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Verdens største database innen bl.a. medisin, sykepleie, helsestell og prekliniske fag
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Verdens største database innen bl.a. medisin, sykepleie, helsestell og prekliniske fag
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Introduction: Persistent smoking after hospitalization for an atherosclerotic vascular event remains common, and only a small proportion attend cardiac rehabilitation or community-based lifestyle support, including smoking cessation programs. This study aimed to identify patient and healthcare...
Background The distribution of students’ personality traits may indicate whether an admission system selects candidates suited to medical practice. While many countries use multi-step selection procedures, Norwegian medical schools admit students based solely on upper-secondary school grade point averages (GPA). We primarily aimed to characterise the personality profiles of medical students at the University of Oslo, and then compare them with previous studies of the Norwegian general population and medical students from systems in countries using alternative admission models. Methods We conducted an observational study of newly admitted medical students, 2022–2026 (mean age = 22.1 years, SD = 4.2; 68% female). Personality was assessed using the Big Five Inventory (BFI; five cohorts, n = 535, response rate (RR) = 89%) and the Myers–Briggs Type Indicator (MBTI; six cohorts, n = 632, RR = 95%). BFI scores were compared with available historical data: general Norwegian workers, German final-year, and French first‑ and third‑year medical students using one‑sample t‑tests. MBTI types were compared with previous studies on U.S. and South Korean medical students and the Norwegian general population using chi-squared tests. Results Norwegian medical students scored significantly higher than Norwegian workers on all BFI dimensions (p < 0.001). They also scored higher in Agreeableness than German final-year and French first- and third-year students (4.33 vs 4.17, 3.80 and 3.60, respectively) and lower in Neuroticism (2.50 vs. 2.85, 3.00 and 3.00; all p < 0.001). Norwegian students’ MBTI personality-type distribution differed significantly from the Norwegian general population and U.S. and South Korean medical students (p < 0.001). Most students were Judging (78%) and Extraverted (70%), with ENFJ the most frequent personality type among women (29%) and ENTJ among men (25%). Conclusions Medical students admitted through the Norwegian GPA-only admission system at UiO demonstrated high Agreeableness and Conscientiousness, with a marked overrepresentation of ENFJ women and ENTJ men. These findings indicate a consistently prosocial and structured, but relatively narrow, personality profile. While this profile includes interpersonal and organisational characteristics that may be relevant to clinical practice, the observed distribution also raises questions about limited diversity in personality type distribution and gender-related patterns in recruitment to medical education.
Aim: To identify and describe health literacy (HL) profiles and possible associations with sociodemographic and clinical characteristics among parents of children with congenital colorectal conditions. Methods: Parents (n = 269) of children with Hirschsprung disease (HD) or anorectal malformation (ARM) completed the Health Literacy Questionnaire-parent version (HLQ-p) and the General Self–Efficacy Scale. Demographic and clinical data were collected. Ward's hierarchical clustering was used to identify clusters across the nine HLQ-p domains. Ethical approval was obtained. Results: Four parental HL profiles were identified. Cluster 1 (n = 75, 28%) showed consistently low HL across all domains, with particular difficulties in information appraisal and social support. This cluster had the lowest self-efficacy, lower educational attainment, nearly half were non-native speakers, and half were not living with the child's other parent. Cluster 2 (n = 57, 21%) demonstrated moderate HL, but distinct challenges in information appraisal. Many had high education, cohabitated, and were native-speaking households. This group had the highest prevalence of child comorbidity. Cluster 3 (n = 109, 41%) exhibited generally high HL and strong engagement with healthcare providers, but struggled with information appraisal. Self-efficacy was high, and most parents lived with the child's other parent. Cluster 4 (n = 28, 10%) had the highest HL and self-efficacy, a high proportion of parents with high education and universal cohabitation. Conclusion: Nearly half of the parents exhibit low HL, including many with traditionally advantageous sociodemographic characteristics. Language diversity and child comorbidity amplified HL challenges, and difficulties in evaluating and applying health information were common across all parent groups.
Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease of the bile ducts that can lead to biliary cancer and end-stage liver disease. PSC is associated with inflammatory bowel disease and an altered gut microbiota. However, the molecular mechanisms underlying gut–liver interactions in PSC remain poorly characterized. Here we show that the gut microbiota-derived metabolite imidazole propionate (ImP) is a disease driver in PSC. Individuals with PSC have higher circulating ImP levels than individuals with related conditions, and high ImP levels predict reduced survival in PSC. Cholangiocytes exposed to ImP show activated mammalian target of rapamycin complex 1 (mTORC1) signalling and secrete pro-inflammatory and pro-fibrogenic factors. Chronic administration of ImP to mice induces liver inflammation and fibrosis through a p38-dependent mechanism, upstream of mTORC1. We propose that chronic exposure to ImP induces cholangiocyte injury, which alone or in concert with other factors causes clinical worsening of PSC. Therefore, targeting ImP production or signalling may represent therapeutic avenues in PSC.
Background Cancer is a complex phenomenon encompassing a range of cultural and biomedical dimensions. Traditional medical curricula often fail to reflect this complexity, highlighting the need for interdisciplinary approaches that help medical students develop a more integrated understanding of disease by connecting diverse knowledge, patient perspectives, and societal contexts. This study evaluates how framing analysis—a method from communication studies—can be used as a pedagogical tool to broaden medical students’ understanding and critical thinking about complex health issues, using cancer as a key example. Methods We conducted a course evaluation of a two-week elective titled “Cancer Communication” within the University of Oslo’s medical program, offered annually to approximately 20 third-year students. Working in teams, students explored research questions related to cancer communication through lectures, workshops, guided research, and excursions. They learned framing analysis by applying a published tool for examining public cancer discourse. Anonymous pre-course free associations and post-course reflections were analyzed thematically to identify changes in students’ understanding of cancer during the course. Students’ team presentations, orally evaluated as part of the final course examination, supported our assessment of how students applied framing analysis to cancer-related communication topics. Results Students’ initial responses reflected relatively simple and emotionally charged associations with cancer, often centered on fear, death, treatment burden, and familiar cancer stereotypes. Their post-course reflections suggested increased media literacy, critical thinking, and the ability to integrate multiple narratives about cancer. In their final presentations, students applied framing analysis to critically evaluate media portrayals and reflect on how different framings shape public and professional perceptions of disease. The post-course reflections further suggested greater empathy for cancer patients and an increased awareness of social and cultural influences on medical practice. Conclusions Integrating framing analysis into medical education appeared to broaden students’ understanding of cancer as a multidimensional phenomenon, supporting reflective and interdisciplinary thinking and encouraging them to move beyond traditional biomedical perspectives. These findings suggest that framing analysis and similar communication-based approaches may serve as useful pedagogical tools in health professions education to enhance critical reflection.
Yeasts belonging to the Candida genus typically reside on the mucosal surface and within the respiratory and gastrointestinal tract as commensals. Under conditions of host vulnerability, they can act as opportunistic pathogens, leading to various forms of candidiasis, including candidemia. Such infections can be particularly problematic when caused by isolates that exhibit resistance to antifungal drugs, which are becoming more prevalent in many regions. One hundred and seven samples of Candida spp. were isolated from patients with candidemia in the hospital San Matteo in Pavia (Italy) over a period of 6 years, from 2015 to the first COVID wave in spring 2020. In order to understand the epidemiology of Candida infections in this hospital setting, the isolates were whole-genome sequenced, confirming that most belonged to C. parapsilosis and C. albicans. Comparative genomics revealed that isolates of C. albicans were genomically diverse, indicative of repeated introductions in the hospital from the community. C. parapsilosis isolates on the other hand belonged to two groups of highly similar isolates, representing strains capable of long-term persistence in the hospital. All isolates of the main persistent group were resistant to fluconazoleresulting from the Y132F substitution in ERG11 and the N455D substitution in UPC2, while presenting variable levels of resistance to voriconazole and itraconazole. Interestingly, with the exception of the single isolate susceptible to both voriconazole and itraconazole, all the 61 isolates presented one unreported missense mutation in MRR1 (S1907C).
Abstract Astroglia, an extended class of homeostatic and defensive cells of the central nervous system (CNS), contribute to the pathogenesis of all known neurological and neuropsychiatric disorders. The pathophysiology of astrocytes is complex, mutable, disease and disease-stage specific. In neuroinflammatory lesions and in various chronic conditions, astrocytes undergo an evolutionary conserved defensive remodeling known as reactive astrogliosis, which produces highly heterogeneous reactive astrocytic phenotypes. Broadly, reactive astrogliosis can be classified into proliferative anysomorphic barrier-forming astrogliosis characteristic of traumatic CNS lesions and nonproliferative isomorphic gliosis widely manifested in chronic neuropathologies. In addition, in many pathologies, astrocytes undergo atrophy and asthenia with resulting loss of homeostatic support and neuroprotection precipitating neuronal damage. Reactive and atrophic astrocytes may coexist or emerge in sequence in a disease-stage-dependent manner. Several classes of astrocyte-specific molecules and processes implicated in various diseases of the CNS represent therapeutic targets. Astrocyte-specific therapeutic strategies may improve both disease-preventing and disease-modifying therapeutic outcomes.
Abstract Purpose: The Nutri-Score categorizes foods by nutritional value per 100 g or 100 ml, which may lead to poor discriminatory ability for products with low energy density and large portion sizes, like ready-to-eat meals. We hypothesized that adapting the Nutri-Score algorithm to account for variation in energy density could better capture nutritional quality, particularly in lower energy-dense foods like ready meals, without substantially affecting other food scores. The aim of this study was to perform a proof‑of‑concept evaluation of adapting the Nutri-Score algorithm for general foods to different levels of energy density. Methods: This study utilized the Norwegian food databases Tradesolution and Unil ( N = 25,813) to compare the energy-adjusted algorithm with the Nutri-Score 2023. Results: The energy-adjusted Nutri-Score shifted food categorizations for 22% of products. Foods with low energy density, such as ready meals, showed increased scoring variation, indicating a more nuanced nutritional quality assessment, as intended. In these foods, we also saw a decline in favourable scores and an increase in unfavourable ones. However, high-energy-density food categories, like cakes and pastries, more often received more favourable scores. Also, the discriminatory ability between low-fat and full-fat products was reduced. Conclusion: While the energy-adjusted Nutri-Score improved scoring differentiation for certain low-energy-density foods, it showed unfavourable side-effects, indicating that overall, it is not superior to the Nutri-Score 2023. Nonetheless, adapting the algorithm to energy density offers potential for improved nutrient profiling methodologies in specific contexts. Further refinement of the weighting system could address observed weaknesses, optimizing this approach for broader application.
Background Colorectal cancer frequently metastasises to the liver. Recurrence after curative-intent treatment of colorectal cancer liver metastases is common. Aspirin has shown preventive and antitumour effects in colorectal cancer, but its role after treatment of metastatic disease is uncertain. We aimed to establish whether adjuvant aspirin improves disease-free survival after curative-intent treatment of colorectal cancer liver metastases. Methods In this phase 3, randomised, double-blind, placebo-controlled trial conducted at 14 centres in Norway, Sweden, and Denmark, patients who had undergone curative-intent treatment for colorectal cancer liver metastases were randomly assigned (1:1), stratified by study site using a centrally generated computerised sequence with variable block sizes, to aspirin 160 mg per day or matching placebo for up to 3 years or until recurrence, death, or treatment discontinuation. The primary outcome was disease-free survival in the full analysis set, comprising all patients who initiated study treatment. The trial is completed and this is the final analysis. This trial is registered with ClinicalTrials.gov, NCT03326791, and EudraCT, 2014-003601-15. Findings Between Dec 15, 2017, and Jan 27, 2022, 466 patients were randomly assigned, of whom 428 initiated study treatment and were included in the full analysis set (217 assigned aspirin and 211 assigned placebo); 272 (64%) were male, 156 (36%) were female, and the mean age was 62·2 years. 269 disease-free survival events occurred (138 in the aspirin group and 131 in the placebo group). Aspirin did not improve disease-free survival (hazard ratio [HR] for recurrence or death 1·08 [95·44% CI 0·85–1·38]; p=0·58). Median disease-free survival was 1·13 years (95·44% CI 0·92–1·44) with aspirin and 1·40 years (1·11–1·69) with placebo. Overall survival at 36 months was 76% (95% CI 69·4–82·7) with aspirin and 85% (79·5–90·8) with placebo (HR for death 1·64 [95% CI 1·01–2·65]; p=0·045). Time to recurrence did not differ between groups (adjusted cause-specific HR 1·06 [95% CI 0·83–1·35]; p=0·64). 24 serious adverse events occurred in 17 (8%) of 217 patients in the aspirin group and five serious adverse events occurred in four (2%) of 211 patients in the placebo group. Clinically relevant adverse events and serious adverse events that occurred more commonly in the aspirin group than in the placebo group were myocardial infarction (two vs 0), epistaxis (four vs 0), duodenal ulcer (two vs 0), and cerebral haemorrhage (two vs 0). There were no treatment-related deaths. Interpretation Adjuvant aspirin did not improve disease-free survival and was associated with lower overall survival and more serious adverse events. These findings do not support routine use of aspirin after curative-intent treatment of colorectal cancer liver metastases.
Targeted therapies have improved outcomes for patients with chronic lymphocytic leukemia (CLL); yet, not all achieve durable responses. Existing prognostic models, developed for chemoimmunotherapy, have limited predictive value for newer targeted combinations. Here, we used data from a randomized phase II clinical trial to identify predictors of progression‐free survival (PFS) in response to Bruton tyrosine kinase (BTK) + B‐cell lymphoma 2 (Bcl‐2) inhibitor combination therapy. We studied the functional, genetic, and clinical characteristics of patients with relapsed/refractory (R/R) CLL treated with ibrutinib + venetoclax in the VISION/HO141 clinical trial (NCT03226301). Ex vivo drug sensitivity testing, (phospho)protein profiling, and immunophenotyping were performed on baseline peripheral blood mononuclear cells from 177 patients. Ex vivo drug sensitivity correlated with clinical responses to single‐agent therapies. (Phospho)protein patterns reflected intracellular pathway activity and predicted ex vivo drug sensitivity. Using stringent feature selection and regularized ridge regression to prevent overfitting, we integrated functional, genetic, and clinical data sets and identified six features—sensitivity to VEGFR‐2‐, JAK1/2 + Bcl‐2‐, and BTK + PI3K‐inhibitors; phosphorylation ratios of Bcl‐2:BTK and p90RSK:PLCγ2; and frequency of CD8 + T cells—that together outperformed the International Prognostic Index for CLL (CLL‐IPI) and other clinical scores in predicting PFS. These findings demonstrate that a prognostic model based on the functional features of CLL cell signaling and interaction with the microenvironment has the potential to improve upon conventional prognostic scores, warranting further clinical validation also in the frontline setting.
While social interactions and actively chosen solitude both contribute to well‐being, existing measures focus solely on one dimension. We developed the SOcial experiences' daiLy Occurrence (SOLO) scale—a brief end‐of‐day diary measure capturing enjoyment of social interactions (including brief encounters with “weak ties”) and solitude experiences. Two scale development and validation studies were conducted: single‐day ( N = 203) and 14‐day ( N = 75) assessments. The final SOLO consists of 13 items forming two scales, the Social Interaction subscale and the Solitude subscale. Both scales demonstrated adequate psychometric properties and meaningful relationships with well‐being measures. The scales were independent, supporting the conceptualization of social enjoyment and solitude preference as distinct dimensions. The SOLO is therefore presented as two distinct scales. A composite score can be calculated if required, although subscale‐level analyses are recommended given the empirical independence of the two dimensions. The SOLO's brief format offers a practical compromise between ecological momentary assessment and retrospective measures, enabling investigation of the distinct roles of social engagement and solitude in everyday life.
Background Power is routinely invoked to explain health inequities and governance failures in global health, yet existing work is conceptually fragmented, weakly connected to empirical analysis, and prone to what is referred to as the “power-as-resource fallacy”: the conflation of power bases (what actors possess) with power relationships (how actors influence one another). This narrative review examines how power is conceptualized and operationalized in global health discourse, identifies systematic analytical gaps, and proposes a relational framework to address them.Methods We conducted a narrative review of literature that explicitly engages with power in relation to global health, governance, or health systems. We synthesized the included texts thematically and, as a supplementary systems-thinking component, developed a causal loop diagram (CLD) based on a subset of quantitative studies to illustrate how different constellations of power interact with health outcomes over time.Results In global health, power is pervasively invoked but rarely operationalized. We organized the reviewed texts into six thematic domains: (1) power as a determinant of health; (2) structural power (class, race, gender, geopolitical hierarchies); (3) power asymmetry; (4) power and governance for health; (5) power and health securitization; and (6) power constellations and health outcomes. Across these domains, we find that discussions of power remain largely qualitative and often stop short of clear operationalization. The CLD translates these insights into interacting feedback loops, illustrating how specific power constellations are associated with particular patterns of policy response and health outcomes, highlighting potential leverage points for governance reform.Conclusion This review maps the existing knowledge on power in global health and provides an actionable framework for future research and governance design. It underscores that power is the fundamental thread connecting global political economy to local health inequities.
Abstract As human microbiome research is globalizing, it raises ethical concerns regarding the European and North American dominance in the field, which may reproduce a colonial bias and perpetuate inequities in global health research and outcomes. We suggest disentangling this ethical quandary into three main concerns: 1) scientific bias toward European and North American populations; 2) limited meaningful community inclusion, participation, and ownership, and 3) scant significant inclusion of diverse global researchers. We then formulate three recommendations for their resolution, deploying co-laboration —joint labor of diverse partners in generating synergies between diverse disciplines, cultures, and knowledges around shared concerns—and co-laborative science —a form of citizen science based on such synergies between diverse partners—to guide meaningful inclusive, participatory, and ethical human microbiome research. To conclude, we promote a programmatic list for putting co-laborative ethical science into practice, benefiting global communities, individuals, and researchers alike and decolonizing and improving health worldwide.
Abstract Aims To assess whether a modified clinical risk-score can stratify baseline risk and estimate expected absolute benefit from beta-blocker therapy in post-MI (myocardial infarction) patients with LVEF (left ventricular ejection fraction) ≥40%. Methods This substudy of the BETAMI-DANBLOCK trial included patients with a recent MI and LVEF ≥40% who were randomized to beta-blocker or no beta-blocker therapy. A modified Thrombolysis in Myocardial Infarction Risk Score for Secondary Prevention (TRS-2P) was constructed, and patients were categorized as low-, intermediate-, or high-risk. The primary outcome was a composite of all-cause mortality, new-MI, unplanned coronary revascularization, ischemic stroke, heart failure, or malignant ventricular arrhythmia. Treatment effects across TRS-2P strata were estimated using Cox proportional hazards and Fine-Gray subdistribution hazard models. Three-year absolute risk reduction (ARR) and number needed to treat (NNT) were calculated for each risk stratum. Results Among 5558 patients, 38.4% were classified as low-risk, 52.8% as intermediate-risk, and 8.8% as high-risk. Event rates increased stepwise with higher modified TRS-2P, with no evidence of heterogeneity in the relative treatment effects across risk-strata (hazard ratios: 0.88, 0.81 and 0.88, respectively). However, the score translated the modest relative effects into clinically distinct absolute benefits: Three-year ARR was 1.4% (NNT=72 [95% CI: 41 to 361]) in low-risk, 2.1% (NNT=47 [95% CI: 27 to 239]) in intermediate-risk, and 3.6% (NNT=28 [95% CI: 16 to 140]) in high-risk patients. Conclusions The modified TRS-2P stratified baseline risk and provided estimates of absolute beta-blocker benefit, supporting further evaluation of individualized, risk-guided treatment after MI in patients with LVEF ≥40%.
Both basic and clinical consciousness research aims to find objective measures that reliably distinguish conscious from unconscious brain states. Electroencephalogram (EEG) measures are widely used, although they may be affected by interference from electrical signals such as those generated by muscles. To assess this source of error, we investigated the impact of neuromuscular blockade (NMB) on proposed measures of awareness (spectral slope, Lempel–Ziv complexity (LZc), connectivity, alpha peak frequency, power in canonical EEG frequency bands) computed from spontaneous high-density EEG recorded from six healthy volunteers in three different conditions: (1) awake-unparalysed (normal wakefulness), (2) awake-paralysed (complete paralysis caused by neuromuscular blocking agent (NMBA)), and (3) sedated-paralysed (deep sedation with propofol, with paralysis by NMBA). The measures we investigated distinguished awake-unparalysed states from sedated-paralysed with close to perfect accuracy in accordance with past findings. However, our analysis revealed a serious failure of most measures to recognise the awake-paralysed condition as an aware state. Errors ranged from 7% of awake-paralysed time segments predicted as unaware (using alpha power) to 100% (using LZc). Using a unique high-density EEG data set, this study clearly demonstrates that many EEG-based measures fail to recognise awareness in awake subjects under the influence of muscle relaxants. These results highlight critical limitations of current EEG-based measures at detecting awareness.
Breast cancer is genetically and histologically heterogenous, and is influenced by a variety of factors, including the tumor microenvironment (TME). The PAM50 subtypes; Luminal A, Luminal B, Normal-like, Basal-like and Her2-enriched, are associated with different tumor phenotypes and overall survival. The quantity and quality of immune cell infiltration in breast tumors play a key role in cancer development and progression and are associated with survival and treatment response. We used multiplex immunohistochemistry, single-cell RNA sequencing, and two deconvolution algorithms to explore the immune landscape across PAM50 subtypes. Immunostaining of CD3+ T cells, tryptase+ mast cells, CD20+ B cells, CD68+ CD163+ macrophages, and CD66b+ granulocytes revealed marked differences in tumor immune infiltrates according to breast cancer subtypes. Luminal tumors were relatively deprived of T cells and B cells, while exhibiting sparse to moderate amounts of macrophage infiltration. In contrast, Her2-enriched tumors exhibited a moderate immune presence, with sparse to moderate T cell infiltration and moderate infiltration of B cells and macrophages. At the other end of the spectrum, Basal-like tumors stood out for their strikingly rich immune environment and are heavily infiltrated by T cells, B cells, and macrophages. The results from the single-cell and deconvolution analyses confirmed subtype-specific immune microenvironments, which also allowed us to observe increased levels of natural killer (NK) and CD8+ T cells in Her2-enriched and Basal-like subtypes. In conclusion, our findings demonstrate significant differences in the immune tumor microenvironmentbetween the established breast cancer molecular subtypes.
