See editorial on page 824. See editorial on page 824. What You Need to KnowBackground and contextWhile most COVID-19 patients clear the infection, some develop severe disease with organ failure. Based on patterns associated with severe COVID-19, underlying mechanisms, we propose a simple, low risk supportive intervention.New FindingsUnsaturated fat intake is associated with increased mortality from COVID-19. Unsaturated fatty acids cause injury, organ failure resembling COVID-19. Early albumin and calcium can bind unsaturated fatty acids, reduce injury.LimitationsWe do not have a clinical trial to support that "keeping a normal serum calcium and albumin all through COVID-19" improved mortality. Such a trial may be helpful in the future.ImpactBoth calcium and albumin are inexpensive, and easily available. If supplemented early during COVID-19 hospitalization, these may reduce organ failure and ICU requirements despite a lack of proven anti-viral therapies. While most COVID-19 patients clear the infection, some develop severe disease with organ failure. Based on patterns associated with severe COVID-19, underlying mechanisms, we propose a simple, low risk supportive intervention. Unsaturated fat intake is associated with increased mortality from COVID-19. Unsaturated fatty acids cause injury, organ failure resembling COVID-19. Early albumin and calcium can bind unsaturated fatty acids, reduce injury. We do not have a clinical trial to support that "keeping a normal serum calcium and albumin all through COVID-19" improved mortality. Such a trial may be helpful in the future. Both calcium and albumin are inexpensive, and easily available. If supplemented early during COVID-19 hospitalization, these may reduce organ failure and ICU requirements despite a lack of proven anti-viral therapies. Although most coronavirus disease 2019 (COVID-19) infections are self-limited, some develop into sepsis and multisystem organ failure (MSOF),1Zhou F. et al.Lancet. 2020; 395: 1054-1062Abstract Full Text Full Text PDF PubMed Scopus (18962) Google Scholar resembling lipotoxic acute pancreatitis.2de Oliveira C. Khatua B. et al.J Clin Invest. 2020; 130: 1931-1947Crossref PubMed Scopus (0) Google Scholar,3Navina S. et al.Sci Transl Med. 2011; 3: 107ra110Crossref PubMed Scopus (190) Google Scholar Understanding underlying mechanisms may guide supportive care while clinical trials are ongoing. Unsaturated fatty acids (UFAs) generated by adipose lipolysis2de Oliveira C. Khatua B. et al.J Clin Invest. 2020; 130: 1931-1947Crossref PubMed Scopus (0) Google Scholar,3Navina S. et al.Sci Transl Med. 2011; 3: 107ra110Crossref PubMed Scopus (190) Google Scholar cause MSOF, including acute lung injury.2de Oliveira C. Khatua B. et al.J Clin Invest. 2020; 130: 1931-1947Crossref PubMed Scopus (0) Google Scholar Severe acute pancreatitis and severe COVID-19 share obesity as a risk factor,4Lighter J. et al.Clin Infect Dis. 2020; Google Scholar along with lipase elevation,5Barlass U. et al.Clin Transl Gastroenterol. 2020; 11 (doi:10.14309/ctg.0000000000000215): e00215Crossref PubMed Scopus (51) Google Scholar hypoalbuminemia,1Zhou F. et al.Lancet. 2020; 395: 1054-1062Abstract Full Text Full Text PDF PubMed Scopus (18962) Google Scholar and hypocalcemia.6Cao M. et al.medRχiv. 2020; (2020.03.04.20030395)Google Scholar The latter 2 may progress undetected because calcium-albumin correction calculations (eg, https://www.mdcalc.com/calcium-correction-hypoalbuminemia) can pseudonormalize calcium values (eg, uncorrected calcium of 5.9 mg/dL and albumin of 0.1 g/dL to corrected calcium of 9.0 mg/dL). Notably, calcium ameliorates MSOF,7Khatua B. et al.J Clin Med. 2020; 9: 263Crossref Google Scholar and UFAs cause nonendocrine hypocalcemia.7Khatua B. et al.J Clin Med. 2020; 9: 263Crossref Google Scholar The ACE2 receptor resides on adipocytes8Liu F. et al.Clin Gastroenterol Hepatol. 