists 11 problems that this causes and sums up "nothing could be more disastrous". I wrote a blog post taking a graphical look at what can happen: Other issues: p. 7 Please operationalize all variables. p 9 Give the SD for agehttp://biostat.mc.vanderbilt.edu/wiki/Main/DynamitePlots)Fig 1: Use a line plot for age and do not use "dynamite plots"  for 2012. They found higher hospitalization rate in the CRIS than NIS, predominantly related to diverse illnesses other than cardiovascular disease.I offer the following suggestions for consideration:1. The concluding statement in the abstract "Adults with CKD appear to have a substantially higher hospitalization rate than those without CKD" is not supported by the results. 2. On page 8, under statistical analysis, please specify the start of follow-up in the CRIC cohort and the median follow-up time. Also, describe how the hospitalization rates were calculated for the NIS.3. Please indicate the reasoning for selecting the year 2012 for NIS data.4. NIS data represent the number of discharge diagnoses per hospital stay, not per patient, so the incidence of any hospitalization is overestimated, an aspect that should be discussed as a limitation. Along this line, it is not clear if the numerator for the CRIC data included the first (incident) hospitalization during the follow-up period, or any hospitalizations. If the former is true, the authors may consider discussing how this aspect affects the comparison with NIS rates. The authors ought to specify how the numerator was counted in each of the two data sources.Reviewer #3: This is an interesting paper and highlights a major issue for patients with even fairly mild chronic kidney disease. The data presented genuinely contribute to novel understanding of this issue and in my opinion will be useful for research, healthcare policy and resource allocation. The CRIC cohort is well known, but this looks like a completely new and more detailed analysis compared to any of their other work. To my reading, this is well presented, the analyses look sound and the tables and figures are informative. I have little to suggest to this and I think this could be a very useful paper for others working in this field.My main comments are around the grammar, or messaging in the paperAbstract.1.I presume they mean 500mg/g of proteinuria? - there is no explanation as to what this measurement refers to. Also why present this threshold in the abstract when most of the thresholds for uPCR in the paper are 150mg/g. Is this correct? I presume this is as 500mg/g is the upper category - it could be clarified as to why this value appears where it does2. Although I accept that the majority of illnesses are not cardiovascular, the single biggest disease by far affecting these patients is cardiovascular disease as their analysis shows (31.8% compared to 8.7% for the next condition down). I think the message should be slightly rephrased to make sure that the message about CVD is not diminished too muchMain textThey should go through this carefully for units etc. I found a few instances where the units had dropped off inappropriately e.g. for GFR on p10. There are probably others. I don't view it as the role of reviewer to be a proof reader!Any attachments provided with reviews can be seen via the following link:[LINK] 30 Sep 2020AttachmentPLOS_Medicine_Response_to_Reviewers.docxSubmitted filename: Click here for additional data file. 26 Oct 2020Dear Dr. Schrauben,Thank you very much for re-submitting your manuscript "Description of Hospitalizations Among Adults with Chronic Kidney Disease: An Observational Longitudinal Cohort Study" (PMEDICINE-D-20-01995R2) 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. I am pleased to say that provided the remaining editorial and production issues are dealt with we are planning to accept the paper for publication in the journal.The remaining issues that need to be addressed are listed at the end of this email. Any accompanying reviewer attachments can be seen via the link below. 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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 At the end of the ms, the acknowledgements are mainly funding, I think, which is in the submission form and can be removed. Please ensure all p-values provided are up to three decimal places. All iterations of p<0.0001 should be changed to p<0.001Comments from Reviewers:Reviewer #1: The authors have addressed my concerns and I now recommend publicationPeter FlomReviewer #2: The authors' responses are satisfactory and i have no further comments. Thank you.Reviewer #3: I have no further commentsAny attachments provided with reviews can be seen via the following link:[LINK] 1 Nov 2020AttachmentResponse to Reviewers.docxSubmitted filename: Click here for additional data file. 5 Nov 2020Dear Dr. Schrauben, On behalf of my colleagues and the academic editor, Dr. Meda E Pavkov, I am delighted to inform you that your manuscript entitled "Hospitalizations Among Adults with Chronic Kidney Disease in the United States: A Cohort Study" (PMEDICINE-D-20-01995R3) has been accepted for publication in PLOS Medicine. PRODUCTION PROCESSBefore publication you will see the copyedited word document (within 5 business days) and a PDF proof shortly after that. The copyeditor will be in touch shortly before sending you the copyedited Word document. We will make some revisions at copyediting stage to conform to our general style, and for clarification. 