Introduction Amplification of the epidermal growth factor receptor 2 (HER2) gene occurs in 15-20% of breast cancers and was historically associated with poor prognosis. The CLEOPATRA trial established pertuzumab added to trastuzumab and chemotherapy as standard of care for metastatic HER2-positive breast cancer, demonstrating a 15.7-month improvement in median overall survival (OS). Strict trial inclusion criteria may limit generalizability to clinical practice. Population-based data can assess whether these survival benefits translate to real-world outcomes. Methods Women diagnosed with HER2-positive metastatic breast cancer in 2012–2021 were identified through the Cancer Registry of Norway and linked to health and treatment databases. Patients were categorized by treatment regimen and year of treatment initiation: pre-CLEOPATRA (2012–2014; trastuzumab ± chemotherapy) and post-CLEOPATRA (2015–2021; trastuzumab + pertuzumab ± chemotherapy). OS was estimated using Kaplan–Meier and Cox regression adjusted for clinical, and socioeconomic factors. Outcomes were benchmarked against CLEOPATRA. Results The cohort comprised 329 women, 23% were aged ≥65 years. Seventy-eight patients (24%) received pre-CLEOPATRA regimens and 251 (76%) post-CLEOPATRA regimens; 59% met minimum one CLEOPATRA exclusion criterion. First-line dual HER2 blockade increased from 0% in 2012 to 75% in 2021. Median OS improved from 69 months to 96 months post-CLEOPATRA. Four-year OS increased from 59% to 65% (adjusted hazard ratio 0.77, 95% CI 0.53–1.12). Real-world OS was consistent with CLEOPATRA outcomes. Conclusions Nationwide real-world data demonstrate favorable survival outcomes following adoption of dual anti-HER2 therapy. While these findings are broadly consistent with the CLEOPATRA trial, the observational design does not allow direct assessment of equivalence between studies.
Mitochondrial homeostasis is majorly maintained through mitochondrial autophagy (mitophagy). Recent research highlights the region- and cell type-specific nature of mitophagy during brain aging; however, these dynamics have largely remained unexplored in living brains. To address this gap, we conducted two-photon mt-Keima imaging in somatosensory cortical neurons and astrocytes in behaving male mice across two age groups, including 2–3-month-old (early-aged) and 18–20-month-old (old-aged) mice. We show reduced mitophagy in both cell types during aging, and we consistently found a higher level of mitophagy in astrocytes compared to neurons at the same age, in both age groups. Pharmacological augmentation of NAD+, a pivotal metabolite that induces mitophagy but normally declines in the aging brain, increased cellular mitophagy in both neurons and astrocytes in old-aged male mice at the dose and method of administration tested. Collectively, our data support an age-dependent reduction of mitophagy in neurons and astrocytes, at least in mouse somatosensory cortex, while NAD+ repletion offsets such reduction.
SUMOylation regulates chromatin states and transcriptional programs that preserve cellular identity, yet how perturbation of the SUMOylation pathway impacts adipocyte plasticity remains unclear. Here, we show that brief pharmacologic inhibition of SUMOylation in human pre-adipocytes using TAK-981 primes stable de novo beige differentiation in the presence of the PPARG agonist rosiglitazone. Transient TAK-981 exposure produces changes in the transcriptome and metabolism of mature adipocytes, including robust induction of canonical beiging markers like UCP1 and increased mitochondrial respiration. Mechanistically, ATAC-seq and RNA-sequencing revealed immediate chromatin remodeling and early mobilization of CEBP family members, followed by stable activation of CEBPA and PPARG regulatory networks. ChIP experiments demonstrated loss of H3K27me3 and gain of H3K27ac at PPAR response elements at thermogenic enhancers, and increased PPARG occupancy across the UCP1 regulatory unit. This mechanism is enforced by enhanced cAMP-PKA-p38 signaling and stabilization of beiging transcription activators. We propose that transient relief of SUMO-mediated repression unlocks dominant regulatory units, notably the UCP1 enhancer cluster, producing a monomorphic reprogramming toward adaptive thermogenesis. These findings identify SUMOylation as a reversible epigenetic barrier to adipocyte beiging and suggest that temporally controlled SUMO pathway inhibition combined with PPARG activation could be exploited to modulate adipose tissue thermogenic capacity.
Background The discovery of meningeal lymphatic vessels (mLVs) has reshaped our understanding of brain waste clearance, positioning them as a very important clearance route. However, quantifying the precise hydrodynamics and solute transport mechanisms within the human dura mater in vivo remains highly challenging due to the multiscale nature of cranial fluid dynamics and imaging resolution limits. Methods We integrated patient-specific intrathecal contrast-enhanced MRI (gMRI) data from a single healthy subject with a novel anatomical segmentation of the cranial dura mater. By employing a hierarchy of inverse mathematical and micro-mechanical models, we estimated previously inaccessible physiological transport parameters. To ensure parameter identifiability, we deliberately modeled a scenario where the meningeal lymphatic vessels act as the sole fluid efflux route, thereby establishing an upper limit for their clearance capacity. These baseline estimates subsequently informed a spatially distributed, double-porosity 3D computational model of the human dura to simulate the fluid dynamics of cranial clearance. Results Our analysis suggests that purely diffusive macroscopic models fail to replicate in vivo tracer distribution. Conversely, a dual-porosity advection-diffusion framework successfully captures the tissue kinetics. The transport within the mLV compartment is characterized by highly convective clearance (with ), with macroscopic fluid velocities and effective lymphatic diffusion coefficients yielding an upper-bound advective capacity theoretically sufficient to clear the total albumin content in the Cerebrospinal Fluid (CSF). Conclusion Based on our findings on a single subject (Gonzo) solute clearance within the human cranial dura mater emerges as multiphasic, advection-dominated process. Rather than relying on passive Fickian diffusion, molecules appear to be actively and rapidly cleared through the meningeal lymphatic network via convective mechanisms. While our assumption of exclusively mLV-driven clearance provides a theoretical upper limit for their capacity, this hierarchical modeling approach successfully bridges clinical imaging and microscopic fluid dynamics, offering quantitative insights into the primary mechanical drivers of dural fluid clearance.
Immunoglobulin G (IgG)–based monoclonal antibodies are effective therapies for cancer, autoimmune diseases, and migraine. However, they are actively transported across the placenta by the neonatal Fc receptor (FcRn), limiting their use during pregnancy. Using mouse models and an ex vivo human placental perfusion system, we show that although FcRn binds albumin independently of IgG, albumin is not transported to the fetus in mice or across human placental tissue. Fusion of IgG to albumin markedly reduced transplacental transport in both models while preserving the prolonged plasma half-life conferred by FcRn. Similarly, fragment antigen–binding fragments fused to engineered albumin with enhanced FcRn binding showed minimal fetal exposure. In a mouse model of fetal and neonatal alloimmune thrombocytopenia, albumin fusion of an anti–human platelet antigen IgG reduced fetal antibody transfer and attenuated thrombocytopenia in the offspring. These findings identify albumin as an attractive fusion partner for biologics intended to minimize fetal exposure during pregnancy.
Patients with colorectal cancer have few molecularly guided treatment options. Cancers with exceptional treatment response are valuable models for discovery of molecular response mechanisms and might reveal new predictive biomarkers to guide treatment selection. However, the rarity of events is a clinical challenge. We performed integrated high-throughput drug sensitivity testing (n = 620 drugs) and molecular analyses of 103 colorectal cancer cell lines to build an in vitro foundation for exceptional treatment responses and their molecular markers. Exceptional responses were scored by a two-way outlier detection approach and were identified in 67 unique cell line-drug pairs (0.13% of all pairs tested). This involved 35 cell lines (34.0%) and 49 drugs (7.9%) representing standard, experimental, and non-oncology drugs of diverse classes. Plausible response mechanisms on the gene, protein, and/or pathway expression levels were identified at baseline in 89.6% of the 67 pairs. Experimental validation confirmed treatment-induced marker suppression in seven of eight selected pairs, including target engagement of kinase inhibitors and downregulation of markers of extended response mechanisms. Recurrent exceptional sensitivity to the same drug in different cell lines involved functionally convergent molecular mechanisms, but rarely precisely the same marker. Most exceptional sensitivities (77.8%) could be predicted with multivariable transcriptomic models. In conclusion, this study provides in vitro support for biomarker-guided prescreening to potentially obtain exceptional treatment response to diverse drugs and therapeutic targets in colorectal cancer. Most exceptional responses have a clear molecular underpinning. The study also provides a large and openly available pharmaco-transcriptomics resource for colorectal cancer cell lines.
The gut microbiome has been linked to colorectal cancer (CRC) development, with microbe-based classifiers distinguishing between CRC patients and healthy controls. However, there is a lack of studies addressing the utility of the microbiome in screening-relevant settings, including both precancers and CRC. In this Norwegian population-based study, we used fecal immunochemical test (FIT) leftovers from 1034 FIT-positive (i.e. positive for occult blood) screening participants for gut metagenome profiling using shotgun sequencing. Using comprehensive clinical, demographic, and lifestyle data, we modeled gut microbiome associations with CRC screening outcomes. Combining microbial profiles with quantitative FIT values improved detection of premalignant lesions beyond optimizing the FIT value alone, even after incorporating established CRC risk factors. Still, the FIT value maintained superior discriminative ability for CRC. We confirmed enrichment of bacteria such as Fusobacterium nucleatum and Peptostreptococcus stomatis in CRC. In contrast, other bacteria previously associated with the presence of CRC, including Hungatella hathewayi and Clostridium symbiosum, as well as pks-negative Escherichia coli, were enriched in those with no neoplastic findings, suggesting that in a FIT-positive population their presence may reflect other conditions causing intestinal bleeding rather than underlying neoplasia. Microbial profiles were predominantly associated with distal rather than proximal lesions. Together, our findings highlight the potential for microbial markers to improve FIT-based CRC screening, especially by differentiating those with premalignant lesions from those who test FIT-positive for other reasons.
Handling latent variables in Structural Equation Models (SEMs) where both the latent variables and their corresponding indicators are random curves presents significant challenges, especially with sparse data. We develop a novel family of Functional Structural Equation Models (FSEMs) incorporating latent variables modeled as Gaussian Processes (GPs). The model adapts to cases when the random curves’ realizations are observed over a sparse subset of the domain. To extract smooth estimates for the functional parameters, we employ a penalized likelihood approach and evaluate the performance of the proposed model using simulation studies and a real data example, suggesting our model performs well. Supplementary materials are available online.
Purpose Identify and describe weekly physical activity (PA) trajectories in adolescent and adult childhood cancer survivors (survivors), describe characteristics of survivors following different PA trajectories, and compare PA trajectories to controls. Methods This study includes adolescent (9–18 years) survivors and controls from the Physical Activity in Childhood Cancer Survivors (PACCS) study and adult (18–49 years) survivors from the survivor fitness (SURfit) study and controls from the Norwegian National Physical Activity Survey 2. Weekly trajectories of accelerometer-measured PA were identified by multivariate latent class mixed models using daily minutes of moderate-to-vigorous and light PA (MVPA, LPA). Survivors’ characteristics related to different PA trajectories were assessed using a descriptive approach, and PA trajectories between survivors and controls were visually compared. Results We identified four PA trajectories among adolescents (Low regular; Medium, drop weekend; Medium, peak Friday; and Medium regular) and four among adult survivors (Medium regular; Medium, drop weekend; Medium regular MVPA, high regular LPA; and High, drop weekend). The main factors related to the different PA trajectories were sex, age at assessment, sleep, and (parental) education, whereas diagnosis seemed important in adolescent survivors only. In adolescents, trajectories were comparable between survivors and controls, while in adults, only three trajectories were comparable. The allocation to the different trajectories was more favorable in adolescent survivors (fewer in the Low trajectory) and adult survivors (no Low regular MVPA trajectory was identified in survivors) compared to controls. Implications for Cancer Survivors Our findings show many different behavioral approaches to accumulate PA over a week. They highlight the need for targeted PA interventions in a subset of survivors (i.e., adolescent, female survivors of CNS tumors). Developing interventions to prevent PA drops on the weekend holds high potential.
Borderline personality disorder (BPD) is a severe mental health condition influenced by environmental risk factors (for example, interpersonal trauma) and genetic factors. We conducted the largest genome-wide association study (GWAS) meta-analysis of BPD so far, with a discovery sample of 12,339 cases and 1,041,717 controls, and a replication study of 685 cases and 107,750 controls (all participants of European ancestry). We identified 11 independent associated genomic loci and 9 risk genes in gene-based analyses. We observed a single-nucleotide polymorphism heritability of 17.3% and derived polygenic scores (PGS) that predicted 4.6% of the phenotypic variance in BPD on the liability scale. BPD showed the strongest positive genetic correlations with GWAS of post-traumatic stress disorder, depression, attention deficit hyperactivity disorder, antisocial behavior, and measures of suicide and self-harm. Phenome-wide analyses in Vanderbilt University Medical Center Biobank and UK Biobank using BPD-PGS confirmed these associations and also identified associations with other medical conditions, including obstructive pulmonary disease and diabetes. These analyses highlight BPD as a polygenic disorder, with the genetic risk showing substantial overlap with psychiatric and physical health conditions.
Recent advancements in image generation have explored in-context learning by presenting a query image alongside context examples and text prompts. Despite these efforts, the generated images often exhibit diminished quality and fidelity when text prompts are omitted, highlighting a significant limitation in the models’ ability to fully exploit visual context. To address this, we introduce Context-Aware Controllable Generation (ContextDiff), a pioneering task designed to generate semantically precise and contextually rich images within specified categories. Our approach establishes a context space and develops a mapping network that aligns this space with the powerful Contrastive Language-Image Pre-training (CLIP) framework, thereby providing a concrete representation of abstract context. To ensure semantic diversity and contextual fidelity, we propose three novel loss functions. Extensive experiments and user studies demonstrate that our model significantly outperforms existing models, resulting in marked improvements in image quality and fidelity.
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.
Introduction Standard differentiation assays sample cell states only at discrete time points, while the underlying progression unfolds continuously and heterogeneously across cells. As a result, different combinations of proliferation, commitment, and maturation dynamics can converge to similar endpoint measurements. This many-to-one mapping between latent trajectories and observable readouts constitutes a partially observed inverse problem that limits mechanistic interpretation. Although this ambiguity is inherent to many experimental systems, it is rarely examined using models that connect cell-state dynamics to assay-level quantities. Methods We present OsteoMin, a coarse-grained cellular automaton that links stochastic transitions between pre-osteoblast and osteoblast states to experimentally measurable readouts of alkaline phosphatase activity, collagen deposition, and mineralization. Model parameters were constrained using literature-reported kinetics and evaluated against dexamethasone and menaquinone-4 perturbations. The framework enables systematic analysis of how cell-state progression, matrix maturation, and external perturbations shape differentiation outcomes. Results OsteoMin reproduces qualitative assay trends and quantifies the identifiability limits of endpoint assays. Distinct perturbation families often produce similar endpoint responses (macro-F1 ≈ 0.42$), indicating limited discriminative power. Incorporating temporal trajectories improves separability (macro-F1 ≈ 0.78$), demonstrating that most identifiable information resides in marker dynamics rather than terminal measurements. Sobol analysis shows that early markers depend on proliferation timing, whereas late mineralization is governed by nonlinear matrix maturation and parameter interactions. Discussion These results show that endpoint assays constrain overall progression but do not uniquely identify underlying mechanisms. OsteoMin provides a framework linking differentiation dynamics to assay observables and a basis for assessing identifiability in endpoint-driven systems.
Clinical implementation of patient cell-based drug testing is hampered by inconsistencies and irreproducible results. Using linear mixed models and drug response data from four cohorts of patients with acute myeloid leukemia (n = 993 samples), we identified sources of variability in ex vivo drug sensitivity testing across the studies. We identified several experimental factors, including the time until sample was tested, the type of culture media and viability assay, which led to systematic differences in drug sensitivity profiles. We further investigated the effects of sample types (fresh or frozen) and disease status (diagnosis, relapse, or refractory), and observed that peripheral blood samples resulted in higher drug sensitivity levels, compared to those derived from bone marrow. Technical factors, such as the type of plate reader and centrifugation procedure, further contributed to the response variability depending on the chosen drug response metric. These factors need to be standardized for improved consistency in functional precision medicine studies.
Abstract Aims To investigate the effect of long-term beta-blocker therapy on physical activity (PA) level after myocardial infarction (MI) in patients without heart failure. Method The BETAMI trial, randomised patients hospitalised with a MI without heart failure (LVEF ≥40%) to beta-blocker or no beta-blocker. In this pre-planned sub-study PA level was assessed by guideline-recommended PA level (≥30 minutes moderate activity ≥5 days/week) or not and self-reported hours/week with light to moderate and vigorous PA. Between-group differences in PA from baseline before randomisation to 18-months were estimated by linear mixed models. Exploratory analysis assessed treatment effects on a composite of all-cause mortality and major adverse cardiovascular events using Cox proportional hazards model. Results Of the 2867 randomised patients, 2185 (76%) responded to the PA questions and were included in this analysis. Mean age was 62.5 (SD 10.1) years, 20.6% were women. No differences in guideline-recommended PA level or mean hours of light to moderate and vigorous PA were reported between the beta-blocker and non-beta-blocker group at baseline or during 18-months follow-up. At 12-month follow-up, 37.0% in the beta-blocker group and 36.7% in the no beta-blocker group reported guideline-recommended PA level (OR 0.97, 95% CI 0.69-1.37). Exploratory, hypothesis-generating analyses did not demonstrate a statistically significant interaction (p for interaction = 0.06) between treatment assignment and baseline PA level for recurrent clinical events. Conclusions Beta-blocker therapy did not result in a change in PA level in post-MI patients without heart failure during the 18 months follow-up.
This perspective article discusses emerging advances at the interface of mechanistic modeling and data-driven machine learning, highlighting opportunities for AI to accelerate discovery, improve predictive modeling, and enhance clinical decision-making. We address critical limitations of current AI approaches and propose a perspective on a future where AI augments mechanistic rigor, clinical relevance, and human creativity under the umbrella of a redefined understanding of Mathematical Oncology.
Background Although physical activity (PA) is associated with a reduced risk of stroke and mortality, its impact among individuals with atrial fibrillation (AF) remains insufficiently explored. Therefore, the aim of this study was to examine the impact of PA on stroke and mortality, both overall and with respect to AF diagnosis. Methods We included 87 340 participants, of which 6539 had AF, from 2 Norwegian population‐based studies, the Tromsø Study and the HUNT (Trøndelag Health Study). Information about AF, stroke, and death were obtained from national health registries. Participants were classified as inactive (reference) or performing low, moderate, or high PA on the basis of a questionnaire. The data were analyzed using multivariable adjusted flexible parametric survival models. Results During a median follow‐up of 13.5 years, 3415 strokes and 7833 deaths occurred. The respective stroke risk reduction associated with low, moderate, and high PA was 9% (95% CI, 1%–16%), 19% (95% CI, 11%–27%) and 18% (95% CI, 8%–26%). Mortality was reduced by 11% (95% CI, 7%–14%), 18% (95% CI, 14%–22%), and 22% (95% CI, 18%–27%). Similar benefits were observed for both stroke and mortality when stratifying by presence or absence of AF. Among individuals with AF, an increased life expectancy was observed, with gains of 0.50 (95% CI, 0.22–0.78), 0.66 (95% CI, 0.31–1.01) and 1.15 (95% CI, 0.77–1.53) years, respectively. Conclusions PA was associated with a reduced risk of stroke and mortality, and similar benefits were observed irrespective of AF diagnosis. Our findings suggest that PA may complement current medical treatment strategies in individuals with AF.
Abstract Purpose: To evaluate the potential of Nutri-Score to identify foods unsuitable for marketing to children by assessing its agreement with two established nutrient profiling models: WHO-EURO 2023 and the Norwegian Regulation on Marketing (NORMA). Further, we explored the impact of additional criteria to improve agreement. Addition, we evaluated the agreement between a modified Nutri-Score, the «NewTools-score», and WHO-EURO 2023 and NORMA. Methods: Products from the Norwegian food composition table (N = 1,944) were used to explore scenarios for Nutri-Score (and NewTools-score) against WHO-EURO and NORMA. The scenarios were: 1) All products scoring C-E not permitted for marketing, 2) Same as scenario 1, but with additional criteria for trans fatty acids, non-sugar sweeteners (NSS), and added sugar for beverages. For NORMA, a third scenario was tested as an extension of scenario 2, additionally banning selected food categories from marketing. Agreement was assessed through cross classification. Results: Under scenario 1, 53% of products were classified as Nutri-Score C-E, and 47% and 23% not permitted for marketing under WHO-EURO and NORMA, respectively. Overall agreement between Nutri-Score C-E and WHO-EURO was 84%, and 66% with NORMA. However, Nutri-Score allowed some products within unhealthy food categories, e.g., ice creams with NSS. Applying additional criteria in scenarios 2 and 3 had important effects on banning such products. Results for the NewTools-score were almost identical. Conclusion: The Nutri-Score and the NewTools-score may be used for identifying a high proportion of products unsuitable for marketing to children. However, some additional criteria, including a complete ban from marketing in selected food categories, seems warranted to better protect children from exposure to marketing of unhealthy products.
Antibiotic resistance is a global priority in health care. Leveraging thousands of whole-genome sequences, here we reveal the core resistance determinants of oral streptococci, focusing on assessing pattern variability and gene exchange across commensals and pathogens. Genomic information was obtained from the National Center for Biotechnology Information. Determinants of antibiotic resistance were identified using AMRFinderPlus and the Comprehensive Antibiotic Resistance Database. ICEscreen was employed for calling of integrative and conjugative elements. Variability and recombination in penicillin-binding protein sequences were assessed with MMseqs2 and fastGEAR. A total of 2,087 genomes from 15 species were included, representing the mitis, mutans, anginosus, salivarius, and bovis groups. We observed 3,576 hits from 55 unique resistance genes conferring resistance to 11 antibiotic classes. The species with the most resistance determinants per genome against unique antibiotic classes were Streptococcus mitis (2.7), Streptococcus oralis (2.5), Streptococcus parasanguinis (1.9), Streptococcus gallolyticus (1.3), and Streptococcus anginosus (1.2). The 2 latter species also presented the most diverse composition of determinants. Over 1,800 integrative and conjugative elements were predicted across all genomes, with nearly 17% carrying at least 1 antibiotic resistance gene. Penicillin-binding protein variation analyses showed a high diversity in the mitis group. Even though S. mitis and S. oralis composed less than 4% of the genomes included in the analyses, they were recognized as sources of DNA for over a third of recombination events in pbp1a and nearly half for both pbp2b and pbp2x in β-lactam-resistant isolates of Streptococcus pneumoniae . In summary, we show that tetracycline and macrolide resistance were highly abundant and tightly connected to integrative and conjugative elements. Further, recent recombination data in pbp loci show frequent genetic exchange from oral streptococci to β-lactam-resistant S. pneumoniae . Fundamentally, assessing triggers and the dynamics of genetic exchange across species is central to the development of strategies aiming to mitigate the impact of antibiotic resistance.
Background: In multiple sclerosis (MS), switching disease modifying treatment is associated with higher relapse rate, healthcare expenses, disease burden, and lower quality of life. We compared drug discontinuation rates of dimethyl fumarate (DMF) between hospitals in Denmark and Norway. Method: Data from national MS registries were analyzed, adjusting for sex, age, disease duration, Expanded Disability Status Scale, and baseline relapses. Between-hospital variation was assessed using median hazard ratios (MHR). Results: 3368 patients with relapsing-remitting MS started DMF at all clinics in Denmark (n = 14) and at a subset of clinics in Norway (n = 6). A median of 44% discontinued DMF. Predictors for discontinuation were female sex, younger age, higher EDSS and number of relapses at baseline. There was a significant difference in the risk of discontinuation between hospitals. The MHR for discontinuation because of treatment failure attributed to treating hospital was 1.51(SE 0.120, p < 0.001) in Norway and 1.34 (SE 0.055, p < 0.001) in Denmark. Conclusion: Discontinuation rates of DMF in MS varies between hospitals, independent of patient characteristics.