2020; 18: 2128-2130.e2Abstract Full Text Full Text PDF PubMed Scopus (434) Google Scholar containing triglycerides and adipocyte triglyceride lipase (ATGL) and on pancreatic acini expressing pancreatic triglyceride lipase (PNLIP).2de Oliveira C. Khatua B. et al.J Clin Invest. 2020; 130: 1931-1947Crossref PubMed Scopus (0) Google Scholar Both oleic acid (C18:1) administration and adipose lipolysis3Navina S. et al.Sci Transl Med. 2011; 3: 107ra110Crossref PubMed Scopus (190) Google Scholar by PNLIP can cause acute lung injury and MSOF. These, and previous data showing that UFAs depolarize mitochondria,2de Oliveira C. Khatua B. et al.J Clin Invest. 2020; 130: 1931-1947Crossref PubMed Scopus (0) Google Scholar inhibit complexes I and V,3Navina S. et al.Sci Transl Med. 2011; 3: 107ra110Crossref PubMed Scopus (190) Google Scholar decrease adenosine triphosphate, release intracellular calcium,3Navina S. et al.Sci Transl Med. 2011; 3: 107ra110Crossref PubMed Scopus (190) Google Scholar and increase inflammatory mediators,3Navina S. et al.Sci Transl Med. 2011; 3: 107ra110Crossref PubMed Scopus (190) Google Scholar made us explore lipotoxicity during severe COVID-19. This approach, culminating in clinical advice to keep calcium and albumin levels normal from early on in the disease, is summarized in Figure 1A and explained diagrammatically in supplementary figure 1. See Supplementary Materials. Seven of 15 hospitalized patients were discharged home by 3. 4 ±1.6 days. One died of hypoxemic failure after declining intubation. Seven patients with severe disease required intensive care (mean, 3.9 ± 2 days after admission). Although otherwise similar to those with mild disease, severely ill patients had higher blood urea nitrogen (BUN) level; lower platelets and lymphocytes (Supplementary Figure 2); early, steady progressive hypocalcemia and hypoalbuminemia; and lower oxygen saturation nadirs (Figure 1B). Mice administered linoleic acid (LA) (C18:2) (Supplementary Figure 3A) but not the saturated fatty acid C16:0 developed hypoalbuminemia. Because albumin and calcium bind fatty acids and reduce toxicity,7Khatua B. et al.J Clin Med. 2020; 9: 263Crossref Google Scholar we graphed serum unbound fatty acids in patients in the intensive care unit (Figure 1C) vs their P/F ratio (ie, the arterial partial pressure of oxygen/percentage of oxygen). Lower P/F ratios (0.97 ± 0.1) were associated with higher unbound fatty acid levels (15.5 ± 7.7 μmol/L vs 4.2 ± 2.3 μmol/L; P < .002), and vice versa (2.36 ± 0.4; P < .003). C18:1, C18:2, and C16:0 make up 10%–50% of dietary fat and adipose triglycerides in humans. Mice given C18:1 (not shown) or C18:2, but not C16:0, (Figure 1D) developed leucopenia, lymphopenia,1Zhou F. et al.Lancet. 2020; 395: 1054-1062Abstract Full Text Full Text PDF PubMed Scopus (18962) Google Scholar lymphocytic injury, relative thrombocytopenia,1Zhou F. et al.Lancet. 2020; 395: 1054-1062Abstract Full Text Full Text PDF PubMed Scopus (18962) Google Scholar hypercytokinemia,1Zhou F. et al.Lancet. 2020; 395: 1054-1062Abstract Full Text Full Text PDF PubMed Scopus (18962) Google Scholar elevated alanine aminotransferase levels,1Zhou F. et al.Lancet. 2020; 395: 1054-1062Abstract Full Text Full Text PDF PubMed Scopus (18962) Google Scholar hypoalbuminemia1Zhou F. et al.Lancet. 2020; 395: 1054-1062Abstract Full Text Full Text PDF PubMed Scopus (18962) Google Scholar, hypocalcemia6Cao M. et al.medRχiv. 2020; (2020.03.04.20030395)Google Scholar, shock,1Zhou F. et al.Lancet. 