Bente Evy Halvorsen

• 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
• 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
• Holven, Kirsten Bjørklund; Dahl, Tuva Børresdatter; Bålsrud, Pia; Christensen, Jacob Juel; Ottestad, Inger Olaug & Rundblad, Amanda [Show all 15 contributors for this article] (2026). Cetoleic acid rich fish oil increases plasma levels of eicosapentaenoic and docosapentaenoic acids in healthy volunteers: a double-blinded, randomised, controlled trial. British Journal of Nutrition. ISSN 0007-1145. p. 1–28. doi: 10.1017/S0007114526107958. Full text in Research Archive Show summary

  Intake of fish and supplementation with n-3 polyunsaturated fatty acids (PUFA) are associated with reduced incidence of cardiovascular disease (CVD). Cetoleic acid promotes n-3 PUFA generation in salmon and human HepG2 cells, but data in humans are scarce. To explore the effect of cetoleic acid on n-3 PUFA levels, we performed a double-blinded randomised controlled trial in healthy adults (37 females and 12 males) for four weeks. The participants were randomised to consume either capsules with mackerel oil, naturally rich in cetoleic acid, or a control oil, both with a similar concentration of n-3 PUFA. Clinicaltrials.gov (NCT04841044). Supplements with mackerel oil resulted in higher plasma levels of the n-3 PUFAs 20:4n-3 (Eicosatetraenoic acid) and 20:5n-3 (Eicosapentaenoic acid) as compared with those receiving control oil. In addition, those who received the cetoleic-rich capsules had higher levels of 20:4n-3 in the RBC membrane and a decrease in expression of elongation of very long chain fatty acids protein 5 in peripheral blood mononuclear cells. We found no differences in lipid, glucose or C-reactive protein between the two treatment groups, consisting of healthy subjects. Our data suggests that supplementation with cetoleic-rich mackerel oil may result in increased levels of certain n-3 PUFAs. Further studies should include patients with or at risk for metabolic and CVD.

• 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
• Myhre, Anders Eivind; Meyer-Myklestad, Malin Holm; Gullaksen, Hanne Hestdal; Søgaard, Ole S.; Tolstrup, Martin & Salgado, Maria [Show all 51 contributors for this article] (2026). Long-term HIV-1 remission achieved through allogeneic haematopoietic stem cell transplant from a CCR5Δ32/Δ32 sibling donor. Nature Microbiology. 11, p. 1374–1386. doi: 10.1038/s41564-026-02304-8. Full text in Research Archive Show summary

  Only few cases of human immunodeficiency virus (HIV) remission have been reported after allogeneic haematopoietic stem cell transplantation (HSCT), mostly involving stem cell donors with the homozygous CCR5Δ32 (CCR5Δ32/Δ32) mutation, which confers resistance to CCR5-tropic HIV-1. Here we report the case of a 63-year-old man in off-treatment HIV remission, 5 years after HSCT with a CCR5Δ32/Δ32 sibling donor for myelodysplastic syndrome. In-depth clinical characterization including virological and immunological analyses of peripheral blood, gut and bone marrow samples revealed that full donor chimerism was achieved. Antiretroviral therapy was discontinued after 24 months, and 48 months after HSCT, no intact HIV DNA was detected in blood or gut biopsies. Replication-competent virus and HIV-specific T cell responses were absent, and HIV antibody responses showed a gradual decline. Full donor chimerism in the gut, which is the primary viral reservoir, underscores the likelihood of a cure.

• 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
• Dukefoss, Henrik B.; Andresen, Kristoffer; Harbo, Markus Borge; Hasselberg, Nina Eide; Grødem, Herman & Korsæth, Truls [Show all 18 contributors for this article] (2026). Validation of shear wave elastography for assessing myocardial fibrosis in patients with end-stage heart failure. European Heart Journal-Cardiovascular Imaging. ISSN 2047-2404. 27(4), p. 778–787. doi: 10.1093/ehjci/jeaf375. 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.

• Høgestøl, Einar August; Brustad, Åge Winje; Celius, Elisabeth Gulowsen; Meling, Martine; Berg-Hansen, Pål & Kro, Grete Anette Birkeland [Show all 13 contributors for this article] (2026). Serum drug levels and JCV assay discrepancies after switching from originator to biosimilar natalizumab. BMJ Neurology Open. 8(1). doi: 10.1136/bmjno-2025-001477. Full text in Research Archive
• Otterdal, Kari; Ueland, Thor; Holter, Jan Cato; Kaarbø, Mari; Schanke, Ylva & Granerud, Beathe Kiland [Show all 18 contributors for this article] (2026). Platelet-derived mediators in hospitalized COVID-19 patients and associations to respiratory failure, ICU admittance and 60-day mortality. Frontiers in Cardiovascular Medicine. 13. doi: 10.3389/fcvm.2026.1685861. Full text in Research Archive Show summary

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

• Ueland, Thor; Andersen, Geir Øystein; Sharanga, Varathalingam; Khan, Yusuf; Holm, Sverre & Limalanathan, Shanmuganathan [Show all 12 contributors for this article] (2026). Circulating B-cell activating factor in acute coronary syndromes – association with adverse outcomes and progression of heart failure. Atherosclerosis. ISSN 0021-9150. 414. doi: 10.1016/j.atherosclerosis.2026.120642. Full text in Research Archive
• Jacobsen, Daniel Pitz; Fjeldstad, Heidi; Olsen, Maria Belland; Sugulle, Meryam; Schjørlien, Therese & Skjelland, Mona Elisabeth [Show all 8 contributors for this article] (2025). Postpartum levels of circulating fetal microchimeric cells are lower after early-onset preeclampsia. Journal of Reproductive Immunology. ISSN 0165-0378. 172. doi: 10.1016/j.jri.2025.104646. Full text in Research Archive Show summary

  Fetal cells may persist in the mother following pregnancy, termed fetal microchimerism. These cells have been attributed positive and negative effects. The number of fetal cells transferred during pregnancy appears to be higher in preeclampsia. Here, we investigate whether fetal cell presence and quantity in the maternal circulation 1–8 years postpartum is influenced by a previous preeclamptic pregnancy. We also relate fetal cells detected postpartum to fetal cells detected during pregnancy, time since index pregnancy, parity, fetal sex and maternal characteristics. A cohort of 139 women was included in the present study: 21 with previous early-onset preeclampsia, 31 with previous late-onset preeclampsia and 87 with a clinically uncomplicated index pregnancy. Circulating fetal microchimerism was detected in maternal buffy coat using qPCR, targeting alleles unique to the fetus. Pregnancy buffy coat samples were available for 129 of the 139 included women. Early-onset, but not late-onset, preeclampsia was associated with reduced quantity of fetal microchimeric cells in maternal circulation postpartum. Fetal cells detected during pregnancy, time since index pregnancy, parity, fetal sex and maternal characteristics were not predictive of microchimerism postpartum in our cohort. Our findings suggest that early-onset, but not late-onset preeclampsia, affects circulating microchimerism postpartum. Our observation that fetal microchimerism postpartum did not correlate with number of fetal cells detected during pregnancy nor time since index pregnancy supports the notion that fetal microchimerism is a dynamic phenomenon, with fetal cells moving in and out of maternal circulation and surrounding tissues, possibly affected by the current physiologic state of the mother.

• Dahl, Tuva Børresdatter; Jimenez, Ana Maria Teresa Quiles; Broch, Kaspar; Anstensrud, Anne Kristine; Gullestad, Lars & Andersen, Geir Øystein [Show all 16 contributors for this article] (2025). The N-6 methyladenosine dynamics in STEMI and the effect of IL-6 inhibition - a hypothesis generating sub-study of the ASSAIL-MI trial. Frontiers in Immunology. 16. doi: 10.3389/fimmu.2025.1532325. Full text in Research Archive Show summary

  Background: Epitranscriptomics, with m6A as the most prevalent in mammals, is a novel treatment target for inflammatory diseases, including cardiovascular diseases. However, little is known about m6A RNA-regulation during myocardial infarction (MI). Methods: In this explorative sub-study of the ASSAIL-MI trial, we used whole blood samples from patients with acute ST-elevation MI (STEMI) (n=6) at admission and after 3–7 days, and from healthy control subjects (n=3). RNA was isolated, and m6A sites were analyzed using human m6A single nucleotide resolution microarray analysis. mRNA levels were analyzed using RNA sequencing analysis. Results: Compared with controls, patients with STEMI had a strikingly different pattern of m6A deposition. In total, 845 m6A methylation sites in whole blood RNA were hypomethylated and 36 were hypermethylated compared with controls. Of the hypomethylated transcripts, 194 transcripts were lower expressed, while 197 transcripts were higher expressed. The m6A pattern changed from an overall hypomethylation at admission to an overall hypermethylation 3–7 day after admission. Anti-inflammatory treatment with tocilizumab further altered the m6A deposition. Conclusions: In this hypothesis generating study, m6A deposition differs STEMI patients and healthy controls. The m6A pattern changes over the course of 3–7 days. This response is, at least to some degree, is modulated by blocking the IL-6 receptor. Our data may suggest that this post-transcriptional regulation of RNA is involved in the immune response during STEMI, highlighting its potential as a target for therapy in MI.

