University of Bergen

There is limited data regarding the rare and aggressive colorectal neuroendocrine carcinoma (CR-NEC). In this large prospective study, molecular-clinical characteristics and treatment outcomes following palliative chemotherapy are reported for 163 metastatic CR-NEC patients, with a comparison to a population-based prospective cohort of 263 metastatic colorectal adenocarcinoma (CR-AC) patients. Eighty-three percent of CR-NEC received first-line platinum-etoposide, while 98% of CR-AC patients received first-line fluorouracil-based chemotherapy. Disease control rate across all first-line regimens in CR-NEC and CR-AC was 43% vs. 74%, immediate progressive disease 46% vs. 15%, progression-free survival 2.4 months (m) (95% CI 2.1-3.3) vs. 7.7 m (95% CI 6.9-8.5), and overall survival 6.7 m (95% CI 5.6-8.8) vs. 16.8 m (95% CI 13.7-20.3), all, p < .001. CR-NEC more often had synchronous metastases, worse performance status, and symptom burden at treatment initiation than CR-AC (all, p < .001). Two-year survival was 9% vs. 37% in CR-NEC and CR-AC (p < .001). BRAF mutations were frequent in CR-NEC and CR-AC (26% vs. 20%, p = .153) and associated with shorter OS in CR-NEC and CR-AC (p = .025 and p = .003). KRAS mutations were less frequent in CR-NEC than CR-AC (34% vs. 45%, p = .041), but only associated with shorter OS in rectal NEC (p = .04). The frequencies of APC and TP53 mutations were similar between the cohorts and did not impact survival. Metastatic CR-NEC and CR-AC are clinically distinct, with NEC demonstrating more aggressive features, limited treatment effect, and worse prognosis. Although they share important driver mutations, the underlying reason for their marked clinical differences remains unclear.

Published data describing epidemiological trends of abdominal injury on a national level are scarce. This study aims to analyse trends in demographics, severity, population-adjusted incidences, and short-term outcomes of abdominal trauma based on national trauma register data. Observational, complete national cohort study of all consecutive traumatic incidents resulting in abdominal injuries reported to the National Trauma Register (NTR) of Norway between 2015 and 2023. The NTR has demonstrated an overall coverage rate of 92.2% of trauma patients, with excellent data accuracy. Standardised incidence rates were estimated using the direct method with standard populations. Temporal trends were evaluated in regression models. Abdominal injuries occurred in 9.0% (7086/78,416) of all registered traumatic incidents. Children represented 18.1% (n = 1275) of the patients, and 14.8% (n = 1047) were elderly. The median age was 35 years (interquartile range, IQR: 19-55) and increased by 0.4 years annually (95% confidence interval, CI: 0.0-0.8). Men accounted for 69.5% (n = 4926) and 30.5% (n = 2160) were female. Blunt injury type dominated with 85.3% (n = 6044). Traffic-related accidents were the most common mechanism (48.0%, n = 3401), followed by falls (26.9%, n = 1903). The median Injury Severity Score (ISS) was 10 (IQR 2-18), and 36.3% (n = 2567) displayed ISS>15 indicating severe injury. Polytrauma occurred in 20.6% (n = 1457) of trauma cases suffering abdominal injury. Age- and sex-adjusted incidence of all abdominal injuries was 14.9/100,000/year (95% CI: 14.5-15.3). The annual increase was 0.43 per 100,000 person-years (95% CI: 0.14-0.71) among children and 0.68 per 100,000 person-years (95% CI: 0.39-0.97) for elderly patients. The subgroup of solid organ injuries showed an adjusted incidence of 7.2/100,000/year (95% CI: 7.0-7.5), and hollow viscus injuries of 1.2/100,000/year (95% CI: 1.1-1.3). Overall 30-day mortality was 3.4% (n = 240), with no statistically significant change during the study period. Trauma patients presenting with abdominal injury are getting older. One third sustained severe injuries and one in five patients suffered polytraumatic injuries. The incidence of abdominal trauma increased over the last decade, predominantly amongst elderly patients and children. The mortality was low, and stable over time. None.