Background Type 2 diabetes poses a growing public health burden in low- and middle-income countries, where major gaps in access to chronic care persist. Task-shifting to Community Health Workers (CHWs) and the use of digital clinical decision support systems may bridge these gaps. Randomized trials evaluating CHW-led care models in which CHWs initiate, titrate, and monitor first-line diabetes treatment are lacking. Methods We conducted a cluster-randomised trial nested within the ComBaCaL (Community-Based Chronic Care Lesotho) cohort (NCT05596773). The cohort spans 103 rural villages in Lesotho, managed by trained, supervised CHWs. After home-based screening of cohort participants ≥40 years old or with body mass index ≥25 kg/m2, all with type 2 diabetes were enrolled in the trial. In intervention villages, CHWs - guided by a tablet-based clinical decision support system - provided care, including initiation and monitoring of metformin, atorvastatin and aspirin. In control villages, participants were referred to facility-based care. The primary analysis included participants with uncomplicated and uncontrolled type 2 diabetes (fasting glucose ≥7 mmol/l) on glycated haemoglobin (HbA1c) at 12 months. Results From 13 May 2023 to 31 January 2024, 5’785 cohort participants were screened, 252 (4·4%) diagnosed with type 2 diabetes, and 103 (51 control, 52 intervention) included in the primary analysis (73·8% female, mean age 62·3 ± 12·8 years, mean HbA1c 7·2 ± 1·4%). At 12 months, HbA1c was 7·1 ± 1·9% in the control arm and 6·5 ± 1·3% in the intervention arm (adjusted mean difference −0·46%, 95%CI −1·14 to 0·22). Engagement in care was higher in the intervention arm. No relevant difference in safety outcomes was observed. Conclusions CHW-led, clinical decision support system-assisted management of type 2 diabetes, including first-line drug prescription, may improve engagement in care and glycaemic control in rural low-resource settings. Larger studies are required to confirm these findings.
Despite thorough characterizations of cellular compositions within the breast tumor microenvironment (TME), their implications for disease progression and patient prognosis remain poorly understood. Unraveling these effects is vital for identifying potential targets to improve treatment outcomes. In this study, we devise an explainable machine learning (XML) pipeline to scrutinize the associations between TME cellular constituents and relapse-free survival (RFS). By applying this pipeline to estimated cell fractions in the METABRIC and TCGA datasets and comparing these results with associations to pathological complete response (pCR) after neoadjuvant chemotherapy (NAC), we create a comprehensive catalog of the TME’s role based on 5000 patient samples. Our findings reveal an unexpected dichotomy in which macrophages correlate positively with pCR but negatively with RFS, particularly within estrogen receptor-positive (ER+) and Luminal A and B (LumA/B) cancer subtypes. We show that this pattern is driven by heterogeneity in breast tumors characterized by increasing levels of macrophage infiltration. Through imaging mass cytometry (IMC) data analysis, we find that macrophages tend to accumulate in the vicinity of HLA-ABChi epithelial cells as their frequency increases in tumor tissues and that they also express elevated levels of HLA-ABC protein. In both IMC and single-cell RNA sequencing (scRNA-seq) data, we uncover a significant association between these HLA-ABChi macrophages and regulatory and exhausted T cells (TReg and TEx), suggesting their involvement in immune suppression, likely by creating a chronically activated immunosuppressive TME. Subsequent cell-cell communication analysis predicts interactions between HLA-ABChi macrophages and TEx cells via the ligands SIGLEC9, ALCAM, and CSF1, and with TReg cells through APP, ANGPTL4, and SIGLEC9 signaling. Considering the clinical relevance of macrophages in ER+ (LumA/B) subtypes, this work enhances the characterization of macrophage-associated immune suppression in these tumors and identifies potential targets for immunomodulatory strategies.
Computational technology opens new possibilities toward understanding the complexity of the human brain, but it requires integrating measurements from different modalities and scales in an anatomical context and exposing them in an interoperable, actionable form. Especially with growing big data resources, accessing information from different scales and modalities coherently for visual exploration, reproducible analysis and application development remains challenging. Here we present siibra, a tool suite that connects diverse data from cloud resources to reference atlases and coordinate spaces. It supports different use cases by making contents accessible through a web viewer, Python library and HTTP application programming interface. Using siibra we implemented a Multilevel Human Brain Atlas linking macro-anatomical concepts and their inter-subject variability with measurements of the microstructural composition and intrinsic variance of brain regions, building on cytoarchitecture as a reference and supporting MRI-based and microscopic templates. The atlas is integrated with the EBRAINS research infrastructure. All software and content are openly accessible.
ABSTRACT Introduction The effectiveness of obesity prevention or obesity reduction policies is co‐determined by policy content, the implementation process, and contextual factors. This systematic review provides insight into implementation strategies used in whole‐of‐community obesity prevention policies aimed at changes in two types of outcomes: (1) a reduction in obesity/overweight prevalence, body mass index–related outcomes, and other weight‐related outcomes, or (2) a change in nutrition behaviors, physical activity, and sedentary behaviors or screen time. We specifically examined implementation strategies using the Expert Recommendations for Implementing Change (ERIC) framework, focusing on policies implemented in low socioeconomic status communities. Methods Following Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines, eight databases were searched. Risk of bias was assessed using the Joanna Briggs Institute (JBI) critical appraisal tool. The efficacy of implementation strategies was considered supported if at least 66% of the studies that applied respective strategies reported significant improvements for a given outcome type across at least three studies. Results A total of 29 original studies were included. Fifteen implementation strategies from the ERIC framework were consistently associated with favorable outcomes. These strategies included altering incentive structures, assessing community readiness, and using data warehousing techniques. Six additional non–ERIC strategies (e.g., cultural adaptation and grassroots mobilization) received support across different outcome domains. Most studies (72%) had a low risk of bias. Conclusion Findings may help prioritize implementation strategies that may drive the success of whole‐of‐community obesity policies targeting disadvantaged populations. The results suggest a need to expand existing implementation taxonomies to include community‐driven strategies.
BACKGROUND Anti-CD20 monoclonal antibodies are effective for relapsing multiple sclerosis. However, data from head-to-head trials are lacking. METHODS In this phase 3, multicenter, double-blind, noninferiority trial, we randomly assigned adults with newly diagnosed relapsing multiple sclerosis and recent disease activity in a 3:2 ratio to receive rituximab or ocrelizumab every 6 months for 24 months. The primary end point was the absence of new or enlarging lesions on T2-weighted magnetic resonance imaging (MRI) from month 6 to month 24. Noninferiority was defined as a lower limit of the 95% confidence interval for the risk difference (ritux- imab minus ocrelizumab) of greater than or equal to −10 percentage points. Secondary end points included efficacy and safety. RESULTS A total of 218 participants underwent randomization; 216 received treatment (132 assigned to the rituximab group and 84 assigned to the ocrelizumab group). Between months 6 and 24, the estimated probability of having no new or enlarging lesions detected on T2-weighted MRI was 92.2% with rituximab and 94.8% with ocrelizumab, corresponding to a risk difference of –2.6 percentage points (95% confidence interval, –9.4 to 4.3), which met the prespecified noninferiority criterion. Relapse rates, dis- ability outcomes, and cognitive-performance profiles appeared to be similar in the two groups. Infections were more common in the rituximab group than in the ocreliz- umab group (in 82% vs. 69% of participants), although the percentage of participants with serious adverse events was similar in the two groups (8% and 7%, respectively). CONCLUSIONS In participants with newly diagnosed relapsing multiple sclerosis and recent disease activity, rituximab was noninferior to ocrelizumab in suppressing disease activity as detected by MRI from 6 to 24 months, with a similar incidence of serious adverse events.
Abstract Recovering full-length, paired B-cell receptor (BCR) sequences from scRNA-seq reads remains difficult, especially in naive and memory B cells where immunoglobulin transcripts are sparse. Incomplete constant-region coverage in current methods limits isoform, subclass, and allele resolution. Here we present GATHeR, an open-source tool that assembles and annotates paired heavy- and light-chain BCR sequences and extends assembled sequences into constant regions. This enables confident subclass and allele assignment and recovery of membrane-bound isoforms, including the transmembrane segment and cytoplasmic tail, thereby distinguishing surface BCRs from secreted antibodies. GATHeR supports Smart-seq2/3 and 10x Genomics libraries and outperforms existing methods across benchmarks, with the largest gains in naive and memory B cells. Notably, in these populations the constant-region extension also enables detection of splice variation, including intron-containing heavy-chain transcripts with read-level support. By delivering high-fidelity receptor, isoform, and clonal lineage information, GATHeR broadens the analytical reach of scRNA-seq for B-cell immunology.
The aim of this study was to investigate the predictive validity of a proposed revision of the Nutri-Score and the current Nutri-Score by investigating associations between the diet quality scores measured in mid-pregnancy and the risk of dispended prescription of medications for hypertension up to 11 years following delivery, and blood pressure mid-pregnancy. The study population (N=70,730) were participants in the Norwegian Mother, Father and Child Cohort Study. Food intake was assessed mid-pregnancy using a food frequency questionnaire. Nutritional scores for each food item were calculated based on content of energy, sugars, saturated fat, salt, fibre, protein, fruit, vegetables, and legumes. Diet quality scores were derived using energy-weighted means of nutritional scores. Anti-hypertensive medications were registered in the national prescription database. We estimated hazard ratios (HR) with 95% confidence intervals (95% CI) using Cox regression models. During a mean follow-up of 6 years, 4,736 (6.7%) women got dispended prescription of medications for hypertension. There was a non-linear association between diet quality and hypertension medication. Compared with the median diet quality score, poorer diet quality (90 th percentile of the score) was associated with higher risk of medications for hypertension (HR=1.08, 95% CI 1.02-1.14) and cross-sectional high diastolic blood pressure (odds ratio=1.18, 95% CI 1.03-1.32). Both diet quality scores yielded similar results overall. Poorer diet quality during pregnancy, assessed with a proposed version, and the current Nutri-Score, were associated with a higher risk of medications for hypertension, indicating its usefulness as a valuable tool for guiding consumers and improving public health.
Naturally derived polysaccharides can activate pattern recognition receptors (PRRs) like Toll-like receptors (TLRs) and Dectin-1, but structure-activity relationships remain unclear. Here, we screened several plant-derived polysaccharides using HEK-Blue™ reporter cells expressing human Toll-like receptor (hTLR) 2, hTLR2/1, hTLR2/6, hTLR3, hTLR4, hTLR5 or hDectin-1a, THP1-Blue™ NF-κB cells and mouse bone marrow-derived macrophages to investigate the correlation between structural features and activity. The polysaccharides included pectins from Gentiana purpurea (GP-AP), Angelica archangelica subsp. archangelica (A-A2-I), Daphne mezereum (DMP-ED-I), Citrullus lanatus (FW), Coffea arabica (CAP) and Citrus sp. (CPA), an arabinogalactan protein (AGP) rich extract from Persea americana (FRAGP), and an arabinoxylan from Livistonia chinensis (LCP). Activation of THP1-Blue™ cells and BMDMs, and interaction with hTLR4 and hTLR2/6 correlated with rhamnogalacturonan-I (RG-I) backbones with galactan, including arabinogalactan-II (AG-II), side chains (GP-AP and DMP-ED-I), and by the presence of AGPs (FRAGP). The presence of 4-O-Me-GlcA in A-A2-I was seemingly negatively correlated with activation of hTLR2/6, despite presence of AG-II structures. The homogalacturonan-rich (HG) polysaccharides investigated in this study, FW, CAP and CPA, did not activate hTLR4 and hTLR2/6, suggesting that HG alone was insufficient for PRR engagement in these models. Several RG-I containing pectins activated hDectin-1a, and higher Mw generally enhanced activity. The AGP and xylose-rich polysaccharides tested in this study did not activate hDectin-1a, and the arabinoxylan LCP was inactive in all assays. None of the polysaccharides activated hTLR3 or hTLR5. In conclusion, several polysaccharides activated multiple PRRs, seemingly associated with presence of RG-I domains with neutral side chains.
Objective Concerns have been raised about doctors shifting jobs from non-profit to for-profit healthcare, leaving non-profit organisations understaffed. This study explores the extent and underlying reasons for such job transitions. A 2024 national survey of Norwegian doctors (n = 1973; 78% response) examined job shifts from non-profit to for-profit healthcare over the past 2 years. Results Fifty-one doctors (2.6%) had shifted from non-profit to for-profit healthcare in the past 2 years; 19 (37%) were still working in for-profit healthcare. A third of the doctors working in non-profit healthcare had considered switching to for-profit work (450/1517). This group was younger, less satisfied with their jobs, and reported higher sickness absence. Working hours were most often cited as a very important reason for shifting jobs.
Background and aims: Commonly measured cardiometabolic biomarkers have not been systematically characterized across the long-term continuum of the postprandial and postabsorptive phases. The aim of the present study was to evaluate how the exact time since last meal impacts test results for lipoprotein particles and inflammatory biomarkers. Methods: We used data from a trial where 34 normal-weighted males and females aged 20-30 y were included. Subjects fasted 12 h, had blood sampled at baseline, then consumed a standardized, habitual breakfast meal, and had blood sampled 13 more times over the next 24 h. NMR metabolomics was used to quantify lipoprotein subclasses and various biomarkers, and ELISA to analyze VCAM-1, ICAM-1, E-selectin, and IL-6. We characterized the postprandial and postabsorptive responses using visualizations and non-linear mixed effects models. Results: Six VLDL subclasses increased by 11-429% within 2-4 h postprandially before returning to baseline levels, followed by another increase 8-10 h after intake of the breakfast meal. IDL and three LDL subclasses increased around 10-12% over 24 h. Four HDL subclasses showed an inverse association with VLDL subclasses, reaching their lowest levels about 1 h after the meal and peaking after 8-10 h with a 5-15% increase from baseline. Participants had an average increase of 325% in IL-6 10 h after breakfast, while other inflammatory biomarkers showed little change over time. For most biomarkers, males generally exhibited higher baseline concentrations compared to females, however the responses over time remained similar. Conclusions: Baseline levels and time of return to baseline varied between individuals, with some sex-specific differences in responses. TG-rich lipoproteins and VLDL increased postprandially and normalized by 12-24 h, whereas IDL and LDL showed minor early changes but increased by 24 h. IL-6 increased markedly during the first 10 h and returned to baseline by 12-24 h, while other inflammatory markers changed little.
Lactate, a well-known metabolite and signalling molecule, holds therapeutic potential for neurodegenerative diseases. Here, we investigated the effects of chronic lactate treatment on cognition and molecular biomarkers in the 5XFAD mouse model of Alzheimer’s disease (AD) and in wild-type (WT) controls using behavioural testing alongside proteomic and transcriptomic analyses. Mice received lactate or vehicle injections 4 days per week for 11 weeks, with behavioural testing before and after the treatment period. Lactate improved working memory in late-treated AD mice, without eliciting anxiety-like behaviour. At the molecular level, lactate reduced Il1b expression, and in a sex-dependent manner, normalised NEFL, and enhanced synaptic integrity proteins (OPCML, PPFIA2, STXBP3, SYT1, VGLUT2, VSNL1) in AD mice, while also augmenting mitochondrial regulators (ATP5G2, GRPEL1, SLC25A23) across genotypes. Notably, lactate upregulated low-abundance ionotropic glutamate receptor mRNAs (Grik3, Grin2c, Grid2ip) in female AD mice, indicating enhanced glutamatergic signalling. In WT mice, lactate increased expression of neurotrophic factors (Bdnf, Igf1, Vegfa), anti-inflammatory cytokines (Il4 and Il13), and the neuronal lactate transporter Mct2, suggesting promoted neuronal resilience. Together, these findings indicate that lactate treatment can mitigate cognitive decline and enhance molecular pathways of resilience in AD, warranting larger, age-stratified studies to validate its therapeutic potential and elucidate underlying mechanisms.
Objective Ultrasound-imaging of subclinical atherosclerosis may refine cardiovascular (CV) risk assessment, but quantification methods vary and often include carotid arteries only. Because atherosclerosis is multiterritory, global (carotid–femoral) plaque quantification may better reflect systemic burden. We examined whether a novel multiterritory measure, weighted total plaque thickness (wTPT), better discriminates established CV disease than traditional risk factors and plaque measures. Methods In 5 418 participants (59.8 ± 8.1 years; 53.0% women) from the Prospective Screening Of Non-invasive Atherosclerosis Risk study, plaque burden was assessed across 12 carotid and femoral segments using wTPT, maximal plaque thickness (MPT), plaque count, and number of arteries with plaque. Discrimination of prior CV disease was evaluated using c-statistics, net reclassification improvement (NRI), and integrated discrimination improvement (IDI). Results Global wTPT showed the strongest discrimination of established CV disease (c-statistic 0.85 [95% CI: 0.83–0.87]), outperforming alternative plaque measures (p < 0.001). Adding global wTPT to risk factors improved discrimination from 0.84 to 0.89 (95% CI: 0.87–0.91), NRI 0.71 (95% CI: 0.57–0.84) and IDI 0.058 (95% CI: 0.004–0.071). Femoral wTPT outperformed carotid wTPT (p < 0.001), and global wTPT exceeded both (p = 0.014). Across wTPT quartiles, odds of prior CV disease increased stepwise: 2.0 (95% CI: 0.89–4.4), 4.2 (95% CI: 2.0–8.6), and 10.0 (95% CI: 5.0–20.1) versus the lowest quartile. Conclusion Global wTPT showed superior discrimination of established CV disease and added substantial incremental discriminative value beyond standard risk factors. These findings support wTPT as a marker of systemic atherosclerosis and a strong candidate for future outcome-based risk refinement. If prospectively validated, wTPT may contribute to improved risk stratification by identifying individuals with a high systemic atherosclerotic burden.
Objectives When patients are hospitalised for heart failure (HF), doctors review and optimise their pharmacotherapy at subsequent care transitions. Studies show that patients, many of whom are old and frail, have adherence rates of only 40%-60%. Few communication studies have examined the burden of optimisation on patients as their regimens evolve. Focusing on prescription changes over multiple care transitions, we aimed to: (1) identify how many changes patients received, (2) characterise the support provided in discharge letters, and (3) assess patients’ implementation of changes at home. Methods We conducted an exploratory, observational cohort study with prospective longitudinal data collection. We recruited 23 older HF patients in Norway, collecting observational data (medical records, discharge letters, interviews, photographs) from their hospital visits (admission, discharge), general practitioner visit, and their homes. We inductively developed a systematic analytical procedure to identify prescription changes and to assess the quality of doctors’ written information about patients’ medication management at home. Results Doctors made a median of six prescription changes per patient (range 2–19) over a median timespan of 25 days, usually leading to more medications. Of the discharge letters patients received, 26% provided clear instructions about all changes and explanations of the benefit. While all patients reported adherence, home visits revealed 17% had discrepancies indicating non-adherence, and 61% dispensed medications from original pharmacy packaging with outdated dosing instructions. Conclusions To adhere to their optimised pharmacotherapy, HF patients needed to implement many incremental changes. Doctors' discharge letters were often unclear or lacked information about the changes. Practice implications To enhance patients’ ability to adhere to treatment, clinicians may consider: (i) improving the quality of discharge letters, including clarifying medication labels (ii) providing updated instructions for old medication packages, (iii) normalising and providing safety-net support for non-adherence to HF regimens. Further research is needed to test these actions.
Abstract Background and Aims The 2021 ESC guidelines on cardiovascular (CV) disease prevention recommend the SMART-REACH lifetime risk model to guide treatment decisions in patients with established atherosclerotic CV disease. The aim was to develop the SMART-REACH2 model for estimating lifetime risk of recurrent CV events and treatment benefits in patients with established atherosclerotic CV disease, with systematic recalibration to the four European and other global risk regions. Methods SMART-REACH2 was derived in 8708 individuals aged 40–90 years with coronary, cerebrovascular, peripheral artery disease and/or abdominal aortic aneurysm from the UCC-SMART cohort. Sex-stratified, cause-specific Cox models for recurrent CV events and non-CV death were fitted using age as timescale and routinely available predictors. Recurrent CV events were defined as a composite of myocardial infarction, stroke, or CV death. Recalibration was based on representative cohorts per risk region. External validation was performed in 2 085 780 patients from 54 countries; model performance was assessed by calibration plots and Harrell's C-statistic. Results In the derivation cohort, 2057 recurrent CV events occurred over a median follow-up of 8.5 years (25th–75th: 4.3–13.0). In external validation, 307 706 events occurred. The pooled C-statistic was 0.68 (95% confidence interval 0.66–0.69) and ranged from 0.66 (0.64–0.69) for European low-risk region up to 0.72 (0.66–0.78) for Latin America, with adequate calibration across risk regions. Performance was consistent across sexes and CV disease subtypes. Using SMART-REACH2, estimated potential gains in CV disease-free life expectancy for a 50-year-old example patient receiving intensified preventive treatment (15 mmHg systolic blood pressure and 1.0 mmol/L low-density lipoprotein cholesterol reduction) ranged from 2 years in the low-risk region to 4.4 years in the very-high-risk region. Conclusions The updated SMART-REACH2 model accounts for geographical and sex-specific variations and allows estimation of short-term and lifetime risk of recurrent CV events and treatment benefits, facilitating shared decision-making as recommended by guidelines.
Background Paradoxically, some studies have found that high sun exposure, a well-known cause of melanoma, is associated with lower mortality among melanoma patients. In the Norwegian Women and Health cohort, we aimed to investigate associations between pre-diagnosis sun exposure and melanoma-specific and overall death, and the potential impact of unmeasured confounding and selection bias (conditioning on melanoma diagnosis) on any observed association between markers of high sun exposure and death. Methods We estimated hazard ratios (HRs) by Cox regression, observed covariate E-values, bias-adjusted HRs, and performed frailty analysis. Results Among 2234 patients with a first melanoma (311 deaths, 168 from melanoma; mean follow-up 8.0 years), we found significantly reduced risk of melanoma-specific (HR=0.41, 95% confidence interval (CI)=0.24–0.68) and overall (HR=0.49, 95%CI=0.33–0.72) death for ever- versus never-sunburn and a negative trend for cumulative number of sunburns (ptrend≤0.001), but not for sunbathing vacations (HR=0.69, 95%CI=0.37–1.27, melanoma-specific death). Neither the E-value approach nor bias-adjusted HRs suggested a large degree of unmeasured confounding for the sunburn-death association. However, frailty analysis suggested that selection may partly explain the association. Conclusion While sunburns appear protective, this association might reflect unobserved heterogeneity in melanoma risk and selection bias, and the associations may not represent a true causal effect.
