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High levels of circulating angiotensin converting enzyme 2 (ACE2) are associated with several chronic diseases and mortality risk. Less is known about the prognostic value of ACE2 in patients with sepsis. In the present study, we aimed to investigate the association between plasma ACE2 levels on admission to the ED and 28-day mortality, organ failure, and level of care in a prospectively recruited observational study sample. Six hundred patients with sepsis admitted to the emergency in Malmö 2013–2015 were included in the analysis. Uni- and multivariable binary logistic regression was conducted to investigate the association between ACE2 and 28-day mortality, organ failure, and level of care. Plasma ACE2 levels were increased in patients with male sex, high age, and comorbidities, including diabetes, cardiovascular disease, and cancer. Plasma ACE2 levels associated with hospitalization and intermediate care unit stay in univariate but not multivariate analysis. Plasma ACE2 did neither associate with 28-day mortality, OR 1.19 (95% CI 0.86–1.65, p = 0.29), nor with organ failure, OR 1.08 (95% CI 0.73–1.56. p = 0.72). Future studies investigating the dynamics of circulating ACE2 levels in patients with sepsis longitudinally are warranted.

Exposure to per- and polyfluorinated substances (PFAS) and hydroxylated polychlorinated biphenyls (OH-PCBs) is associated with adverse human health effects, including immunosuppression. It is unknown if these substances can affect the course of autoimmune diseases. This study was based on 907 individuals with multiple sclerosis (MS) and 907 matched controls, where the MS cases were followed longitudinally using the Swedish MS register. We demonstrate sex- and disease-specific differences in serum PFAS concentrations between individuals with MS and controls. Moreover, two OH-PCBs (4-OH-CB187 and 3-OH-CB153) are associated with an increased risk of developing multiple sclerosis, regardless of sex and immigration status. With a clinical follow-up time of up to 18 years, an increase in serum concentrations of perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), and perfluorodecanoic acid (PFDA) decreases the risk of confirmed disability worsening in both sexes, as well as perfluoroheptanesulfonic acid (PFHpS) and perfluorononanoic acid (PFNA), only in males with MS. These results show previously unknown associations between OH-PCBs and the risk of developing MS, as well as the inverse associations between PFAS exposure and the risk of disability worsening in MS.

BACKGROUND: Obesity has been associated with onset and progression of chronic kidney disease (CKD) but causal relationship remains uncertain. This study investigated how obesity causally affects estimated glomerular filtration rate.

METHODS: Cross-sectional and magnetic resonance imaging (MRI) data analyses were performed within the Prospective Investigation of Obesity, Energy, and Metabolism (POEM) study (502 participants, all aged 50 years). Additionally Mendelian randomization was performed using published summary data. Outcomes were creatinine- and cystatin C-based eGFR. Body mass index (BMI) and waist circumference (WC) were used as exposure variables in the cross-sectional and Mendelian randomization analyses. In the imaging data analyses, eGFR was regressed non-parametrically on tissue volume for each 3D voxel and visualized as a correlation "Imiomics" map.

RESULTS: Negative correlations were shown between cystatin C-based eGFR and BMI [beta = -0.190 (95% CI: -0.280 to -0.100)] and WC [beta = -0.160 (95% CI: -0.250 to -0.060)] in an adjusted model. In contrast, a positive association was found for creatinine-based eGFR [BMI beta = 1.20 (95% CI: 0.030 to 0.210) and WC beta = 0.160 (95% CI: 0.070 to 0.260)]. Similar patterns were found using MRI analysis (Imiomics map). Mendelian randomization implied a negative causal effect of obesity-related measures on cystatin C-based eGFR [BMI beta = -0.031 (95% CI: -0.037 to -0.026) and WC beta = -0.038 (95% CI: -0.045 to -0.031)], but no statistically significant effect was found for creatinine-based eGFR.

CONCLUSION: This study suggests a causal negative effect of obesity on cystatin C-based, but not creatinine-based eGFR. These findings warrant further research regarding estimations of kidney function when assessing obesity and CKD.

PURPOSE: Assess if cystatin C-derived measures of kidney function are associated with mortality in septic- and non-septic intensive care unit (ICU) patients.