• 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
• Melnes, Torunn; Bogsrud, Martin Prøven; Christensen, Jacob J.; Rundblad, Amanda; Retterstøl, Kjetil & Narverud, Ingunn [Show all 10 contributors for this article] (2025). LDL cholesterol burden in elderly patients with familial hypercholesterolemia: Insights from real-world data. American Journal of Preventive Cardiology. 22. doi: 10.1016/j.ajpc.2025.100986. Full text in Research Archive Show summary

  Background and aims Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated low-density lipoprotein cholesterol (LDL-C) and increased risk of premature coronary heart disease (CHD). While current LDL-C levels usually guides therapy, the cumulative exposure to LDL-C (the LDL-C burden) is suggested to offer a more precise estimate of cardiovascular risk in people with FH. Therefore, using real-world data, this study aimed to estimate the LDL-C burden at different ages in elderly FH patients with and without CHD, and to assess the LDL-C burden at CHD onset. Methods Data was retrospectively collected from the medical records of elderly (>60 years) FH patients at the Lipid Clinic in Oslo. The LDL-C burden (mM-years) was estimated based on repeated LDL-C measurements and information on lipid-lowering medication. Time-weighted average (TWA) LDL-C was calculated as LDL-C burden divided by years. Results We included 112 FH patients, of which 55 (49 %) had experienced at least one CHD-event, and 58 (52 %) were females. Median age at first and last visit were 50 years and 68 years, respectively, with a median of 9 (range; 2–14) available LDL-C measurements. Subjects with CHD had higher LDL-C burden at all ages tested (45, 50 and 60 years) compared with the non-CHD group (p < 0.01, also after adjusting for sex), and had higher TWA LDL-C before treatment at the Lipid Clinic (p = 0.004), but not during follow-up (p = 0.6). There were no sex differences in LDL-C burden at all ages tested, also after adjusting for CHD (p > 0.1). However, women had higher TWA LDL-C during follow-up at the Lipid Clinic (p = 0.01). Median LDL-C burden at CHD onset was 352 mM-years; numerically lower in women than in men (320 vs. 357 mM-years, respectively. p = 0.1). Conclusion Elderly FH patients with CHD had higher estimated LDL-C burden compared with FH patients without CHD, due to higher burden prior to treatment, highlighting the importance of early detection and treatment.

• 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 .

• Thulin, Malin Hagberg; Ramberg, Håkon; Nielsen, Heidi Kristin; Grytli, Helene Hartvedt; Sivanesan, Shivanthe & Pandya, Abhilash D. [Show all 15 contributors for this article] (2025). Beta-blockers prolong response to androgen deprivation therapy in prostate cancer through modulation of the neuro-immuno-oncology axis. Journal of Translational Medicine. 23(1). doi: 10.1186/s12967-025-06644-7. Full text in Research Archive Show summary

  Background The therapeutic impact of beta-blockers (BB), beta-adrenergic receptor antagonists, on prostate cancer remains controversial. The underlying health conditions of BB users complicate the ability to isolate and evaluate the specific effects of these drugs on the tumour cells. This study investigated whether BBs, by inhibiting sympathetic nerve signalling, extended the duration of androgen deprivation therapy (ADT) effectiveness in patients with de novo metastatic hormone sensitive prostate cancer and in prostate cancer xenograft models, while also uncovering the molecular mechanisms involved. Methods An analysis was conducted on prospectively collected data from the Cancer Registry of Norway, Norwegian Prescription Database, and Norwegian Cause of Death Registry focusing on patients with de novo metastatic prostate cancer undergoing ADT using the commencement of second-line treatment as the endpoint. In addition, the causal effect of BB treatment was studied in two different hormone-sensitive prostate cancer xenograft mouse models. Prior to treatment, mice were surgically castrated, to mimic ADT, and tumour progression was tracked by measuring serum PSA levels. RNA sequencing was performed on xenografted orthotopic tumours to investigate the underlying mechanisms, utilizing annotation based on human data and protein levels were validated by the Protein Simple Immunoassay. Immune-related effects were evaluated using immunohistochemistry on tumour tissue and measuring neopterin levels, along with 92 analytes, using the OLINK proximity extension assay on serum samples from xenografted mice and prostate cancer patients, both BB users and non-users. Results A competitive risk analysis indicated that BB treatment postponed the initiation of second-line treatment in prostate cancer patients on ADT. Additionally, in both prostate cancer xenograft models, BB treatment reduced tumour burden and delayed progression to castration-resistant prostate cancer. Mechanistically, BB treatment suppressed androgen receptor signalling and induced a metabolic shift by up-regulating oxidative phosphorylation transcripts and down-regulating those involved in fatty acid synthesis and the PI3K/AKT/mTOR pathway. Additionally, BB treatment increased serum pro-inflammatory cytokines, such as the IL23/IL17 axis, in both xenografted mice and in patient samples. Enhanced intra-tumoral CD68+ immune cell infiltration was also observed in the tumours. Conclusion The data suggest that BB combined with ADT delay the progression to castration-resistant prostate cancer. This may be achieved by influencing androgen receptor activity, adjusting energy metabolism and fostering a pro-inflammatory antitumoral microenvironment

• Saeed, Sahrai; Eriksen, Erlend; Aukrust, Pål; Halvorsen, Bente; Løland, Kjetil Halvorsen & Bleie, Øyvind [Show all 7 contributors for this article] (2025). Clinical outcomes and patients' perspective of fatigue following spontaneous coronary artery dissection. Coronary Artery Disease. ISSN 0954-6928. 36(6), p. e62–e63. doi: 10.1097/MCA.0000000000001499. Full text in Research Archive
• 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
• Granerud, Beathe Kiland; Kaarbø, Mari; Al-Baldawi, Huda; Heggelund, Lars; Tveita, Anders & Müller, Karl Erik [Show all 42 contributors for this article] (2025). Droplet Digital PCR or Real-Time PCR as a Method for Quantifying SARS-CoV-2 RNA in Plasma-Is There a Difference? Viruses. 17(6). doi: 10.3390/v17060772. Full text in Research Archive Show summary

  The aim of this study is to ascertain whether qRT-PCR (reverse transcriptase real-time PCR) or RT-ddPCR (reverse transcriptase digital droplet PCR) is more effective for detecting SARS-CoV-2 RNA (severe acute respiratory syndrome coronavirus 2 RNA) in blood plasma from COVID-19 (coronavirus infectious disease-19) patients. The E-gene of SARS-CoV-2 RNA was quantified using both methods in 128 plasma samples from 70 hospitalized patients, followed by a statistical analysis to compare the sensitivity and concordance between the methods. Out of the 128 samples, 89 yielded consistent results irrespective of the method used, whereas 39 samples showed discrepancies between the two different methods. RT-ddPCR frequently registered higher viral quantities compared to qRT-PCR; however, the results did not demonstrate a clear superiority in sensitivity for RT-ddPCR. Although RT-ddPCR registered higher viral quantities, this study concludes that both methods provide comparable results for detecting SARS-CoV-2 E-gene RNA in plasma.

• 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
• 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
• 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]

• Udjus, Camilla; Halvorsen, Bente; Kong, Xiang Yi; Sagen, Ellen Lund; Martinsen, Marita & Yang, Kuan [Show all 10 contributors for this article] (2024). Alveolar hypoxia induces organ-specific inflammasome-related inflammation in male mouse lungs. Physiological Reports. 12:e16143(14), p. 1–13. doi: 10.14814/phy2.16143. Full text in Research Archive Show summary

  Inflammation through activation of caspase-1, seems to play a role in pulmonary hypertension induced by alveolar hypoxia. Whether alveolar hypoxia induces caspase-1-mediated inflammation and influx of leukocytes in other organs than the lungs, is not known. Our aim was to explore sites of caspase-1-related inflammation in alveolar hypoxia. Wild type (WT) mice were exposed to environmental hypoxia or room-air, and organs were analyzed. Right heart catheterization was performed after 14 days of alveolar hypoxia in WT mice and mice transplanted with WT or caspase-1−/− bone marrow. Hypoxia induced leukocyte accumulation and increased caspase-1 protein in the lungs, not in other organs. WT mice transplanted with WT or caspase-1−/− bone marrow showed no difference in pulmonary leukocyte accumulation or development of pulmonary hypertension after alveolar hypoxia. Caspase-1 and IL-18 were detected in bronchial epithelium in WT mice, and hypoxia induced IL-18 secretion from bronchial epithelial cells. IL-18 stimulation generated IL-6 mRNA in monocytes. Phosphorylated STAT3 was increased in hypoxic lungs, not in other organs. Alveolar hypoxia induces caspase-1 activation and leukocyte accumulation specific to the lungs, not in other organs. Caspase-1 activation and IL-18 secretion from bronchial epithelial cells might initiate hypoxia-induced inflammation, leading to pulmonary hypertension.

• 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.

• Olsen, Maria Belland; Kong, Xiang Yi; Louwe, Maria; Lauritzen, Knut Husø; Schanke, Ylva & Kaasbøll, Ole Jørgen [Show all 14 contributors for this article] (2024). SLAMF1-derived peptide exhibits cardio protection after permanent left anterior descending artery ligation in mice. Frontiers in Immunology. 15. doi: 10.3389/fimmu.2024.1383505. Full text in Research Archive Show summary

  Acute myocardial infarction (MI) results in tissue damage to affected areas of the myocardium. The initial inflammatory response is the most damaging for residual cardiac function, while at later stages inflammation is a prerequisite for proper healing and scar formation. Balancing the extent and duration of inflammation during various stages after MI is thus pivotal for preserving cardiac function. Recently, a signaling lymphocytic activation molecule 1 (SLAMF1)-derived peptide (P7) was shown to reduce the secretion of inflammatory cytokines and protected against acute lipopolysaccharide-induced death in mice. In the present study, we experimentally induced MI by permanent ligation of the left anterior descending artery (LAD) in mice and explored the beneficial effect of immediately administering P7, with the aim of dampening the initial inflammatory phase without compromising the healing and remodeling phase. Blood samples taken 9 h post-LAD surgery and P7 administration dampened the secretion of inflammatory cytokines, but this dampening effect of P7 was diminished after 3 days. Echocardiography revealed less deterioration of cardiac contraction in mice receiving P7. In line with this, less myocardial damage was observed histologically in P7-treated mice. In conclusion, the administration of a SLAMF1-derived peptide (P7) immediately after induction of MI reduces the initial myocardial inflammation, reduces infarct expansion, and leads to less deterioration of cardiac contraction.

