Isolated abnormal diffusing capacity for carbon monoxide (iso↓DLco) is associated with increased respiratory symptom burden in people with HIV infection

Katerina L. Byanova; Jessica Fitzpatrick; Amanda K. Jan; Maggie McGing; Marlena Hartman-Filson; Carly K. Farr; Michelle Zhang; Kendall Gardner; Jake Branchini; Robert Kerruish; Sharvari Bhide; Aryana Bates; Jenny Hsieh; Rebecca Abelman; Peter W. Hunt; Richard J. Wang; Kristina A. Crothers; Laurence Huang

doi:10.1371/journal.pone.0288803

Peer Review History

Original SubmissionJanuary 31, 2023
27 Apr 2023 Decision Letter - Koustubh Panda, Editor PONE-D-23-02834Isolated abnormal diffusing capacity for carbon monoxide (iso↓DLco) is associated with increased respiratory symptom burden in people with HIVPLOS ONE Dear Dr. Byanova, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. You may consider revising your manuscript in lines with the comments/suggestions of the reviewers given below. Although there are no major reservations expressed by the reviewers kindly ensure to address all the comments/suggestions with appropriate responses to enable us to further consider your manuscript for publication. 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Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. Additional Editor Comments: Kindly modify the title to 'Isolated abnormal diffusing capacity for carbon monoxide (iso↓DLco) is associated with increased respiratory symptom burden in people with HIV infection' [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: line 98: Ref 12 this ref shows that the preponderance of pts with decreased DLCO had combined emphysema/ILD causing presumed pseudonormalization of PFTs. This should be mentioned. line 121: Refs 12 & 20 indicate that decreased DLCO is associated with respiratory symptoms. I would delete this line as it doesn't help. line 127: Excellent statement of intent! Materials, Methods, Design, Collection, Analysis are all excellent, as expected from this group. Table 1: while not the outcome, a plot of viral load against DLCO (whether % predicted or absolute or corrected is up to you from a data vis perspective) would be helpful. I wonder if this ends up a ^-shaped curve since the VL is low in normal DLCO, high in mild DLCO, and low in severe DLCO. If you do this, it will have to be discussed in the text. Table 2: Can there be a model "d" that includes accounting for viral load? line 326: This analysis feels like an afterthought, and is hard for many to understand (% predicted per 1% decrease), but DLCO is a continuous variable and a continuous analysis rather than categorical is very important. line 326-335: can we get a plot of DLCO against symptoms to perhaps identify that there is a different threshold that we should use other than 60%? line 341: "Together, these findings suggest that isoVDLCO lung function is a distinct condition that has clinically relevant symptom correlates...." Since this isn't a genetic study, the use of phenotype is misleading and too casual a use of the term phenotype. line 374: You should note that the mod-severe DLCO group had a lower viral load. It is counterintuitive, but an important outlier from the "expected" outcomes. line 390 : replace "function phenotype" with "disease process" line 397-399: should you put in presumed measures like ILD score, emphysema scores, RVSP, and evolution of restriction and obstruction? line 420, right before the last word "these", perhaps insert "These findings are borne out in analysis of DLCO as a continuous variable and suggest a severity cutoff for clinical use of <40%, 50%, 60%, whatever the plot shows>" Reviewer #2: -This is a well written manuscript and topic is very relevant. - Can you please specify whether an echo was done to further assess isolated reduction in diffusion capacity. As HIV is a risk factor for pulmonary hypertension which can cause reduced diffucion capacity with relatively normal lungs volumes. - Did patients go through chest imaging to further asses the cause of low diffusion capacity. Combined pulmonary fibrosis and emphysema (CPFE) can also give pseudo-normal PFTs with significant reduction in diffusion capacity. -HIV is also associated with heart disease. And patients with chronic heart failure may also have low diffusion capacity. Can you please specify whether patients were screened for signs of heart failure. ****** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: Yes: Arjun B. "Raja" Chatterjee, MD, MS Reviewer #2: No ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0288803.r001
Revision 1
