We aimed to summarize the pathogenic role of IL-6 in atherothrombosis and myocardial infarction (MI), with focus on novel pathogenic mechanisms and current IL-6 targeted therapy in clinical cohorts. IL-6 plays a major role in the pathogenesis of cardiovascular disease interacting with aging- and metabolic-driven inflammation, two conditions with overlapping molecular mechanisms. A novel pathogenic mechanism in cardiovascular disease (CVD) is the interaction between IL-6 and clonal hematopoiesis of indeterminate potential, CHIP, that involve the ten-eleven translocation-2 gene, a molecule with role in epigenetics. Recent studies showed reduced inflammation, a reduction in Lp (a) and inhibitory effects on platelets by anti-IL-6 (ziltivekimab) therapy in patients at risk for CVD. Anti-IL-6 receptor therapy (tocilizumab) showed reduced inflammation and improved myocardial function in MI patients, involving reduced degranulation in neutrophils and modulation of monocytes. Studies with clinical endpoints are still lacking and there also a need for developing therapy that selectively block the harmful IL-6 trans-signaling. IL-6 plays an important and many-faceted role in atherothrombosis including MI and ischemic stroke, and the IL-6 system represent a promising but still evolving therapeutic approach. A comprehensive understanding of the complexity of IL-6 signaling is needed to improve such treatment strategies.

BackgroundPlatelet activation is documented in COVID-19, but data on platelet-derived mediators are scarce.ObjectiveTo 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.MethodsPlasma 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.ResultsOur 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.ConclusionOur 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.

Background B cells and B-cell activating factor (BAFF) are involved in the development of myocardial infarction (MI), but data on the regulation and role of BAFF in MI are scarce. Objectives To examine possible associations between plasma BAFF levels and outcomes in non-ST-elevation MI (NSTEMI) and STEMI. Methods We analyzed plasma BAFF at hospital admission by enzyme immunoassay in 732 patients with NSTEM and 261 patients with STEMI, and in STEMI also during follow-up. Plasma levels were related to pre-defined clinical outcomes (mortality and a composite of major adverse cardiac events [MACE]) in both groups and included infarct size and left ventricular ejection fraction (LVEF) evaluated by cardiac magnetic resonance imaging (CMR) in the STEMI group. Results Our major findings were: (i) BAFF levels at hospital admission were associated with adverse clinical outcome (i.e., mortality and MACE) in NSTEMI, also after adjustment for demographic variables, but only MACE was significant after adjustment for CRP, TnT and eGFR. (ii) In STEMI, BAFF levels increased from baseline and were highest at 4-months in patients who died during long term follow-up. Levels at 4 months were associated with all-cause death in adjusted analysis including CRP, TnT and the Thrombolysis in Myocardial Infarction (TIMI) risk score. (iii) STEMI patients with the largest infarct size and those with LVEF <50% at 4 months, had higher levels of BAFF at 4 months, compared with the other STEMI patients. Conclusion Our study supports a role for BAFF in the development of MI, potentially also in post-MI remodeling.

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

BackgroundAn 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.PurposeWe 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.MethodsThirty 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.ResultsCompared 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.ConclusionPatients 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.