• Zamani, Mahtab; Skagen, Karolina Ryeng; Lindberg, Beate; Bjerkeli, Vigdis; Aukrust, Pål & Halvorsen, Bente [Show all 7 contributors for this article] (2024). Relationship between fibroblast growth factor in plasma and carotid plaque neovascularization: a pilot study. Frontiers in Immunology. 15, p. 1–6. doi: 10.3389/fimmu.2024.1385377. Full text in Research Archive Show summary

  Background: Unstable atherosclerotic carotid plaques with intraplaque neovascularization (IPN) carry a substantial risk for ischemic stroke. Conventional ultrasound methods fall short in detecting IPN, where superb microvascular imaging (SMI) has emerged as a promising tool for both visualizing and quantification. High levels of fibroblast growth factor 23 (FGF-23) have, in observational studies, been suggested as related to cardiovascular morbidity and mortality. The association of FGF-23 to atherosclerotic carotid plaque instability remains relatively unexplored. Methods: A cohort of twenty-nine patients with ≥50% atherosclerotic carotid stenosis underwent conventional carotid ultrasound, SMI, and blood tests, including measurement of FGF-23 in plasma. Nineteen patients were characterized as symptomatic and ten as asymptomatic. Results: Our major findings were: i) Higher FGF-23 levels were strongly correlated with increased SMI-assessed IPN. ii) Neo-vessel count recorded by quantitative SMI was positively correlated to increased FGF-23 levels, but not with basic FGF levels. (iii) In contrast, traditional risk factors for plaque instability exhibited no noteworthy associations with SMI-assessed IPN or with FGF-23 levels. Conclusion: This pilot study suggest the potential of FGF-23 as a valuable marker for neovascularization and atherosclerotic carotid plaque instability as a risk factor for ischemic stroke. Further research involving larger cohorts and prospective data is necessary to understand FGF-23’s role in this context comprehensively.

• Alirezaylavasani, Amin; Egner, Ingrid Marie; Dahl, Tuva Børresdatter; Chopra, Adity; Kasahara, Taissa de Matos & Goll, Guro Løvik [Show all 15 contributors for this article] (2024). Deficient SARS-CoV-2 hybrid immunity during inflammatory bowel disease. Clinical Immunology. ISSN 1521-6616. 271, p. 1–13. doi: 10.1016/j.clim.2024.110404. Full text in Research Archive Show summary

  Patients with Inflammatory Bowel Disease (IBD) undergoing immunosuppressive therapies face heightened susceptibility to severe COVID-19. An in-depth understanding of systemic inflammation and cellular immune responses after SARS-CoV-2 vaccination and breakthrough infections (BTI) is required for optimizing vaccine strategies in this population. While the prevalence of high serological responders post- third COVID-19 vaccine dose was lower, and the antibody waning was higher in IBD patients than in healthy donors (HD), IBD patients showed an increase in anti-RBD Wild Type IgG levels and cross-reactive Spike -specific memory B cells following BTI. However, there was no significant enhancement in cellular immune responses against anti-SARS-CoV-2 post-BTI, with responses instead characterized by activation of SARS-CoV-2 specific and also bystander CD8 T cells. These results suggest a complex interaction between chronic inflammation in IBD and the generation of new immune responses, highlighting the need for tailored vaccine regimens and anti-inflammatory therapies to boost cellular immunity against SARS-CoV-2.

• 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
• Holme, Fredric André; Huse, Camilla; Kong, Xiang Yi; Broch, Kaspar; Gullestad, Lars & Anstensrud, Anne Kristine [Show all 15 contributors for this article] (2024). Circular RNA Profile in Atherosclerotic Disease: Regulation during ST-Elevated Myocardial Infarction. International Journal of Molecular Sciences. ISSN 1661-6596. 25(16), p. 1–15. doi: 10.3390/ijms25169014. Full text in Research Archive Show summary

  Circular (circ) RNAs are non-coding RNAs with important functions in the nervous system, cardiovascular system, and cancer. Their role in atherosclerosis and myocardial infarction (MI) remains poorly described. We aim to investigate the potential circRNAs in immune cells during atherogenesis and examine the most regulated during MI and the modulation by interleukin (IL)-6 receptor inhibition by tocilizumab. Wild-type (WT) and ApoE−/− mice were fed an atherogenic diet for 10 weeks, and the circRNA profile was analyzed by circRNA microarray. Whole blood from patients with ST-elevated MI (STEMI) and randomized to tocilizumab (n = 21) or placebo (n = 19) was collected at admission, 3–7 days, and at 6 months, in addition to samples from healthy controls (n = 13). Primers for human circRNA were designed, and circRNA levels were measured using RT-qPCR. mRNA regulation of predicted circRNA targets was investigated by RNA sequencing. The expression of 867 circRNAs differed between atherogenic and WT mice. In STEMI patients, circUBAC2 was significantly lower than in healthy controls. CircANKRD42 and circUBAC2 levels were inversely correlated with troponin T, and for circUBAC2, an inverse correlation was also seen with final infarct size at 6 months. The predicted mRNA targets for circUBAC2 and circANKRD42 were investigated and altered levels of transcripts involved in the regulation of inflammatory/immune cells, apoptosis, and mitochondrial function were found. Finally, tocilizumab induced an up-regulation of circANKRD42 and circUBAC2 3–7 days after percutaneous coronary intervention. CircRNA levels were dysregulated in STEMI, potentially influencing the immune system, apoptosis, and mitochondrial function.

• Melnes, Torunn; Bogsrud, Martin Prøven; Christensen, Jacob Juel; Rundblad, Amanda; Narverud, Ingunn & Retterstøl, Kjetil [Show all 10 contributors for this article] (2024). Gene expression profiling in elderly patients with familial hypercholesterolemia with and without coronary heart disease. Atherosclerosis. ISSN 0021-9150. 392. doi: 10.1016/j.atherosclerosis.2024.117507. Full text in Research Archive Show summary

  Background and aims Elderly familial hypercholesterolemia (FH) patients are at high risk of coronary heart disease (CHD) due to high cholesterol burden and late onset of effective cholesterol-lowering therapies. A subset of these individuals remains free from any CHD event, indicating the potential presence of protective factors. Identifying possible cardioprotective gene expression profiles could contribute to our understanding of CHD prevention and future preventive treatment. Therefore, this study aimed to investigate gene expression profiles in elderly event-free FH patients. Methods Expression of 773 genes was analysed using the Nanostring Metabolic Pathways Panel, in peripheral blood mononuclear cells (PBMCs) from FH patients ≥65 years without CHD (FH event-free, n = 44) and with CHD (FH CHD, n = 39), and from healthy controls ≥70 years (n = 39). Results None of the genes were differentially expressed between FH patients with and without CHD after adjusting for multiple testing. However, at nominal p < 0.05, we found 36 (5%) differentially expressed genes (DEGs) between the two FH groups, mainly related to lipid metabolism (e.g. higher expression of ABCA1 and ABCG1 in FH event-free) and immune responses (e.g. lower expression of STAT1 and STAT3 in FH event-free). When comparing FH patients to controls, the event-free group had fewer DEGs than the CHD group; 147 (19%) and 219 (28%) DEGs, respectively. Conclusions Elderly event-free FH patients displayed a different PBMC gene expression profile compared to FH patients with CHD. Differences in gene expression compared to healthy controls were more pronounced in the CHD group, indicating a less atherogenic gene expression profile in event-free individuals. Overall, identification of cardioprotective factors could lead to future therapeutic targets.

• 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.

• 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).

• Alirezaylavasani, Amin; Skeie, Linda Gail; Egner, Ingrid Marie; Chopra, Adity; Dahl, Tuva Børresdatter & Prebensen, Christian Haugland [Show all 16 contributors for this article] (2024). Vaccine responses and hybrid immunity in people living with HIV after SARS-CoV-2 breakthrough infections. npj Vaccines. 9(1), p. 1–15. doi: 10.1038/s41541-024-00972-3. Full text in Research Archive Show summary

  The COVID-19 pandemic posed a challenge for people living with HIV (PLWH), particularly immune non-responders (INR) with compromised CD4 T-cell reconstitution following antiretroviral therapy (CD4 count <350 cells per mm3). Their diminished vaccine responses raised concerns about their vulnerability to SARS-CoV-2 breakthrough infections (BTI). Our in-depth study here revealed chronic inflammation in PLWH and a limited anti-Spike IgG response after vaccination in INR. Nevertheless, the imprinting of Spike-specific B cells by vaccination significantly enhanced the humoral responses after BTI. Notably, the magnitude of cellular CD4 response in all PLWH was comparable to that in healthy donors (HD). However, the polyfunctionality and phenotype of Spike-specific CD8 T cells in INR differed from controls. The findings highlight the need for additional boosters with variant vaccines, and for monitoring ART adherence and the durability of both humoral and cellular anti-SARS-CoV-2 immunity in INR.

• 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.

• 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.

• 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.

• Yang, Mingyi; Kaarbø, Mari; Myhre, Vegard; Reims, Henrik Mikael; Karlsen, Tom Hemming & Wang, Junbai [Show all 13 contributors for this article] (2024). Altered Genome-Wide DNA Methylation in the Duodenum of Common Variable Immunodeficiency Patients. Journal of Clinical Immunology. ISSN 0271-9142. 44(6), p. 1–16. doi: 10.1007/s10875-024-01726-5. Full text in Research Archive Show summary

  Purpose A large proportion of Common variable immunodeficiency (CVID) patients has duodenal inflammation with increased intraepithelial lymphocytes (IEL) of unknown aetiology. The histologic similarities to celiac disease, lead to confusion regarding treatment (gluten-free diet) of these patients. We aimed to elucidate the role of epigenetic DNA methylation in the aetiology of duodenal inflammation in CVID and differentiate it from true celiac disease. Methods DNA was isolated from snap-frozen pieces of duodenal biopsies and analysed for differences in genome-wide epigenetic DNA methylation between CVID patients with increased IEL (CVID_IEL; n = 5) without IEL (CVID_N; n = 3), celiac disease (n = 3) and healthy controls (n = 3). Results The DNA methylation data of 5-methylcytosine in CpG sites separated CVID and celiac diseases from healthy controls. Differential methylation in promoters of genes were identified as potential novel mediators in CVID and celiac disease. There was limited overlap of methylation associated genes between CVID_IEL and Celiac disease. High frequency of differentially methylated CpG sites was detected in over 100 genes nearby transcription start site (TSS) in both CVID_IEL and celiac disease, compared to healthy controls. Differential methylation of genes involved in regulation of TNF/cytokine production were enriched in CVID_IEL, compared to healthy controls. Conclusion This is the first study to reveal a role of epigenetic DNA methylation in the etiology of duodenal inflammation of CVID patients, distinguishing CVID_IEL from celiac disease. We identified potential biomarkers and therapeutic targets within gene promotors and in high-frequency differentially methylated CpG regions proximal to TSS in both CVID_IEL and celiac disease.

