Vestre Viken Hospital Trust

Brain network architecture is anticipated to influence future grey matter loss in individuals at Clinical High Risk (CHR) for psychosis. However, existing studies on grey matter structural network properties in CHR are scarce and constrained by small sample sizes. Here, we examined network topology differences comparing a) CHR versus healthy controls (HC); b) CHR who transitioned to psychosis (CHR-T) versus those who did not (CHR-NT); and c) different subsyndromes. We included structural scans from 1842 CHR individuals and 1417 HC individuals from 31 sites within the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) consortium. At the global level, CHR individuals exhibited lower structural covariance (q < 0.001; Cohen's d = 0.164) and less optimal structural network configuration than HC (lower global efficiency and clustering coefficient, d = 0.100,0.087, qs <= 0.027). Though no global difference between CHR-T and CHR-NT, network distinctiveness of the frontal and temporal surface area networks was higher in CHR-T than CHR-NT (d = 0.223,0.237) and HC (d = 0.208,0.219) (qs < 0.001). Network distinctiveness of the frontal cortical thickness network was lower in CHR-T (d = 0.218, q < 0.001) than CHR-NT and HC (d = 0.165, q < 0.001). Importantly, higher network distinctiveness was associated with worse positive symptoms in CHR-NT (frontal surface area, q = 0.008, R2 = 0.013) and at trend with worse negative symptoms in CHR-T (frontal thickness, q = 0.063, R2 = 0.049). Further, the brief intermittent psychotic syndrome subgroup showed more severe network alterations. Together, brain structural networks inform symptoms and the risk of transition to psychosis in CHR individuals.

IntroductionCoronary artery disease (CAD) is the clinical manifestation of atherosclerosis, an inflammatory disorder of the coronary arteries, characterized by endothelial dysfunction, lipid accumulation, immune activation, and formation of atherosclerotic plaques. Despite management of conventional risk factors, CAD is a progressive disease, and may develop vulnerable lesions prone to rupture, causing atherothrombosis and acute coronary syndrome (ACS). Neutrophil extracellular traps (NETs), composed of chromatin and proteases, have been implicated in vascular inflammation and thrombosis, while the von Willebrand Factor (VWF)-ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motifs, member 13) axis plays a central role in platelet-mediated thrombus formation. Evidence suggest that NETs may interact with VWF to amplify thromboinflammation. The clinical relevance of this interplay and the prognostic utility of the NETs marker citrullinated histone H3 (CitH3) in CAD remains unclear.AimsIn stable CAD patients we aimed to 1) examine associations between CitH3, cardiovascular risk factors, and clinical outcome, 2) explore potential interactions between NETs and the VWF-ADAMTS13 axis, and 3) evaluate the predictive value of combined biomarker profiles.MethodsBetween 2003 and 2010, patients with angiographically verified symptomatic CAD (n = 1,000) were enrolled in the Aspirin Nonresponsiveness and Clopidogrel Endpoint Trial (ASCET) (NCT00222261). The primary composite endpoint (n = 73) at two-year follow-up comprised non-hemorrhagic stroke (n = 28), myocardial infarction (n = 36) and death (n = 9). Analyses were performed on baseline blood samples.ResultsCitH3 levels were similar between patients with and without endpoints. CitH3 correlated with neutrophil count (r = 0.221, p < 0.001) and was higher in younger patients (<62 years) and in those with BMI above mean (>27.4 kg/m2). CitH3 alone did not predict clinical outcome. However, patients with high VWF, low ADAMTS13, and elevated NETs biomarkers had increased odds of reaching the composite endpoint (adjusted odds ratio 3.14 and 3.68). This subgroup also exhibited higher leukocyte counts and high-sensitivity C-reactive protein.ConclusionCitH3 alone was not predictive of adverse events in stable CAD. However, combined extreme levels of thromboinflammatory biomarkers VWF, ADAMTS13 and NETs, identified patients at higher risk of adverse events. These findings suggest that integrated thromboinflammatory biomarker profiles may improve risk stratification in stable CAD and warrant validation in independent cohorts.