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Exposure to environmental chemicals may be a modifiable risk factor for progression of chronic kidney disease (CKD). The purpose of this study was to examine the impact of serially assessed exposure to bisphenol A (BPA) and phthalates on measures of kidney function, tubular injury, and oxidative stress over time in a cohort of children with CKD.2-isoprostane). Clinical renal function measures included estimated glomerular filtration rate (eGFR), proteinuria, and blood pressure. Linear mixed models were fit to estimate the associations between urinary concentrations of 6 chemical exposure measures  and clinical renal outcomes and urinary concentrations of KIM-1, NGAL, 8-OHdG, and F2-isoprostane controlling for sex, age, race/ethnicity, glomerular status, birth weight, premature birth, angiotensin-converting enzyme inhibitor use, angiotensin receptor blocker use, BMI z-score for age and sex, and urinary creatinine. Urinary concentrations of BPA, PA, and phthalate metabolites were positively associated with urinary KIM-1, NGAL, 8-OHdG, and F2-isoprostane levels over time. For example, a 1-SD increase in ∑di-n-octyl phthalate metabolites was associated with increases in NGAL , KIM-1 , 8-OHdG , and F2-isoprostane  over time. BPA and phthalate metabolites were not associated with eGFR, proteinuria, or blood pressure, but PA was associated with lower eGFR over time. For a 1-SD increase in ln-transformed PA, there was an average decrease in eGFR of 0.38 ml/min/1.73 m2 . Limitations of this study included utilization of spot urine samples for exposure assessment of non-persistent compounds and lack of specific information on potential sources of exposure.Samples were collected between 2005 and 2015 from 618 children and adolescents enrolled in the Chronic Kidney Disease in Children study, an observational cohort study of pediatric CKD patients from the US and Canada. Most study participants were male (63.8%) and white (58.3%), and participants had a median age of 11.0 years (interquartile range 7.6 to 14.6) at the baseline visit. In urine samples collected serially over an average of 3.0 years (standard deviation [SD] 1.6), concentrations of BPA, phthalic acid (PA), and phthalate metabolites were measured as well as biomarkers of tubular injury  and oxidative stress (8-hydroxy-2′-deoxyguanosine [8-OHdG] and FAlthough BPA and phthalate metabolites were not associated with clinical renal endpoints such as eGFR or proteinuria, there was a consistent pattern of increased tubular injury and oxidative stress over time, which have been shown to affect renal function in the long term. This raises concerns about the potential for clinically significant changes in renal function in relation to exposure to common environmental toxicants at current levels. Melanie H. Jacobson and colleagues investigate correlations between exposures to chemicals and kidney function in children. The prevalence of chronic kidney disease has been steadily increasing over the last 40 years.While there are several known risk factors, such as diabetes and hypertension, few are potentially modifiable.Recent work has suggested kidney function may be affected by exposure to environmental chemicals such as bisphenols and phthalates, which are synthetic compounds used in the manufacturing of plastics and other consumer products.However, these chemicals are non-persistent, and no longitudinal studies to our knowledge have been conducted to investigate their potential impact on kidney function over time.In urine samples collected annually over 5 years from 618 children and adolescents with chronic kidney disease, we measured bisphenol A, phthalates, and biomarkers of tubular injury and oxidative stress.Clinical renal function outcomes were also monitored and collected over 5 years.We found that bisphenol A and phthalates were associated with increased tubular injury and oxidative stress biomarkers.Although phthalic acid was associated with lower estimated glomerular filtration rate over time, neither bisphenol A nor other phthalates were associated with clinical renal outcomes.Bisphenol A and phthalates were not associated with clinical renal function outcomes, but showed consistent positive associations with tubular injury and oxidative stress, which may signal the potential for clinical events to manifest with prolonged follow-up.These findings raise concern about the potential for clinically