Objectives. Thoracic aortic aneurysms (TAAs) are often found in younger individuals and approximately 20% may be associated with heritable thoracic aortic disease (HTAD). There are some data on genomic biomarkers reflecting inflammation and extracellular matrix remodelling in HTAD. However, data that accurately reflect the corresponding protein changes are scarce. Our aim was to quantify proteins by using targeted proteomics in HTAD patients versus healthy controls, to better understand the underlying pathophysiology. Methods. Patients with Loeys-Dietz syndrome (LDS, n = 8), Marfan syndrome (MFS, n = 11), and familial TAA 6, i.e. actin alpha 2 (ACTA2, n = 7) pathogenic variants were recruited at our outpatient clinic. For comparison, blood samples were drawn from 16 healthy controls. Plasma samples were analysed by targeted proteome analysis of 276 proteins using immunoaffinity proteomics. Results. Whereas oncostatin M and pentraxin 3 levels appeared generally higher in HTAD patients, after adjusting for several confounders, significantly higher levels for these markers as well as TNF receptor superfamily member 9 (TNFRSF9), granulysin (GNLY), CD5, vasorin and glycoprotein 1b-α (GP1BA) were only observed in LDS patients compared to healthy controls. Levels of TNFRSF9, GNLY, GP1BA and CD5 correlated positively with Th17 and platelet counts. Conclusions. This discovery study suggests that LDS could represent a particular inflammatory subgroup of HTAD patients potentially reflecting the involvement of Th17 and platelet related mechanisms in the progression of TAA. Larger studies are needed to evaluate if the identified proteins could be used as biomarkers in these patients.

A substantial proportion of Common Variable Immunodeficiency (CVID) patients has autoimmune and inflammatory complications (CVIDCOMP), associated with T‑cell and monocyte pathology, but the underlying molecular mechanisms remain unclear. We aimed to identify novel immunopathogenic pathways in this inflammation‑prone CVID phenotype. We performed RNA‑seq and mass‑spectrometry–based proteomics on isolated CD3⁺ T cells and CD14⁺ monocytes from CVID patients and healthy controls (HC). Differentially expressed genes (DEGs), proteins (DEPs) and pathways (Hallmark GSEA) were assessed. Plasma IL‑1β and CXCL10 were measured by multiplex assay, IL‑18 and CXCL9 by EIA. CVIDCOMP patients (RNAseq: n = 5, proteomics: n = 13) showed broader transcriptional and proteomic changes in CD14⁺ monocytes than in CD3⁺ T cells. In CD14⁺ monocytes, RNAseq revealed enrichment of “TNFα/NF-κB” signalling and “Interferon γ response”, while proteomics showed enrichment of “Interferon α response”. Conversely, proteomic analyses of cells from CVID without inflammatory/autoimmune complications (n = 5–9) showed only minor differences compared with HC (n = 10). In CVIDCOMP, GBP1, GBP4, GBP5, STAT1 and LGALS3BP were upregulated at both mRNA and protein levels, and several of these interferon‑/inflammasome‑related genes were upregulated in an independent CVID cohort from a public dataset. Plasma levels of IL‑1β, IL‑18, CXCL9 and CXCL10, reflecting inflammasome and interferon activity, were increased in two additional CVID cohorts (CVID = 104/60, HC = 22/30), with the highest concentrations in CVIDCOMP. This integrated analysis supports an inflammatory signature in CVIDCOMP monocytes, involving interferon‑ and inflammasome‑related pathways. The findings highlight CD14⁺ monocytes and their downstream mediators as potential targets for future mechanistic and therapeutic studies.

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.

BACKGROUND:The bidirectional interaction between inflammation and thrombus formation plays an important role in myocardial infarction (MI) with IL (interleukin)-6 as a central mediator. If anti-inflammatory therapy modulates coagulation factors, and platelet activation in patients with MI is not clear. METHODS:We have shown that tocilizumab, a monoclonal antibody targeting IL-6R (IL-6 receptor), improves myocardial salvage index in patients with ST-elevation MI. Herein, we measured levels of soluble markers of platelet activation (P-selectin, sCD40L [soluble CD40 ligand]) and coagulation (TF [tissue factor], TFPI [TF pathway inhibitor], PAI [plasminogen activator inhibitor]-1, and D-dimer) in 136 patients with ST-segment-elevation MI (70 tocilizumab and 66 placebo). Platelet-poor EDTA plasma samples were obtained at admission and after 24 and 168 hours. Temporal changes were related to TnT (troponin T), as well as infarct size and myocardial salvage index, assessed by cardiac magnetic resonance imaging. RESULTS:Our major findings were given as follows: (1) patients had higher sCD40L, P-selectin, TFPI, and D-dimer than 28 healthy controls, and these increased during 1-week follow-up, while TFPI decreased; (2) tocilizumab attenuated P-selectin in patients with short symptom duration at 24 hours in particular in those with high C-reactive protein, and this change correlated positively with indices of myocardial damage; (3) tocilizumab augmented TF at 168 hours, and this change correlated positively with infarct size and negatively with myocardial salvage index; (4) change in D-dimer at 168 hours correlated positively with infarct size and negatively with myocardial salvage index in particular in those with long symptom durations or treated with placebo; tocilizumab attenuated these changes; and (5) the use of heparin attenuated sCD40L levels and increased TFPI levels in admission samples and TF levels after 168 hours. CONCLUSIONS:Our findings support attenuation of platelet activation/coagulation by tocilizumab in patients with ST-segment-elevation MI. The marked rise in TF could be a hereto unrecognized side effects of tocilizumab, which need further investigation.

