Annika Elisabet Michelsen

• Ueland, Thor; Michelsen, Annika Elisabet; Qvigstad, Elisabeth; Roland, Marie Cecilie; Westerberg, Ane Cecilie & Michelsen, Trond Melbye [Show all 9 contributors for this article] (2026). Secreted frizzled-related protein 3 is associated with metabolic disturbances in gestational diabetes. Frontiers in Endocrinology. 17. doi: 10.3389/fendo.2026.1905877. Full text in Research Archive
• Ravnestad, Håvard; Ahmed, Salaheldin; Østby, Carol Margaret; Gude, Einar; Kvitting, John-Peder & Broch, Kaspar [Show all 10 contributors for this article] (2026). The association between soluble ST2 and transplant-free survival in precapillary pulmonary hypertension. JHLT Open. 14. doi: 10.1016/j.jhlto.2026.100661. Full text in Research Archive
• Zamani, Mahtab; Skagen, Karolina Ryeng; Lindberg, Beate; Bjerkeli, Vigdis; Dahl, Tuva Børresdatter & Michelsen, Annika Elisabet [Show all 10 contributors for this article] (2026). Plasma levels of soluble Flt-1 and Tie-2 correlate with neovascularization in human carotid atherosclerotic plaques - a pilot study. Frontiers in Immunology. 17, p. 1–10. doi: 10.3389/fimmu.2026.1791571. Full text in Research Archive
• Ueland, Thor; Dahl, Tuva Børresdatter; Michelsen, Annika Elisabet; Kleveland, Ola; Andersen, Geir Øystein & Anstensrud, Anne Kristine [Show all 13 contributors for this article] (2026). Effect of Interleukin-6 Receptor Inhibition by Tocilizumab on Platelet Activation and Markers of Thrombus Formation: A Substudy of the ASSAIL-MI Trial. Arteriosclerosis, Thrombosis and Vascular Biology. ISSN 1079-5642. doi: 10.1161/ATVBAHA.125.323587. Full text in Research Archive
• Lekva, Tove; Frøystad, Monica; Michelsen, Annika Elisabet; Khan, Yusuf; Aukrust, Pål & Halvorsen, Bente Evy [Show all 8 contributors for this article] (2026). Circulating MALAT1 in Preeclampsia and Association With Cardiometabolic Risk. Hypertension. ISSN 0194-911X. 83(3). doi: 10.1161/HYPERTENSIONAHA.125.26379. Full text in Research Archive Show summary

  BACKGROUND: Preeclampsia is a hypertensive disorder affecting 2% to 8% of pregnancies. Women with a history of preeclampsia have an increased risk of cardiovascular disease. The long noncoding RNA MALAT1 is shown to regulate inflammatory responses linked to cardiovascular disease. MALAT1 is decreased in preeclampsia placentas and may have a cis-regulatory function on neighboring RNAs. METHODS: Expression of MALAT1, NEAT1, mascRNA, SCYL1, and FRMD8 was assessed in peripheral blood mononuclear cells, and MALAT1 in plasma and extracellular vesicles, at 22 to 24 and 36 to 38 weeks of gestation in healthy (n=214) and preeclampsia (n=37) women from the STORK cohort study (STORe barn og Komplikasjoner, translated as Large Babies and Complications) and at 5-year follow-up in women with and without history of preeclampsia (n=29; n=271). We investigated their associations with established markers of disease activity and later cardiometabolic risk. MALAT1 was silenced in lipopolysaccharide-stimulated THP-1 differentiated macrophages in vitro. RESULTS: MALAT1, NEAT1, mascRNA, and FRMD8 are decreased in peripheral blood mononuclear cells during preeclampsia development. At follow-up in women with a previous preeclampsia diagnosis, MALAT1 and NEAT1 are decreased in peripheral blood mononuclear cells and show associations with cardiometabolic markers. Silencing MALAT1 in macrophages increased secretion of IL (interleukin)-6 and reduced MMP9 (matrix metalloproteinase-9) and VEGF (vascular endothelial growth factor) A levels. CONCLUSIONS: Given the association of MALAT1 and neighboring RNAs with preeclampsia during pregnancy and at follow-up, as well as with cardiometabolic markers and results from silencing experiments, these transcripts may be potential targets for preeclampsia development and cardiometabolic risk in women with previous preeclampsia.

• Nilsen, Dennis WT; Næsgaard, Patrycja; Poenitz, Volker; Andersen, Trygve Brugger; Grundt, Magnea Heidi Jonsdottir & Michelsen, Annika Elisabet [Show all 9 contributors for this article] (2026). C-X-C Motif Chemokine Ligand 5 (CXCL5) Exhibits a U-Shaped Risk Profile for Mortality in Patients with Suspected Coronary Chest Pain. International Journal of Molecular Sciences. ISSN 1661-6596. 27(6). doi: 10.3390/ijms27062744. Full text in Research Archive Show summary

  CXCL5 is a platelet-derived chemokine which promotes inflammatory responses in neutrophils and monocytes through CXCR2. Previous studies on CXCL5 in atherogenesis are to some degree conflicting, with scarce outcome data following acute coronary syndrome. This study aimed to assess the utility and risk profile of CXCL5 as a prognostic marker of all-cause mortality at 5-year follow-up in patients hospitalized for chest pain of suspected coronary origin. We measured CXCL5 levels in platelet-poor plasma in 826 consecutive patients included in the “Risk Markers in the Acute Coronary Syndrome” (RACS) study (ClinicalTrials.gov Identifier: NCT00521976). Stepwise Cox regression models, applying quintiles, were fitted for the biomarker with all-cause mortality within 5 years as the dependent variable. At 5-year follow-up, 250 (30.3%) of the population had died; 34.5% in Quintile (Qt)-1, 32.1% in Qt-2, 23.5% in Qt-3, 29.1% in Qt-4, and 32.1% in Qt-5. Using Qt-3 as a reference, both the univariate and multivariable analysis showed a U-shaped association between CXCL5 and all-cause mortality. Univariate analysis: Qt-1 vs. Qt-3: HR 1.59 (95% CI 1.06–2.39), p = 0.026, and Qt-5 vs. Qt-3: HR 1.44 (0.95–2.18), p = 0.082, respectively. Multivariable analysis: Qt-1 vs. Qt-3: HR 1.65 (1.09–2.48), p = 0.017, and Qt-5 vs. Qt-3: HR 1.52 (1.00–2.30), p = 0.049, respectively. The U-shaped relationship was statistically strengthened, employing a composite endpoint consisting of all-cause mortality, MI or stroke. Our findings suggest that both too-low and too-high levels of CXCL5 may be harmful in patients admitted to hospital with chest pain of suspected coronary origin.

• Otterdal, Kari; Ueland, Thor; Holter, Jan Cato; Kaarbø, Mari; Schanke, Ylva & Granerud, Beathe Kiland [Show all 18 contributors for this article] (2026). Platelet-derived mediators in hospitalized COVID-19 patients and associations to respiratory failure, ICU admittance and 60-day mortality. Frontiers in Cardiovascular Medicine. 13. doi: 10.3389/fcvm.2026.1685861. Full text in Research Archive Show summary

  Background: Platelet activation is documented in COVID-19, but data on platelet-derived mediators are scarce. Objective: To examine the levels of various platelet-derived mediators in relation to adverse outcomes defined as the need for treatment at intensive care unit (ICU) and/or respiratory failure (RF) and 60-day total mortality in hospitalized COVID-19 patients. Methods: Plasma levels of RANTES/CCL5, PF4/CXCL4, ENA78/CXCL5, NAP-2/CXCL7, SDF-1/CXCL12, P-selectin, soluble CD40 ligand (sCD40L) and vascular endothelial cell growth factor A (VEGF-A) were measured in 245 hospitalized COVID-19 patients and in a subpopulation of the patients, also at three, six and 12 months after hospitalization. Results: Our main findings were: (i) High levels of P-selectin was associated with ICU/RF, while low levels of PF4/CXCL4, ENA-78/CXCL5 and NAP-2/CXCL7 were associated with 60-days mortality. (ii) Most of the mediators were normalized after hospitalization, but plasma levels of sCD40L, ENA-78/CXCL7 and VEGF-A were markedly elevated compared to healthy controls for up to 12 months after hospitalization. (iii) In vitro, inactivated SARS-CoV-2 induced a dose-dependent release of NAP-2, P-selectin, RANTES, sCD40L and VEGF-A from isolated platelets. Conclusion: Our findings underscore the role of platelet-derived inflammatory mediators in the pathogenesis of COVID-19, potentially involving direct effects of SARS-CoV-2. The study also points to a persistent platelet activation following hospitalization.

• Ueland, Thor; Andersen, Geir Øystein; Sharanga, Varathalingam; Khan, Yusuf; Holm, Sverre & Limalanathan, Shanmuganathan [Show all 12 contributors for this article] (2026). Circulating B-cell activating factor in acute coronary syndromes – association with adverse outcomes and progression of heart failure. Atherosclerosis. ISSN 0021-9150. 414. doi: 10.1016/j.atherosclerosis.2026.120642. Full text in Research Archive
• Holt, Margrethe Flesvig; Michelsen, Annika Elisabet; Flø, August Magnus Stensrød; Russell, Kristoffer; Beitnes, Jan Otto & Kløve, Sophie Foss [Show all 12 contributors for this article] (2025). Increased dipeptidyl peptidase 4 in patients with concomitant transthyretin cardiac amyloidosis and severe aortic stenosis. International journal of cardiology: Heart and Vasculature (IJCHA). 61. doi: 10.1016/j.ijcha.2025.101820. Full text in Research Archive Show summary

  Background Due to overlapping symptoms and signs, it can be challenging to diagnose transthyretin amyloid cardiomyopathy (ATTR-CM) in the setting of concomitant aortic stenosis. Biomarkers may discriminate between heart failure with ATTR-CM and heart failure without ATTR-CM, but it is not known if these markers can differentiate between AS with and AS without concomitant ATTR-CM. Methods In 9 patients with ATTR-CM and AS, 161 patients with lone AS, and 23 healthy controls, we measured 8 plasma proteins previously identified by proteomic analysis as potential candidates for diagnosing ATTR-CM. We assessed differences between groups and association with indices of heart failure and AS severity. Results Plasma levels of dipeptidyl peptidase 4 (DPP4) were significantly higher in patients with AS and ATTR-CM than in patients with lone AS and in healthy controls. Lower levels of DPP4 were also associated with worse left ventricular function, higher New York Heart Association functional class, and low-flow, low-gradient aortic stenosis. Conclusions Our findings suggest that DPP4 may be a marker of ATTR-CM in patients with severe AS. In all AS patients, those with and without coexisting ATTR-CM, high DPP4 levels were asociated with better cardiac function.

• Ueland, Thor; Traaen, Gunn Marit; Hunt, Tove Elizabeth Frances; Aakerøy, Lars; Øverland, Britt & Bendz, Christina [Show all 14 contributors for this article] (2025). High levels of the adipokines leptin and metrnl in patients with paroxysmal atrial fibrillation and obstructive sleep apnea are not associated with the severity of sleep apnea or the burden of atrial fibrillation. Sleep Medicine. ISSN 1389-9457. 136. doi: 10.1016/j.sleep.2025.106862. Full text in Research Archive
• Ueland, Thor; Cox, Rebecca Jane; Michelsen, Annika Elisabet; Fjelltveit, Elisabeth Berg; Otterdal, Kari & Dahl, Tuva Børresdatter [Show all 12 contributors for this article] (2025). Markers of T cell activation and exhaustion in plasma are associated with persistent symptoms up to 18 months following mild SARS-CoV-2 infection. Frontiers in Immunology. 16. doi: 10.3389/fimmu.2025.1578208. Full text in Research Archive Show summary

  Background Persistent symptoms following SARS-CoV-2 is an increasing problem after COVID-19 disease. The pathogenesis of this persistent post Covid-19 Condition (PCC) is, however, largely unknown. We hypothesized that persistent T cell activation and exhaustion play a role in PCC development. Methods We examined plasma levels of soluble (s) CD25, TIM-3 and LAG-3, all markers of T cell activation/exhaustion, by enzyme immunoassays in 170 home-isolated and 53 hospitalized patients for up to 18 months after COVID-19 in relation to persistent symptomatology. Results Our major findings were: (i) Cases with persistent dyspnea and fatigue had markedly higher sCD25 at 6–18 months with a more modest increase in sTIM-3. (ii) Cases with memory problems at 12–18 months had increased sLAG-3 iii) sCD25 correlated with SARS-CoV-2 antibody titers and microneutralization titers only in cases with PCC while sTIM-3 correlated with these parameters irrespectively of symptoms. iv) Although hospitalized patients had markedly elevated levels of T cell activation/exhausting markers during follow-up, there was no relation to PCC symptoms. Conclusion Our study indicates a role for T cell activation/exhaustion in PCC following home isolated COVID-19 infection, with somewhat different patterns of sCD25, sTIM-3 and sLAG-3, but not in hospitalized COVID-19 patients where disease severity may be more important.

• Huse, Camilla; Murphy, Sarah Louise Mikalsen; Yang, Kuan; Balzer, Nora Reka; Stokke, Mathis Korseberg & Anstensrud, Anne Kristine [Show all 27 contributors for this article] (2025). The effects of interleukin-6-receptor inhibition on monocytes in STEMI: a substudy of the ASSAIL-MI trial. EBioMedicine. 121, p. 105960–105960. doi: 10.1016/j.ebiom.2025.105960. Full text in Research Archive
• Aamodt, Anne Hege; Ueland, Thor; Boldingh, Marion Ingeborg; Bezgal, Burcu; Argren, Maria Bengtson Argren & Dunne, Cecilia Adele [Show all 29 contributors for this article] (2025). Altered amyloid plasma profile in patients with disabling headaches after SARS-CoV-2 infection and vaccination. BMJ Neurology Open. 7(2). doi: 10.1136/bmjno-2024-001013. Full text in Research Archive Show summary

  Background and objectives Persistent headache has emerged as a symptom following acute COVID-19 and, to a lesser extent, after SARS-CoV-2 vaccination. However, the underlying mechanisms remain poorly understood. This study aimed to evaluate plasma levels of amyloid-related biomarkers in patients experiencing persistent headaches after COVID-19 or SARS-CoV-2 vaccination. Methods In this prospective observational cohort, patients presenting with severe headache as the dominating symptom after COVID-19 (n=29) or SARS-CoV-2 vaccination (n=31) had neurological assessments with reassessments after 6 months. Plasma levels of amyloid precursor protein (APP), pregnancy zone protein (PZP), cathepsin L1 (CTSL) and serum Amyloid A (SAA1) were measured using ELISA and compared with levels in healthy controls (n=16). Results We found a strong and persistent upregulation of APP in patients with headache after COVID-19 as compared with the two other groups. Notably, APP levels remained elevated at both inclusion and after 6 months in individuals with accompanying cognitive symptoms. In contrast, PZP levels were increased in patients with headache after SARS-CoV-2 vaccination at both time points relative to healthy controls. CTSL was only elevated in the post-COVID-19 at baseline, whereas SAA1 showed levels comparable across all groups. Conclusion Altered plasma levels of soluble markers, potentially reflecting changes in amyloid processing, were found in patients with persistent headache following SARS-CoV-2 vaccine, particularly in those with persistent headache after COVID-19. In the latter group, we also found some association with cognitive symptoms. Trial registration numbers NCT04576351 and NCT05235776 .

• Wikan, Vårin Eiriksdatter; Øverli, Øyvind; Ueland, Thor; Mollnes, Tom Eirik; Brækkan, Sigrid Kufaas & Michelsen, Annika Elisabet [Show all 9 contributors for this article] (2025). Complement activation assessed by C3bc and C5b-9 terminal complex as diagnostic biomarkers for deep vein thrombosis. PLOS ONE. 20(10). doi: 10.1371/journal.pone.0333206. Full text in Research Archive Show summary

  Background The overuse of compression ultrasound procedures on patients with suspected deep vein thrombosis compromise the cost-effectiveness of deep vein thrombosis management and emphasize room for improvement of the current diagnostic algorithm. As the complement system and hemostasis are comprehensively intertwined, we aimed to investigate complement activation products as diagnostic tests for acute deep vein thrombosis alone or together with D-dimer. Methods We performed a cross-sectional study using consecutive sampling of outpatients referred to the emergency department with suspected first-time deep vein thrombosis of the lower limbs, to investigate the diagnostic utility of the index tests C3bc and C5b-C9 terminal complex (TCC) with compression ultrasound as reference standard. For comparison of receiver operating characteristics, analyses were also performed for D-dimer and C-reactive protein in addition to analyses for the index tests on a D-dimer positive patient subgroup. Results Of the 366 included patients, 103 had deep vein thrombosis. The calculated effect sizes of differences between groups (Cohen’s d) with 95% confidence intervals (95%CI) were 0.25 (95%CI 0.03–0.48) for C3bc, 0.33 (95%CI 0.09–0.57) for C5b-C9 terminal complex (TCC), 0.88 (95%CI 0.61–1.15) for C-reactive protein, and 1.64 (95%CI 1.37–1.91) for D-dimer. The areas under the curves derived from comparison receiver operating characteristics analyses with corresponding 95%CIs for C3bc, C5b-C9 terminal complex (TCC), C-reactive protein and D-dimer were 0.56 (95%CI 0.50–0.63), 0.64 (95%CI 0.58–0.69), 0.73 (95%CI 0.67–0.79) and 0.92 (95%CI 0.89–0.95), respectively. Conclusion The plasma levels of the complement activation products C3bc and C5b-C9 terminal complex (TCC) were elevated in patients with acute deep vein thrombosis but displayed low diagnostic performance for deep vein thrombosis alone or together with D-dimer.

• Nilsen, Dennis WT; Fuente, Ricardo Leon de la; Gallo, P.; Næsgaard, Patrycja; Ashur, S. Dib & Michelsen, Annika Elisabet [Show all 9 contributors for this article] (2025). High admission levels of interleukin-1 receptor antagonist in acute myocardial infarction patients are associated with increased rates of all-cause mortality and cardiac death at five years follow-up. International Journal of Cardiology. ISSN 0167-5273. 439. doi: 10.1016/j.ijcard.2025.133674. Full text in Research Archive
• Hunt, Tove Elizabeth Frances; Traaen, Gunn Marit; Aakerøy, Lars; Øverland, Britt; Bendz, Christina & Michelsen, Annika Elisabet [Show all 15 contributors for this article] (2025). Systemic markers of inflammation and immune activation in patients with obstructive sleep apnea and paroxysmal atrial fibrillation. European journal of internal medicine. ISSN 0953-6205. 139. doi: 10.1016/j.ejim.2025.05.028. Full text in Research Archive Show summary

  Background Atrial fibrillation (AF) and obstructive sleep apnea (OSA) frequently coexist, contributing to cardiovascular risk, possibly through shared inflammatory pathways. The specific role of inflammatory markers in patients with AF and OSA is not well established. Aim This study aimed to determine whether markers of inflammation and immune activation are elevated in patients with paroxysmal AF and OSA, assess the effects of continuous positive airway pressure (CPAP) and pulmonary vein isolation (PVI) on these markers, and evaluate their association with clinical outcomes, such as AF recurrence and thromboembolic risk. Methods We studied 143 patients with paroxysmal AF and moderate to severe OSA (apnea-hypopnea index ≥15). Of these, 99 were randomised to receive CPAP plus standard care (n = 51) or standard care alone (n = 48). A comparison group of 19 patients with paroxysmal AF and mild/no OSA (AHI <15) and 22 healthy controls were also included. Inflammatory markers related to leukocyte activation, vascular inflammation, and extracellular matrix remodelling were assessed at baseline, 6 months and 12 months follow-up. Results Patients with OSA and paroxysmal AF had higher levels of NGAL, PTX-3, GDF-15, MMP-9, VCAM1 and ANGP2 than healthy controls. These markers correlated poorly with AF and OSA severity. There was no modifying effect of CPAP on any marker. PTX3 was associated with AF recurrence and a high-risk score for thromboembolic stroke. Conclusion Moderate to severe OSA and AF are associated with elevated inflammatory markers. However, CPAP therapy did not significantly affect these levels. PTX-3 may hold prognostic value for AF recurrence and thromboembolic risk.

