Thor Ueland

• Onsaker, Asbjørn Lund; Vlieg, Astrid van Hylckama; Ueland, Thor; Aukrust, Pål; Brækkan, Sigrid Kufaas & Hansen, John Bjarne [Show all 7 contributors for this article] (2026). Plasma levels of adiponectin and risk of future incident venous thromboembolism. Journal of Thrombosis and Haemostasis. ISSN 1538-7933. 24(10), p. 3702–3710. doi: 10.1016/j.jtha.2026.07.023.
• 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
• Broch, Kaspar; Andreassen, Arne K.; Anstensrud, Anne Kristine; Woxholt, Sindre; Flø, August Magnus Stensrød & Bjørkelund, Elisabeth [Show all 13 contributors for this article] (2026). Lipoprotein(a) in acute myocardial infarction – insights from the randomised ASSAIL-MI trial. Atherosclerosis. ISSN 0021-9150. 422. doi: 10.1016/j.atherosclerosis.2026.121903. 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
• Sundet, Birgitte Kordt; Fiskå, Bendik Seth; Staff, Anne Cathrine; Jacobsen, Daniel Pitz; Bratseth, Vibeke & Palmero, Sheryl [Show all 13 contributors for this article] (2026). Circulating neutrophil extracellular traps and deoxyribonuclease in gestational diabetes mellitus. Journal of Reproductive Immunology. ISSN 0165-0378. 176. doi: 10.1016/j.jri.2026.104928.
• Stø, Kristine; Skagen, Karolina Ryeng; Bjerkeli, Vigdis; Ueland, Per Magne; Hov, Johannes Espolin Roksund & Trøseid, Marius [Show all 10 contributors for this article] (2026). Gut microbiota derived indoles are altered and associate with immune activation in moderate and severe carotid stenosis. Frontiers in Immunology. 17. doi: 10.3389/fimmu.2026.1796312. Full text in Research Archive Show summary

  Background: An imbalance of gut microbiota, their metabolites as well as inflammatory mediators have been increasingly linked to both atherosclerosis and stroke. However, data on microbiota derived tryptophan and histidine metabolites in carotid atherosclerosis are scarce. Purpose: We investigated serum microbiota derived indoles, imidazole propionate (ImP) and trimethylamine N-oxide (TMAO), representing three distinct gut bacterial-related metabolites, in patients with carotid atherosclerosis compared with healthy controls with normal findings on carotid ultrasound. We aimed to examine their relation to plaque characteristics, immune activation markers and traditional cardiovascular risk factors. Methods: Thirty patients scheduled for carotid endarterectomy and 18 control subjects were included in this cross-sectional study. Carotid arteries were investigated with ultrasound. Indoles, ImP and TMAO were analyzed by liquid chromatography-tandem mass spectrometry, and Lipopolysaccharide (LPS) by a Limulus Amebocyte Lysate chromogenic assay. Results: Compared to controls, patients exhibited lower levels of indole-3-propionic acid (IPA) (p=0.004) and indole-3-acetic acid (IAA) (p = 0.030). In patients, higher levels of indole metabolites were associated with lower C-reactive protein. ImP and TMAO did not differ between patients and controls. Conclusion: Patients with carotid atherosclerosis exhibited reduced serum concentrations of IPA and IAA, thought to have anti-inflammatory effects, and increased inflammatory markers, possibly suggesting disruptions in the gut–vascular-immune axis.

• 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
• Godang, Kristin; Wessel, Maren Ileby; Khan, Yusuf; Ueland, Thor; Lekva, Tove & Berg, Jens Petter [Show all 8 contributors for this article] (2026). Targeted proteomics reveals novel biomarkers of disease activity and inflammation in acromegaly. European Journal of Endocrinology (EJE). ISSN 0804-4643. 194(5), p. 732–743. doi: 10.1093/ejendo/lvag083. 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
• Stø, Kristine; Skagen, Karolina Ryeng; Holm, Kristian; Ueland, Thor; Vestad, Beate & Bjerkeli, Vigdis [Show all 10 contributors for this article] (2026). Oral Eikenella as a potential new biomarker of symptomatic carotid atherosclerosis. Journal of Oral Microbiology. 18(1). doi: 10.1080/20002297.2026.2613521. Full text in Research Archive
• Fiskå, Bendik Seth; Turowski, Gitta Erika; Rocha, Maria Linda; Lekva, Tove; Ueland, Thor & Staff, Anne Cathrine [Show all 7 contributors for this article] (2026). Placenta tissue-based and circulating markers of cellular senescence in gestational diabetes mellitus. Placenta. ISSN 0143-4004. 177, p. 8–16. doi: 10.1016/j.placenta.2026.02.015. 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.

• Kildal, Anders Benjamin; Ueland, Thor; Mirlashari, Mohammad Reza; Nissen-Meyer, Lise Sofie; Granerud, Beathe Kiland & Riise, Anne Margarita Dyrhol [Show all 44 contributors for this article] (2026). Serial blood serum measurements of calprotectin and deoxyribonuclease in COVID-19 patients during hospitalization and recovery until one year: a prospective, multicenter, observational study. BMC Infectious Diseases. 26. doi: 10.1186/s12879-026-12939-x. Full text in Research Archive Show summary

  Objectives: To examine circulating calprotectin and deoxyribonuclease (DNase) serum levels during hospitalization in COVID-19 patients, their continuity post-discharge and dynamics in relation to disease severity. Methods: Serum levels were measured in samples collected from 252 COVID-19 patients during hospitalization (admission, days 3–5 and 7–10), at 3 months and after 1 year, and related to admission to intensive care unit (ICU) or high dependency unit (HDU), and 60-day total mortality. Results: During hospitalization, calprotectin and DNase levels were significantly elevated compared to healthy controls (HC). Calprotectin was increased in ICU/HDU patients compared to those at wards during hospitalization and in non-survivors compared to survivors during prolonged hospitalization. High calprotectin levels at admission were associated with male sex, PaO2/FiO2 ratio and national COVID-19 wave 2 and 3 compared to wave 1. High admission levels of both calprotectin and ferritin were associated with an approximately twofold higher odds ratio for ICU/HDU admission than either marker alone. DNase was lower at admission in non-survivors compared to survivors. Post-discharge, DNase but not calprotectin levels remained elevated extending to 1-year follow-up compared to HC. Conclusions: COVID‑19 non‑survivors showed persistently higher calprotectin levels during prolonged hospitalization, and elevated admission calprotectin was associated with later pandemic waves and poorer oxygenation. Incorporating calprotectin with ferritin improved prediction of ICU/HDU admission. DNase levels were lower at admission in non‑survivors, while overall DNase remained elevated from hospitalization through 1‑year follow‑up compared with HC, suggesting a possible role in long‑term COVID‑19–related immune alterations.

• 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.

• Sellevoll, Hilde Bastøe; Andresen, Ina Jungersen; Westerberg, Ane Cecilie; Degnes, Maren-Helene Langeland; Ueland, Thor & Zucknick, Manuela [Show all 7 contributors for this article] (2026). Placental Protein Release and Uptake From the Fetal Circulation in Healthy Term Pregnancies—A Human In Vivo Exploratory Study. The FASEB Journal. ISSN 0892-6638. 40(3). doi: 10.1096/fj.202503626R. Full text in Research Archive
• 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
• Gjerde, Kristian Varden; Bartz-Johannessen, Christoffer; Løberg, Else-Marie; Steen, Vidar Martin; Steen, Nils Eiel & Andreassen, Ole [Show all 13 contributors for this article] (2026). Neural and vascular cellular adhesion molecules are associated with cognitive function in patients with schizophrenia-spectrum disorders: A longitudinal study. Schizophrenia Research. ISSN 0920-9964. 290, p. 34–41. doi: 10.1016/j.schres.2026.01.021. Full text in Research Archive Show summary

  Background Schizophrenia patho-etiology may involve endothelial inflammation and blood-brain barrier (BBB) dysregulation with cellular adhesion molecules (CAMs) as important mediators. CAMs are essential for cellular integrity but can show increased levels in inflammation. Cognitive dysfunction precedes and exists independently of psychotic symptoms in schizophrenia patients. CAMs could impact cognition through influence on BBB integrity. To gain insights into disease mechanisms and potential therapeutic targets, we explored the relationship between CAMs protein levels and neurocognitive tests in schizophrenia-spectrum disorders in the BeSt InTro study. Methods Seventy-one in- and out-patients underwent CAMs measurements and neuropsychological testing on a minimum of one time point: baseline, 6, 26, or 52 weeks. Cognitive domains included working memory, processing speed, verbal abilities, executive functions, and overall cognition. CAMs analyzed were neural CAMs: junctional adhesion molecule (JAM-A) and neural cadherin (N-CAD); vascular CAMs: intercellular adhesion molecule (ICAM)-1, vascular adhesion molecule (VCAM)-1, mucosal addressin cell adhesion molecule (MADCAM), and platelet (P)-selectin from fasting blood samples. Linear mixed effects models, adjusted for age, sex, body mass index, smoking, education, and drug naivety, estimated CAMs effect on cognitive outcome measures. Results N-CAD levels correlated positively with overall cognition (p = 0.002), working memory (p = 0.034), and executive functions (p = 0.0011). ICAM-1 levels correlated positively with overall cognition (p = 0.037). Conversely, JAM-A levels correlated negatively with executive functions (p = 0.021). Conclusion Associations between CAMs (N-CAD, ICAM-1, JAM-A) and neurocognitive tests suggest CAMs may impact cognition in schizophrenia. Contrary to our hypothesis, most associations between CAMs levels and cognitive tests were positive. Future research on mechanisms is mandatory.

• 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.

• Dingen, Håvard; Jordal, Stina; Dalén, Magnus; Bratt, Sorosh; Jakobsen, Øyvind & Svenarud, Peter [Show all 11 contributors for this article] (2025). The Impact of Left Ventricular Structure and Function on Mortality in Patients with Aortic Valve Infective Endocarditis Treated with Aortic Valve Replacement. Cardiology. ISSN 0008-6312. doi: 10.1159/000549459. Full text in Research Archive Show summary

  Introduction: Left ventricular (LV) ejection fraction (LVEF) and LV end-diastolic diameter (LVEDd) are well-established predictors of adverse cardiovascular events. However, the possible association with survival in patients with infective endocarditis (IE) treated with aortic valve replacement (AVR) is underexplored. Additionally, it is important to investigate whether sex modifies these associations. Methods: We retrospectively recruited 170 consecutive patients with IE treated with AVR from three cardiac surgery tertiary hospitals in Scandinavia. Echocardiography was performed both pre- and postoperatively. Baseline characteristics, preoperative blood samples, postoperative complications, echocardiographic, and angiographic data were compared between surviving and deceased patients at both short- (1-year) and long-term (5-year) follow-up. Results: The mean age in the entire study population was 58.5 ± 15.1 years, and 80.0% were males. The mean LVEF was 54 ± 11% preoperatively, decreasing to 51 ± 11% postoperatively. The mean baseline LVEDd was 5.8 ± 0.9 cm in males and 5.0 ± 0.9 cm in females (p < 0.001), decreasing to 5.2 ± 0.9 cm in males and 4.7 ± 0.6 cm in females after surgery (p = 0.006). At short-term follow-up, reduced postoperative LVEF (<50%) was more common in non-survivors (46.2% vs. 26.2%, p = 0.040), with the strongest association observed in females (71.4% vs. 25.9%, p = 0.025). Similarly, during long-term follow-up, deceased female patients had a higher prevalence of reduced preoperative LVEF (<50%) compared to surviving female patients (30.0% vs. 4.2%, p = 0.033). LVEDd was significantly greater in female non-survivors compared to survivors at both short-term (5.7 ± 1.1 cm vs. 4.9 ± 0.8 cm, p = 0.043) and long-term follow-up (5.5 ± 0.9 cm vs. 4.8 ± 0.8 cm, p = 0.046), an association not observed in male patients. Conclusion: Our study found that both pre- and postoperative LVEF, as well as preoperative LVEDd, were associated with poorer outcomes in patients with IE undergoing AVR, particularly among female patients. These results highlight the importance of tailored clinical management strategies based on sex-specific risk profiles. Further research is needed to validate these findings and develop interventions to mitigate the observed risks.