IntroductionCommon variable immunodeficiency (CVID) is frequently complicated by duodenal inflammation, but the underlying molecular mechanisms remain poorly understood. While epigenetic alterations have been described in CVID, the epitranscriptome is largely unexplored. We therefore investigated whether RNA N6-methyladenosine (m6A) modifications in duodenal tissue are altered in CVID and whether such changes are associated with the local microbiota or m6A-related enzymes.Methodsm6A modification levels were analysed in snap-frozen duodenal biopsies from CVID patients with intraepithelial lymphocytosis and inflammation (CVID_IEL; n = 5), CVID patients with normal duodenal histology (CVID_N; n = 5) and controls with normal biopsies (n = 5) using m6A-RNA immunoprecipitation followed by microarray profiling and gene set enrichment analysis. Duodenal bacterial microbiota from the same anatomical region were characterised by 16S ribosomal RNA gene sequencing, and selected m6A-regulating enzymes were quantified in biopsies by targeted proteomics.ResultsIn total, 4,134 differentially methylated transcripts were identified, and unsupervised principal component analyses revealed partially overlapping, but clearly divergent m6A signatures for CVID_IEL, CVID_N and controls, with a gradient along the first principal component. Pathway analysis showed relative hypermethylation of mitochondria- and ribosome-related gene sets in both CVID subgroups versus controls, and hypomethylation of pathways linked to ubiquitination, proteasomal degradation, glycosylation and post-transcriptional gene silencing in CVID_IEL versus CVID_N. Sparse canonical correlation models demonstrated significant associations between specific duodenal bacterial genera and m6A-modified transcripts in CVID, but not in controls, whereas expression levels of the examined m6A-regulating enzymes did not differ between groups.DiscussionThese findings suggest that duodenal inflammation in CVID may be associated with a distinct m6A epitranscriptomic signature that is linked to specific features of the mucosal microbiota, providing preliminary, hypothesis-generating evidence for a potential interaction between microbiota, epitranscriptomic regulation and local immune dysregulation in CVID.

Background: The high prevalence of patients with post-COVID-19 condition, also called long COVID, even among those with mild initial disease, may have a large impact on both the individual and society. Disability in everyday life, reduced health-related quality of life and work capacity, strain on the health care system, and substantial socioeconomic costs are associated with long COVID. More research to investigate the effectiveness of rehabilitation services is warranted. Objective: This study aims to examine the effectiveness of tailored individual follow-ups versus a 1-day group course in patients with long COVID. Additionally, the feasibility and use of a mobile app for self-monitoring goal achievement will be assessed. Methods: This is a single-center, parallel-group, superiority randomized controlled trial with a 1:1 allocation ratio. A total of 62 outpatients aged 18-65 years with long COVID will be randomized to either a rehabilitation program with individual follow-up consultations or a 1-day self-management group course. The individual intervention incorporates setting goals, teaching cognitive behavioral strategies, energy management (pacing), and a supervised gradual increase in both physical and cognitive activities tailored to individual tolerance levels. The primary outcome is the between-group difference in health-related quality of life, measured using the EQ-5D-5L index at 6 months. Secondary outcomes include improvements in symptoms, work participation, neurocognitive function, and app usability, assessed at 3, 6, and 12 months, depending on the outcome measure. Results: Data enrollment started in October 2023. A total of 62 participants were included by November 2024. Data collection is planned to be completed in November 2025. Conclusions: Long COVID poses substantial challenges for both individuals and society, underscoring the need for effective rehabilitation strategies. This study will provide valuable insights into the benefits of an individualized outpatient rehabilitation program. The results from this clinical trial will help guide future treatment recommendations and may improve long-term outcomes for affected patients. Additionally, the study will generate important knowledge about neuropsychological function and digital self-management tools in long COVID rehabilitation.