• Lauritzen, Knut Husø; Yang, Kuan; Frisk, Michael; Louwe, Maria Cornelia; Olsen, Maria Belland & Ziegler, Mathias [Show all 11 contributors for this article] (2024). Apigenin inhibits NLRP3 inflammasome activation in monocytes and macrophages independently of CD38. Frontiers in Immunology. 15. doi: 10.3389/fimmu.2024.1497984. Full text in Research Archive Show summary

  Introduction: CD38, a regulator of intracellular calcium signalling, is highly expressed in immune cells. Mice lacking CD38 are very susceptible to acute bacterial infections, implicating CD38 in innate immune responses. The effects of CD38 inhibition on NLRP3 inflammasome activation in human primary monocytes and monocyte-derived macrophages have not been investigated. Apigenin is a naturally occurring flavonoid known to inhibit CD38. However, apigenin has also been proposed to inhibit the extracellular ATP receptor P2XR7, an upstream activator of NLRP3. In this study we aimed to investigate whether apigenin attenuates NLRP3 inflammasome activation in human monocytes and monocyte-derived macrophages through CD38 inhibition. Methods: LPS-primed human monocytes and monocyte-derived macrophages were treated with apigenin, the CD38 inhibitor 78c, antagonists of CD38 second messengers (8-br-ADPR and 8-br-cADPR) or the ATP hydrolase, apyrase, prior to NLRP3 activation with ATP, monosodium urate crystals (MSU) or nigericin. IL-1β and TNF secretion and mRNA expression, as well as N-terminal gasdermin-D formation were quantified. Ca2+ mobilization was determined by live confocal microscopy. NLRP3 activity was also compared in WT and CD38-/- mouse bone marrow-derived macrophages (BMDMs) with and without CD38 inhibitors. Results: Apigenin significantly inhibited IL-1β release from LPS-primed monocytes and macrophages activated with ATP, MSU, or nigericin. CD38 inhibition with 78c also attenuated NLRP3-dependent IL-1β release. Apigenin was a potent inhibitor of Ca2+ flux from the endoplasmic reticulum to the cytosol in human monocyte-derived macrophages. Apyrase attenuated IL-1β release induced by ATP or MSU, but not by nigericin. However, the NLRP3 inflammasome is not compromised in CD38-/- bone marrow-derived macrophages compared to corresponding WT cells, and apigenin moderated IL-1β release in both genotypes. Discussion: Our data support that apigenin attenuates NLRP3 activation independently of CD38. Our results also suggest that MSU crystals activate NLRP3 through autocrine or paracrine ATP signalling.

• 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
• 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.

• Gregersen, Ida; Kong, Xiang Yi; Kooijman, Sander; Foyn, Håvard; Grannes, Helene & Olsen, Maria Belland [Show all 25 contributors for this article] (2024). T cells with increased responsiveness cause obesity in mice without diet intervention. iScience. 27(4). doi: 10.1016/j.isci.2024.109471. Full text in Research Archive Show summary

  Obesity is a complex multicausal disease that can cause morbidity and mortality, and there is need for improved knowledge on the underlying mechanisms. Using a mouse model of increased T cell responsiveness, we show that development of obesity can be driven by immune cells. This was confirmed with bone marrow transplantation and adoptive T cell transfer to several recipient mouse models. Single-cell RNA sequencing and CyTOF analysis showed that the mice display altered composition of circulating T cells and increased T cell activation in visceral adipose tissue, suggesting activated T cells as critical players in the increased fat mass. In this study, we provide evidence that obesity can be driven by immune cell activity and in particular by T cells, which could have broad implications for prevention and treatment of this condition.

• Olsen, Maria Belland; Louwe, Maria; Yang, Kuan; Øgaard, Jonas Daniel Sjøberg; Dahl, Tuva Børresdatter & Gregersen, Ida [Show all 16 contributors for this article] (2024). Continuous infusion of resolvin D2 in combination with Angiotensin-II show contrary effects on blood pressure and intracardiac artery remodeling. Biochemical and Biophysical Research Communications - BBRC. ISSN 0006-291X. 733. doi: 10.1016/j.bbrc.2024.150706. Full text in Research Archive Show summary

  Specialized pro-resolving mediators (SPMs) are key effectors of resolution of inflammation. This is highly relevant for cardiac and vessel remodeling, where the net inflammatory response contributes to determine disease outcome. Herein, we used a mice model of angiotensin (Ang)–II–induced hypertension to study the effect of the SPM Resolvin D2 (RvD2), on hypertension and cardiac remodeling. By using subcutaneous osmotic minipumps, mice were treated with PBS or Ang-II in combination with or without RvD2 for two weeks. Mice receiving RvD2 gained less blood pressure increase compared to Ang-II alone. Surprisingly, however, examination of intracardiac arteries revealed that RvD2 treatment in combination with Ang-II exacerbated Ang–II–induced fibrosis. Measures of vascular smooth muscle cell dedifferentiation correlated with the level of vascular remodeling, indicating that this dedifferentiation, including increased proliferation and migration, is a contributing factor. RNA sequencing of left ventricle cardiac tissue supported these findings as pathways related to cell proliferation and cell differentiation were upregulated in mice treated with Ang-II in combination with RvD2. Additionally, the RNA sequencing also showed upregulation of pathways related to SPM metabolism. In line with this, Mass spectrometry analysis of lipid mediators showed reduced cardiac levels of the arachidonic acid derived metabolite leukotriene E4 in RvD2 treated mice. Our study suggests that continuous infusion through osmotic minipumps should not be the recommended route of RvD2 administration in future studies.

• 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.

• Raju, Sajan; Molinaro, Antonio; Awoyemi, Ayodeji Olawale; Jørgensen, Silje Fjellgård; Braadland, Peder Rustøen & Nendl, Andraz [Show all 19 contributors for this article] (2024). Microbial-derived imidazole propionate links the heart failure-associated microbiome alterations to disease severity. Genome Medicine. 16(1), p. 27–27. doi: 10.1186/s13073-024-01296-6. Full text in Research Archive Show summary

  <p><i>Background</i> Interactions between the gut microbiota, diet, and host metabolism contribute to the development of cardiovascular disease, but a firm link between disease-specific gut microbiota alterations and circulating metabolites is lacking. <p><i>Methods</i> We performed shot-gun sequencing on 235 samples from 166 HF patients and 69 healthy control samples. Separate plasma samples from healthy controls (n = 53) were used for the comparison of imidazole propionate (ImP) levels. Taxonomy and functional pathways for shotgun sequencing data was assigned using MetaPhlAn3 and HUMAnN3 pipelines. <p><i>Results</i> Here, we show that heart failure (HF) is associated with a specific compositional and functional shift of the gut microbiota that is linked to circulating levels of the microbial histidine-derived metabolite ImP. Circulating ImP levels are elevated in chronic HF patients compared to controls and associated with HF-related gut microbiota alterations. Contrary to the microbiota composition, ImP levels provide insight into etiology and severity of HF and also associate with markers of intestinal permeability and systemic inflammation. <p><i>Conclusions</i> Our findings establish a connection between changes in the gut microbiota, the presence, etiology, and severity of HF, and the gut-microbially produced metabolite ImP. While ImP appears promising as a circulating biomarker reflecting gut dysbiosis related to HF, further studies are essential to demonstrate its causal or contributing role in HF pathogenesis.

• 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.

• Ratajczak-Tretel, Barbara; Lambert, Anna Tancin; Al-Ani, Riadh Ibrahim Mahmud; Arntzen, Kathrine Grønning; Bakkejord, Grete & Bekkeseth, Hanna Marie Otterholt [Show all 32 contributors for this article] (2023). Prediction of underlying atrial fibrillation in patients with a cryptogenic stroke: results from the NOR-FIB Study. Journal of Neurology. ISSN 0340-5354. 270, p. 4049–4059. doi: 10.1007/s00415-023-11680-8. Full text in Research Archive Show summary

  Background Atrial fibrillation (AF) detection and treatment are key elements to reduce recurrence risk in cryptogenic stroke (CS) with underlying arrhythmia. The purpose of the present study was to assess the predictors of AF in CS and the utility of existing AF-predicting scores in The Nordic Atrial Fibrillation and Stroke (NOR-FIB) Study. Method The NOR-FIB study was an international prospective observational multicenter study designed to detect and quantify AF in CS and cryptogenic transient ischaemic attack (TIA) patients monitored by the insertable cardiac monitor (ICM), and to identify AF-predicting biomarkers. The utility of the following AF-predicting scores was tested: AS5F, Brown ESUS-AF, CHA2DS2-VASc, CHASE-LESS, HATCH, HAVOC, STAF and SURF. Results In univariate analyses increasing age, hypertension, left ventricle hypertrophy, dyslipidaemia, antiarrhythmic drugs usage, valvular heart disease, and neuroimaging findings of stroke due to intracranial vessel occlusions and previous ischemic lesions were associated with a higher likelihood of detected AF. In multivariate analysis, age was the only independent predictor of AF. All the AF-predicting scores showed significantly higher score levels for AF than non-AF patients. The STAF and the SURF scores provided the highest sensitivity and negative predictive values, while the AS5F and SURF reached an area under the receiver operating curve (AUC) > 0.7. Conclusion Clinical risk scores may guide a personalized evaluation approach in CS patients. Increasing awareness of the usage of available AF-predicting scores may optimize the arrhythmia detection pathway in stroke units.