BackgroundCentral retinal artery occlusion can result in permanent vision loss. Effective treatment is lacking.MethodsWe conducted a phase 3, double-blind, double-dummy, randomized, controlled trial involving adults with acute, nonarteritic central retinal artery occlusion who had symptom onset within 4.5 hours before treatment. Patients were assigned, in a 1:1 ratio, to receive intravenous tenecteplase (at a dose of 0.25 mg per kilogram of body weight) and oral placebo or intravenous placebo and oral aspirin (at a dose of 300 mg). The primary end point was vision recovery, defined as a best corrected visual acuity (BCVA) in the affected eye at 30 days of up to 0.7 logMAR (logarithm of the minimum angle of resolution; equivalent to ≥20/100). Key secondary visual end points were a BCVA of up to 0.5 logMAR (equivalent to ≥20/63), mean improvement in BCVA, and perimetry score at 30 days. Key safety end points included symptomatic intracranial hemorrhage, major bleeding, and death.ResultsA total of 78 patients at 16 sites in six countries underwent randomization, with 40 assigned to receive tenecteplase and 38 to receive aspirin. At 30 days, 8 patients (20%) in the tenecteplase group and 9 patients (24%) in the aspirin group had vision recovery (risk difference, −3.7 percentage points; 95% confidence interval, −22.0 to 14.7; P=0.69). The outcomes with regard to the secondary visual end points did not differ substantially between the groups. There was a greater incidence of adverse events in the tenecteplase group, including one fatal intracranial hemorrhage.ConclusionsIntravenous tenecteplase administered within 4.5 hours after onset of central retinal artery occlusion did not result in significantly greater vision recovery at 30 days than oral aspirin but was associated with serious safety concerns. (Funded by Oslo University Hospital and others; TenCRAOS ClinicalTrials.gov number, NCT04526951; EU Clinical Trials number, 2024-517606-29-00.)

A positive surgical margin (PSM) after radical prostatectomy (RP) is considered an adverse surgical feature, but the clinical implications have been debated. Further motive to aim for negative margins (NSM) may be patient anxiety due to PSM, but studies on psychological consequences are lacking. We explored associations between psychological factors and PSM on a consecutive group of men after RP. Men with suspected prostate cancer were invited to a study on psychological factors. Patient reported outcome measurement questionnaires were collected before diagnosis, and at 6, 12 and 24 months from those who underwent RP. Multivariable mixed models and post hoc pairwise comparisons were used to explore associations between PSM and psychological outcomes. In total, 387 men had RP and 94 (24%) had PSM. General psychological outcomes were not associated with margin status. At 12 months, men with PSM considered their personal risk of recurrence 6% (30% vs. 24%) points higher and had clinical fear of recurrence (FoR) 14% (47% vs. 33%) more often than men with NSM. In adjusted and stratified analyses, men with pathological (p-)T2-stage and NSM had less FoR than the rest of the sample. In pT3-disease, PSM had no additional impact on FoR. A limitation was the small size of the pT2 group with PSM and the lack of information on how patients were informed. After RP, PSM was associated with higher FoR, particularly in men with pT2-cancer. Improved counselling and further research into causes and mitigation of FoR, is warranted.

Fatigue is common in Crohn's disease (CD) and ulcerative colitis (UC), but the pathogenesis remains poorly understood. This study aimed to assess changes in fatigue prevalence during the first year after diagnosis and examine the association between disease course and substantial fatigue (SF) at the 1-year follow-up. Adults with newly diagnosed CD or UC were recruited from the population-based IBSEN III cohort. Fatigue was assessed at diagnosis and the 1-year follow-up using the Fatigue Questionnaire. Associations between SF at the 1-year follow-up and disease-related factors were quantified using multivariate logistic regression adjusted for sex, age and comorbidities. In total, 596 patients were included (CD: 196, UC: 400). SF was present at both baseline and after one year of disease for 46.9% (n = 92/196) and 40.5% (n = 162/400) of patients with CD and UC, respectively. In CD, development of endoscopically non-passable stricture and/or surgically treated stricture within first year of disease (OR = 4.52, 95%CI [1.61;12.68]), self-reported flares since diagnosis (OR = 2.55, 95%CI [1.26;5.16]), female sex (OR = 3.12, 95%CI [1.53;6.37]) and comorbidities (OR = 4.05, 95%CI [1.89;8.69]) were independently associated with SF at the 1-year follow-up. In UC, SF was associated with current biological treatment (OR = 5.14, 95%CI [1.56;16.96]), increasing Mayo endoscopic score at the 1-year follow-up (OR = 1.54, 95%CI [1.01;2.35]), self-reported flares since diagnosis (OR = 2.66, 95%CI [1.24;5.72]) and female sex (OR = 2.20, 95%CI [1.06;4.57]). Fatigue frequently persists through the first year after IBD diagnosis. Clinical factors reflecting a more severe disease course were associated with SF one year after diagnosis in both CD and UC.