2020; 395: 1054-1062Abstract Full Text Full Text PDF PubMed Scopus (18962) Google Scholar and renal failure resembling lethal COVID-19. Because adipose triglyceride composition corresponds to dietary fat composition, we compared dietary fat patterns to other risk factors for COVID-19 mortality from countries with >1000 COVID-19 cases reported between March 25, 2020, and April 8, 2020 (61 countries; 1,476,418 patients). We first did a univariate analysis using the linear mixed model, accounting for daily reported percent mortality vs dietary and other factors (Figure 1E). Because of skewness, log-transformed mortality was used in the model. Only saturated fat intake (kg/capita/y) was negatively associated (P = .05), and percent UFA intake was positively associated (P < .001) with mortality (Figure 1F and G). The rate ratio indicates the relative change in mortality for each parameter; for example, a rate ratio of 0.97 for saturated fat intake indicates that for a 1-unit increase in saturated fat, there is a 3% reduction in mortality: (1 – 0.97) × 100% = 3%. Multivariate analysis showed only percent UFA as significantly associated with mortality (P < .0001). Interestingly, per capita GDP consistently and positively correlated with tests/million (not shown), and COVID-19 cases/million (Supplementary Figure 3B), with the infliction point noted above US$10,000. Thus, COVID-19 may be undiagnosed in low-income countries. We next studied how dietary and adipose triglyceride saturation could protect from severe COVID-19. Because it is not known which lipase is active in COVID-19, we examined how saturation affects triglyceride interaction with ATGL. On unbiased in silico docking simulation, the linoleic acid triglyceride trilinolein (LLL) docked to the ATGL homology model with a GlideScore of –6.71 kcal/mol and 7.02 Å between the catalytic Ser47 hydroxyl and the carbonyl C atom of the glycerol backbone (Figure 1H). Substituting palmitate at Sn-3, 1,2-dilinoleoyl-3-palmitoyl-racglycerol (LLP) docked with a GlideScore of –3.34 kcal/mol and 8.49 Å from the catalytic serine (Figure 1I). Thus, saturation reduces lipolysis by making the complex less energetically and structurally favorable. Exposure of an established human umbilical vein endothelial cell (HUV-EC-C) cell monolayer to UFAs decreased transendothelial resistance and increased dextran permeability and apoptotic peripheral blood mononuclear cells (Figure 1J–L). LA increased the baseline and frequency of cytosolic calcium elevation in spontaneously beating cardiomyocytes (Figure 1M). Thus, UFAs may cause vascular (albumin) leak, inflammatory injury, and arrhythmia during severe COVID-19. On isothermal titration calorimetry, albumin-bound LA strongly (stoichiometry ≈ 6:1; enthalpy, –230 KJ/mol) (Figure 1N). However, adding albumin 30 minutes after LA to macrophages did not reduce necrosis. Although preincubating HEK293 cells with albumin and calcium (Figure 1 O and P) completely prevented necrosis, delayed addition of albumin only partially blocked or reversed LA-induced mitochondrial depolarization2de Oliveira C. Khatua B. et al.J Clin Invest. 2020; 130: 1931-1947Crossref PubMed Scopus (0) Google Scholar (Figure 1Q and R). Therefore, early neutralization of UFAs may prevent mitochondrial dysfunction and injury resulting in MSOF.3Navina S. et al.Sci Transl Med. 2011; 3: 107ra110Crossref PubMed Scopus (190) Google Scholar In vivo, prophylactic calcium and albumin prevented LA-induced MSOF (not shown). Thus, early supplementation with albumin and calcium may be better than correcting deficiencies later during severe COVID-19 infection or sepsis, which may be too little, too late. Calcium binds C18:2 more weakly7Khatua B. et al.J Clin Med. 2020; 9: 263Crossref Google Scholar (–20 kJ/mol) than albumin. However, calcium's total concentration (2.25–2.75 mmol/L) is 3–5 times higher, and it ameliorates MSOF.7Khatua B. et al.J Clin Med. 2020; 9: 263Crossref Google Scholar Thus, supplementing calcium (eg, oral calcium carbonate) and albumin to normal values early during COVID-196Cao M. et al.medRχiv. 