• 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
• Westerberg, Ane Cecilie; Degnes, Maren-Helene Langeland; Andresen, Ina Jungersen; Sellevoll, Hilde Bastøe; Lekva, Tove & Ueland, Thor [Show all 11 contributors for this article] (2025). Placenta-Derived Proteins in Preeclampsia: A Human In Vivo Study. Hypertension. ISSN 0194-911X. 82(12), p. 2125–2139. doi: 10.1161/hypertensionaha.125.24886. Full text in Research Archive Show summary

  BACKGROUND: Placental dysfunction, a key feature of preeclampsia, has been linked to altered placental release of proteins into the maternal circulation. However, the identity of placenta-derived proteins in preeclampsia is unclear due to the inaccessibility of the placenta during pregnancy. This study aimed to identify placenta-derived proteins in preeclampsia, characterize their associated biological processes, and assess their biomarker potential. METHODS: We used the 4-vessel sampling method to collect blood from the ingoing and outgoing vessels of the placenta during cesarean section to identify proteins secreted from the placenta. Prospectively collected samples from a separate pregnancy cohort were also included. Proteins were quantified on the SomaLogic 5000-plex platform. RESULTS: We identified 620 placenta-derived proteins, including 229 proteins released in both healthy pregnancies and in preeclampsia, 345 proteins released in preeclampsia only, and 46 proteins released in healthy controls only. Biological process gene ontologies linked to oxidative stress and cellular turnover were enriched among the placenta-derived proteins in preeclampsia, but not in healthy pregnancies. In the prospective cohort, 21 of the 620 placenta-derived proteins had altered levels in preeclampsia at least 3 weeks before, and on average >7 weeks before delivery. Among these, prediction performance for preeclampsia was promising for 11 biomarker candidates in single protein models (area under the curve >0.7) and 17 significantly improved prediction when combined with clinical variables as compared with a clinical model alone. CONCLUSIONS: Using a unique in vivo sampling method, we identified placenta-derived proteins in preeclampsia, several of which showed promising biomarker potential.

• 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 .

• Sundet, Birgitte Kordt; Sugulle, Meryam; Jacobsen, Daniel Pitz; Bratseth, Vibeke; Palmero, Sheryl & Kindberg, Kristine Lovise Mørk [Show all 13 contributors for this article] (2025). Predelivery maternal circulating neutrophil extracellular traps and deoxyribonuclease in placental dysfunction and preeclampsia. American Journal of Obstetrics and Gynecology. ISSN 0002-9378. 234(2), p. 550–569. doi: 10.1016/j.ajog.2025.10.003. Full text in Research Archive Show summary

  Background Neutrophil extracellular traps consist of DNA and protein and are secreted by neutrophils upon activation. They are stable structures but may be degraded by deoxyribonucleases. Neutrophil extracellular traps can induce endothelial dysfunction, an important feature of the preeclampsia pathophysiology. However, the levels of neutrophil extracellular traps biomarkers and deoxyribonuclease in the maternal circulation during preeclampsia, gestational hypertension, and fetal growth restriction, as well as potential associations to placental dysfunction, remain to be elucidated. Objective We aimed to investigate levels of circulating neutrophil extracellular traps biomarkers and deoxyribonuclease in women with early-onset and late-onset preeclampsia, gestational hypertension, and isolated fetal growth restriction compared to clinically healthy pregnancies. Additionally, we aimed to compare these biomarkers with circulating placental dysfunction biomarkers and maternal as well as fetal clinical proxies of placental dysfunction in women with preeclampsia. Study design Plasma and serum samples from women categorized as having early-onset preeclampsia (n=49), late-onset preeclampsia (n=202), gestational hypertension (n=105), isolated fetal growth restriction (n=50), and normotensive, euglycemic controls (n=1126) were analyzed by immunoassays for the circulating neutrophil extracellular traps biomarkers citrullinated histone H3 and myeloperoxidase-DNA and deoxyribonuclease and for the placental dysfunction biomarkers soluble fms-like tyrosine kinase-1 and placental growth factor. The Kruskal-Wallis H test was used to compare biomarker levels across groups. Post hoc pairwise comparisons were conducted using Dunn's test, with Bonferroni correction applied to adjust for multiple comparisons. In women with early-onset and late-onset preeclampsia, the residuals were not normally distributed. Therefore, univariable and multivariable quantile (median) regression for estimating models for the conditional median function were used to study associations between our biomarkers of interest and proxies for placental dysfunction. A 2-sided P value of <.05 was considered statistically significant. Results Women with early-onset and late-onset preeclampsia, but not gestational hypertension or isolated fetal growth restriction, had lower median levels of circulating citrullinated histone H3 (both adjusted P<.001) and deoxyribonuclease (both adjusted P<.001) compared to controls. Women with late-onset preeclampsia had lower myeloperoxidase-DNA (adjusted P<.001) compared to controls. Univariable regression analyses within the preeclampsia group revealed positive associations between citrullinated histone H3 and placental growth factor (P=.004) and negative associations between citrullinated histone H3 and soluble fms-like tyrosine kinase-1 (P=.034) and between deoxyribonuclease and soluble fms-like tyrosine kinase-1 (P=.038). In multivariable regression analyses, citrullinated histone H3 and placental growth factor (P=.009) and deoxyribonuclease and gestational age at blood sampling (P=.001) were positively associated, whereas citrullinated histone H3 (P=.027) and deoxyribonuclease (P=.034) were negatively associated with systolic blood pressure. Finally, citrullinated histone H3 was associated with newborn weight ≤10th percentile, representing a fetal proxy for placental dysfunction (P=.036). Conclusion The lower levels of circulating neutrophil extracellular traps and deoxyribonuclease in women with preeclampsia, but not in gestational hypertension or isolated fetal growth restriction, as well as associations between citrullinated histone H3 and biomarkers of placental dysfunction may indicate that neutrophil extracellular traps play a role in the placental dysfunction that exclusively characterizes preeclampsia. Additionally, the association between low citrullinated histone H3, low deoxyribonuclease, and high maternal blood pressure may suggest that insufficient presence of circulating deoxyribonucleases contributes to the excessive vascular inflammation in women with preeclampsia.

• 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.

• Xavier, Samantha; Wikan, Vårin Eiriksdatter; Ullsten-Wahlund, Casper Jan Elis; Latysheva, Nadezhda; Øverli, Øyvind & Antoun, Christopher [Show all 12 contributors for this article] (2025). Total and extracellular vesicle–bound plasma P-selectin as diagnostic biomarkers for acute deep vein thrombosis. Research and Practice in Thrombosis and Haemostasis (RPTH). 9(7). doi: 10.1016/j.rpth.2025.103171. Full text in Research Archive Show summary

  Background Plasma P-selectin has shown moderate diagnostic potential for deep vein thrombosis (DVT). In plasma, P-selectin is found in soluble form and bound to extracellular vesicles (EVs). It is unknown whether specific detection of EV-bound P-selectin would improve the diagnostic performance of P-selectin. We aimed to investigate the diagnostic performance of EV-bound and total P-selectin for acute DVT, alone and in combination with D-dimer. Objectives We aimed to investigate the diagnostic potential of total extracellular vesicle-bound plasma P-selectin as diagnostic biomarkers for acute deep vein thrombosis in a cohort of patients admitted to hospital with suspected DVT. Methods A bead-based flow cytometric assay was developed for selective detection of EV-bound P-selectin. Total and EV-bound P-selectin was measured in 2 cohorts of patients (n = 168 and n = 200) referred to hospital with suspected DVT. DVT was confirmed or ruled out by compression ultrasound. Results DVT was confirmed in 53 patients and ruled out in 115 patients (first cohort) and in 54 and 146 patients (replication cohort), respectively. Only 2% of plasma P-selectin was bound to EVs, and EV-bound P-selectin showed poor diagnostic performance with an area under the receiver-operating characteristic curve (AUC) of 0.55 (95% CI, 0.45-0.65). Total plasma P-selectin had an AUC of 0.70 (95% CI, 0.62-0.78) in the first cohort and 0.77 (95% CI, 0.69-0.85) in the replication cohort. Combination of total P-selectin with D-dimer had diagnostic performance (AUC, 0.88; 95% CI, 0.84-0.91) inferior to D-dimer alone (AUC, 0.92; 95% CI, 0.89-0.95). Conclusion The proportion of P-selectin bound to EVs in plasma was low and could not discriminate between patients with and without acute DVT. The diagnostic performance of total P-selectin, alone or in combination with D-dimer, was inferior to the diagnostic performance of D-dimer alone.

• 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
• Ormerod, Monica Bettina E. Greenwood; Sheikh, Mashhood Ahmed; Ueland, Thor; Hjell, Gabriela; Rødevand, Linn & Sæther, Linn Sofie [Show all 15 contributors for this article] (2025). Minor immunomodulatory effects of psychotropics suggested in severe mental disorders: Associations of antipsychotics with beta defensin 2, antidepressants with C-reactive protein, and mood stabilizers with soluble interleukin 2 receptor. European psychiatry. ISSN 0924-9338. 68(1). doi: 10.1192/j.eurpsy.2025.10104. Full text in Research Archive Show summary

  Background: Immunomodulatory effects of psychotropic agents used to treat severe mental disorders (SMDs) have been suggested. We investigated associations between immune marker levels and antipsychotic- (AP), antidepressant- (AD), and mood stabilizing agents (MS) use in SMDs. Methods: We included 1215 participants with SMDs (777 with schizophrenia spectrum disorders and 438 with bipolar disorders). Circulating levels of 45 immune markers were determined by enzyme-immunoassay or immunoturbidimetry and analyzed for associations with use, doses, and serum concentrations of AP, AD, and MS. Extensive adjustments for potential confounders were performed. Immune marker levels of 1008 healthy controls served as a reference. Results: AP use was significantly associated with higher plasma levels of beta defensin 2 (BD-2) ( β  = 0.094, p  = 0.8E-4), AD use with higher serum levels of CRP ( β  = 0.072, p  = 0.8E-3), and MS use with higher plasma levels of soluble interleukin 2 receptor (sIL-2R) ( β  = 0.063, p  = 0.9E-4). These findings were paralleled by positive associations with psychotropic agent dose and serum concentrations: AP dose was associated with BD-2 levels ( β  = 0.045, p  = 2.3E-4), AD dose with CRP levels ( β  = 0.039, p  = 0.001), MS dose with sIL-2R levels ( β  = 0.048, p  = 0.001), and serum concentration of AD was nominally positively associated with CRP ( β  = 0.072, p  = 0.002). Conclusions: The findings suggest that AP and MS use affect pathways involved in immune homeostasis and inflammatory regulation in individuals with SMDs, while AD use augments low-grade systemic inflammation reflected by CRP.