Abstract Background and aims Brain-derived tau (BD-tau) is a sensitive blood-based biomarker of neuronal injury in acute ischemic stroke; but its relevance in conditions characterized by chronic cerebral hypoperfusion remains unclear. Moyamoya angiopathy (MMA) is a progressive steno-occlusive disorder causing regional cerebral hypoperfusion, impaired vasomotor reserve, and heterogenous clinical phenotypes, including cognitive impairment, complicating risk stratification. Biomarkers reflecting hypoperfusion-related neuronal injury may complement imaging and clinical assessment in neurosurgical decision- making. We investigated serum BD-tau levels in MMA patients and healthy controls and explored relations with cognitive performance. Methods This cross-sectional, register-based case-control study included MMA patients without recent stroke (n = 37) and healthy controls (n = 14). Serum total BD-tau levels were compared using Mann-Whitney U test. MMA patients underwent comprehensive neuropsychological assessment across nine cognitive domains. A Global Cognitive Impairment Index (GCII) was calculated as the proportion of domains with at least one test score ≥1 standard deviation below normative means. Associations between BD-tau and GCII were assessed using Spearman´s rank correlation. Results Median serum BD-tau levels were 12.38 [9.40–14.96] pg/mL in the MMA group and 9.97 [9.27–13.77] pg/mL in the control group, without significant between-group difference (p = 0.263). Within the MMA group, BD-tau levels showed no significant correlation with GCII (p = 0.061). Conclusions Serum BD-tau levels were not elevated in MMA patients and were not associated with global impairment. Despite small sample size, these findings suggest limited general utility of BD-tau in MMA, though its potential in selected subgroups warrants further investigation in larger cohorts. Conflict of interest Jesper Sømark: nothing to disclose. Mona Skjelland: non-personal research grants from South-Eastern Norway Regional Health Authority (2024). Bente Halvorsen: is an SAB member in CircM, Linkøping, Sweden and is an evaluator in MH panel, Swedish Research council.. Thor Ueland: nothing to disclose.Vigdis Bjerkeli: nothing to disclose. Pål Aukrust: nothing to disclose. Tonje Nordenmark: nothing to disclose. Markus K.H. Wiedmann: nothing to disclose. Anne Hege Aamodt: has received personal fees for lectures/advisory boards; Novartis, Abbvis, TEVA, Roche, Lundbeck, Pfizer, Boehringer Ingelheim, non-personal research grants from Norwegian National Association for Public Health, South-Eastern Norway regional Health Authority, Odd Fellow, National Program for Clinical Treatment Research in the Specialist Health Service (KLINBEFORSK), EU, Boehringer Ingelheim, Medtronic, BMS. Figure 1 - belongs to Conclusions

