Association between pan-immune-inflammation value and clinical outcomes in critically ill patients with hyperlipidemia: An observational study

Xiao-Ying Huang; Xiang Zheng

doi:10.1371/journal.pone.0349954

Peer Review History

Original SubmissionOctober 29, 2025
25 Jan 2026 Decision Letter - Erfan Ghadirzadeh, Editor -->PONE-D-25-56394-->-->Association between Pan-immune-inflammation value and clinical outcomes in hyperlipidemia patients: An observational study-->-->PLOS One Dear Dr. huang, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.-->--> -->-->Please submit your revised manuscript by Mar 11 2026 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript:--> A letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We look forward to receiving your revised manuscript. Kind regards, Erfan Ghadirzadeh, MD Academic Editor PLOS One Journal Requirements: When submitting your revision, we need you to address these additional requirements. 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf 2. Please amend the manuscript submission data (via Edit Submission) to include author Xiang-Zheng. 3. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information. 4. If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise. [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: Partly Reviewer #2: Yes Reviewer #3: Yes ******** -->2. Has the statistical analysis been performed appropriately and rigorously? --> Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: 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: No Reviewer #2: No Reviewer #3: 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: No Reviewer #3: 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: In this study, the authors demonstrated that elevated pan-immune-inflammation value (PIV) was independently associated with mortality and adverse outcomes in critically ill patients with hyperlipidemia admitted to the ICU. Based on the results, the authors concluded that PIV may be used as a simple and cost-effective prognostic tool for early risk stratification in critically ill patients with hyperlipidemia. However, to confirm the conclusions of this study, the following points need to be reconsidered: 1.Since all of the patients in this study were critically ill, the title should include "critically ill patients with hyperlipidemia." 2.Although blood glucose levels are used in model 3 of the multivariate analysis, it is unclear whether they were measured fasting or at any time, so HbA1c is likely to provide a more accurate indication of the presence or absence of the influence of abnormal glucose metabolism. 3.White blood cell counts are also significantly affected by the presence or absence of glucocorticoids, which are often administered to critically ill patients, but how was this factor taken into account in this analysis? 4.Looking at the AUC of the ROC analysis, it appears that simply using lymphocyte count as an indicator would be sufficient as a prognostic predictor without the need to use PIV, but it is necessary to clearly explain to readers the benefits of using PIV. Reviewer #2: Reviewer Comments This manuscript investigates the association between the pan-immune-inflammation value (PIV) and short- and long-term clinical outcomes in critically ill patients with hyperlipidemia using the MIMIC-IV database. The topic is clinically relevant, as inflammation-based biomarkers are increasingly recognized as valuable tools for risk stratification in critically ill populations. The sample size is large, the statistical analyses are generally robust and the findings suggest that elevated PIV is independently associated with increased mortality and adverse outcomes such as AKI and delirium. The manuscript is generally well organized and clearly written. However, several methodological clarifications, additional analyses and improvements in interpretation are required to strengthen the validity and clinical applicability of the findings. Major Comments 1.Hyperlipidemia is defined solely based on ICD-9/10 codes, without stratification by lipid subtype (e.g., hypertriglyceridemia, hypercholesterolemia, mixed dyslipidemia). 2.Given that different lipid abnormalities may have distinct inflammatory and prognostic implications, the authors should clarify which lipid phenotypes are primarily represented. 3.If available, subgroup or sensitivity analyses based on triglyceride or cholesterol levels would substantially enhance the clinical relevance of the study. 4.Although the authors adjusted for APS III, SOFA and SIRS scores, PIV is itself strongly correlated with disease severity. 5.The possibility of residual confounding or overadjustment should be discussed more explicitly. 