• Lambert, Anna Tancin; Ratajczak-Tretel, Barbara; Al-Ani, Riadh Ibrahim Mahmud; Arntzen, Kathrine Grønning; Bakkejord, Grete & Bekkeseth, Hanna Marie Otterholt [Show all 35 contributors for this article] (2023). Biomarkers predictive of atrial fibrillation in patients with cryptogenic stroke. Insights from the Nordic Atrial Fibrillation and Stroke (NOR-FIB) study. European Journal of Neurology. ISSN 1351-5101. 30(5), p. 1352–1363. doi: 10.1111/ene.15746. Full text in Research Archive Show summary

  Background There are currently no biomarkers used to select cryptogenic stroke (CS) patients for monitoring with insertable cardiac monitors (ICMs), the most effective tool for diagnosing atrial fibrillation (AF) in CS. The purpose of this study was to assess clinically available biomarkers as predictors of AF. Methods Eligible CS and cryptogenic transient ischemic attack (TIA) patients underwent 12-month monitoring with ICMs, clinical follow-up, and biomarker sampling. Levels of cardiac and thromboembolic biomarkers, taken within 14 days from symptom onset, were compared between patients diagnosed with AF (n=74) during monitoring and those without AF (n=185). Receiver operating characteristic (ROC) curves were created. Biomarkers reaching area under ROC curve (AUC) ≥ 0.7 were dichotomized by finding optimal cut-off values and used in logistic regression establishing their predictive value for increased risk of AF in unadjusted and adjusted models. Results B-type natriuretic peptide (BNP), N-terminal pro-brain natriuretic peptide (NT-proBNP), creatine kinase, D-dimer, high-sensitivity cardiac Troponin I and T were significantly higher in the AF than non-AF group. BNP and NT-proBNP reached predefined AUC level, 0.755 and 0.725 respectively. Optimal cut-off values were 33.5 ng/L for BNP, and 87 ng/L for NT-proBNP. Regression analysis showed that NT-proBNP was a predictor of AF in both unadjusted, odds ratio (OR) 7.72 (95% confidence interval [CI] 3.16–18.87), and age and sex adjusted models, OR 4.82 (95% CI 1.79–12.96). Conclusion Several clinically established biomarkers were associated with AF. NT-proBNP performed best as AF predictor and could be used for selecting patients for long-term monitoring with ICMs.

• Trøseid, Marius; Arribas, José R.; Assoumou, Lambert; Holten, Aleksander Rygh; Poissy, Julien & Terzić, Vida [Show all 56 contributors for this article] (2023). Efficacy and safety of baricitinib in hospitalized adults with severe or critical COVID‑19 (Bari‑SolidAct): a randomised, double‑blind, placebo‑controlled phase 3 trial. Critical Care. ISSN 1364-8535. 27(9), p. 1–15. doi: 10.1186/s13054-022-04205-8. Full text in Research Archive Show summary

  Background Baricitinib has shown efficacy in hospitalized patients with COVID-19, but no placebo-controlled trials have focused specifically on severe/critical COVID, including vaccinated participants. Methods Bari-SolidAct is a phase-3, multicentre, randomised, double-blind, placebo-controlled trial, enrolling participants from June 3, 2021 to March 7, 2022, stopped prematurely for external evidence. Patients with severe/critical COVID-19 were randomised to Baricitinib 4 mg once daily or placebo, added to standard of care. The primary endpoint was all-cause mortality within 60 days. Participants were remotely followed to day 90 for safety and patient related outcome measures. Results Two hundred ninety-nine patients were screened, 284 randomised, and 275 received study drug or placebo and were included in the modified intent-to-treat analyses (139 receiving baricitinib and 136 placebo). Median age was 60 (IQR 49–69) years, 77% were male and 35% had received at least one dose of SARS-CoV2 vaccine. There were 21 deaths at day 60 in each group, 15.1% in the baricitinib group and 15.4% in the placebo group (adjusted absolute difference and 95% CI − 0.1% [− 8·3 to 8·0]). In sensitivity analysis censoring observations after drug discontinuation or rescue therapy (tocilizumab/increased steroid dose), proportions of death were 5.8% versus 8.8% (− 3.2% [− 9.0 to 2.7]), respectively. There were 148 serious adverse events in 46 participants (33.1%) receiving baricitinib and 155 in 51 participants (37.5%) receiving placebo. In subgroup analyses, there was a potential interaction between vaccination status and treatment allocation on 60-day mortality. In a subsequent post hoc analysis there was a significant interaction between vaccination status and treatment allocation on the occurrence of serious adverse events, with more respiratory complications and severe infections in vaccinated participants treated with baricitinib. Vaccinated participants were on average 11 years older, with more comorbidities. Conclusion This clinical trial was prematurely stopped for external evidence and therefore underpowered to conclude on a potential survival benefit of baricitinib in severe/critical COVID-19. We observed a possible safety signal in vaccinated participants, who were older with more comorbidities. Although based on a post-hoc analysis, these findings warrant further investigation in other trials and real-world studies.

• Stø, Kristine; Skagen, Karolina Ryeng; Valeur, Jørgen; Yang, Kuan; Bjerkeli, Vigdis & Aukrust, Pål [Show all 8 contributors for this article] (2023). Increased plasma levels of non-sugar sweeteners in patients with symptomatic carotid atherosclerosis. Scandinavian Cardiovascular Journal. ISSN 1401-7431. 57(1). doi: 10.1080/14017431.2023.2205068. Full text in Research Archive Show summary

  Purpose. The non-sugar sweeteners acesulfame K and saccharin are considered safe, but there is conflicting evidence on their effects on cardiovascular health. Materials and methods. In this explorative pilot study, we measured plasma levels of acesulfame K and saccharin in 15 patients with symptomatic carotid atherosclerosis, 18 asymptomatic patients and 15 control subjects. Fecal microbiota and short-chain fatty acids were analyzed. Dietary and medical history was assessed. Results. Symptomatic patients had higher levels of acesulfame K and saccharin compared to controls. Acesulfame K was associated with increased leukocyte count. Saccharin was associated with more severe carotid stenosis, as well as lower fecal butyric acid.

• Ratajczak-Tretel, Barbara; Lambert, Anna Tancin; Al-Ani, Riadh Ibrahim Mahmud; Bekkeseth, Hanna Marie Otterholt; Bakkejord, Grete & Bjerkeli, Vigdis [Show all 31 contributors for this article] (2023). Underlying causes of cryptogenic stroke and TIA in the nordic atrial fibrillation and stroke (NOR-FIB) study – the importance of comprehensive clinical evaluation. BMC Neurology. 23(1), p. 1–10. doi: 10.1186/s12883-023-03155-0. Full text in Research Archive Show summary

  Background Cryptogenic stroke is a heterogeneous condition, with a wide spectrum of possible underlying causes for which the optimal secondary prevention may differ substantially. Attempting a correct etiological diagnosis to reduce the stroke recurrence should be the fundamental goal of modern stroke management. Methods Prospective observational international multicenter study of cryptogenic stroke and cryptogenic transient ischemic attack (TIA) patients clinically monitored for 12 months to assign the underlying etiology. For atrial fibrillation (AF) detection continuous cardiac rhythm monitoring with insertable cardiac monitor (Reveal LINQ, Medtronic) was performed. The 12-month follow-up data for 250 of 259 initially included NOR-FIB patients were available for analysis. Results After 12 months follow-up probable stroke causes were revealed in 43% patients, while 57% still remained cryptogenic. AF and atrial flutter was most prevalent (29%). In 14% patients other possible causes were revealed (small vessel disease, large-artery atherosclerosis, hypercoagulable states, other cardioembolism). Patients remaining cryptogenic were younger (p<0.001), had lower CHA2DS2-VASc score (p<0.001) on admission, and lower NIHSS score (p=0.031) and mRS (p=0.016) at discharge. Smoking was more prevalent in patients that were still cryptogenic (p=0.014), while dyslipidaemia was less prevalent (p=0.044). Stroke recurrence rate was higher in the cryptogenic group compared to the group where the etiology was revealed, 7.7% vs. 2.8%, (p=0.091). Conclusion Cryptogenic stroke often indicates the inability to identify the cause in the acute phase and should be considered as a working diagnosis until efforts of diagnostic work up succeed in identifying a specific underlying etiology. Timeframe of 6-12-month follow-up may be considered as optimal. Trial registration ClinicalTrials.gov Identifier NCT02937077, EudraCT 2018-002298-23

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

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

• Jørgensen, Silje Fjellgård; Macpherson, Magnhild Eide; Skarpengland, Tonje; Berge, Rolf Kristian; Fevang, Børre & Halvorsen, Bente [Show all 7 contributors for this article] (2023). Disturbed lipid profile in common variable immunodeficiency – a pathogenic loop of inflammation and metabolic disturbances. Frontiers in Immunology. 14. doi: 10.3389/fimmu.2023.1199727. Full text in Research Archive Show summary

  The relationship between metabolic and inflammatory pathways play a pathogenic role in various cardiometabolic disorders and is potentially also involved in the pathogenesis of other disorders such as cancer, autoimmunity and infectious diseases. Common variable immunodeficiency (CVID) is the most common primary immunodeficiency in adults, characterized by increased frequency of airway infections with capsulated bacteria. In addition, a large proportion of CVID patients have autoimmune and inflammatory complications associated with systemic inflammation. We summarize the evidence that support a role of a bidirectional pathogenic interaction between inflammation and metabolic disturbances in CVID. This include low levels and function of high-density lipoprotein (HDL), high levels of triglycerides (TG) and its major lipoprotein very low-density lipoprotein (VLDL), and an unfavorable fatty acid (FA) profile. The dysregulation of TG, VLDL and FA were linked to disturbed gut microbiota profile, and TG and VLDL levels were strongly associated with lipopolysaccharides (LPS), a marker of gut leakage in blood. Of note, the disturbed lipid profile in CVID did not include total cholesterol levels or high low-density lipoprotein levels. Furthermore, increased VLDL and TG levels in blood were not associated with diet, high body mass index and liver steatosis, suggesting a different phenotype than in patients with traditional cardiovascular risk such as metabolic syndrome. We hypothesize that these metabolic disturbances are linked to inflammation in a bidirectional manner with disturbed gut microbiota as a potential contributing factor.