• Kreis, Isabel; Wold, Kristin Fjelnseth; Åsbø, Gina; Flaaten, Camilla Bärthel; Engen, Magnus Johan & Lyngstad, Siv Hege [Show all 13 contributors for this article] (2025). Recent cannabis use affects the association between baseline immune markers and long-term outcomes in psychosis. Translational Psychiatry. 15(1). doi: 10.1038/s41398-025-03498-x. Full text in Research Archive Show summary

  Aberrant levels of blood markers reflecting inflammation and immune system activation have been implicated in psychotic disorders and linked to psychotic symptom severity. However, their predictive value for the long-term course of psychotic symptoms as well as the potential confounding and moderating role of cannabis use remain underexplored. We tested if baseline levels of immune markers previously linked to psychotic symptoms or treatment response (CRP, IL-1RA, sIL-2R, sTNFR1, sgp130) predicted 10-year outcomes in a first-episode psychosis sample (N = 320), and whether associations were moderated by baseline cannabis use. We assessed psychiatric (re)admissions and number of psychotic episodes during each year of the follow-up period, as well as change in positive psychotic symptom severity from baseline. Apart from sTNFR1, none of the immune markers significantly predicted psychosis outcomes independently of cannabis use. Baseline sTNFR1 was linked to lower risk of both (re)admissions and psychotic episodes, with an increasingly negative association over time. The statistical effects of CRP, IL-1RA, and sgp130 were all dependent on cannabis use. Specifically, negative (CRP, IL-1RA) or positive associations (sgp130) with psychiatric (re)admission risk or psychotic episode risk were observed in cannabis users only. Similarly, sgp130 was negatively associated with symptom change in cannabis users only. Some of these associations varied by follow-up year of the measured outcome (sgp130, IL-1RA). These findings challenge the prognostic and etiological significance of baseline immune markers for the course of positive psychotic symptoms and emphasize the importance of accounting for cannabis use.

• Andreou, Dimitrios; Steen, Nils Eiel; Jørgensen, Kjetil Nordbø; Nerland, Stener; Ueland, Thor & Wortinger, Laura Anne [Show all 13 contributors for this article] (2025). Toxoplasma gondii associated with psychotic symptom load and cortisol in severe mental illness. Schizophrenia. 11(80). doi: 10.1038/s41537-025-00630-0. Full text in Research Archive Show summary

  Toxoplasma gondii (TG) is a prevalent parasite that establishes lifelong latency after primary infection. TG has been linked to severe mental illness (SMI), potentially through dopamine dysregulation in the brain. There is a bidirectional interaction between dopamine and the hypothalamic-pituitary-adrenal axis, where dopamine may influence cortisol regulation and cortisol may affect dopamine release. We hypothesised that TG would be associated with elevated circulatory cortisol levels, increased severity of psychotic symptoms, and structural brain aberrations in SMI. Our study included 765 patients with SMI (515 with schizophrenia spectrum disorders and 250 with bipolar disorders) and 541 healthy controls (HC). TG immunoglobulin G seropositivity and circulatory cortisol concentrations were measured with immunoassays, and T1-weighted MRI scans were processed using FreeSurfer. Psychotic symptom scores were evaluated using the Positive and Negative Syndrome Scale. In SMI, TG seropositivity was associated with higher cortisol levels (p = 0.002), but not in HC. Seropositive patients had lower total psychotic symptom scores (p = 0.006) than seronegative patients, driven by the schizophrenia subgroup (p = 0.002). This effect was observed for positive, negative, and general psychotic symptom scores, but only for patients with an illness duration of 10 years or more. In an exploratory analysis, TG seropositivity was nominally associated with smaller thalamus, nucleus accumbens, and middle temporal volumes in SMI, and with smaller fusiform, parahippocampal, and pars triangularis volumes in HC. In conclusion, TG exposure in SMI was linked to elevated cortisol levels and reduced psychotic symptom scores, suggesting that its impact on SMI may be more complex and context-dependent than previously assumed.

• 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.

• Ormerod, Monica Bettina E. Greenwood; Ueland, Thor; Aas, Monica; Hjell, Gabriela; Rødevand, Linn & Sæther, Linn Sofie [Show all 16 contributors for this article] (2025). Limited evidence of association between dysregulated immune marker levels and telomere length in severe mental disorders. Acta Neuropsychiatrica. ISSN 0924-2708. 37. doi: 10.1017/neu.2024.62. Full text in Research Archive Show summary

  Objective: Accelerated ageing indexed by telomere attrition is suggested in schizophrenia spectrum- (SCZ) and bipolar disorders (BD). While inflammation may promote telomere shortening, few studies have investigated the association between telomere length (TL) and markers of immune activation and inflammation in severe mental disorders. Methods: Leucocyte TL defined as telomere template/amount of single-copy gene template (T/S ratio), was determined in participants with SCZ (N = 301) or BD (N = 211) and a healthy control group (HC, N = 378). TL was analysed with linear regressions for associations with levels of 12 immune markers linked to SCZ or BD. Adjustments were made for a broad range of potential confounding variables. TL was measured by quantitative polymerase chain reaction (qPCR) and the immune markers were measured by enzyme immunoassays. Results: A positive association between levels of soluble tumour necrosis factor receptor 1A (sTNF-R1) and TL in SCZ (β = 0.191, p = 0.012) was observed. Plasma levels of the other immune markers were not significantly associated with TL in the BD, SCZ or HC groups. Conclusion: There was limited evidence of association between immune markers and TL in SCZ and BD. The results provide little support for involvement of immune dysregulation, as reflected by current systemic markers, in telomere attrition-related accelerated ageing in severe mental disorders.

• 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
• Heldal, Torbjørn Fossum; Åsberg, Anders; Ueland, Thor; Reisæter, Anna Varberg; Pischke, Soeren & Mollnes, Tom Eirik [Show all 11 contributors for this article] (2025). Systemic inflammation is an important risk factor and predictor of graft loss and mortality one year after kidney transplantation. Frontiers in Immunology. 16. doi: 10.3389/fimmu.2025.1529812. 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.

• Edvardsen, Magnus; Hansen, Ellen-Sofie; Ueland, Thor; Latysheva, Nadezhda; Aukrust, Pål & Snir, Omri [Show all 8 contributors for this article] (2025). Effect of plasma levels of factor VIII according to procoagulant phospholipids on the risk of future venous thromboembolism. Research and Practice in Thrombosis and Haemostasis (RPTH). 9(1). doi: 10.1016/j.rpth.2024.102636. Full text in Research Archive
• Eriksson, Elin Svedlund; Rodriguez, Marta Lantero; Halvorsen, Bente; Johansson, Inger; Mårtensson, Anna K. F. & Wilhelmson, Anna S. [Show all 25 contributors for this article] (2025). Testosterone exacerbates neutrophilia and cardiac injury in myocardial infarction via actions in bone marrow. Nature Communications. 16(1). doi: 10.1038/s41467-025-56217-x. Full text in Research Archive
• 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.

• Myhrer, Dina-Marie Munkelien; Frøystad, Monica; Roland, Marie Cecilie; Ueland, Thor & Lekva, Tove (2024). The long non-coding RPPH1 is decreased in leukocytes and increased in plasma from women developing pre-eclampsia†. Biology of Reproduction. ISSN 0006-3363. 111(2), p. 427–435. doi: 10.1093/biolre/ioae069. Full text in Research Archive Show summary

  Previous studies show differentially expressed long non-coding RNA present in the placenta from women with pre-eclampsia, potentially playing a vital role in the pathogenesis of the complication. In a published microarray study, Ribonuclease P RNA component H1 was decreased in leukocytes from women that later developed pre-eclampsia. We hypothesized that Ribonuclease P RNA component H1 decreased during pregnancy in women developing pre-eclampsia and important for the development of the complication. We isolated RNA from extracellular vesicles, leukocytes and plasma using blood samples taken at weeks 22–24 and 36–38 in women who subsequently developed pre-eclampsia and from healthy pregnancy. The expression of Ribonuclease P RNA component H1 was quantified using qPCR. Expression of Ribonuclease P RNA component H1 at 22–24 weeks was further examined to investigate its discriminatory potential of subsequent pre-eclampsia and association with clinical markers. We found lower expression of Ribonuclease P RNA component H1 in leukocytes at 22–24 and 36–38 weeks amongst women who subsequent developed pre-eclampsia compared with those who did not, while increased Ribonuclease P RNA component H1 expression was found in plasma at 36–38 weeks. Pre-eclampsia risk factors could not account for this difference in the Ribonuclease P RNA component H1 expression. Prediction of pre-eclampsia at 22–24 weeks using Ribonuclease P RNA component H1 expression in leukocytes in addition to the screening algorithm used today had a significantly better performance. In conclusion, Ribonuclease P RNA component H1 expression in leukocytes was significantly decreased in women with pre-eclampsia, and the expression at 22–24 weeks associated with the subsequent development of pre-eclampsia. Ribonuclease P RNA component H1 in leukocytes may be a useful biomarker for prediction and/or early detection of pre-eclampsia and an unknown regulator of the signaling affecting immune cells.