6.Consider performing sensitivity analyses excluding severity scores or using alternative adjustment strategies to confirm the robustness of the association. 7.The restricted cubic spline analysis identifies a threshold lnPIV value (≈5.15) beyond which mortality risk increases sharply. 8.However, the clinical meaning of this threshold is not sufficiently discussed. 9.The authors should translate this lnPIV value back to the original PIV scale and discuss how it could be applied in real-world clinical decision-making. 10.Although lnPIV showed a higher AUC than individual blood cell parameters, the overall discriminative ability remains modest (AUC ≈0.66). 11.The manuscript should more cautiously interpret the predictive performance and clarify that PIV may complement, rather than replace, existing risk models. 12.Comparison with established prognostic scores (e.g., SOFA alone vs. SOFA + PIV) would strengthen the argument for clinical utility. 13.The manuscript states that multiple imputation was used for variables with <20% missingness, but the imputation method, number of imputations and variables included in the imputation model are not described. 14.These details should be clearly reported to ensure transparency and reproducibility. 15.The study is based on a single-center database from a U.S. tertiary care hospital. 16.The authors should more explicitly discuss the limitations regarding external validity, particularly for non-ICU settings and populations with different ethnic, socioeconomic, or healthcare characteristics. Minor Comments 1.Although MIMIC-IV studies are exempt from IRB approval, a brief ethics statement should be explicitly included in the Methods section, consistent with journal requirements. 2.Minor grammatical and stylistic issues are present (e.g., “imbalance lipid metabolism” should be “imbalance in lipid metabolism”). 3.A thorough language edit would improve readability. 4.The manuscript alternates between “hospital mortality” and “in-hospital mortality.” Please standardize terminology throughout the text and tables. 5.Figure legends should be more descriptive, particularly for the restricted cubic spline and subgroup analyses, to allow interpretation without referring back to the main text. 6.Units for laboratory values should be consistently reported across all tables. 7.The Discussion would benefit from a clearer comparison of the present findings with prior studies evaluating PIV or related inflammatory indices (e.g., NLR, PLR, SII) in critically ill or dyslipidemic populations. Reviewer #3: n studies examining the Pan-Immune-Inflammation Value (PIV)—including observational research in hyperlipidemia patients—there is no single universally accepted “normal value.” This is because PIV is a composite inflammatory index and its reference range depends on the study population and clinical context.Based on published observational and cardiovascular/metabolic studies: Author should need to incuat Healthy individuals / low-risk populations: ≈ 200–400 Patients with metabolic disorders (including hyperlipidemia): ≈ 300–600 High inflammatory burden / poor prognosis groups: > 600–800 (sometimes much higher depending on disease severity) In hyperlipidemia cohorts specifically, many studies use: Cutoff values should ideally be: Derived from your study population Adjusted for age, sex, comorbidities, and statin use Most studies define “high PIV” using ROC analysis or percentile grouping, not standard laboratory reference ranges ****** -->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: Ken-ichi Aihara Reviewer #2: Yes: Dr. Khurshid Ahmad Padder Reviewer #3: Yes: Dr. Momtaz Ahmed ******** [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.] To ensure your figures meet our technical requirements, please review our figure guidelines: https://journals.plos.org/plosone/s/figures You may also use PLOS’s free figure tool, NAAS, to help you prepare publication quality figures: https://journals.plos.org/plosone/s/figures#loc-tools-for-figure-preparation. NAAS will assess whether your figures meet our technical requirements by comparing each figure against our figure specifications. https://doi.org/10.1371/journal.pone.0349954.r001
Revision 1