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

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

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

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

• Nendl, Andraz; Raju, Sajan; Broch, Kaspar; Mayerhofer, Christiane Caroline; Holm, Kristian & Halvorsen, Bente [Show all 12 contributors for this article] (2023). Intestinal fatty acid binding protein is associated with cardiac function and gut dysbiosis in chronic heart failure. Frontiers in Cardiovascular Medicine. 10. doi: 10.3389/fcvm.2023.1160030. Full text in Research Archive Show summary

  Background: The gut microbiota in patients with chronic heart failure (HF) is characterized by low bacterial diversity and reduced ability to synthesize beneficial metabolites. These changes may facilitate leakage of whole bacteria or bacterial products from the gut into the bloodstream, which may activate the innate immune system and contribute to the low-grade inflammation seen in HF. In this exploratory cross-sectional study, we aimed to investigate relationships between gut microbiota diversity, markers of gut barrier dysfunction, inflammatory markers, and cardiac function in chronic HF patients.<p> <p>Methods: In total, 151 adult patients with stable HF and left ventricular ejection fraction (LVEF) < 40% were enrolled. We measured lipopolysaccharide (LPS), LPS-binding protein (LBP), intestinal fatty acid binding protein (I-FABP), and soluble cluster of differentiation 14 (sCD14) as markers of gut barrier dysfunction. N-terminal pro-B-type natriuretic peptide (NT-proBNP) level above median was used as a marker of severe HF. LVEF was measured by 2D-echocardiography. Stool samples were sequenced using 16S ribosomal RNA gene amplification. Shannon diversity index was used as a measure of microbiota diversity. <p>Results: Patients with severe HF (NT-proBNP > 895 pg/ml) had increased I-FABP (p < 0.001) and LBP (p = 0.03) levels. ROC analysis for I-FABP yielded an AUC of 0.70 (95% CI 0.61–0.79, p < 0.001) for predicting severe HF. A multivariate logistic regression model showed increasing I-FABP levels across quartiles of NT-proBNP (OR 2.09, 95% CI 1.28−3.41, p = 0.003). I-FABP was negatively correlated with Shannon diversity index (rho = −0.30, p = <0.001), and the bacterial genera Ruminococcus gauvreauii group, Bifidobacterium, Clostridium sensu stricto, and Parasutterella, which were depleted in patients with severe HF. <p>Conclusions: In patients with HF, I-FABP, a marker of enterocyte damage, is associated with HF severity and low microbial diversity as part of an altered gut microbiota composition. I-FABP may reflect dysbiosis and may be a marker of gut involvement in patients with HF.

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

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

• Berg, Janna; Halvorsen, Ann Rita; Bengtson, May-Bente; Lindberg, Morten; Halvorsen, Bente & Aukrust, Pål [Show all 8 contributors for this article] (2022). Circulating T Cell Activation and Exhaustion Markers Are Associated With Radiation Pneumonitis and Poor Survival in Non-Small-Cell Lung Cancer. Frontiers in Immunology. 13. doi: 10.3389/fimmu.2022.875152. Full text in Research Archive Show summary

  Persistent inflammation and immune activation in the lungs are associated with adverse outcomes such as radiation pneumonitis (RP) and poor survival in non-small-cell lung cancer (NSCLC) patients. However, it is unknown how this is reflected by leukocyte activation markers in serum. Objective: The aim was to evaluate the serum levels of activation of different leukocyte subsets and to examine those in relation to the pathogenesis of RP and survival in NSCLC. Methods: We analyzed the serum levels of MPO, sCD25, sTIM-3, sPD-L1, sCD14, sCD163, CCL19 and CCL21 in 66 inoperable NSCLC patients with stage IA-IIIA disease. The patients were treated with stereotactic body radiation therapy (SBRT) or concurrent chemoradiation therapy (CCRT), followed by regular blood sampling for 12 months after treatment and for 5 years for survival. Results: Nineteen (29%) patients developed RP, which occurred more frequently and earlier in patients receiving CCRT than in those receiving SBRT. Increases in sCD25, sTIM-3 and CCL21 levels were observed at the last 6 months of follow-up in patients who had RP after SBRT. Patients who had RP after CCRT had higher sTIM-3 levels during the first 3 months of follow-up. Baseline sCD25 was independently associated with both 2- and 5-year mortality outcomes, while baseline sTIM-3 was independently associated with 2-year mortality. Conclusion: We showed that T cell activation and exhaustion markers such as sCD25 and sTIM-3 are enhanced in patients developing RP and are associated with poor survival in NSCLC.

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

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

• Stø, Kristine; Valeur, Jørgen; Ueland, Thor; Malmstrøm, Gunn Helen; Bjerkeli, Vigdis & Trøseid, Marius [Show all 12 contributors for this article] (2022). Fecal level of butyric acid, a microbiome-derived metabolite, is increased in patients with severe carotid atherosclerosis. Scientific Reports. 12(1), p. 1–9. doi: 10.1038/s41598-022-26759-x. Full text in Research Archive Show summary

  Abstract The short-chain fatty acid (SCFA) butyric acid maintains a healthy gut barrier and vascular endothelium. We aimed to investigate the association between fecal butyric acid, carotid atherosclerosis and risk factors for ischemic stroke. Patients with severe carotid atherosclerosis (i.e. ≥ 50% stenosis) (n = 43) were compared with healthy controls (n = 38). We analyzed fecal SCFAs by gas chromatography, microbiota composition by 16S rRNA sequencing, markers of gut barrier damage and inflammasome activation by immunoassay, and plasma SCFAs by ultra-high performance liquid chromatography-tandem mass spectroscopy. Patients had higher fecal butyric acid level ( p  = 0.024), along with increased functional potential of microbial butyric acid production ( p  = 0.031), compared with controls. Dietary fiber intake was comparable. Patients had higher levels of gut barrier damage markers CCL25 and IFABP, and the inflammasome activation marker IL-18, whereas plasma level of butyric was similar. Increased fecal butyric acid was associated with higher BMI, waist-hip ratio, HbA1c, CRP and leukocyte count. Contrary to our hypothesis, patients with severe carotid atherosclerosis had higher fecal butyric acid level, and increased microbial production, compared with controls. Gut barrier damage in patients might indicate decreased absorption of butyric acid and hence contribute to the higher fecal level.

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

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

• Huroz, Sergio Carracedo; Lirussi, Lisa; Alsøe, Lene; Segers, Filip; Wang, Changliang & Bartosova, Zdenka [Show all 21 contributors for this article] (2022). SMUG1 regulates fat homeostasis leading to a fatty liver phenotype in mice. DNA Repair. ISSN 1568-7864. 120. doi: 10.1016/j.dnarep.2022.103410. Full text in Research Archive
• Lee-Ødegård, Sindre; Ueland, Thor; Thorsby, Per Medbøe; Aukrust, Pål; Michelsen, Annika Elisabet & Halvorsen, Bente [Show all 8 contributors for this article] (2022). Fetuin-A mediates the difference in adipose tissue insulin resistance between young adult pakistani and norwegian patients with type 2 diabetes. BMC Endocrine Disorders. 22. doi: 10.1186/s12902-022-01127-y. Full text in Research Archive Show summary

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

• Granerud, Beathe Kiland; Ueland, Thor; Lind, Andreas; Søraas, Arne Vasli; Fevang, Børre & Steffensen, Anne Katrine [Show all 14 contributors for this article] (2022). Omicron Variant Generates a Higher and More Sustained Viral Load in Nasopharynx and Saliva Than the Delta Variant of SARS-CoV-2. Viruses. 14(11). doi: 10.3390/v14112420. Full text in Research Archive Show summary

  The Omicron variant of SARS-CoV-2 spreads more easily than earlier variants, possibly as a result of a higher viral load in the upper respiratory tract and oral cavity. Hence, we investigated whether the Omicron variant generates a higher viral load than that of the Delta variant in saliva and nasopharynx. Both specimens were collected from 52 Omicron and 17 Delta cases at two time points one week apart and analyzed by qRT-PCR. Viral load was measured as 10 log RNA genome copies per 1000 human cells according to the WHO reference standard. We found that Omicron cases carried a higher viral load and had more sustained viral shedding compared to the Delta cases, especially in the nasopharynx.

• Quiles-Jiménez, Ana M T; Dahl, Tuva Børresdatter; Bjørås, Magnar; Alseth, Ingrun; Halvorsen, Bente & Gregersen, Ida (2022). Epitranscriptome in Ischemic Cardiovascular Disease: Potential Target for Therapies. Stroke. ISSN 0039-2499. 53(6), p. 2114–2122. doi: 10.1161/STROKEAHA.121.037581. Full text in Research Archive
• Tveita, Anders Aune; Murphy, Sarah Louise Mikalsen; Holter, Jan Cato; Kildal, Anders Benjamin; Michelsen, Annika Elisabet & Lerum, Tøri Vigeland [Show all 28 contributors for this article] (2022). High Circulating Levels of the Homeostatic Chemokines CCL19 and CCL21 Predict Mortality and Disease Severity in COVID-19. Journal of Infectious Diseases. ISSN 0022-1899. 226(12), p. 2150–2160. doi: 10.1093/infdis/jiac313. Full text in Research Archive Show summary

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

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

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

• Kaarbø, Mari; Yang, Mingyi; Hov, Johannes Espolin Roksund; Holm, Kristian; Sousa, Mirta & Macpherson, Magnhild Eide [Show all 15 contributors for this article] (2022). Duodenal inflammation in common variable immunodeficiency has altered transcriptional response to viruses. Journal of Allergy and Clinical Immunology. ISSN 0091-6749. doi: 10.1016/j.jaci.2022.09.029. Full text in Research Archive Show summary