• Inova, Amina; Birkenæs, Viktoria; Quintana, Daniel; Ormerod, Monica Bettina E. Greenwood; Ueland, Torill & Ueland, Thor [Show all 10 contributors for this article] (2024). Cortisol and C-reactive protein (CRP) regulation in severe mental disorders. Psychoneuroendocrinology. ISSN 0306-4530. 172. doi: 10.1016/j.psyneuen.2024.107272. Full text in Research Archive Show summary

  Background People with schizophrenia (SZ) and bipolar disorder (BD) show abnormalities in the biological stress system and low-grade inflammation. However, whether the hypothalamic-pituitary-adrenal (HPA) axis-immune regulation is disrupted in SZ and BD, is yet to be determined. Methods Cortisol and C-reactive protein (CRP) were measured in blood samples collected at or before 10 am in participants with SZ (N = 257), BD (N = 153), and healthy controls (N = 40). Cortisol/CRP ratio was calculated as an indicator of the balance between HPA axis activity and inflammatory activity, called HPA axis-immune regulation. Global functioning and symptom levels were obtained using the Global Assessment of Functioning (GAF) Scale and Positive and Negative Syndrome Scale (PANSS). Standardized neuropsychological tests were used to assess cognitive function. All analyses were adjusted for demographic variables (age and sex) and the time of blood sampling. Results Participants with a SZ or BD diagnosis had lower cortisol/CRP ratios (F=5.93, p = 0.003) compared to healthy controls. The difference was no longer statistically significant (p > 0.1) when BMI was added as a covariate to the model. Within patients, those on psychotropic treatment (n = 337) had lower cortisol/CRP ratio than those not taking psychotropic agents (n = 59) (F=4.72, p = 0.03). Compared to HC, only patients on regular psychotropic agents had lower cortisol/CRP ratio (p = 0.02). Within the SZ group, lower cortisol/CRP ratio was associated with having poorer general functioning as measured by GAF (ß=-0.18, p = 0.01), and more severe negative and general symptomatology as measured by PANSS (ß=0.19, p = 0.007 and ß=0.18, p = 0.01, respectively). In SZ, lower cortisol/CRP ratio was also associated with poorer verbal memory, learning, and processing speed (ß=-0.20 p = 0.007, ß=-0.19 p = 0.01, ß=-0.25, p > 0.001, respectively). No associations were observed between cortisol/CRP ratio and clinical and cognitive functioning in the BD group. Conclusion These findings may indicate HPA axis-immune dysregulation in SZ. Our study further indicates that disrupted HPA axis-immune regulation in people with SZ and BD is associated with psychotropic treatment and fat mass, highlighting the clinical importance of weight control and regular psychotropic treatment follow-ups within this group.

• Kindberg, Kristine Lovise Mørk; Broch, Kaspar; Andersen, Geir Øystein; Anstensrud, Anne Kristine; Åkra, Sissel & Woxholt, Sindre [Show all 23 contributors for this article] (2024). Neutrophil Extracellular Traps in ST-Segment Elevation Myocardial Infarction: Reduced by Tocilizumab and Associated With Infarct Size. JACC: Advances. 3(9). doi: 10.1016/j.jacadv.2024.101193. Full text in Research Archive Show summary

  Background - Interleukin-6-receptor inhibition with tocilizumab improves myocardial salvage in patients with ST-segment elevation myocardial infarction (STEMI). Reduced levels of neutrophil extracellular traps (NETs), which consist of nuclear material studded with proteins released upon neutrophil activation, might contribute to this effect.<p> <p>Objectives - The purpose of this study was to evaluate the effect of tocilizumab on NETs and investigate the association between NETs and myocardial injury in patients with STEMI.<p> <p>Methods - In the ASSAIL-MI study, 199 patients with STEMI were randomized to tocilizumab or placebo during percutaneous coronary intervention. In this substudy, we analyzed blood levels of the NET markers double-stranded deoxyribonucleic acid (dsDNA), myeloperoxidase-DNA, and citrullinated histone 3 (H3Cit) at admission and after 24 hours and 3 to 7 days. In a subgroup of patients, we assessed regulation of transcripts related to the formation of NETs. We also investigated associations between NET markers and the myocardial salvage index (MSI).<p> <p>Results - All NET markers were lower in the tocilizumab group than in the placebo group at 3 to 7 days (all P < 0.04). Several NET-related pathways were downregulated in the tocilizumab group. The beneficial effect of tocilizumab on the MSI seemed to be partly dependent on reduction of NETs (structural equation modeling: 0.05, P = 0.001 [dsDNA] and 0.02, P = 0.055 [H3Cit]). Patients with NETs in the 3 lowest quartiles had higher MSI than patients in quartile 4 (β = 10.9 [95% CI: 4.0-15.0] [dsDNA] and β = 8.9 [95% CI: 2.0-15.9] [H3Cit], both P = 0.01).<p> <p>Conclusions - NETs were reduced by tocilizumab and associated with myocardial injury. The effect of tocilizumab on MSI might be mediated through reduced NETs. (ASSessing the Effect of Anti-IL-6 Treatment in Myocardial Infarction: The ASSAIL-MI Trial [ASSAIL-MI]

• 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.

• Falch, Camilla Maria; Godang, Kristin; Lekva, Tove; Ueland, Thor; Heck, Ansgar & Bollerslev, Jens [Show all 7 contributors for this article] (2024). Long-term depot specific changes in adipose tissue after treatment of acromegaly. European Journal of Endocrinology (EJE). ISSN 0804-4643. 190(3), p. K37–K42. doi: 10.1093/ejendo/lvae016. Full text in Research Archive Show summary

  Context Patients with active acromegaly present a decreased adipose tissue (AT) mass, and short-term studies show that treatment leads to AT depot-specific gain. However, it remains unclear if the increase is persistent in the long-term perspective and/or is sex-dependent. Design To characterize the depot-specific changes of AT after treatment of acromegaly and identify contributing factors. Methods Adipose tissue, including visceral (VAT), subcutaneous (SAT), and total (TAT), and android to gynoid ratio (A/G ratio) were measured by dual energy X-ray absorptiometry at diagnosis (n = 62), and after treatment at short-term (median (IQR) 1.9 (1.5-2.3)) and long-term 5.5 (3.9-9.5) years, and correlated to clinical and biochemical measurements. Growth hormone (GH), insulin-like growth factor 1 (IGF-1), glucose and HbA1c levels, gonadal status, and the presence of diabetes mellitus were recorded. Remission status was assessed at the long-term visit (IGF-1/ULN ≤ 1.3). Differences in the temporal course of AT from baseline to short- and long-term follow-up according to sex, diabetes, gonadal, and remission status were evaluated by mixed model analysis, adjusted for age. Results Despite a stable body mass index, VAT and A/G ratio increased at both time points, whereas SAT mainly increased at short-term, plateauing afterwards (P < .05 for all). Visceral adipose tissue and A/G ratio were higher in men (P = .035 and P < .001), and the A/G ratio increased more than in women (P = .003). Glucose and HbA1c decreased short-term (P < .05) and remained stable at long-term. The increase in AT depots correlated with the decrease of disease activity at long-term. Remission status had no effect on changes in AT mass during follow-up. Conclusion Treatment of acromegaly leads to an increase in AT mass in a depot- and sex-specific manner both at short-term and long-term follow-up. Glucose metabolism improves rapidly after disease control and persists.

• 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.

• Barratt-Due, Andreas; Pettersen, Kristin; Dahl, Tuva Børresdatter; Holter, Jan Cato; Grønli, Renathe Henriksen & Dyrhol-Riise, Anne Ma [Show all 20 contributors for this article] (2024). Escalated complement activation during hospitalization is associated with higher risk of 60-day mortality in SARS-CoV-2-infected patients. Journal of Internal Medicine. ISSN 0954-6820. 296(1), p. 80–92. doi: 10.1111/joim.13783. Full text in Research Archive Show summary

  Background: The complement system, an upstream recognition system of innate immunity, is activated upon SARS-CoV-2 infection. To gain a deeper understanding of the extent and duration of this activation, we investigated complement activation profiles during the acute phase of COVID-19, its persistence post-recovery and dynamic changes in relation to disease severity. Methods: Serial blood samples were obtained from two cohorts of hospitalized COVID-19 patients (n = 457). Systemic complement activation products reflecting classical/lectin (C4d), alternative (C3bBbP), common (C3bc) and terminal pathway (TCC and C5a) were measured during hospitalization (admission, days 3–5 and days 7–10), at 3 months and after 1 year. Levels of activation and temporal profiles during hospitalization were related to disease severity defined as respiratory failure (PO2/FiO2 ratio <26.6 kPa) and/or admission to intensive care unit, 60-day total mortality and pulmonary pathology after 3 months. Findings: During hospitalization, TCC, C4d, C3bc, C3bBbP and C5a were significantly elevated compared to healthy controls. Severely ill patients had significantly higher levels of TCC and C4d (p < 0.001), compared to patients with moderate COVID-19. Escalated levels of TCC and C4d during hospitalization were associated with a higher risk of 60-day mortality (p < 0.001), and C4d levels were additionally associated with chest CT changes at 3 months (p < 0.001). At 3 months and 1 year, we observed consistently elevated levels of most complement activation products compared to controls. Conclusion: Hospitalized COVID-19 patients display prominent and long-lasting systemic complement activation. Optimal targeting of the system may be achieved through enhanced risk stratification and closer monitoring of in-hospital changes of complement activation products.

• Andreou, Dimitrios; Steen, Nils Eiel; Mørch-Johnsen, Lynn Egeland; Jørgensen, Kjetil Nordbø; Wortinger, Laura Anne & Barth, Claudia [Show all 19 contributors for this article] (2024). Toxoplasma gondii infection associated with inflammasome activation and neuronal injury. Scientific Reports. 14(1). doi: 10.1038/s41598-024-55887-9. Full text in Research Archive Show summary

  Toxoplasma gondii (TOXO) infection typically results in chronic latency due to its ability to form cysts in the brain and other organs. Latent toxoplasmosis could promote innate immune responses and impact brain function. A large body of evidence has linked TOXO infection to severe mental illness (SMI). We hypothesized that TOXO immunoglobulin G (IgG) seropositivity, reflecting previous infection and current latency, is associated with increased circulating neuron-specific enolase (NSE), a marker of brain damage, and interleukin-18 (IL-18), an innate immune marker, mainly in SMI. We included 735 patients with SMI (schizophrenia or bipolar spectrum) (mean age 32 years, 47% women), and 518 healthy controls (HC) (mean age 33 years, 43% women). TOXO IgG, expressed as seropositivity/seronegativity, NSE and IL-18 were measured with immunoassays. We searched for main and interaction effects of TOXO, patient/control status and sex on NSE and IL-18. In the whole sample as well as among patients and HC separately, IL-18 and NSE concentrations were positively correlated (p < 0.001). TOXO seropositive participants had significantly higher NSE (3713 vs. 2200 pg/ml, p < 0.001) and IL-18 levels (1068 vs. 674 pg/ml, p < 0.001) than seronegative participants, and evaluation within patients and HC separately showed similar results. Post-hoc analysis on cytomegalovirus and herpes simplex virus 1 IgG status showed no associations with NSE or IL-18 which may suggest TOXO specificity. These results may indicate ongoing inflammasome activation and neuronal injury in people with TOXO infections unrelated to diagnosis.

• Heck, Ansgar; Pretorius, Mikkel; Lundstam, Karolina; Godang, Kristin; Hellström, Mikael & Ueland, Thor [Show all 7 contributors for this article] (2024). No effect of surgery on kidney and cardiovascular risk factors in mild primary hyperparathyroidism: secondary analyses from a 10-year randomized controlled trial. European Journal of Endocrinology (EJE). ISSN 0804-4643. 191(3), p. 354–360. doi: 10.1093/ejendo/lvae109. Full text in Research Archive Show summary

  Objective Renal function and the skeleton are classic target organs in primary hyperparathyroidism (PHPT), affected by the chronic course of the disease. Most patients diagnosed today exhibit mild PHPT, characterized by slight hypercalcemia and no or unspecific symptoms. Concerns have been raised that PHPT could promote deteriorating kidney function and increase cardiovascular risk directly. To examine the effect of parathyroidectomy (PTX) on mild PHPT on renal function and markers for bone turnover, cardiovascular disease (CVD), and vascular inflammation. Design Prospective randomized controlled trial. ClinicalTrials.gov: NCT00522028. Setting Eight Scandinavian referral centers. Participants From 1998 to 2005, 191 patients with mild PHPT were included in Sweden, Norway, and Denmark. Of these 150 were included in the present analyses. Intervention Seventy patients were randomized to PTX and 80 to observation without intervention (OBS). Measures e-GFR was calculated based on creatinine and cystatin C. Markers of CVD and systemic inflammation: osteoprotegerin, vascular cell adhesion molecule 1, soluble CD40 ligand, interleukin-1 receptor antagonist, von Willebrand factor. Bone turnover markers: C-terminal telopeptide of type 1 collagen (CTX-1) and serum Procollagen type 1 N-terminal propeptide. Results No differences in the development of renal function or vascular and systemic inflammation were detected. CTX-1 was lower in PTX after 10 years. Limitations Secondary analyses of a randomized controlled trial. Conclusion PTX does not appear to affect renal function or markers of CVD and vascular inflammation in mild PHPT in a ten-year perspective.