17 Apr 2026 Author Response Response to Reviewers Manuscript ID: PONE-D-25-56394 Title: Association between Pan-immune-inflammation value and clinical outcomes in critically ill patients with hyperlipidemia: An observational study Dear Editor and Reviewers, We sincerely thank the editor and reviewers for their valuable time and insightful comments on our manuscript. We have carefully addressed each point raised and revised the manuscript accordingly. Below is our point-by-point response following the order of the decision letter. Responses to Editorial Comments Comment 1: PLOS ONE style requirements Please ensure that your manuscript meets PLOS ONE's style requirements Response:We have carefully reviewed the PLOS ONE formatting guidelines and revised the manuscript accordingly. Comment 2: Author information Please amend the manuscript submission data to include author Xiang-Zheng. Response:We have updated the manuscript submission data to include author Xiang-Zheng as a co-author. Comment 3: Supporting Information captions Please include captions for your Supporting Information files at the end of your manuscript. Response: We have added detailed captions for all Supporting Information files at the end of the main manuscript. --- Responses to Journal Questions Question 1: Is the manuscript technically sound, and do the data support the conclusions? Reviewer #1: Partly Reviewer #2: Yes Reviewer #3: Yes Response: We thank the reviewers for their assessment. To address Reviewer #1's concerns, we have made substantial revisions including: (1) adding HbA1c as a covariate, (2) adjusting for glucocorticoid use, and (3) demonstrating the incremental value of PIV beyond SOFA. These changes strengthen the technical soundness of our manuscript. Question 2: Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: Yes Response: We appreciate the reviewers' positive assessment of our statistical analyses. We have further enhanced the rigor by adding sensitivity analyses, multiple imputation details, and incremental value assessments. Question 3: Have the authors made all data underlying the findings in their manuscript fully available? Reviewer #1: No Reviewer #2: No Reviewer #3: Yes Response: We have now made all data and code publicly available. The GitHub repository (https://github.com/huangxiaoying5676/PIV-hyperlipidemia-analysis) contains: - Complete R analysis scripts - Aggregated datasets (cleaned and imputed data) - README file with replication instructions --- ## Responses to Reviewer #1's Specific Comments Comment 1.1: Since all of the patients in this study were critically ill, the title should include "critically ill patients with hyperlipidemia." Response: We thank the reviewer for this suggestion. We have revised the title to: "Association between Pan-immune-inflammation value and clinical outcomes in critically ill patients with hyperlipidemia: An observational study." This change has been made on the title page (Page 1,Title). Comment 1.2:Although blood glucose levels are used in model 3.HbA1c is likely to provide a more accurate indication of the presence or absence of the influence of abnormal glucose metabolism. Response: We thank the reviewer for this insightful methodological suggestion. We agree that HbA1c provides a more stable and accurate measure of long-term glucose metabolism compared to random blood glucose measurements, which may be influenced by acute illness, stress, and time of measurement. We have now included HbA1c as a covariate in all multivariable models(Page 14,”Model 3 adjusted for age, sex, race, heart rate, respiratory rate, MBP, potassium, chloride, bicarbonate, anion gap, BUN, creatinine, glucose, HbA1c…”) .To assess whether the prognostic value of PIV differs according to glycemic control, we performed subgroup analyses stratifying patients by clinically relevant HbA1c thresholds (<6.5% vs. ≥6.5%) (Page 20, Figure 5: Subgroup analysis for the effect of lnPIV on 28-day all-cause mortality.) Comment 1.3: White blood cell counts are also significantly affected by the presence or absence of glucocorticoids , which are often administered to critically ill patients, but how was this factor taken into account in this analysis? Response: We thank the reviewer for raising this important confounding factor. Glucocorticoid use is indeed common in critically ill patients and can significantly influence white blood cell counts, particularly neutrophils and lymphocytes, which are key components of the PIV calculation. To address this concern, we have included glucocorticoid use as a covariate in all fully adjusted models (Page 14,”Model 3 adjusted for …medications used.”). Glucocorticoid use was defined as administration of any systemic glucocorticoid (e.g., hydrocortisone, methylprednisolone, dexamethasone) during ICU stay, based on medication administration records. To assess whether the prognostic value of PIV differs between patients who received glucocorticoids and those who did not, we performed subgroup analyses stratifying patients by glucocorticoid use(Page 20, Figure 5: Subgroup analysis for the effect of lnPIV on 28-day all-cause mortality.). The attenuated effect in glucocorticoid users may be explained by the fact that glucocorticoids themselves