8 Jun 2023 Author Response Please refer to uploaded "Response to Reviewers" document for a copy of these comments and formatted tables. Re: PONE-D-23-02834, “Isolated abnormal diffusing capacity for carbon monoxide (iso↓DLco) is associated with increased respiratory symptom burden in people with HIV” Dear Dr. Panda and PLOS ONE reviewers: Thank you for your review and insightful feedback on our manuscript “Isolated abnormal diffusing capacity for carbon monoxide (iso↓DLco) is associated with increased respiratory symptom burden in people with HIV.” Please see below for our point-by-point response to your comments and recommendations. Responses to the editor’s comments: 1. Kindly modify the title to 'Isolated abnormal diffusing capacity for carbon monoxide (iso↓DLco) is associated with increased respiratory symptom burden in people with HIV infection' Response: We have modified the title of our manuscript in accordance with your recommendation: “Isolated abnormal diffusing capacity for carbon monoxide (iso↓DLco) is associated with increased respiratory symptom burden in people with HIV infection”. Responses to reviewers' comments: Reviewer #1: 1. Line 98: Ref 12 this ref shows that the preponderance of pts with decreased DLCO had combined emphysema/ILD causing presumed pseudonormalization of PFTs. This should be mentioned. Response: Thank you for highlighting this important point. We have added a sentence to the paragraph to explain the findings in Aduen et al, “One study specifically noted that in their single-center experience, iso↓DLco was a result of pseudonormalization of spirometry due to the presence of combined emphysema and restrictive lung disease[12].” 2. Line 121: Refs 12 & 20 indicate that decreased DLCO is associated with respiratory symptoms. I would delete this line as it doesn't help. Response: We were unable to find reporting of an association between DLco and respiratory symptoms in Raju et al’s manuscript (reference 20). While you are correct that Aduen et al does evaluate based on respiratory symptoms, our original intent was to say that among people with HIV, this issue has not been specifically addressed. In order to improve clarity, we have amended our statement to say, “Whether iso↓DLco among PWH is associated with any respiratory symptoms or whether it is simply a marker of future complications is not currently known.” 3. Line 127: Excellent statement of intent! Response: Thank you. 4. Materials, Methods, Design, Collection, Analysis are all excellent, as expected from this group. Table 1: while not the outcome, a plot of viral load against DLCO (whether % predicted or absolute or corrected is up to you from a data vis perspective) would be helpful. I wonder if this ends up a ^-shaped curve since the VL is low in normal DLCO, high in mild DLCO, and low in severe DLCO. If you do this, it will have to be discussed in the text. Response: This is an excellent suggestion. We have produced two figures showing the distribution of viral load across measured and %predicted DLco (see below). While you are correct that most people with high viral loads are in the mild iso↓DLco group, there are also a lot of individuals with low or suppressed viral RNA in the same group, suggesting that overall, there is no clear relationship between viremia and abnormal DLco in this group. Therefore, we do not think that the pattern is significant enough to warrant the addition of a figure or further discussion in the text. 5. Table 2: Can there be a model "d" that includes accounting for viral load? Response: Thank you for this excellent suggestion. We did not initially include viral load in our models based on P>0.2 for viral load in our bivariate analyses. Per your recommendation, we performed a sensitivity analysis, in which we added viral load as a covariate (coded as a binary variable, ‘detectable’ vs ‘undetectable’). Please see below the results for table A (equivalent to table 2 in manuscript) and table B (equivalent to table 3 in manuscript) after addition of viral load. In the first table, the only difference in statistical significance between the original analysis and this one is that the association between SGRQ and mild iso↓DLco was attenuated after addition of viral load (p=0.079). In table 3, the association between cough and DLco %predicted newly reached statistical significance with p=0.048 in the sensitivity analysis. Because these results do not substantively change our interpretation of the results, we have chosen to keep the original analysis in our paper. Associations of iso↓DLco and symptom scores after additional adjustment for viral load. Table A: Results from multivariable analyses of mMRC scores, grouped as mMRC <2 and mMRC≥2, CAT, and SGRQ. Multivariable Analysis of Symptom Scores Mild iso↓DLco (LLN > DLco > 60% predicted) Moderate-severe iso↓DLco (DLco ≤ 60% predicted) DLCO, % predicted per 1 % decrease Adjusted Estimate (95% CI) P-value Adjusted Estimate (95% CI) P-value Adjusted Estimate (95% CI) P-value mMRC (N=180), ≥ 2 vs <2a 1.57 (0.54, 4.58) 0.41 6.97 (1.64, 29.5) 0.008 1.05 (1.01, 1.08) 0.004 CAT Scores (N =145)b 2.72 (-0.57, 5.96) 0.10 9.29 (2.40, 16.2) 0.008 0.14 (0.055, 0.22) 0.001 SGRQ Scores (N=176)c 8.53 (-0.99, 18.06) 0.079 25.65 (4.58, 46.78) 0.017 0.41 (0.21, 0.60) <0.001 The adjusted estimates represent odds ratios for mMRC and the predicted mean increase in symptoms score for CAT and SGRQ. aModel adjusted for age, sex, BMI, smoking status, cohort (Seattle or San Francisco), history of bacterial pneumonia, and detectable HIV viral load bModel adjusted for age, sex, BMI, smoking status, and history of bacterial pneumonia and detectable HIV viral load cModel adjusted for age, sex, BMI, smoking status, ever injection drug use, history of bacterial pneumonia, and cohort (Seattle or San Francisco) and detectable HIV viral load Table B: Results from multivariable analyses of individual CAT questions. Multivariable Analysis of Symptom Scores Mild iso↓DLco (LLN > DLco > 60% predicted) Moderate-severe iso↓DLco (DLco ≤ 60% predicted) DLCO, % predicted per 1 % decrease Individual CAT Questionsd Adjusted Estimate (95% CI) P-value Adjusted Estimate (95% CI) P-value Adjusted Estimate (95% CI) P-value Cough 1.50 (0.61, 3.67) 0.38 3.11 (0.91, 11.0) 0.071 1.02 (1.00, 1.04) 0.048 Phlegm 2.08 (0.80, 5.32) 0.13 1.34 (0.34, 4.95) 0.67 1.01 (0.99, 1.04) 0.37 Chest Tightness 0.99 (0.31, 2.91) 0.99 2.46 (0.63, 8.93) 0.18 1.02 (0.99, 1.04) 0.32 Breathlessness 2.03 (0.85, 4.89) 0.11 14.6 (3.72, 64.6) <0.001 1.05 (1.02, 1.07) <0.001 Activities 2.37 (0.82, 6.65) 0.10 10.30 (3.06, 35.5) <0.001 1.05 (1.03, 1.08) <0.001 Confidence 1.70 (0.33, 6.96) 0.48 8.99 (1.90, 42.2) 0.0050 1.03 (0.99, 1.07) 0.13 Sleep 1.07 (0.35, 3.03) 0.89 1.62 (0.42, 5.65) 0.47 1.01 (0.98, 1.03) 0.50 Energy 2.38 (0.94, 6.11) 0.067 9.54 (2.83, 33.8) <0.001 1.04 (1.02, 1.06) 0.010 The adjusted estimates represent odds ratios. dModel adjusted for age, sex, BMI, smoking status, history of bacterial pneumonia, and detectable HIV viral load 6. Line 326: This analysis feels like an afterthought, and is hard for many to understand (% predicted per 1% decrease), but DLCO is a continuous variable and a continuous analysis rather than categorical is very important. Response: We appreciate this insight. The analysis was performed because we wanted to capture associations and trends that may be lost when using a categorical variable based on ‘severity’ cutoffs. Ultimately, we highlighted the categorical outcomes more than the outcome for continuous DLco %predicted in order to emphasize that the most significant pathology is likely to be found in the moderate-severe iso↓DLco group, and that this group should receive the greatest clinical and scientific attention. For clarity, we expanded the first sentence in this section to reflect our intent in evaluating DLco as a continuous outcome (lines 355-357), and we rephrased lines 357-358 in the revised manuscript to be explicit in the interpretation of the odds ratios: “Finally, we performed multivariable analyses of our symptom scores using DLco as a continuous variable in order to ensure that we have not missed any important trends when using iso↓DLco as a categorical variable. We found that for mMRC, each 1% decrease in % predicted DLco increased the odds of having an mMRC≥2 by 5% (aOR 1.05, 95% CI 1.01, 1.08; P=0.004; Table 2).” 7. Line 326-335: can we get a plot of DLCO against symptoms to perhaps identify that there is a different threshold that we should use other than 60%? Response: Thank you for this excellent suggestion. We have produced scatterplots of CAT and SGRQ scores against DLco % predicted (see below). Based on these plots, we were not able to identify a more suitable cutoff for normal/abnormal DLco. This is likely a reflection of both the multiple possible etiologies that could drive iso↓DLco and respiratory symptoms, as well as of the fact that these questionnaires are not specific for the assessment of iso↓DLco but rather a range of pulmonary pathologies. 8. Line 341: "Together, these findings suggest that isoVDLCO lung function is a distinct condition that has clinically relevant symptom correlates...." Since this isn't a genetic study, the use of phenotype is misleading and too casual a use of the term phenotype. Response: We understand your point. Our use of the word ‘phenotype’ was based on Merriam-Webster’s dictionary’s definition of the word as “the observable characteristics or traits of a disease.” However, we do recognize that iso↓DLco is a presentation of one or more possible underlying conditions, and, therefore, we have changed the word “phenotype” to “pattern” in the line you pointed out, as well as in line 145 of the revised manuscript (which are the only two occurrences in the text) to keep our language more precise. The sentence in line 374-375 of the revised manuscript now reads, “Together, these findings suggest that the iso↓DLco lung function pattern has clinically relevant symptom correlates and warrants further study.” 9. Line 374: You should note that the mod-severe DLCO group had a lower viral load. It is counterintuitive, but an important outlier from the "expected" outcomes. Response: Your point is well taken. We have added a sentence in line 413-415 of the revised manuscript that discusses this issue: “Interestingly, the moderate-severe iso↓DLco group had a lower HIV viral load, suggesting better virologic control in this group.” 10. Line 390: replace “function phenotype” with “disease process” Response: This change has been made: “Given that iso↓DLco has a higher prevalence among PWH and demonstrates a unique biomarker signature, iso↓DLco may represent a unique HIV pulmonary disease process.” 11. Line 397-399: should you put in presumed measures like ILD score, emphysema scores, RVSP, and evolution of restriction and obstruction? Response: We have updated the last sentence of the paragraph (revised manuscript lines 437-442) to be explicit about the kinds of measurements we would like to make in our future analyses: “Correlation with high-resolution computed tomography (CT) of the chest and echocardiography, which will allow us to assess metrics such as % interstitial lung abnormalities, % emphysema, pulmonary artery systolic pressure, and left ventricular ejection fraction, as well as longitudinal lung function testing and additional testing of inflammatory and immune activation biomarkers are currently being collected and will help address this question.” 