• Szabo, Attila; O'Connell, Kevin Sean; Akkouh, Ibrahim Ahmed; Ueland, Thor; Sønderby, Ida Elken & Hope, Sigrun [Show all 16 contributors for this article] (2024). Elevated levels of peripheral and central nervous system immune markers reflect innate immune dysregulation in autism spectrum disorder. Psychiatry Research. ISSN 0165-1781. 342. doi: 10.1016/j.psychres.2024.116245. Full text in Research Archive Show summary

  Background Evidence suggests dysregulated immune functions in the pathophysiology of Autism spectrum disorder (ASD), although specific immune mechanisms are yet to be identified. Methods We assessed circulating levels of 25 immune/neuroinflammatory markers in a large ASD sample (n = 151) and matched controls (n = 72) using linear models. In addition, we performed global brain transcriptomics analyses of relevant immune-related genes. We also assessed the expression and function of factors and pathway elements of the inflammasome system in peripheral blood mononuclear cells (PBMC) isolated from ASD and controls using in vitro methods. Results We found higher circulating levels of IL-18 and adhesion factors (ICAM-1, MADCAM1) in individuals with ASD relative to controls. Consistent with this, brain levels of ICAM1 mRNA were also higher in ASD compared to controls. Furthermore, we found higher expression/activity of Caspase-1 and the inflammasome sensor NLRP3 in PBMCs in ASD, both at baseline and following inflammatory challenge. This corresponded with higher levels of secreted IL-18, IL-1β, and IL-8, as well as increased expression of adhesion factors following inflammasome activation in ASD PBMC cultures. Inhibition of the NLRP3-inflammasome rescued the observed immune phenotype in ASD in vitro. Conclusion Our results suggest a role for inflammasome dysregulation in ASD pathophysiology.

• Sæther, Linn Sofie; Szabo, Attila; Akkouh, Ibrahim Ahmed; Haatveit, Beathe; Mohn, Christine & Vaskinn, Anja [Show all 14 contributors for this article] (2024). Cognitive and inflammatory heterogeneity in severe mental illness: Translating findings from blood to brain. Brain, Behavior, and Immunity. ISSN 0889-1591. 118, p. 287–299. doi: 10.1016/j.bbi.2024.03.014. Full text in Research Archive Show summary

  Recent findings link cognitive impairment and inflammatory-immune dysregulation in schizophrenia (SZ) and bipolar (BD) spectrum disorders. However, heterogeneity and translation between the periphery and central (blood-to-brain) mechanisms remains a challenge. Starting with a large SZ, BD and healthy control cohort (n = 1235), we aimed to i) identify candidate peripheral markers (n = 25) associated with cognitive domains (n = 9) and elucidate heterogenous immune-cognitive patterns, ii) evaluate the regulation of candidate markers using human induced pluripotent stem cell (iPSC)-derived astrocytes and neural progenitor cells (n = 10), and iii) evaluate candidate marker messenger RNA expression in leukocytes using microarray in available data from a subsample of the main cohort (n = 776), and in available RNA-sequencing deconvolution analysis of postmortem brain samples (n = 474) from the CommonMind Consortium (CMC). We identified transdiagnostic subgroups based on covariance between cognitive domains (measures of speed and verbal learning) and peripheral markers reflecting inflammatory response (CRP, sTNFR1, YKL-40), innate immune activation (MIF) and extracellular matrix remodelling (YKL-40, CatS). Of the candidate markers there was considerable variance in secretion of YKL-40 in iPSC-derived astrocytes and neural progenitor cells in SZ compared to HC. Further, we provide evidence of dysregulated RNA expression of genes encoding YKL-40 and related signalling pathways in a high neuroinflammatory subgroup in the postmortem brain samples. Our findings suggest a relationship between peripheral inflammatory-immune activity and cognitive impairment, and highlight YKL-40 as a potential marker of cognitive functioning in a subgroup of individuals with severe mental illness.

• Bredholt, Geir; Sævik, Marianne; Søyland, Hanne; Ueland, Thor; Zhou, Fan & Pathirana, Rishi Delan [Show all 19 contributors for this article] (2024). Three doses of Sars-CoV-2 mRNA vaccine in older adults result in similar antibody responses but reduced cellular cytokine responses relative to younger adults. Vaccine: X. 20. doi: 10.1016/j.jvacx.2024.100564. Full text in Research Archive Show summary

  Objectives Booster COVID-19 vaccinations are used to protect the elderly, a group vulnerable to severe disease. We compared humoral and cellular immunity in older versus younger adults up to eight months after administering a BNT16b2 booster vaccine dose. Next, we analyzed the plasma levels of soluble T cell activation/exhaustion markers. Methods Home-dwelling older adults (n = 68, median age 86) and younger healthcare workers (n = 35, median age 39), previously vaccinated with two doses of BNT162b2, were given a booster dose at ten months after the initial dose. Our analysis consisted of spike-specific IgG, neutralizing antibodies, memory B cells, IFN-γ and IL-2 secreting T cells and soluble T cell exhaustion/activation markers. Results Following the initial two doses, the elderly cohort exhibited lower humoral and IFN-γ responses compared to younger adults. The booster dose increased the humoral responses in both older and younger adults. At two months after the booster dose, older and younger vaccinees had comparable levels of antibodies and the responses were maintained up to 18 months. The younger cohort elicited an increase in the cellular response, while no increase was detected in the elderly. The elderly had higher plasma levels of soluble forms of the T cell activation/exhaustion markers CD25 and TIM-3, which inversely correlated with age and T-cell cytokine responses. This suggests that these markers may be related to the observed dysfunctional cellular cytokine response in older adults. However, both elderly and younger adults who experienced breakthrough infections after booster vaccination, elicited more robust humoral and IFN-γ responses. Conclusions The booster dose elicited neutralizing and spike-specific antibody responses in the elderly that were comparable with that of the younger cohort. However, the lack of a strong cellular cytokine response to the third dose in the elderly may explain their vulnerability to severe infection and may be a consequence of exhausted or senescent T cell responses. (https://clinicaltrials.gov/study/NCT04706390).

• Løvheim, Eirin Brenna; Retterstøl, Kjetil; Narverud, Ingunn; Bogsrud, Martin Prøven; Halvorsen, Bente & Ueland, Thor [Show all 8 contributors for this article] (2024). Adherence to the Healthy Nordic Food Index is associated with reduced plasma levels of inflammatory markers in patients with heterozygous familial hypercholesterolemia. Atherosclerosis Plus. ISSN 2667-0909. 58, p. 38–45. doi: 10.1016/j.athplu.2024.10.003. Full text in Research Archive Show summary

  Background and aims Familial hypercholesterolemia (FH) is an inherited disease associated with hypercholesterolemia, and dietary treatment is part of the treatment. We aimed to assess the dietary pattern in relation to the Healthy Nordic Food Index (HNFI) in adults with and without heterozygous FH (HeFH), and to examine the associations between dietary quality and biomarkers related to cardiovascular disease in adults with HeFH. Methods We included 205 adults (≥18 years) with HeFH who received follow-up at the Lipid Clinic in Oslo and compared them to controls (n = 228). Dietary intake was assessed using a food frequency questionnaire and dietary quality was assessed using the HNFI. Blood samples were analysed for levels of blood lipids, plasma fatty acids (FAs), and markers of inflammation and platelet activation. Results The HeFH patients (median 60 years; 50.2 % female; 25.9 % in secondary prevention) had lower intake of total and saturated fat compared to controls (32.6 energy percent (E%) vs. 34.9 E%, and 9.6 E% vs 12.0 E%, respectively; p < 0.001 for both). In the HeFH patients, increasing dietary quality was associated with increased plasma levels of the n-3 polyunsaturated FAs (PUFAs) eicosapentaenoic acid and docosahexaenoic acid, and the n-6 PUFA linoleic acid, and lower plasma levels of the inflammatory cytokines Tumor Necrosis Factor and interleukin-6, and of the platelet-derived inflammatory cytokines Platelet Factor 4 and Neutrophil-Activating Peptide-2. Conclusion Norwegian patients with HeFH followed up at a Lipid Clinic eat healthier than controls. Adherence to a healthy dietary pattern is associated with higher plasma levels of n-3 and n-6 PUFA, and lower levels of inflammatory markers, including platelet markers. This may suggest that adherence to an overall healthy dietary pattern might be beneficial for HeFH patients independent of the cholesterol-lowering effect of the diet.

• Szabo, Attila; Akkouh, Ibrahim Ahmed; Osete, Jordi Requena; Assis, Denis Reis de; Kondratskaya, Elena & Hughes, Timothy [Show all 9 contributors for this article] (2024). NLRP3 inflammasome mediates astroglial dysregulation of innate and adaptive immune responses in schizophrenia. Brain, Behavior, and Immunity. ISSN 0889-1591. 124, p. 144–156. doi: 10.1016/j.bbi.2024.11.030. Full text in Research Archive Show summary

  Mounting evidence indicates the involvement of neuroinflammation in the development of schizophrenia (SCZ), but the potential role of astroglia in this phenomenon remains poorly understood. We assessed the molecular and functional consequences of inflammasome activation using induced pluripotent stem cell (iPSC)-derived astrocytes generated from SCZ patients and healthy controls (CTRL). Screening protein levels in astrocytes at baseline identified lower expression of the NLRP3-ASC complex in SCZ, but increased Caspase-1 activity upon specific NLRP3 stimulation compared to CTRL. Using transcriptional profiling, we found corresponding downregulations of NLRP3 and ASC/PYCARD in both iPSC-derived astrocytes, and in a large (n = 429) brain postmortem case-control sample. Functional analyses following NLRP3 activation revealed an inflammatory phenotype characterized by elevated production of IL-1β/IL-18 and skewed priming of helper T lymphocytes (Th1/Th17) by SCZ astrocytes. This phenotype was rescued by specific inhibition of NLRP3 activation, demonstrating its dependence on the NLRP3 inflammasome. Taken together, SCZ iPSC-astrocytes display unique, NLRP3-dependent inflammatory characteristics that are manifested via various cellular functions, as well as via dysregulated innate and adaptive immune responses.