• Louwe, Maria Cornelia; Gialeli, Chrysostomi; Michelsen, Annika Elisabet; Holm, Sverre; Edsfeldt, Andreas & Skagen, Karolina Ryeng [Show all 21 contributors for this article] (2025). Alternative Complement Pathway in Carotid Atherosclerosis: Low Plasma Properdin Levels Associate With Long-Term Cardiovascular Mortality. Journal of the American Heart Association (JAHA). 14(3). doi: 10.1161/JAHA.124.038316. Full text in Research Archive
• Nilsen, Dennis WT; Aarsetøy, Reidun; Pønitz, Volker; Ueland, Thor; Aukrust, Pål & Michelsen, Annika Elisabet [Show all 9 contributors for this article] (2025). Sex-related differences in the prognostic utility of inflammatory and thrombotic cardiovascular risk markers in patients with chest pain of suspected coronary origin. International journal of cardiology: Heart and Vasculature (IJCHA). 56. doi: 10.1016/j.ijcha.2025.101600. Full text in Research Archive Show summary

  Background: α1-antichymotrypsin (SERPINA3), high sensitivity C-reactive protein (hsCRP) and pentraxin 3 (PTX3) are acute phase proteins triggered by inflammation, whereas D-dimer, fibrin monomer and α2-antiplasmin are thrombo-fibrinolytic markers. Sex differences in relation to cardiovascular disease were investigated. Methods: A total of 871 consecutive patients (61.0 % males; females: 77.3 years, males 69.1 years) were included. Of these, 380 were diagnosed with an acute myocardial infarction (MI). Stepwise Cox regression models, applying normalized continuous loge/SD values, were fitted for the biomarkers with all-cause mortality, MI and stroke, respectively, and a composite endpoint within 7 years as the dependent variables. Results: Except for α2-antiplasmin, all biomarkers were significantly associated with all-cause mortality and the combined endpoint in the univariate analysis. None of the inflammatory biomarkers predicted all-cause mortality in females after multivariable adjustment but were significant predictors in males (SERPINA3: HR 1.34 (95 %CI 1.16–1.56), p < 0.0001. hsCRP: HR 1.19 (95 %CI 1.02–1.38), p = 0.027. PTX3: HR 1.22 [95 %CI 1.04–1.44], p = 0.018. The p-value for interaction suggests a sex difference in the prognostic weighting of SERPINA3 (p = 0.015). None of the thrombo-fibrinolytic biomarkers predicted all-cause mortality in males after adjustment, but D-dimer and fibrin monomer were significant predictors of all-cause mortality in females (HR 1.51 [1.29–1.78], p < 0.0001, and HR 1.28 [1.08–1.53] p = 0.005, respectively). A trend towards interaction for D-dimer (p = 0.07) may suggest a sex difference in its prognostic weighting. Conclusion: SERPINA3, hsCRP and PTX3 predicted long-term all-cause mortality in males but not in females. The opposite relationship was observed for D-dimer and fibrin monomer.

• Holt, Margrethe Flesvig; Michelsen, Annika Elisabet; Flø, August Magnus Stensrød; Khan, Yusuf; Bjørnø, Vilde & Skjelland, Mona [Show all 17 contributors for this article] (2025). Hepatocyte Growth Factor: A Marker of Cardiac Function, Mortality, and Disease Subtype in Cardiac Amyloidosis. JACC: Advances. 4(6). doi: 10.1016/j.jacadv.2025.101828. Full text in Research Archive
• Lekva, Tove; Roland, Marie Cecilie; Qvigstad, Elisabeth; Khan, Yusuf; Godang, Kristin & Michelsen, Annika Elisabet [Show all 7 contributors for this article] (2025). Oxidative stress, senescence and mRNA decay in peripheral blood mononuclear cells of women with gestational diabetes mellitus-link to increased cardiovascular disease risk. Diabetes, obesity and metabolism. ISSN 1462-8902. 27(9), p. 4802–4811. doi: 10.1111/dom.16521. Full text in Research Archive Show summary

  Aims Women who develop gestational diabetes mellitus (GDM) have a pancreatic β-cell defect that cannot compensate for the insulin resistance of pregnancy. The glucose intolerance may, in addition to direct effects, negatively impact lipid metabolism, promote vascular dysfunction and contribute to cardiovascular disease (CVD). We assessed associations between oxidative stress and senescence markers with indices of glucose and lipid metabolism in women developing GDM and with CVD risk after 5 years. Materials and Methods The oxidative stress and senescence markers NRF2, GPX4, TERC, XRN1 and DCP2 were assessed in peripheral blood mononuclear cells (PBMCs), advanced oxidation protein products (AOPP) and β-galactosidase in plasma, from healthy (n = 253) and women with GDM (n = 31) during pregnancy and at 5-year follow-up, from the STORK study. We investigated their associations with established markers of disease activity and later CVD. Results Plasma AOPP and β-galactosidase were increased early in pregnancy in women developing GDM later and associated with indices of glucose metabolism and TG/HDL-Cholesterol. RNA levels of transcripts involved in telomer maintenance and antioxidant responses were decreased in women with GDM during pregnancy and at follow-up. DCP2 and XRN1 expression were positively associated with β-cell function at all timepoints and with pulse wave velocity at 5-year follow-up in women with previous GDM. Conclusions Markers of vascular oxidative stress and senescence are increased and correlate with indices of glucose and lipid metabolism early in pregnancy in women developing GDM. Cellular markers reflecting attenuated defence against oxidative stress and senescence decrease throughout pregnancy and at 5-year follow-up and correlate with aortic stiffness in women with previous GDM.

• Jørgensen, Silje Fjellgård; Braadland, Peder Rustøen; Ueland, Thor; Fraz, Mai Sasaki Aanensen; Michelsen, Annika Elisabet & Holm, Kristian [Show all 12 contributors for this article] (2025). Tryptophan–kynurenine metabolites associate with inflammation and immunologic phenotypes in common variable immunodeficiency. Journal of Allergy and Clinical Immunology. ISSN 0091-6749. 156(3), p. 814–824. doi: 10.1016/j.jaci.2025.04.031. Full text in Research Archive Show summary

  Background A large proportion of patients with common variable immunodeficiency (CVID) have autoimmune and inflammatory manifestations characterized by chronic T-cell– and monocyte/macrophage activation of unknown etiology. The tryptophan–kynurenine pathway has previously been linked to immune activation involving T cells and monocytes/macrophages, as well as with gut microbial dysbiosis in some inflammatory diseases. Objective We aimed to characterize the tryptophan–kynurenine pathway in CVID and its potential association with clinical/immunologic phenotype and gut microbial dysbiosis. Methods Serum concentrations of a set of tryptophan–kynurenine pathway metabolites and neopterin were measured using liquid chromatography–tandem mass spectrometry in a discovery cohort (n = 40), a validation cohort (n = 53), and healthy controls (n = 60). B-cell phenotype was analyzed in both cohorts, whereas inflammatory markers (enzyme immunoassay), lipopolysaccharide, gut microbial composition, and food frequency questionnaire were measured in the discovery cohort. Results Compared to healthy controls, CVID patients had increased metabolism of the tryptophan–kynurenine pathway as assessed by increased kynurenine/tryptophan ratio, quinolinic acid, and 3-hydroxykynurenine in both the discovery and validation cohorts. The findings were most pronounced in the subgroup with autoimmune/inflammatory complications but was to some degree also observed in CVID patients with infection only. In CVID, the metabolites in the tryptophan–kynurenine pathway associated with soluble (s) markers of monocyte (sCD14, sCD163, neopterin) and T-cell (sCD25) activation as well as B-cell phenotype (eg, naïve B cells). Individual gut microbial taxa may influence tryptophan–kynurenine pathway metabolites, but not lipopolysaccharide or diet. Conclusion We found altered levels of several metabolites in the tryptophan–kynurenine pathway in two different CVID cohorts associated with systemic inflammation and B-cell phenotype.

• Ueland, Thor; Astrup, Elisabeth; Otterdal, Kari; Lekva, Tove; Janardhanan, Jeshina & Michelsen, Annika Elisabet [Show all 9 contributors for this article] (2025). C-C Motif Ligand 7 and C-C Motif Chemokine Receptor 3 Dysregulation in Patients With Scrub Typhus and Association With Mortality. Journal of Infectious Diseases. ISSN 0022-1899. 231(1), p. e59–e67. doi: 10.1093/infdis/jiae401. Full text in Research Archive Show summary

  Background Scrub typhus, caused by Orientia tsutsugamushi, involves infiltration of a mixture of perivascular lymphocytes and macrophages into affected organs. We investigated if this is characterized by chemokine dysregulation. Methods mRNA expression of chemokines and receptors was screened in whole blood by cDNA microarray in a subgroup of patients and controls. Regulated transcripts were analyzed in plasma by enzyme immunoassays (chemokines) and in whole blood by quantitative polymerase chain reaction (receptors) from patients with scrub typhus (n = 129), patients with similar febrile illness without O tsutsugamushi infection (n = 31), and healthy controls (n = 31). Results cDNA microarray identified dysregulation of the chemokines CCL18 and CCL23 and the receptor CCR3 in severe scrub typhus. Plasma CCL7 (a ligand for CCR3), CCL18, and CCL23 were higher in patients with scrub typhus, with a decline during follow-up. Conversely, mRNA levels of CCR3 and CCR8 (the receptor for CCL18) were decreased in whole blood at hospital admission, followed by an increase during follow-up. CCL7 was independently associated with disease severity. Admission CCL7 levels were associated with short-time mortality. Conclusions Our findings suggest that CCL7 could represent a hitherto unknown pathogenic mediator in O tsutsugamushi infection, contributing to local and systemic inflammation.

• Viermyr, Hans-Kittil; Halvorsen, Bente; Sagen, Ellen Lund; Michelsen, Annika Elisabet; Barratt-Due, Andreas & Kåsine, Trine [Show all 73 contributors for this article] (2024). High viral loads combined with inflammatory markers predict disease severity in hospitalized COVID-19 patients: Results from the NOR-Solidarity trial. Journal of Internal Medicine. ISSN 0954-6820. 296(3), p. 249–259. doi: 10.1111/joim.13820. Full text in Research Archive Show summary

  Objectives To investigate temporal changes in the association between SARS-CoV2 viral load (VL) and markers of inflammation during hospitalization, as well as the ability of these markers alone or in combination to predict severe outcomes. Methods Serial oropharyngeal and blood samples were obtained from hospitalized COVID-19 patients (n = 160). Levels of inflammatory markers and oropharyngeal VL were measured during hospitalization (admission, days 3–5, and days 7–10) and related to severe outcomes (respiratory failure/intensive care unit admission). Results Elevated admission levels of IL (interleukin)-6, IL-33, IL-8, monocyte chemoattractant protein-1 (MCP-1), interferon-γ-induced protein 10 (IP-10), IL-1β, and IL-1Ra were associated with severe outcomes during hospitalization. Although no inflammatory markers correlated with VL at baseline, there was a significant correlation between VL and levels of IP-10 and MCP-1 at days 3–5, accompanied by IL-8 and IL-6 at days 7–10. Finally, there was a seemingly additive effect of IP-10, MCP-1, and IL-6 in predicting severe outcomes when combined with high VL at baseline. Conclusions An increasing number of inflammatory markers were associated with VL during the first 10 days of hospitalization, and several of these markers were associated with severe outcomes, in particular when combined with elevated VL. Future studies should assess the potential for combining antiviral and immunomodulatory treatment, preferably guided by viral and inflammatory biomarkers, for the selection of high-risk patients.

• Viermyr, Hans-Kittil; Tonby, Kristian; Ponzi, Erica; Trouillet-Assant, Sophie; Poissy, Julien & Arribas, José R. [Show all 49 contributors for this article] (2024). Safety of baricitinib in vaccinated patients with severe and critical COVID-19 sub study of the randomised Bari-SolidAct trial. EBioMedicine. 111. doi: 10.1016/j.ebiom.2024.105511. Full text in Research Archive Show summary

  Background The Bari-SolidAct randomized controlled trial compared baricitinib with placebo in patients with severe COVID-19. A post hoc analysis revealed a higher incidence of serious adverse events (SAEs) among SARS-CoV-2-vaccinated participants who had received baricitinib. This sub-study aimed to investigate whether vaccination influences the safety profile of baricitinib in patients with severe COVID-19. Methods Biobanked samples from 146 participants (55 vaccinated vs. 91 unvaccinated) were analysed longitudinally for inflammation markers, humoral responses, tissue viral loads, and plasma viral antigens on days 1, 3, and 8. High-dimensional analyses, including RNA sequencing and flow cytometry, were performed on available samples. Mediation analyses were used to assess relationships between SAEs, baseline-adjusted biomarkers, and treatment-vaccination status. Findings Vaccinated participants were older, more frequently hospitalized, had more comorbidities, and exhibited higher nasopharyngeal viral loads. Baricitinib treatment did not affect antibody responses or viral clearance, but reduced markers of T-cell and monocyte activation compared to placebo (sCD25, sCD14, sCD163, sTIM-3). Age, baseline levels of plasma viral antigen, and several inflammatory markers, as well as IL-2, IL-6, Neopterin, CXCL16, sCD14, and suPAR on day 8 were associated with the occurrence of SAEs. However, mediation analyses of markers linked to SAEs, baricitinib treatment, or vaccination status did not reveal statistically significant interactions between vaccination status and SAEs. Interpretation This sub-study did not identify any virus- or host-related biomarkers significantly associated with the interaction between SARS-CoV-2 vaccination status and the safety of baricitinib. However, caution should be exercised due to the moderate sample size.

• Gregersen, Ida; Scarth, Morgan Elizabeth; Abdullah, Rang; Thorsby, Per Medbøe; Hauger, Lisa Evju & Haugaa, Kristina Ingrid Helena Hermann [Show all 14 contributors for this article] (2024). Elevated interleukin 8 and matrix metalloproteinase 9 levels are associated with myocardial pathology in users of anabolic-androgenic steroids. European Journal of Preventive Cardiology (EJPC). ISSN 2047-4873. 31(12), p. 1469–1476. doi: 10.1093/eurjpc/zwae126. Full text in Research Archive Show summary

  Aims In the current paper, we aim to explore the effect of both current and former long-term anabolic-androgenic steroid (AAS) use on regulation of systemic inflammatory markers and mediators of extracellular matrix (ECM) remodelling and their association with hormones and echocardiographic myocardial pathology in weightlifters. Methods and results In a cross-sectional study, 93 weightlifting AAS users, of whom 62 were current and 31 were past users, with at least 1-year cumulative AAS use (mean 11 ± 7 accumulated years of AAS use), were compared with 54 non-using weightlifting controls (WLCs) using clinical interview, blood pressure measurements, and echocardiography. Serum levels of interleukin (IL)-6, IL-8, tumour necrosis factor (TNF), interferon (IFN)-γ, growth differentiation factor (GDF)-15, and matrix metalloproteinase (MMP)-9, sex hormones, and lipids were analysed. It was found that serum levels of IL-8, GDF-15, and MMP-9 were significantly increased in current AAS users compared with former users and WLCs. Matrix metalloproteinase 9, but not IL-8, correlated consistently with sex hormone levels, and sex hormone levels correlated consistently with mean wall thickness, in current users. Moreover, HDL cholesterol was significantly lower in current vs. former AAS users and significantly inversely correlated with MMP-9 in current users. Further, in current users, MMP-9 and IL-8 correlated with markers of myocardial strain, and MMP-9 also correlated with indices of cardiac mass, which was not seen in former users. Mediation analyses suggested that MMP-9 could partly explain hormone-induced alterations in markers of myocardial damage in current users. Conclusion Long-term AAS is associated with increased levels of markers of inflammation and ECM remodelling, which seems to have a hormone-dependent (MMP-9) and a hormone-independent (IL-8) association with markers of myocardial dysfunction.

• Halvorsen, Bente; Viermyr, Hans-Kittil; Ueland, Thor; Sagen, Ellen Lund; Michelsen, Annika Elisabet & Bjerkeli, Vigdis [Show all 14 contributors for this article] (2024). IL-22 is increased in hospitalized patients with COVID-19 and associates with cardiac involvement. Journal of Infection. ISSN 0163-4453. 89(1). doi: 10.1016/j.jinf.2024.106176. Full text in Research Archive
• Damås, Jan Kristian; Otterdal, Kari; Astrup, Elisabeth; Lekva, Tove; Janardhanan, Jeshina & Michelsen, Annika Elisabet [Show all 9 contributors for this article] (2024). Canonical notch activation in patients with scrub typhus: association with organ dysfunction and poor outcome. Infection. ISSN 0300-8126. 52(4), p. 1357–1365. doi: 10.1007/s15010-024-02192-2. Full text in Research Archive Show summary

  Purpose: The mechanisms that control inflammation in scrub typhus are not fully elucidated. The Notch pathways are important regulators of inflammation and infection, but have not been investigated in scrub typhus. Methods: Plasma levels of the canonical Notch ligand Delta-like protein 1 (DLL1) were measured by enzyme immunoassay and RNA expression of the Notch receptors (NOTCH1, NOTCH2 and NOTCH4) in whole blood was analyzed by real-time PCR in patients with scrub typhus (n = 129), in patients with similar febrile illness without O. tsutsugamushi infection (n = 31) and in healthy controls (n = 31); all from the same area of South India. Results: Our main results were: (i) plasma DLL1 was markedly increased in scrub typhus patients at hospital admission with a significant decrease during recovery. (ii) RNA expression of NOTCH4 was decreased at admission in whole blood. (iii) A similar pattern for DLL1 and NOTCH4 was seen in febrile disease controls. (iv) Admission DLL1 in plasma was associated with disease severity and short-term survival. (vi) Regulation of Notch pathways in O. tsutsugamushi-infected monocytes as evaluated by public repository data revealed enhanced canonical Notch activation with upregulation of DLL1 and downregulation of NOTCH4. Conclusion: Our findings suggest that scrub typhus patients are characterized by enhanced canonical Notch activation. Elevated plasma levels of DLL1 were associated with organ dysfunction and poor outcomes in these patients.

• Hoel, Hedda; Dahl, Tuva Børresdatter; Yang, Kuan; Skeie, Linda Gail; Michelsen, Annika Elisabet & Ueland, Thor [Show all 13 contributors for this article] (2024). Chronic HIV Infection Increases Monocyte NLRP3 Inflammasome-Dependent IL-1α and IL-1β Release. International Journal of Molecular Sciences. ISSN 1661-6596. 25(13). doi: 10.3390/ijms25137141. Full text in Research Archive Show summary

  Antiretroviral treatment (ART) has converted HIV from a lethal disease to a chronic condition, yet co-morbidities persist. Incomplete immune recovery and chronic immune activation, especially in the gut mucosa, contribute to these complications. Inflammasomes, multi-protein complexes activated by innate immune receptors, appear to play a role in these inflammatory responses. In particular, preliminary data indicate the involvement of IFI16 and NLRP3 inflammasomes in chronic HIV infection. This study explores inflammasome function in monocytes from people with HIV (PWH); 22 ART-treated with suppressed viremia and 17 untreated PWH were compared to 33 HIV-negative donors. Monocytes were primed with LPS and inflammasomes activated with ATP in vitro. IFI16 and NLRP3 mRNA expression were examined in a subset of donors. IFI16 and NLRP3 expression in unstimulated monocytes correlated negatively with CD4 T cell counts in untreated PWH. For IFI16, there was also a positive correlation with viral load. Monocytes from untreated PWH exhibit increased release of IL-1α, IL-1β, and TNF compared to treated PWH and HIV-negative donors. However, circulating monocytes in PWH are not pre-primed for inflammasome activation in vivo. The findings suggest a link between IFI16, NLRP3, and HIV progression, emphasizing their potential role in comorbidities such as cardiovascular disease. The study provides insights into inflammasome regulation in HIV pathogenesis and its implications for therapeutic interventions.

• Grannes, Helene; Ueland, Thor; Simeone, Paola; Liani, Rossella; Guagnano, Maria Teresa & Aukrust, Pål [Show all 14 contributors for this article] (2024). Liraglutide and not lifestyle intervention reduces soluble CD163 after comparable weight loss in obese participants with prediabetes or type 2 diabetes mellitus. Cardiovascular Diabetology. 23(1). doi: 10.1186/s12933-024-02237-8. Full text in Research Archive Show summary

  Background The GLP-1 receptor agonist liraglutide is used to treat hyperglycemia in type 2 diabetes but is also known to induce weight loss, preserve the beta cell and reduce cardiovascular risk. The mechanisms underlying these effects are however still not completely known. Herein we explore the effect of liraglutide on markers of immune cell activity in a population of obese individuals with prediabetes or newly diagnosed type 2 diabetes mellitus. Method Plasma levels of the monocyte/macrophage markers, soluble (s)CD163 and sCD14, the neutrophil markers myeloperoxidase (MPO) and neutrophil gelatinase‐associated lipocalin (NGAL),the T-cell markers sCD25 and T-cell immunoglobulin mucin domain-3 (sTIM-3) and the inflammatory marker TNF superfamily (TNFSF) member 14 (LIGHT/ TNFSF14) were measured by enzyme-linked immunosorbent assays in obese individuals with prediabetes or diabetes diagnosed within the last 12 months, prior to and after comparable weight loss achieved with lifestyle changes (n=20) or liraglutide treatment (n=20), and in healthy subjects (n=13). Results At baseline, plasma levels of the macrophage marker sCD163, and the inflammatory marker LIGHT were higher in cases as compared to controls. Plasma levels of sCD14, NGAL, sTIM-3 and sCD25 did not differ at baseline between patients and controls. After weight reduction following lifestyle intervention or liraglutide treatment, sCD163 decreased significantly in the liraglutide group vs. lifestyle (between-group difference p=0.023, adjusted for visceral adipose tissue and triglycerides basal values). MPO and LIGHT decreased significantly only in the liraglutide group (between group difference not significant). Plasma levels of MPO and in particular sCD163 correlated with markers of metabolic dysfunction and inlfammation. After weight loss, only sCD163 showed a trend for decreased levels during OGTT, both in the whole cohort as in those of liraglutide vs lifestyle group.