METHODS: Data from adult patients staying >24 h in four ICUs in Sweden from November 2015-December 2018 included. Outcomes were mortality and need for renal replacement therapy (RRT) due to acute kidney injury. Associations between cystatin C-estimated glomerular filtration rate (eGFRcys) and shrunken pore syndrome (SPS) and outcomes were assessed with Cox-regression in unadjusted and analyses adjusted for sex, age, illness severity, chronic kidney disease and creatinine. SPS was defined as a ratio between eGFRcys and eGFRcreatinine <0.6.

RESULTS: In total, 4455 patients were included in the analysis, of which 32 % had sepsis. SPS was present in 7.4 % of the cohort, and 90-day mortality was 30.8 %. In sepsis- and non-sepsis patients, SPS and eGFRcys were associated with 90-day-, 1-year mortality and RRT in unadjusted analyses. In an adjusted analysis, SPS was associated with 1-year mortality in sepsis patients (hazard ratio [HR] 1.4, 95 % CI 1.1-1.9, p = 0.021), and eGFRcys was associated with RRT in both sepsis and non-sepsis patients (HR 3.1, 95 % CI 1.6-6.0, p < 0.001, eGFRcys <20 vs ≥60 ml/min/1.73m²). No other associations between eGFRcys, SPS and mortality were detected in adjusted analyses.

CONCLUSION: Our finding that SPS is more robustly associated with mortality in sepsis patients than in non-sepsis patients suggests that the association between SPS and mortality may depend on underlying pathophysiology. A cystatin C-based estimate of GFR is independently associated with RRT in sepsis and non-sepsis.

Patients with rheumatoid arthritis (RA) are at increased risk of diffuse large B cell lymphoma (DLBCL) compared to the general population. Here, we explored the inflammatory profiles in the blood of RA patients who had developed DLBCL. RA-DLBCL patients had significantly higher levels of the pro-inflammatory markers TNF, IL-8, CXCL9, APRIL, and particularly CXCL13 (median 796 vs. 206 pg/mL, p = 0.001), compared to RA controls. By including an extensive autoantibody panel of rheumatoid factor, IgG anti-CCP2, anti-citrullinated protein antibodies (ACPA) fine-specificities, and other anti-modified protein antibodies, all RA-DLBCL patients were autoantibody seropositive. Yet, RA-DLBCL patients did not display significantly different autoantibody signatures compared to RA controls. The levels of immunoglobulin free light chains and C-reactive protein were similar in RA-DLBCL patients and RA controls. In conclusion, RA-DLBCL patients exhibit pro-inflammatory signatures with elevated markers that are important for B cells and may contribute to enhanced B-cell activation and promote lymphoma development.

BACKGROUND: Creatinine-based estimated glomerular filtration rate (eGFR) equations are widely used in clinical practice but exhibit inherent limitations. On the other side, measuring GFR is time consuming and not available in routine clinical practice. We developed and validated machine learning models to assess the trustworthiness (i.e. the ability of equations to estimate measured GFR (mGFR) within 10%, 20% or 30%) of the European Kidney Function Consortium (EKFC) equation at the individual level.

METHODS: This observational study used data from European and US cohorts, comprising 22,343 participants of all ages with available mGFR results. Four machine learning and two traditional logistic regression models were trained on a cohort of 9,202 participants to predict the likelihood of the EKFC creatinine-derived eGFR falling within 30% (p30), 20% (p20) or 10% (p10) of the mGFR value. The algorithms were internally and then externally validated on cohorts of respectively 3,034 and 10,107 participants. The predictors included in the models were creatinine, age, sex, height, weight, and EKFC.

RESULTS: The random forest model was the most robust model. In the external validation cohort, the model achieved an area under the curve of 0.675 (95%CI 0.660;0.690) and an accuracy of 0.716 (95%CI 0.707;0.725) for the P30 criterion. Sensitivity was 0.756 (95%CI 0.747;0.765) and specificity was 0.485 (95%CI 0.460; 0.511) at the 80% probability level that EKFC falls within 30% of mGFR. At the population level, the PPV of this machine learning model was 89.5%, higher than the EKFC P30 of 85.2%. A free web-application was developed to allow the physician to assess the trustworthiness of EKFC at the individual level.

CONCLUSIONS: A strategy using machine learning model marginally improves the trustworthiness of GFR estimation at the population level. An additional value of this approach lies in its ability to provide assessments at the individual level.