  Background A substantial proportion of common variable immunodeficiency (CVID) patients has duodenal inflammation of largely unknown etiology. However, because of its histologic similarities with celiac disease, gluten sensitivity has been proposed as a potential mechanism. Objective We aimed to elucidate the role of the duodenal microenvironment in the pathogenesis of duodenal inflammation in CVID by investigating the transcriptional, proteomic, and microbial signatures of duodenal biopsy samples in CVID. Methods DNA, total RNA, and protein were isolated from snap-frozen pieces of duodenal biopsy samples from CVID (with and without duodenal inflammation), healthy controls, and patients with celiac disease (untreated). RNA sequencing, mass spectrometry–based proteomics, and 16S ribosomal DNA sequencing (bacteria) were then performed. Results CVID separated from controls in regulation of transcriptional response to lipopolysaccharide and cellular immune responses. These differences were independent of mucosal inflammation. Instead, CVID patients with duodenal inflammation displayed alterations in transcription of genes involved in response to viral infections. Four proteins were differently regulated between CVID patients and healthy controls—DBNL, TRMT11, GCHFR, and IGHA2—independent of duodenal inflammation. Despite similar histology, there were major differences in CVID with duodenal inflammation and celiac disease both at the RNA and protein level. No significant difference was observed in the bacterial gut microbial signature between CVID, celiac, and healthy controls. Conclusion Our findings suggest the existence of altered functions of the duodenal epithelium, particularly in response to lipopolysaccharide and viruses. The latter finding was related to duodenal inflammation, suggesting that viruses, not gluten sensitivity, could be related to duodenal inflammation in CVID. Key words CVID RNA sequencing proteomics microbiome gut microbiota microbiota gastrointestinal tract duodenum celiac disease Primary immunodeficiency IgA

• Ratajczak-Tretel, Barbara; Lambert, Anna Tancin; Al-Ani, Riadh Ibrahim Mahmud; Arntzen, Kathrine Grønning; Bakkejord, Grete & Bekkeseth, Hanna Marie Otterholt [Show all 33 contributors for this article] (2022). Atrial fibrillation in cryptogenic stroke and TIA patients in The Nordic Atrial Fibrillation and Stroke (NOR-FIB) Study: Main results. European Stroke Journal. ISSN 2396-9873. 8(1), p. 148–156. doi: 10.1177/23969873221123122. Full text in Research Archive Show summary

  Introduction: Secondary stroke prevention depends on proper identification of the underlying etiology and initiation of optimal treatment after the index event. The aim of the NOR-FIB study was to detect and quantify underlying atrial fibrillation (AF) in patients with cryptogenic stroke (CS) or transient ischaemic attack (TIA) using insertable cardiac monitor (ICM), to optimise secondary prevention, and to test the feasibility of ICM usage for stroke physicians. Patients and methods: Prospective observational international multicenter real-life study of CS and TIA patients monitored for 12 months with ICM (Reveal LINQ) for AF detection. Results: ICM insertion was performed in 91.5% by stroke physicians, within median 9 days after index event. Paroxysmal AF was diagnosed in 74 out of 259 patients (28.6%), detected early after ICM insertion (mean 48 ± 52 days) in 86.5% of patients. AF patients were older (72.6 vs 62.2; p< 0.001), had higher pre-stroke CHA₂DS₂-VASc score (median 3 vs 2; p< 0.001) and admission NIHSS (median 2 vs 1; p= 0.001); and more often hypertension (p = 0.045) and dyslipidaemia (p = 0.005) than non-AF patients. The arrhythmia was recurrent in 91.9% and asymptomatic in 93.2%. At 12-month follow-up anticoagulants usage was 97.3%.Discussion and conclusions: ICM was an effective tool for diagnosing underlying AF, capturing AF in 29% of the CS and TIA patients. AF was asymptomatic in most cases and would mainly have gone undiagnosed without ICM. The insertion and use of ICM was feasible for stroke physicians in stroke units. © The Author(s) 2022.

• Fontaine, Margaux A. C.; Jin, Han; Gagliardi, Mick; Rousch, Mat; Wijnands, Erwin & Stoll, Monika [Show all 23 contributors for this article] (2022). Blood Milieu in Acute Myocardial Infarction Reprograms Human Macrophages for Trauma Repair. Advanced Science. p. 1–14. doi: 10.1002/advs.202203053. Full text in Research Archive Show summary

  Acute myocardial infarction (AMI) is accompanied by a systemic trauma response that impacts the whole body, including blood. This study addresses whether macrophages, key players in trauma repair, sense and respond to these changes. For this, healthy human monocyte-derived macrophages are exposed to 20% human AMI (n = 50) or control (n = 20) serum and analyzed by transcriptional and multiparameter functional screening followed by network-guided data interpretation and drug repurposing. Results are validated in an independent cohort at functional level (n = 47 AMI, n = 25 control) and in a public dataset. AMI serum exposure results in an overt AMI signature, enriched in debris cleaning, mitosis, and immune pathways. Moreover, gene networks associated with AMI and with poor clinical prognosis in AMI are identified. Network-guided drug screening on the latter unveils prostaglandin E2 (PGE2) signaling as target for clinical intervention in detrimental macrophage imprinting during AMI trauma healing. The results demonstrate pronounced context-induced macrophage reprogramming by the AMI systemic environment, to a degree decisive for patient prognosis. This offers new opportunities for targeted intervention and optimized cardiovascular disease risk management.

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

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

• Segers, Filip Marcel Elza; Ruder, Adele V.; Westra, Marijke M.; Lammers, Twan; Dadfar, Seyed Mohammadali & Roemhild, Karolin [Show all 17 contributors for this article] (2022). Magnetic resonance imaging contrast-enhancement with superparamagnetic iron oxide nanoparticles amplifies macrophage foam cell apoptosis in human and murine atherosclerosis. Cardiovascular Research (CVR). ISSN 0008-6363. 118(17), p. 3346–3359. doi: 10.1093/cvr/cvac032. Full text in Research Archive
• Karlsen, Tom Rune; Olsen, Maria Belland; Kong, Xiang Yi; Yang, Kuan; Quiles-Jiménez, Ana M T & Kroustallaki, Pinelopi [Show all 15 contributors for this article] (2022). NEIL3-deficient bone marrow displays decreased hematopoietic capacity and reduced telomere length. Biochemistry and Biophysics Reports. 29. doi: 10.1016/j.bbrep.2022.101211. Full text in Research Archive Show summary

  Deficiency of NEIL3, a DNA repair enzyme, has significant impact on mouse physiology, including vascular biology and gut health, processes related to aging. Leukocyte telomere length (LTL) is suggested as a marker of biological aging, and shortened LTL is associated with increased risk of cardiovascular disease. NEIL3 has been shown to repair DNA damage in telomere regions in vitro. Herein, we explored the role of NEIL3 in telomere maintenance in vivo by studying bone marrow cells from atherosclerosis-prone NEIL3-deficient mice. We found shortened telomeres and decreased activity of the telomerase enzyme in bone marrow cells derived from Apoe−/−Neil3−/− as compared to Apoe−/− mice. Furthermore, Apoe−/−Neil3−/− mice had decreased leukocyte levels as compared to Apoe−/− mice, both in bone marrow and in peripheral blood. Finally, RNA sequencing of bone marrow cells from Apoe−/−Neil3−/− and Apoe−/− mice revealed different expression levels of genes involved in cell cycle regulation, cellular senescence and telomere protection. This study points to NEIL3 as a telomere-protecting protein in murine bone marrow in vivo.

• Olsen, Maria Belland; Huse, Camilla; Sousa, Mirta; Murphy, Sarah Louise Mikalsen; Sarno, Antonio & Obermann, Tobias Sebastian [Show all 20 contributors for this article] (2022). DNA Repair Mechanisms are Activated in Circulating Lymphocytes of Hospitalized Covid-19 Patients. Journal of Inflammation Research. 15, p. 6629–6644. doi: 10.2147/JIR.S379331. Full text in Research Archive Show summary

  Purpose: Reactive oxygen species (ROS) are an important part of the inflammatory response during infection but can also promote DNA damage. Due to the sustained inflammation in severe Covid-19, we hypothesized that hospitalized Covid-19 patients would be characterized by increased levels of oxidative DNA damage and dysregulation of the DNA repair machinery. Patients and Methods: Levels of the oxidative DNA lesion 8-oxoG and levels of base excision repair (BER) proteins were measured in peripheral blood mononuclear cells (PBMC) from patients (8-oxoG, n = 22; BER, n = 17) and healthy controls (n = 10) (Cohort 1). Gene expression related to DNA repair was investigated in two independent cohorts of hospitalized Covid-19 patients (Cohort 1; 15 patents and 5 controls, Cohort 2; 15 patients and 6 controls), and by publicly available datasets. Results: Patients and healthy controls showed comparable amounts of oxidative DNA damage as assessed by 8-oxoG while levels of several BER proteins were increased in Covid-19 patients, indicating enhanced DNA repair in acute Covid-19 disease. Furthermore, gene expression analysis demonstrated regulation of genes involved in BER and double strand break repair (DSBR) in PBMC of Covid-19 patients and expression level of several DSBR genes correlated with the degree of respiratory failure. Finally, by re-analyzing publicly available data, we found that the pathway Hallmark DNA repair was significantly more regulated in circulating immune cells during Covid-19 compared to influenza virus infection, bacterial pneumonia or acute respiratory infection due to seasonal coronavirus. Conclusion: Although beneficial by protecting against DNA damage, long-term activation of the DNA repair machinery could also contribute to persistent inflammation, potentially through mechanisms such as the induction of cellular senescence. However, further studies that also include measurements of additional markers of DNA damage are required to determine the role and precise molecular mechanisms for DNA repair in SARS-CoV-2 infection.

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

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

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

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

• Lekva, Tove; Ueland, Thor; Halvorsen, Bente; Murphy, Sarah Louise Mikalsen; Dyrhol-Riise, Anne Ma & Tveita, Anders Aune [Show all 14 contributors for this article] (2022). Markers of cellular senescence is associated with persistent pulmonary pathology after COVID-19 infection. Infectious Diseases. ISSN 2374-4235. 54(12), p. 918–923. doi: 10.1080/23744235.2022.2113135. Full text in Research Archive Show summary

  Background The lungs are the organ most likely to sustain serious injury from coronavirus disease 2019 (COVID-19). However, the mechanisms for long-term complications are not clear. Patients with severe COVID-19 have shorter telomere lengths and higher levels of cellular senescence, and we hypothesized that circulating levels of the telomere-associated senescence markers chitotriosidase, β-galactosidase, cathelicidin antimicrobial peptide and stathmin 1 (STMN1) were elevated in hospitalized COVID-19 patients compared to controls and could be associated with pulmonary sequelae following hospitalization. Methods Ninety-seven hospitalized patients with COVID-19 who underwent assessment for pulmonary sequelae at three-month follow-up were included in the study. β-Galactosidase and chitotriosidase were analysed by fluorescence; stathmin 1 and cathelicidin antimicrobial peptide were analysed by enzyme immuno-assay in plasma samples from the acute phase and after three-months. In addition, the classical senescence markers cyclin-dependent kinase inhibitor 1A and 2A were analysed by enzyme immuno-assay in peripheral blood mononuclear cell lysate after three months. Results We found elevated plasma levels of the senescence markers chitotriosidase and stathmin 1 in patients three months after hospitalization with COVID-19, and these markers in addition to protein levels of cyclin-dependent kinase inhibitor 2A in cell lysate, were associated with pulmonary pathology. The elevated levels of these markers seem to reflect both age-dependent (chitotriosidase) and age-independent (stathmin 1, cyclin-dependent kinase inhibitor 2A) processes. Conclusions We suggest that accelerated ageing or senescence could be important for long-term pulmonary complications of COVID-19, and our findings may be relevant for future research exploring the pathophysiology and management of these patients.