Recycling of cellular components through autophagy maintains homeostasis in changing nutrient environments. Although its core mechanisms are extensively studied, understanding of its systems-wide dynamic regulation remains limited, particularly regarding how autophagy is inactivated once nutrients are restored. Here we mapped the genetic network that controls activation and inactivation of autophagy during nitrogen changes by combining time-resolved high-content imaging, deep learning and latent feature analysis. This dataset, termed AutoDRY, categorizes 5,919 mutants based on nutrient response kinetics and their contributions to autophagosome formation and clearance. Integrating these profiles with functional and genetic network data uncovered hierarchical and multilayered control of autophagy and revealed multiple new regulatory pathways. Notably, we identified the retrograde pathway as a pivotal time-varying modulator that tunes the expression of core autophagy genes and plays a central role in autophagy inactivation. Together, this study establishes a systems-level resource to guide future investigations of autophagy.
Synaptic dysfunction is a candidate mechanism in psychotic disorders, yet the precise underlying substrates remain elusive. We investigated how combining in vivo electroencephalography (EEG) and in vitro human cortical spheroid (hCS)-based methods can further our understanding of psychosis pathophysiology during fetal stages of neurodevelopment. Ten individuals with schizophrenia (SZ) or bipolar disorder (BD; 5 males and 5 females) and five controls (CTRL; 3 males and 2 females) underwent EEG assessments, including long-term potentiation (LTP)-like cortical plasticity and mismatch negativity (MMN). hCS were generated from induced pluripotent stem cells of all participants, and immunohistochemistry, Seahorse bioenergetics and patch-clamp recordings were performed. EEG-based LTP-like plasticity was reduced in individuals with SZ and BD. Basal respiration was decreased in BD hCS and VGLUT1 levels were reduced in both SZ and BD hCS. There was a positive association between EEG-based LTP-like plasticity and hCS basal respiration which survived correction. Our data provide further support for roles of mitochondrial and glutamatergic impairments in the synaptic dysfunction of psychosis and demonstrate the potential of combining EEG- and hCS-based methods for early development mechanistic studies of brain disorders.
The Norwegian School Fruit Program is financed by parents or local municipalities. The aim of this study was to explore contextual barriers and facilitators that influence the adoption of the program by schools using the Context and Implementation of Complex Interventions (CICI) framework. We conducted semi-structured interviews with 21 participants (mainly principals) from 20 lower secondary schools (classes 8–10). We analyzed the data using a deductive qualitative approach based on the CICI framework. We compared findings across schools offering the program (1) with no-parental-payment, (2) by parental subscription, and schools that (3) discontinued or (4) never offered the program. Economic costs were perceived as the main barrier to adoption across all schools. Although most schools recognized the need for such a program, some preferred to make their own arrangements. Except for schools offering the parental subscription option, many schools perceived asking parents to pay for the program as unfair, not in line with Norwegian values, and unlikely to allow the program to reach those who need it the most. Further barriers were the lack of legislation making the program obligatory and potential political changes causing uncertainty regarding the programme’s continuation from one year to the next. Social aspects of eating together were recognized as a facilitator. Food provision programs should be compatible with school priorities such as academic performance and mental health. Context and setting are dynamic and should be continuously evaluated to ensure they are in line with evolving school priorities and needs.
Abstract Background and Aims In patients with myocardial infarction (MI), no heart failure, and left ventricular ejection fraction (LVEF) ≥ 40%, the combined BETAMI-DANBLOCK trial showed that beta-blockers reduced the risk of all-cause mortality or major adverse cardiovascular events. This study evaluated the representativeness of the trial. Methods Participants in BETAMI (n = 2867) and DANBLOCK (n = 2707) were compared with a cohort of revascularized MI patients with LVEF ≥40%, and no heart failure from the Norwegian Myocardial Infarction Registry (the NORMI cohort)(n = 20 804). Baseline characteristics were evaluated, and absolute risks of all-cause mortality and/or MI were estimated. A transportability analysis was conducted by weighting the BETAMI-DANBLOCK population according to the NORMI cohort. Results Median age was 66 years (interquartile range [IQR]: 57–74) in the NORMI cohort and 63 years (IQR: 55–70) in BETAMI and DANBLOCK. Patients in the NORMI cohort had a higher prevalence of diabetes, previous coronary artery disease, and LVEF 40–49%, compared with trial participants. At 3-year follow-up, the absolute risk of all-cause mortality or MI was 12.0% in the NORMI cohort, 7.7% in BETAMI, and 7.8% in DANBLOCK. Corresponding risks of MI were 6.3%, 5.6%, and 4.3%, respectively. The treatment effects of beta-blockers were similar when the trial population was weighted according to the characteristics of the NORMI cohort. Conclusions Compared with the NORMI cohort, participants in BETAMI and DANBLOCK were younger, had a lower proportion of certain comorbidities, and experienced a lower risk of all-cause mortality and MI. Despite these differences, the effect of beta-blockers remained consistent when the trial population was weighted according to the NORMI cohort.
Rationale As cannabis legalization and decriminalization have expanded, it is increasingly perceived as a low-risk substance. Concurrently, the potency of cannabis products and the number of young adults seeking treatment for cannabis use disorder have risen markedly. A growing body of research links early onset, frequent use, and high potency cannabis products to a range of adverse outcomes. Objective This study aimed to examine whether frequent cannabis use during late adolescence affects cognitive functioning and increases the risk of developing anxiety in adulthood. Methods Male Sprague-Dawley rats were administered tetrahydrocannabinol (THC; 5 mg/kg/day) or vehicle from postnatal day (PND) 42 to 62. After a drug-free period, anxiety-like behavior was assessed in the elevated plus maze (EPM) and Light-Dark transition tests, while cognitive function was evaluated in the novel object recognition and Morris water maze (MWM) tests. THC concentrations in blood and brain tissue were quantified using ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Results The rats displayed blood THC concentrations comparable to human cannabis users and reduced body weight during the exposure period – an effect that persisted for over two months following the final injection. Adolescent THC exposure impaired novelty preference in young adult animals, whereas effects on spatial memory were less definitive. THC-exposed rats showed anxiety-like behavior in the EPM test, but not in the Light-Dark transition test. Conclusion Our findings suggest that frequent cannabis exposure during adolescence may lead to long-term reductions in body weight, reduced novel object recognition, and increased vulnerability to certain aspects of anxiety-related behavior in adulthood.
Background Patients living in rural districts may have limited access to acute stroke treatment due to long transport times to hospital facilities with radiology and revascularization therapy. This study simulates the utility of transferring acute diagnostics and treatment into rural areas by deployment of rural Computed Tomography (CT) services. Methods In Hallingdal county, Norway, a CT and thrombolytic station is operated in a local medical centre. We hypothetically deployed similar stations in rural Norway to explore the impact of such model of prehospital rural acute stroke treatment on ambulance transport times and patient outcomes after ischemic stroke. In addition, we described consequent changes in transport strategy for patients with suspected Large Vessel Occlusion (LVO) stroke. Results Significant reductions in hypothetical transport times were obtained after deployment of 30 rural CT stations. The part of the Norwegian population not eligible for thrombolysis within the recommended time window due to long transport time decreased from 11% to 1% (p< 0.001). By simulation of 1000 ischemic strokes, the estimated odds ratio for good outcome judged by modified Rankin Scale after thrombolysis for the rural population increased from 1.37 to 1.61 (p < 0.001). When LVO stroke was suspected, rural CT stations slightly increased the geographical area in which patients would receive local thrombolysis before transport to endovascular treatment. Conclusions Deployment of rural CT stations may facilitate rapid triage and early thrombolysis for patients with acute ischemic stroke living furthest away from hospital and this concept may be applicable to other health care systems worldwide. However, further research is needed to confirm its utility in the clinical setting.
Most children with acute lymphoblastic leukemia (ALL) achieve long-term survival due to intensive multimodal chemotherapy. However, the use of cytotoxic DNA-damaging agents is frequently associated with severe long-term side effects, prompting continued efforts to improve treatment strategies. This study explores the potential of starving the leukemic cells to enhance the efficacy of DNA-damaging therapy in ALL. Previous work demonstrated that cAMP signaling attenuates DNA damage-induced apoptosis in ALL cells, both in vitro and in a xenograft model. The current findings show that glucose and serum deprivation reverse the effect of cAMP, converting it from a survival factor to a promoter of DNA damage-induced apoptosis in ALL-derived cell lines and patient-derived leukemic cells in vitro. The starvation-induced sensitization was independent of p53 but was shown to require increased levels of reactive oxygen species (ROS). In turn, the elevated ROS levels enhanced the activation of the mitogen-activated protein kinase p38 (p38 MAPK). The resulting augmented cell death was inhibited both by the ROS scavenger N-acetyl cysteine and the p38 MAPK inhibitor SB 202190. The translational potential of increasing the efficacy of DNA damaging agents in starving ALL cells was supported by in vivo data showing that intermittent fasting, combined with subtherapeutic doses of irradiation, significantly inhibits the leukemia progression in a xenograft model of severe combined immunodeficiency mice.
Glioblastomas are the most prevalent and aggressive malignant brain tumors, characterized by hypertranscription and dependence on neurodevelopmental transcription factors. The transcriptional cycle is regulated by phosphorylation of the C-terminal domain (CTD) of RNA polymerase II (RNAPII) by transcriptional cyclin-dependent kinases (tCDKs), including CDK7, CDK9, CDK12, and CDK13. Here we find that glioblastoma stem cells (GSCs) are selectively sensitive to CDK12/CDK13 inhibition, whereas CDK7 and CDK9 inhibition cause non-specific cytotoxicity. This selective targeting halts GSC and organoid proliferation, curtails GSC invasion and suppresses tumor growth in a xenograft mouse model. In GSCs, CDK12/CDK13 inhibition leads to a rapid and genome-wide loss of serine-2 phosphorylation (pSer2) of the RNAPII CTD, abolishing transcriptional elongation and a transcriptional program sustained by key neurodevelopmental transcription factors. CDK12/CDK13 inhibition unexpectedly arrests DNA replication and replication fork progression in a manner distinct from the effect of inhibiting other tCDKs. This dramatic arrest precedes DNA damage response activation and cell cycle arrest, directly linking RNAPII elongation to replication fork dynamics and revealing a previously unrecognized dependence of DNA replication on CDK12/CDK13-RNAPII regulation.
Laboratory studies indicate a mechanistic role for serine in the metabolic benefits induced by dietary restriction of methionine and cysteine. To investigate the association of plasma serine with metabolic health markers in humans, we conducted a cross-sectional analysis of a subset of data from The Maastricht Study (n = 1199). Linear regression analyses (adjusted for confounding variables) were conducted to investigate whether plasma serine is associated with markers of lipid metabolism, glucose homeostasis, and body composition. Interaction analyses were conducted to investigate whether sex, diabetes status, and plasma total cysteine modify the association of serine with metabolic markers. Correlations between dietary intake of sulfur amino acids and plasma amino acids, including methionine and total cysteine, were also investigated. Elevated plasma serine was associated with favorable changes in markers of lipid metabolism (triglycerides, total cholesterol, and indices of multiple fatty acid desaturases), glucose homeostasis (insulin resistance and glucose tolerance), fat utilization (β-hydroxybutyrate, acetoacetate, and acetone), and body composition (visceral and subcutaneous adipose depots, liver fat, and body mass index). Some associations were stronger in males than in females and in individuals with prediabetes and diabetes than in those without diabetes. Associations of plasma serine with body mass index, total fat mass, total lean mass, and subcutaneous adipose tissue weakened as plasma cysteine increased. Combined methionine and cysteine intake was inversely associated with plasma serine. Findings suggest that plasma serine is strongly associated with improved metabolic health in humans. Additional studies are required to confirm whether the associations are causal.
Experience-dependent modulation of the visual evoked potential (VEP) can be used as a non-invasive human correlate of invasive measurements of long-term potentiation (LTP)-type neuroplasticity in animal research. However, conventional electroencephalogram (EEG) recording is high burden and time consuming, hindering adoption. Further, reliability of participant-level VEP modulation measures, even in highly controlled conditions, has been disappointing. To increase the practicality and utility of the assessment we trialled a short (11-min) paradigm with wireless dry-EEG headset and applied multiscale frequency-domain analyses to extract more precise measures of neuroplasticity. This approach was tested in healthy participants in laboratory (n = 17) and Phase 1 clinical studies (n = 33). Typical session duration was < 30 min. Test–retest reliability of VEP waveforms were compared to literature on full-length paradigms with wet-EEG hardware. Group-level time-domain event-related potential (ERP) analyses showed post-modulation P1 amplitude increase in both groups (Cohen’s d = 0.77, 0.78, respectively) and N1b amplitude decrease in clinical study group (Cohen’s d = − 0.52). Timeseries-based test–retest reliability of the VEP modulation effect was low but was substantially improved to moderate levels (some intraclass correlation ≥ 0.5) with a wavelet-based analysis. This suggests that VEP modulation assessments could be employed across multiple sites to objectively measure experience-dependent plasticity in real-world clinical trials of central nervous system therapies.
Recent clinical trial data show curative potential of cell therapy for diabetes, however the cells required are a bottleneck. Cell differentiation exhibits substantial variability, even among clones of stem cells generated from the same patient. Human experts struggle to see the difference between highly- and lowly-efficient cell clones early. We therefore propose an image-based deep learning model to guide the selection of the most efficient clones. We apply different deep learning models to learn the morphological differences between good and bad stem cell clones and classify them based on phase-contrast imaging. To gain insight into the learned features, we use layer-wise relevance propagation, and Fourier-based frequency analysis. Using an EfficientNet-V2-S model, we obtain a novel early prediction for the outcome of the differentiation process from patient-derived stem cells to β -cells using imaging. Clone level accuracy is 96.7 % at 53 hours after start of differentiation. The analysis of learned features shows that the structure of the cell population is an important predictive feature. This study is a proof-of-concept that deep learning combined with label-free imaging can be highly predictive and guide selection of stem cell clones, thereby reducing cost of β -cell production.
Aim This study aimed to assess the prevalence of genetic variants responsible for extreme levels of high-density lipoprotein cholesterol (HDL-C) and evaluate the adequacy of current thresholds for genetic testing of HDL-related dyslipidemia. Methods Using data from the Tromsø Study, a population-based cohort in Northern Norway, we identified 210 individuals with HDL-C levels ≤ 0.5 mmol/L or ≥ 3.0 mmol/L. Six HDL-related genes (ABCA1, APOA1, CETP, LCAT, PLTP, SCARB1) were sequenced in these participants. We classified variants according to ACMG guidelines, incorporating functional assays and UK Biobank data for additional phenotype-genotype associations. Results We identified 38 variants of interest across six HDL-related genes, of which 10 were considered potentially causative, found in 14 individuals. Genetic causes were detected in 33.3% of individuals with low HDL-C and 5.05% of those with high HDL-C. Sex-specific analyses showed that using HDL-C thresholds aligned with population distributions improved detection of individuals with pathogenic variants, particularly among women with high HDL-C and men with low HDL-C. These findings suggest that current uniform thresholds may overlook clinically relevant cases and that incorporating sex-specific HDL-C distributions could enhance the identification of individuals with suspected genetic HDL disorders. Conclusions Genetic testing for HDL-related dyslipidemia is underutilized, with many individuals not meeting the current extreme HDL-C threshold criteria. Revised sex-specific thresholds for genetic testing will improve the identification of pathogenic variants and provide more accurate diagnoses of HDL-related disorders. Continued research is essential to refine our understanding of HDL genetics and its clinical implications.
Background & Aim Climate change and evolving of population dynamics, including ageing and changes in population size, are reshaping temperature-attributable mortality patterns. However, there is limited evidence on the prospective trajectory of heat- and cold-attributable mortality in Oslo, particularly under combined scenarios of global warming and population development. This study aims to project heat- and cold-attributable mortality in Oslo and assess the distinct contributions of each of these drivers, utilising high-resolution data. Methods We conducted a two-step approach with time series analysis with distributed lag non-linear models to estimate heat- and cold-attributable mortality relationship based on mean daily ambient temperature. Then, we performed a health impact assessment to compute the attributable mortality to heat and cold in the baseline period (2010–2019) and by the end of the century using regional population projections, mortality rates and projected daily temperature under two climate scenarios: RCP4.5 and RCP8.5. Results For the RCP4.5/Medium Road scenario, the attributable mortality fractions for heat and cold are projected to increase over time, with values ranging from 9.05% (95%CI: 1.55–15.90) in 2010–2019 to 9.78% (95% CI: 2.96–15.86) in 2090–2099. Cold mortality consistently dominates the total, while heat mortality remains relatively low, starting at 1.80% (95%CI: 0.10–3.68) at baseline and increasing slightly to 3.12% (95%CI: 0.34–5.94) by the end of the century. In contrast, the RCP8.5/Strong Ageing scenario shows a more pronounced rise, with temperature-attributable mortality increasing from 9.07% (95%CI: 1.53–15.89) in 2010–2019 to 11.86% (95%CI: 4.29–18.53) in 2090–2099. In this scenario, heat mortality contributes significantly more, rising from 1.83% (95%CI: 0.12–3.85) in 2010–2019 to 5.99% (95%CI: 1.23–10.35) by 2090–2099, reflecting the greater climate and population impact under RCP8.5 and the Strong Ageing pathway. Conclusions Our findings highlight the need for climate and population dynamics to be considered in public health policies. Tailored interventions are crucial to mitigate heat and cold-attributable mortality, particularly for vulnerable populations. Future research should integrate socio-economic factors and explore adaptation strategies to refine mortality projections and inform policy.
Background The modified Atkins diet is increasingly used as an adjunctive therapy for drug-resistant epilepsy. Recent evidence suggests that such dietary interventions may affect the pharmacokinetics of antiseizure medications and induce DNA methylation changes. However, it remains unclear whether epigenetic regulation of drug-metabolizing enzymes contributes to variability in medication serum levels. Results We analyzed 58 adults with drug-resistant epilepsy treated with a modified Atkins diet for 12 weeks. DNA methylation was profiled in peripheral blood before diet initiation (baseline) and after 4 weeks and 12 weeks using a genome-wide array. A total of 131 cytosine-phosphate-guanine (CpG) sites mapped to 13 candidate genes involved in antiseizure medication metabolism were assessed. One CpG in the CES1 gene showed significant methylation changes from baseline to 4 weeks, 12 weeks, and across all timepoints (FDR = 0.0018), indicating consistent longitudinal effects. Repeated measures correlation analyses were used to evaluate within-individual associations between DNA methylation and antiseizure medication serum concentrations. Two CpG–drug associations showed strong positive intra-individual correlations: CYP3A5 methylation was significantly associated with carbamazepine serum levels (repeated measures correlation coefficient = 0.81, FDR = 0.023), whereas CYP3A4 methylation showed a similarly strong but borderline association with topiramate (correlation coefficient = 0.76, FDR = 0.051). Conclusions This study finds that a modified Atkins diet may be associated with DNA methylation variation at genes involved in drug metabolism. Furthermore, DNA methylation levels were strongly associated with individual serum concentrations of certain antiseizure medications. These findings are consistent with the concept of a diet–epigenome–drug metabolism axis and warrant further investigation in larger studies to assess clinical implications for personalized dietary and pharmacological management in epilepsy.
Background The impact of acute subdural hematoma (aSDH) on measures of glymphatic–meningeal lymphatic function has not previously been reported. We present a descriptive observational study including a small case series—one patient following unilateral aSDH, three following unilateral subarachnoid hemorrhage (SAH), and three control subjects—providing new insights into the differential effects of surface intracranial bleeds. Methods The magnetic resonance imaging (MRI) contrast agent gadobutrol (0.5 mmol), administered intrathecally, was used as a cerebrospinal fluid (CSF) tracer. Multiphase contrast-enhanced MRI was performed to assess glymphatic tracer enrichment. CSF tracer clearance to blood, serving as a proxy for dural lymphatic function, was estimated using population pharmacokinetic modeling. All hemorrhagic cases involved unilateral bleeds, allowing within-subject comparison between affected and unaffected hemispheres. Results The series included one patient with aSDH (2.8 months post-event), three patients with unilateral SAH (mean 5.8 months post-event), and three age-matched, near-healthy reference subjects. Compared with controls, glymphatic tracer enrichment 24 h post-injection was slightly increased on the affected hemisphere in the aSDH case, whereas SAH patients showed markedly reduced enrichment on the affected side. Tracer distribution in controls was symmetrical. CSF clearance to blood was notably reduced in the aSDH case compared with references, suggesting impaired dural lymphatic function. Conclusion This small descriptive series suggests that aSDH and SAH may differentially affect glymphatic and dural lymphatic functions. While glymphatic enrichment appeared only modestly altered after aSDH, it was severely impaired following SAH. In contrast, CSF clearance to blood was markedly reduced in the aSDH case, potentially reflecting compromised dural lymphatic drainage. The limited number of cases prevent broad generalization, but these findings offer novel hypothesis-generating observations that may inform future studies on the effects of surface intracranial hemorrhages on brain clearance pathways.
Telemonitoring has emerged as a promising alternative to conventional heart failure (HF) management, but randomized trials show conflicting results, and data from high-risk populations with frailty, is scarce. The Individually Tailored monitoring at home after HEART failure (IT-HEART) trial evaluates whether a non-invasive multi-component telemonitoring program improves outcomes in HF patients after HF-hospitalization. The aim of this study is to describe flow of patients and baseline characteristics of the IT-HEART trial population. This multicenter, open-label, blinded-endpoint trial randomized HF patients to either written information and a standardized self-treatment plan (Control) or HF education, a personalized self-treatment plan, and three months of home telemonitoring (Intervention). The primary endpoint is the total number of HF hospitalizations or cardiovascular death. Of 1016 consecutively screened patients, 200 (19.7%) were randomized. At baseline, median age was 78 (IQR 70–83) years, and 29.5% were women. Participants were multimorbid (median 6 diagnoses) with a median Clinical Frailty Scale score 4 (IQR 4–5). Median score of the European Heart Failure Self-care Behaviour Scale was 53 (IQR 35–67), and 75.5% had inadequate self-care. Self-rated knowledge on HF management was 3 (IQR 0–7) on a 0–10 Likert scale. Only 35.5% (n = 71) weighed themselves weekly whereas 1% (n = 2) reported having a self-care plan. In conclusion, patients enrolled after a recurrent HF hospitalization were multimorbid and frail, and scored low on self‑care and health literacy. The IT-HEART intervention is targeted to these factors and has the potential to improve clinical and patient‑reported outcomes, and costs.