alter white blood cell counts (inducing neutrophilia and lymphopenia), which may partially obscure the inflammatory signal captured by PIV (Page 21, line 21,”Glucocorticoids, often used for anti-inflammatory…”). Additionally, glucocorticoid use often indicates greater disease severity, where mortality risk may be driven by factors beyond immune-inflammatory status alone. Comment 1.4: Looking at the AUC of the ROC analysis, it appears that simply using lymphocyte count as an indicator would be sufficient as a prognostic predictor without the need to use PIV, but it is necessary to clearly explain to readers the benefits of using PIV. Response: We thank the reviewer for this critical and important question. We agree that lymphocyte count alone shows predictive value (AUC = 0.662), which is consistent with its central role in immune regulation(Supporting information,Page 4). However, to demonstrate the added value of PIV beyond single lymphocyte count, we have conducted comprehensive analyses including comparison with the SOFA score, integrated discrimination improvement (IDI), net reclassification improvement (NRI), and decision curve analysis. In the Discussion section (Page 22,line 10-17),we have expanded the explanation of why PIV offers advantages over single lymphocyte count.Below we detail our findings and revisions. Although the AUC values are similar, PIV captures a broader spectrum of the immune-inflammatory response by integrating neutrophils, monocytes, and platelets in addition to lymphocytes. To demonstrate clinical utility, we evaluated whether PIV provides incremental prognostic information beyond the established SOFA score, which is widely used in ICU settings. We compared two models: SOFA alone and SOFA + PIV(Supporting information,Page 5). Decision curve analysis was performed to assess the clinical utility of adding PIV to SOFA across a range of threshold probabilities. This analysis quantifies the net benefit of using a model for clinical decision-making by weighing true positives against false positives(Supporting information,Page 5,7). --- ## Responses to Reviewer #2's Specific Comments Major Comments Comment 2.1-3: Hyperlipidemia is defined solely based on ICD-9/10 codes, without stratification by lipid subtype (e.g., hypertriglyceridemia, hypercholesterolemia, mixed dyslipidemia). Given that different lipid abnormalities may have distinct inflammatory and prognostic implications, the authors should clarify which lipid phenotypes are primarily represented. If available, subgroup or sensitivity analyses based on triglyceride or cholesterol levels would substantially enhance the clinical relevance of the study. Response: We thank the reviewer for this important methodological critique. We fully agree that different lipid subtypes may have distinct inflammatory and prognostic implications, and that stratification by lipid phenotype would enhance the clinical relevance of our findings. Using the multiply imputed datasets, we performed subgroup analyses stratifying patients by clinically relevant lipid thresholds: Triglycerides: ≤150 mg/dL (1.7 mmol/L) vs. >150 mg/dL Total cholesterol: ≤200 mg/dL (5.2 mmol/L) vs. >200 mg/dL The results demonstrated that the association between lnPIV and 28-day mortality was consistent across all lipid subgroups(Page 20, Figure 5: Subgroup analysis for the effect of lnPIV on 28-day all-cause mortality.). Regarding which lipid phenotypes are primarily represented in our cohort, based on the imputed lipid data: Hypertriglyceridemia (TG >150 mg/dL), Hypercholesterolemia (TC >200 mg/dL), Mixed dyslipidemia (both TG >150 and TC >200). Although we performed subgroup analyses based on triglyceride and cholesterol levels, the possibility of residual confounding from unmeasured lipid parameters (e.g., LDL-C, HDL-C, lipoprotein(a)) cannot be completely excluded. Future studies with complete lipid profiles are needed to further elucidate the relationship between specific lipid subtypes and PIV's prognostic value. Comment 2.4-6:Although the authors adjusted for APS III, SOFA and SIRS scores, PIV is itself strongly correlated with disease severity. The possibility of residual confounding or overadjustment should be discussed more explicitly. Consider performing sensitivity analyses excluding severity scores or using alternative adjustment strategies to confirm the robustness of the association. Response: We thank the reviewer for this important methodological critique. In our final revised models, we have taken a different approach: rather than adjusting for severity scores, we intentionally excluded them from Model 3 to avoid potential overadjustment, given that PIV itself is correlated with disease severity (Page 