relevant changes to renal function to develop over time in relation to environmental exposures at current levels.This study suggests that exposure to environmental chemicals may be a potentially modifiable risk factor for the progression of chronic kidney disease. Chronic kidney disease (CKD) is a growing health problem in children and adults . In the There are a number of traditional risk factors associated with CKD progression to ESKD in children including hypertension, obesity, diabetes, and altered divalent mineral metabolism ,10–12. ISurveys of healthy children and adults in the US indicate that exposure to BPA and phthalates is ubiquitous –28, and We previously reported findings from a cross-sectional analysis of urinary BPA and phthalate levels in relation to kidney function in children and adolescents with CKD enrolled in the Chronic Kidney Disease in Children (CKiD) observational study ,42. Our 2-isoprostane.In this study, we evaluated the associations between longitudinally measured urinary BPA and phthalates and the trajectory of renal function over a 5-year observation period using a variety of measures over time: eGFR, proteinuria, systolic and diastolic blood pressure , and urinary biomarkers of tubular injury: kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL). In addition, in order to assess the plausibility of a potential mechanism of action, we examined the associations between longitudinally measured urinary BPA and phthalates and serially assessed urinary oxidative stress biomarkers: 8-hydroxy-2′-deoxyguanosine (8-OHdG) and FA prospective analysis plan was followed and is provided in The CKiD study is a multi-center prospective cohort study of children aged 6 months to 16 years with mild-to-moderate CKD with the overall goal of identifying predictors and sequelae of CKD progression. The CKiD study procedures and protocol have been previously described ,49. BrieThe institutional review board at each CKiD study site approved the study protocol, and all research was performed in accordance with established guidelines. Written informed consent was obtained from all parents or legal guardians, and assent from all participants depending on their age and institutional guidelines. The New York University School of Medicine Institutional Review Board deemed this project exempt from review due to data collection being complete and the dataset de-identified.Longitudinally collected and stored urine samples were used for exposure assessment. Phthalic acid (PA), 21 individual phthalate metabolites, BPA, and creatinine were analyzed at the Wadsworth Center, New York State Department of Health, Albany, NY. Details on the analytic methods for the phthalates and BPA have been previously described . BrieflyFor all exposures, measures below the limit of detection (LOD) were imputed by the LOD divided by the square root of 2 . For sta2) = 0.413 × height (cm)/serum creatinine.Several correlates of renal function were examined over time. The primary outcome was eGFR, calculated using the modified Schwartz  equation : eGFR , SBP, and DBP. Analytical methods for these measures in the CKiD study have been previously described. All laboratory measures were conducted at the central CKiD laboratory (University of Rochester) ,53. Brieh Report .Two biomarkers of tubular injury were measured: kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL). KIM-1 and NGAL were measured in urine samples at the New York University High Throughput Biology Laboratory. They were quantified by solid phase sandwich ELISAs using the Quantikine Human TIM-1 Immunoassay and Quantikine Human Lipocalin-2 Immunoassay, respectively , according to the manufacturer protocol. All analyses were conducted in duplicate. Intra-assay coefficients of variation (CVs) ranged from 3.6% to 3.7% for KIM-1 and from 2.3% to 3.9% for NGAL. Inter-assay CVs ranged from 0.7% to 4.3% for KIM-1 and from 0.6% to 4.8% for NGAL. Measures below the LOD were imputed by the LOD divided by the square root of 2 .2-isoprostane at the New York University High Throughput Biology Laboratory . 8-OHdG was quantified by competitive ELISA using the OxiSelect Oxidative DNA Damage ELISA . Similarly, F2-isoprostane was measured with a competitive enzyme-linked immunoassay, the OxiSelect 8-iso-Prostaglandin F2α ELISA Kit (Cell Biolabs). All analyses were conducted in duplicate as directed by the manufacturer. Intra-assay CVs ranged from 4.6% to 11.1% for 8-OHdG and from 6.8% to 9.7% for F2-isoprostane. Inter-assay CVs ranged from 3.9% to 16.6% for 8-OHdG and from 14.2% to 15.9% for F2-isoprostane. Measures below the LOD were imputed by the LOD divided by the square root of 2 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. Please submit a clean version of the paper as the main article file; a version with changes marked should be uploaded as a marked up manuscript.In revising the manuscript for further consideration, your revisions should address the specific points made by each reviewer and the editors. Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/figures. While revising your submission, please upload your figure files to the 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. 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 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 24 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  in the subtitle .Abstract – Please add summary demographic information, including mean age and please ensure here and throughout that p values are provided for all quantifiable data and where 95% Cis are given. Please provide a brief outline of the study’s limitations as the final sentence of the ‘Methods and Findings’ section of the abstract. Data – you state that some restrictions apply, then provide a link for the data. Can you clarify what restrictions there are? Is all of the data used in your analysis in the given link?https://journals.plos.org/plosmedicine/s/revising-your-manuscript#loc-author-summaryAt this stage, we ask that you include a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract. Please see our author guidelines for more information: References – in the main text please use square brackets instead if rounded.Line 151- “several sites”, please for relevance provide some of the cities.Was written consent provided (from parents / guardians)?Please provide a call-out to the analysis plan at the start of the Methods section (S1text)Please address the comments from the Academic Editor below as well as the referee's comments. Comments from an Academic Editor:The findings should be interpreted in the context of the fact that no associations were observed between the exposures and clinically relevant outcomes including eGFR (identified as the primary outcome), UPCR, SBP or DBP. Urinary NGAL and KIM-1 are recognised as markers of tubular injury but have not been shown to add additional prognostic value to traditional markers like eGFR and UPCR. In addition, the effect size was modest such that a 1 SD increase in exposure was associated with only a 9% increase in urinary NGAL or a 12% increase in urinary KIM-1.A major limitation of the study is that assessment of chemical exposure was based on assays performed on random spot urine samples. As mentioned by the authors, the half life of these chemical is short (3-16 hours) so it is not clear whether random urine values accurately reflect 24 excretion.Comments from the reviewers:Reviewer #1: Statistical reviewThis study is a cohort study examining association between exposure to bisphenol A and phthalates on various measures of kidney function and damage amongst children with chronic kidney disease.I have some comments on the statistical methods and reporting, which are listed below. 1. Abstract - just for clarity it should be clear how many separate phthalate metabolites were tested for association.2. Abstract - if possible within space constraints, report the association between phthalic acid and eGFR over time as is done for the other associations above.3. Were the groupings of phthalates pre-specified?4. Page 10 - what is the interpretation of the intra- and inter-assay CVs? They seem broadly within the rules of thumb of being below 10 and 15 respectively, but not all. What effect would higher CVs have on the analysis?5. Page 11 - I think for some cases it would be useful to explore how well the model fits the data. The authors do provide a sensitivity analysis to explore how cumulative effects of the exposures affect the clinical variables. When the results differed from the two approaches, perhaps the AIC could be used to show which model fitted better? 6. Page 11 - was there much missing data, and how was it handled? Were there many patients who developed ESKD, and how were they accounted for in the analysis?7. Methods/results - for biomarkers such as NGAL and KIM-1 where multiple exposures were associated, did the authors consider models with more than one exposure included? I would recommend this might be useful if the exposures are correlated, in order to determine whether they were independent associations or not.James WasonReviewer #2: see attachmentAny attachments provided with reviews can be seen via the following link:[LINK] 16 Jul 2020AttachmentReview PLOS Medicine_R1.docxSubmitted filename: Click here for additional data file. 19 Aug 2020Dear Dr. Jacobson,Thank you very much for re-submitting your manuscript "Serially assessed bisphenol A and phthalate exposure and kidney function in children with chronic kidney disease: a longitudinal cohort study" (PMEDICINE-D-20-00109R2) for review by PLOS Medicine.I have discussed the paper with my colleagues and the academic editor and it was also seen again by one reviewer. I am pleased to say that provided the remaining editorial and production issues are dealt with we are planning to accept the paper for publication in the journal.The remaining issues that need to be addressed are listed at the end of this email. Any accompanying reviewer attachments can be seen via the link below. Please take these into account before resubmitting your manuscript:[LINK]plosmedicine@plos.org) will be in touch shortly about the production requirements for your paper, and the link and deadline for resubmission. DO NOT RESUBMIT BEFORE YOU'VE RECEIVED THE PRODUCTION REQUIREMENTS.Our publications team  and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***In revising the manuscript for further consideration here, please ensure you address the specific points made by each reviewer and the editors. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments and the changes you have made in the manuscript. Please submit a clean version of the paper as the main article file. A version with changes marked must also be uploaded as a marked up manuscript file.http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. If you haven't already, we ask that you provide a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract.Please also check the guidelines for revised papers at plosmedicine@plos.org) if you have any questions or concerns.We expect to receive your revised manuscript within 1 week. Please email us , 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 b. Please mention any factors adjusted for in your analyses.c. Please use square brackets when nesting, eg.: “(…[…]…)”d. Please quantify all results with 95% CIs and p values (eg. lines 58-59), including statistically non-significant findings mentioned here (eg. lines 60-61).e. Please remove this sentence (lines 70-73): "This is the first study to examine environmental exposures and biomarkers of tubular injury and oxidant stress in a pediatric population with CKD, and may provide evidence for oxidant stress as a plausible biologic pathway for environmental chemicals to influence kidney function.”6. Line 87: Please correct to “…bisphenol A, phthalates and biomarkers…”7. Line 93: Please correct to "…neither bisphenol A nor other..."8. Please remove spaces from within citation callouts, eg. “…prenatally and in early life ,…”, but keep the space between the text and the callout itself as is.9. Methods:a. 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)." b. Line 193: Please provide exact sample collection dates, including month and day.c. Line 198: Please clarify whether parental consent was written or oral.d. Line 250: Please remove trademark symbols.e. Line 299 (and 423 in the main Discussion): Please avoid causal language: “effects”; please replace with “associations”.10. Line 357: PLOS does not permit "data not shown.” Please remove this claim, or do one of the following:a) If you are the owner of the data relevant to this claim, please provide the data in accordance with the PLOS data policy, and update your Data Availability Statement as needed.b) If the data not shown refer to a study from another group that has not been published, please cite personal communication in your manuscript text (it should not be included in the reference section). Please provide the name of the individual, the affiliation, and date of communication. The individual must provide PLOS Medicine written permission to be named for this purpose.c) For any other circumstance, please contact the journal office ASAP.11. At line 361, should that be "inversely associated"?12. In the limitations paragraph in the Discussion (line 437 onwards), please mention the limited study size and the possibility of unmeasured confounding.13. Line 443: Please delete extra comma.14. Please provide full access details (eg. DOI or URL) for references 5, 58, and 59. Please also give author names for reference 1, and journal names for references 19-21. Please double check that all references are complete and accurate.15. Table 4 and throughout, please report “p<0.0001” as “p<0.001” instead.-----------Comments from Reviewers:Reviewer #1: Thank you to the authors for addressing my previous comments well. I have no further issues to raise.Any attachments provided with reviews can be seen via the following link:[LINK] 11 Sep 2020Dear Dr. Jacobson, On behalf of my colleagues and the academic editor, Dr. Maarten Taal, I am delighted to inform you that your manuscript entitled "Serially assessed bisphenol A or phthalate exposure and association with kidney function in children with chronic kidney disease in the US and Canada: a longitudinal cohort study" (PMEDICINE-D-20-00109R3) 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. We will make some revisions at the copyediting stage to conform to our general style, and for clarification. 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. PROFILE INFORMATIONhttps://www.editorialmanager.com/pmedicine, log in, and click on the "Update My Information" link at the top of the page. Please update your user information to ensure an efficient production and billing process.Now that your manuscript has been accepted, please log into EM and update your profile. Go to Thank you again for submitting the manuscript to PLOS Medicine. We look forward to publishing it. Best wishes, Maarten Taal, Renal Medicine PLOS Medicineplosmedicine.org