• 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.

• Ueland, Thor; Butt, Noreen; Lekva, Tove; Ørn, Stein; Manhenke, Cord Arend & Aukrust, Pål [Show all 7 contributors for this article] (2024). High dose statin treatment reduces circulating Dickkopf-1 following acute myocardial infarction. International Journal of Cardiology. ISSN 0167-5273. 406. doi: 10.1016/j.ijcard.2024.132035. Full text in Research Archive Show summary

  Background Secreted glycoproteins of the Dickkopf (DKK) family modify Wnt signaling and may influence plaque destabilization but their modulation by statins in MI patients is not known. Methods We measured plasma DKK-1 and DKK-3 in patients with acute ST-segment elevation MI (STEMI) before percutaneous coronary intervention (PCI) and after 2 and 7 days and 2 months in patients receiving short-term high-dose (40 mg rosuvastatin, given before PCI; n = 25) and moderate dose (20 mg simvastatin, given the day after PCI; n = 34). In vitro modulation of DKK-1 in human umbilical vein endothelial cells (HUVECs) by statins were assessed. Results (i) Patients receiving high dose rosuvastatin had a marked decline in DKK-1 at day 2 which was maintained throughout the study period. However, a more prevalent use of β-blockers in the simvastatin group, that could have contributed to higher DKK-1 levels in these patients. (ii) There was a strong correlation between baseline DKK-1 levels and change in DKK-1 from baseline to day 2 in patients receiving high dose rosuvastatin treatment. (iii) DKK-3 increased at day 2 but returned to baseline levels at 2 months in both treatment groups. (iv) Statin treatment dose-dependently decreased DKK-1 mRNA and protein levels in HUVEC. Conclusions Our findings suggest that high dose statin treatment with 40 mg rosuvastatin could persistently down-regulate DKK-1 levels, even at 2 months after the initial event in STEMI patients.

• Antoun, Christopher; Wikan, Vårin Eiriksdatter; Øverli, Øyvind; Ueland, Thor; Yeganeh, Gholamreza Jafari & Brækkan, Sigrid Kufaas [Show all 8 contributors for this article] (2024). Plasma microRNA-145-5p as a diagnostic biomarker for acute deep vein thrombosis. Research and Practice in Thrombosis and Haemostasis (RPTH). 9(1). doi: 10.1016/j.rpth.2024.102671. Full text in Research Archive
• 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.

• Dingen, Håvard; Jordal, Stina; Bratt, Sorosh; Aukrust, Pål; Busund, Rolf & Jakobsen, Øyvind [Show all 12 contributors for this article] (2024). Clinical profile, microbiology and outcomes in infective endocarditis treated with aortic valve replacement: a multicenter case-control study. BMC Infectious Diseases. 24(1). doi: 10.1186/s12879-024-09782-3. Full text in Research Archive Show summary

  Background Aortic valve infective endocarditis (IE) is associated with significant morbidity and mortality. We aimed to describe the clinical profile, risk factors and predictors of short- and long-term mortality in patients with aortic valve IE treated with aortic valve replacement (AVR) compared with a control group undergoing AVR for non-infectious valvular heart disease. Methods Between January 2008 and December 2013, a total of 170 cases with IE treated with AVR (exposed cohort) and 677 randomly selected non-infectious AVR-treated patients with degenerative aortic valve disease (controls) were recruited from three tertiary hospitals with cardiothoracic facilities across Scandinavia. Crude and adjusted hazard ratios (HR) were estimated using Cox regression models. Results The mean age of the IE cohort was 58.5 ± 15.1 years (80.0% men). During a mean follow-up of 7.8 years (IQR 5.1-10.8 years), 373 (44.0%) deaths occurred: 81 (47.6%) in the IE group and 292 (43.1%) among controls. Independent risk factors associated with IE were male gender, previous heart surgery, underweight, positive hepatitis C serology, renal failure, previous wound infection and dental treatment (all p < 0.05). IE was associated with an increased risk of both short-term (≤ 30 days) (HR 2.86, [1.36–5.98], p = 0.005) and long-term mortality (HR 2.03, [1.43–2.88], p < 0.001). In patients with IE, chronic obstructive pulmonary disease (HR 2.13), underweight (HR 4.47), renal failure (HR 2.05), concomitant mitral valve involvement (HR 2.37) and mediastinitis (HR 3.98) were independent predictors of long-term mortality. Staphylococcus aureus was the most prevalent microbe (21.8%) and associated with a 5.2-fold increased risk of early mortality, while enterococci were associated with the risk of long-term mortality (HR 1.78). Conclusions In this multicenter case-control study, IE was associated with an increased risk of both short- and long-term mortality compared to controls. Efforts should be made to identify, and timely treat modifiable risk factors associated with contracting IE, and mitigate the predictors of poor survival in IE.

• Gjerde, Kristian Varden; Bartz-Johannessen, Christoffer; Steen, Vidar Martin; Andreassen, Ole A.; Steen, Nils Eiel & Ueland, Thor [Show all 12 contributors for this article] (2024). Cellular adhesion molecules in drug-naïve and previously medicated patients with schizophrenia-spectrum disorders. Schizophrenia Research. ISSN 0920-9964. 267, p. 223–229. doi: 10.1016/j.schres.2024.03.029. Full text in Research Archive Show summary

  Background Endothelial inflammation may be involved in the pathogenesis of schizophrenia, and cellular adhesion molecules (CAMs) on endothelial cells may facilitate leukocyte binding and transendothelial migration of cells and inflammatory factors. The aim of the present study was to assess levels of soluble cellular adhesion molecules, including intercellular adhesion molecule (ICAM)-1, vascular adhesion molecule (VCAM)-1, mucosal addressin cell adhesion molecule (MADCAM), junctional adhesion molecule (JAM-A) and neural cadherin (N-CAD) in patients with schizophrenia compared to healthy controls. Methods The study population consists of 138 patients with schizophrenia-spectrum disorder, of whom 54 were drug-naïve, compared to 317 general population controls. The potential confounders age, gender, smoking and body mass index (BMI) were adjusted for in linear regression models. Results The total patient group showed significantly higher levels of ICAM-1 (p < 0.001) and VCAM-1 (p < 0.001) compared to controls. Previously medicated patients showed higher ICAM-1 levels compared to drug-naïve patients (p = 0.042) and controls (p < 0.001), and elevated VCAM-1 levels compared to controls (p < 0.001). Drug-naive patients had elevated levels of VCAM-1 (p = 0.031) compared to controls. Conclusions In our study, patients with schizophrenia – including the drug-naïve – have higher levels of soluble CAMs compared to healthy controls. These findings suggest activation of the endothelial system as in inflammation.

• 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
• Farbu, Bjørn Hoftun; Lydersen, Stian; Mohus, Randi Marie; Ueland, Thor; Mollnes, Tom Eirik & Klepstad, Pål [Show all 7 contributors for this article] (2024). The detrimental effects of intestinal injury mediated by inflammation are limited in cardiac arrest patients: A prospective cohort study. Resuscitation Plus. 18:100639, p. 1–8. doi: 10.1016/j.resplu.2024.100639. Full text in Research Archive Show summary

  Background: Ischaemic intestines could be a driver of critical illness through an inflammatory response. We have previously published reports on a biomarker for intestinal injury, plasma Intestinal Fatty Acid Binding Protein (IFABP), and inflammatory biomarkers after out-of-hospital cardiac arrest (OHCA). In this post-hoc study we explored the potential indirect effects of intestinal injury mediated through the inflammatory response on organ dysfunction and mortality. Methods: We measured IFABP and twenty-one inflammatory biomarkers in 50 patients at admission to intensive care unit after OHCA. First, we stratified patients on median IFABP and compared biomarkers between “low” and “high” IFABP. Second, by causal mediation analysis, we assessed effects of IFABP through the two most important inflammatory biomarkers, interleukin (IL)-6 and terminal complement complex (TCC), on day two circulatory variables, Sequential Organ Failure Assessment (SOFA)-score, and 30-day mortality. Results: Cytokines and complement activation were higher in the high IFABP group. In mediation analysis, patients on the 75th percentile of IFABP, compared to the 25th percentile, had 53% (95% CI, 33–74; p < 0.001) higher risk of dying, where 13 (95% CI, 3–23; p = 0.01) percentage points were mediated through an indirect effect of IL-6. Similarly, the indirect effect of IFABP through IL-6 on SOFA-score was significant, but smaller than potential other effects. Effects through IL-6 on circulatory variables, and all effects through TCC, were not statistically significant and/or small. Conclusion: Effects of intestinal injury mediated through inflammation on organ dysfunction and mortality were limited. Small, but significant, effects through IL-6 were noted.

• 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.

• Woxholt, Sindre; Ueland, Thor; Aukrust, Pål; Anstensrud, Anne Kristine; Broch, Kaspar & Tøllefsen, Ingvild Maria [Show all 15 contributors for this article] (2024). Effect of tocilizumab on endothelial and platelet-derived CXC-chemokines and their association with inflammation and myocardial injury in STEMI patients undergoing primary PCI. International Journal of Cardiology. ISSN 0167-5273. 418. doi: 10.1016/j.ijcard.2024.132613. Full text in Research Archive Show summary

  Background: Tocilizumab improves myocardial salvage in ST-elevation myocardial infarction (STEMI) patients when administered before percutaneous coronary intervention (PCI). The mechanisms underlying ischemia-reperfusion injury remain unclear. In this sub-study, we investigated whether endothelial and platelet-derived CXC chemokines are involved, as they represent inflammatory mediators from two cell types relevant to myocardial infarction. Associations between these chemokines and neutrophils, C-reactive protein (CRP), troponin T (TnT), myocardial salvage index (MSI), microvascular obstruction (MVO), and infarct size. Methods: This is a sub-study of the ASSAIL-MI trial, a double-blind clinical trial that randomized 199 STEMI patients to receive either 280 mg tocilizumab (n = 101) or placebo (n = 98) intravenously before PCI. Blood samples were collected prior to infusion, at day 1–2, 3–7, and at 3 and 6 months. Heparin was administered before baseline in 150 patients, while 49 received it after. We measured CXC-chemokines CXCL4, CXCL5, CXCL6, CXCL7, and CXCL12 using immunoassays. Cardiac MRI was performed in the first week and at 6 months. Results: Tocilizumab did not significantly affect CXC-chemokines levels. Although some correlations were observed between chemokine levels and neutrophil counts and CRP, none of the CXC chemokines were associated with infarct size, MSI, MVO, or TnT levels. Notably, CXCL 12 levels increased in patients who received heparin before baseline, while other CXC-chemokines decreased significantly. Conclusion: This study suggests that the beneficial effects of tocilizumab in STEMI patients are not due to changes in circulating endothelial or platelet-derived CXC-chemokines, compared to placebo. However, heparin significantly influences the levels of these chemokines.