2020; (2020.03.04.20030395)Google Scholar could reduce lipotoxic MSOF without violating the calcium-albumin correction. Despite COVID-19 being underdiagnosed in lower-income countries, mortality in diagnosed COVID-19 is likely from the infection and, thus, supports our conclusions. Additionally, while we did incorporate the number of ventilators per country, the numbers quoted are in some cases more than 8 years old, and therefore may not be reliable. Similarly, the number of ICU beds available may not reflect the exact number in each country. Although our clinical study is small and retrospective and experimental studies are correlative, their congruence to severe COVID-19 is supported by larger published studies1Zhou F. et al.Lancet. 2020; 395: 1054-1062Abstract Full Text Full Text PDF PubMed Scopus (18962) Google Scholar,6Cao M. et al.medRχiv. 2020; (2020.03.04.20030395)Google Scholar and can be validated by future interventional studies. Thus, keeping calcium and albumin levels normal through COVID-19 is a low-cost, low-risk strategy to improve outcomes. Lipotoxicity in COVID-19 Study Group contributors: Bara El-Kurdi, Biswajit Khatua, Christopher Rood, Christine Snozek, Sergiy Kostenko, Shubham Trivedi, Clifford Folmes, Katherine Minter Dykhouse, Sumbal Babar, Yu-Hui Chang, Rahul Pannala, Rodrigo Cartin-Ceba, and Vijay P. Singh. We are extremely thankful to Jill Lauritsen, Sheila Sandolo, and the staff at the Mayo Clinic Arizona Biospecimen repository and accession core for their help. We acknowledge the websites worldometers.info/coronavirus, the Johns Hopkins University Coronavirus resource center (https://coronavirus.jhu.edu/), Wikipedia.com, the World Bank website (https://data.worldbank.org/) and World Health Organization website (https://apps.who.int/gho/data/view.main.HS07v) and data publicly provided by www.ourworldindata.org/. Bara El-Kurdi, MD (Data curation: Equal; Investigation: Equal; Methodology: Equal; Writing – original draft: Equal); Biswajit Khatua, PhD (Data curation: Equal; Investigation: Equal; Methodology: Equal); Christopher Rood, BS (Data curation: Equal; Formal analysis: Equal; Methodology: Equal); Christine Snozek, PhD (Data acquisition -Equal, Methodology: Equal, Writing – subsequent draft: Equal); Rodrigo Cartin-Ceba, MD (Data curation: Equal; Funding acquisition: Equal; Investigation: Equal; Methodology: Equal; Project administration: Equal; Supervision: Equal; Writing – original draft: Supporting); Vijay P. Singh, M.D. (Conceptualization: Lead; Data curation: Lead; Formal analysis: Lead; Funding acquisition: Lead; Investigation: Lead; Methodology: Lead; Project administration: Lead; Resources: Lead; Supervision: Lead; Validation: Lead; Visualization: Lead; Writing – original draft: Lead); The Lipotoxicity in COVID-19 Study Group (Data curation: Equal; Formal analysis: Equal; Investigation). Protocols (14-003999, 18-005104) were approved by the Mayo Clinic institutional review board (IRB). Chart review of patients admitted with COVID-19 infection from March 20, 2020, and April 7, 2020 was done (by VPS and RCC). More than 1 admission over a 2-week period was counted as 1. Data were collated into an Excel spreadsheet (Microsoft, Redmond, WA), graphed, and statistically compared. Unbound fatty acids were measured on residual serum samples remaining after all clinical testing was done, as per the approved IRB protocol. All consenting requirements stipulated by the approved IRB protocol were followed. Real-time database searches between March 25, 2020, and April 8, 2020, were done. Total COVID-19 cases and deaths (www.worldometers.info/coronavirus) were validated from (https://coronavirus.jhu.edu/) for all countries, with a total of >1000 cases. All countries reporting >20 deaths were included until day 7. A country's area, population (in millions), gross domestic product (GDP) (in billions of US dollars), latitude, hospital beds/1000 population, and ICU beds/100,000 population were from Wikipedia