Background In many countries, lifespan has been increasing faster than healthspan, leading to more years spent with late-life disease and highlighting the need for reliable biomarkers to measure biological aging. Methods We used data from the Berlin Aging Study II (BASE-II, 60–80 years of age at baseline, average follow-up 7.4 ± 1.5 years, range 3.9–10.4, n = 1,083) to compare 14 biomarkers of aging recently consented by an expert panel for the use as outcome measures in intervention studies: physiological (insulin-like growth factor 1 (IGF-1), growth-differentiating factor-15 (DNA methylation derived, DNAmGDF15)), inflammatory (high sensitivity C-reactive protein (CRP), interleukin-6 (IL-6)), functional (muscle mass, muscle strength, hand grip strength (HGS), Timed-Up-and-Go (TUG), gait speed, standing balance test, frailty phenotype (FP), cognitive health, blood pressure), and epigenetic (epigenetic clock, DunedinPACE). Cox proportional hazard regression analyses were performed to investigate their role in prediction of all-cause as well as cause-specific mortality. Results were adjusted for age, sex, lifestyle factors, and genetic ancestry. Results In adjusted models of all-cause mortality, HGS, IL-6, standing balance, cognitive health, and the epigenetic clock (DunedinPACE) statistically significantly predicted mortality, with the epigenetic clock (DunedinPACE) emerging as the strongest predictor. CRP, gait speed, IGF-1, blood pressure, muscle mass, DNAmGDF15, FP and TUG were not associated with mortality in this study. These results were corroborated in subgroup analyses stratified by cause of death. Feature selection identified a minimal biomarker set consisting of muscle mass, standing balance, and epigenetic clock (DunedinPACE) that predicted mortality with nearly the same discriminative accuracy (C-index = 0.63) as the full model including all biomarkers (C-index = 0.65). Conclusion Among the fourteen investigated biomarkers of aging, DunedinPACE emerged with the strongest and most consistent association with mortality.
Downregulation and inactivation of the Repressor Element 1-Silencing Transcription factor (REST) is shown in Alzheimer’s disease (AD) and likely contributes to its progression, but the exact molecular mechanism linking REST reduction to AD remains unclear. We examined changes in REST expression in the entorhinal cortex and hippocampus across different Braak stages of tauopathy. We show that alterations in REST expression and sub-cellular localization are partially responsible for AD pathology, as REST overexpression improves cognition, reduces amyloid-β and phosphorylated Tau deposition, and restores mitochondrial and synaptic homeostasis. Mechanistically, the NAD+/SIRT1 axis modulates REST expression through chromatin remodelling in the promoter region of REST, leading to changes in the expression of REST target genes involved in mitophagy and synaptic function. These findings reveal a new mechanism of action for NAD+ and highlight REST as a promising therapeutic target for AD therapy.
BACKGROUND: Comparisons of long-term mortality between alcohol-use-disorder (AUD) and opioid-use-disorder (OUD) groups within clinical cohorts are scarce. This study aimed to do this within one clinical cohort comprising groups suffering various severe substance use disorders. METHODS: Design: Observational cohort design. Prospective study of mortality 1998–2016, Cox regression. Sample/setting: 464 persons in specialist SUD treatment at start of observation period. Three subgroups defined by SUD characteristics at the beginning of the observation period, were studied: participants with 1) OUD, on opioid agonist treatment (OAT), (OUD/OAT-group), 2) AUD, no other SUDs (AUD-alone group), 3) AUD as part of a poly-substance-use disorder (AUD/PSUD group). Measures/covariates: Comparison of mortality risks and causes of death (somatic diseases/traumatic causes/substance-induced deaths/unknown cause) between OUD/OAT versus AUD-alone, and AUD-alone versus AUD/PSUD groups. Hazard ratio (HR) adjusted for baseline age (1 January 1998), sex, and socioeconomic/SUD characteristics. RESULTS: AUD-alone versus OUD/OAT: Unadjusted mortality risk was higher in the AUD-alone group [HR 1.99 (95% CI 1.33–2.99)]. However, in adjusted analysis type of SUD showed no statistically significant association with increased mortality [aHR 0.91 (0.54–1.54)], only male sex and increasing baseline age were independently associated with increased mortality risk. Cause-of-death distributions were very similar and somatic diseases caused over 50% of deaths in both groups. AUD-alone versus AUD/PSUD: Unadjusted mortality risk was higher in the AUD-alone group [(HR 2.57 (1.65–4.00)]. However, in adjusted analysis type of SUD showed no statistically significant association with increased mortality [aHR 1.40 (0.81–2.44)], only male sex, increasing baseline age, and “not being in work or education at study inclusion” were independently associated with increased mortality risk. Substance-induced deaths were most common in the AUD/PSUD group (43%). CONCLUSION: In adjusted analyses there were no statistically significant differences in mortality risk between the three subgroups. Somatic diseases were the main cause of death. Besides efforts to improve social rehabilitation and to treat the substance use disorders as such, early and targeted lifestyle interventions, and measures for early detection, treatment and follow-up of somatic disorders are essential to reduce mortality in both AUD and OUD populations. CLINICAL TRIAL NUMBER: Not applicable
Background Enantiomeric composition may impact binding and potentially performance of a drug product but is not routinely tested and minimum acceptance criteria are not always established. Some batches of the precursors FAPI-46 and FAPI-74 used clinically contain a mixture of (S)- and (R)-enantiomers. This study investigates the in vitro pharmacodynamic characteristics of different enantiomeric compositions of FAP-targeting radioligands FAPI-46 and FAPI-74 and in vivo pharmacokinetics of FAPI-46 in naïve mice. Results (S)-, (R)-, and (S/R)-enantiomers of radiolabeled FAPI-46 and FAPI-74 were evaluated for stability in human serum, binding affinity, internalization, retention, and selectivity using HT1080-hFAP cells and HEK293-hCD26 cells. All enantiomeric compositions showed high stability in human serum with minimal serum protein adhesion. (S)- and (S/R)-enantiomers exhibited comparable binding, internalization, and retention characteristics. High selectivity for FAP over CD26/DPP4 was maintained. (R)-enantiomers showed no specific binding to FAP. Additionally, the same enantiomers of 68Ga-labeled FAPI-46 were evaluated by dynamic positron emission tomography (PET) imaging (0–60 min post-injection) and ex vivo organ biodistribution in naïve BALB/c mice (10, 30, and 60 min, or 4 h post-injection) to compare their pharmacokinetic profiles. PET imaging revealed nearly identical time-activity curves for the enantiomers of [68Ga] Ga-FAPI-46, indicating similar whole-body distribution within 1 h post-injection, with rapid renal clearance and minimal muscle uptake. Ex vivo organ biodistribution confirmed comparable pharmacokinetic profiles between enantiomers, with no significant differences in tissue distribution. Conclusion These findings provide important validation that current clinical (S/R)-mixtures of FAPI-46/-74 exhibit pharmacokinetic and pharmacodynamic behavior comparable to pure (S)-enantiomers, supporting regulatory confidence and cross-trial reproducibility in the global FAPI-46/-74 imaging landscape.
Alzheimer’s disease (AD) and HIV-associated neurocognitive disorder (HAND) are significant global health concerns characterized by cognitive impairment and shared pathological features, including chronic neuroinflammation, amyloid deposition, and immune dysregulation. However, the precise molecular connections between these disorders remain unclear. Here, we identify IFIT3 as a critical shared mediator of neuroinflammatory responses in both AD and HAND. Using complementary approaches, including neuronal and microglial cell cultures, the APP/PS1 mouse model, and human postmortem brain tissues, we demonstrate consistent IFIT3 upregulation in response to amyloid-beta (Aβ) and HIV-1 exposure, with notably enhanced expression under combined conditions. Treatment with combination antiretroviral therapy (cART) partially mitigated IFIT3 induction. Additionally, siRNA-mediated silencing of IFIT3 significantly reduced key inflammatory mediators, including mitochondrial antiviral signaling protein (MAVS), nuclear factor-κB, and proinflammatory cytokines. Clinically, elevated IFIT3 expression was associated with early HAND and progressively increased across advancing AD Braak stages. Together, these findings identify IFIT3 as a potential molecular bridge between HAND and AD, highlighting its promise as both a biomarker and a therapeutic target for inflammation-driven neurodegeneration.
The HCLS1-Binding Protein 3 (HS1BP3) interacts with the SH3 domain of cortactin (CTTN), a protein that contributes to a malignant phenotype in cancers. Here, we demonstrate that high expression of HS1BP3 is associated with reduced survival for gastric adenocarcinoma and triple negative breast carcinoma patients and that HS1BP3 is specifically upregulated in these cancers. We mapped the HS1BP3-cortactin interaction site to the third proline-rich region (PRR3.1) of HS1BP3 and show that this interaction is important for cancer cell proliferation, extracellular matrix degradation and secretion. HS1BP3 expression was found to correlate with expression of the invadopodia scaffold protein TKS5 and we show that the localisation of TKS5 inside multivesicular endosomes is increased in cells expressing an HS1BP3 PRR3.1 mutant. Overall, our results highlight the importance of the direct interaction between HS1BP3 and cortactin in cancer development by regulating cell proliferation, secretion and invasion, which may provide an explanation for the negative correlation between HS1BP3 levels and the survival of gastric adenocarcinoma and triple negative breast cancer patients.
Background Alcohol consumption is one of the major risk factors of colorectal cancer (CRC), yet the mechanisms underlying this relationship, particularly the role of gut microbes, are not fully understood. Objective To study associations of alcohol intake with the gut microbiome and colorectal lesions among CRC screening participants. Of particular interest was the potential role of gut microbes in mediating the association between alcohol intake and colorectal lesions. Methods Screening participants with a positive faecal immunochemical test at ages 55–77 were eligible for the CRCbiome study. Alcohol intake was assessed using a validated, semi-quantitative food frequency questionnaire and linked with shotgun metagenome based gut microbial profiles to study associations with screen-detected colorectal lesions. The potential role of alcohol-associated gut microbes in mediating the association between alcohol intake and colorectal lesions was examined using causal mediation analysis. Results Of 1468 participants with dietary data, 414 were diagnosed with advanced lesions. Alcohol intake was positively associated with advanced lesions in a dose-dependent manner (ptrend = 0.008), with odds ratio of 1.09 (95% confidence interval, 1.00, 1.19) per 10 g/day increase. Compared to non-consumers, those consuming alcohol were characterized by a distinct microbial profile, manifested as modest, but consistent, shifts in α- and β-diversity, and differentially abundant bacteria. A causal mediation analysis showed that 12% of the association between alcohol intake and advanced lesions was mediated by alcohol-associated gut bacteria. Conclusion Alcohol consumption was associated with a distinct microbial profile, which partly explained the association between alcohol intake and advanced colorectal lesions.
Background and aims: Women with familial hypercholesterolaemia (FH) lose substantial treatment time during their reproductive years as most lipid-lowering therapies are contraindicated from the preconception through the end of breastfeeding. We examined the duration of real-life pregnancy-related off-treatment time in 27 women with FH in Norway. Methods: Women with FH in Norway who had completed the ongoing FH-FEMINA study (ClinicalTrials.gov ID NCT05367310) were included. Women were followed from 36th week of gestation and until one year after delivery or until end of breastfeeding. Information on use of medication before, during and after the current and previous pregnancies was collected. Pregnancy-related off-treatment time was calculated from discontinuation of lipid-lowering therapy when planning pregnancy, throughout pregnancy, and after delivery. Results: The total duration of pregnancy-related off-treatment time after all childbirths (median 1, range 1-3) per woman was a median of 2.9 years (25th-75th percentile; 1.6-4.0), ranging from 0.8 to 12 years. The pregnancy itself accounted for median of 42.1% of the pregnancy-related off-treatment time, whereas the time before and after pregnancy accounted for a median of 57.9% (range 11.4% to 91.2%). When including untreated years in childhood and/or prior to diagnosis, the lifelong off-treatment time represented a median of 66.3% (range 41.9 to 100%) of lifetime without treatment. Conclusion: Early diagnosis and initiation of treatment is essential in girls with FH to compensate for pregnancy-related off-treatment time later in life. To minimize these pregnancy-related off-treatment periods, healthcare professionals should support women with FH to resume lipid-lowering therapy immediately after breastfeeding and between pregnancies. In addition, more knowledge on the potential effects of statin use during pregnancy and breastfeeding on maternal and offspring health is urgently needed.
Accurate prediction of patient survival using high-dimensional multi-omics data requires effective feature selection methods that balance predictive performance, sparsity, and stability to enable reproducible and transparent prognostic biomarker discovery. Existing approaches often rely on ad hoc thresholds, limiting their reproducibility and clinical utility. We developed a hybrid ensemble feature selection (hEFS) framework that integrates data subsampling with multiple prognostic models, combining embedded and wrapper-based strategies for survival prediction. Features are ranked using a voting-theory-inspired aggregation approach across models and subsamples, while the optimal feature subset is determined via Pareto front optimization, eliminating the need for user-defined thresholds. We benchmarked hEFS against conventional CoxLasso using 100 Monte Carlo cross-validation iterations on multi-omics datasets from three pancreatic ductal adenocarcinoma (PDAC) cohorts, assessing sparsity, stability, redundancy, discrimination, and computational cost. Across all cohorts, hEFS selected substantially fewer and more stable features than CoxLasso (~10 vs. ~60 per modality), with lower variance, while still maintaining comparable discrimination performance with clinical baselines (C-index ~0.54–0.60). Feature redundancy was low, and ensemble subsampling further improved stability. Prognostic performance depended mainly on modality choice, rather than integration model, with gene expression plus clinical variables achieving the highest discrimination power (C-index ~0.64). hEFS provides a fully automated, interpretable, and reproducible framework for multi-omics biomarker discovery in high-dimensional survival analysis. By producing sparse, yet stable biomarker panels without loss of predictive power, hEFS represents a practical tool for integrative multi-omics modeling and it is openly available in the mlr3fselect R package.
Objective Explore treatment trajectories over a two-year follow-up among patients with musculoskeletal disorders (MSDs) in Norway and investigate the associations with education and country of origin. Design Register-based cohort study. Settings Data were obtained from three national registers, the Norwegian Control and Payment of Health Reimbursements Database (KUHR), the Norwegian Patient Registry (NPR) and Statistics Norway (SSB). Subjects Patients diagnosed with MSDs in 2015 in primary healthcare according to the International Classification of Primary Care, second edition (ICPC-2). Main outcome measures Treatment trajectory classes of healthcare use over a 2-years follow-up were generated using group-based multi-trajectory modelling, for all patients registered with MSDs and three common diagnoses: spine pain, osteoarthritis and fibromyalgia. Results From the analysis, four treatment trajectory classes of healthcare use were identified for MSD patients overall; low (75%), stable (10%), descending (9%) and high use (5%). The pattern was almost similar for the three diagnostic groups. High use was primarily caused by consistent high use of physiotherapy. For MSD patients overall, low education increased the probability of being in the low and stable use classes, while high education increased the probability of being in the descending use class. Patients with Norway as country of origin, were less likely to be in the class with low use and more likely to be in the class with descending use. Conclusion Using nationwide register data and group-based multi-trajectory modelling show that about 75% of all patients with MSD, consulting primary healthcare in Norway, were classified as low users of healthcare services and 5% were classified as high users. Overall, both education and country of origin were associated with the treatment trajectory classes. However, high use was not associated with neither education nor country of origin.
Bacterial polysaccharide capsules contribute to antigenic diversity and immune evasion. Escherichia coli infections, including those caused by extraintestinal pathogenic E. coli (ExPEC), cause substantial antimicrobial resistance-associated morbidity and mortality. However, much-needed genotypic methods for E. coli capsule typing to aid epidemiological analysis and therapeutic design are lacking. Here we describe the curation of an in silico typing database for group 2 and 3 ATP-binding cassette transporter-dependent capsule (K) loci from 18,185 kps-positive E. coli genomes from all continents and its application to carriage and ExPEC disease cohorts. Capsules K1, K5 and K2 were the most common types in European BSIs, and together with K100 and K52 they were responsible for 58% of multidrug resistance, with differing associations with invasiveness. Homologous recombination, insertion sequences and plasmids were associated with capsular gene exchange. These findings improve understanding of capsule epidemiology and evolution to inform future diagnostic and therapeutic strategies to combat ExPEC infections.
Common epilepsies are heterogeneous neurological disorders with significant heritability. Recent large-scale molecular genetic studies have identified both common and rare genetic variants affecting the risk of common epilepsies, suggesting the involvement of thousands of genetic variants. Most of these are common and individually have minuscule effects on disease risk. To date, more than 20 genomic loci with genome-wide significant common variant associations have been identified for genetic generalized epilepsies, implicating genes related to excitatory and GABAergic neurons, intracellular signal transduction, and synaptic excitability. While only a few common variant associations have reached genome-wide significance for focal epilepsies, exome-wide sequencing studies have robustly implicated protein-truncating ultrarare variants in genes encoding parts of the GATOR1 complex. Emerging data suggest a partly convergent genetic signal across subtypes of epilepsy and across common and rare variants. Furthermore, the genetic associations for common epilepsies overlap with a wide range of clinically related phenotypes, including cognitive ability and comorbid psychiatric and neurological disorders. Presently, genetic risk prediction tools that summarize an individual's common variant risk burden have limited clinical utility, but may eventually improve as statistical power increases. This review describes recent advances in the genetics of common epilepsies and outlines clinical implications and remaining challenges.
Background Nutritional interventions may reduce the prevalence of malnutrition in patients with head and neck cancer; however, implementation often fails due to barriers at various levels. Process evaluations can provide an understanding of implementation outcomes, mechanisms of impact, and context and provide information about feasibility and acceptability. Objectives To perform a process evaluation of the Nutrition Throughout the Treatment Course (NUTREAT) intervention, including use of the MyFood app and web report. Specifically, we aimed to evaluate 1) the acceptability, adoption, appropriateness, feasibility, and fidelity of the intervention, 2) the implementation plan, and 3) patient adherence to the intervention. Methods A mixed methods approach was applied, including individual interviews, a focus group discussion, log data from electronic patient records (EPRs), an experience questionnaire, and information from the MyFood web report. Proctor’s implementation outcomes guided the development of the interview guide and analysis. Themes were deductively established using codebook thematic analysis. The implementation plan was evaluated through logs of completed activities. Log data from EPRs were collected to evaluate fidelity among healthcare professionals (HCPs), and information from the MyFood web report informed patient adherence to the intervention. Results Individual interviews were conducted with patients (n = 8), registered nurses (n = 3), and leaders (n = 2), and a focus group discussion was conducted with registered dietitians (n = 6). Patients, registered nurses, registered dietitians, and leaders found the intervention acceptable, appropriate, and feasible. Patient adherence was high, whereas fidelity among HCPs was low. Conclusions The NUTREAT intervention increased patients’ awareness of their own nutritional requirements and was considered helpful by HCPs in preparing for patient consultations. However, fidelity among HCPs was low. Future efforts should focus on identifying strategies to improve fidelity among HCPs and study the long-term sustainability of the intervention.
During the first year of the COVID‐19 pandemic, reported cancer cases declined in the Nordic countries, potentially reflecting delays in cancer diagnosis. We compared 1‐year relative survival (RS) and excess mortality of patients diagnosed with cancer in the Nordic countries in March–December 2020 with that expected based on patients diagnosed in 2011–2019. We used flexible parametric RS models, defining excess mortality as the difference in total mortality between patients with cancer and the national population without cancer. We report the ratio between the observed and expected excess mortality (EMR) and the difference in 1‐year RS in percentage points (pp) by country, age, sex, and cancer site. Excess mortality of patients diagnosed during the pandemic was increased in all Nordic countries except Iceland. Swedish men had the highest EMR of 1.12 (95% CI 1.06, 1.17), corresponding to a 1.4 pp reduction in 1‐year RS (87.1%–85.8%). In women, the highest EMR was 1.10 (95% CI 1.03, 1.18) in Norway, corresponding to a 1‐year RS decrease of 1.2 pp (86.6%–85.5%). The largest site‐specific decreases in 1‐year RS were observed for liver cancer in Finnish and Swedish men, with decreases of 10.2 pp (45.3%–35.1%) and 7.2 pp (55.7%–48.5%), respectively. We found reduced 1‐year RS among Nordic patients diagnosed with cancer during the COVID‐19 pandemic in 2020, especially in older patients and those with aggressive cancers. These reductions coincided with restrictions and potential delays in seeking healthcare.
Abstract Background Registry-based randomised clinical trials are increasingly applied in clinical research, providing advantages in feasibility and data capture. However, registry-based data may introduce bias through misclassification or missing information. Methods In the BETAMI-DANBLOCK trial, 5,574 patients with myocardial infarction (MI) and no heart failure were randomised to beta-blocker or no beta-blocker therapy. The primary endpoint events (all-cause mortality, MI, ischemic stroke, heart failure, unplanned coronary revascularisation, and malignant ventricular arrhythmias) were identified from the Danish/Norwegian national patient registries, self-reported questionnaires, and medical records. All registry-identified events, except all-cause mortality, underwent blinded adjudication. We compared non-adjudicated and adjudicated events by calculating incidence rates and hazard ratios (HRs) for beta-blocker therapy versus controls. Results National registries captured 99.7% of primary endpoint events registered by self-report and medical records. Of the primary endpoint events identified through the registries, 75% were confirmed by adjudication (incidence rate 6.23 versus 4.43/100 person-years). The confirmation rate was lower during the first six months and varied by event type (from 92% for ischemic stroke to 45% for unplanned coronary revascularisations and heart failure). Estimated treatment effects were consistent for the primary endpoint with non-adjudicated and adjudicated events (HR 0.88, 95% confidence interval (CI): 0.78-0.98 and HR 0.85, 95% CI: 0.75-0.98, respectively), with no apparent differences across event types except for heart failure and revascularisation. Conclusion Registry data provided effect estimates of beta-blockers comparable to adjudicated data. However, adjudication substantially reduced the number of cardiovascular endpoint events and event-specific misclassification appeared, particularly during the first months after the index-event.
Osteosarcoma (OS) is an aggressive bone cancer that most commonly affects children and young adults. OS exhibits a high degree of genomic complexity, as well as cellular plasticity, and dynamic transcriptional regulation is suggested to contribute to treatment resistance and metastasis. Cell lines are well characterized as models to advance our knowledge on OS biology. HOS and U2OS cells have increased invasiveness and higher migratory ability compared with MG63. In this study, we employed a tandem array of consensus transcription factor response elements (catTFREs) proteomic approach to characterize transcription factor (TF) regulatory networks related to OS aggressiveness. We mapped 7,594 proteins and enriched 352 transcription factors and coregulators. When we integrated proteomics with cell line specific gene expression and chromatin accessibility we classified the proteins into different OS cell line dependent sub-clusters and identified TFs and coregulators common for all cell lines and specific for individual cell lines. We demonstrate that RUNX2, MYBL2 and HMGA2 are specifically enriched in HOS and U2OS and may be linked to the cell aggressiveness. ETV5, JUNB, NFIX and ZEB1 were among TFs specific to MG63. Our analysis provides a more comprehensive understanding of the transcriptional drivers that shape OS regulatory landscapes and may have future therapeutic implications.