• Nilsen, Dennis WT; Aarsetøy, Reidun; Pønitz, Volker; Ueland, Thor; Aukrust, Pål & Michelsen, Annika Elisabet [Show all 9 contributors for this article] (2024). α1-Antichymotrypsin Complex (SERPINA3) Is an Independent Predictor of All-Cause but Not Cardiovascular Mortality in Patients Hospitalized for Chest Pain of Suspected Coronary Origin. Cardiology. ISSN 0008-6312. 149(4), p. 338–346. doi: 10.1159/000537919. Full text in Research Archive Show summary

  Introduction: SERPINA3 is an acute phase protein triggered by inflammation. It is upregulated after an acute myocardial infarction (AMI). Data on its long-term prognostic value in MI patients are scarce. We aimed to assess the utility of SERPINA3 as a prognostic marker in patients hospitalized for chest pain of suspected coronary origin. Methods: A total of 871 consecutive patients, 386 diagnosed with AMI, were included. Stepwise Cox regression models, applying continuous loge-transformed values, were fitted for the biomarker with all-cause mortality and cardiac death within 2-years or all-cause mortality within median 7 years as dependent variables. An analysis of MI and stroke, and combined endpoints, respectively, was added. The hazard ratio (HR) (95% CI) was assessed in a univariate and multivariable model. Results: Plasma samples from 847 patients were available. By 2 years follow-up, 138 (15.8%) patients had died, of which 86 were cardiac deaths. The univariate analysis showed a significant association between SERPINA3 and all-cause mortality [HR 1.41 (95% 1.19-1.68), p<0.001], but not for cardiac death. Associations after adjustment were non-significant. By 7 years follow-up, 332 (38.1%) patients had died. SERPINA3 was independently associated with all-cause mortality from the third year onwards. The HR was 1.14 (95% CI, 1.02-1.28), p=0.022. Similar results applied to combined endpoints, but not for MI and stroke, respectively. The prognostic value of SERPINA3 was limited to non-AMI patients. No independent associations were noted among AMI patients. Conclusions: SERPINA3 predicts long-term all-cause mortality, but failed to predict outcome in AMI patients.

• Murphy, Sarah Louise Mikalsen; Balzer, Nora Reka; Ranheim, Trine; Sagen, Ellen Lund; Huse, Camilla & Bjerkeli, Vigdis [Show all 19 contributors for this article] (2024). Extracellular matrix remodelling pathway in peripheral blood mononuclear cells from severe COVID-19 patients: an explorative study. Frontiers in Immunology. 15. doi: 10.3389/fimmu.2024.1379570. Full text in Research Archive Show summary

  There is a reciprocal relationship between extracellular matrix (ECM) remodelling and inflammation that could be operating in the progression of severe COVID-19. To explore the immune-driven ECM remodelling in COVID-19, we in this explorative study analysed these interactions in hospitalised COVID-19 patients. RNA sequencing and flow analysis were performed on peripheral blood mononuclear cells. Inflammatory mediators in plasma were measured by ELISA and MSD, and clinical information from hospitalised COVID-19 patients (N=15) at admission was included in the analysis. Further, we reanalysed two publicly available datasets: (1) lung tissue RNA-sequencing dataset (N=5) and (2) proteomics dataset from PBCM. ECM remodelling pathways were enriched in PBMC from COVID-19 patients compared to healthy controls. Patients treated at the intensive care unit (ICU) expressed distinct ECM remodelling gene profiles compared to patients in the hospital ward. Several markers were strongly correlated to immune cell subsets, and the dysregulation in the ICU patients was positively associated with plasma levels of inflammatory cytokines and negatively associated with B-cell activating factors. Finally, our analysis of publicly accessible datasets revealed (i) an augmented ECM remodelling signature in inflamed lung tissue compared to non-inflamed tissue and (ii) proteomics analysis of PBMC from severe COVID-19 patients demonstrated an up-regulation in an ECM remodelling pathway. Our results may suggest the presence of an interaction between ECM remodelling, inflammation, and immune cells, potentially initiating or perpetuating pulmonary pathology in severe COVID-19.

• Kong, Xiang Yi; Lauritzen, Knut Husø; Dahl, Tuva Børresdatter; Holm, Sverre; Olsen, Maria Belland & Skjelland, Mona [Show all 12 contributors for this article] (2024). CD38 deficient mice are not protected from atherosclerosis. Biochemical and Biophysical Research Communications - BBRC. ISSN 0006-291X. 705. doi: 10.1016/j.bbrc.2024.149734. Full text in Research Archive
• Nilsen, Dennis WT; Aarsetøy, Reidun; Pønitz, Volker; Ueland, Thor; Aukrust, Pål & Michelsen, Annika Elisabet [Show all 9 contributors for this article] (2024). Chemokine ligand 18 predicts all-cause mortality in patients hospitalized with chest pain of suspected coronary origin. International Journal of Cardiology: Cardiovascular Risk and Prevention (IJCCRP). 21. doi: 10.1016/j.ijcrp.2024.200264. Full text in Research Archive Show summary

  Introduction: Chemokines mediate recruitment and activation of leucocytes. Chemokine ligand 18 (CCL18) is mainly expressed by monocytes/macrophages and dendritic cells. It is highly expressed in chronic inflammatory diseases, and locally in atherosclerotic plaques, particularly at sites of reduced stability, and systemically in acute coronary syndrome patients. Reports on its prognostic utility in the latter condition, including myocardial infarction (MI), are scarce. Aim: To assess the utility of CCL18 as a prognostic marker of recurrent cardiovascular events in patients hospitalized with chest pain of suspected coronary origin. Methods: The population consisted of 871 consecutive chest-pain patients, of whom 386 were diagnosed with acute myocardial infarction (AMI) based on Troponin-T (TnT) levels >50 ng/L. Stepwise Cox regression models, applying normalized continuous loge/SD values, were fitted for the biomarkers with cardiac mortality within 2 years and total mortality within 2 and 7 years as the dependent variables. Results: Plasma samples from 849 patients were available. By 2 years follow-up, 138 (15.8%) patients had died, of which 86 were cardiac deaths. Univariate analysis showed a positive, significant association between CCL18 and total death [HR 1.55 (95% 1.30–1.83), p < 0.001], and for cardiac death [HR 1.32 (95% 1.06–1.64), p = 0.013]. Associations after adjustment were non-significant. By 7 years follow-up, 332 (38.1%) patients had died. CLL18 was independently associated with all-cause mortality [HR 1.14 (95% CI, 1.01–1.29), p = 0.030], but not with MI (n = 203) or stroke (n = 55). Conclusion: CCL18 independently predicts long-term all-cause mortality but had no independent prognostic bearing on short-term cardiac death and CVD events.

• Ueland, Thor; Nkele, Isaac; Hoel, Hedda; Lockman, Shahin; Michelsen, Annika Elisabet & Moshomo, Thato [Show all 10 contributors for this article] (2024). Markers of extracellular matrix degradation and inflammasome activation are associated with carotid plaques in virally suppressed people with HIV in Botswana. AIDS (London). ISSN 0269-9370. 39(1), p. 22–30. doi: 10.1097/QAD.0000000000004014. Full text in Research Archive
• Grannes, Helene; Sharma, Archana; Suntharalingam, Anita; Michelsen, Annika Elisabet; Aukrust, Pål & Ueland, Thor [Show all 10 contributors for this article] (2024). Plasma soluble TIM-3 is increased in normoglycemic South Asian women compared to Nordic women after gestational diabetes mellitus and associated with markers of metaflammation. Heliyon. 10(22). doi: 10.1016/j.heliyon.2024.e40339. Full text in Research Archive Show summary

  Background - Women with South Asian ethnicity have a higher risk of developing type 2 diabetes mellitus (T2DM) compared with white women of European descent, especially after gestational diabetes mellitus (GDM). Central obesity and adipose tissue dysfunction have been linked to their higher risk of T2DM, but the mechanisms are not known. We hypothesize that low-grade, persistent immune cell activation is involved in metabolic disturbances following GDM with different influence according to ethnicity.<p> <p>Methods - We measured plasma levels of T cell exhaustion marker soluble T cell immunoglobin mucin domain 3 (sTIM-3), sCD25, sCD27 and soluble lymphocyte activation gene (sLAG)-3 in 266 women of South Asian (n = 160) and white Nordic (n = 106) ethnic background with a history of GDM.<p> <p>Results - Baseline plasma concentration of sTIM-3 was higher in South Asian women compared to Nordic women (p < 0.001). This difference was driven by higher sTIM-3 in South Asian women with NGT, compared to their Nordic counterparts (p = 0.005) but there were no significant differences comparing Nordic and South Asian women with altered glucose tolerance (AGT). Soluble TIM-3 correlated positively with waist-height ratio (WHtR) and body mass index across all groups, but whereas sTIM-3 correlated moderately and consistently with markers of metaflammation in South Asians, this pattern was not found in Nordic women. Mediation analysis indicated that 15 % of the difference found in adipose insulin resistance between ethnicities could be mediated by sTIM-3, and that 33 % of the difference in sTIM-3 concentrations could be mediated by WHtR. Moreover, T cell markers sCD27 and sLAG3 were also increased in South Asian women compared with Nordic women, further supporting involvement of T cell activation in these women.<p> <p>Conclusion - We found increased levels of sTIM-3, as well as additional markers of T cell activation/exhaustion, in a population of normoglycemic South Asian women with previous gestational diabetes as compared to women of Nordic descent. The possible causal relationship between T cell activation and metabolic dysfunction in high-risk South Asian women is however still elusive and merits further investigation.

• Lekva, Tove; Michelsen, Annika Elisabet; Roland, Marie Cecilie; Norwitz, Errol R.; Estensen, Mette-Elise & Olstad, Ole Kristoffer [Show all 11 contributors for this article] (2023). Increased ferroptosis in leukocytes from preeclamptic women involving the long non-coding taurine upregulated gene 1 (TUG1). Journal of Internal Medicine. ISSN 0954-6820. 295(2), p. 181–195. doi: 10.1111/joim.13732. Full text in Research Archive Show summary

  Abstract Background Ferroptosis plays a key role in placental development and physiology, and abnormal ferroptosis has been implicated in trophoblast injury leading to preeclampsia (PE). We hypothesize that leukocytes isolated from PE exhibit increased ferroptosis and that extracellular vesicles contain long non‐coding (lnc) RNA/mRNAs that modulate oxidative stress and iron toxicity in vascular endothelial cells. Methods We measured the expression of key regulators of ferroptosis in leukocytes and extracellular vesicles as well as circulating biomarkers of iron homeostasis and oxidative stress in plasma from women with/without PE at different timepoints during pregnancy. For markers that were dysregulated, we assessed their temporal correlation with established markers of disease activity and marker of endothelial activation. For markers dysregulated in early pregnancy, we assessed their ability to predict the development of PE. Results We found decreased lncRNA/mRNAs in leukocytes, but not extracellular vesicles, in PE that may modulate oxidative stress and iron toxicity. This decrease in anti‐ferroptotic markers does not appear to be related to maternal disease activity or plasma oxidative stress status but rather to attenuated anti‐inflammatory expression in these cells. Circulating ferritin was elevated in PE, supporting the hypothesis that PE represents a disbalance in iron homeostasis. Low lncRNA taurine upregulated gene 1 RNA levels in leukocytes at 22–24 weeks were strongly associated with the development of PE. Conclusions Our findings suggest that maternal leukocytes in PE show decreased anti‐ferroptotic activity that correlates with anti‐inflammatory expression. Moreover, some of these changes in ferroptotic activity appear to precede the development of PE.

• Lekva, Tove; Sundaram, Arvind; Roland, Marie Cecilie; Åsheim, June; Michelsen, Annika Elisabet & Norwitz, Errol R. [Show all 9 contributors for this article] (2023). Platelet and mitochondrial RNA is decreased in plasma-derived extracellular vesicles in women with preeclampsia—an exploratory study. BMC Medicine. 21(1). doi: 10.1186/s12916-023-03178-x. Full text in Research Archive Show summary

  Background - Circulating extracellular vesicles (EVs) are increased in preeclampsia (PE) and are associated with severity and progression. We examined in this exploratory cohort study if the mRNAs and long noncoding RNAs (lncRNAs) in plasma-derived EVs were dysregulated in PE compared to normal pregnancy and display different temporal patterns during gestation.<p> <p>Methods - We isolated EVs from plasma at weeks 22–24 and 36–38 in women with and without PE (n=7 in each group) and performed RNA-seq, focusing on mRNAs and lncRNAs. We validated highly expressed mitochondrial and platelet-derived RNAs discovered from central pathways in 60 women with/without PE. We examined further one of the regulated RNAs, noncoding mitochondrially encoded tRNA alanine (MT-TA), in leukocytes and plasma to investigate its biomarker potential and association with clinical markers of PE.<p> <p>Results - We found abundant levels of platelet-derived and mitochondrial RNAs in EVs. Expression of these RNAs were decreased and lncRNAs increased in EVs from PE compared to without PE. These findings were further validated by qPCR for mitochondrial RNAs MT-TA, MT-ND2, MT-CYB and platelet-derived RNAs PPBP, PF4, CLU in EVs. Decreased expression of mitochondrial tRNA MT-TA in leukocytes at 22–24 weeks was strongly associated with the subsequent development of PE.<p> <p>Conclusions - Platelet-derived and mitochondrial RNA were highly expressed in plasma EVs and were decreased in EVs isolated from women with PE compared to without PE. LncRNAs were mostly increased in PE. The MT-TA in leukocytes may be a useful biomarker for prediction and/or early detection of PE.

• Selvakumar, Joel Pradeepkumar; Havdal, Lise Beier; Drevvatne, Martin Solstrand; Brodwall, Elias Myrstad; Lund-Berven, Lise & Stiansen-Sonerud, Tonje [Show all 19 contributors for this article] (2023). Prevalence and Characteristics Associated With Post-COVID-19 Condition Among Nonhospitalized Adolescents and Young Adults. JAMA Network Open. 6(3). doi: 10.1001/jamanetworkopen.2023.5763. Full text in Research Archive Show summary

  Importance The prevalence and baseline risk factors of post–COVID-19 condition (PCC) remain unresolved among the large number of young people who experienced mild COVID-19. Objectives To determine the point prevalence of PCC 6 months after the acute infection, to determine the risk of development of PCC adjusted for possible confounders, and to explore a broad range of potential risk factors. Design, Setting, and Participants This cohort study included nonhospitalized individuals from 2 counties in Norway between ages 12 and 25 years who underwent reverse transcription–polymerase chain reaction (RT-PCR) testing. At the early convalescent stage and at 6-month follow-up, participants underwent a clinical examination; pulmonary, cardiac, and cognitive functional testing; immunological and organ injury biomarker analyses; and completion of a questionnaire. Participants were classified according to the World Health Organization case definition of PCC at follow-up. Association analyses of 78 potential risk factors were performed. Exposures SARS-CoV-2 infection. Main Outcomes and Measures The point prevalence of PCC 6 months after RT-PCR testing in the SARS-CoV-2–positive and SARS-CoV-2–negative groups, and the risk difference with corresponding 95% CIs. Results A total of 404 individuals testing positive for SARS-CoV-2 and 105 individuals testing negative were enrolled (194 male [38.1%]; 102 non-European [20.0%] ethnicity). A total of 22 of the SARS-CoV-2–positive and 4 of the SARS-CoV-2–negative individuals were lost to follow-up, and 16 SARS-CoV-2–negative individuals were excluded due to SARS-CoV-2 infection in the observational period. Hence, 382 SARS-CoV-2–positive participants (mean [SD] age, 18.0 [3.7] years; 152 male [39.8%]) and 85 SARS-CoV-2–negative participants (mean [SD] age, 17.7 [3.2] years; 31 male [36.5%]) could be evaluated. The point prevalence of PCC at 6 months was 48.5% in the SARS-CoV-2–positive group and 47.1% in the control group (risk difference, 1.5%; 95% CI, −10.2% to 13.1%). SARS-CoV-2 positivity was not associated with the development of PCC (relative risk [RR], 1.06; 95% CI, 0.83 to 1.37; final multivariable model utilizing modified Poisson regression). The main risk factor for PCC was symptom severity at baseline (RR, 1.41; 95% CI, 1.27-1.56). Low physical activity (RR, 0.96; 95% CI, 0.92-1.00) and loneliness (RR, 1.01; 95% CI, 1.00-1.02) were also associated, while biological markers were not. Symptom severity correlated with personality traits. Conclusions and Relevance The persistent symptoms and disability that characterize PCC are associated with factors other than SARS-CoV-2 infection, including psychosocial factors. This finding raises questions about the utility of the World Health Organization case definition and has implications for the planning of health care services as well as for further research on PCC.

• Macpherson, Magnhild Eide; Skarpengland, Tonje; Hov, Johannes Espolin Roksund; Ranheim, Trine; Vestad, Beate & Dahl, Tuva Børresdatter [Show all 14 contributors for this article] (2023). Increased Plasma Levels of Triglyceride-Enriched Lipoproteins Associate with Systemic Inflammation, Lipopolysaccharides, and Gut Dysbiosis in Common Variable Immunodeficiency. Journal of Clinical Immunology. ISSN 0271-9142. 43, p. 1229–1240. doi: 10.1007/s10875-023-01475-x. Full text in Research Archive Show summary

  Purpose: Triglycerides (TG) and their major transport lipoprotein in the circulation (VLDL) appear to be related to inflammation. Patients with common variable immunodeficiency (CVID) have inflammatory complications associated with gut microbial dysbiosis. We hypothesized that CVID patients have disturbed TG/VLDL profiles associated with these clinical characteristics. Methods: We measured plasma concentrations of TGs, inflammatory markers, and lipopolysaccharide (LPS) in 95 CVID patients and 28 healthy controls. Additionally, in 40 CVID patients, we explored plasma lipoprotein profiling, fatty acid, gut microbial dysbiosis, and diet. Results: TG levels were increased in CVID patients as compared to healthy controls (1.36 ± 0.53 mmol/l versus 1.08 ± 0.56 [mean, SD], respectively, P = 0.008), particularly in the clinical subgroup “Complications,” characterized by autoimmunity and organ-specific inflammation, compared to “Infection only” (1.41 mmol/l, 0.71[median, IQR] versus [1.02 mmol/l, 0.50], P = 0.021). Lipoprotein profile analyses showed increased levels of all sizes of VLDL particles in CVID patients compared to controls. TG levels correlated positively with CRP (rho = 0.256, P = 0.015), IL-6 (rho = 0.237, P = 0.021), IL-12 (rho = 0.265, P = 0.009), LPS (r = 0.654, P = 6.59 × 10−13), CVID-specific gut dysbiosis index (r = 0.315, P = 0.048), and inversely with a favorable fatty acid profile (docosahexaenoic acid [rho =  − 0.369, P = 0.021] and linoleic acid [rho =  − 0.375, P = 0.019]). TGs and VLDL lipids did not appear to be associated with diet and there were no differences in body mass index (BMI) between CVID patients and controls. Conclusion: We found increased plasma levels of TGs and all sizes of VLDL particles, which were associated with systemic inflammation, LPS, and gut dysbiosis in CVID, but not diet or BMI.

• Skjeflo, Espen Waage; Evensen, Line Holtet; Jensen, Søren Beck; Latysheva, Nadezhda; Michelsen, Annika Elisabet & Ueland, Thor [Show all 11 contributors for this article] (2023). Complement factors B, D, C3bBbP and risk of future venous thromboembolism. Clinical Immunology. ISSN 1521-6616. 249:109278, p. 1–7. doi: 10.1016/j.clim.2023.109278. Full text in Research Archive Show summary

  The complement system appears to be involved in the pathogenesis of venous thromboembolism (VTE). We investigated the association of complement factors (CF) B, D, and the alternative pathway convertase, C3bBbP, measured at inclusion, with the risk of future VTE in a nested case-control study; 380 VTE patients and 804 age- and sex-matched controls derived from the Tromsø study. Odds ratios (ORs) with 95% confidence intervals (95% CI) for VTE across tertiles of CF concentrations were estimated using logistic regression. There was no association between CFB or CFD and risk of future VTE. Higher levels of C3bBbP gave an increased risk of provoked VTE; subjects in Q4 had a 1.68-fold higher OR compared with Q1 in the age-, sex- and BMI-adjusted model (OR 1.68; 95% CI 1.08–2.64). There was no increased risk of future VTE in individuals with higher levels of complement factors B or D of the alternative pathway. Increased levels of the alternative pathway activation product, C3bBbP, showed an association with future risk of provoked VTE.

• Murphy, Sarah Louise Mikalsen; Halvorsen, Bente; Holter, Jan Cato; Huse, Camilla; Tveita, Anders & Trøseid, Marius [Show all 24 contributors for this article] (2023). Circulating markers of extracellular matrix remodelling in severe COVID-19 patients. Journal of Internal Medicine. ISSN 0954-6820. 294(6), p. 784–797. doi: 10.1111/joim.13725. Full text in Research Archive Show summary

  Background Abnormal remodelling of the extracellular matrix (ECM) has generally been linked to pulmonary inflammation and fibrosis and may also play a role in the pathogenesis of severe COVID-19. To further elucidate the role of ECM remodelling and excessive fibrogenesis in severe COVID-19, we examined circulating levels of mediators involved in various aspects of these processes in COVID-19 patients.<p> <p>Methods Serial blood samples were obtained from two cohorts of hospitalised COVID-19 patients (n = 414). Circulating levels of ECM remodelling mediators were quantified by enzyme immunoassays in samples collected during hospitalisation and at 3-month follow-up. Samples were related to disease severity (respiratory failure and/or treatment at the intensive care unit), 60-day total mortality and pulmonary pathology after 3-months. We also evaluated the direct effect of inactivated SARS-CoV-2 on the release of the different ECM mediators in relevant cell lines. <p>Results Several of the measured markers were associated with adverse outcomes, notably osteopontin (OPN), S100 calcium-binding protein A12 and YKL-40 were associated with disease severity and mortality. High levels of ECM mediators during hospitalisation were associated with computed tomography thorax pathology after 3-months. Some markers (i.e. growth differential factor 15, galectin 3 and matrix metalloproteinase 9) were released from various relevant cell lines (i.e. macrophages and lung cell lines) in vitro after exposure to inactivated SARS-CoV-2 suggesting a direct link between these mediators and the causal agent of COVID-19. <p>Conclusion Our findings highlight changes to ECM remodelling and particularly a possible role of OPN, S100A12 and YKL-40 in the pathogenesis of severe COVID-19.