BACKGROUND:Adiponectin, a hormone-like protein primarily secreted by adipocytes, is typically decreased in obesity. Adiponectin has been shown to have antithrombotic properties through regulation of hemostatic factors in vitro. However, the association between adiponectin and venous thromboembolism (VTE) remains unclear. OBJECTIVES:To investigate the association between plasma adiponectin levels and risk of future first lifetime VTE. METHODS:A population-based nested case-control study, including 381 VTE cases and 772 age-and sex-matched controls, was derived from the Tromsø4 survey (1994/95-2007). Adiponectin was measured in samples collected at cohort inclusion. Logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs) for VTE across adiponectin quartiles (Q) determined in controls using sex-specific quartile cut-offs. To investigate short-term associations, time-restricted analysis was performed including VTE cases occurring up to 5 years after cohort inclusion. RESULTS:High adiponectin levels were associated with decreased VTE risk, with an OR of 0.69 (95% CI 0.48-0.99) for Q4 vs Q1 (reference) in age- and sex-adjusted analysis for the entire study period. The inverse association between adiponectin and VTE risk was stronger with analysis restricted to the first 5 years after cohort inclusion, with an OR of 0.40 (95% CI 0.20-0.77) for Q4 vs Q1. The additional adjustment for body mass index and C-reactive protein had minor impact on risk estimates. CONCLUSION:Our results suggest that high plasma adiponectin levels are associated with decreased risk of future first lifetime VTE, particularly shortly after cohort inclusion, and that adiponectin might play a role in the pathogenesis of VTE.

Abstract Background and aims Endovascular thrombectomy (EVT) has substantially improved outcomes in acute ischemic stroke (AIS); however, many patients do not achieve functional independence. Secondary brain injury related to post-ischemic and ischemia–reperfusion–associated neuroinflammation is increasingly recognized as a contributor to infarct expansion after EVT. Interleukin-6 (IL-6) is a central inflammatory mediator in AIS and is consistently associated with infarct growth and unfavorable outcomes. IL-6 receptor inhibition with tocilizumab has demonstrated neuroprotective effects in experimental stroke models and early clinical studies. The ILLUMINATE trial is designed to evaluate whether IL-6 receptor blockade reduces infarct growth in patients with AIS undergoing EVT. Methods ILLUMINATE is an ongoing multicentre, randomized, placebo-controlled, double-blind phase II trial. Adults with AIS scheduled for EVT are randomized 1:1 to receive a single intravenous infusion of tocilizumab or placebo administered before or during EVT. The primary endpoint is infarct growth, defined as the change in diffusion-weighted imaging lesion volume between MRI performed within 8 hours after EVT and at 72 hours. Secondary endpoints include NIHSS, functional outcomes, health-related quality of life, brain-derived tau, inflammatory biomarkers, and safety outcomes including symptomatic intracranial haemorrhage, infections, and mortality up to 90 days. Results Recruitment is ongoing at centres in Norway and Denmark. Updated enrollment numbers will be presented. Conclusions LLUMINATE addresses a mechanistically defined and clinically relevant target in AIS. By combining standardized MRI-based infarct growth assessment with clinical and biological endpoints, the trial aims to generate evidence on IL-6–mediated neuroinflammation and inform adjunctive strategies in patients undergoing EVT. Conflict of interest