The Norwegian COVID-19 vaccination campaign of adolescents from April 2021 necessitated surveillance of potential adverse events following immunization (AEFI). In this nationwide study of 496,432 adolescents, AEFI incidence rate ratios (IRRs) after first- and second-dose SARS-CoV-2 mRNA vaccination were compared to IRRs in unvaccinated subjects, and a self-controlled case series analysis was done as a secondary analysis. Seventeen pre-selected potential AEFIs were investigated: Anaphylactic reaction, Acute appendicitis, Lymphadenopathy, Arrhythmia, Cerebrovascular events, Death, Encephalomyelitis and meningitis, Epilepsy and convulsions, Facial nerve palsy, Herpes zoster, Idiopathic thrombocytopenic purpura, Myocarditis and pericarditis, Venous thromboembolic events, Arthropathy, Guillain-Barré syndrome, IgA vasculitis, and Multisystem inflammatory syndrome in children. Most AEFI were rare among adolescents, with few cases, and there was no statistically significant increase in the incidence of AEFIs after first-dose vaccination. Increased IRRs of anaphylactic reaction, lymphadenopathy, appendicitis, and myocarditis and pericarditis were observed following second-dose vaccination.
Cancer metastasis is the leading cause of cancer-related death. While organs such as the lung are hotspots for metastases, others -like skeletal muscle- remain rarely colonized, a phenomenon that remains poorly understood. In this study, we show that EO771 breast cancer cells proliferated robustly when co-cultured with MLg lung stromal cells, whereas their proliferation was restrained when maintained in direct contact with differentiated C2C12 skeletal muscle myotubes. Notably, these effects were not cell-type-specific, as similar results were obtained with 4T1 breast cancer cells and Sol8 myotubes. After two days of co-culture, both cancer and host cells (MLg and C2C12) exhibited distinct niche-specific transcriptional remodeling. Strikingly, the poorly proliferative EO771 cells co-cultured with C2C12 myotubes acquired a hypoxia-associated gene-expression signature despite normoxic conditions (~20% O₂), showing that muscle cells reprogram cancer cells into a hypoxic, anti-proliferative state. Under hypoxic conditions, we confirmed that the depletion of oxygen allows C2C12 cells to nearly abolish EO771 proliferation. Neither exogenous lactate, culture acidosis, their combination, altered glucose levels, nor conditioned medium could reproduce the suppressive environment created by C2C12 myotubes. In contrast, MLg cells induced minimal transcriptional changes in EO771 cells and were themselves broadly reprogrammed by the cancer cells. Moreover, hypoxia enhanced EO771 proliferation in MLg co-cultures, emphasizing the permissive nature of the MLg environment. Collectively, these findings uncover a unique, paradoxical, muscle-induced pseudo-hypoxic program that restricts cancer cell proliferation. They also highlight the need for caution in targeting hypoxia signaling in anti-metastatic therapies, as such interventions could weaken skeletal muscle’s natural defense against tumor colonization.
Abstract Objectives Studies have reported promising results regarding artificial intelligence (AI) as a tool for improved mammographic screening interpretive performance. We analyzed AI malignancy risk scores from two versions of the same commercial AI model. Materials and methods This retrospective cohort study used data from 117,709 screening examinations performed in BreastScreen Norway 2009–2018. The mammograms were processed by two versions of the commercially available AI model, Transpara (version 1.7 and 2.1). The distributions of exam-level risk scores (AI score 1–10) and risk categories were evaluated for both AI versions on all examinations, including 737 screen-detected and 200 interval cancers. Scores between 1–7 were categorized as low risk, 8–9 as intermediate risk, and 10 as high risk of malignancy. Results Area under the receiver operating curve was 0.908 (95% CI: 0.986–0.920) for version 1.7 and 0.928 (95% CI: 0.917–0.939) for 2.1 when screen-detected and interval cancers were considered as positive cases ( p < 0.001). A total of 87.1% (642/737) and 93.5% (689/737) of the screen-detected cancers had an AI score of 10 with version 1.7 and 2.1, respectively. Among interval cancers, 45.0% (90/200) had AI score 10 with version 1.7 and 44.5% (89/200) had AI score 10 with version 2.1. Conclusion A higher proportion of screen-detected breast cancers had the highest AI score of 10 with the newer version of the AI model compared to the older version. For interval cancers, there was no difference in the proportion of cases assigned to the highest score between the two versions. Key Points Question Studies have reported promising results regarding the use of AI in mammography screening, but comparisons of updated versus older versions are less studied . Findings In our study, 87.1% (642/737) of the screen-detected cancers were classified with a high malignancy risk score by the old version, while it was 93.5% (689/737) for the newer version . Clinical relevance Understanding how version updates of AI models might impact screening mammography performance will be important for future quality assurance and validation of AI models .
Abstract Objectives Diagnostic delay is common in pediatric inflammatory bowel disease (PIBD), and fecal calprotectin (FCP) is often limited by challenges with sample collection. Therefore, we aimed to identify and validate a blood‐based diagnostic protein signature of PIBD. Methods Proteins were analyzed using proximity extension assay in plasma samples from treatment‐naïve pediatric patients in a Swedish inception cohort referred for suspected inflammatory bowel disease (IBD) and validated in an independent Norwegian population‐based pediatric inception cohort. Diagnostic performance was estimated by the area under the curve (AUC) with 95% confidence intervals (CIs). Results The discovery cohort included 58 patients with PIBD and 36 symptomatic controls without evidence of IBD, while the validation cohort consisted of 79 patients with PIBD and 37 symptomatic controls. In total, 154 proteins were examined. Univariable analyses identified 26 differentially regulated proteins for PIBD versus symptomatic controls in the discovery cohort ( q < 0.05), whereas 29 proteins were differentially regulated in the validation cohort. Using regularized logistic regression, we identified a diagnostic model of 31 proteins that differentiated PIBD from symptomatic controls in the discovery cohort (AUC = 0.83; 95% CI: 0.74–0.90). The protein signature was further reduced to a clinically relevant biomarker consisting of high‐sensitivity C‐reactive protein (hsCRP) and seven other proteins with diagnostic capacity (AUC = 0.85, 95% CI: 0.78–0.92) outperforming hsCRP in the validation cohort ( p = 0.006). Conclusions We identified and validated a blood‐based protein signature for PIBD with superior diagnostic performance compared to hsCRP. Given the challenges of fecal sample collection, further assay development may enable integration of these biomarkers into diagnostic pathways for PIBD. Trial Registration ClinicalTrials.gov identifier: NCT02727959.
Abstract Purpose Targeted therapies have improved survival in human epidermal growth factor receptor 2 positive breast cancer (HER2 + BC). However, patients over 75 years of age are often excluded from clinical trials of anti-HER2 therapies, and it is unclear to what extent they receive these treatments in routine care. To address this, we examined age-related patterns of anti-HER2 therapy use in real-world clinical practice in Norway. Methods In a nationwide registry-based cohort, we identified women diagnosed with stage I-III HER2 + BC during 2012–2021. We investigated treatment patterns using descriptive statistics and estimated the direct effect of age on anti-HER2 therapy use by Poisson regression. Results Among 3526 women with HER2 + BC, anti-HER2 therapy use was consistently high (83–95%) in those under 75 years, decreased to 60% at ages 75–79, and declined further with advancing age to 8% at ≥ 90 years. Neoadjuvant anti-HER2 therapy also decreased with age (from 24% in patients under 75 to 12% in patients over 75 years). Accounting for cancer characteristics, comorbidities, polypharmacy, and socio-economic factors, older patients had reduced likelihood of receiving any anti-HER2 therapy compared with patients younger than 55 (RR 0.75, 95% CI 0.66–0.85, p < 0.001, at age 75–84 and RR 0.21, 95% CI 0.11–0.41, p < 0.001, at age 85 +). Conclusions Anti-HER2 therapy use declined substantially after the age of 75 even when accounting for comorbidities and polypharmacy. Chronological age appears important in planning treatment for patients with HER2 + BC. Specific guidelines pertaining to older patients with HER2 + BC are needed to avoid potential undertreatment.
Background & Aims Traumatic spinal cord injury (SCI) induces rapid and adverse changes in body composition, yet effective strategies to prevent excess fat accumulation are limited. This study aimed to evaluate the effect of an individualized dietitian-led nutrition intervention on change in fat mass and related markers of adiposity during the first year following SCI. Methods In this single-center, open-label randomized controlled trial, adults with subacute traumatic SCI were randomized to an individualized dietitian-led intervention or usual care. The primary outcome was change in total fat mass (FM) over one year, assessed by multifrequency bioimpedance analysis. Secondary outcomes included fat mass index (FMI), visceral adipose tissue (VAT), waist circumference, fat-free mass (FFM), fat-free mass index (FFMI), body weight, body mass index (BMI) and biomarkers (fasting glucose, 2-hour oral glucose tolerance test, HbA1c, LDL, HDL and triglycerides). Intention-to-treat analyses used mixed-effects models adjusted for age, sex, and neurological severity. Results Sixty-two participants were randomized (32 intervention, 30 control). Participants were predominantly male (76%) with a mean age of 48 (SD 17) years. At 1 year, the adjusted between-group difference in FM change was −1.5 kg (95% CI −4.8 to 1.9; p = 0.39). Significant between-group differences were observed for VAT (−0.5 L; 95% CI −1.0 to −0.1; p = 0.02) and waist circumference (−4.0 cm; 95% CI −7.0 to −1.0; p = 0.01), with borderline significance for FMI (−1.6 kg/m2; 95% CI −3.2 to 0.0; p = 0.05). No significant between-group differences were observed for body weight, BMI, fat-free mass, or biomarkers. Sensitivity and per-protocol analyses yielded consistent results. Conclusions Although the intervention did not significantly affect the primary endpoint of total fat mass, between-group differences were observed for VAT and waist circumference. These findings suggest that structured, individualized dietetic care initiated during SCI rehabilitation and continued post-discharge may attenuate accumulation of abdominal adiposity. Longer-term follow-up is needed to determine whether early attenuation of abdominal adiposity translates into reduced cardiometabolic risk and improved functional outcomes.
The comet assay is one of the most popular tests for genotoxicity in cell cultures, non-animal species, animals and humans. It has high sensitivity to detect low levels of DNA damage, can be applied to non-proliferating cells, requires relatively few cells, is technically simple, and is low cost. The Organisation for Economic Co-operation and Development (OECD) adopted in 2016 the in vivo comet assay for measurement of DNA strand breaks in animal tissues. There is a desire to expand the comet assay to genotoxicity testing in cell cultures, including the detection of oxidatively damaged DNA by incubation of gel-embedded nucleoids with DNA repair enzymes, especially formamidopyrimidine DNA glycosylase (Fpg) which converts oxidised purines to DNA breaks. Based on available information in the literature, this review provides a retrospective evaluation of the validation status of this assay, focusing on accuracy and reliability in genotoxicity testing in vitro. Information on accuracy is scarce, although limited evidence suggests levels of Fpg-sensitive sites are similar to those obtained by Fpg-linked alkaline unwinding and alkaline elution assays. Several ring studies have shown that estimated background levels of DNA breaks vary within and between laboratories. However, ring studies indicate good intra- and inter-laboratory reproducibility of the standard assay on ionizing radiation-exposed and the Fpg-linked assay on potassium bromate exposed cells. Further studies are needed to assess the reproducibility in multiple laboratories using coded samples of non-genotoxins and genotoxins. Nevertheless, the available results indicate the comet assay is a reliable in vitro genotoxicity test.
ABSTRACT Introduction: Smoking remains prevalent after hospitalization for atherosclerotic vascular disease, even with cessation programs. Understanding the clinical and psychosocial factors influencing long-term abstinence is essential for identifying patients who may benefit from tailored interventions. This study aimed to identify clinical and psychosocial factors associated with sustained smoking cessation in patients with atherosclerotic disease who were admitted to hospital for an elective or unplanned vascular event and enrolled in a cessation intervention study. Methods: This is a prespecified analysis of two randomized intervention trials that recruited participants from three secondary care hospitals in Norway between 2021 and 2023. Patients who smoked at least one cigarette daily before admission were randomized to: 1) motivational counselling and proactive referral to municipal cessation services (intervention); or 2) brief advice and contact information (control). Data were collected from medical records, a questionnaire, and telephone interviews. Logistic regression analyses were used to identify the prespecified factors associated with smoking status at 12 months. Results: In the total study population (n=262), 34% (n=88) reported 12-month sustained smoking abstinence. Anxiety diagnosis (adjusted odds ratio, AOR=4.2), shorter sleep duration per hour (AOR=1.3), living alone (AOR=2.2), somatic comorbidity per point on the Charlson score (AOR=1.5), and being in the precontemplation stage (AOR=2.9) were associated with persistent smoking. Increasing motivation per point on a 0–10 Likert scale (AOR=0.7), being in the preparation stage (AOR=0.4), and myocardial infarction or stroke as the index diagnosis (AOR=0.5) were associated with smoking abstinence. Results were generally consistent across intervention allocation groups. Conclusions: Motivation and readiness for smoking cessation were key predictors of abstinence. Living alone, anxiety disorders, and shorter sleep duration were associated with persistent smoking. These factors may help identify subgroups who could benefit from more targeted support.
This study uses two different quantitative phase imaging techniques (QPI) and for the first time measures the height, volume, and mass dynamics of Madin-Darby Canine Kidney (MDCK) monolayers. We demonstrate novel methods to determine the height of confluent monolayers of cells from 2D and 3D QPI data and validate that the two methods agree. We developed a novel cell segmentation method adapted to QPI images of confluent cell layers and present a robust measure of relative error. We also demonstrate that height statistics of cells can be obtained without segmenting the images. We obtain the following precisions of cell density (1 %), height (3 %), area (5 %) and volume (6 %). Cell height varies 15-25 % over a monolayer and increases 50-100 % when cell density doubles. The average refractive index and the dry mass fraction of the cells, on the other hand, are constant over the entire density range.
Importance Previous studies suggest that critically injured patients are at increased risk of suicide following discharge, but these have mainly been single-center studies or had limited data on comorbidities and socioeconomic factors. Objective To examine the risk of suicide after hospitalization for traumatic injuries. Design, Setting, and Participants This nationwide register-based cohort study used data from 5 Norwegian nationwide health registries and Statistics Norway between 2014 and 2020. Patients registered in the Norwegian Trauma Registry (NTR) for whom trauma team activation at hospital arrival was mandated by national guidelines between 2015 and 2018 were matched to general-population controls on gender and birth year in a 1:10 ratio according to a matched cohort design. Patients discharged alive were followed-up for a minimum of 2 years. All Norwegian hospitals treating patients with traumatic injuries provide data to the NTR. The final analysis was conducted in April 2025. Exposures Traumatic injury, admitted to hospital, and registered in the NTR. Main Outcomes and Measures The outcome of interest was suicide, as registered in the Norwegian Cause of Death Registry. Cumulative incidence ratios (CIR) of suicide with 95% CIs, taking nonsuicidal death as a competing event into account, were estimated. Adjustments for Charlson Comorbidity Index, previous psychiatric illness, and socioeconomic position (SEP) were conducted using inverse probability of treatment weights. Results A total of 25 536 patients with traumatic injuries (165 897 [67%] male; mean [SD] age, 41 [23] years) were matched to 247 095 controls, with a mean (SD) age of 41 (23) years and 68% male. The cumulative incidences of suicide were 0.18% at 2 years and 0.34% and 5 years for patients with traumatic injuries and 0.02% at 2 years and 0.05% at 5 years for controls (2-year CIR, 9.3 [95% CI, 5.4-13.0]; 5-year CIR, 6.9 [95% CI, 4.4-9.1]). Patients with traumatic injury were older at the age of suicide compared with controls (mean [SD] age, 43 [19] years vs 36 [17] years; P = .03) and female patients with traumatic injury had higher incidence of suicide compared with female controls (36% vs 17%; P = .005). Conclusions and Relevance In this cohort study of patients in Norway discharged alive after critical injury, a 9-fold increased risk of suicide after 2 years was observed. These findings suggest that follow-up is warranted for possible psychological distress in this patient group.
Background/Objectives: Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder affecting approximately 5–10% of the population, with many individuals reporting insufficient improvement from treatment options. This study aimed to explore whether time-restricted eating (TRE) could alleviate symptoms in patients with IBS. Methods: This single-group, pre–post pilot study included participants with IBS who followed an 8-week time-restricted eating protocol, defined as a daily 16 h fasting period and an 8 h eating window (16:8). Symptom changes were assessed using the validated IBS Symptom Severity Scale (IBS-SSS) at baseline and post-intervention. The study was retrospectively registered after completion of data collection. Results: A total of 134 patients were enrolled, of whom 97 completed the intervention. Participants demonstrated a mean reduction in the IBS-SSS score of −100.2 (p < 0.001). Subgroup analysis also demonstrated mean reductions in the IBS-SSS scores for participants with IBS-constipation (IBS-C) (−125.2, p < 0.001), IBS-diarrhea (IBS-D) (−76.0, p < 0.005), and IBS-mixed (IBS-M) (−93.1, p < 0.001). Additionally, the participants experienced improvements in both self-reported physical and mental health. Conclusions: These preliminary findings suggest that TRE may represent a promising behavioral strategy for IBS symptom management, warranting controlled trials.
Abstract Aims Population-based data on cardiac-related symptoms in individuals without diagnosed cardiac disease remain limited, despite important implications for early detection and management. We aimed to assess the prevalence of self-reported symptoms and the association with quality of life (QoL) among adults ≥65 years with ≥1 additional stroke risk factor, but without diagnosed cardiac disease. Methods Cross-sectional study of the NORSCREEN trial population at baseline. NORSCREEN is an ongoing, nationwide, randomised atrial fibrillation screening study in adults aged ≥65 years at increased risk of stroke (CHA2DS2-VA ≥2). All participants completed a baseline questionnaire capturing clinical information, symptoms, and QoL. Results Of 50,549 participants enrolled from 2023 to 2025, 39,281 (78%) reported no diagnosed cardiac disease. Among those, 17,069 (43%) reported cardiac-related symptoms compared to 7,551 (67%) of 11,268 individuals with known cardiac disease. Most common symptoms were fatigue, exertional dyspnoea and tachycardia. Female sex (adjusted odds ratio 1.66, [95% CI 1.58–1.75], physical inactivity (1.43 [1.32–1.55]), current smoking (1.24 [1.12–1.37]), age <75 years (1.14 [1.08-1.20]), living alone (1.13 [1.07–1.20]), and comorbidities including chronic obstructive pulmonary disease (6.51 [5.63-7.54]) and anxiety (3.99 [3.64-4.38]) were associated with cardiac-related symptoms. Symptomatic individuals reported significantly lower RAND-36 QoL scores across all domains compared to those without symptoms. Conclusion In this cohort of individuals ≥65 years at increased risk of stroke, but without diagnosed cardiac disease, nearly half reported cardiac-related symptoms, which were associated with substantially reduced QoL. These findings suggest there might be unmet needs in identifying and managing cardiovascular disease.
Functional neurological disorder (FND) is a common condition with debilitating neurological symptoms emerging from brain network alterations; yet, neuroimaging findings are often of unclear neurobiological significance. Contemporary mechanistic accounts indicate disturbances in hierarchical brain processing involving arousal, interoception, salience attribution, affective-motor integration, and self-agency. The findings of abnormal brain function with only partially consistent neuroimaging abnormalities imply that relevant pathology may occur below the resolution or contrast capabilities of conventional clinical MRI. Ultra-high field MRI (UHF, 7T and above) provides substantially improved spatial resolution, contrast sensitivity, and physiological specificity needed to interrogate microcircuit-, mesoscale-, and neurochemical-level mechanisms. We review how UHF-enhanced structural, diffusion, functional, and spectroscopic techniques can address long-standing mechanistic questions in FND. Selected targets that operate at different spatial scales are used to illustrate how UHF MRI can resolve features that are either inaccessible or not fully reliable at standard magnetic field strengths (1.5–3T). To synthesize these advances, we propose a biophysical multimodal MRI framework that integrates quantitative MRI, diffusion MRI, functional MRI, and MR spectroscopy to derive biologically interpretable markers spanning microstructure, white matter architecture, circuit dynamics, and neurometabolic domains. This approach aligns with contemporary computational and neurobiological models of FND and offers a scalable roadmap for future research. Together, UHF MRI and biophysically grounded multimodal imaging can enable a new generation of mechanistic studies in FND, with potential implications for diagnosis, subtype stratification, and biomarker development.
An educational gradient in mortality persists in the absence of smoking and is more pronounced among the unmarried. Marital status appears to modify the relationship between education and mortality, underscoring the need to consider social and relational factors in health inequality research.
Current benchmarks for long-context reasoning in Large Language Models (LLMs) often blur critical factors like intrinsic task complexity, distractor interference, and task length. To enable more precise failure analysis, we introduce CogniLoad, a novel synthetic benchmark grounded in Cognitive Load Theory (CLT). CogniLoad generates natural-language logic puzzles with independently tunable parameters that reflect CLT's core dimensions: intrinsic difficulty ($d$) controls intrinsic load; distractor-to-signal ratio ($\rho$) regulates extraneous load; and task length ($N$) serves as an operational proxy for conditions demanding germane load. Evaluating 22 SotA reasoning LLMs, CogniLoad reveals distinct performance sensitivities, identifying task length as a dominant constraint and uncovering varied tolerances to intrinsic complexity and U-shaped responses to distractor ratios. By offering systematic, factorial control over these cognitive load dimensions, CogniLoad provides a reproducible, scalable, and diagnostically rich tool for dissecting LLM reasoning limitations and guiding future model development.
Background: Smoking is closely linked to socioeconomic status and risk of death. We examined the extent to which educational disparities in mortality can be explained by smoking. Methods: We analysed data from 513,552 men and women aged 25–69 years, excluding individuals with a history of cardiovascular disease, diabetes or cancer. The educational level was lower (less than 10 years), upper (10–12 years) and higher (13 or more years). We employed the direct method to estimate age-adjusted mortality rates and used the Cox proportional hazards model to calculate hazard ratios, using a higher educational level as the reference level. We ran models among non-smokers with interaction terms, educational level and another variable. Based on Akaike information criterion, we performed stratified analyses by marital status among non-smokers. Results: The hazard ratio for lower educational level in men was 1.38 (1.31–1.45) in non-smokers and 1.57 (1.49–1.66) in smokers. The figures for women were almost identical. Among non-smoking men, the hazard ratio for lower educational level was 1.28 (1.21–1.35) for the ever married and 2.20 (1.93–2.52) for the unmarried men. In women the figures were the same. For non-smoking men and women combined, the population attributable risk ascribed to upper or lower educational level was 17% for the ever married and 35% for the unmarried. Conclusions: An educational gradient in mortality persists in the absence of smoking and is more pronounced among the unmarried. Marital status appears to modify the relationship between education and mortality, underscoring the need to consider social and relational factors in health inequality research.