The complex etiology of autism spectrum disorder (ASD) is still unresolved. Preterm birth (<37 weeks of gestation) and its complications are the leading cause of death of babies in the world, and those who survive often have long-term health problems. Length of gestation, including preterm birth, has been linked to ASD risk, but robust estimates for the whole range of gestational ages (GAs) are lacking. The primary objective of this study was to provide a detailed and robust description of ASD risk across the entire range of GAs while adjusting for sex and size for GA.p-value < 0.001), 1.35 , and 1.37 , respectively. The main limitation of this study is the lack of data on potential causes of pre- or postterm birth. Also, the possibility of residual confounding should be considered.Our study had a multinational cohort design, using population-based data from medical registries in three Nordic countries: Sweden, Finland, and Norway. GA was estimated in whole weeks based on ultrasound. Children were prospectively followed from birth for clinical diagnosis of ASD. Relative risk (RR) of ASD was estimated using log-binomial regression. Analyses were also stratified by sex and by size for GA. The study included 3,526,174 singletons born 1995 to 2015, including 50,816 (1.44%) individuals with ASD. In the whole cohort, 165,845 (4.7%) were born preterm. RR of ASD increased by GA, from 40 to 24 weeks and from 40 to 44 weeks of gestation. The RR of ASD in children born in weeks 22–31, 32–36, and 43–44 compared to weeks 37–42 were estimated at 2.31  is a neurodevelopmental disorder characterized by persistent impairments in social communication and restricted and repetitive behaviors.The etiology remains unresolved. Length of gestation, including preterm birth, has been linked to risk of ASD, but reliable estimates of risks for the whole range of gestational ages (GAs) are lacking.The primary objective of this study was to provide a detailed and robust description of ASD risk across the entire range of GA while taking fetal sex and size at birth into account.This study was based on population-based data from national medical registries in three Nordic countries—Sweden, Finland, and Norway—and included 3,526,174 singletons born 1995 to 2015.Relative risks (RRs) of ASD by GA at birth were estimated with log binominal regression.The RR of ASD increased by each week of GA, pre- as well as postterm, from 40 to 24 weeks of gestation and from 40 to 44 weeks of gestation, independently of sex and birth weight for GA.On a population level, the risks of ASD were increased in children born either pre- or postterm, including children born close to week 40.We found that the risk of ASD increased weekly, with each week further away from 40 weeks of gestation. Autism spectrum disorder (ASD) is a neurodevelopmental disorder, affecting 1%–2% of children worldwide –5. ASD iThe proportion of preterm birth is rising in many parts of the world, including in the United States , with anThe current study is, to our knowledge, the largest to date. In our cohort, comprising more than 3.5 million individuals, we investigated the association between GA and risk of ASD for children born across the GA continuum. We also investigated the potentially modifying effect of sex and size for GA.www.recap-preterm.eu) 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. Please submit a clean version of the paper as the main article file; a version with changes marked should be uploaded as a marked up manuscript.In revising the manuscript for further consideration, your revisions should address the specific points made by each reviewer and the editors. Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/figures. While revising your submission, please upload your figure files to the 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. 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 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 May 15 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  could contact the national databases quoted as the source of the data- many thanks.*Please revise your title according to PLOS Medicine's style. Your title must be nondeclarative and not a question. It should begin with main concept if possible. "Effect of" should be used only if causality can be inferred, i.e., for an RCT. Please place the study design  in the title after a colon. *In the Methods section, please clarify if the analytical plan for the study was prespecified prior to collection of data , or if it was only established after data were collected. *In the last sentence of the Abstract Methods and Findings section, please describe the main limitation(s) of the study's methodology.