BACKGROUND:Long-term symptoms are common after acute COVID-19, particularly fatigue, cognitive problems, and dyspnoea. Cohort studies have suggested that antiviral treatment of acute COVID-19 might prevent development of post-COVID-19 condition (also known as long COVID), but the efficacy of antivirals has yet to be verified in prospective studies. We aimed to investigate whether treatment of acute SARS-CoV-2 infection with nirmatrelvir-ritonavir would reduce the risk of long COVID. METHODS:In this double-blind, randomised, placebo-controlled trial, participants were recruited from the municipal health-care service at three sites in Norway (Bergen, Oslo, and Ålesund). Non-hospitalised adults aged 18-65 years with SARS-CoV-2 infection confirmed by PCR or lateral flow test and symptoms for 5 days or fewer were eligible for inclusion. Key exclusion criteria included pregnancy or lactation, chronic renal impairment or chronic liver dysfunction, and any person judged by the investigator to need nirmatrelvir-ritonavir treatment due to increased risk of hospitalisation or death. Participants were allocated in a 1:1 ratio to receive oral 300 mg nirmatrelvir and 100 mg ritonavir, or placebo, twice a day for 5 days using a pre-generated randomisation list without stratification or block adjustment. Participants, clinicians, and the study team were masked to treatment allocation. The primary outcome was long COVID, defined as patient-reported fatigue, dyspnoea, and/or cognitive symptoms at 3 months' follow-up. Safety was analysed as a secondary outcome, and included adverse events, hospital admissions, and deaths. Both the primary outcome and safety were assessed in the intention-to-treat population. The trial is registered with ClinicalTrials.gov (NCT05852873) and is now closed to new participants. FINDINGS:Between May 12, 2023, and June 11, 2025, we enrolled 144 participants, of whom 66 were assigned to nirmatrelvir-ritonavir and 78 to placebo. In the protocol we planned to enrol 2000 participants, but the trial was stopped prematurely by the steering committee due to insufficient recruitment. Among the 143 participants who completed follow-up, the risk of long COVID at 3 months was significantly reduced in the nirmatrelvir-ritonavir group (17 [26%] of 66) compared with the placebo group (33 [43%] of 77), corresponding to a relative risk after imputation of data for the single missing value in the placebo group of 0·60 (95% CI 0·37-0·98; p=0·039). In the nirmatrelvir-ritonavir group, five patients discontinued treatment due to adverse events. The most common adverse events in the nirmatrelvir-ritonavir group were change in taste or smell (57 [86%] of 66 in the nirmatrelvir-ritonavir group vs 14 [18%] of 78 in the placebo group) and nausea or vomiting (19 [29%] vs eight [10%]). Inversely, palpitations were more common in the placebo group (ten [13%] of 78) than in the nirmatrelvir-ritonavir group (two [3%] of 66). No severe adverse events were reported. INTERPRETATION:Treatment with nirmatrelvir-ritonavir for acute COVID-19 was associated with a significant reduction in the risk of long COVID at 3 months' follow-up. The limited sample size precludes firm conclusions, and further clinical trials are warranted. FUNDING:National Health Authorities' KlinBeForsk programme, Western Norway Regional Health Authority, Helse Møre og Romsdal Hospital Trust, and The Influenza Centre, Haukeland University Hospital and University of Bergen, Bergen, Norway.

AimsSecreted modulators of the Wingless (WNT) pathways are associated with cardiometabolic dysregulation. Among these, Dickkopf-1 (DKK1) and secreted frizzled-related protein-3 (sFRP3) are abundantly expressed in placental tissue and secreted into the maternal circulation. We hypothesized their plasma levels would be dysregulated in women with gestational diabetes mellitus (GDM) and correlate with indices of metabolic health.MethodsA total of 284 women during pregnancy and at 5 years postpartum participated in this longitudinal cohort study. Secreted Wnt modulators were analyzed by enzyme immunoassay 4 times during pregnancy and postpartum. Lipids and indices of glucose tolerance were assessed twice in pregnancy and at follow-up. Body composition and pulse wave velocity analysis was assessed at follow-up.ResultsOur main findings: i) plasma DKK1 was lower throughout pregnancy in women with GDM. ii) sFRP3 was lower early in pregnancy in women with GDM and correlated with indices of obesity and adipose tissue related inflammation, insulin resistance, poor β-cell function and unfavorable lipid ratios. iii) low DKK1 during pregnancy was associated with higher aortic stiffness at follow-up.ConclusionsLow plasma sFRP3 during early pregnancy is associated with metabolic and inflammatory dysregulation while persistently low DKK1 may be associated with future cardiovascular disease risk in GDM pregnancies.