Reconstructing the complex human behaviours that manifest in the Palaeolithic archaeological record remains an elusive but important challenge for capturing traces of how the human mind evolved. The roughly 1.5 million years of handaxe-making throughout the Acheulean provides a consistently preserved manifestation of hominin technological skills. Here, we analyse 1108 3D scans of handaxes from 12 sites in the Great Rift Valley of eastern Africa and the southern Levant spanning much of the Acheulean. We set out to chart the evolution of Acheulean toolmaking skill using a suite of computational 3D methods to quantify how well these handaxes have been thinned, shaped, and sharpened; traits which demand manual dexterity, planning, and hierarchical cognition. We find evidence that cognitive evolution likely played a role in improvements in handaxe-making skill, but only in the first half of the Acheulean. The most skilfully made handaxes among our sample begin to be made by about one million years ago. Any increases in cranial capacity, cognitive complexity, or manual dexterity after this point do not make a noticeable impact on how skilfully handaxes were made, and nor does raw material quality. Instead, the techno-morphology of handaxes appears to be relatively untethered from evolutionary constraints after about a million years ago, at which point we need to seek alternative explanations for handaxe variability. Above all, we show that the difficult pursuit of lowering bifacial asymmetry was more often achieved than any other skilful attribute, suggesting it was a fundamental goal of handaxe-making. Attempting to maintain 3D symmetry appears to be a common goal throughout the entire Acheulean and was routinely achieved by its second half. This capacity to consistently maintain bifacial balance while knapping was in place by at least 1.0 Ma, revealing the evolved technological abilities and hierarchical cognition of Acheulean hominins. • We analyse 1108 3D scans of Acheulean handaxes from 12 sites from the Great Rift Valley. • Computational 3D methods were used to estimate how skilfully each handaxe was made. • Hominins enacted handaxe reduction sequences with equivalent fidelity on raw materials of different qualities. • Early improvements in handaxe-making skill were likely governed by cognitive evolution, but not later improvements. • Acheulean knappers appear to be aiming to minimise bifacial asymmetry and routinely achieved this by one million years ago.

Understanding the long-term biological consequences of crude oil exposure on marine fish is essential for the sustainability of ecologically and economically important species such as Atlantic cod (Gadus morhua). While the direct effects of crude oil on early life stages are well documented, adult reproductive vulnerability and intergenerational consequences remain poorly understood, despite their pivotal role in spawning stock viability. Paternal contributions to next-generation outcomes are particularly underexplored. This study examined how parental exposure to a water-soluble fraction of crude oil affects transcriptomic profiles and survival outcomes in Atlantic cod offspring. Adult fish were exposed for 20days prior to spawning, and offspring were produced by in vitro cross-fertilization to generate four groups: control (unexposed parents), maternally exposed, paternally exposed and biparentally exposed. Embryos were reared under control conditions, and transcriptome profiles were analyzed from fertilization to hatching, alongside assessments of cardiac function and morphology post-hatch. Offspring from exposed females failed to survive to hatching. Eggs were smaller, and transcriptomic data revealed severe downregulation of genes involved in early developmental processes. Chemical analyses confirmed maternal transfer of a diverse range of petroleum aromatic hydrocarbons to oocytes. Our findings point to disrupted oocyte provisioning, likely linked to endocrine and epigenetic disturbances during oocyte maturation. Paternal exposure had minimal effect on RNA expression, and morphology at hatching. However, reduced survival in early larval stages suggests sublethal effects emerging later, possibly through epigenetic mechanisms, a hypothesis requiring further investigation.

We aimed to assess the association between body mass index and polyunsaturated fatty acids to determine potential links and metabolic differences between Alzheimer's disease and dementia with Lewy bodies. We performed a cross-sectional study of enrolment data with 133 patients with mild AD (n = 75) and DLB (n = 58) from a Norwegian cohort study. We used linear regression models adjusting for age, sex, and diagnosis to explore the association between PUFA concentrations and BMI estimates. In DLB patients, BMI was positively associated with downstream omega-6 PUFA, including gamma-linolenic acid (GLA; β = 0.285, p = 0.012), arachidonic acid (AA; β = 0.320, p = 0.005), and adrenic acid (β = 0.303, p = 0.005). BMI was also related to increased Δ6-desaturase n-6 activity (β = 0.383, p = 0.002) and Δ6-desaturase n-3 activity (β = 0.335, p = 0.011), along with reduced elongase n-6 (β = -0.396, p = 0.002) and elongase n-3 (β = -0.376, p = 0.004), suggesting increased fatty acid turnover. No significant associations were found in the AD group. BMI in DLB patients was positively associated with elevated downstream omega-6 metabolites and desaturase and elongase activity, compatible with higher fatty‑acid turnover and systemic inflammatory state hypothesized in DLB. These findings highlight the distinct metabolic alterations across dementia subtypes that are relevant for personalized nutritional strategies in dementia care.