• Ueland, Thor; Michelsen, Annika Elisabet; Tveita, Anders; Kåsine, Trine; Dahl, Tuva Børresdatter & Finbråten, Ane-Kristine [Show all 16 contributors for this article] (2023). Coagulopathy and adverse outcomes in hospitalized patients with COVID-19: results from the NOR-Solidarity trial. Research and Practice in Thrombosis and Haemostasis (RPTH). 8(1). doi: 10.1016/j.rpth.2023.102289. Full text in Research Archive Show summary

  Background - Several studies have examined parameters of increased thrombogenicity in COVID-19, but studies examining their association with long-term outcome and potential effects of antiviral agents in hospitalized patients with COVID-19 are scarce.<p> <p>Objectives - To evaluate plasma levels of hemostatic proteins during hospitalization in relation to disease severity, treatment modalities, and persistent pulmonary pathology after 3 months.<p> <p>Methods - In 165 patients with COVID-19 recruited into the NOR-Solidarity trial (NCT04321616) and randomized to treatment with hydroxychloroquine, remdesivir, or standard of care, we analyzed plasma levels of hemostatic proteins during the first 10 days of hospitalization (n = 160) and at 3 months of follow-up (n = 100) by enzyme immunoassay.<p> <p>Results - Our main findings were as follows: (i) tissue plasminogen activator (tPA) and tissue factor pathway inhibitor (TFPI) were increased in patients with severe disease (ie, the combined endpoint of respiratory failure [Po2-to-FiO2 ratio, <26.6 kPa] or need for treatment at an intensive care unit) during hospitalization. Compared to patients without severe disease, tPA levels were a median of 42% (P < .001), 29% (P = .002), and 36% (P = .015) higher at baseline, 3 to 5 days, and 7 to 10 days, respectively. For TFPI, median levels were 37% (P = .003), 25% (P < .001), and 10% (P = .13) higher in patients with severe disease at these time points, respectively. No changes in thrombin-antithrombin complex; alpha 2-antiplasmin; a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; or antithrombin were observed in relation to severe disease. (ii) Patients treated with remdesivir had lower levels of TFPI than those in patients treated with standard of care alone. (iii) TFPI levels during hospitalization, but not at 3 months of follow-up, were higher in those with persistent pathology on chest computed tomography imaging 3 months after hospital admission than in those without such pathology. No consistent changes in thrombin-antithrombin complex, alpha 2-antiplasmin, ADAMTS-13, tPA, or antithrombin were observed in relation to pulmonary pathology at 3 months of follow-up.<p> <p>Conclusion - TFPI and tPA are associated with severe disease in hospitalized patients with COVID-19. For TFPI, high levels measured during the first 10 days of hospitalization were also associated with persistent pulmonary pathology even 3 months after hospital admittance.

• Farbu, Bjørn Hoftun; Langeland, Halvor; Ueland, Thor; Michelsen, Annika Elisabet; Krüger, Andreas Jørstad & Klepstad, Pål [Show all 7 contributors for this article] (2023). Intestinal injury in cardiac arrest is associated with multiple organ dysfunction: A prospective cohort study. Resuscitation. ISSN 0300-9572. 185. doi: 10.1016/j.resuscitation.2023.109748. Full text in Research Archive Show summary

  Background The impact of intestinal injury in cardiac arrest is not established. The first aim of this study was to assess associations between clinical characteristics in out-of-hospital cardiac arrest (OHCA) and a biomarker for intestinal injury, Intestinal Fatty Acid Binding Protein (IFABP). The second aim was to assess associations between IFABP and multiple organ dysfunction and 30-day mortality. Methods We measured plasma IFABP in 50 patients at admission to intensive care unit (ICU) after OHCA. Demographic and clinical variables were analysed by stratifying patients on median IFABP, and by linear regression. We compared Sequential Organ Failure Assessment (SOFA) score, haemodynamic variables, and clinical-chemistry tests at day two between the “high” and “low” IFABP groups. Logistic regression was applied to assess factors associated with 30-day mortality. Results Several markers of whole body ischaemia correlated with intestinal injury. Duration of arrest and lactate serum concentrations contributed to elevated IFABP in a multivariable model (p < 0.01 and p = 0.04, respectively). At day two, all seven patients who had died were in the “high” IFABP group, and all six patients who had been transferred to ward were in the “low” group. Of patients still treated in the ICU, the “high” group had higher total, renal and respiratory SOFA score (p < 0.01) and included all patients receiving inotropic drugs. IFABP predicted mortality (OR 16.9 per standard deviation increase, p = 0.04). Conclusion Cardiac arrest duration and lactate serum concentrations were risk factors for intestinal injury. High levels of IFABP at admission were associated with multiple organ dysfunction and mortality.

• Falch, Camilla Maria; Arlien-Søborg, Mai Christiansen; Dal, Jakob; Sundaram, Arvind; Michelsen, Annika Elisabet & Ueland, Thor [Show all 11 contributors for this article] (2023). Gene expression profiling of subcutaneous adipose tissue reveals new biomarkers in acromegaly. European Journal of Endocrinology (EJE). ISSN 0804-4643. 188(3), p. 310–321. doi: 10.1093/ejendo/lvad031. Full text in Research Archive Show summary

  Abstract Context Active acromegaly is characterized by lipolysis-induced insulin resistance, which suggests adipose tissue (AT) as a primary driver of metabolic aberrations. Objective To study the gene expression landscape in AT in patients with acromegaly before and after disease control in order to understand the changes and to identify disease-specific biomarkers. Methods RNA sequencing was performed on paired subcutaneous adipose tissue (SAT) biopsies from six patients with acromegaly at time of diagnosis and after curative surgery. Clustering and pathway analyses were performed in order to identify disease activity-dependent genes. In a larger patient cohort (n = 23), the corresponding proteins were measured in serum by immunoassay. Correlations between growth hormone (GH), insulin-like growth factor I (IGF-I), visceral AT (VAT), SAT, total AT, and serum proteins were analyzed. Results 743 genes were significantly differentially expressed (P-adjusted &amp;lt; .05) in SAT before and after disease control. The patients clustered according to disease activity. Pathways related to inflammation, cell adhesion and extracellular matrix, GH and insulin signaling, and fatty acid oxidation were differentially expressed. Serum levels of HTRA1, METRNL, S100A8/A9, and PDGFD significantly increased after disease control (P &amp;lt; .05). VAT correlated with HTRA1 (R = 0.73) and S100A8/A9 (R = 0.55) (P &amp;lt; .05 for both). Conclusion AT in active acromegaly is associated with a gene expression profile of fibrosis and inflammation, which may corroborate the hyper-metabolic state and provide a means for identifying novel biomarkers.

• Oppen, Kjersti; Brede, Cato; Skadberg, Øyvind; Steinsvik, Trude; Holter, Jan Cato & Michelsen, Annika Elisabet [Show all 7 contributors for this article] (2023). Hepcidin analysis in pneumonia: Comparison of immunoassay and LC-MS/MS. Annals of Clinical Biochemistry. ISSN 0004-5632. 60(5), p. 298–305. doi: 10.1177/00045632231159529. Full text in Research Archive Show summary

  Background: The iron-regulatory hormone hepcidin is a promising biomarker to differentiate anaemia of inflammation from iron deficiency. Plasma hepcidin concentrations increase substantially during inflammation, and the amount of smaller, non-biologically active isoforms of hepcidin increase in inflammatory conditions. These smaller isoforms are measured in some, but not all analytical methods. Thus, we evaluated the comparability of two analytical methods with different isoform selectivity during and after acute-phase pneumonia as a highly inflammatory model disease. Methods: Blood samples from a cohort of 267 hospitalized community-acquired pneumonia patients collected at admission and a 6-week follow-up were analysed. Hepcidin was measured in plasma by an immunoassay, which recognizes all hepcidin isoforms, and a liquid chromatography tandem mass spectrometry (LC-MS/MS), which selectively measures the bioactive hepcidin-25. Additionally, a subset of serum samples was analysed by LC-MS/MS. Results: Hepcidin measurements by immunoassay were higher compared with LC-MS/MS. The relative mean difference of hepcidin plasma concentrations between the two analytical methods was larger in admission samples than in follow-up samples (admission samples <200 ng/mL: 37%, admission samples >200 ng/mL: 78%, follow-up samples >10 ng/mL: 22%). During acute-phase pneumonia, serum concentrations were on average 22% lower than plasma concentrations when measured by LC-MS/MS. Conclusions: Immunoassay measured higher hepcidin concentrations compared with LC-MS/MS, with more pronounced differences in high-concentration samples during acute-phase pneumonia. These findings should be considered in local method validations and in future harmonization and standardization optimization of hepcidin measurements.

• Dahlberg, Daniel; Holm, Sverre; Sagen, Ellen Lund; Michelsen, Annika Elisabet; Stensland, Maria & Souza, Gustavo Antonio De [Show all 11 contributors for this article] (2023). Bacterial Brain Abscesses Expand Despite Effective AntibioticTreatment: A Process Powered by Osmosis Due to NeutrophilCell Death. Neurosurgery. ISSN 0148-396X. doi: 10.1227/neu.0000000000002792. Full text in Research Archive Show summary

  BACKGROUND AND OBJECTIVES: A bacterial brain abscess is an emergency and should be drained of pus within24 hours of diagnosis, as recently recommended. In this cross-sectional study, we investigated whether delaying pusdrainage entails brain abscess expansion and what the underlying mechanism might be.METHODS: Repeated brain MRI of 47 patients who did not undergo immediate pus drainage, pus osmolarity measurements, immunocytochemistry, proteomics, and 18F-fluorodeoxyglucose positron emission tomography.RESULTS: Time from first to last MRI before neurosurgery was 1 to 14 days. Abscesses expanded in all but 2 patients: Themedian average increase was 23% per day (range 0%-176%). Abscesses expanded during antibiotic therapy and even ifthe pus did not contain viable bacteria. In a separate patient cohort, we found that brain abscess pus tended to behyperosmolar (median value 360 mOsm; range 266-497; n = 14; normal cerebrospinal fluid osmolarity is ∼290 mOsm).Hyperosmolarity would draw water into the abscess cavity, causing abscess expansion in a ballooning manner throughincreased pressure in the abscess cavity. A mechanism likely underlying pus hyperosmolarity was the recruitment ofneutrophils to the abscess cavity with ensuing neutrophil cell death and decomposition of neutrophil proteins and othermacromolecules to osmolytes: Pus analysis showed the presence of neutrophil proteins (protein-arginine deiminases,citrullinated histone, myeloperoxidase, elastase, cathelicidin). Previous studies have shown very high levels of osmolytes(ammonia, amino acids) in brain abscess pus. 18F-fluorodeoxyglucose positron emission tomography showed focalneocortical hypometabolism 1 to 8 years after brain abscess, indicating long-lasting damage to brain tissue.CONCLUSION: Brain abscesses expand despite effective antibiotic treatment. Furthermore, brain abscesses cause lastingdamage to surrounding brain tissue. These findings support drainage of brain abscesses within 24 hours of diagnosis.

• Seim, Bjørn Edvard; Holt, Margrethe Flesvig; Ratajska, Aleksandra; Michelsen, Annika Elisabet; Ringseth, Monica Myklebust & Halvorsen, Bente [Show all 14 contributors for this article] (2022). Markers of extracellular matrix remodeling and systemic inflammation in patients with heritable thoracic aortic diseases. Frontiers in Cardiovascular Medicine. 9, p. 1–9. doi: 10.3389/fcvm.2022.1073069. Full text in Research Archive Show summary

  Background: In approximately 20% of patients with thoracic aortic aneurysms or dissections a heritable thoracic aortic disease (HTAD) is suspected. Several monogenic connective tissue diseases imply high risk of aortic disease, including both non-syndromic and syndromic forms. There are some studies assessing inflammation and extracellular matrix remodeling in patients with non-hereditary aortic disease, but such studies in patients with hereditary diseases are scarce.<p> <p>Aims: To quantify markers of extracellular matrix (ECM) and inflammation in patients with vascular connective tissue diseases versus healthy controls. <p>Methods: Patients with Loeys-Dietz syndrome (LDS, n = 12), Marfan syndrome (MFS, n = 11), and familial thoracic aortic aneurysm 6 (FTAA6, n = 9), i.e., actin alpha 2 (ACTA2) pathogenic variants, were recruited. Exome or genome sequencing was performed for genetic diagnosis. Several markers of inflammation and ECM remodeling were measured in plasma by enzyme immunoassays. Flow cytometry of T-cell subpopulations was performed on a subgroup of patients. For comparison, blood samples were drawn from 14 healthy controls. <p>Results: (i) All groups of HTAD patients had increased levels matrix metalloproteinase-9 (MMP-9) as compared with healthy controls, also in adjusted analyses, reflecting altered ECM remodeling. (ii) LDS patients had increased levels of pentraxin 3 (PTX3), reflecting systemic inflammation. (iii) LDS patients have increased levels of soluble CD25, a marker of T-cell activation. <p>Conclusion: Our data suggest that upregulated MMP-9, a matrix degrading enzyme, is a common feature of several subgroups of HTAD. In addition, LDS patients have increased levels of PTX3 reflecting systemic and in particular vascular inflammation.

• Ueland, Thor; Sørvoll, Ingvild Hausberg; Mørtberg, Trude Victoria; Dahl, Tuva Børresdatter; Lerum, Tøri Vigeland & Michelsen, Annika Elisabet [Show all 16 contributors for this article] (2022). Anti-PF4/polyanion antibodies in COVID-19 patients are associated with disease severity and pulmonary pathology. Platelets. ISSN 0953-7104. 33(4), p. 640–644. doi: 10.1080/09537104.2022.2042238. Full text in Research Archive Show summary

  Thromboembolic events are frequent and associated with poor outcome in severe COVID-19 disease. Anti-PF4/polyanion antibodies are related to heparin-induced thrombocytopenia (HIT) and thrombus formation, but data on these antibodies in unselected COVID-19 populations are scarce. We assessed the presence of anti-PF4/polyanion antibodies in prospectively collected serum from an unselected cohort of hospitalized COVID-19 patients and evaluated if elevated levels could give prognostic information on ICU admission and respiratory failure (RF), were associated with markers of inflammation, endothelial activation, platelet activation, coagulation and fibrosis and were associated with long-term pulmonary CT changes. Five out of 65 patients had anti-PF4/polyanion reactivity with OD ≥0.200. These patients had more severe disease as reflected by ICU admission without any evidence of HIT. They also had signs of enhanced inflammation and fibrinogenesis as reflected by elevated ferritin and osteopontin, respectively, during the first 10 days of hospitalization. Increased ferritin and osteopontin persisted in these patients at 3 months follow-up, concomitant with pulmonary CT pathology. Our finding shows that the presence of anti-PF4/polyanion antibodies in unselected hospitalized COVID−19 patients was not related to HIT, but was associated with disease severity, inflammation, and pulmonary pathology after 3 months.

• Lee-Ødegård, Sindre; Ueland, Thor; Thorsby, Per Medbøe; Aukrust, Pål; Michelsen, Annika Elisabet & Halvorsen, Bente [Show all 8 contributors for this article] (2022). Fetuin-A mediates the difference in adipose tissue insulin resistance between young adult pakistani and norwegian patients with type 2 diabetes. BMC Endocrine Disorders. 22. doi: 10.1186/s12902-022-01127-y. Full text in Research Archive Show summary

  Background South-Asian immigrants to Western countries have a high prevalence of type 2 diabetes mellitus (T2DM) and increased adipose tissue insulin resistance (AT-IR), as compared to their Western counterparts. Fetuin-A is a hepatokine known to influence AT-IR. Aim Can plasma fetuin-A concentrations explain an ethnic difference in adipose tissue insulin resistance? Methods We performed a two-step euglycemic-hyperinsulinaemic clamp and measured plasma concentrations of fetuin-A and non-esterified fatty acids (NEFA), in 18 Pakistani and 21 Norwegians with T2DM (age 29–45y) in Norway. AT-IR was calculated as NEFA-suppression during the clamp. The adipokines/cytokines leptin, adiponectin, visfatin, PTX3, IL-1β, INF-γ, and IL-4 were measured in fasting plasma. Liver fat was estimated by CT-scans. Results Despite a lower BMI, Pakistani patients displayed higher AT-IR than Norwegians. NEFA-suppression during clamp was lower in Pakistani than Norwegians (mean=-20.6%, 95%CI=[-40.8, -0.01] and p = 0.046). Plasma fetuin-A concentration was higher in Pakistani than Norwegians (43.4 ng/mL[12.7,74.0], p = 0.007) and correlated negatively to %NEFA-suppression during clamp (rho=-0.39, p = 0.039). Plasma fetuin-A concentration explained 22% of the ethnic difference in NEFA-suppression during the clamp. Pakistani patients exhibited higher plasma leptin and lower PTX3 levels than Norwegian, and plasma visfatin correlated positively to plasma fetuin-A levels in the Pakistani patients. We observed no correlation between plasma fetuin-A and liver fat, but fetuin-A correlated negatively with plasma IL-1β, INF-γ, and IL-4 concentrations. Plasma IL-4 concentration was lower in Pakistani than in Norwegian patients. Conclusion Fetuin-A may contribute to explain the discrepancy in T2DM prevalence between Pakistani and Norwegians patients by influencing AT-IR.

• Tveita, Anders Aune; Murphy, Sarah Louise Mikalsen; Holter, Jan Cato; Kildal, Anders Benjamin; Michelsen, Annika Elisabet & Lerum, Tøri Vigeland [Show all 28 contributors for this article] (2022). High Circulating Levels of the Homeostatic Chemokines CCL19 and CCL21 Predict Mortality and Disease Severity in COVID-19. Journal of Infectious Diseases. ISSN 0022-1899. 226(12), p. 2150–2160. doi: 10.1093/infdis/jiac313. Full text in Research Archive Show summary

  Background Immune dysregulation is a major factor in the development of severe coronavirus disease 2019 (COVID-19). The homeostatic chemokines CCL19 and CCL21 have been implicated as mediators of tissue inflammation, but data on their regulation in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is limited. We thus investigated the levels of these chemokines in COVID-19 patients. Methods Serial blood samples were obtained from patients hospitalized with COVID-19 (n = 414). Circulating CCL19 and CCL21 levels during hospitalization and 3-month follow-up were analyzed. In vitro assays and analysis of RNAseq data from public repositories were performed to further explore possible regulatory mechanisms. Results A consistent increase in circulating levels of CCL19 and CCL21 was observed, with high levels correlating with disease severity measures, including respiratory failure, need for intensive care, and 60-day all-cause mortality. High levels of CCL21 at admission were associated with persisting impairment of pulmonary function at the 3-month follow-up. Conclusions Our findings highlight CCL19 and CCL21 as markers of immune dysregulation in COVID-19. This may reflect aberrant regulation triggered by tissue inflammation, as observed in other chronic inflammatory and autoimmune conditions. Determination of the source and regulation of these chemokines and their effects on lung tissue is warranted to further clarify their role in COVID-19.

• Trøseid, Marius; Dahl, Tuva Børresdatter; Holter, Jan Cato; Kildal, Anders Benjamin; Murphy, Sarah Louise Mikalsen & Yang, Kuan [Show all 28 contributors for this article] (2022). Persistent T-cell exhaustion in relation to prolonged pulmonary pathology and death after severe COVID-19: Results from two Norwegian cohort studies. Journal of Internal Medicine. ISSN 0954-6820. 292(5), p. 816–828. doi: 10.1111/joim.13549. Full text in Research Archive Show summary

  Background: T-cell activation is associated with an adverse outcome in COVID-19, but whether T-cell activation and exhaustion relate to persistent respiratory dysfunction and death is unknown. Objectives: To investigate whether T-cell activation and exhaustion persist and are associated with prolonged respiratory dysfunction and death after hospitalization for COVID-19. Methods: Plasma and serum from two Norwegian cohorts of hospitalized patients with COVID-19 (n = 414) were analyzed for soluble (s) markers of T-cell activation (sCD25) and exhaustion (sTim-3) during hospitalization and follow-up. Results: Both markers were strongly associated with acute respiratory failure, but only sTim-3 was independently associated with 60-day mortality. Levels of sTim-3 remained elevated 3 and 12 months after hospitalization and were associated with pulmonary radiological pathology after 3 months. Conclusion: Our findings suggest prolonged T-cell exhaustion is an important immunological sequela, potentially related to long-term outcomes after severe COVID-19.