Hundreds of loci have been robustly associated with obesity-related traits, but functional characterization of candidate genes remains a bottleneck. Aiming to systematically characterize candidate genes for a role in accumulation of lipids in adipocytes and other cardiometabolic traits, we developed a pipeline using CRISPR/Cas9, non-invasive, semi-automated fluorescence imaging and deep learning-based image analysis in live zebrafish larvae. Results from a dietary intervention show that 5 days of overfeeding is sufficient to increase the odds of lipid accumulation in adipocytes by 10 days post-fertilization (dpf, n = 275). However, subsequent experiments show that across 12 to 16 established obesity genes, 10 dpf is too early to detect an effect of CRISPR/Cas9-induced mutations on lipid accumulation in adipocytes (n = 1014), and effects on food intake at 8 dpf (n = 1127) are inconsistent with earlier results from mammals. Despite this, we observe effects of CRISPR/Cas9-induced mutations on ectopic accumulation of lipids in the vasculature (sh2b1 and sim1b) and liver (bdnf); as well as on body size (pcsk1, pomca, irs1); whole-body LDLc and/or total cholesterol content (irs2b and sh2b1); and pancreatic beta cell traits and/or glucose content (pcsk1, pomca, and sim1a). Taken together, our results illustrate that CRISPR/Cas9- and image-based experiments in zebrafish larvae can highlight direct effects of obesity genes on cardiometabolic traits, unconfounded by their - not yet apparent - effect on excess adiposity.

BACKGROUND: Critical COVID-19 is associated with high mortality, and acute kidney injury (AKI) is common. Endostatin has emerged as a promising prognostic biomarker for predicting AKI and mortality in intensive care. This study aimed to investigate plasma endostatin at intensive care unit (ICU) admission as a biomarker for AKI, renal replacement therapy (RRT), and 90-day mortality in COVID-19.

METHODS: A pre-planned retrospective analysis of a prospectively collected cohort of admissions with a primary SARS-CoV-2 infection to six ICUs in southern Sweden between May 2020 and May 2021 was undertaken. Endostatin at ICU admission was evaluated with multivariable logistic regression analyses adjusted for age, sex, C-reactive protein, and creatinine. Net reclassification index analyses were also performed.

RESULTS: Four hundred eighty-four patients were included. Endostatin showed a non-linear association with AKI, RRT, and 90-day mortality. Endostatin levels of 100-200 ng/mL were associated with AKI on ICU day 1 (OR 5.1, 95% CI 1.5-18, p = 0.0097), RRT during the ICU stay (OR 3.5, 95% CI 1.1-12, p = 0.039), and 90-day mortality (OR 4.2, 95% CI 1.6-11, p = 0.0037). Adding endostatin to creatinine improved prediction of AKI on ICU day 1, while adding it to a model containing age, sex, CRP, and creatinine improved prediction of both AKI on ICU day 1 and 90-day mortality, but not RRT.

CONCLUSIONS: Endostatin at ICU admission was independently associated with AKI, RRT, and 90-day mortality in ICU patients with COVID-19. In addition, endostatin improved the prediction of AKI and 90-day mortality, highlighting its potential as a biomarker for early risk stratification in intensive care.

BACKGROUND: Neutrophil granulocytes are important parts of the defence against bacterial infections. Their action is a two-edged sword, the mediators killing the intruding bacteria are at the same time causing tissue damage. Neutrophil activation is part of the dysregulated immune response to infection defining sepsis and neutrophil elastase is one of the powerful proteases causing both effects and damage. Inhibition of neutrophil elastase has been tried in sepsis and ARDS, so far with inconclusive results.

METHODS: We used positron emission tomography (PET) combined with computed tomography (CT) and the selective and specific neutrophil elastase inhibitor PET-tracer [¹¹C]GW457427 ([¹¹C]NES), in an intensive care unit porcine Escherichia coli sepsis model with the primary aim to visualise the biodistribution of neutrophil elastase in the initial acute phase of the septic reaction. Repeated PET-CT investigations were performed before and after induction of sepsis.

RESULTS: At baseline [¹¹C]NES uptake was found in the bone marrow, spleen and liver. The uptake in the bone marrow was markedly increased two hours into the sepsis, whereas in spleen and liver the uptake was not as markedly changed compared to baseline. At 4 h after the sepsis induction [¹¹C]NES in the bone marrow decreased while the uptake increased in the spleen, liver and lungs.