• Andreou, Dimitrios; Steen, Nils Eiel; Jørgensen, Kjetil Nordbø; Ueland, Thor; Wortinger, Laura Anne & Mørch-Johnsen, Lynn Egeland [Show all 11 contributors for this article] (2024). Increased Herpes simplex virus 1, Toxoplasma gondii and Cytomegalovirus antibody concentrations in severe mental illness. Translational Psychiatry. 14(1). doi: 10.1038/s41398-024-03198-y. Full text in Research Archive Show summary

  Infections with Cytomegalovirus (CMV), Herpes simplex virus 1 (HSV1) and Toxoplasma gondii (TG) have been implicated in severe mental illness. All three pathogens have high seroprevalence in the human population, are neurotropic and establish a persistent infection. We hypothesized that exposed (seropositive) patients with severe mental illness would show higher immunoglobulin G (IgG) concentrations than exposed healthy controls (HC). We included 765 patients with severe mental illness (schizophrenia n = 515, bipolar disorder n = 250) and 541 HC. CMV, HSV1 and TG IgG seropositivity and concentrations were measured with immunoassays (seropositivity: CMV, n = 447 patients vs. 296 HC; HSV1, n = 355 vs. 238; and TG, n = 159 vs. 126). Among seropositive participants, patients had higher HSV1 (p < 0.001) and TG (p = 0.003) IgG concentrations than HC. Stratifying by diagnosis, both schizophrenia (p = 0.001) and bipolar disorder (p = 0.001) had higher HSV1 IgG concentrations, while schizophrenia only had higher TG (p = 0.009) and CMV (p = 0.045) IgG concentrations than HC. In SZ, higher HSV1 IgG concentrations were associated with higher psychotic (p = 0.030) and manic (p = 0.008) symptom scores, but only among CMV- or TG-infected patients which suggests synergistic effects. Among all participants, HSV1 IgG concentrations were inversely associated with interleukin-18 (p < 0.001) and positively associated with high-sensitivity C-reactive protein (p = 0.002) and B cell-activating factor (p = 0.004), possibly indicating T cell exhaustion, enhanced inflammation, and increased B-cell response, respectively. Patients with severe mental illness exhibit a heightened immune system response to HSV1, TG, and CMV infections suggesting immune system dysfunction and/or a more severe infection. For HSV1, higher IgG concentrations were linked to a greater clinical burden.

• Gregersen, Ida; Narverud, Ingunn; Christensen, Jacob J.; Hovland, Anders Wilhelm; Øyri, Linn Kristin Lie & Ueland, Thor [Show all 11 contributors for this article] (2024). Plasma legumain in familial hypercholesterolemia: associations with statin use and cardiovascular risk markers. Scandinavian Journal of Clinical and Laboratory Investigation. ISSN 0036-5513. 84(1), p. 24–29. doi: 10.1080/00365513.2024.2309617. Full text in Research Archive Show summary

  Legumain is known to be regulated in atherosclerotic disease and may have both pro- and anti-atherogenic properties. The study aimed to explore legumain in individuals with familial hypercholesterolemia (FH), a population with increased cardiovascular risk. Plasma legumain was measured in 251 subjects with mostly genetically verified FH, of which 166 were adults (≥18 years) and 85 were children and young adults (<18 years) and compared to 96 normolipidemic healthy controls. Plasma legumain was significantly increased in the total FH population compared to controls (median 4.9 versus 3.3 pg/mL, respectively, p < 0.001), whereof adult subjects with FH using statins had higher levels compared to non-statin users (5.7 versus 3.9 pg/mL, respectively, p < 0.001). Children and young adults with FH (p = 0.67) did not have plasma legumain different from controls at the same age. Further, in FH subjects, legumain showed a positive association with apoB, and markers of inflammation and platelet activation (i.e. fibrinogen, NAP2 and RANTES). In the current study, we show that legumain is increased in adult subjects with FH using statins, whereas there was no difference in legumain among children and young adults with FH compared to controls. Legumain was further associated with cardiovascular risk markers in the FH population. However the role of legumain in regulation of cardiovascular risk in these individuals is still to be determined.

• Sæther, Linn Sofie; Ueland, Thor; Haatveit, Beathe; Vaskinn, Anja; Flaaten, Camilla Bärthel & Mohn, Hanne Christine [Show all 12 contributors for this article] (2024). Longitudinal course of inflammatory-cognitive subgroups across first treatment severe mental illness and healthy controls. Psychological Medicine. ISSN 0033-2917. 54, p. 3519–3529. doi: 10.1017/S003329172400206X. Full text in Research Archive Show summary

  Background - While inflammation is associated with cognitive impairment in severe mental illnesses (SMI), there is substantial heterogeneity and evidence of transdiagnostic subgroups across schizophrenia (SZ) and bipolar (BD) spectrum disorders. There is however, limited knowledge about the longitudinal course of this relationship.<p> <p>Methods - Systemic inflammation (C-Reactive Protein, CRP) and cognition (nine cognitive domains) was measured from baseline to 1 year follow-up in first treatment SZ and BD (n = 221), and healthy controls (HC, n = 220). Linear mixed models were used to evaluate longitudinal changes separately in CRP and cognitive domains specific to diagnostic status (SZ, BD, HC). Hierarchical clustering was applied on the entire sample to investigate the longitudinal course of transdiagnostic inflammatory-cognitive subgroups.<p> <p>Results - There were no case-control differences or change in CRP from baseline to follow-up. We confirm previous observations of case-control differences in cognition at both time-points and domain specific stability/improvement over time regardless of diagnostic status. We identified transdiagnostic inflammatory-cognitive subgroups at baseline with differing demographics and clinical severity. Despite improvement in cognition, symptoms and functioning, the higher inflammation – lower cognition subgroup (75% SZ; 48% BD; 38% HC) had sustained inflammation and lower cognition, more symptoms, and lower functioning (SMI only) at follow-up. This was in comparison to a lower inflammation – higher cognition subgroup (25% SZ, 52% BD, 62% HC), where SMI participants showed cognitive functioning at HC level with a positive clinical course.<p> <p>Conclusions - Our findings support heterogenous and transdiagnostic inflammatory-cognitive subgroups that are stable over time, and may benefit from targeted interventions.

• Ildstad, Fredrik; Wethal, Torgeir; Ellekjær, Hanne; Lydersen, Stian; Mollnes, Tom Eirik & Ueland, Thor [Show all 8 contributors for this article] (2024). Five-Year Risk of Cardiovascular Events after Transient Ischemic Attack: Results from a Prospective Cohort. Acta Neurologica Scandinavica. ISSN 0001-6314. 2024:982336, p. 1–9. doi: 10.1155/2024/4982336. Full text in Research Archive Show summary

  Objectives. There are few contemporary, prospective studies reporting on the long-term risk of stroke and other cardiovascular (CV) events after transient ischemic attack (TIA). The primary aim was to examine the risk of new CV events within 5 years after TIA. The secondary aim was to identify baseline predictors of long-term CV events, including inflammatory biomarkers in a subgroup analysis. Materials and Methods. In a prospective, multicenter study, we enrolled 577 TIA patients between 2012 and 2014. The primary outcome was a composite of stroke, acute coronary syndrome, and CV death. We used data from the Norwegian Cardiovascular Disease Registry. In a subgroup of 112 patients, blood samples were analyzed for inflammatory biomarkers. Results. The primary outcome occurred in 108 patients (18.7%), of which 69 patients (12.0%) had a stroke. Sixty-one (56.5%) of the events occurred during year two through five. Increasing age (HR 1.05; 95% CI, 1.03-1.08), male sex (HR 1.82; 95% CI, 1.16-2.85), hypertension (HR 1.67; 95% CI, 1.04-2.67), and acute infarction on brain imaging (HR 1.84; 95% CI, 1.17-2.91) were significant predictors for the primary outcome. In the subgroup analysis, none of the blood inflammatory biomarkers were associated with CV events. Conclusions. The risk of CV events was highest during the first year after TIA, with a lower but sustained risk throughout the follow-up. This emphasizes the importance of both early initiation of and long-term continuation of secondary preventive treatment after TIA. Inflammatory biomarkers are probably not important as prognostic markers of cardiovascular disease in TIA patients.

• Steen, Nils Eiel; Rahman, Zillur; Szabo, Attila; Hindley, Guy; Parker, Nadine & Cheng, Weiqiu [Show all 20 contributors for this article] (2023). Shared Genetic Loci Between Schizophrenia and White Blood Cell Counts Suggest Genetically Determined Systemic Immune Abnormalities. Schizophrenia Bulletin. ISSN 0586-7614. 49(5), p. 1345–1354. doi: 10.1093/schbul/sbad082. Full text in Research Archive Show summary

  Background: Immune mechanisms are indicated in schizophrenia (SCZ). Recent genome-wide association studies (GWAS) have identified genetic variants associated with SCZ and immune-related phenotypes. Here, we use cutting edge statistical tools to identify shared genetic variants between SCZ and white blood cell (WBC) counts and further understand the role of the immune system in SCZ. Study Design: GWAS results from SCZ (patients, n = 53 386; controls, n = 77 258) and WBC counts (n = 56 3085) were analyzed. We applied linkage disequilibrium score regression, the conditional false discovery rate method and the bivariate causal mixture model for analyses of genetic associations and overlap, and 2 sample Mendelian randomization to estimate causal effects. Study Results: The polygenicity for SCZ was 7.5 times higher than for WBC count and constituted 32%–59% of WBC count genetic loci. While there was a significant but weak positive genetic correlation between SCZ and lymphocytes (rg = 0.05), the conditional false discovery rate method identified 383 shared genetic loci (53% concordant effect directions), with shared variants encompassing all investigated WBC subtypes: lymphocytes, n = 215 (56% concordant); neutrophils, n = 158 (49% concordant); monocytes, n = 146 (47% concordant); eosinophils, n = 135 (56% concordant); and basophils, n = 64 (53% concordant). A few causal effects were suggested, but consensus was lacking across different Mendelian randomization methods. Functional analyses indicated cellular functioning and regulation of translation as overlapping mechanisms. Conclusions: Our results suggest that genetic factors involved in WBC counts are associated with the risk of SCZ, indicating a role of immune mechanisms in subgroups of SCZ with potential for stratification of patients for immune targeted treatment.

• Woxholt, Sindre; Ueland, Thor; Aukrust, Pål; Anstensrud, Anne Kristine; Broch, Kaspar & Tøllefsen, Ingvild Maria [Show all 20 contributors for this article] (2023). Cytokine pattern in patients with ST-elevation myocardial infarction treated with the interleukin-6 receptor antagonist tocilizumab. Open heart. 10(2), p. 1–8. doi: 10.1136/openhrt-2023-002301. Full text in Research Archive Show summary

  Background Tocilizumab improves myocardial salvage index (MSI) in patients with ST-elevation myocardial infarction (STEMI), but its mechanisms of action are unclear. Here, we explored how cytokines were affected by tocilizumab and their correlations with neutrophils, C-reactive protein (CRP), troponin T, MSI and infarct size. Methods STEMI patients were randomised to receive a single dose of 280 mg tocilizumab (n=101) or placebo (n=98) before percutaneous coronary intervention. Blood samples were collected before infusion of tocilizumab or placebo at baseline, during follow-up at 24–36, 72–168 hours, 3 and 6 months. 27 cytokines were analysed using a multiplex cytokine assay. Cardiac MRI was performed during hospitalisation and 6 months. Results Repeated measures analysis of variance showed significant (p<0.001) between-group difference in changes for IL-6, IL-8 and IL-1ra due to an increase in the tocilizumab group during hospitalisation. IL-6 and IL-8 correlated to neutrophils in the placebo group (r=0.73, 0.68, respectively), which was attenuated in the tocilizumab group (r=0.28, 0.27, respectively). A similar pattern was seen for MSI and IL-6 and IL-8 in the placebo group (r=−0.29, –0.25, respectively) in patients presenting ≤3 hours from symptom onset, which was attenuated in the tocilizumab group (r=−0.09,–0.14, respectively). Conclusions Tocilizumab increases IL-6, IL-8 and IL-1ra in STEMI. IL-6 and IL-8 show correlations to neutrophils/CRP and markers of cardiac injury in the placebo group that was attenuated in the tocilizumab group. This may suggest a beneficial effect of tocilizumab on the ischaemia-reperfusion injury in STEMI patients.