• Sommen, Silke Lauren; Havdal, Lise Beier; Selvakumar, Joel Pradeepkumar; Einvik, Gunnar; Leegaard, Truls Michael & Lund-Johansen, Fridtjof [Show all 12 contributors for this article] (2022). Inflammatory markers and pulmonary function in adolescents and young adults 6 months after mild COVID-19. Frontiers in Immunology. 13, p. 1–12. doi: 10.3389/fimmu.2022.1081718. Full text in Research Archive Show summary

  Introduction: Both public and scientific attention have shifted from the acute COVID-19 illness to the chronic disability experienced by a proportion of COVID-19 convalescents. Post COVID-19 condition, a term used for long-lasting symptoms after COVID-19, can affect individuals across all disease severity and age groups. Data on post-COVID-19 symptomatology, epidemiology and pathophysiology in adolescents and young adults are scarce. To date, little is known on the immunological and pulmonary trends in these patients after COVID-19. This study investigated immunological markers and pulmonary function in non-hospitalized patients in this group at 6 months after initial mild COVID-19 infection. Methods: Non-hospitalized SARS-CoV-2 positive (n = 405) and SARS-CoV-2 negative (n = 111) adolescents and young adults (aged 12-25 years) were followed prospectively for six months after SARS-CoV-2 PCR testing. At baseline and at six months follow-up, all participants underwent an assessment including clinical examination, questionnaires, spirometry, and blood sampling. Cross-sectional comparisons of blood biomarkers; including white blood cell counts, CRP, GDF-15, a 27-multiplex cytokine assay, complement activation products and SARS-CoV-2 antibodies; and spirometry measures were performed after classification of all participants according to their COVID-19 status and adherence to post-COVID-19 case criteria. Associations between biomarkers and COVID-19 symptoms were explored. Results: No difference in pulmonary function was detected between the groups. COVID-19 convalescents had higher levels of chemokines eotaxin, MCP-1 and IP-10 than non-infected controls. The increase was modest and not associated with long-lasting COVID-19 symptoms. Discussion: Elevated inflammatory mediators were found in adolescents and young adults six months after mild COVID-19, but there was no association with post-COVID-19 condition.

• Søraas, Arne Vasli; Grødeland, Gunnveig; Granerud, Beathe Kiland; Ueland, Thor; Lind, Andreas & Fevang, Børre [Show all 32 contributors for this article] (2022). Breakthrough infections with the omicron and delta variants of SARS-CoV-2 result in similar re-activation of vaccine-induced immunity. Frontiers in Immunology. 13:964525, p. 1–12. doi: 10.3389/fimmu.2022.964525. Full text in Research Archive Show summary

  Background: Results showing that sera from double vaccinated individuals have minimal neutralizing activity against Omicron have been interpreted as indicating the need for a third vaccine dose for protection. However, there is little information about early immune responses to Omicron infection in double vaccinated individuals. Methods: We measured inflammatory mediators, antibodies to the SARS-CoV-2 spike and nucleocapsid proteins, and spike peptide-induced release of interferon gamma in whole blood in 51 double-vaccinated individuals infected with Omicron, in 14 infected with Delta, and in 18 healthy controls. The median time points for the first and second samples were 7 and 14 days after symptom onset, respectively. Findings: Infection with Omicron or Delta led to a rapid and similar increase in antibodies to the receptor-binding domain (RBD) of Omicron protein and spike peptide-induced interferon gamma in whole blood. Both the Omicron- and the Delta-infected patients had a mild and transient increase in inflammatory parameters. Interpretation: The results suggest that two vaccine doses are sufficient to mount a rapid and potent immune response upon infection in healthy individuals of with the Omicron variant.

• Nilsen, Dennis W.T.; Røysland, Michelle; Ueland, Thor; Aukrust, Pål; Michelsen, Annika Elisabet & Staines, Harry [Show all 10 contributors for this article] (2022). The Effect of Protease-Activated Receptor-1 (PAR-1) Inhibition on Endothelial-Related Biomarkers in Patients with Coronary Artery Disease. Thrombosis and Haemostasis. ISSN 0340-6245. doi: 10.1055/s-0042-1760256. Full text in Research Archive Show summary

  Abstract Background: Vorapaxar has been shown to reduce cardiovascular mortality in postmyocardial infarction (MI) patients. Pharmacodynamic biomarker research related to protease-activated receptor-1 (PAR-1) inhibition with vorapaxar in humans has short follow-up (FU) duration and is mainly focused on platelets rather than endothelial cells. Aim: This article assesses systemic changes in endothelial-related biomarkers during vorapaxar treatment compared with placebo at 30 days’ FU and beyond, in patients with coronary heart disease. Methods: Local substudy patients in Norway were included consecutively from two randomized controlled trials; post-MI subjects from TRA2P-TIMI 50 and non-ST-segment elevation MI (NSTEMI) patients from TRACER. Aliquots of citrated blood were stored at–80°C. Angiopoietin-2, angiopoietin-like 4, vascular endothelial growth factor, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin, von Willebrand factor, thrombomodulin, and plasminogen activator inhibitor-1 and -2 were measured at 1-month FU and at study completion (median 2.3 years for pooled patients). Results: A total of 265 consecutive patients (age median 62.0, males 83%) were included. Biomarkers were available at both FUs in 221 subjects. In the total population, angiopoietin-2 increased in patients on vorapaxar as compared with placebo at 1-month FU (p ¼ 0.034). Angiopoietin-like 4 increased (p ¼ 0.028) and plasminogen activator inhibitor-2 decreased (p ¼ 0.025) in favor of vorapaxar at final FU. In postMI subjects, a short-term increase in E-selectin favoring vorapaxar was observed, p ¼ 0.029. Also, a short-term increase in von Willebrand factor (p ¼ 0.032) favoring vorapaxar was noted in NSTEMI patients. Conclusion: Significant endothelial biomarker changes during PAR-1 inhibition were observed in post-MI and NSTEMI patients.

• Huse, Camilla; Anstensrud, Anne Kristine; Michelsen, Annika Elisabet; Ueland, Thor; Broch, Kaspar & Woxholt, Sindre [Show all 29 contributors for this article] (2022). Interleukin-6 inhibition in ST-elevation myocardial infarction: Immune cell profile in the randomised ASSAIL-MI trial. EBioMedicine. 80(104013). doi: 10.1016/j.ebiom.2022.104013. Full text in Research Archive Show summary

  We recently showed that interleukin (IL)-6 inhibition by tocilizumab improves myocardial salvage in ST-elevation myocardial infarction (STEMI). However, the mechanisms for this effect are not clear. Methods In this exploratory sub-study of the ASSAIL-MI trial, we examined leukocyte differential counts and their relation to myocardial salvage and peak troponin T (TnT) in STEMI patients randomised to tocilizumab (n = 101) or placebo (n = 98). We performed RNA-sequencing on whole blood (n = 40) and T cells (n = 20). B and T cell subpopulations were examined by flow cytometry (n = 69). Findings (i) STEMI patients had higher neutrophil counts at hospitalisation compared with stable angina patients. (ii) After percutaneous coronary intervention there was a gradual decline in neutrophils, which was significantly more pronounced in the tocilizumab group. (iii) The decrease in neutrophils in the tocilizumab group was associated with improved myocardial salvage and lower peak TnT. (iv) RNA-sequencing suggested that neutrophil function was also attenuated by tocilizumab. (v) B and T cell sub-populations changed only minimally after STEMI with minor effects of tocilizumab, supported as well by RNA-sequencing analyses of T cells. (vi) However, a low CD8+ count was associated with improved myocardial salvage in patients admitted to the hospital > 3 h after symptom onset. Interpretation Tocilizumab induced a rapid reduction in neutrophils and seemed to attenuate neutrophil function in STEMI patients potentially related to the beneficial effects of tocilizumab on myocardial salvage.

• Simeone, Paola; Tripaldi, Romina; Michelsen, Annika Elisabet; Ueland, Thor; Liani, Rossella & Ciotti, Sonia [Show all 14 contributors for this article] (2022). Effects of liraglutide vs. lifestyle changes on soluble suppression of tumorigenesis-2 (sST2) and galectin-3 in obese subjects with prediabetes or type 2 diabetes after comparable weight loss. Cardiovascular Diabetology. 21(1). doi: 10.1186/s12933-022-01469-w. Full text in Research Archive Show summary

  Background Soluble suppression of tumorigenesis-2 (sST2) and galectin (Gal)-3 are two biomarkers related to inflammation, metabolic disturbances and to myocardial fibrosis that characterize several cardiac pathological conditions. Increased circulating levels of these molecules have been associated with risk of cardiovascular death. Treatment with liraglutide, a glucagon-like peptide 1 analog, is associated with weight loss, improved glycemic control, and reduced cardiovascular risk. We wanted to assess (I) potential differences between subjects with prediabetes or type 2 diabetes mellitus (T2DM) and healthy controls in sST2 and Gal-3 circulating levels, and their relationship with glycemic control and markers of beta cell function and myocardial injury; (II) whether liraglutide treatment modulates these markers in subjects with prediabetes or early T2DM independently of weight loss; (III) whether baseline levels of any of these two molecules may predict the response to liraglutide treatment. Methods Forty metformin-treated obese subjects (BMI ≥ 30) with prediabetes [impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) or both (n = 23)] or newly diagnosed T2DM (n = 17), were randomized to liraglutide or lifestyle counseling until achieving a comparable weight loss (7% of initial body weight). Thirteen subjects were enrolled as healthy controls for baseline sST2 and Gal-3 levels. Results Baseline sST2 levels were comparable between controls and obese patients (p = 0.79) whereas Gal-3 levels were significantly higher in patients as compared to controls (p < 0.001). Liraglutide treatment, but not weight loss achieved by lifestyle counseling, decreased plasma sST2 levels (− 9%, beta = − 14.9, standard deviation 6.9, p = 0.037) while Gal-3 levels did not change. A reduction in serum hs-Troponin I was observed after intervention, due to a 19% (p = 0.29) increase in the lifestyle arm, and a 25% decrease (p = 0.033) in the liraglutide arm (between-group difference p = 0.083). Lower baseline Gal-3 levels predicted a better improvement in beta cell function after liraglutide treatment. Conclusions Liraglutide-induced reduction in sST2 and possibly hs-TnI suggests that in obese patients with prediabetes or early T2DM this drug may have a positive effect on (cardiac) fibrosis, whereas plasma level of Gal-3 before liraglutide initiation may predict response to the drug in terms of beta cell function improvement. Trial registration Eudract: 2013-001356-36

• Berven, Lise; Selvakumar, Joel Pradeepkumar; Havdal, Lise Beier; Stiansen-Sonerud, Tonje; Einvik, Gunnar & Leegaard, Truls Michael [Show all 10 contributors for this article] (2022). Inflammatory Markers, Pulmonary Function, and Clinical Symptoms in Acute COVID-19 Among Non-Hospitalized Adolescents and Young Adults. Frontiers in Immunology. 13:837288, p. 1–11. doi: 10.3389/fimmu.2022.837288. Full text in Research Archive Show summary

  Summary: Mild, subacute COVID-19 in young people show inflammatory enhancement, but normal pulmonary function. Inflammatory markers are associated with age and male sex, whereas clinical symptoms are associated with age and female sex, but not with objective disease markers. Background: Coronavirus Disease 2019 (COVID-19) is widespread among adolescents and young adults across the globe. The present study aimed to compare inflammatory markers, pulmonary function and clinical symptoms across non-hospitalized, 12 – 25 years old COVID-19 cases and non-COVID-19 controls, and to investigate associations between inflammatory markers, clinical symptoms, pulmonary function and background variables in the COVID-19 group. Methods: The present paper presents baseline data from an ongoing longitudinal observational cohort study (Long-Term Effects of COVID-19 in Adolescents, LoTECA, ClinicalTrials ID: NCT04686734). A total of 31 plasma cytokines and complement activation products were assayed by multiplex and ELISA methodologies. Pulmonary function and clinical symptoms were investigated by spirometry and questionnaires, respectively. Results: A total of 405 COVID-19 cases and 111 non-COVID-19 controls were included. The COVID-19 group had significantly higher plasma levels of IL-1β, IL-4, IL-7, IL-8, IL-12, TNF, IP-10, eotaxin, GM-CSF, bFGF, complement TCC and C3bc, and significantly lower levels of IL-13 and MIP-1α, as compared to controls. Spirometry did not detect any significant differences across the groups. IL-4, IL-7, TNF and eotaxin were negatively associated with female sex; eotaxin and IL-4 were positively associated with age. Clinical symptoms were positively associated with female sex and age, but not with objective disease markers. Conclusions: Among non-hospitalized adolescents and young adults with COVID-19 there was significant alterations of plasma inflammatory markers in the subacute stage of the infection. Still, pulmonary function was normal. Clinical symptoms were independent of inflammatory and pulmonary function markers, but positively associated with age and female sex.

• Oppen, Kjersti; Ueland, Thor; Michelsen, Annika Elisabet; Aukrust, Pål; Steinsvik, Trude & Skadberg, Øyvind [Show all 11 contributors for this article] (2022). Hepcidin predicts 5-year mortality after community-acquired pneumonia. Infectious Diseases. ISSN 2374-4235. 54(6), p. 403–409. doi: 10.1080/23744235.2021.2022194. Full text in Research Archive Show summary

  Background Virtually all living organisms, including microbes and humans, depend on iron to survive and grow. During an infection, the plasma level of iron and several iron-related proteins change substantially. We hypothesized that iron and iron-related proteins could predict short- and long-term outcomes in community-acquired pneumonia. Methods Blood samples from a prospective cohort of 267 in-patients with community-acquired pneumonia were analysed for hepcidin, ferritin, iron, transferrin, transferrin saturation, and soluble transferrin receptor at admission and 6-weeks post-discharge. Adverse short-term outcome was defined as admission to intensive care unit or death within 30 days, and long-term outcome was assessed as 5-year overall mortality. Logistic regression, Kaplan Meier survival curves, and Cox regression models with cut-offs at median for the potential biomarkers were used for statistical evaluation. Results Low admission levels of hepcidin predicted 5-year overall mortality, independently of age, sex, comorbid conditions, and anaemia. Low levels of ferritin at admission as well as low levels of iron and transferrin saturation and high levels of soluble transferrin receptor at the 6-week follow-up were predictors of 5-year overall mortality in univariable, but not in multivariable analyses. Neither of these potential biomarkers predicted adverse short-term outcomes. Conclusions In hospitalized patients with community-acquired pneumonia, low levels of hepcidin at admission predicted 5-year overall mortality, but not short-term adverse outcome.

• Vestad, Beate; Ueland, Thor; Lerum, Tøri Vigeland; Dahl, Tuva Børresdatter; Holm, Kristian & Barratt-Due, Andreas [Show all 37 contributors for this article] (2022). Respiratory dysfunction three months after severe COVID-19 is associated with gut microbiota alterations. Journal of Internal Medicine. ISSN 0954-6820. 291(6), p. 801–812. doi: 10.1111/joim.13458. Full text in Research Archive Show summary

  Background: Although coronavirus disease 2019 (COVID-19) is primarily a respiratory infection, mounting evidence suggests that the gastrointestinal (GI) tract is involved in the disease, with gut barrier dysfunction and gut microbiota alterations being related to disease severity. Whether these alterations persist and are related to long-term respiratory dysfunction remains unknown. Methods: Plasma was collected during hospital admission and after three months from the NOR-Solidarity trial (n = 181) and analysed for markers of gut barrier dysfunction and inflammation. At the three-month follow-up, pulmonary function was assessed by measuring the diffusing capacity of the lungs for carbon monoxide (DLCO ). Rectal swabs for gut microbiota analyses were collected (n = 97) and analysed by sequencing the 16S rRNA gene. Results: Gut microbiota diversity was reduced in COVID-19 patients with respiratory dysfunction, defined as DLCO below the lower limit of normal three months after hospitalisation. These patients also had an altered global gut microbiota composition, with reduced relative abundance of 20 bacterial taxa and increased abundance of five taxa, including Veillonella, potentially linked to fibrosis. During hospitalisation, increased plasma levels of lipopolysaccharide-binding protein (LBP) were strongly associated with respiratory failure, defined as pO2 /fiO2 -(P/F ratio)

• Fraz, Mai Sasaki Aanensen; Michelsen, Annika Elisabet; Moe, Natasha; Aaløkken, Trond Mogens; Macpherson, Magnhild Eide & Nordøy, Ingvild [Show all 12 contributors for this article] (2022). Raised Serum Markers of T Cell Activation and Exhaustion in Granulomatous-Lymphocytic Interstitial Lung Disease in Common Variable Immunodeficiency. Journal of Clinical Immunology. ISSN 0271-9142. p. 1–11. doi: 10.1007/s10875-022-01318-1. Full text in Research Archive Show summary

  Purpose About 20–30% of patients with common variable immunodefciency (CVID) develop granulomatous-lymphocytic interstitial lung disease (GLILD) as one of several non-infectious complications to their immunodefciency. The purpose of this study was to identify biomarkers that could distinguish GLILD from other non-infectious complications in CVID.<p> <p>Methods We analyzed serum biomarkers related to infammation, pulmonary epithelium injury, fbrogenesis, and extracellular matrix (ECM) remodeling, and compared three subgroups of CVID: GLILD patients (n=16), patients with other non-infectious complications (n=37), and patients with infections only (n=20). <p>Results We found that GLILD patients had higher levels of sCD25, sTIM-3, IFN-γ, and TNF, refecting T cell activation and exhaustion, compared to both CVID patients with other infammatory complications and CVID with infections only. GLILD patients also had higher levels of SP-D and CC16, proteins related to pulmonary epithelium injury, as well as the ECM remodeling marker MMP-7, than patients with other non-infectious complications. <p>Conclusion GLILD patients have elevated serum markers of T cell activation and exhaustion, pulmonary epithelium injury, and ECM remodeling, pointing to potentially important pathways in GLILD pathogenesis, novel targets for therapy, and promising biomarkers for clinical evaluation of these patients.

• Hansen, Ellen-Sofie; Rinde, Fridtjof Balteskard; Edvardsen, Magnus; Hindberg, Kristian; Latysheva, Nadezhda & Aukrust, Pål [Show all 11 contributors for this article] (2021). Elevated plasma D-dimer levels are associated with risk of future incident venous thromboembolism. Thrombosis Research. ISSN 0049-3848. 208, p. 121–126. doi: 10.1016/j.thromres.2021.10.020. Full text in Research Archive Show summary

  <p><i>Background</i> D-dimer, a global biomarker for activation of the coagulation and fibrinolysis systems, is useful in assessing individual risk of venous thromboembolism (VTE) recurrence. However, there is limited information on the association between D-dimer and risk of a first lifetime VTE event. <p><i>Objectives</i> To investigate the association between plasma D-dimer levels and risk of future incident VTE. <p><i>Methods</i> A population-based nested case-control study, comprising 414 VTE patients and 843 randomly selected age- and sex-matched controls, was derived from the Tromsø Study (1994–2007). D-dimer was measured in plasma samples collected at cohort baseline (1994–95). Odds ratios (ORs) for VTE with 95% confidence intervals (CIs) were estimated according to quartile cut-offs of D-dimer levels determined in controls. <p><i>Results</i> The risk of VTE increased across quartiles of D-dimer levels (P_trend = 0.014) in the age- and sex-adjusted model. Participants with plasma D-dimer levels in the highest quartile (≥152 ng/mL) had an OR for VTE of 1.65 (95% CI 1.14–2.40) compared with those in the lowest quartile (<94 ng/mL). The ORs were marginally attenuated after additional adjustment for body mass index (BMI) (OR 1.51, 95% CI 1.04–2.20) and C-reactive protein (CRP) (OR 1.34, 95% CI 0.90–1.98). Similar results were obtained for VTE subgroups, i.e. deep vein thrombosis, pulmonary embolism, and provoked/unprovoked events. <p><i>Conclusion</i> Our results indicate that elevated plasma D-dimer levels are associated with increased risk of incident VTE. However, the attenuation of risk estimates upon additional adjustment for BMI and CRP suggests that D-dimer partly reflects underlying conditions associated with obesity and an inflammatory state.

• Fevang, Børre; Wyller, Vegard Bruun Bratholm; Mollnes, Tom Eirik; Pedersen, Maria; Asprusten, Tarjei Tørre & Michelsen, Annika Elisabet [Show all 8 contributors for this article] (2021). Lasting Immunological Imprint of Primary Epstein-Barr Virus Infection With Associations to Chronic Low-Grade Inflammation and Fatigue. Frontiers in Immunology. 12. doi: 10.3389/fimmu.2021.715102. Full text in Research Archive Show summary

  Background: Epstein-Barr virus (EBV) causes infectious mononucleosis (IM) that can lead to chronic fatigue syndrome. The CEBA-project (Chronic fatigue following acute EBV infection in Adolescents) has followed 200 patients with IM and here we present an immunological profiling of adolescents with IM related to clinical characteristics. Methods: Patients were sampled within 6 weeks of debut of symptoms and after 6 months. Peripheral blood mononuclear cells (PBMC) were cultured and stimulated in vitro (n=68), and supernatants analyzed for cytokine release. Plasma was analyzed for inflammatory markers (n=200). The Chalder Fatigue Questionnaire diagnosed patients with and without chronic fatigue at 6 months (CF+ and CF- group, respectively) (n=32 and n=91, in vitro and plasma cohorts, respectively. Results: Broad activation of PBMC at baseline, with high levels of RANTES (Regulated on activation, normal T-cell expressed and secreted) in the CF+ group, and broad inflammatory response in plasma with high levels of T-cell markers was obeserved. At 6 months, there was an increased β-agonist response and RANTES was still elevated in cultures from the CF+ group. Plasma showed decrease of inflammatory markers except for CRP which was consistently elevated in the CF+ group. Conclusion: Patients developing chronic fatigue after IM have signs of T-cell activation and low-grade chronic inflammation at baseline and after 6 months.

