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Thank you for submitting the revised version of your manuscript. I have carefully evaluated the revised version, as well as your point-by-point rebuttal, and I am pleased to confirm that you have satisfactorily addressed the issues raised in the previous review round. The reviewer has also confirmed that all requested revisions—including correction of the odds ratios, acknowledgement that serum sodium outperformed calculated osmolarity in AUC analysis, and the addition of c-statistics and discrimination measures—have now been satisfactorily addressed.
I am happy to inform you that your manuscript is now accepted for publication.
Congratulations, and thank you for your careful and constructive revisions.
The authors have revised the analysis to address my comments. Their response and modification addressed my comments. I have no more comments.
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**PeerJ Staff Note:** Please ensure that all review, editorial, and staff comments are addressed in a response letter and that any edits or clarifications mentioned in the letter are also inserted into the revised manuscript where appropriate.
The study has a specific goal to determine the prognostic value of serum osmolarity in COVID. The authors have addressed my comments. The new version has improved. I have a few additional comments.
Using the AUC calculation, the authors should acknowledge that Na outperforms the osmolarity.
I used the provided data to regenerate the multivariable logistic regression. Apparently, the ORs for ETI and Inotropic agents are reversed. The ORs should be 5.20 and 3.73, respectively. Therefore, the ORs and 95% CI should be corrected.
In addition, please calculate the c-statistics and discrimination measure (Sen, Spe) for this model, and add to Table 2.
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**PeerJ Staff Note:** Please ensure that all review, editorial, and staff comments are addressed in a response letter and that any edits or clarifications mentioned in the letter are also inserted into the revised manuscript where appropriate.
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Overall, your paper flows well. However, it would benefit from English editing. There are nuances in English grammar that may not have translated well. I have outlined some below, but there are too many for me to highlight. As it reads now in English, it is difficult to follow the flow of ideas.
Abstract
Page 1, line 27- please replace "had confirmed COVID-19" with "with confirmed COVID-19"
Page 2 - Conclusion. Lines 43-46- please revise this entire sentence. It does not read well.
Introduction
Overall, the flow of the introduction could use revision. In the first paragraph, it reads as if random facts were grouped together without consideration of flow. There is no strong transition between the paragraphs. In paragraph 2, you continue to jump through random thoughts, with items that should be connected several sentences apart, without appropriate transitions.
Page 2 Line 52 - hypernatremia is not (always) a fluid imbalance. Please clarify.
Page 2 Line 54 - Please be more explicit about how long serum osmolarity has been considered standard of care. Avoid using subjective phrases such as "long been." Also, please cite this statement. Not all clinicians use this biomarker as much as you indicate. How often is it used in clinical practice?
Page 2, Lines 50-59 - Every factual statement in this first paragraph requires citation. You do not cite anything until the end of the paragraph, and the citations utilized are quite old. This is important because you make bold statements that assume practice points by clinicians, which, in my practice, are not often true.
Page 2 Line 55-56 - In my practice, we only obtain serum osmolarity when we have a specific need - and we we obtain it, we do directly measure it. This is true for many of my peers in other locations. Your comment about automation being preferred does not seem to align with clinical practice. It may be that automation has shown preference in survey data, but you provide no citation to support this. Please provide a citation that reflects current practice. You could also just remove this statement, as it does not add benefit to the paper.
Introduction
Page 3 Lines 99-101 - Starting with "In this study" through "April 30, 2022." This information should be moved to the start of the paragraph and merged with the 2nd sentence.
Page 3, Lines 101-108 - Rather than being a separate statement, pregnancy and age could be merged with the exclusion criteria.
Page 3 line 105 - please remove "of known diseases such as" and simply say "presence of nephrotic syndrome". Also, in line 106, remove "presence of" before diabetes insipidus.
Page 3, lines 106-107 - I think you mean syndrome of inappropriate antidiuretic hormone
Page 3 line 106 - remove "or" before liver.
Page 4, Lines 124-128 - please rewrite. This does not read well. Please state "Our primary outcome was....". "Secondary outcomes included...."
Abstract
Page 1 line 22: "long been used" is a subjective phrase. Please be more specific about how long serum osmolarity has been part of the standard diagnostic process.
Page 2, Lines 43-44- please do not include information in the conclusion that is not reviewed in the results section.
Page 2, Lines 46-47 - With the exception of sodium, your abstract does not discuss the management of any other electrolyte abnormalities. Please do not extrapolate information that does not have data to support the statement.
Materials & Methods
Page 3 Line 89 - How did you duly inform participants?
Page 3 Line 90 - Here, you refer to this as an observational study, but in the abstract, you refer to the study as retrospective. Please be consistent in describing your study design.
Page 3 Line 91 - How many hospitals were involved? How many emergency departments? How many ICUs? Were the ICUs all the same type, or were they different in terms of patient population (e.g., medical ICU, burn ICU, surgical ICU, etc.)?