and were validated from https://data.worldbank.org/, https://apps.who.int/gho/data/view.main.HS07v, and www.ourworldindata.org/. The calculated parameters were "% deaths," "COVID positive/million," "population density," and "per capita GDP." The per capita (kg/capita/year) food intake of each country was recorded from http://www.fao.org/faostat/en/#data/FBS, by choosing "country," and then "Element" as "food supply quantity (kg/capita/year)". Under "items aggregated," "Animal products (list)" and "vegetable oils (list)" were chosen, as was year "2017". Data were downloaded as a .csv file and converted to Excel. Cold-source (unsaturated) fat intake (kg/capita/year) was as total vegetable oil intake (excluding palm oil) + fish fat (10% of weight of fish consumed). The warm-source fat (saturated) intake (kg/capita/year) was palm oil + ghee + butter + cream + raw animal fat + 15% of red meat and mutton weight + 8% of pork weight + 14% of poultry weight + 2% of milk weight. The percent cold-source (ie, unsaturated) fat was calculated as a percentage of cold + warm sources. National life expectancy, median age, and infant mortality were from https://www.un.org/development/desa/publications/publication, and COVID-19 doubling time were from www.ourworldindata.org/. The univariate analysis was performed by fitting a linear mixed model to evaluate the relationship between daily mortality and each variable, with a random intercept for each country to account for the clustering effect. The logarithm transformation estimates reflect the differences in the log of mortality rate per 1-unit increase in each explanatory variable. To quantify the association in the original scale of mortality rate, we exponentiated the model estimate, and hence, the value represents the rate ratio per 1-unit increase in an explanatory variable. A rate ratio of <1 indicates that an explanatory variable is negatively associated with mortality, a rate ratio of >1 indicates a positive association, and a ratio equal to 1 indicates no statistical association. The analysis was conducted based on the aggregated information from countries with available data. The statistical analysis was performed by the use of R 3.6.2 (R Project for Statistical Computing, Vienna, Austria). Male, 8–10-week-old Institute for Cancer Research (ICR) mice (Charles River Laboratories, Wilmington, MA) were used as previously described.1Zhou F. et al.Lancet. 2020; 395: 1054-1062Abstract Full Text Full Text PDF PubMed Scopus (18962) Google Scholar There were 4 groups: control and intraperitoneal C18:2,2de Oliveira C. Khatua B. et al.J Clin Invest. 2020; 130: 1931-1947Crossref PubMed Scopus (0) Google Scholar C18:1,1Zhou F. et al.Lancet. 2020; 395: 1054-1062Abstract Full Text Full Text PDF PubMed Scopus (18962) Google Scholar and C16:0 at 0.2%, 0.3%, and 0.5% body weight, respectively. These cohorts overlapped with but were not identical to the previous ones. All protocols were approved by the Institutional Animal Care and Use Committee of the Mayo Clinic Foundation. All reagents, including dimethyl sulfoxide (DMSO), were from Sigma-Aldrich (St Louis, MO). As previously reported,2de Oliveira C. Khatua B. et al.J Clin Invest. 2020; 130: 1931-1947Crossref PubMed Scopus (0) Google Scholar fatty acids were sonicated into phosphate-buffered saline (10 s/pulse × 3). C16:0 (insoluble in phosphate-buffered saline) was a 60-mmol/L stock in DMSO. Final DMSO (0.16%–0.5%) does not affect results, as shown previously.4Lighter J. et al.Clin Infect Dis. 2020; Google Scholar All data shown are from a 3–5 independent experiments. Primary pancreatic acini peripheral blood mononuclear cells were harvested and used as described previously5Barlass U. et al.Clin Transl Gastroenterol. 2020; 11 (doi:10.14309/ctg.0000000000000215): e00215Crossref PubMed Scopus (51) Google Scholar,6Cao M. et al.medRχiv. 