Pharmacological treatments for attention-deficit/hyperactivity disorder (ADHD) are efficacious and safe; however, substantial interindividual variability in treatment response persists, with many patients experiencing suboptimal outcomes or early discontinuation. Although genetic factors have been proposed as contributors to this variability, clinically actionable predictors remain elusive. Here, we present the first meta-analysis evaluating whether polygenic liability for ADHD and related psychiatric and behavioral-cognitive phenotypes is associated with clinically meaningful response to methylphenidate in 1000 ADHD cases from Norway, Brazil, and Spain assessed in real-world settings. Polygenic scores (PGS) for ADHD, autism, bipolar disorder, educational attainment, major depressive disorder, neuroticism, and schizophrenia were calculated separately for each cohort. Treatment response was assessed using evaluations of global clinical improvement and harmonized by categorizing individuals as responders or non-responders. Cohort-specific associations were combined using fixed-effects meta-analysis. No PGS showed a significant association with treatment response. Effect sizes were small, consistent across cohorts, and characterized by minimal between-study heterogeneity. Sensitivity analyses incorporating clinical and treatment-related covariates yielded convergent results. As the first meta-analytic evaluation of polygenic predictors evaluating clinically meaningful ADHD stimulant response, these findings delineate the current limits of PGS in pharmacogenomic applications. Rather than supporting immediate clinical utility, our results highlight key methodological and conceptual constraints, including limited sample sizes, heterogeneous outcome definitions, and the indirect nature of susceptibility-based PGS for predicting treatment response. By mapping these boundaries, this study provides a framework to recalibrate research priorities and guide the next generation of ADHD pharmacogenomic studies toward larger, harmonized, and more informative definitions of treatment response.

Impaired clinical insight is common in schizophrenia spectrum disorders (SSDs) and predicts poor treatment adherence and outcomes. It is linked to disorganised, positive, negative, and hostility symptoms. However, few studies repeatedly assess insight after antipsychotic initiation while comparing pharmacologically distinct agents. This study examined how symptom levels and changes predict the development and endpoint of clinical insight over 6 weeks, contrasting the partial dopamine agonist aripiprazole (PDA) with two dopamine antagonists (DAs). Data from 144 SSD patients in the Bergen-Stavanger-Innsbruck-Trondheim (BeSt InTro) trial, a pragmatic, semi-randomised study of amisulpride, aripiprazole, and olanzapine, were analysed using latent growth curve models. Insight was measured by PANSS Item G12; symptom factors (positive, negative, hostility, cognitive/disorganised) were derived from PANSS. Lower baseline symptoms and greater improvement between weeks 3 and 6 predicted better insight at 6 weeks across all factors. For positive symptoms, improvement between weeks 1 and 3 (b = 0.57, p = 0.009) also predicted better insight. Patients on aripiprazole showed less improvement in insight, though some findings lost significance after correction. Symptom reduction is associated with improved insight, with early changes in positive symptoms exerting the fastest effect. Despite symptom improvement, aripiprazole PDA treatment was linked to less insight gain than DA treatment. These preliminary findings warrant further study.

Cardiac organ damage (OD) is associated with increased risk of cardiovascular disease. However, limited knowledge exists on cardiac OD in young patients with cryptogenic ischaemic stroke (CIS). To explore prevalence and covariates of cardiac OD in patients with CIS compared to controls participating in the SECRETO study. We analysed data from 427 patients with CIS aged <50 years and 361 age- and sex-matched controls. OD was defined as presence of abnormal left ventricular (LV) geometry (LV hypertrophy or concentric remodelling) or left atrial enlargement (LAE) assessed by echocardiography, using sex-specific threshold values. Compared to controls, patients had higher prevalences of obesity and tobacco smoking, patent foramen ovale (PFO) (52% vs. 25%) and abnormal LV geometry (12% vs. 7%, all p < 0.01), while presence of LAE did not differ. In multivariable analyses, CIS was associated with presence of abnormal LV geometry (odds ratio 1.86 [95% confidence interval 1.09-3.20], p=0.024). In separate multivariable analyses in patients only, obesity was associated with both abnormal LV geometry and LAE (both p < 0.01), and higher systolic blood pressure only with presence of abnormal LV geometry (p < 0.001). No significant association with PFO was found. In young patients with CIS participating in the SECRETO study, abnormal LV geometry was more prevalent compared to age- and sex-matched controls and associated with presence of higher blood pressure and obesity. The results point to the importance of blood pressure and weight control in CIS to prevent progression of cardiac OD and recurrent cardiovascular events.