Page 3 Line 91 - Were all patients evaluated?
Page 3 Line 95 - Do you truly mean inotropic agents (e.g., dobutamine, dopamine) here, or do you actually mean vasopressor (e.g., norepinephrine, epinephrine, phenylephrine)? Patients with critical COVID-19 did not need inotropic support as much as they did vasopressor support. If you did mean inotropic support, why did you not evaluate the more frequently encountered need for vasopressor support?
Page 3 lines 96-99 - Were these biomarkers collected throughout the study, at study admission, or at some other time point?
Page 3, line 102 - Was any burn a cause of exclusion or a certain percentage?
Page 3, line 103 - exclusion of patients with alcohol consumption of any amount reduces the external validity of your results. I understand excluding those with intoxication or even chronic alcohol use, but one drink would not impact your results enough to exclude the patient.
Page 3 Line 103 - How many of your patients use mannitol " regularly"? In the U.S., this is a hospital-specific medication. Were you excluding patients with head injuries?
Page 3 line 104-105 - Do you mean that you excluded patients with chronic or home steroid treatments or use of any steroid (including those needing it for acute issues)?
Page 3, lines 110-112 - This entire section can be removed. It is already stated in the previous paragraph.h
Pages 3,-4 Lines 115-122 - please integrate this into the previous paragraph. You can discuss (and condense) information about which formula was used when discussing data collection. The statement about excluding patients without enough data can be integrated into exclusion criteria.
Page 4, Lines 130-142 - you have categorical data presented as survivors vs. non-survivors, but you have not integrated many statistical tests, including basics such as a chi-square test. You also restate the significance level in line 138 again in line 142.
Results
Overall, you seem to become distracted from the primary purpose of your study in your results section. You discuss a lot of data and connect it to mortality, with the primary endpoint buried in the middle, and only mentioned along with other data that is not part of your primary objective. When reading the results, it's difficult to determine if you've actually evaluated your primary endpoint and addressed your primary objective.
Page 4 Line 146 - please state the number of patients either in the methods section or the results, but not in both. It is generally more appropriate in the results section.
Page 4 Lines 148-149 - You mention that there were 203 non-survivors, but it is important to clarify the cause of death, particularly since the study extended to 2022, when fewer deaths from COVID-19 occurred. Were these patients' deaths FROM COVID-19 (e.g., that was the cause of death recorded), or did a patient WITH COVID-19 die, but from another cause? That impacts your entire results. Your mortality rate of 76% seems excessively high, even in the early days of the pandemic.
Page 5 line 158 - while there is a statistical difference in procalcitonin levels between groups, both groups have a median level that is consistent with viral infections. There is no known difference in thresholds for viral infections and severity of illness, like there is with bacterial or fungal infections. There is no clinically significant difference in this result. That should be clarified.
Page 5 Line 159-160 - as noted previously, please clarify whether you mean literal inotropic agents (e.g., dobutamine) or if you actually mean vasopressors. If you mean vasopressors, the difference in use of these agents would be more consistent with the data you have provided, and with mortality.
Page 5, line 61 - you mention that survivors were intubated more frequently. What about other forms of oxygen support? What about non-invasive ventilation or high-flow oxygen delivery, which were much more commonly employed towards the end of 2020 through the end of your data-collection period?
Page 4-5 Lines 152-162 - Is your paper really focused on mortality and serum osmolarity in patients with COVID-19? If so, the correlations with these endpoints and mortality do not make sense. You do not make any connection with these and sodium levels or osmolarity. It also does not make sense why you presented this data first when it appears to be of secondary or exploratory interest. Why is your data on mortality correlation with sodium and osmolality not the first thing that you present?
Discussion
Page 5, Lines 190-193 - please remember that your primary objective was to evaluate a link between serum osmolarity and mortality. Here you discuss many other factors. You can discuss them in a later paragraph after you give appropriate attention to your primary purpose.
Page 6, Lines 213-220 - you should not introduce new data in the discussion section. Here, you mention that the main cause of hypo-osmolarity was low sodium, but this was not clearly depicted in the results section.
The knowledge gap is not well identified. It is unclear why serum osmolarity could be important in critically ill patients with COVID-19.
The analysis is not related to the study goal.
The discussion is not accurate.
The authors should begin by addressing the knowledge gap. List the important prognostic factors in COVID-19 (ICU). The analysis should be redone. The primary analysis goal is to measure the incremental value of serum osmolality for inpatient mortality. Therefore, the AUC of two prognostic models (with and without osmolarity) should be compared. The base model should be developed based on preexisting knowledge.
The forward variable selection has no value in this study.
The discussion should clearly explain the importance of osmolality as a prognostic factor and how it could be treated. The important components of osmolality (Na, BUN, and Glucose) are among the prognostic values in the ICU setting.
The study conclusions are not accurately listed.
Why do the n for age in Table 1 not add up to N = 267?
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