• Aarsetøy, Reidun; Ueland, Thor; Aukrust, Pål; Michelsen, Annika Elisabet; Fuente, Ricardo Leon de la & Grundt, Magnea Heidi Jonsdottir [Show all 9 contributors for this article] (2021). Complement component 7 is associated with total- and cardiac death in chest-pain patients with suspected acute coronary syndrome. BMC Cardiovascular Disorders. 21(1), p. 1–12. doi: 10.1186/s12872-021-02306-w. Full text in Research Archive Show summary

  Background Complement activation has been associated with atherosclerosis, atherosclerotic plaque destabilization and increased risk of cardiovascular events. Complement component 7 (CC7) binds to the C5bC6 complex which is part of the terminal complement complex (TCC/C5b-9). High-sensitivity C-reactive protein (hsCRP) is a sensitive marker of systemic inflammation and may reflect the increased inflammatory state associated with cardiovascular disease. Aim To evaluate the associations between CC7 and total- and cardiac mortality in patients hospitalized with chest-pain of suspected coronary origin, and whether combining CC7 with hsCRP adds prognostic information. Methods Baseline levels of CC7 were related to 60-months survival in a prospective, observational study of 982 patients hospitalized with a suspected acute coronary syndrome (ACS) at 9 hospitals in Salta, Argentina. A cox regression model, adjusting for conventional cardiovascular risk factors, was fitted with all-cause mortality, cardiac death and sudden cardiac death (SCD) as the dependent variables. A similar Norwegian population of 871 patients was applied to test the reproducibility of results in relation to total death. Results At follow-up, 173 patients (17.7%) in the Argentinean cohort had died, of these 92 (9.4%) were classified as cardiac death and 59 (6.0%) as SCD. In the Norwegian population, a total of 254 patients (30%) died. In multivariable analysis, CC7 was significantly associated with 60-months all-cause mortality [hazard ratio (HR) 1.26 (95% confidence interval (CI), 1.07–1.47) and cardiac death [HR 1.28 (95% CI 1.02–1.60)], but not with SCD. CC7 was only weakly correlated with hsCRP (r = 0.10, p = 0.002), and there was no statistically significant interaction between the two biomarkers in relation to outcome. The significant association of CC7 with total death was reproduced in the Norwegian population. Conclusions CC7 was significantly associated with all-cause mortality and cardiac death at 60-months follow-up in chest-pain patients with suspected ACS.

• Holt, Margrethe Flesvig; Michelsen, Annika Elisabet; Shahini, Negar; Bjørkelund, Elisabeth; Bendz, Christina & Massey, Richard J [Show all 15 contributors for this article] (2021). The Alternative Complement Pathway Is Activated Without a Corresponding Terminal Pathway Activation in Patients With Heart Failure. Frontiers in Immunology. 12. doi: 10.3389/fimmu.2021.800978. Full text in Research Archive Show summary

  Objective Dysregulation of the complement system has been described in patients with heart failure (HF). However, data on the alternative pathway are scarce and it is unknown if levels of factor B (FB) and the C3 convertase C3bBbP are elevated in these patients. We hypothesized that plasma levels of FB and C3bBbP would be associated with disease severity and survival in patients with HF. Methods We analyzed plasma levels of FB, C3bBbP, and terminal C5b-9 complement complex (TCC) in 343 HF patients and 27 healthy controls. Results Compared with controls, patients with HF had elevated levels of circulating FB (1.6-fold, p &lt; 0.001) and C3bBbP (1.3-fold, p &lt; 0.001). In contrast, TCC, reflecting the terminal pathway, was not significantly increased (p = 0.15 vs controls). FB was associated with NT-proBNP, troponin, eGFR, and i.e., C-reactive protein. FB, C3bBbP and TCC were not associated with mortality in HF during a mean follow up of 4.3 years. Conclusion Our findings suggest that in patients with HF, the alternative pathway is activated. However, this is not accompanied by activation of the terminal pathway.

• Langeland, Halvor Johannes Breivik; Damås, Jan Kristian; Mollnes, Tom Eirik; Ludviksen, Judith K; Ueland, Thor & Michelsen, Annika Elisabet [Show all 11 contributors for this article] (2021). The inflammatory response is related to circulatory failure after out-of-hospital cardiac arrest: A prospective cohort study. Resuscitation. ISSN 0300-9572. 170, p. 115–125. doi: 10.1016/j.resuscitation.2021.11.026. Full text in Research Archive Show summary

  Background: Whole body ischemia and reperfusion injury after cardiac arrest leads to the massive inflammation clinically manifested in the post-cardiac arrest syndrome. Previous studies on the inflammatory effect on circulatory failure after cardiac arrest have either investigated a selected patient group or a limited part of the inflammatory mechanisms. We examined the association between cardiac arrest characteristics and inflammatory biomarkers, and between inflammatory biomarkers and circulatory failure after cardiac arrest, in an unselected patient cohort. Methods: This was a prospective study of 50 consecutive patients with out-of-hospital cardiac arrest. Circulation was invasively monitored from admission until day five, whereas inflammatory biomarkers, i.e. complement activation, cytokines and endothelial injury, were measured daily. We identified predictors for an increased inflammatory response, and associations between the inflammatory response and circulatory failure. Results: We found a marked and broad inflammatory response in patients after cardiac arrest, which was associated with clinical outcome. Long time to return of spontaneous circulation and high lactate level at admission were associated with increased complement activation (TCC and C3bc), pro-inflammatory cytokines (IL-6, IL-8) and endothelial injury (syndecan-1) at admission. These biomarkers were in turn significantly associated with lower mean arterial blood pressure, lower cardiac output and lower systemic vascular resistance, and increased need of circulatory support in the initial phase. High levels of TCC and IL-6 at admission were significantly associated with increased 30-days mortality. Conclusion: Inflammatory biomarkers, including complement activation, cytokines and endothelial injury, were associated with increased circulatory failure in the initial period after cardiac arrest.

• Otterdal, Kari; Berg, Åse; Michelsen, Annika Elisabet; Yndestad, Arne; Patel, Sam & Gregersen, Ida [Show all 10 contributors for this article] (2021). IL-18 and IL-18 binding protein are related to disease severity and parasitemia during falciparum malaria. BMC Infectious Diseases. 21. doi: 10.1186/s12879-021-06751-y. Full text in Research Archive Show summary

  Background: Several inflammatory molecules participate in the immune response to malaria. Interleukin (IL)-18 is an inflammatory cytokine activated by NLRP3 inflammasomes. In clinical falciparum malaria, with and without HIV co-infection, data on IL-18 and in particular on its binding protein, IL-18bp, is scarce. Methods: Clinical data and blood samples were collected from adults in Mozambique with P. falciparum infection, with (n = 70) and without (n = 61) HIV co-infection, from HIV-infected patients with similar symptoms without malaria (n = 58) and from healthy controls (n = 52). In vitro studies were performed in endothelial cells using hemozoin crystals. Results: (i) IL-18 and IL-18bp were markedly up-regulated during falciparum malaria with particular high levels in malaria patients co-infected with HIV and severe malaria disease. (ii) In the malaria group as a whole, both IL-18 and IL-18bp were positively correlated with disease severity, parasitemia, and endothelial cell activation as assessed by vWF in plasma. (iii) Whereas there was no change in IL-18 levels in malaria patients co-infected with HIV during follow-up, the patients with malaria only had slightly increased IL-18 levels. Further, the IL-18pb levels declined and thereby contributed to an increase in IL-18/IL-18bp ratio in all subgroups of malaria patients. (iv) IL-27, previously shown to be up-regulated in this malaria cohort, markedly induced a release of IL-18bp from endothelial cells in vitro, and notably, this presumably anti-inflammatory effect was counteracted by hemozoin. Conclusions: Our findings suggest that the IL-18 system could be an important mediator in the immune pathogenesis during falciparum malaria, potentially also representing a target for therapy.

• Oppen, Kjersti; Ueland, Thor; Siljan, William Ward; Skadberg, Øyvind; Brede, Cato & Lauritzen, Trine [Show all 12 contributors for this article] (2021). Hepcidin and ferritin predict microbial etiology in community-acquired pneumonia. Open Forum Infectious Diseases. 8(4). doi: 10.1093/ofid/ofab082. Full text in Research Archive Show summary

  Background Iron is crucial for survival and growth of microbes. Consequently, limiting iron availability is a human antimicrobial defense mechanism. We explored iron and iron-related proteins as potential biomarkers in community-acquired pneumonia and hypothesized that infection-induced changes in these potential biomarkers differ between groups of pathogens and could predict microbial etiology. Methods Blood samples from a prospective cohort of 267 patients with community-acquired pneumonia were analyzed for hepcidin, ferritin, iron, transferrin, and soluble transferrin receptor at admission, clinical stabilization, and a 6-week follow-up. A total of 111 patients with an established microbiological diagnosis confined to 1 microbial group (atypical bacterial, typical bacterial, or viral) were included in predictive analyses. Results High admission levels of ferritin predicted atypical bacterial versus typical bacterial etiology (odds ratio [OR], 2.26; 95% confidence interval [CI], 1.18–4.32; P = .014). Furthermore, hepcidin and ferritin predicted atypical bacterial versus viral etiology (hepcidin: OR = 3.12, 95% CI = 1.34–7.28, P = .008; ferritin: OR = 2.38, 95% CI = 1.28–4.45, P = .006). The findings were independent of C-reactive protein and procalcitonin. Conclusions Hepcidin and ferritin are potential biomarkers of microbial etiology in community-acquired pneumonia.

• Grimnes, Gro; Bhoelan, Soerajja; Hindberg, Kristian; Davids, Mark; Nieuwdorp, Max & Mollnes, Tom E. [Show all 11 contributors for this article] (2021). Impact of a Vancomycin-Induced Shift of the Gut Microbiome in a Gram-Negative Direction on Plasma Factor VIII:C Levels: Results from a Randomized Controlled Trial. Thrombosis and Haemostasis. ISSN 0340-6245. 0, p. 1–12. doi: 10.1055/s-0041-1733906. Full text in Research Archive Show summary

  Rationale - Inflammation is present in several conditions associated with risk of venous thromboembolism. The gut microbiome might be a source of systemic inflammation and activation of coagulation, by translocation of lipopolysaccharides from gram-negative bacteria to the systemic circulation.<p> <p>Objective - To investigate whether a vancomycin-induced shift of the gut microbiome in a gram-negative direction influences systemic inflammation and plasma factor (F) VIII procoagulant activity (FVIII:C).<p> <p>Methods and Results - We performed a randomized controlled trial including 43 healthy volunteers aged 19 to 37 years. Twenty-one were randomized to 7 days of oral vancomycin intake and 22 served as controls. Feces and blood were sampled at baseline, the day after the end of intervention, and 3 weeks after intervention. Gut microbiome composition was assessed by amplicon sequencing. FVIII:C was measured using an activated partial thromboplastin time-based assay, cytokines were measured using multiplex technology, complement activation was measured using the enzyme-linked immunosorbent assay, and high-sensitivity C-reactive protein (CRP) was measured by an immunoturbidimetric assay. Vancomycin intake reduced gut microbiome diversity and increased the abundance of gram-negative bacteria. Change in FVIII:C in the intervention group was +4 IU/dL versus −6 IU/dL (p = 0.01) in the control group. A similar change was observed for log-transformed CRP (+0.21 mg/dL vs. −0.25 mg/dL, p = 0.04). The cytokines and complement activation markers remained similar in the two groups.<p> <p>Conclusion - The found slight increases in FVIII:C and CRP levels might support the hypothesis that a vancomycin-induced gram-negative shift in the gut microbiome could induce increased systemic inflammation and thereby a procoagulant state.

• Helseth, Ragnhild; Kleveland, Ola; Ueland, Thor; Wiseth, Rune; Damås, Jan Kristian & Broch, Kaspar [Show all 11 contributors for this article] (2021). Tocilizumab increases citrullinated histone 3 in non-ST segment elevation myocardial infarction. Open heart. 8(1). doi: 10.1136/openhrt-2020-001492. Full text in Research Archive Show summary

  Objective Beyond reducing inflammation and troponin T (TnT) release, the interleukin-6 receptor antagonist tocilizumab reduces neutrophil counts in patients with non-ST segment elevation myocardial infarction (NSTEMI). It is unclear if this is related to formation of neutrophil extracellular traps (NETs), carrying inflammatory and thrombotic properties. Methods In a placebo-controlled trial, 117 patients with NSTEMI were randomised to a single dose of tocilizumab (n=58) or placebo (n=59) before coronary angiography. The NETs related markers double-stranded DNA (dsDNA), myloperoxidase–DNA (MPO–DNA) and citrullinated histone 3 (H3Cit) were measured at five consecutive time points during hospitalisation (days 1–3). Results Our major findings were: (1) H3Cit levels were significantly higher in the tocilizumab compared with the placebo group at all time points (all p<0.05), and H3Cit area under the curve (AUC) was 2.3 fold higher in the tocilizumab compared with placebo group (p<0.0001). (2) MPO–DNA and dsDNA did not differ between the groups. (3) In both treatment arms, dsDNA AUC was associated with TnT AUC. (4) Neutrophil count AUC correlated inversely to H3Cit AUC (p=0.015) in the total population. Conclusions In patients with NSTEMI, treatment with tocilizumab is associated with increased circulating H3Cit levels, suggesting that tocilizumab enhances NETosis. Further studies should clarify whether NETosis is a relevant side effect of tocilizumab. Regardless of tocilizumab, dsDNA associated with TnT release, indicating a link between extracellular nuclear material and myocardial injury.

• Aarsetøy, Reidun; Ueland, Thor; Aukrust, Pål; Michelsen, Annika E.; Fuente, Ricardo Leon de la & Pønitz, Volker [Show all 10 contributors for this article] (2021). Angiopoietin-2 and angiopoietin-like 4 protein provide prognostic information in patients with suspected acute coronary syndrome. Journal of Internal Medicine. ISSN 0954-6820. 290(4), p. 1–16. doi: 10.1111/joim.13339. Full text in Research Archive Show summary

  Background Plasma levels of angiopoietin-2 (ANGPT2) and angiopoietin-like 4 protein (ANGPTL4) reflect different pathophysiological aspects of cardiovascular disease. We evaluated their association with outcome in a hospitalized Norwegian patient cohort (n = 871) with suspected acute coronary syndrome (ACS) and validated our results in a similar Argentinean cohort (n = 982). Methods A cox regression model, adjusting for traditional cardiovascular risk factors, was fitted for ANGPT2 and ANGPTL4, respectively, with all-cause mortality and cardiac death within 24 months and all-cause mortality within 60 months as the dependent variables. Results At 24 months follow-up, 138 (15.8%) of the Norwegian and 119 (12.1%) of the Argentinian cohort had died, of which 86 and 66 deaths, respectively, were classified as cardiac. At 60 months, a total of 259 (29.7%) and 173 (17.6%) patients, respectively, had died. ANGPT2 was independently associated with all-cause mortality in both cohorts at 24 months [hazard ratio (HR) 1.27 (95% confidence interval (CI), 1.08–1.50) for Norway, and HR 1.57 (95% CI, 1.27–1.95) for Argentina], with similar results at 60 months [HR 1.19 (95% CI, 1.05–1.35) (Norway), and HR 1.56 (95% CI, 1.30–1.88) (Argentina)], and was also significantly associated with cardiac death [HR 1.51 (95% CI, 1.14–2.00)], in the Argentinean population. ANGPTL4 was significantly associated with all-cause mortality in the Argentinean cohort at 24 months [HR 1.39 (95% CI, 1.15–1.68)] and at 60 months [HR 1.43 (95% CI, 1.23–1.67)], enforcing trends in the Norwegian population. Conclusions ANGPT2 and ANGPTL4 were significantly associated with outcome in similar ACS patient cohorts recruited on two continents.

• Ueland, Thor; Astrup, Elisabeth; Otterdal, Kari; Lekva, Tove; Janardhanan, Jeshina & Prakash, John A. [Show all 11 contributors for this article] (2021). Secreted wnt antagonists in scrub typhus. PLoS Neglected Tropical Diseases. ISSN 1935-2727. 15(4), p. 1–12. doi: 10.1371/journal.pntd.0009185. Full text in Research Archive Show summary

  Background The mechanisms that control local and systemic inflammation in scrub typhus have only been partially elucidated. The wingless (Wnt) signaling pathways are emerging as important regulators of inflammation and infection, but have not been investigated in scrub typhus. Methodology/Principal findings Plasma levels of secreted Wnt antagonists (i.e. DKK-1, sFRP-3, WIF-1 and SOST) were analyzed in patients with scrub typhus (n = 129), patients with similar febrile illness without O. tsutsugamushi infection (n = 31), febrile infectious disease controls, and in healthy controls (n = 31) from the same area of South India, and were correlated to markers of inflammation, immune and endothelial cell activation as well as for their association with organ specific dysfunction and mortality in these patients. We found i) Levels of SOST and in particular sFRP-3 and WIF-1 were markedly increased and DKK-1 decreased in scrub typhus patients at admission to the hospital compared to healthy controls. ii) In recovering scrub typhus patients, SOST, sFRP-3 and WIF-1 decreased and DKK-1 increased. iii) SOST was positively correlated with markers of monocyte/macrophage and endothelial/vascular activation as well as with renal dysfunction and poor outcome iv) Finally, regulation of Wnt pathways by O. tsutsugamushi in vitro in monocytes and ex vivo in mononuclear cells isolated from patients with scrub typhus, as evaluated by gene expression studies available in public repositories, revealed markedly attenuated canonical Wnt signaling. Conclusions/Significance Our findings suggest that scrub typhus is characterized by attenuated Wnt signaling possibly involving dysregulated levels of several secreted pathway antagonists. The secreted Wnt antagonist SOST was strongly associated with renal dysfunction and poor prognosis in these patients.

• Schultz, Nina Haagenrud; Sørvoll, Ingvild Hausberg; Michelsen, Annika; Munthe, Ludvig Andre; Lund-Johansen, Fridtjof & Ahlen, Maria Therese [Show all 11 contributors for this article] (2021). Thrombosis and thrombocytopenia after CHADOX1 NCoV-19 vaccination. New England Journal of Medicine. ISSN 0028-4793. 384(22), p. 2124–2130. doi: 10.1056/NEJMoa2104882. Full text in Research Archive Show summary

  We report findings in five patients who presented with venous thrombosis and thrombocytopenia 7 to 10 days after receiving the first dose of the ChAdOx1 nCoV-19 adenoviral vector vaccine against coronavirus disease 2019 (Covid-19). The patients were health care workers who were 32 to 54 years of age. All the patients had high levels of antibodies to platelet factor 4–polyanion complexes; however, they had had no previous exposure to heparin. Because the five cases occurred in a population of more than 130,000 vaccinated persons, we propose that they represent a rare vaccine-related variant of spontaneous heparin-induced thrombocytopenia that we refer to as vaccine-induced immune thrombotic thrombocytopenia.

• Holm, Sverre; Kared, Hassen; Michelsen, Annika Elisabet; Kong, Xiang Yi; Dahl, Tuva Børresdatter & Schultz, Nina Haagenrud [Show all 21 contributors for this article] (2021). Immune complexes, innate immunity, and NETosis in ChAdOx1 vaccine-induced thrombocytopenia. European Heart Journal. ISSN 0195-668X. 42(39), p. 4064–4072. doi: 10.1093/eurheartj/ehab506. Full text in Research Archive Show summary

  Aims - We recently reported five cases of vaccine-induced immune thrombotic thrombocytopenia (VITT) 7–10 days after receiving the first dose of the ChAdOx1 nCoV-19 adenoviral vector vaccine against corona virus disease 2019 (COVID-19). We aimed to investigate the pathogenic immunological responses operating in these patients.<p> <p>Methods and results - We assessed circulating inflammatory markers by immune assays and immune cell phenotyping by flow cytometry analyses and performed immunoprecipitation with anti-platelet factor (PF)4 antibody in plasma samples followed by mass spectrometry from all five patients. A thrombus was retrieved from the sinus sagittal superior of one patient and analysed by immunohistochemistry and flow cytometry. Precipitated immune complexes revealed multiple innate immune pathway triggers for platelet and leucocyte activation. Plasma contained increased levels of innate immune response cytokines and markers of systemic inflammation, extensive degranulation of neutrophils, and tissue and endothelial damage. Blood analyses showed activation of neutrophils and increased levels of circulating H3Cit, dsDNA, and myeloperoxidase–DNA complex. The thrombus had extensive infiltration of neutrophils, formation of neutrophil extracellular traps (NETs), and IgG deposits.<p> <p>Conclusions - The results show that anti-PF4/polyanion IgG-mediated thrombus formation in VITT patients is accompanied by a massive innate immune activation and particularly the fulminant activation of neutrophils including NETosis. These results provide novel data on the immune response in this rare adenoviral vector-induced VITT.

• Hoel, Hedda Benedicte; Ueland, Thor; Knudsen, Andreas; Kjær, Andreas; Michelsen, Annika & Sagen, Ellen Lund [Show all 12 contributors for this article] (2020). Soluble Markers of Interleukin 1 Activation as Predictors of First-Time Myocardial Infarction in HIV-Infected Individuals. Journal of Infectious Diseases. ISSN 0022-1899. 221(4), p. 506–509. doi: 10.1093/infdis/jiz253. Full text in Research Archive
• Hoel, Hedda Benedicte; Ueland, Thor; Hove-Skovsgaard, Malene; Hartling, Hans Jakob; Gelpi, Marco & Benfield, Thomas [Show all 11 contributors for this article] (2020). Soluble T-Cell Immunoglobulin Mucin Domain-3 Is Associated With Hepatitis C Virus Coinfection and Low-Grade Inflammation During Chronic Human Immunodeficiency Virus Infection. Open Forum Infectious Diseases. 29(7). doi: 10.1093/ofid/ofaa033. Full text in Research Archive Show summary

  Abstract Background In well treated human immunodeficiency virus infection (HIV), there is a residual immune activation and immune exhaustion that may contribute to increased risk of comorbidities. T-cell immunoglobulin mucin domain-3 (Tim-3) is an inhibitory molecule involved in HIV-associated T-cell dysfunction. The Tim-3 can be cleaved to soluble Tim-3 (sTim-3) that may serve as a soluble marker of immune exhaustion. Methods We measured sTim-3 with enzyme-linked immunosorbent assay DuoSets in a cross-sectional cohort of 1010 people with HIV (PWH) on antiretroviral therapy (ART), and 76 controls from the Copenhagen Co-Morbidity in HIV Infection (COCOMO) study, and in a longitudinal cohort of 60 PWH before and during ART. Results In the cross-sectional cohort, levels of sTim-3 were elevated in PWH on ART compared with controls, especially in hepatitis C virus (HCV)-coinfected individuals, and were associated with HCV viremia and inflammation. In the longitudinal cohort, pretreatment sTim-3 correlated with HIV viral load and decreased after ART initiation. Pretreatment sTim-3 correlated inversely with CD4 counts, but it did not predict immunological response in multivariable analyses. Conclusions Levels of sTim-3 decreased after ART initiation. In a cross-sectional cohort, levels of sTIM-3 were higher in PWH than in controls and were independently associated with HCV coinfection and high-sensitivity C-reactive protein, representing a potential link between immune exhaustion, inflammation, and risk of comorbidities.