14,”Model 3 adjusted for …”). Instead, we evaluated the incremental value of PIV beyond severity by directly comparing SOFA alone vs. SOFA + PIV(Supporting information,Page 5). Comment 2.7-9: The restricted cubic spline analysis identifies a threshold lnPIV value (≈5.15) beyond which mortality risk increases sharply. However, the clinical meaning of this threshold is not sufficiently discussed. The authors should translate this lnPIV value back to the original PIV scale and discuss how it could be applied in real-world clinical decision-making. Response: We thank the reviewer for this valuable suggestion to enhance the clinical translatability of our findings. Identifying a clinically meaningful threshold is essential for translating statistical findings into practical risk stratification tools. We have addressed this concern through the following revisions. The threshold identified by restricted cubic spline analysis was lnPIV = 5.152. We have back-transformed this value to the original PIV scale using exponential transformation: PIV ≈ e^5.152 = 172. This threshold is now explicitly reported in Page 18,line 1. The threshold of PIV ≈ 172 has several important clinical implications: Patients with PIV values above 172 at ICU admission may be identified as high-risk and flagged for closer monitoring, more frequent clinical assessments, or consideration of early interventions. However, we emphasize that this threshold requires external validation before clinical application, and should be interpreted in the context of other clinical parameters rather than as a standalone decision-making tool. Comment 2.10-12:Although lnPIV showed a higher AUC than individual blood cell parameters, the overall discriminative ability remains modest (AUC ≈0.66). The manuscript should more cautiously interpret the predictive performance and clarify that PIV may complement, rather than replace, existing risk models. Comparison with established prognostic scores (e.g., SOFA alone vs. SOFA + PIV) would strengthen the argument for clinical utility. Response: We thank the reviewer for these important observations regarding the appropriate interpretation of predictive performance and the need to position PIV as a complementary rather than replacement tool. We have addressed these concerns through several revisions throughout the manuscript. We agree with the reviewer that an AUC of 0.66 represents modest discriminative ability, and we have revised the manuscript to reflect this more cautiously. We have added explicit statements throughout the manuscript clarifying that PIV is intended to complement, not replace, existing risk models.(Page 18,line 5-13; Page 21,line 8-12;” ROC curve analysis showe...”). To strengthen the argument for clinical utility, we have directly compared the predictive performance of SOFA alone, PIV alone, and SOFA + PIV(Supplementary Figure S2). Comment 2.13-14: The manuscript states that multiple imputation was used... but the imputation method, number of imputations and variables included are not described. These details should be clearly reported to ensure transparency and reproducibility. Response: We thank the reviewer for emphasizing the importance of methodological transparency. We agree that complete reporting of multiple imputation procedures is essential for reproducibility. In response, we have substantially expanded the Statistical Analysis section to provide comprehensive details of our imputation approach. The following text has been added to the Statistical Analysis section: "For covariates with missing rates <20%, multiple…”(Page 8, line.15-21). To demonstrate the validity of our imputation approach, we added density plots comparing observed versus imputed values for key variables with missing data(Supplementary Figure S1). Comment 2.15-16:The study is based on a single-center databasefrom a U.S. tertiary care hospital. The authors should more explicitly discuss the limitations regarding external validity, particularly for non-ICU settings and populations with different ethnic, socioeconomic, or healthcare characteristics. Response: We thank the reviewer for this important reminder to explicitly address external validity. We agree that single-center studies require careful discussion of generalizability. We have substantially expanded the Limitations section to provide a more nuanced and comprehensive discussion of external validity(Page 24,line18-20,” Second, this was a single-center analysis…”).. Minor Comments Comment 2.17: Although MIMIC-IV studies are exempt from IRB approval, a brief ethics statement should be explicitly included in the Methods section, consistent with journal requirements. Response: We thank the reviewer for this important