Background: Accurate methods for estimating resting energy expenditure (REE) are important to ensure adequate nutritional treatment in colorectal cancer (CRC) survivors. Objective: To determine the agreement between REE estimated by commonly used predictive equations and by whole-room indirect calorimetry (WRIC). Design: This cross-sectional study included 31 CRC survivors (age: 53–78 years; mean (standard deviation (SD)) body mass index (BMI) 28.7 (4.28) kg/m2), who underwent curative surgery. Body composition was measured by dual-energy x-ray absorptiometry (DXA). Predicted REE from equations in clinical use and derived from DXA and bioelectrical impedance analysis (BIA) were compared against REE measured by 30-min WRIC. Equations included Harris-Benedict, Mifflin-St. Jeor, FAO/WHO/UNU, Henry, Mifflin-St. JeorDXA, and FAO/WHO/UNUBIA. Paired sample t-test, Lin’s concordance correlation coefficient (CCC) and Bland-Altman analysis were used to determine the agreement between measured REEWRIC and predicted REE. Accuracy was defined as the percentage of predicted REE values that fell within ± 10 % of REEWRIC. Results: Mean (SD) REEWRIC was 1710 kcal/d (353), and respiratory quotient (RQ) was 0.79 (0.05). Most equations underestimated REE. On average, Harris-Benedict, Henry, and FAO/WHO/UNUBIA showed the best overall agreement with REEWRIC. However, these equations showed low accuracy with 65 %, 68 %, and 62 % of predicted REE values within ± 10 % of REEWRIC, respectively. Conclusions: Most predictive equations tended to underestimate REE in CRC survivors compared with REEWRIC. The Harris-Benedict, Henry and FAO/WHO/UNUBIA equations showed both best accuracy and agreement with WRIC. They were still inaccurate, with individual variability for a relevant part of the sample. Future studies need to develop improved predictive equations for CRC survivors.
Background Klebsiella pneumoniae is an important pathogen of humans and animals. In the past five years, increasing reports of convergent strains that carry both virulence factors and antimicrobial resistance genes (ARGs) have raised serious public health concerns. The aim of this study is to describe the global diversity of plasmids carrying iuc3 (a key virulence factor in K pneumoniae associated with pigs and clinical isolates) from diverse settings, and their role in the emergence of convergent strains through hybridisation with plasmids carrying ARGs. Methods This population genomic analysis study was designed to describe both the global and local diversity of iuc3-carrying plasmids from diverse sources, and the co-occurrence of iuc3 with ARGs. We used all 4148 Klebsiella spp isolates from two large One-Health studies (SpARK, Italy, and OH-DART, Thailand), including 191 Klebsiella isolates from pigs, 635 from clinical isolates, 1040 from hospital and community carriage, and 2282 from other sources. Short-read sequencing of Klebsiella isolates was performed as part of the SpARK study. We sequenced Klebsiella isolates from the OH-DART (MicrobesNG, Birmingham, UK; HiSeq and NovaSeq, Illumina San Diego, CA, USA; GridION, Oxford Nanopore Technologies, Oxford, UK) and SpARK (MinION or GridION, Oxford Nanopore Technologies, Oxford, UK) studies. We also retrieved plasmid sequences carrying iuc3 from the National Centre for Biotechnology Information (NCBI). To ascertain the degree of diversity, evolutionary dynamics, and structuring across ecological and geographical axes, we detected ARGs and virulence loci, analysed clustering patterns and generated approximate maximum-likelihood phylogenetic trees. Findings We identified 48 K pneumoniae isolates with iuc3 in the SpARK data and 79 in the OH-DART data. Three (2·4%) of these 127 isolates were from clinical sources, 73 (57·5%) were from pig or pork meat. iuc3 isolates corresponded to multiple (n=47) host sequence types (STs), with ST35, ST45, ST881, ST25, and ST967 harbouring iuc3 in both datasets. We generated hybrid assemblies for 44 (SpARK) and 36 (OH-DART) isolates, plus a single iuc3 isolate from Germany. 53 (65·4%) of these isolates were from pigs, three (3·7%) from clinical sources, and 25 (30·9%) from other sources. There were an additional 48 iuc3 positive isolates from our collections for which only short read data was available. A single iuc3-positive Klebsiella oxytoca isolate from a pig farm was detected in the SpARK data, which was also sequenced. We identified 330 iuc3-positive isolates and 58 iuc3-carrying plasmid assemblies from NCBI, of which 83 (21·4%) were from clinical sources, 120 from pigs (30·9%), and 185 (47·7%) from other sources or of unknown provenance. These isolates were from K pneumoniae except two isolates of Klebsiella quasipneumoniae subsp similipneumoniae and one of Enterobacter hormaechei. The combined dataset of 517 iuc3 plasmids ranged in size from 110 375 bp to 365 580 bp and mostly corresponded to multiple IncFIB(K) and IncFII replicon types. We found seven convergent K pneumoniae plasmids in the Thai data: six from fresh markets and one from a neighbouring hospital. These plasmids emerged through the hybridisation of cocirculating iuc3 plasmids and plasmids encoding extended-spectrum β-lactamases (ESBLs), although none of these seven plasmids carried genes encoding carbapenemases. We also identified putative cocirculating parental plasmids carrying iuc3 and ESBL-encoding genes. Clustering and phylogenetic analysis resolved the iuc3 plasmid sequences into three groups, which were consistent using both complete plasmid sequences (n=139) and short-read data (n=517). In the complete plasmid sequence data, 66 strains contained group 1 plasmids, 38 strains contained group 2 plasmids, and 35 strains contained group 3 plasmids. Group 3 plasmids are mostly carried by isolates circulating in hospitals throughout Asia, with occasional examples in Europe and elsewhere, and carry multiple ARGs and potential virulence factors. By contrast, group 1 plasmids are commonly carried by porcine isolates in Europe, and group 2 are a heterogeneous mixture of geographical and ecological sources. Interpretation Plasmid hybridisation occurs frequently outside of the health-care environment and can lead to the convergence of resistance and virulence traits. Generating complete plasmid sequences from regional population-scale samples facilitates the identification of convergent plasmids and their putative parental plasmids. Three robust groups of iuc3 plasmids were resolved, which show both epidemiological and geographical differences; one of these groups was associated with clinical isolates in Asia and warrants targeted plasmid surveillance.
Background Total daily energy expenditure (TDEE) is vital for energy balance and cardiometabolic health, yet its trajectory across the lifespan, particularly in females, remains poorly understood. Objectives We sought to examine the effects of aging and sex on body composition and TDEE. Methods In a cross-sectional analysis of data from research centers across 9 European Countries and the United States from the International Atomic Energy Agency database, TDEE and body composition measures of 2326 participants (1560W/766M; 50.7 ± 12 .6 y) were stratified across age groups: young (30–39 y; YOUNG), middle-aged (40–54 y; MID), and old (55–70 y; OLD). Doubly labeled water was used to estimate TDEE and fat-free mass (FFM). Fat mass (FM) was calculated as the difference between body mass and FFM, and %fat was ratio between FM and body mass as a percentage. Linear models were used for analysis. Results Females demonstrated greater FM and lower FFM with each age group, compared with males (P < 0.001). In females, OLD had lower absolute TDEE than YOUNG (−217 kcal/d, P < 0.001) and MID (−208 kcal/d, P < 0.001). Male absolute TDEE was lowered across all age groups (OLD compared with YOUNG: −334 kcal/d; OLD compared with MID: −210 kcal/d; MID compared with YOUNG: −124 kcal/d; P < 0.001). Adjusted TDEE was similar within age groups between females and males. Conclusions These results suggest that age influences changes in body composition and energy expenditure similarly between males and females. The most significant change in TDEE occurs as individuals transition from middle age to older adulthood. Females generally have a higher percentage of %fat and FM, along with lower FFM, compared with males across all age groups. These findings are important for understanding how aging affects metabolism and body composition, which could inform sex-specific health strategies and interventions.
Reliable instruments are essential for studying perceptions of individuals convicted of sexual offences across cultural contexts. This study evaluates the psychometric properties of the Perceptions of Sex Offenders Scale (PSO) among Norwegian students in nursing, social education, social work, and police education (N = 282). Using confirmatory factor analysis, we tested the fit of the PSO’s original three-factor structure. The model showed mixed fit (RMSEA = .072; SRMR = .072; CFI = .86; TLI = .84). Internal consistency was satisfactory for Sentencing and Management and Stereotype Endorsement (α = .82 and .70), but low for Risk Perception (α = .53). Internal validity indices were uneven: composite reliability was acceptable for Sentencing and Management and Stereotype Endorsement (CR = .89 and .71), but not for Risk Perception (CR = .58), and AVE values were below recommended thresholds across factors, particularly for Risk Perception (AVE = .227). Free-text responses indicated that participants primarily had rape and child sexual abuse in mind when responding to the PSO. Overall, the PSO shows promise in a Norwegian student context, but the Risk Perception dimension appears to require refinement before the scale can be used confidently for research and educational purposes.
Abstract Epigenetic regulation is a key determinant of adipocyte fate, driving the differentiation toward white or thermogenic beige phenotypes in response to environmental cues. To dissect the mechanisms orchestrating this plasticity in human adipocytes, we conducted an integrative analysis of transcriptomic, epigenomic and enhancer connectome dynamics throughout white and beige adipogenesis. Using a machine learning approach, we show that the white transcriptional program is tightly linked to promoter-level modulation of H3K27ac and chromatin accessibility, whereas the beige-specific induction of mitochondrial genes is driven by promoter remodeling of H3K4me3, underscoring distinct epigenetic mechanisms for white or beige specification. Adipocyte beiging is accompanied by a targeted reorganization of the 3D genome, characterized by increased recruitment of short-range enhancers controlling thermogenesis genes, enriched for C/EBP transcription factor binding sites. Our findings highlight the multimodal regulation of the beige adipocyte fate, driven by the interplay of chromatin state transitions, enhancer rewiring, and transcription factor dynamics.
The cerebral cortex spontaneously displays different patterns of activity that evolve over time according to the brain state. Sleep, wakefulness, resting states, and attention are examples of a wide spectrum of physiological states that can be sustained by the same structural network. Furthermore, additional states are generated by drugs (e.g., different levels of anesthesia) or by pathological conditions (e.g., brain lesions, disorders of consciousness). While the significance of understanding brain states in relation to brain dynamics and behavior has become increasingly evident over the past two decades, a unified definition of brain states remains elusive. In this review, we focus on two extremes of this spectrum: synchronous versus asynchronous states. These functional states predominantly underlie unconsciousness and consciousness, respectively, although exceptions exist. Our aim is to integrate data from different levels into a multiscale understanding, ranging from local circuits to whole-brain dynamics, including properties such as cortical complexity, functional connectivity, synchronization, wave propagation, and excitatory-inhibitory balance that vary across states and characterize them. Experimental and clinical data, as well as computational models (at micro-, meso-, and macrocortical levels) associated with the discussed brain states, are made available to readers.
Background Skin-to-skin contact (SSC) provides extensive benefits for preterm infants and is highly recommended. However, parental SSC duration in Neonatal Intensive Care Units (NICU) varies considerably, with contributing factors poorly understood. Parents' perspectives on, and prior experiences with touch may influence SSC duration. Aims To investigate how parental attitudes toward and experiences with touch relate to SSC and holding durations, and to explore how these durations vary by relationship (mother/father), infant gestational age (GA) and parents' level of education. Study design Observational Study. Subjects Parents (n = 123) of preterm infants (n = 69), GA 270–366, admitted to a Norwegian family-centered care NICU providing 24/7 parental presence, participated. Outcome measures Daily parental SSC and holding durations (one week), video-evaluation of occurrence of slow, gentle and faster stroking, and Touch Experiences and Attitudes Questionnaire. Results Mothers provided significantly more SSC (p = .024) and holding (p = .005) than fathers. Parents provided significantly more SSC for infants at GA 27–30 (p = .029) and GA 31–33 (p = .036) than for GA 34–36, while significantly more holding for GA 31–33 (p = .022) and GA 34–36 (p = .001) than GA 27–30. No relation between parents' touch attitudes and experiences, affective touch awareness, or education, and SSC and holding duration was observed. Conclusion Maternal status and GA predicted SSC and holding duration yet explained the variance only partially. Parents' touch attitudes and experiences showed no association. This suggests that contextual, clinical or systemic factors may predominantly determine SSC and holding provision.
Background Detailed knowledge about the disease burden from unhealthy diet in Nordic and Baltic countries is lacking. This study quantifies and compares deaths and disability-adjusted life-years (DALYs) from dietary risks in these countries. Methods Data from the Global Burden of Disease study 2023 (GBD 2023) was used. Attributable disease burden from 15 dietary risks was analysed using the comparative risk assessment framework. Steps included: (1) estimating dietary intake; (2) assessing relative risks of dietary factors on disease endpoints; (3) determining theoretical minimum risk exposure levels (TMREL); and (4) estimating dietary risk-attributable disease burden as numbers and age-standardised rates (ASR) of deaths and DALYs. Findings Across the Nordic and Baltic countries (total population = 34,064,020), dietary risks resulted in 38,450 attributed deaths (95% uncertainty interval 10,749–59,386) and 735,284 DALYs (242,417–1,06,638) in 2023. Leading dietary risks included high intake of processed meat and low intake of fruits and whole grains. Dietary risks accounted for 24.9% of cardiovascular disease burden (5.0–37.6), 29.6% of diabetes and kidney disease burden (18.6–40.0), and 7.8% of neoplasm burden (2.9–12.1), with higher burden in the Baltic countries and Greenland than in the Nordic countries. Interpretation A substantial disease burden can be attributed to dietary risks in the Nordic and Baltic countries. Knowledge about the impact from unhealthy diet can inform targeted public health policies. Funding Gates Foundation and Norwegian Institute of Public Health.
The medial entorhinal cortex (MEC) is pivotal in spatial computations and episodic memory. In particular, an animal’s position can be decoded from the activity of entorhinal grid cells. However, it remains elusive whether MEC could play a more general role in different types of associative learning and how the representations develop during the learning process. It has been shown that the postrhinal cortex (POR), which is directly connected to MEC, integrates visual stimuli with salient outcomes. Here, we use a non-spatial visual association task to investigate whether MEC neurons represent low-level visual cues during learning. Using a Go/NoGo visual association task, we recorded neural activity in MEC and POR throughout the learning phase as mice associated drifting gratings with rewarded, aversive, or neutral outcomes. Our findings reveal that the neural tuning curves in both the POR and MEC change with the learning of the task. From the start of training, the POR neurons exhibited response tuning to the visual cues, and the tuning was stable to cue orientations during learning. In contrast, MEC neurons did not initially respond very strongly to visual cues but developed a robust tuning toward the rewarded trials. While the MEC’s representation of visual information was limited, it encoded other task elements. A large fraction of the neurons formed distinct functional clusters that were either activated or suppressed by reward-related behavior. Remarkably, these clusters segregated anatomically in MEC and maintained strong within-cluster correlations before and after training. Notably, although the same functional clusters were apparent in the POR, they did not show any anatomical structure as in the MEC. Task reversal induced significant changes in network responses across both regions, with a decrease in overall task-responsive neurons but a slight increase in stimulus representation. Strikingly, information about the choice to lick emerged with learning in both brain areas, and most significantly within the functional cell clusters representing reward consumption and plus-cue stimulus. Our results demonstrate that although neurons in MEC and POR develop behavior-modulated tuning during learning of a non-spatial visual association task, the MEC exhibits stronger within-cluster correlations and anatomical organization. Conversely, the POR population exhibits less structural organization and more specific stimulus-tuning, which is reflective of being a higher visual association area. Our findings reveal that the MEC can encode task– and behavior-related variables beyond spatial information.
Long non-coding RNA transcripts (lncRNAs) are important regulators of various cellular processes, including gene expression. However, whether they are involved in the regulation of anoxia-induced transcriptomic changes in crucian carp ( Carassius carassius ), a species that can survive without oxygen for months at low temperatures, has remained unexplored. The existing genome annotation includes mainly protein-coding genes, which are more straightforward to annotate than the lower-expressed lncRNAs. Therefore, this study aimed to annotate lncRNAs in the crucian carp genome, investigate their potential involvement in regulating mRNA abundance in response to anoxia and reoxygenation, and further characterize any differentially regulated lncRNAs and their potential interaction partners (nearby genes). Using next-generation RNA sequencing of brain samples from crucian carp across normoxia, anoxia, and reoxygenation conditions (n=10 per group), 145,264 transcripts were assembled with a reference-guided approach. Using the bioinformatic tools CPC2, CNCI, CPAT, and FEELnc, we identified 6,072 lncRNAs among the assembled transcripts. We observed a substantial transcriptomic response to anoxia, with a total of 56,440 differentially expressed (DE) transcripts (adjusted p-value < 0.05; | log2(fold change)| > 0.38), including 1,321 lncRNAs. The FEELnc classification module identified multiple proximal RNA transcripts that may help to predict lncRNA functions, and due to their proximity to potential interaction partners (IPs), were likely cis -acting. Most (60%) of the interaction sites between DElncRNAs and their targets were located between genes (intergenic), predominantly on the same strand in intergenic subtypes, and primarily nested in the genic context. The log2-fold changes in RNA abundance of DE predicted IPs exhibited a positive correlation with the log2-fold changes of their corresponding DElncRNAs. These findings indicate that lncRNAs are at least co-expressed with and may regulate transcription of specific genes in crucian carp during anoxia and reoxygenation.
For high dimensional data where the dimension p of the observation vector is larger than the group sample sizes ni,i = 1,2, classical approaches based on asymptotic theory are no longer valid. A recent parametric projection test shows a comparable type I error but with a substantial power improvement. However, the asymptotic theory of all such statistics may not hold with small ni, especially, in the presence of strong correlation structures. We here propose the use of a permutation test based on the same parametric projection test statistic. Extensive simulation results show that the permutation versions are more accurate under the null hypothesis than the parametric projection test when sample sizes are small and, especially when there is a strong correlation in the data. A significant test of “Sell in May and Go Away” for the manufacturing sector in China’s A-share market from May 2001 to October 2017 illustrates its application.
In studies of medical treatments, individuals often experience post-treatment events that predict their future outcomes. In this work, we study how to use initial observations of a recurrent event—a type of post-treatment event—to offer updated treatment recommendations in settings where no, or few, individuals are observed to switch between treatment arms. Specifically, we formulate an estimand quantifying the average effect of switching treatment on subsequent events. We derive bounds on the value of this estimand under plausible conditions and propose non-parametric estimators of the bounds. Furthermore, we define a value and regret function for a dynamic treatment-switching regime, and use these to determine 3 types of optimal regimes under partial identification: the pessimist (maximin value), optimist (maximax value), and opportunist (minimax regret) regimes. The pessimist regime is guaranteed to perform at least as well as the standard of care. We apply our methods to data from the Systolic Blood Pressure Intervention Trial.
Background Oral lichen planus (OLP) is a chronic mucocutaneous autoimmune skin disease without a proper pathophysiology and approved therapy. As a result, several repurposed drugs have been used in clinical practice, and it remains unclear which one holds greater potential. Aim The present study employs a network pharmacology to explore the disease biology and further investigate the target-specific binding efficacy of repurposed drugs. Materials and methods Twenty-eight repurposed drug’s (D1-D28) efficacies against twelve targets were investigated using PyRx 0.8-AutoDock 4.2 software. Further, drug stability and reactivity were studied using molecular dynamics (MD) simulation at 200 ns, Gibbs free energy, frontier molecular orbital theory, and structural activity relationship. Results The above computational investigation suggested betamethasone (D2/BETA) and triamcinolone acetonide (D28/TACA) are two potential drugs, predominantly demonstrating higher binding efficacy against the glucocorticoid receptor (GR). Further, MD simulation, free-energy calculation revealed that D28/TACA was comparatively more stable than D2/BETA. Conclusion The network pharmacology explored possible drug targets for drug discovery and showed that D28/TACA is a more effective treatment option among repurposed drugs.
It is generally assumed that population size of all wild animal species is regulated through density-dependent mechanisms, but the mechanisms responsible have been difficult to identify for elephants and large whales. We have used information on physiological reproductive mechanisms in humans in a stochastic computer simulation study to explore how known density-dependent fertility mechanisms in humans could regulate population size in a hypothetical large mammal species, assuming no deliberate interference with sexual or reproductive processes. Two physiological reproductive mechanisms in women are dependent on nutrition in utero or early life: age at menarche and post-partum amenorrhea during lactation and were included in the model. If large female mammals in general have physiological reproductive mechanisms similar to human females, strong density-dependence mechanisms will be the result, but with a substantial delay, 20 to 50 years. The model results are discussed in relation to what is known about populations of the Eastern North Pacific gray whales (Eschrichtius robustus), Antarctic minke whales (Balaenoptera bonaerensis) and elephants (Loxodonta africana) in Amboseli National Park, Kenya.
Pseudomonas aeruginosa is an important nosocomial pathogen which can cause serious infections across diverse anatomic locations. Infections can spread within an individual to different body sites, but the rate and directionality of this process is unknown. Here, we explore within-host diversity as well as the body site translocation dynamics using de-convoluted metagenomic P. aeruginosa reads from 256 hospital patients sampled at both respiratory and gut sites. Of the 84 patients where P. aeruginosa genomes could be recovered, there were 27 cases where the same P. aeruginosa clone was detected across multiple body sites. Using a simulation approach, we find that the majority of body site sharing is likely due to within-patient translocation of clones rather than independent acquisition from the hospital environment. Using ancestral reconstruction, we predict that most clones likely occupied a respiratory niche, and that the probable direction of clone transmission is lung-to-gut. Analysis of within-patient variation highlights strong enrichment of mutations in genes associated with antimicrobial resistance, irrespective of sample type. We report significantly more translocation than has been previously reported and highlight that lower respiratory tract infections can result in persistent gut colonisation of P. aeruginosa, a major risk factor for sepsis in vulnerable patients.
In the prevailing pandemic, the emergence of several variants has created concerns, as none of the vaccines have 100% effectiveness. As a countermeasure to combat the infection of SARS-CoV-2 and its variants and to minimize the morbidity, alternative therapeutics have been prioritized, mainly including phytocompounds. In our recent studies, we have considered polyphenols, such as catechin, curcumin, and 8-Hydroxydihydrosanguinarine (8-HDS), for this purpose and found their tendency to bind to the receptor-binding domain of S-protein, thereby inhibiting viral infiltration into the cell. In the current scenario, with the appearance of multiple viral strains, we have furthered our studies on two highly infectious variants of SARS-CoV-2: D614G and B.1.1.7, commonly identified as the UK variant. Our research incorporates various computational methodologies to decipher the potential role of our previously studied phytocompounds and the curcumin derivative, half-curcumin, inhibiting viral attachment and entry for both D614G and the B.1.1.7 lineage. The physicochemical characterization of the spike (S) protein of the UK variant suggests it is less thermostable, which raises questions about its transmissibility in warmer regions of the globe. All the studied phytocompounds have an immense ability to hinder the S protein interaction towards the human cell receptor ACE2 for both the variants. The half-curcumin has also potential drug suitability, which is confirmed through its characterization of ADME (Physicochemical, Water Solubility, Lipophilicity, Drug-likeness, and Pharmacokinetics) properties, and can be considered as a future therapeutic molecule for anti-COVID-19 drug design.