• 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.

• Hindley, Guy; Drange, Ole Kristian; Lin, Aihua; Kutrolli, Gleda; Shadrin, Alexey & Parker, Nadine [Show all 20 contributors for this article] (2023). Cross-trait genome-wide association analysis of C-reactive protein level and psychiatric disorders. Psychoneuroendocrinology. ISSN 0306-4530. 157. doi: 10.1016/j.psyneuen.2023.106368. Full text in Research Archive Show summary

  C-reactive protein (CRP) tends to be elevated in individuals with psychiatric disorders. Recent findings have suggested a protective effect of the genetic liability to elevated CRP on schizophrenia risk and a causative effect on depression despite weak genetic correlations, while causal relationships with bipolar disorder were inconclusive. We investigated the shared genetic underpinnings of psychiatric disorders and variation in CRP levels. Genome-wide association studies for CRP (n = 575,531), bipolar disorder (n = 413,466), depression (n = 480,359), and schizophrenia (n = 130,644) were used in causal mixture models to compare CRP with psychiatric disorders based on polygenicity, discoverability, and genome-wide genetic overlap. The conjunctional false discovery rate method was used to identify specific shared genetic loci. Shared variants were mapped to putative causal genes, which were tested for overrepresentation among gene ontology gene-sets. CRP was six to ten times less polygenic (n = 1400 vs 8600–14,500 variants) and had a discoverability one to two orders of magnitude higher than psychiatric disorders. Most CRP-associated variants were overlapping with psychiatric disorders. We identified 401 genetic loci jointly associated with CRP and psychiatric disorders with mixed effect directions. Gene-set enrichment analyses identified predominantly CNS-related gene sets for CRP and each of depression and schizophrenia, and basic cellular processes for CRP and bipolar disorder. In conclusion, CRP has a markedly different genetic architecture to psychiatric disorders, but the majority of CRP associated variants are also implicated in psychiatric disorders. Shared genetic loci implicated CNS-related processes to a greater extent than immune processes, which may have implications for how we conceptualise causal relationships between CRP and psychiatric disorders.

• Ueland, Thor; Waagsbø, Bjørn; Berge, Rolf Kristian; Trøseid, Marius; Aukrust, Pål & Damås, Jan Kristian (2023). Fatty Acids Composition and HIV Infection: Altered Levels of n-6 Polyunsaturated Fatty Acids Are Associated with Disease Progression. Viruses. 15(7). doi: 10.3390/v15071613. Full text in Research Archive Show summary

  Fatty acids (FAs) are important regulators of immune responses and innate defense mechanisms. We hypothesized that disturbed FA metabolism could contribute to the progression of HIV infection. Plasma levels of 45 FAs were analyzed with gas chromatography in healthy controls and HIV-infected patients with regard to Mycobacterium avium complex (MAC) infection. In vitro, we assessed MAC-PPD-induced release of inflammatory cytokines in peripheral and bone marrow mononuclear cells (PBMC and BMMC) according to levels of n-6 polyunsaturated fatty acids (PUFAs). While plasma saturated FAs were higher in HIV infection, PUFAs, and in particular the n-6 PUFA arachidonic acid (AA), were lower in patients with advanced disease. The ratio between AA and precursor dihomo-γ-linolenic acid, reflecting Δ5-desaturase activity, was markedly lower and inversely correlated with plasma HIV RNA levels in these patients. Depletion of AA was observed prior to MAC infection, and MAC-PPD-induced release of TNF and IL-6 in PBMC and BMMC was lower in patients with low plasma AA. Our findings suggest that dysregulated metabolism of n-6 PUFAs may play a role in the progression of HIV infection. While high AA may contribute to chronic inflammation in asymptomatic HIV-infected patients, low AA seems to increase the susceptibility to MAC infection in patients with advanced disease.

• Hansen, Ellen-Sofie; Edvardsen, Magnus; Aukrust, Pål; Ueland, Thor; Hansen, John Bjarne & Brækkan, Sigrid Kufaas [Show all 7 contributors for this article] (2023). Combined effect of high factor VIII levels and high mean platelet volume on the risk of future incident venous thromboembolism. Journal of Thrombosis and Haemostasis. ISSN 1538-7933. doi: 10.1016/j.jtha.2023.06.022. Full text in Research Archive Show summary

  Background - High factor VIII (FVIII) levels and large platelets, as reflected by a high mean platelet volume (MPV), are separately associated with increased risk of venous thromboembolism (VTE). Whether the combination of high FVIII levels and large platelets has a supra-additive effect on VTE risk is unknown.<p> <p>Objectives - We aimed to investigate the joint effect of high FVIII levels and large platelets, as reflected by high MPV, on the risk of future incident VTE.<p> <p>Methods - A population-based nested case-control study with 365 incident VTE cases and 710 controls was derived from the Tromsø study. FVIII antigen levels and MPV were measured in blood samples drawn at baseline. Odds ratios with 95% CIs were estimated across FVIII tertiles (<85%, 85%-108%, and ≥108%) and within predefined MPV strata (<8.5, 8.5-9.5, and ≥9.5 fL).<p> <p>Results - VTE risk increased linearly across FVIII tertiles (Ptrend < .001) in models adjusted for age, sex, body mass index, and C-reactive protein. In the combined analysis, participants with FVIII levels in the highest tertile and an MPV of ≥9.5 fL (ie, joint exposure) had an odds ratio for VTE of 2.71 (95% CI, 1.44-5.11) compared with those with FVIII levels in the lowest tertile and an MPV of <8.5 fL (reference). In the joint exposure group, 52% (95% CI, 17%-88%) of VTEs were attributable to the biological interaction between FVIII and MPV.<p> <p>Conclusion - Our results suggest that large platelets, as reflected by high MPV, might play a role in the mechanism by which high FVIII level increases the risk of incident VTE.

• Swamy, Samantha; Ueland, Thor; Hansen, John Bjarne; Snir, Omri & Brækkan, Sigrid Kufaas (2023). Plasma levels of P-selectin and future risk of incident venous thromboembolism. Journal of Thrombosis and Haemostasis. ISSN 1538-7933. 21(9), p. 2451–2460. doi: 10.1016/j.jtha.2023.04.038. Full text in Research Archive Show summary

  Background - P-selectin levels are elevated following acute deep vein thrombosis and reported to predict recurrent venous thromboembolism (VTE) and cancer-associated VTE. Yet, it is unknown whether plasma P-selectin levels are associated with incident VTE.<p> <p>Objectives - We aimed to investigate the association between plasma P-selectin levels and risk of future incident VTE.<p> <p>Methods - We performed a nested case-control study in 415 patients with VTE and 843 age- and sex-matched controls derived from the general population (Tromsø IV Study). Plasma P-selectin levels were measured using enzyme-linked immunosorbent assay. Logistic regression models were used to estimate odds ratios (ORs) for VTE across quartiles of plasma P-selectin level. Sex-stratified analysis was also performed.<p> <p>Results - Plasma P-selectin levels were higher in men (41.4 ng/mL) than in women (38.7 ng/mL, p = .0046). We found no association between plasma P-selectin levels and risk of VTE in the overall analyses. However, sex-stratified analyses revealed that women with P-selectin levels in the highest quartile (>44.3 ng/mL) had higher risk of VTE (OR, 1.63; 95% CI, 1.01-2.64) than women with P-selectin levels in the lowest quartile (≤29.9 ng/mL). In contrast, higher levels of P-selectin were apparently associated with lower risk of VTE in men (OR for highest vs lowest quartile of P-selectin, 0.69; 95% CI, 0.42-1.15). The observed associations were stronger when the time between blood sampling and VTE was shorter.<p> <p>Conclusion - Elevated levels of plasma P-selectin were associated with increased risk of VTE in women but not in men, suggesting a differential impact of sex on the association between P-selectin and VTE risk.

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• Nilsen, Dennis WT; Fuente, Ricardo Leon de la; Gallo, P.; Næsgaard, Patrycja; Ashur, S. Dib & Michelsen, A.E. [Show all 9 contributors for this article] (2025). Reply to: Reinterpreting interleukin-1 receptor antagonist elevation in acute myocardial infarction. International Journal of Cardiology. ISSN 0167-5273. 441, p. 133797–133797. doi: 10.1016/j.ijcard.2025.133797. 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: 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.

• Dahl, Tuva Børresdatter; Aftab, Friha; Prebensen, Christian Haugland; Berdal, Jan-Erik; Ueland, Thor & Barratt-Due, Andreas [Show all 15 contributors for this article] (2025). Imidazole propionate is increased in severe COVID-19 and correlates with cardiac involvement. Journal of Infection. ISSN 0163-4453. 90(6). doi: 10.1016/j.jinf.2025.106494. Full text in Research Archive
• 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
• Hansen, Ellen-Sofie; Edvardsen, Magnus; Aukrust, Pål; Ueland, Thor; Hansen, John Bjarne & Brækkan, Sigrid Kufaas [Show all 7 contributors for this article] (2024). Galectin-3-binding protein and future venous thromboembolism. Research and Practice in Thrombosis and Haemostasis (RPTH). 8(1). doi: 10.1016/j.rpth.2023.102311. Full text in Research Archive
• Hindley, Guy; Drange, Ole Kristian; Lin, Aihua; Kutrolli, Gleda; Shadrin, Alexey & Parker, Nadine [Show all 20 contributors for this article] (2024). Corrigendum to “Cross-trait genome-wide association analysis of C-reactive protein level and psychiatric disorders” [Psychoneuroendocrinology 157 (2023) 106368] (Psychoneuroendocrinology (2023) 157, (S0306453023003463), (10.1016/j.psyneuen.2023.106368)). Psychoneuroendocrinology. ISSN 0306-4530. doi: 10.1016/j.psyneuen.2024.106980. 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.

• Gjerde, Kristian Varden; Bartz-Johannessen, Christoffer; Løberg, Else-Marie; Steen, Vidar Martin; Steen, Nils Eiel & Andreassen, Ole [Show all 12 contributors for this article] (2024). Cellular adhesion molecules and cognition in drug-naïve and previously medicated patients with schizophrenia-spectrum disorders: A longitudinal study. Full text in Research Archive

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