reminder. We agree that all manuscripts should include a clear ethics statement, regardless of exemption status, to ensure transparency and compliance with journal requirements. We have added a comprehensive ethics statement to the Methods section(Page 5,line 5-10.) and Supporting information(Page 9). Comment 2.18:Minor grammatical and stylistic issues are present (e.g., "imbalance lipid metabolism" should be "imbalance in lipid metabolism"). A thorough language edit would improve readability. Response: We thank the reviewer for these specific language suggestions. We agree that clear and accurate language is essential for scientific communication.The example provided by the reviewer has been corrected throughout the manuscript.(Page 2,line 17,” an imbalance in lipid metabolism.”) Comment 2.19:The manuscript alternates between "hospital mortality" and "in-hospital mortality." Please standardize terminology throughout the text and tables. Response: We thank the reviewer for this careful observation. Consistent terminology is essential for clarity and professionalism in scientific writing. We have thoroughly reviewed the entire manuscript and standardized the terminology as suggested.(Page13-14, Table 2; Page15 Table 3) Comment 2.20: Figure legends should be more descriptive, particularly for the restricted cubic spline and subgroup analyses, to allow interpretation without referring back to the main Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0349954.r002
8 May 2026 Decision Letter - Erfan Ghadirzadeh, Editor Association between Pan-immune-inflammation value and clinical outcomes in critically ill patients with hyperlipidemia: An observational study PONE-D-25-56394R1 Dear Dr. Xiang, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. For questions related to billing, please contact billing support. 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, Erfan Ghadirzadeh, MD Academic Editor PLOS One Additional Editor Comments (optional): Reviewers' comments: Reviewer's Responses to Questions -->Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.--> Reviewer #1: All comments have been addressed Reviewer #3: All comments have been addressed ******** -->2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. --> Reviewer #1: Yes Reviewer #3: Yes ****** -->3. Has the statistical analysis been performed appropriately and rigorously? --> Reviewer #1: I Don't Know Reviewer #3: Yes ****** -->4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.--> Reviewer #1: Yes Reviewer #3: 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 #1: Yes Reviewer #3: Yes ****** -->6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)--> Reviewer #1: I have no further comment for the responses of the authors to the concerns I raised in the original version. Reviewer #3: This manuscript is well-written and clearly presented. All data and the findings are adequately available and supported. The statistical analysis has been performed appropriately, and all previous comments have been satisfactorily addressed. However, further research on Pan-Immune-Inflammation is recommended to strengthen the study and expand its scientific impact. ****** -->7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.--> Reviewer #1: Yes: Ken-ichi Aihara Reviewer #3: Yes: Dr. Momtaz Ahmed Head of National Diabetes Centre, Suva, Fiji Senior Fellow International Diabetes Federation ******** https://doi.org/10.1371/journal.pone.0349954.r003
Formally Accepted
Acceptance Letter - Erfan Ghadirzadeh, Editor PONE-D-25-56394R1 PLOS One Dear Dr. Xiang, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS One. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset You will receive further instructions from the production team, including instructions on how to review your proof when it is ready. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few days to review your paper and let you know the next and final steps. Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. You will receive an invoice from PLOS for your publication fee after your manuscript has reached the completed accept phase. If you receive an email requesting payment before acceptance or for any other service, this may be a phishing scheme. Learn how to identify phishing emails and protect your accounts at https://explore.plos.org/phishing. If we can help with anything else, please email us at customercare@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Erfan Ghadirzadeh Academic Editor PLOS One https://doi.org/10.1371/journal.pone.0349954.r004

Open letter on the publication of peer review reports

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

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

Learn more at ASAPbio .