Abstract Background Endoscopic activity indices for ulcerative colitis (UC) demonstrate limited accuracy, particularly in acute severe UC (ASUC). Artificial intelligence-based scoring (AI) may enhance this. We investigated whether the DovaVision UC AI tool could detect differences in endoscopic response rates between personalised and standard infliximab (IFX) dosing in ASUC patients enrolled in the prospective randomised TITRATE trial, that were previously not detected with human assessment. Methods In TITRATE, adult IFX-naive steroid-refractory ASUC patients were randomised 1:1 to standard dosing (SD) or personalised dosing (PD) with IFX. After an initial 5 mg/kg IFX infusion, patients in the SD group received 5 mg/kg IFX at week 2 and 6. In the PD arm, additional 5 mg/kg IFX infusions were administered guided by a Bayesian pharmacokinetic algorithm (iDose™) aiming to achieve prospectively defined target IFX serum concentrations until day 42. Endoscopies were recorded at baseline and at week 6. Definitions of endoscopic response were ≥2-point improvement in UC endoscopic index of severity (UCEIS) and ≥1-point improvement in Mayo endoscopic subscore (MES) at week 6 compared to baseline. Patients with missing endoscopic data were classified as non-responders. Endoscopic activity was previously scored on blinded videos by 2 independent human experts, with a third for adjudication (1). Here, we applied the DovaVision UC AI tool to the blinded videos. This scored the UCEIS and MES on individual frames and aggregated results to yield final procedure-level scores. Results In total, 48 patients were randomised to PD (n = 23) or SD (n = 25) (Table 1). Human UCEIS or MES assessments could not distinguish differences in response rates (UCEIS: 13 (56.5%) in the PD and 11 (44.0%) in the SD group (p = 0.540); MES: 14 (60.8%) in PD and 10 (40.0%) in SD group (p = 0.250)) (1).Using AI-assessed UCEIS, 27/48 (56.2%) patients achieved endoscopic response, comprising 18/23 (78.3%) in the PD and 9/25 (36.0%) in the SD group (p = 0.004). Using AI-assessed MES, 24/48 patients (50.0%) responded (16/23 (69.6%) in PD and 8/25 (32.0%) in SD group (p = 0.020)) (Figure 1). Conclusion In ASUC patients treated with IFX, the AI tool was able to detect endoscopic response at 6 weeks of IFX treatment, regardless of the endoscopic activity index that was used. The AI tool could also distinguish response rate differences between personalised and standard dosing of IFX. In the original study, human UCEIS or MES assessments could not distinguish such differences. This is the first IBD study in which AI was able to distinguish treatment effects between different treatment strategies, demonstrating its potential to fundamentally improve clinical trial methodology.

Abstract Background Fatigue is common in Crohn's disease (CD) and ulcerative colitis (UC), but the pathogenesis remains poorly understood. Aims This study aimed to assess changes in fatigue prevalence during the first year after diagnosis and examine the association between disease course and substantial fatigue (SF) at the 1-year follow-up. Methods Adults with newly diagnosed CD or UC were recruited from the population-based IBSEN III cohort. Fatigue was assessed at diagnosis and the 1-year follow-up using the Fatigue Questionnaire. Associations between SF at the 1-year follow-up and disease-related factors were quantified using multivariate logistic regression adjusted for sex, age and comorbidities. Results In total, 596 patients were included (CD: 196, UC: 400). SF was present at both baseline and after one year of disease for 46.9% (n=92/196) and 40.5% (n=162/400) of patients with CD and UC, respectively. In CD, development of endoscopically non-passable stricture and/or surgically treated stricture within first year of disease (OR=4.52, 95%CI [1.61;12.68]), self-reported flares since diagnosis (OR=2.55, 95%CI [1.26;5.16]), female sex (OR=3.12, 95%CI [1.53;6.37]) and comorbidities (OR=4.05, 95%CI [1.89;8.69]) were independently associated with SF at the 1-year follow-up. In UC, SF was associated with current biological treatment (OR=5.14, 95%CI [1.56;16.96]), increasing Mayo endoscopic score at the 1-year follow-up (OR=1.54, 95%CI [1.01;2.35]), self-reported flares since diagnosis (OR=2.66, 95%CI [1.24;5.72]) and female sex (OR=2.20, 95%CI [1.06;4.57]). Conclusions Fatigue frequently persists through the first year after IBD diagnosis. Clinical factors reflecting a more severe disease course were associated with SF one year after diagnosis in both CD and UC.