*Please change the referencing format (this should be easy if you've used reference manager software) to call out references using numbers in square brackets rather than superscript numbers. Many thanks*As the paper reports findings from an observational study (prospective cohort), we'd advise the authors to ensure the study is reported according to the STROBE guideline, and include the completed STROBE 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)."-----------------------------------------------------------Comments from the reviewers:Reviewer #1: This is a very clear and well-designed evaluation of the relationship of gestational age to the risk of autism spectrum disorder (ASD), with analysis of whether sex modifies the gestational age - ASD risk association. The authors have succinctly described the gap in knowledge that this paper fills. The sample size is very large and I have no concerns about the quality of the data. This is an important contribution to the epidemiological literature on ASD. -----------------------------------------------------------Reviewer #2: The authors present their work evaluating the association between gestational age and the risk of autism using a large linked dataset.Specific comments:1. The author's may wish to reconsider using "U-shaped" to describe the nature of the association between gestational age and ASD. Only in the Finland curve does the shape actually appear close to "U" with the risk in the post-term being as high as the risk in the very pre-term time frame. The composite curve shows a gradual decrease in risk from 24 to 40 weeks with a small rise between 40 and 44 weeks.2. In the last paragraph of the abstract and elsewhere in the manuscript, the authors state "Even though the absolute numbers may seem low, ASD is a rare disorder." Both of these clauses seem to say the same thing - perhaps the "although" is not necessary or perhaps the authors intended to make a different statement. Please check this.3. The authors state that there are conditions associated with preterm and postterm birth (page 9); this needs to be more fully explored in the discussion section. Intraamniotic infection is highly associated with preterm and very preterm birth, and also associated with subsequent diagnosis of ASD. Postterm birth is associated with delayed maturation of the fetal hypothalamic-pituitary-adrenal axis, and is also associated with ASD. These mechanisms are likely more common than the genetic factors related to preterm birth. The discussion section of this manuscript would benefit from consultation with an expert in mechanisms of parturition (both preterm and postterm) and also an obstetrician or maternal-fetal medicine specialist. These consultations may also assist in further refining some of the implied statements regarding obstetric interventions to reduce the risk of ASD (i.e. induction of labor at 40 weeks)4. -----------------------------------------------------------Reviewer #3: I confine my remarks to statistical aspects of this paper. The general approach is fine, but I have some issues to resolve before I can recommend publication.One overall issue. Since the researchers have the population, many statisticians (including me) would argue that tests of significance and confidence intervals and so on make no sense. There's no population to infer to since you have thge whole population. There are some who argue that it could be a sample from a "super population" but I don't think this makes a lot of sense - how can it be a random sample from a hypothetical population? I wouldn't forbid publication for this reason (since some people do it and it's not completely wrong) but I'd prefer to have all those things  removed.p. 5 - it is good that GA was treated both ways. Categorical is useful for tables, but continuous is better for analysis. - why was birth year categorized? It should be left continuous and maybe a spline effect added.  - same for maternal age at birth, and size for gestational age. The former should be "week" and the latter percentile. Categorizing independent variables is a bad idea. In *Regression Modelling Strategies* Frank Harrell lists 11 problems with it and summarizes "nothing could be more disastrous".Generally, though, a good job.Peter Flom-----------------------------------------------------------Any attachments provided with reviews can be seen via the following link:[LINK] 29 May 2020Dear Dr. Persson,Thank you very much for re-submitting your manuscript "GESTATIONAL AGE AND THE RISK OF AUTISM ; A PROSPECTIVE COHORT STUDY" (PMEDICINE-D-20-00561R2) for consideration at PLOS Medicine.I have discussed the paper with editorial colleagues and it was also seen again by two reviewers. I am pleased to tell you that, provided the remaining editorial and production issues are fully dealt with, we expect to be able to accept the paper for publication in the journal.The remaining issues that need to be addressed are listed at the end of this email. Any accompanying reviewer attachments can be seen via the link below. Please take these into account before resubmitting your manuscript:[LINK]plosmedicine@plos.org) will be in touch shortly about the production requirements for your paper, and the link and deadline for resubmission. DO NOT RESUBMIT BEFORE YOU'VE RECEIVED THE PRODUCTION REQUIREMENTS.Our publications team  and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***In revising the manuscript for further consideration here, please ensure you address the specific points made by each reviewer and the editors. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments and the changes you have made in the manuscript. Please submit a clean version of the paper as the main article file. A version with changes marked must also be uploaded as a marked up manuscript file.http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. If you haven't already, we ask that you provide a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract.Please also check the guidelines for revised papers at plosmedicine@plos.org) if you have any questions or concerns.We hope to receive your revised manuscript within 1 week. Please email us , 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 .Please review your reference list to ensure that all citations meet journal style. Six author names should be listed (rather than 3) prior to "et al."; and italics should be converted to plain text. Please ensure that journal names are abbreviated consistently .We may have missed the STROBE checklist with your submission. Please ensure that this is present as a supplementary document, referred to in your methods section . In the checklist, please ensure that individual items are referred to by section  and paragraph number, not line or page numbers - the latter generally change in the event of publication. Please also supply your analysis plan as a supplementary file, referred to in your methods section . We noted some instances of "p<0.0001" in your supplementary files. Please ensure that all p values are quoted as "p<0.001" or exact values, unless there is a specific statistical rationale to the contrary. Comments from Reviewers:*** Reviewer #2: 1. The wording of the second sentence of the abstract is a bit confusing, and I think better stated elsewhere in the manuscript. "RR increased from 40 weeks of gestation to 24 weeks" would seem like an obvious error to the reader. Perhaps stating in terms of weeks before/after 40 weeks, which is done elsewhere in the paper, would be helpful.2. Page 10, 2nd paragraph. While genetics likely plays a role in timing of birth, many other mechanisms  are likely more responsible than "genetics" for onset of labor. This paragraph should be reworked with a more rigorous discussion of the factors controlling parturition. Consultation with an expert in the mechanisms of parturition would be most helpful for this discussion.3. What are the policy differences between countries that would lead to a higher rate of birth at 42 weeks in Sweden than in the other two countries. The policy(ies) should be explained in the text.4. The lack of information on whether preterm birth was spontaneous or iatrogenic is a significant limitation and should be described similarly.5. The statement in the last paragraph "If risks of ASD in offspring born near term could be avoided by delivery at 40 weeks gestation remains to be investigated" should be removed. It is essentially speculative in nature, and not really supported by the findings in this study.*** Reviewer #3: On my first point regarding statistical tests applied to the population, the authors' reply is satisfactory. I would ask the authors to comment in their limitations section on categorizing variables, regarding the available data on maternal age.I accept the authors' response on the question of gestational age.I believe that the authors can proceed with minor revision.Peter Flom***Any attachments provided with reviews can be seen via the following link:[LINK] 7 Aug 2020Dear Dr. Persson, On behalf of my colleagues and the academic editor, Dr. Michael Fassett, I am delighted to inform you that your manuscript entitled "GESTATIONAL AGE AND THE RISK OF AUTISM SPECTRUM DISORDER IN SWEDEN, FINLAND AND NORWAY; A  COHORT STUDY" (PMEDICINE-D-20-00561R3) 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. We will make some revisions at the copyediting stage to conform to our general style, and for clarification. 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. PROFILE INFORMATIONhttps://www.editorialmanager.com/pmedicine, log in, and click on the "Update My Information" link at the top of the page. Please update your user information to ensure an efficient production and billing process.Now that your manuscript has been accepted, please log into EM and update your profile. Go to Thank you again for submitting the manuscript to PLOS Medicine. We look forward to publishing it. Best wishes, Richard Turner, PhDSenior Editor PLOS Medicineplosmedicine.org