CONCLUSION: The neutrophil elastase PET-tracer [¹¹C]NES is a novel and unique instrument to study the acute innate neutrophil immune response in sepsis and associated vital organ failure. We here present images and quantitative data of the neutrophil elastase distribution the first hours of acute experimental sepsis. Surprisingly, a pronounced increase of neutrophil elastase was found in the bone marrow 2 h into the sepsis reaction followed at 4 h by increase in the liver, spleen and lungs and a concomitant reduction of the tracer uptake in bone marrow.

first_pagesettings Order Article Reprints Open AccessArticleSerum CD5L Responds Positively to Selenium and Coenzyme Q10 Supplementation with Relation to Thyroid Hormones, Mortality, and Health-Related Quality-of-Life—A Sub-Analysis of a Double-Blind Randomised Placebo-Controlled Trial in Elderly Low in Seleniumby Urban Alehagen 1,*, Jan O. Aaseth 2,3 , Trine B. Opstad 4,5, Anders Larsson 6 , Sabrina Asaad 7, Lutz Schomburg 7  and Jan Alexander 8   1Division of Cardiovascular Medicine, Department of Medical and Health Sciences, Linköping University, 581 85 Linköping, Sweden2Department of Research, Innlandet Hospital Trust, 2380 Brumunddal, Norway3Faculty of Health and Social Sciences, University of Inland Norway, 2605 Lillehammer, Norway4Oslo Center for Clinical Heart Research—Laboratory, Department of Cardiology, Oslo University Hospital Ullevål, 0450 Oslo, Norway5Faculty of Medicine, University of Oslo, 0372 Oslo, Norway6Department of Medical Sciences, Uppsala University, 751 85 Uppsala, Sweden7Institut für Experimentelle Endokrinologie, Charité-Universitätsmedizin Berlin, 10115 Berlin, Germany8Norwegian Institute of Public Health, 0213 Oslo, Norway*Author to whom correspondence should be addressed.Antioxidants 2025, 14(3), 366; https://doi.org/10.3390/antiox14030366Submission received: 8 February 2025 / Revised: 12 March 2025 / Accepted: 12 March 2025 / Published: 20 March 2025(This article belongs to the Section Health Outcomes of Antioxidants and Oxidative Stress)

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AbstractThe Cluster of Differentiation 5-like protein (CD5L) is produced by tissue-resident macrophages. It is an innate immune mediator protein with a multitude of functions, such as binding of invading microorganisms and oxidised LDL, and it is associated with clinical conditions, i.e., atherosclerosis and inflammation. The circulating CD5L level has been reported to correlate to selenium status and thyroid hormone activity. In order to test this hypothesis, we analysed CD5L in serum samples from a randomized controlled trial (RCT) with selenium and coenzyme Q10 supplementation and examined associations between CD5L and thyroid hormones, health-related quality-of-life (Hr-QoL), and mortality in an elderly population low in selenium. Circulating levels of CD5L and thyroid hormones were determined in 359 elderly community-living individuals enrolled in an RCT at inclusion and after 48 months of supplementation (179 received selenium and coenzyme Q10, and 180 placebo). Hr-QoL was recorded at both time-points using Short Form 36. Pre-intervention plasma selenium was low, mean 67 µg/L. CD5L correlated positively to free tri-iodothyronine (fT3) and showed an inverse relation with thyroid stimulating hormone (TSH). Low CD5L concentrations at inclusion in the placebo group were associated with increased cardiovascular mortality during 10 years of follow-up, and impaired Hr-QoL at 48 months. Selenium and coenzyme Q10 supplementation significantly increased CD5L and fT3 levels, in association with a better health outcome. The data indicate that circulating CD5L positively responds to selenium and coenzyme Q10 supplementation, correlates with thyroid hormone status, and associates with positive health indices. The observed effect may be due to increased selenium-dependent deiodinase isozyme expression that converts thyroxine (T4) to T3 locally and supports thyroid hormone activities. Whether the observed associations with Hr-QoL and cardiovascular mortality are a direct effect of circulating CD5L or local thyroid hormone activity is unclear and should be further investigated.