2020; (2020.03.04.20030395)Google Scholar in HEPES buffer pH 7.4 (20 mmol/L HEPES, 120 mmol/L NaCl, 5 mmol/L KCl, 1 mmol/L MgCl2, 10 mmol/L glucose, 10 mmol/L sodium pyruvate, 1 mmol/L CaCl2), as were HEK293 cells.2de Oliveira C. Khatua B. et al.J Clin Invest. 2020; 130: 1931-1947Crossref PubMed Scopus (0) Google Scholar J774A.1 cells cultured as per American Type Culture Collection (Manassas, VA) were gently scraped, washed 3 times in HEPES buffer at 37°C, exposed to LA for 2 hours (75 revolutions/minute). LDH leakage was calculated as for HEK293 cells. Human endothelial cell Established human umbilical vein endothelial cell (HUV-EC-C) monolayers (on 0.4-μm polyester Transwell permeable membrane [Corning, NY] precoated with type IV collagen) were grown in Kaighn's modification of Ham's F-12 medium, and supplemented with 10% fetal bovine serum, 1% penicillin/streptomycin, 0.1 mg/mL heparin, and 50 μg/mL Corning Endothelial Cell Growth Supplement, as per American Type Culture Collection. TEER measurement (in Ωcm2) using the EVOM2 Epithelial Volt/Ohm Meter with an STX2 electrode (World Precision Instruments, Sarasota, FL) and 10-kD dextran Alexa Fluor 647 permeability tracer flux assay (added to the upper chamber, measured in the lower chamber) were done in HEPES buffer over 2 hours of non-esterifed fatty acid (NEFA) treatment. Mitochondrial depolarization (ψm) studies were done as described previously.4Lighter J. et al.Clin Infect Dis. 2020; Google Scholar,7Khatua B. et al.J Clin Med. 2020; 9: 263Crossref Google Scholar, 8Liu F. et al.Clin Gastroenterol Hepatol. 2020; 18: 2128-2130.e2Abstract Full Text Full Text PDF PubMed Scopus (434) Google Scholar, 1de Oliveira C. Khatua B. Noel P. et al.Pancreatic triglyceride lipase mediates lipotoxic systemic inflammation.J Clin Invest. 2020; 130: 1931-1947Crossref PubMed Scopus (84) Google Scholar Unbound fatty acids were measured following manufacturer's protocol for the ADIFAB2 kit (FFA Sciences, San Diego, CA). Readings were calibrated against NEFA standards made in DMSO. This was done by using isothermal titration calorimetry at 37°C as recently described2de Oliveira C. Khatua B. et al.J Clin Invest. 2020; 130: 1931-1947Crossref PubMed Scopus (0) Google Scholar by using 850-μmol/L fatty acid–free bovine serum albumin in the burette, with 10 μmol/L/injection into 1 mmol/L C18:2. The crystal structure of human ATGL has yet to be elucidated, which necessitated the construction of an ATGL homology model with SWISS-MODEL2Khatua B. Yaron J.R. El-Kurdi B. et al.Ringer's lactate prevents early organ failure by providing extracellular calcium.J Clin Med. 2020; 9: 263Crossref Scopus (30) Google Scholar to perform molecular docking simulations. Triglycerides trilinolein; LLL (compound CID: 5322095), 1,2-dilinoleoyl-3-palmitoyl-rac-glycerol; LLP (compound CID: 9544106), 1-linoleoyl-2-oleoyl-3-palmitoyl-sn-glycerol; and LOP (compound CID: 99647498) were docked to the ATGL homology model using the Induced Fit Docking protocol within Schrodinger Maestro.3Khatua B. Trivedi R.N. Noel P. et al.Carboxyl ester lipase may not mediate lipotoxic injury during severe acute pancreatitis.Am J Pathol. 2019; 189: 1226-1240Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar Cardiomyocytes were generated from human induced pluripotent stem cells (IRB 13-007298 and 18-010099) by using the chemically defined medium 3 (CMD3) protocol4Navina S. Acharya C. DeLany J.P. et al.Lipotoxicity causes multisystem organ failure and exacerbates acute pancreatitis in obesity.Sci Transl Med. 2011; 3: 107ra110Crossref PubMed Scopus (308) Google Scholar with modifications.5Noel P. Patel K. Durgampudi C. et al.Peripancreatic fat necrosis worsens acute pancreatitis independent of pancreatic necrosis via unsaturated fatty acids increased in human pancreatic necrosis collections.Gut. 2016; 65: 100-111Crossref PubMed Scopus (105) Google Scholar Briefly, induction of differentiation was achieved by using 8 μmol/L CHIR-99021 and 10 nmol/L activin A for 20 hours, followed by treatment with 5 μmol/L IWP2 and 10 ng/mL of recombinant human BMP-4. Cardiomyocytes were not subject to lactate selection before dissociation on day 15 and were seeded on fibronectin-coated, glass-bottomed plates for imaging. These were loaded with Fluo-4AM and imaged6Patel K. Trivedi R.N. Durgampudi C. et al.Lipolysis of visceral adipocyte triglyceride by pancreatic lipases converts mild acute pancreatitis to severe pancreatitis independent of necrosis and inflammation.Am J Pathol. 2015; 185: 808-819Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar (Zeiss LSM 800; Carl Zeiss, Oberkochen, Germany) in HEPES buffer/37°C/every 9.5 seconds ± LA. Fluorescence (arbitrary units) was quantified on fixed areas of serial images using ImageJ software (National Institutes of Health, Bethesda, MD).Supplementary Figure 2(A) Table comparing the demographics and comorbidities of patients with COVID-19 who were discharged home vs those who were admitted to the ICU or died (ICU/died). (B) Time course starting at the day of admission or –4 days (whichever came first) leading to the event on day 0, which is the day of discharge; death; or ICU admission. The green lines show the trends of those who were discharged to home, and the red lines show those who were transferred to the ICU or died. From top to bottom, these are morning (AM) laboratory values for platelet counts, serum alanine aminotransferase, and C -reactive protein. ∗Significant (P < .05) difference for the whole time course matched for each day when comparing red and green values on t test. One patient who died had myelodysplastic syndrome and was excluded. (C) The patterns for BUN, total WBC counts, and absolute lymphocyte counts. The patients excluded are mentioned, along with the underlying comorbidity. #Significant difference between red and green values for the day. ALT, alanine aminotransferase; BMI, body mass index; BUN, blood urea nitrogen; CKD, chronic kidney disease; CLL, chronic lymphocytic leukemia; CRP, C-reactive protein; COPD, chronic obstructive pulmonary disease; degn., degenerative; F, female; hosp., hospital; M, male; SD, standard deviation; WBC, white blood cell; Yr., years.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Supplementary Figure 3(A) Time course of serum albumin levels in mice given the UFA LA (C18:2, red line) vs those give palmitic acid (C16:0, green line). There were 8 mice per group. ∗P < .0001 vs for same-day values measured in the 2 groups of mice. (B) Nonlinear correlation of the number of COVID-19 cases diagnosed/million population of a country and its per capita GDP as of April 8, 2020, which was the last day of the study. Note that the inflection point for increase in testing is noted at approximately US$15,000. The table on the right gives the name of the country corresponding to the number shown. PA, palmitic acid; Sr., serum; UAE, United Arab Emirates.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Lipotoxicity and Cytokine Storm in Severe Acute Pancreatitis and COVID-19GastroenterologyVol. 159Issue 3PreviewSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–induced coronavirus disease-2019 (COVID-19) has become a pandemic affecting >7 million people worldwide so far.1 The relatively high mortality of COVID-19 (around 10% of closed cases) is often linked to multiorgan failure, which supports the notion that an inappropriate host response to the viral infection might play a role in disease outcomes. In this issue of Gastroenterology, the Lipotoxicity in COVID-19 Study Group from the Mayo Clinic reports the enticing observation that progression of COVID-19 to multiorgan failure resembles lipotoxic organ failure during severe acute pancreatitis. Full-Text PDF