12. Line 420, right before the last word "these", perhaps insert "These findings are borne out in analysis of DLCO as a continuous variable and suggest a severity cutoff for clinical use of <40%, 50%, 60%, whatever the plot shows>" Response: Thank you for this excellent point. Since the additional analyses did not show a better cutoff for %predicted DLco, we edited the sentence to highlight that attention should be paid to moderate-severe iso↓DLco abnormalities: “These findings indicate that moderate-severe iso↓DLco is a clinically important PFT finding, and further studies of its underlying mechanism are needed to guide therapeutic interventions.” Reviewer #2: 1. This is a well written manuscript and topic is very relevant. Can you please specify whether an echo was done to further assess isolated reduction in diffusion capacity. As HIV is a risk factor for pulmonary hypertension which can cause reduced diffusion capacity with relatively normal lungs volumes. Response: Thank you for your comment. We do not have research echocardiograms in our study population, although this is part of our next steps for investigating the etiology of iso↓DLco. We have explained this in our limitations and future studies part of the discussion (lines 437-442): “Correlation with high-resolution computed tomography (CT) of the chest and echocardiography, which will allow us to assess metrics such as % interstitial lung abnormalities, % emphysema, pulmonary artery systolic pressure, and left ventricular ejection fraction, as well as longitudinal lung function testing and additional testing of inflammatory and immune activation biomarkers are currently being collected and will help address this question.” Additionally, we did a retrospective chart review for a subset of participants with iso↓DLco who had available clinical echocardiograms in our hospital system, and we found that 15/55 individuals had PASP >30 cm H2O. However, these echocardiograms were not closely matched in time to PFTs and were typically obtained during time of acute illness. Thus, these results were not reliable enough to be included in this manuscript but provide additional support for obtaining TTEs systematically in our cohort. 2. Did patients go through chest imaging to further assess the cause of low diffusion capacity. Combined pulmonary fibrosis and emphysema (CPFE) can also give pseudo-normal PFTs with significant reduction in diffusion capacity. Response: Thank you again for the comment. This is an excellent point, but similar to above, we did not have chest CTs as part of our research study. We reviewed available clinical CT images from 32 participants and did not find a consistent pattern that was associated with iso↓DLco. Having recognized the lack of imaging data as a limitation, we are currently working on obtaining matched CTs and PFTs for our study participants to address this question. 3. HIV is also associated with heart disease. And patients with chronic heart failure may also have low diffusion capacity. Can you please specify whether patients were screened for signs of heart failure. Response: Thank you for this comment. Patients were not formally screened for clinical signs of chronic heart failure during study visits, and as explained above, as of now we lack research echocardiography data. However, in our clinical TTE review, we found only one individual who had evidence of left heart disease with an ejection fraction of 45%. We are hoping to address this question in the future by obtaining research TTEs. We believe that these revisions have strengthened and improved the manuscript and appreciate your helpful suggestions for improvement. We look forward to your reply. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0288803.r002
4 Jul 2023 Decision Letter - Koustubh Panda, Editor Isolated abnormal diffusing capacity for carbon monoxide (iso↓DLco) is associated with increased respiratory symptom burden in people with HIV infection PONE-D-23-02834R1 Dear Dr. Byanova, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Koustubh Panda, M. Tech., Ph.D Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #2: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #2: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #2: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #2: Yes ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #2: My questions in from prior review have been answered. I wish good luck to the authors for continued research work. ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #2: No ******** https://doi.org/10.1371/journal.pone.0288803.r003
Formally Accepted
10 Jul 2023 Acceptance Letter - Koustubh Panda, Editor PONE-D-23-02834R1 Isolated abnormal diffusing capacity for carbon monoxide (iso↓DLco) is associated with increased respiratory symptom burden in people with HIV infection Dear Dr. Byanova: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Professor Koustubh Panda Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0288803.r004

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