Background: Metabolic disturbances are a hallmark of COVID-19, yet the pathways linking systemic inflammation, microbial dysbiosis, and clinical outcomes remain incompletely defined. Tryptophan metabolism lies at the interface of immune activation and gut microbial function and may provide insight into both acute disease severity and recovery. Methods: We performed targeted metabolomic profiling of tryptophan-related metabolites in a cohort of hospitalized COVID-19 patients (n=118) and in another cohort assessed 3 months after hospitalization (n=69), comparing both groups with matched healthy controls. Results: Acute infection was characterized by interferon-driven activation of indoleamine 2,3-dioxygenase, reflected by elevated levels of kynurenine, 3-hydroxykynurenine, quinolinic acid, and an increased kynurenine-to-tryptophan ratio. This was accompanied by inflammation-associated depletion of pyridoxal 5′-phosphate, the active form of vitamin B6 required for key kynurenine pathway enzymes, and profound suppression of microbiota-derived indole metabolites, including indole-3-propionic acid, indole-3-acetic acid, indole-3-carboxaldehyde, and 3-indoxyl sulfate. These alterations suggest inflammation-related functional reprogramming of the host-microbiota-micronutrient-tryptophan axis during acute infection. Although the differences between the 3-month cohort and healthy controls were more modest, indole-3-propionic acid and pyridoxal 5′-phosphate remained reduced. Exploratory analyses indicated associations between gut microbiota features, markers of gut barrier dysfunction, and circulating tryptophan-derived indole metabolites at three months, which were further associated with persistent pulmonary computed tomography abnormalities. Conclusion: Together, these findings demonstrate coordinated disruption of the host-microbiota-vitamin B6 tryptophan axis during acute COVID-19 and suggest that incomplete restoration of this network may contribute to persistent pulmonary dysfunction.

Objective:To determine whether circulating soluble Flt-1 (sFlt-1) and soluble Tie-2 (sTie-2) are associated with intraplaque neovascularization (IPN) in human carotid atherosclerotic plaques. Methods:Forty-four patients with ≥50% carotid stenosis underwent conventional carotid ultrasound and superb microvascular imaging (SMI); 29 had plasma collected and 11 provided carotid endarterectomy specimens for histology. IPN was quantified as neovessel counts in 2-minute SMI cine loops and as microvessel counts in excised plaques. Plasma VEGF-A/B/C/D, Ang-2, sFlt-1, and sTie-2 were measured by immunoassays. Public single-cell RNA-seq data from human carotid plaques were interrogated to map FLT1, TEK, VEGFA, ANGPT1, and ANGPT2 expression to specific plaque cell populations. Results:IPN was detected in 33/44 (75%) patients, with 0-16 neovessels on SMI (median 4). Plasma sFlt-1 correlated with SMI neovessel counts (r=0.42, p=0.030), with a similar trend for sTie-2 (r=0.37, p=0.057), whereas VEGF-A/B/C/D and Ang-2 showed no significant relationships. In the surgical subgroup, histological neovessel counts correlated with sFlt-1 (r=0.65, p=0.030) and SMI neovessel count (r= 0.68, p =0.02) but not sTie-2. sFlt-1 and sTie-2 correlated with BMI (and sTie-2 also with age), yet log-sFlt-1 remained independently associated with SMI-derived neovessel counts after adjustment for age and BMI (B = 13.24, 95% CI 0.17-26.30, p=0.047; R²=0.18), while sTie-2 was not. No significant associations were observed between IPN or sFlt-1/sTie-2 and lipid profile, CRP, leukocyte counts, or other conventional risk factors. Single-cell transcriptomics showed FLT1 and ANGPT2 broadly expressed across endothelial, smooth-muscle, and myeloid clusters, with TEK largely confined to endothelial cells and ANGPT1 to smooth-muscle cells, supporting local activation of VEGF-FLT1 and Ang-TEK/Tie-2 signaling within plaques. Conclusion:In this pilot study, higher plasma sFlt-1, and, to a lesser degree sTie-2, correlated with carotid IPN on SMI and histology, independent of age and BMI. These findings suggest that soluble VEGF- and Ang/Tie-2-receptor pathways may serve as circulating, context-sensitive markers of intraplaque angiogenesis and plaque vulnerability, meriting evaluation in larger longitudinal cohorts.