• Gelpi, Marco; Vestad, Beate; Hansen, Simen Hyll; Holm, Kristian; Drivsholm, Ninna & Götz, Alexandra [Show all 17 contributors for this article] (2020). Impact of human immunodeficiency virus-related gut microbiota alterations on metabolic comorbid conditions. Clinical Infectious Diseases. ISSN 1058-4838. 71(8), p. e359–e367. doi: 10.1093/cid/ciz1235. Full text in Research Archive Show summary

  Abstract Background We aimed to identify a human immunodeficiency virus (HIV)–related microbiota signature, independent of sexual preferences and demographic confounders, in order to assess a possible impact of the microbiome on metabolic comorbid conditions. Methods Bacterial 16S ribosomal RNA analyses were performed on stool samples from 405 HIV-infected and 111 uninfected participants of the Copenhagen Comorbidity in HIV Infection (COCOMO) study. Individuals were stratified according to sexual behavior (men who have sex with men [MSM] vs non-MSM). Results After excluding MSM-associated microbiota traits and adjusting for confounders, we identified an HIV-related microbiota signature, consisting of lower biodiversity, increased relative abundance of the bacterial clades Gammaproteobacteria and Desulfovibrionaceae and decrease in several Clostridia. This microbiota profile was associated with a 2-fold excess risk of metabolic syndrome, driven by increase in Desulfovibrionaceae and decrease in Clostridia (Butyrivibrio, Coprococcus 2, Lachnospiraceae UCG-001 and CAG-56). This association was accentuated (5-fold excess risk) in individuals with previous severe immunodeficiency, which also modified the association between HIV-related microbiota signature and visceral adipose tissue (VAT) area (P for interaction = .01). Accordingly, HIV-related microbiota was associated with 30-cm2 larger VAT in individuals with history of severe immunodeficiency, but not in those without. Conclusion The HIV-related microbiota was associated with increased risk of metabolic syndrome and VAT accumulation, particularly in individuals with previous severe immunodeficiency, driven by increased Desulfovibrionaceae and lower abundance of several Clostridia. Our findings suggest a potential interplay between HIV-related microbiota, immune dysfunction and metabolic comorbid conditions. Interventions targeting the gut microbiome may be warranted to reduce cardiovascular risk, particularly in individuals with previous immunodeficiency.

• Hoel, Hedda Benedicte; Heggelund, Lars; Reikvam, Dag Henrik; Stiksrud, Birgitte; Ueland, Thor & Michelsen, Annika [Show all 15 contributors for this article] (2020). Elevated markers of gut leakage and inflammasome activation in COVID-19 patients with cardiac involvement. Journal of Internal Medicine. ISSN 0954-6820. 289(4). doi: 10.1111/joim.13178. Full text in Research Archive Show summary

  Background A high proportion of COVID‐19 patients have cardiac involvement, even those without known cardiac disease. Downregulation of angiotensin converting enzyme 2 (ACE2), a receptor for SARS‐CoV‐2 and the renin‐angiotensin system, as well as inflammatory mechanisms have been suggested to play a role. ACE2 is abundant in the gut and associated with gut microbiota composition. We hypothesized that gut leakage of microbial products, and subsequent inflammasome activation could contribute to cardiac involvement in COVID‐19 patients. Methods Plasma levels of a gut leakage marker (LPS‐binding protein, LBP), a marker of enterocyte damage (intestinal fatty acid binding protein, IFABP), a gut homing marker (CCL25, ligand for chemokine receptor CCR9) and markers of inflammasome activation (IL‐1β, IL‐18 and their regulatory proteins) were measured at three time points (day 1, 3–5 and 7–10) in 39 hospitalized COVID‐19 patients and related to cardiac involvement. Results Compared to controls, COVID‐19 patients had elevated plasma levels of LBP and CCL25 but not IFABP, suggesting impaired gut barrier function and accentuated gut homing of T cells without excessive enterocyte damage. Levels of LBP were twice as high at baseline in patients with elevated cardiac markers compared with those without and remained elevated during hospitalization. Also, markers of inflammasome activation were moderately elevated in patients with cardiac involvement. LBP was associated with higher NT‐pro‐BNP levels, whereas IL‐18, IL‐18BP and IL‐1Ra were associated with higher troponin levels. Conclusion Patients with cardiac involvement had elevated markers of gut leakage and inflammasome activation, suggestive of a potential gut‐heart axis in COVID‐19.

• Arain, Fizza Kanwal; Abraityte, Judita Aurelija; Bogdanova, Mariia; Solberg, Ole Geir; Michelsen, Annika & Lekva, Tove [Show all 19 contributors for this article] (2020). YKL-40 (Chitinase-3-Like Protein 1) Serum Levels in Aortic Stenosis. Circulation: Heart Failure. ISSN 1941-3289. 13(10), p. e006643–e006643. doi: 10.1161/CIRCHEARTFAILURE.119.006643. Full text in Research Archive Show summary

  BACKGROUND: Identification of novel biomarkers could provide prognostic information and improve risk stratification in patients with aortic stenosis (AS). YKL-40 (chitinase-3-like protein 1), a protein involved in atherogenesis, is upregulated in human calcific aortic valves. We hypothesized that circulating YKL-40 would be elevated and associated with the degree of AS severity and outcome in patients with symptomatic AS. METHODS: Plasma YKL-40 was analyzed in 2 AS populations, one severe AS (n=572) with outcome measures and one with mixed severity (n=67). YKL-40 expression in calcified valves and in an experimental pressure overload model was assessed. RESULTS: We found (1) patients with AS had upregulated circulating YKL-40 compared with healthy controls (median 109 versus 34 ng/mL, P<0.001), but levels were not related to the degree of AS severity. (2) High YKL-40 levels (quartile 4) were associated with long-term (median follow-up 4.7 years) all-cause mortality (adjusted hazard ratio, 1.93 [95% CI, 1.37–2.73], P<0.001). (3) YKL-40 protein expression in human calcific valves co-localized with its putative receptor IL-13rα2 in close proximity to valve interstitial cells. (4) Myocardial YKL-40 increased in experimental pressure overload (6-fold in decompensated versus sham mice). CONCLUSIONS: YKL-40 levels were elevated in AS and associated with mortality but not with other metrics of disease severity including the degree of AS severity. Despite scientific rationale for its role in AS, the clinical utility of circulating YKL-40 as a biomarker is limited.

• Ueland, Thor; Heggelund, Lars; Lind, Andreas; Holten, Aleksander Rygh; Tonby, Kristian & Michelsen, Annika [Show all 26 contributors for this article] (2020). Elevated plasma sTIM-3 levels in patients with severe COVID-19. Journal of Allergy and Clinical Immunology. ISSN 0091-6749. 147(1), p. 92–98. doi: 10.1016/j.jaci.2020.09.007. Full text in Research Archive Show summary

  Background The pathogenesis of coronavirus disease 2019 (COVID-19) is still incompletely understood, but it seems to involve immune activation and immune dysregulation. Objective We examined the parameters of activation of different leukocyte subsets in COVID-19–infected patients in relation to disease severity. Methods We analyzed plasma levels of myeloperoxidase (a marker of neutrophil activation), soluble (s) CD25 (sCD25) and soluble T-cell immunoglobulin mucin domain-3 (sTIM-3) (markers of T-cell activation and exhaustion), and sCD14 and sCD163 (markers of monocyte/macrophage activation) in 39 COVID-19–infected patients at hospital admission and 2 additional times during the first 10 days in relation to their need for intensive care unit (ICU) treatment. Results Our major findings were as follows: (1) severe clinical outcome (ICU treatment) was associated with high plasma levels of sTIM-3 and myeloperoxidase, suggesting activated and potentially exhausted T cells and activated neutrophils, respectively; (2) in contrast, sCD14 and sCD163 showed no association with need for ICU treatment; and (3) levels of sCD25, sTIM-3, and myeloperoxidase were inversely correlated with degree of respiratory failure, as assessed by the ratio of Pao2 to fraction of inspired oxygen, and were positively correlated with the cardiac marker N-terminal pro-B–type natriuretic peptide. Conclusion Our findings suggest that neutrophil activation and, in particular, activated T cells may play an important role in the pathogenesis of COVID-19 infection, suggesting that T-cell–targeted treatment options and downregulation of neutrophil activation could be of importance in this disorder.

• Pihlstrøm, Hege; Ueland, Thor; Michelsen, Annika; Aukrust, Pål; Gatti, Francesca & Hammarström, Clara Louise [Show all 15 contributors for this article] (2020). Exploring the potential effect of paricalcitol on markers of inflammation in de novo renal transplant recipients. PLOS ONE. 15:e0243759(12), p. 1–14. doi: 10.1371/journal.pone.0243759. Full text in Research Archive Show summary

  Following a successful renal transplantation circulating markers of inflammation may remain elevated, and systemic inflammation is associated with worse clinical outcome in renal transplant recipients (RTRs). Vitamin D-receptor (VDR) activation is postulated to modulate inflammation and endothelial function. We aimed to explore if a synthetic vitamin D, paricalcitol, could influence systemic inflammation and immune activation in RTRs. Newly transplanted RTRs were included in an open-label randomized controlled trial on the effect of paricalcitol on top of standard care over the first post-transplant year. Fourteen pre-defined circulating biomarkers reflecting leukocyte activation, endothelial activation, fibrosis and general inflammatory burden were analyzed in 74 RTRs at 8 weeks (baseline) and 1 year post-engraftment. Mean changes in plasma biomarker concentrations were compared by t-test. The expression of genes coding for the same biomarkers were investigated in 1-year surveillance graft biopsies (n = 60). In patients treated with paricalcitol circulating osteoprotegerin levels increased by 0.19 ng/ml, compared with a 0.05 ng/ml increase in controls (p = 0.030). In graft tissue, a 21% higher median gene expression level of TNFRSF11B coding for osteoprotegerin was found in paricalcitol-treated patients compared with controls (p = 0.026). Paricalcitol treatment did not significantly affect the blood- or tissue levels of any other investigated inflammatory marker. In RTRs, paricalcitol treatment might increase both circulating and tissue levels of osteoprotegerin, a modulator of calcification, but potential anti-inflammatory treatment effects in RTRs are likely very modest.

• Otterdal, Kari; Berg, Åse; Michelsen, Annika; Patel, Sam; Gregersen, Ida & Sagen, Ellen Lund [Show all 11 contributors for this article] (2020). Plasma levels of interleukin 27 in falciparum malaria is increased independently of co-infection with HIV: Potential immune-regulatory role during malaria. BMC Infectious Diseases. 20(65), p. 1–11. doi: 10.1186/s12879-020-4783-8. Full text in Research Archive Show summary

  Background The immune response during falciparum malaria mediates both harmful and protective effects on the host; however the participating molecules have not been fully defined. Interleukin (IL)-27 is a pleiotropic cytokine exerting both inflammatory and anti-inflammatory effects, but data on IL-27 in malaria patients are scarce. Methods Clinical data and blood samples were collected from adults in Mozambique with P. falciparum infection, with (n = 70) and without (n = 61) HIV-1 co-infection, from HIV-infected patients with similar symptoms without malaria (n = 58) and from healthy controls (n = 52). In vitro studies were performed in endothelial cells and PBMC using hemozoin crystals. Samples were analyzed using enzyme immunoassays and quantitative PCR. Results (i) IL-27 was markedly up-regulated in malaria patients compared with controls and HIV-infected patients without malaria, showing no relation to HIV co-infection. (ii) IL-27 was correlated with P. falciparum parasitemia and von Willebrand factor as a marker of endothelial activation, but not with disease severity. (iii) In vitro, IL-27 modulated the hemozoin-mediated cytokine response in endothelial cells and PBMC with enhancing effects on IL-6 and attenuating effects on IL-8. Conclusion Our findings show that IL-27 is regulated during falciparum malaria, mediating both inflammatory and anti-inflammatory effects, potentially playing an immune-regulatory role during falciparum malaria.

• Gregersen, Ida; Michelsen, Annika; Lunde, Ngoc Nguyen; Åkerblom, Axel; Lakic, Tatevik G. & Skjelland, Mona [Show all 20 contributors for this article] (2020). Legumain in Acute Coronary Syndromes: A Substudy of the PLATO (Platelet Inhibition and Patient Outcomes) Trial. Journal of the American Heart Association (JAHA). e016360. doi: 10.1161/JAHA.120.016360. Full text in Research Archive Show summary

  <i>Background</i> - The cysteine protease legumain is increased in patients with atherosclerosis, but its causal role in atherogenesis and cardiovascular disease is still unclear. The aim of the study was to investigate the association of legumain with clinical outcome in a large cohort of patients with acute coronary syndrome.<p><p> <i>Methods and Results</i> - Serum levels of legumain were analyzed in 4883 patients with acute coronary syndrome from a substudy of the PLATO (Platelet Inhibition and Patient Outcomes) trial. Levels were analyzed at admission and after 1 month follow‐up. Associations between legumain and a composite of cardiovascular death, spontaneous myocardial infarction or stroke, and its individual components were assessed by multivariable Cox regression analyses. At baseline, a 50% increase in legumain level was associated with a hazard ratio (HR) of 1.13 (95% CI, 1.04–1.21), <i>P</i>=0.0018, for the primary composite end point, adjusted for randomized treatment. The association remained significant after adjustment for important clinical and demographic variables (HR, 1.10; 95% CI, 1.02–1.19; <i>P</i>=0.013) but not in the fully adjusted model. Legumain levels at 1 month were not associated with the composite end point but were negatively associated with stroke (HR, 0.62; 95% CI, 0.44–0.88; <i>P</i>=0.0069), including in the fully adjusted model (HR, 0.57; 95% CI, 0.37–0.88; <i>P</i>=0.0114).<p><p> <i>Conclusions</i> - Baseline legumain was associated with the primary outcome in patients with acute coronary syndrome, but not in the fully adjusted model. The association between high levels of legumain at 1 month and decreased occurrence of stroke could be of interest from a mechanistic point of view, illustrating the potential dual role of legumain during atherogenesis and acute coronary syndrome.

• Ueland, Thor; Åkerblom, Axel; Ghukasyan, Tatevik; Michelsen, Annika; Becker, Richard C. & Bertilsson, Maria [Show all 13 contributors for this article] (2019). Admission levels of DKK1 (Dickkopf-1) are associated with future cardiovascular death in patients with acute coronary syndromes. Arteriosclerosis, Thrombosis and Vascular Biology. ISSN 1079-5642. 39(2), p. 294–302. doi: 10.1161/ATVBAHA.118.311042. Full text in Research Archive

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• Nilsen, Dennis WT; Fuente, Ricardo Leon de la; Gallo, P.; Næsgaard, Patrycja; Ashur, S. Dib & Michelsen, Annika Elisabet [Show all 9 contributors for this article] (2025). Reply to: Letter to the editor: High admission levels of interleukin-1 receptor antagonist in acute myocardial infarction patients. International Journal of Cardiology. ISSN 0167-5273. 441, p. 133807–133807. doi: 10.1016/j.ijcard.2025.133807. Full text in Research Archive
• Nilsen, Dennis WT; Fuente, Ricardo Leon de la; Gallo, P.; Næsgaard, Patrycja; Ashur, S. Dib & Michelsen, Annika Elisabet [Show all 9 contributors for this article] (2025). Reply to: Could interleukin-1 receptor antagonist be a reliable predictor of prognosis in acute myocardial infarction? International Journal of Cardiology. ISSN 0167-5273. 441, p. 133812–133812. doi: 10.1016/j.ijcard.2025.133812. Full text in Research Archive
• Nilsen, Dennis WT; Fuente, Ricardo Leon de la; Gallo, Patricio; Næsgaard, Patrycja; Ashur, Silvia Dib & Michelsen, Annika Elisabet [Show all 9 contributors for this article] (2025). Reply to: Letter regarding the study by Nilsen et al. on IL-1RA and 5-Year Mortality Risk: Redefining the Threshold for high admission levels of IL-1RA - PubMed. International Journal of Cardiology. ISSN 0167-5273. doi: 10.1016/j.ijcard.2025.133806. Full text in Research Archive Show summary

  Reply to: Letter regarding the study by Nilsen et al. on IL-1RA and 5-Year Mortality Risk: Redefining the Threshold for high admission levels of IL-1RA

• Nilsen, Dennis WT; Fuente, Ricardo Leon de la; Næsgaard, Patrycja; Michelsen, Annika Elisabet; Aukrust, Pål & Staines, Harry [Show all 7 contributors for this article] (2025). ESC 365 - High admission levels of Interleukin-1 receptor antagonist (IL-1RA) in acute MI patients are associated with increased rates of all-cause mortality and cardiac death at 5 years follow-up. escardio.org. doi: https:/esc365.escardio.org/presentation/309255. Full text in Research Archive Show summary

  Access this presentation on ESC 365 from ESC Congress 2025 on Biomarkers by Doctor R. LEON DE LA FUENTE (Argentina,AR) on ESC 365.

• Nilsen, Dennis WT; Næsgaard, Patrycja; Pønitz, Volker; Andersen, Trygve Brugger; Grundt, Magnea Heidi Jonsdottir & Fuente, Ricardo Leon de la [Show all 10 contributors for this article] (2025). ESC 365 - C-X-C motif chemokine ligand 5 (CXCL5) is associated with risk of all-cause mortality in a U-shaped manner in patients admitted with chest pain of suspected coronary origin. escardio.org. doi: https:/esc365.escardio.org/presentation/309254. Full text in Research Archive Show summary

  Access this presentation on ESC 365 from ESC Congress 2025 on Biomarkers by Doctor P. Naesgaard (Norway,NO) on ESC 365.

• Holm, Sverre; Michelsen, Annika Elisabet; Schultz, Nina Haagenrud; Ueland, Thor; Reikvam, Håkon & Holme, Pål Andre [Show all 8 contributors for this article] (2024). Human papilloma virus vaccine induced thrombocytopenia accompanied by a wide spectrum of reversible inflammatory responses – a case report. Scandinavian Journal of Clinical and Laboratory Investigation. ISSN 0036-5513. 84(6). doi: 10.1080/00365513.2024.2400663. Full text in Research Archive
• Jørgensen, Silje Fjellgård; Macpherson, Magnhild Eide; Bjørnetrø, Tonje; Holm, Kristian; Kummen, Martin & Rashidi, Azita [Show all 18 contributors for this article] (2024). Retraction to: Rifaximin alters gut microbiota profile, but does not affect systemic inflammation - a randomized controlled trial in common variable immunodeficiency (Scientific Reports, (2019), 9, 1, (167), 10.1038/s41598-018-35367-7). Scientific Reports. 14(1). doi: 10.1038/s41598-024-54117-6. Full text in Research Archive
• Nilsen, Dennis WT; Andersen, Trygve Brugger; Aarsetøy, Reidun; Ueland, Thor; Michelsen, Annika Elisabet & Aukrust, Pål [Show all 9 contributors for this article] (2024). Circulation 2024; 150(Suppl. 1):Abstract 4137965. Volume 150, Number Suppl_1D-dimer as a 5-year predictor of death in females admitted with chestpain of suspected coronary origin surpasses that of males. Full text in Research Archive Show summary

  Background: D-dimer (DD) and fibrin monomer (FM) are endstage markers of activated coagulation and reflect prothrombotic states, and α2-antiplasmin (SERPINF2 -SF2) is the main inhibitor of fibrinolysis at the level of plasmin. Women may experience a higher rate of morbidity and mortality compared to men following a myocardial infarction (MI). We present the prognostic potential of DD, FM and SF2 in females as compared to males during 5 years follow-up in a population admitted with chest pain of suspected coronary origin. Methods: A total of 871 consecutive patients with a median age of 72.6 years (females 77.3, males 69.1) were admitted in the study. Of these, 386 were diagnosed with an acute MI based on Troponin-T (TnT) levels >50 ng/L. Stepwise Cox regression models, applying normalized continuous loge/SD values, were fitted for the biomarkers with total mortality within 5 years as the dependent variable. Results: Death was recorded in 246 patients; 34.4% females vs. 27.2% males (Chi-squared test p-value = 0.02). Blood samples were available for analysis of DD, FM and SF2 in 820, 810 and 846 patients, respectively. Females had a significantly higher mean of DD (p<0.0001) and FM (p=0.0020) than males and SF2 did not differ (p=0.0825). In the univariate analysis, a highly significant association between DD and total death was observed in both sexes (p<0.001). However, after adjusting for confounders in the multivariable analysis, the associations remained significant in females but not in males, with an HR of 1.62 (95%CI 1.36 – 1.93), p<0.0001 vs. 1.16 (95%CI 0.98 - 1.39, p=0.094, respectively, (p for interaction <0.001). Similar findings were noted in the multivariable analysis of FM with HR 1.46 (95%CI 1.19 – 1.80), p=0.0003 in females vs. 1.12 (95%CI 0.93 -1.35), p=0.22 in males (p for interaction 0.056). In the univariate analysis, SF2 was not associated with all-cause mortality; p=0.56 in females vs. p=0.83 in males, and remained essentially unchanged after adjustment; p=0.84 vs. HR 0.92 (95%CI 0.78 – 1.09). p=0.35 in males, yielding a p=0.36 for interaction. Conclusion: Activated endstage coagulation was associated with total death at 5 years FU in females admitted with chest pain of suspected coronary origin, whereas plasmin inhibition was not. A significant p-value for interaction between the two sexes indicates that the prognostic value of DD surpasses that of men.