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

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

• Hassel, Bjørnar; Niehusmann, Pitt; Halvorsen, Bente & Dahlberg, Daniel (2022). Pro-inflammatory cytokines in cystic glioblastoma: A quantitative study with a comparison with bacterial brain abscesses. With an MRI investigation of displacement and destruction of the brain tissue surrounding a glioblastoma. Frontiers in Oncology. doi: 10.3389/fonc.2022.846674. Full text in Research Archive Show summary

  Cystic glioblastomas are aggressive primary brain tumors that may both destroy and displace the surrounding brain tissue as they grow. The mechanisms underlying these tumors’ destructive effect could include exposure of brain tissue to tumor-derived cytokines, but quantitative cytokine data are lacking. Here, we provide quantitative data on leukocyte markers and cytokines in the cyst fluid from 21 cystic glioblastomas, which we compare to values in 13 brain abscess pus samples. The concentration of macrophage/microglia markers sCD163 and MCP-1 was higher in glioblastoma cyst fluid than in brain abscess pus; lymphocyte marker sCD25 was similar in cyst fluid and pus, whereas neutrophil marker myeloperoxidase was higher in pus. Median cytokine levels in glioblastoma cyst fluid were high (pg/mL): TNF-α: 32, IL-6: 1064, IL-8: 23585, tissue factor: 28, the chemokine CXCL1: 639. These values were not significantly different from values in pus, pointing to a highly pro-inflammatory glioblastoma environment. In contrast, levels of IFN-γ, IL-1β, IL-2, IL-4, IL-10, IL-12, and IL-13 were higher in pus than in glioblastoma cyst fluid. Based on the quantitative data, we show for the first time that the concentrations of cytokines in glioblastoma cyst fluid correlate with blood leukocyte levels, suggesting an important interaction between glioblastomas and the circulation. Preoperative MRI of the cystic glioblastomas confirmed both destruction and displacement of brain tissue, but none of the cytokine levels correlated with degree of brain tissue displacement or peri-tumoral edema, as could be assessed by MRI. We conclude that cystic glioblastomas are highly pro-inflammatory environments that interact with the circulation and that they both displace and destroy brain tissue. These observations point to the need for neuroprotective strategies in glioblastoma therapy, which could include an anti-inflammatory approach.

• Skarpengland, Tonje; Macpherson, Magnhild Eide; Hov, Johannes R.; Kong, Xiang Yi; Bohov, Pavol & Halvorsen, Bente [Show all 10 contributors for this article] (2021). Altered Plasma Fatty Acids Associate with Gut Microbial Composition in Common Variable Immunodeficiency. Journal of Clinical Immunology. ISSN 0271-9142. p. 1–12. doi: 10.1007/s10875-021-01146-9. Full text in Research Archive
• Kong, Xiang Yi; Huse, Camilla; Yang, Kuan; Øgaard, Jonas; Jimenez, Natalia Berges & Vik, Erik Sebastian [Show all 24 contributors for this article] (2021). Endonuclease v regulates atherosclerosis through c-c motif chemokine ligand 2-mediated monocyte infiltration. Journal of the American Heart Association (JAHA). 10(14). doi: 10.1161/JAHA.120.020656. Full text in Research Archive Show summary

  Background: In cardiovascular diseases, atherosclerotic disorder are the most frequent and important with respect to morbidity and mortality. Inflammation mediated by immune cells is central in all parts of the atherosclerotic progress, and further understanding of the underlying mechanisms is needed. Growing evidence suggests that deamination of adenosine‐to‐inosine in RNA is crucial for a correct immune response; nevertheless, the role of adenosine‐to‐inosine RNA editing in atherogenesis has barely been studied. Several proteins have affinity for inosines in RNA, one being ENDOV (endonuclease V), which binds and cleaves RNA at inosines. Data on ENDOV in atherosclerosis are lacking. Methods and Results: Quantitative polymerase chain reaction on ENDOV mRNA showed an increased level in human carotid atherosclerotic plaques compared with control veins. Inosine‐ribonuclease activity as measured by an enzyme activity assay is detected in immune cells relevant for the atherosclerotic process. Abolishing EndoV in atherogenic apolipoprotein E‐deficient (ApoE−/−) mice reduces the atherosclerotic plaque burden, both in size and lipid content. In addition, in a brain stroke model, mice without ENDOV suffer less damage than control mice. Finally, lack of EndoV reduces the recruitment of monocytes to atherosclerotic lesions in atherogenic ApoE−/− mice. Conclusions: ENDOV is upregulated in human atherosclerotic lesions, and data from mice suggest that ENDOV promotes atherogenesis by enhancing the monocyte recruitment into the atherosclerotic lesion, potentially by increasing the effect of CCL2 activation on these cells.

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• 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
• Melnes, Torunn; Bogsrud, Martin Prøven; Christensen, Jacob J.; Rundblad, Amanda; Narverud, Ingunn & Retterstøl, Kjetil [Show all 10 contributors for this article] (2023). Difference in PBMC gene expression between elderly event-free FH patients and FH patients with CHD. Full text in Research Archive
• Melnes, Torunn; Bogsrud, Martin Prøven; Christensen, Jacob J.; Rundblad, Amanda; Narverud, Ingunn & Retterstøl, Kjetil [Show all 10 contributors for this article] (2023). Difference in PBMC gene expression between elderly event-free FH patients and FH patients with CHD. Full text in Research Archive
• Rundblad, Amanda; Hansen, Anna Lena; Christensen, Jacob Juel; Melnes, Torunn; Ottestad, Inger Olaug & Narverud, Ingunn [Show all 12 contributors for this article] (2023). Patients with familial hypercholesterolemia have shorter telomeres than controls in older, but not in young subjects: a cross-sectional study. Full text in Research Archive
• Quiles-Jiménez, Ana M T; Sousa, Mirta; Huse, Camilla; Dyrhol-Riise, Anne Ma; Holter, Jan Cato & Christensen, Erik Egeland [Show all 12 contributors for this article] (2023). Severely ill COVID-19 patients have altered circulating levels of proteins controlling the epitranscriptome. Journal of Infection. ISSN 0163-4453. doi: 10.1016/j.jinf.2023.03.002. Full text in Research Archive
• Halvorsen, Bente; Aukrust, Pål; Dahl, Tuva Børresdatter & Gregersen, Ida (2023). Increased cardiovascular mortality during the COVID-19 pandemic: do not neglect causality. European Heart Journal Open (EHJ Open). 3(6). doi: 10.1093/ehjopen/oead119. Full text in Research Archive
• Ueland, Thor; Äikäs, Lauri A.O.; Dahl, Tuva Børresdatter; Gregersen, Ida; Olsen, Maria Belland & Michelsen, Annika Elisabet [Show all 20 contributors for this article] (2023). Low-density lipoprotein particles carrying proinflammatory proteins with altered aggregation pattern detected in COVID-19 patients 3 months after hospitalization. Journal of Infection. ISSN 0163-4453. 86(5), p. 489–492. doi: 10.1016/j.jinf.2023.02.024. Full text in Research Archive
• Melnes, Torunn; Bogsrud, Martin Prøven; Christensen, Jacob J.; Rundblad, Amanda; Narverud, Ingunn & Retterstøl, Kjetil [Show all 10 contributors for this article] (2023). Difference in PBMC gene expression between elderly event-free FH patients and FH patients with CHD. Full text in Research Archive
• Gregersen, Ida; Ueland, Thor; Holter, Jan Cato; Olsen, Maria Belland; Michelsen, Annika Elisabet & Murphy, Sarah L [Show all 22 contributors for this article] (2022). CXCL16 associates with adverse outcome and cardiac involvement in hospitalized patients with Covid-19. Journal of Infection. ISSN 0163-4453. 85(6), p. 735–738. doi: 10.1016/j.jinf.2022.09.029. Full text in Research Archive
• Murphy, Sarah Louise Mikalsen; Halvorsen, Bente; Barratt-Due, Andreas; Dyrhol-Riise, Anne Ma; Aukrust, Pål & Trøseid, Marius [Show all 7 contributors for this article] (2022). Remdesivir modifies interferon response in hospitalized COVID-19 patients. Journal of Infection. ISSN 0163-4453. 85(5), p. 573–607. doi: 10.1016/j.jinf.2022.07.021. Full text in Research Archive
• Berg, Janna; Halvorsen, Ann Rita; Bengtson, May-Bente; Lindberg, Morten; Halvorsen, Bente & Aukrust, Pål [Show all 8 contributors for this article] (2022). Corrigendum: Circulating T cell activation and exhaustion markers are associated with radiation pneumonitis and poor survival in non-small-cell lung cancer, (Front. Immunol, (2022), 13, (875152), 10.3389/fimmu.2022.875152). Frontiers in Immunology. 13. doi: 10.3389/fimmu.2022.1051156. Full text in Research Archive
• Stavik, Benedicte; Andresen, Marianne Seierstad; Holm, Sverre; Skjelland, Mona; Tinholt, Mari & Sandset, Per Morten [Show all 8 contributors for this article] (2021). Increased levels of coagulation factor V in atherosclerotic plaques - an immune regulated response? Research and Practice in Thrombosis and Haemostasis (RPTH). 5. Full text in Research Archive

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