• Nilsen, Dennis WT; Aarsetøy, Reidun; Pønitz, Volker; Ueland, Thor; Michelsen, Annika Elisabet & Aukrust, Pål [Show all 9 contributors for this article] (2024). Circulation 2024; 150 (Suppl. 1): Abstract 4141048. Inflammatory biomarkers predict long-term all-cause mortality in males but not in females. Full text in Research Archive Show summary

  Background: α1-antichymotrypsin (SERPINA3), high sensitivity C-reactive proten (hsCRP) and Pentraxin 3 (PTX3) are acute phase proteins triggered by inflammation. Hepatocytes are a primary source of SERPINA3 and CRP, while PTX3 is produced by a variety of tissues including endothelial cells. These inflammatory markers are upregulated after an acute myocardial infarction (AMI). Comparisons of their long-term prognostic value in acute coronary syndrome (ACS) patients by gender are scarce. We aimed to assess their long-term prognostic utility in females and males, respectively, hospitalized for chest pain of suspected coronary origin. Methods: A total of 871 consecutive patients (39.0% females) with a median age of 72.6 years (females 77.3, males 69.1) were admitted in the study. Of these, 386 were diagnosed with an acute MI based on Troponin-T (TnT) levels >50 ng/L. Stepwise Cox regression models, applying normalized continuous loge/SD values, were fitted for the biomarkers with total mortality within 7 years as the dependent variable. Results: At 7-year follow-up, 332 patients had died; 44.1 % females vs. 34.1 % males (χ2(1) = 9.368; p = 0.0022). Blood samples were available for analysis of SERPINA3, hsCRT and PTX3 in 847, 868 and 795 patients, respectively. There was no significant differences between the means of the sexes for SERPINA3 (p = 0.20), hsCRT (p = 0.84) and PTX3 (p = 0.068), respectively. None of the biomarkers predicted long-term outcome in females after multivariable adjustment (p=0.92, p=0.40 and p=0.57, respectively), but were good predictors in males [SERPINA3: HR 1.34 (95%CI 1.16-1.56), p=0.00001. hsCRP: HR 1.19 (95%CI 1.02-1.38), p=0.027. PTX3: HR 1.22 (95%CI 1.04-1.44), p=0.018]. Furthermore, the p-values for interaction would suggest a gender difference in the prognostic weighting, favoring SERPINA3 (p=0.015) and to a lesser degree hsCRP (p=0.074) and PTX3 (p=0.14). Conclusion: SERPINA3, hsCRT and PTX3 are good predictors of long-term all-cause mortality in males admitted with chest pain of suspected coronary origin, but were not shown to predict outcome among females of that population. The prognostic utility of the studied inflammatory biomarkers may essentially be related to males.

• Ueland, Thor; Äikäs, Lauri A.O.; Dahl, Tuva Børresdatter; Gregersen, Ida; Olsen, Maria Belland & Michelsen, Annika Elisabet [Show all 20 contributors for this article] (2023). Low-density lipoprotein particles carrying proinflammatory proteins with altered aggregation pattern detected in COVID-19 patients 3 months after hospitalization. Journal of Infection. ISSN 0163-4453. 86(5), p. 489–492. doi: 10.1016/j.jinf.2023.02.024. Full text in Research Archive
• Nilsen, Dennis WT; Pønitz, Volker; Aarsetøy, Reidun; Ueland, Thor; Aukrust, Pål & Michelsen, Annika Elisabet [Show all 9 contributors for this article] (2023). Circulation 2023; 148: Suppl_17 (Nov.). Abstract 14288. α1-Antichymotrypsin Complex (SERPINA3) is an Independent Predictor of Long-Term All-Cause Mortality, but Did Not Predict CVD Events. Full text in Research Archive Show summary

  Circulation 2023:148, Suppl_17: SERPINA3 is an acute phase protein triggered by inflammation. It inhibits neutrophil cathepsin which cleaves protease-activated receptor 4 (PAR-4) via a thrombin-independent pathway, and mast cell chymase which mediates the production of angiotensin-II via an ACE-independent pathway. SERPINA3 is upregulated after an acute myocardial infarction (MI), but data on its long-term prognostic value in MI patients are scarce.Aim: To assess the utility of SERPINA3 as a prognostic marker in patients hospitalized for chest pain of suspected coronary origin.Methods: A total of 871 consecutive patients were included (ClinicalTrials.gov Identifier: NCT00521976). Stepwise Cox regression models, applying continuous loge-transformed values, were fitted for each of the biomarkers with all-cause mortality and cardiac death within median 24-months (mo) and all-cause mortality within median 7 years (y) as the dependent variables, adding an analysis of 1) all-cause mortality or MI, and 2) all-cause mortality or MI or stroke at 7 y follow up (FU). The hazard ratio (HR) (95% CI) was assessed in a univariate and multivariable model, adjusting for traditional clinical cardiovascular risk factors, adding BNP, hsCRP, TnT.Results: Plasma samples from 847 patients were available. At 24 mo FU, 138 (15.8%) patients had died, of which 86 were cardiac deaths. The univariate analysis showed a positive, significant association between SERPINA3 and total death [HR 1.42 (95% 1.19-1.68), p =0.000], but was not significant for cardiac death. Associations after multivariable adjustment were statistically non-significant. At 7 y FU, 332 (38.1%) patients had died. After adjustment, SERPINA3 was independently associated with all-cause mortality [HR 1.14 (95% CI, 1.02-1.28), p=0.022], but not for MI (n=203), and stroke (n=55), respectively, and remained essentially unaffected for all-cause mortality or MI combined (n=404) [HR 1.12 (95% CI, 1.01-1.24), p=0.031], slightly weakened when stroke also was added (n=422) [HR 1.10 (95% CI, 1.00-1.22), p=0.060].Conclusions: SERPINA3 predicts long-term all-cause mortality, but had no prognostic bearing on short-term cardiac death. Introducing non-fatal CVD events during long-term FU did not improve its prognostic value.

• Nilsen, Dennis WT; Aarsetøy, Reidun; Ueland, Thor; Aukrust, Pål; Michelsen, Annika Elisabet & Pønitz, Volker [Show all 9 contributors for this article] (2023). Circulation 2023;148:A14503: Chemokine Ligand 18 (CCL18) is a Long-Term Predictor of All-Cause Mortality, but Did Not Predict CVD Events. Full text in Research Archive Show summary

  Circulation 2023 (Nov.): 148 (Suppl. 1), Abstract 14503. . Chemokines mediate leukocyte recruitment and activation. Chemokine ligand 18 (CCL18) is mainly expressed by a broad range of cells such as monocytes/macrophages and dendritic cells. It is highly expressed in chronic inflammatory diseases, and locally in atherosclerotic plaques, particularly at sites of reduced stability. Circulating CCL18 levels are transiently elevated in patients admitted with unstable angina pectoris, but data on myocardial infarction (MI) are scarce. Aim: To assess the utility of CCL18 as a prognostic marker of CVD in patients hospitalized for chest pain of suspected coronary origin. Methods: The population consisted of 871 consecutive patients (ClinicalTrials.gov Identifier: NCT00521976). Stepwise Cox regression models, applying continuous loge-transformed values, were fitted for each of the biomarkers with all-cause mortality and cardiac death within 24-months and all-cause mortality within median 7 years (y) as the dependent variables, adding an analysis of 1) all-cause mortality or MI, and 2) all-cause mortality or MI or stroke at 7 y follow up (FU). The hazard ratio (HR) (95% CI) was assessed in a univariate and multivariable model, adjusting for traditional clinical cardiovascular risk factors, adding BNP, hsCRP, and TnT. Results: Plasma samples from 849 patients were available. By 24 months FU, 138 (15.8%) patients had died; 86 were cardiac deaths. The univariate analysis showed a positive, significant association between CCL18 and total death [HR 1.55 (95% 1.30-1.83), p=0.000], and for cardiac death [HR 1.32 (95% 1.06-1.64), p=0.013]. Applying multivariable analysis, the associations were no longer significant. At 7 y FU, a total of 332 (38.1%) patients had died. After multivariable adjustment, CLL18 was independently associated with all-cause mortality [HR 1.14 (95% CI, 1.01-1.29), p=0.030], but not for MI (n=203) or stroke (n=55). The positive association between CCL18 and all-cause mortality was lost when combined with CVD events; all-cause mortality or MI (n=404, p=0.75), and all-cause mortality or MI or stroke (n=422, p=0.79). Conclusions: CCL18 predicts long-term all-cause mortality, but had no independent prognostic bearing on short-term cardiac death and CVD events during long-term FU.

• Gregersen, Ida; Ueland, Thor; Holter, Jan Cato; Olsen, Maria Belland; Michelsen, Annika Elisabet & Murphy, Sarah L [Show all 22 contributors for this article] (2022). CXCL16 associates with adverse outcome and cardiac involvement in hospitalized patients with Covid-19. Journal of Infection. ISSN 0163-4453. 85(6), p. 735–738. doi: 10.1016/j.jinf.2022.09.029. Full text in Research Archive
• Nilsen, Dennis W.T.; Røysland, Michelle; Ueland, Thor; Aukrust, Pål; Michelsen, Annika Elisabet & Staines, Harry [Show all 10 contributors for this article] (2022). Circulation 2022;146:A10315.The Effect of Protease-Activated Receptor-1 Inhibition With Vorapaxar in Post-mi and Nstemi Patients on Selected Biomarkers Reflecting Endothelial Function. Full text in Research Archive Show summary

  Circulation 2022;146:A10315 Introduction: Biomarker research related to protease-activated receptor-1 (PAR-1) inhibition with vorapaxar in humans has essentially focused on platelets. Follow-up (FU) time has been short, whereas in the current study, focus has been on endothelial function during both short- and long-term PAR-1 inhibition. Aim: To assess short- and long-term effects of vorapaxar (V) as compared to Placebo (PL) on the following biomarkers: Angiopoietin-2 (ANGPT2), Angiopoietin-like 4 (ANGPTL4), VEGF, ICAM-1, VCAM-1, E-Selectin (ESEL), von Willebrand Factor (VWF), Thrombomodulin (TM), PAI-1 and PAI-2. Methods: In an independent collective subproject performed in Norway, post-MI patients at steady state were recruited from the “Trial to Assess the Effects of Vorapaxar in Preventing Heart Attack and Stroke in Patients with Atherosclerosis” (TRA2ᵒP-TIMI 50) and NSTEMI patients were recruited from the “Thrombin Receptor Antagonist for Clinical Event Reduction in acute coronary syndrome” (TRACER) trial. Biomarkers were measured in duplicate by enzyme immunoassays (EIA) in citrated plasma at one month follow-up and at study completion (median 2.3 years) for subjects recruited from both trials. Results: Biomarkers were measured in 265 consecutive patients [age median 62.0 years (Q1-Q3: 55.0-68.0 years), males 83%] with at least one change from baseline value. Among these, biomarkers were available at both short- and long-term follow-up in 221 subjects. ANGPT2 increased significantly in V as compared to PL at 1-month follow-up in the total population (p=0.034), and in males in both post-MI (p=0.031) and NSTEMI subjects (p=0.012), respectively. ANGPTL4 increased (p=0.028) and PAI-2 decreased (p=0.025) significantly in the total population in favor of V at final FU. In the total post-MI subgroup and among males of that group, a short-term significant increase in ESEL in favor of V was observed, p=0.029 and p=0.018, respectively. Also, a transient significant increase in VWF (p=0.032) in favor of V was seen at one month in NSTEMI patients. Conclusions: Significant changes suggesting potential harmful effects in some biomarkers were observed during 1-month and long-term PAR-1 inhibition as compared to placebo in post-MI and acute coronary syndrome patients.

• Aarsetøy, Reidun; Ueland, Thor; Aukrust, Pål; Michelsen, Annika; Pønitz, Volker & Andersen, Trygve Brugger [Show all 8 contributors for this article] (2020). Angiopoietin-2 is a long-term predictor of all-cause mortality, cardiac death and sudden cardiac death in chest-pain patients with suspected acute coronary syndrome. Full text in Research Archive Show summary

  Background: Angiopoietin-2 (ANGPT2) is an important regulator of angiogenesis. Higher levels of ANGPT2 have been found to be associated with an adverse cardiovascular risk factor profile potentially reflecting maladaptive vascular remodelling including atherosclerotic plaque destabilization. Purpose: To evaluate the prognostic utility of ANGPT2 added to conventional clinical risk factors for coronary heart disease, including B-type natriuretic peptide (BNP), troponin T (TnT) and C-reactive protein (CRP), in patients with suspected acute coronary syndrome (ACS). Methods: 871 chest-pain patients with clinically suspected ACS from South-Western Norway and 982 patients from Northern Argentina were consecutively included in a prospective transatlantic cohort study. We measured plasma-concentrations of ANGPT2 in admission-samples from 1815 patients by enzyme immunoassay. Univariable- and multivariable Cox proportional-hazards models, applying both loge-transformed continuous values and quartiles (Q1-4), were fitted for the analysis of all-cause mortality, cardiac death and sudden cardiac death (SCD) within 24-month follow-up. Of the patients with suspected ACS, 838 patients had TnT release above the detection-limit of 0.01 ng/mL. We performed subgroup analysis for all-cause mortality in patients with and without TnT release. Results: Median age in the total population was 66.0 (Q1-Q3; 55.0 – 76.8) years and 60.4% were males. At 24-month follow-up, 254 patients (14%) had died, of which 150 (8.3%) suffered cardiac death and 76 (4.2%) SCD. ANGPT2 levels were significantly higher in patients who died compared to long-term survivors [3.87 (2.40 – 7.54) ng/mL versus 2.11 (1.48 – 3.22) ng/mL (median, 25 and 75% percentiles), p < 0.001]. In multivariable analysis, ANGPT2 concentrations in the highest quartile (Q4) as compared to the lowest (Q1) were significantly associated with all-cause mortality [Hazard Ratio (HR) 1.96 (95% confidence interval (CI); 1.12 – 3.42), p = 0.018) and cardiac death [HR 2.23 (95% CI; 1.01 – 4.92), p = 0.047] at 24-month follow-up. For SCD, ANGPT2 concentrations in both Q3 [HR 3.59 (95% CI; 1.05 -12.3), p = 0.041] and Q4 [HR 3.81 (95% CI; 1.12 – 12.9), p = 0.032] as compared to Q1 were significantly related to outcome. These results were confirmed using loge-transformed continuous values of ANGPT2. ANGPT2 was also an independent predictor of all-cause mortality in both patients with and without TnT release. For patients with TnT > 0.01 ng/mL, HR for ANGPT2 in Q4 as compared to Q1 was 2.77 (95% CI; 1.41 – 5.44), p = 0.003. For patients with TnT ≤ 0.01, HR for ANGPT2-Q4 was 2.67 (95% CI; 1.08 – 6.62), p = 0.034. Conclusion: High levels of ANGPT2 were found to independently predict all-cause mortality, cardiac death and sudden cardiac death in chest-pain patients with suspected ACS, irrespective of clinical demographics, troponin-release, CRP and BNP.

• Aarsetøy, Reidun; Ueland, Thor; Aukrust, Pål; Michelsen, Annika; Pønitz, Volker & Andersen, Trygve Brugger [Show all 9 contributors for this article] (2020). Complement component-7 is a long-term predictor of all-cause mortality in chest-pain patients with suspected acute coronary syndrome. ESC 365 Library. Full text in Research Archive Show summary

  Introduction: The complement cascade is an important component of the innate immune system. Complement activation plays a major role in chronic inflammation and has been associated with atherosclerosis, atherosclerotic plaque destabilization and increased risk of cardiovascular events. Complement component 7 (C7) binds C5bC6 complex being part of the terminal complement complex (TCC/C5b-9). Purpose: To investigate the prognostic utility of complement C7 for long-term outcome in patients with suspected acute coronary syndrome (ACS). Methods: Complement C7 plasma-levels were measured by enzyme immunoassay in admission samples from 1823 patients included in a transatlantic prospective cohort study, which consecutively included hospital admitted chest-pain patients with clinically suspected ACS from South-Western Norway and Northern Argentina. Data were pooled for analysis. Univariable- and multivariable Cox proportional-hazards models were fitted for the analysis of all-cause mortality, cardiac death and sudden cardiac death (SCD) within 24 months, applying both quartiles (Q1-4) and loge-transformed continuous values of complement C7. Results: There were 253 (13.9%) deaths, of which 150 (8.2%) were categorized as cardiac death and 76 (4.2%) as SCD. Complement C7 levels were significantly higher in patients who died as compared to long-term survivors [176.9 (142.1 – 228.7) µg/mL versus 139.8 (110.6 – 179.7) µg/mL (median, 25 and 75% percentile), p < 0.001], and were significantly associated with 24-month survival [log rank p < 0.001 for all-cause mortality and cardiac death, log rank p = 0.035 for SCD]. In univariable analysis, patients with complement C7-concentrations in the highest quartiles had significantly increased risk of all-cause mortality (Figure 1), cardiac death [Q4: Hazard Ratio (HR) 4.58 (95% confidence interval (CI); 2.65 – 7.92), p < 0.001, Q3: HR 2.69 (95% CI; 1.51 – 4.80), p = 0.001] and SCD [Q4: HR 2.83 (95% CI; 1.36 – 5.90), p = 0.005, Q3: HR 2.33 (95% CI; 1.10 – 4.92), p = 0.027] compared to patients in the lowest quartile (Q1). After adjusting for conventional clinical risk factors for coronary heart disease, complement C7-concentrations in Q4 [HR 2.09 (95% CI; 1.23 – 3.57), p = 0.007] and Q3 [HR 2.21 (95% CI; 1.29 – 3.81), p = 0.004] remained significantly associated with all-cause mortality, reproduced using loge-transformed continuous values. Conclusion: High levels of complement C7 were found to independently predict long-term all-cause mortality in chest-pain patients with clinically suspected ACS.

• Aarsetøy, Reidun; Ueland, Thor; Aukrust, Pål; Michelsen, Annika; Pønitz, Volker & Andersen, Trygve Brugger [Show all 10 contributors for this article] (2020). Angiopoietin-like 4 protein is a long-term predictor of outcome in chest-pain patients with suspected acute coronary syndrome. ESC 365 Library. Full text in Research Archive Show summary

  Introduction: Angiopoietin-like 4 protein (ANGPTL4) has multiple physiological functions including modulation of angiogenesis, vascular permeability and lipid-metabolism. Acting as an inhibitor of lipoprotein lipase, ANGPTL4 has previously been found to be associated with lipid levels and risk of coronary artery disease. Purpose: To assess the prognostic value of ANGPTL4 for long-term outcome, in addition to conventional clinical risk factors, in chest-pain patients admitted with clinically suspected acute coronary syndrome (ACS). Methods: 1853 patients from Norway and Northern-Argentina were consecutively included in this prospective 2-center cohort study. ANGPTL4 concentrations were measured in 1829 admission-samples by enzyme immunoassay. Data were pooled for analysis. Multivariable Cox proportional-hazards models were fitted for the analysis of all-cause mortality, cardiac death and sudden cardiac death (SCD) within 24-months, comparing event rates across ANGPTL4-quartiles (Q1-4). Of patients with suspected ACS, 845 had a troponin T (TnT) value above the detection-limit. Subgroup analysis was performed for all-cause mortality in patients stratified according to TnT release >/≤ 0.01 ng/mL. Results: During 24-months follow-up, 254 patients (13.9%) died, of which 150 (8.2%) suffered cardiac death and 76 (4.2%) SCD. Patients who died had significantly higher admission-levels of ANGPTL4 compared to long-term survivors [4.99 (3.54 – 8.37) ng/mL versus 3.18 (2.14 – 4.78) ng/mL (median, 25 and 75% percentiles), p < 0.001]. A stepwise increase in risk of all-cause death was seen with increasing quartiles of ANGPTL4, Figure 1. For cardiac death, ANGPTL4-levels in Q4 [Hazard Ratio (HR) 2.86 (95% confidence interval (CI); 1.10 – 7.45), p = 0.031] as compared to Q1 were found to be an independent predictor of outcome. Similar results were seen for SCD in adjusted analysis for ANGPTL4-Q4 [HR 7.37 (95% CI; 1.75 – 31.1), p = 0.007] as compared to Q1. In subgroup analysis, ANGPTL4 concentrations in the highest quartile were significantly associated with increased risk of all-cause mortality in patients with TnT-release [HR 2.07 (95% CI, 1.06 – 4.02), p = 0.032], but not in patients without TnT-release. Conclusion: High admission-levels of ANGPTL4 were found to be an independent long-term predictor of all-cause mortality, cardiac death and SCD in patients with suspected ACS.

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