Background: Pancreatic ductal adenocarcinoma (PDAC) remains largely unresponsive to immunotherapy because of its highly immunosuppressive tumor microenvironment. Aryl hydrocarbon receptor (AHR), a ligand-dependent transcription factor, has emerged as a key regulator of immune homeostasis and inflammation. However, its systemic immunomodulatory role in PDAC, particularly outside the tumor microenvironment, remains poorly understood. Methods: Peripheral blood mononuclear cells (PBMCs) from patients with PDAC and healthy donors were isolated and treated ex vivo with two AHR agonists (Carbidopa and Tapinarof) and one antagonist (BAY 2416964). The samples were stratified into Low and High/Medium AHR expression groups. Flow cytometry (FC), qPCR, ELISA, Luminex assays, and immunofluorescence imaging were used to evaluate immune checkpoint expression, cytokine secretion, monocyte polarization, and subcellular AHR localization. Overall survival analysis was performed based on the baseline AHR expression levels. Results: Baseline AHR expression strongly influenced the immunological effects of AHR modulators. In High/Medium AHR PBMCs, Carbidopa increased PD-L1 and soluble PD-1 (sPD-1) levels, while IL10 expression was suppressed. In contrast, BAY significantly reduced PD-1 and sPD-1 levels in Low AHR PBMCs, whereas Tapinarof induced the highest IL10 expression. All modulators reduced the proportion of M2-like monocytes, indicating a shift toward less immunosuppressive phenotypes. Nuclear translocation of AHR protein varied across treatments and expression levels. Kaplan–Meier analysis revealed a non-significant trend toward improved overall survival in the High/Medium AHR group (log-rank p = 0.276). Conclusion: Baseline AHR expression critically shapes the immune response to pharmacological modulation in PBMCs from PDAC patients. These findings suggest that AHR profiling may serve as a clinically relevant biomarker for stratifying patients and guiding personalized immunotherapy approaches for PDAC.
Abstract The shared environment is a key component in estimating the heritability of phenotypic traits from familial data. Unlike the genetic components, defined by the kinship parameters, the shared environment stems from complex, latent processes that vary in nature and impact across traits. This concept is intricate, encompassing latent variables and ambiguous interpretations that differ across scientific disciplines. A common approach assumes a 100% correlation for the shared environment among all family members. However, this model has inherent limitations and may fail to capture the dynamics of the conditions that constitute the shared environment within and across traits. This study explores aspects of the shared environment and adopts a more general approach to modeling its correlation structure. We introduce models that represent different dynamic structures, enabling alternative interpretations of shared environmental influence on the transmission of phenotypic traits. A more realistic correlation structure for the shared environment will result in more accurate and precise heritability estimates for a given trait, as well as deeper understanding of its etiology. We demonstrate the performance of our proposed models through simulations and application to data on body mass index and systolic blood pressure from Norwegian health surveys linked to family data.
Background Different risk classification criteria are used to select patients with localized soft tissue sarcoma of the extremities and trunk wall for neoadjuvant/adjuvant chemotherapy. The two most frequently used risk classification methods are PERSARC and Sarculator prediction models. The main aim was to evaluate and compare these two methods. Materials and methods The study cohort consisted of 664 patients treated at Oslo University Hospital from 1998 to 2017. Predicted probabilities of distant metastasis (DM) and overall survival (OS) were calculated, and risk classification was carried out according to previously defined thresholds. Hazard ratios were estimated using Cox proportional hazards regression models. Interaction between neoadjuvant/adjuvant chemotherapy and risk groups was included in the models to investigate the effect of chemotherapy according to risk group. Results A high degree of correlation was found between PERSARC and Sarculator in predicted 5-year probability of DM and 5-year OS. A total of 215 of 664 (32%) and 221 of 569 (39%) patients were classified as high-risk according to Sarculator and PERSARC, respectively, with agreement found in 511 of 569 patients (90%). Patients classified as high-risk by only one method had similar disease-free survival and OS as patients who were high-risk using both methods. Based on this, patients classified as high-risk by at least one method were grouped as ‘combined high-risk’ and compared with previously established risk classification criteria. Neoadjuvant/adjuvant chemotherapy was associated with improved OS and disease-free survival in all high-risk groups. Conclusions A high degree of agreement between PERSARC and Sarculator predictions was observed. Patients classified as high-risk by only one method had similar outcomes to those who were high-risk using both. Chemotherapy was associated with improved outcome in the PERSARC, Sarculator, and combined high-risk group. Patients classified as high-risk by one of these methods could be considered for neoadjuvant/adjuvant chemotherapy.
Abstract Extra-intestinal pathogenic Escherichia coli ubiquitously colonize the human gut and represent clinically the most significant bacterial species causing urinary tract infections and bacteremia. During the last two decades clades of the ST131 lineage have spread globally, but it remains unknown how their transmission dynamics compare to the basic reproduction numbers ( R 0 ) for viral pandemics. We develop a compartmental model for asymptomatic gut colonization and onward transmission coupled with an epidemiological observation model and fit it on the major ST131 clades. Our results indicate that the ST131-A transmission potential ( R 0 = 1.47) can be comparable to pandemic influenza viruses, while the significantly lower transmissibility of ST131-C1 ( R 0 = 1.18) and ST131-C2 ( R 0 = 1.13) suggests that their dissemination has been aided by antibiotic selection pressure and healthcare facilities. Our results provide an advance in understanding the relative transmissibility of these opportunistic pathogens.
Exposure to heavy metals such as lead, arsenic and chromium is associated with genotoxicity and increased risk of cancer. In this systematic review and meta-analysis, we have assessed effects of heavy metal exposure on levels of DNA strand breaks in leukocytes, measured by the comet assay, in human biomonitoring studies. We distinguish between traditional toxic metals (lead), semi-metals/metalloids (arsenic), transition metals (chromium), and other heavy metals. The literature search led to 66 studies, which were assessed by meta-analysis. Using standardized mean difference and 95 % confidence interval (CI), the meta-analyses show increased levels of DNA strand breaks in subjects exposed to lead (1.99, 95 % CI: 1.47, 2.51), arsenic (1.36, 95 % CI: 0.94, 1.77), chromium/welding fume (2.03, 95 % CI: 1.48, 2.57), and other heavy metals (0.81, 95 % CI: 0.45, 1.18). Subgroup analysis indicates that all studies combined from middle-income countries have higher effect size (1.99, 95 % CI: 1.63, 2.35) than have studies from high-income countries (0.81, 95 % CI: 0.37, 1.26). The lower effect size in high-income countries may be due to differences in exposure levels, related to stricter regulation of emissions or more awareness/use of personal protective equipment in the working environment. Sensitivity analysis does not unequivocally link effect size to comet assay measurement bias, inferred by insufficient information on comet assay procedures, missing assay controls, non-blinded analysis of samples, or exposure misclassification. In conclusion, this systematic review and meta-analysis shows that exposure to heavy metals - lead, arsenic and chromium – is associated with increased levels of DNA strand breaks in human leukocytes.
Protein content in foods has historically been estimated by multiplying measured nitrogen content with a universal nitrogen-to-protein conversion factor (NCF) of 6.25. Despite scientific consensus that this approach leads to systematic overestimations due to variations in amino acid composition and non-protein nitrogen (NPN) content, no universally accepted revision has been implemented. This review critically examines diverse perspectives on protein quantification and their implications for Food Composition Databases (FCDBs). A structured definition of protein for FCDBs is proposed, including amino acid residues, free amino acids and small peptides, while explicitly excluding NPN and prosthetic groups. Furthermore, analytical methods and NCF calculations are evaluated in order to provide more accurate assessments of protein content across a range of food matrices. The review highlights the importance of selecting food-specific NCFs to reduce overestimations, ensuring both scientific accuracy and practical feasibility. By addressing methodological shortcomings and proposing a refined protein quantification framework, this work aims to facilitate the transition toward more precise and harmonized protein values in FCDBs, benefiting nutritional research, dietary guidelines, and food labeling regulations.
The gut–skin axis is an active and bidirectional communication in which gut microbiota impacts skin health and disease. One of the most common microbial metabolites is short-chain fatty acids (SCFAs), which are composed of acetate, propionate, and butyrate generated from the fermentation of dietary fibers. SCFAs are bioactive in nature that are essential in regulating inflammation, immune signalling, oxidative stress, and skin barrier function. In addition, SCFAs stimulate the differentiation of keratinocytes, acetylation of collagen, and have antimicrobial properties, which are important in establishing skin homeostasis and longevity. Currently, new approaches are underway to develop dietary patterns, probiotic strategies, functional food, and delivery systems to induce SCFA generation and function in vivo. Relevant research and review articles were collected using databases such as PubMed, Google Scholar, and Scopus for the information required for this comprehensive review. Key terms used for literature search included gut-skin axis, SCFA, functional food, epithelial integrity, skin aging, inflammation, etc. In this review, we tried to summarised the role and mechanisms of SCFA in gut-skin aging from the published research evidence and discussed on the role of functional foods in managing aging-related diseases.
Colorectal cancer (CRC) is one of the most common cancers, with an incidence that has increased significantly over the last 20 years. The World Health Organization (WHO), under its cancer program, identifies CRC as the third most prevalent cancer worldwide with a high mortality rate, especially in patients under the age of 50. Despite advances in surgery, chemotherapy, radiotherapy, and molecular targeted therapy, CRC shares a low survival rate and poor prognosis due to late diagnosis. To address these challenges, research into alternative diagnostic and therapeutic strategies has increasingly focused on molecular mechanisms, including noncoding RNAs (ncRNAs). Circular RNAs (circRNAs), a subclass of endogenous ncRNAs characterized by their covalently enclosed loop structure, demonstrate greater stability than linear RNAs, making them potential candidates for clinical applications. The circRNAs possess differential expressions in cancers and function as tumor suppressive or oncogenic activities. This review discusses the recent findings on circRNAs and their potential for biomarkers and therapeutic targets in CRC. As circRNAs can serve as miRNA sponges, increase or decrease mRNA expression, and function to regulate an oncogenic or tumor suppressor pathway, there may be the possibility for an early diagnosis, prognosis, or therapeutic role of circRNAs in CRC. Highlighting the clinical implications of circRNAs, this review discusses their potential to transform current CRC management strategies and address critical gaps in timely diagnosis and effective treatment. It also emphasized the need for further clinical research to validate their utility and translate these findings into practice.
The introduction of immune checkpoint inhibitors (ICIs) has revolutionized cancer therapy, offering durable responses in multiple malignancies by targeting regulatory pathways such as programmed cell death protein 1 (PD-1), its ligand (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). These pathways, which normally maintain immune tolerance and homeostasis, can be exploited by tumors to evade immune surveillance. Dual blockade using monoclonal antibodies (mAbs) targeting PD-1/PD-L1 and CTLA-4 has shown synergistic effects, improving response rates, overall survival, and progression-free survival in several cancer types. The U.S. Food and Drug Administration (FDA) has approved two such combinations: nivolumab plus ipilimumab and durvalumab plus tremelimumab, based on demonstrated clinical benefit in melanoma, renal cell carcinoma, colorectal cancer, hepatocellular carcinoma, non-small cell lung cancer, pleural mesothelioma, and esophageal squamous cell carcinoma. However, clinical benefit has not been consistent across all tumor types, with limited efficacy observed in cancers such as glioblastoma, head and neck squamous cell carcinoma, and Merkel cell carcinoma. Additionally, combination therapy is associated with a higher incidence of immune-related adverse events, affecting multiple organ systems and necessitating careful dosing strategies to balance efficacy and toxicity. This review summarizes the current landscape of FDA-approved PD-1/PD-L1 and CTLA-4 combinations, their therapeutic achievements, clinical limitations, and supports future research in combination immunotherapy.
Mitochondria are membrane-bound cell organelles that undertake the majority of the energetic and metabolic processes within the cell. They are also responsible for mediating multiple apoptotic pathways, balancing redox charges, and scavenging reactive oxygen species. MicroRNAs, which are short, non-coding RNAs widely known for regulating gene expression at the post-transcriptional level, regulate many of these processes. The specific microRNAs that directly or indirectly control mitochondrial dynamics are called mitochondrial miRNAs (mitomiRs). The broadest classification of this type of ncRNA encompasses nuclear-encoded miRNAs that interact with cytoplasmatic mRNAs associated with mitochondrial activity. At the same time, a more specific subset comprises nuclear-encoded miRNAs that translocate into the mitochondria to interact with mRNAs inside of this organelle. Finally, the smallest group of mitomiRs includes those codified by mtDNA and can regulate endogenous mitochondrial transcripts or be transported into the cytoplasm to modulate circulating mRNAs. Regardless of the origin or action mechanism, mitomiRs have been recently recognized to have a key role in the progression of a variety of chronic disorders, such as neurodegenerative and cardiovascular diseases, diabetes, asthma, depression, and even cancer. All of these progressive pathologies have been tightly linked to mitochondrial dysregulation. They are further associated with an aberrant expression of specific miRNAs that regulate cellular metabolism, positioning mitomiRs as reliable biomarkers for diagnosing several chronic diseases. These molecular indicators have also provided insights into how these conditions progress, allowing for the development of different miRNA-based treatment strategies that target dysregulated mitochondrial-related genes, reestablishing their baseline activity and restricting further disease progression.
Hepatocellular carcinoma (HCC) is a significant global health challenge, being one of the leading causes of cancer-related mortality. This review focuses on the intricate interactions within the tumor microenvironment and mesenchymal stem cells (MSCs) and it’s secretome in HCC and possible therapeutic responses. MSCs, characterized by their multipotent differentiation and self-renewal capabilities, can influence tumor behavior maybe through its secreted factors, including cytokines, growth factors and extracellular vesicles. This review summarizes the recent findings on role of MSCs in HCC, highlighting its involvement in different cell signaling pathways, including NF-κB, Wnt/β-catenin, Notch1, Stat3, and TGF-β, which play a significant role in HCC and possibly exhibit both tumor-suppressive and/or tumor-promoting effects depending on the activation or deactivation of signaling pathways. Publications related to the topic between 2016 to 2025 were searched using databases like PubMed, Scopus, Google Scholar with keywords viz. HCC, mesenchymal stem cells, secretome, tumor microenvironment, and signaling pathways. Findings from different research studies depict that MSCs and their secretome can exert anti-tumor effects by inducing apoptosis and enhancing immune responses, they may also promote alternate effects like tumor proliferation and metastasis under certain conditions, related to the activation or deactivation of different signalling pathways. This review aims to provide a comprehensive understanding of the multifaceted roles of MSCs in HCC. The dual role and the complexities of MSCs is context dependent. However, advancements in MSC research showed that the modifications of MSCs and secretome-based therapies and targeting the signaling pathways may have the potential to overcome challenges like drug resistance in HCC treatment.
The immune system protects the body against dangers that include pathogens, damage and cancer. Modern cancer therapies have sought to bolster immune responses against cancer using immunotherapy, which may include various forms of immune checkpoint therapy (ICT) in addition to methods of adoptive cell transfer (ACT), which is often associated with transfer of chimeric antigen receptor (CAR) T cells. Despite favorable outcomes in some patients and some cancers, as many as 60-80% of patients fail to benefit from ICT due to primary or adaptive resistance. This highlights the need for deeper understanding of how cancers suppress the immune system. Solid tumors, which make up approximately 90% of all cancers, are characterized by an immunosuppressive tumor microenvironment (TME). A hallmark of the TME is dysfunctional vascularization and impaired perfusion, which hinder effective drug delivery and promote hypoxia-induced metabolic reprograming in both cancer and immune cells. As the TME imposes intense metabolic stress through nutrient competition and lactate-driven acidification – both of which activates immunosuppressive pathways, targeting the TME itself may be beneficial in enhancing the efficacy of immunotherapy. Here we will briefly discuss the potential of targeting the metabolism of the TME as a means to promote normalized tumor vascularization and/or enhance anti-tumor immune responses.
Chalcones isolated from natural sources are the primary metabolites of numerous biologically intriguing and pharmacologically essential drugs. Chalcones’ pharmacological properties are believed to result from a double bond conjugated to carbonyl functionality. This review aims to summarise the research findings, showing naturally occurring chalcones as a preferred scaffold in medicinal chemistry. Natural chalcones have an intense antimicrobial activity that targets many pathogens, including viruses, bacteria, fungi, and protozoa. Strong antibiotic qualities are exhibited by chalcones, including 4-hydroxyderricin, licochalcone A and C, isobavachalcone, and pinocembrin chalcone. Furthermore, chalcones are promising pharmacological agents for cancer treatment; they inhibit angiogenesis, decrease metastasis, and induce death in tumor cells via diverse mechanisms. Chalcones are also considered promising therapeutic agents for diabetes, neurodegenerative diseases, and cardiovascular diseases because of their anti-inflammatory and antioxidant characteristics and ability to modify enzyme functioning. This review emphasizes several aspects, such as the biosynthesis of chalcones, preparation of chalcone derivatives, isolation of chalcones, structural features of chalcones, structure-activity relationship study, the role of natural chalcones in managing various diseases and illustrates their action mechanism to control disease progression.
Unhealthy dietary patterns are a major modifiable risk factor for atherosclerotic cardiovascular disease (ASCVD). International guidelines recommend reducing saturated fatty acid intake while increasing polyunsaturated and monounsaturated fatty acids (MUFAs) to mitigate cardiovascular risk. However, evidence regarding MUFAs and risk of ASCVD remains conflicting, with recent studies raising concern about a potential higher risk associated with MUFA intake. The aim of this narrative review is to provide an overview of current knowledge and gaps in the literature regarding MUFAs and the risk of ASCVD with a focus on intake, individual types, and content in adipose tissue as a biomarker of endogenous exposure. Main findings reveal that most studies have inappropriately combined all MUFAs together, despite individual MUFA types having different biological effects and showing varying correlations between dietary intake and adipose tissue content. Adipose tissue composition may serve as a biomarker of long-term MUFA exposure, reflecting cumulative intake over one to two years while minimizing biases inherent in dietary assessments. However, tissue levels reflect both dietary intake and endogenous synthesis, complicating interpretation. Importantly, the source of MUFAs appears critical, with plant-derived MUFAs potentially offering advantages over animal-derived sources. In conclusion, we suggest that future research should focus on individual MUFA types rather than treating them as a homogeneous group, investigate their specific dietary sources and associations with ASCVD risk, and use adipose tissue biomarkers to improve exposure assessment and clarify causal relationships while considering overall dietary patterns.
Peroxisomes are eukaryotic organelles for fatty acid oxidation and other metabolic tasks. They can differentiate into subpopulations via lumenal cores leading to uneven enzyme distribution and metabolic comaprtmentalization. Externally, they interact with other organelles at contact sites, supporting dynamic cellular positioning and metabolic cooperation.
For high-dimensional omics data, sparsity-inducing regularization methods such as the Lasso are widely used and often yield strong predictive performance, even in settings when the assumption of sparsity is likely violated. We demonstrate that under a specific dense model, namely the high-dimensional joint latent variable model, the Lasso produces sparse prediction rules with favorable prediction error bounds, even when the underlying regression coefficient vector is not sparse at all. We further argue that this model better represents many types of omics data than sparse linear regression models. We prove that the prediction bound under this model in fact decreases with increasing number of predictors, and confirm this through simulation examples. These results highlight the need for caution when interpreting sparse prediction rules, as strong prediction accuracy of a sparse prediction rule may not imply underlying biological significance of the individual predictors.
Abstract Purpose PARP7 is a negative regulator of type I interferon (IFN-I) and aryl hydrocarbon receptor (AHR) signalling and has important roles in cell proliferation and antitumor immunity. Recently, several cancer cell lines have been reported to be sensitive to the antiproliferative effect of PARP7 inhibition by RBN2397; however, the roles of AHR and IFN-I signalling in this effect are not fully understood. Methods Murine mammary cancer cells were treated with AHR ligands, RBN2397 and with the stimulator of interferon genes (STING) agonist, DMXAA. The impact of ligand treatments on AHR and IFN-I signalling and cell proliferation was determined. Results RBN2397 enhanced AHR ligand signalling and STING-induced IFN-I responses in both cell lines. Py8119 but not Py230, 4T1 or EO771 cells were sensitive to the antiproliferative effects of RBN2397. In agreement with FOS-related antigen 1 (FOSL1) being required for sensitivity to RBN2397, Py8119 but not Py230 cells expressed FOSL1. However, RBN2397 insensitive 4T1 and EO771 cell lines also expressed FOSL1, suggesting that the role of FOSL1 in RBN2397-mediated growth inhibition exhibits cell line specificity. In Py8119 cells, RBN2397 induced apoptosis which was independent of AHR ligand treatment and DMXAA-induced STING activation. Although Py230 cells were resistant to the antiproliferative effects RBN2397 alone, combined treatment of DMXAA with RBN2397 reduced their proliferation, which was further reduced by AHR loss or its inhibition. Conclusion These findings highlight the complexity of the interplay among PARP7, AHR and STING-induced IFN signalling in regulating cancer cell proliferation but also suggest that for some cell lines STING activation might increase their sensitivity to the anti-proliferative effects of RBN2397.
Background. Ongoing shortages of organs for transplantation have prompted the critical question of which countries have the highest organ donation rates and how each can increase those rates. The existing metric of donors per million population is flawed because it does not sufficiently account for important differences in the underlying population, including age distributions of deaths in the population. Methods. We sought to develop a better approach to analyze country-specific data on organ donation, including deaths stratified by age, to allow assessment of performance across the world. We used death data from the World Health Organization and donation data from 17 countries across 3 continents. We calculated age group-stratified organ donation rates as donors per 1000 deaths and estimated each country’s potential to increase donation if the age group-specific donation rate mirrored that of the highest-performing country in each age group. Results. There was a 4-fold difference in overall donation rates, with far greater variability within age strata, including a 10-fold difference in donation rates for the oldest age group (70 y and older). The United States showed the greatest potential to increase donations in absolute terms (>8000 increased donors per year), whereas Argentina, Germany, and Hungary had the greatest potential in relative terms. Conclusions. Although countries may have similar overall donation rates, the breakdown within specific age groups varies widely. Examining age-specific donation rates is a necessary step for accurate international comparisons of transplant systems and can enable targeted interventions to augment donation.
Primary sclerosing cholangitis (PSC) is an idiopathic, progressive and incurable liver disease. Here, we aimed for systematic analyses of adaptive immune responses in PSC. By profiling the T cell repertoires of 504 individuals with PSC and 904 healthy controls, we identified 1,008 clonotypes associated with PSC. A substantial fraction of these clonotypes was restricted to known PSC human leukocyte antigen susceptibility alleles and known to target Epstein–Barr virus (EBV) epitopes. We further utilized phage-immunoprecipitation sequencing to determine antibody epitope repertoires of 120 individuals with PSC and 202 healthy controls, which showed a higher burden of anti-EBV responses in PSC than controls. EBV-specific monoclonal antibodies isolated from B cells in PSC livers corroborated convergent B and T cell responses against EBV. By analyzing electronic health records of >116 million people, we identified an association between infectious mononucleosis and PSC (odds ratio, 12; 95% confidence interval, 6.3–22.9), suggesting a link between EBV and PSC.
Translational medicine for neurodegenerative diseases can advance through the use of in vitro models incorporating human neural cells derived from patient-specific induced pluripotent stem cells (iPSCs). Previously, we investigated whether motor neuron (MN) progenitors derived from human iPSCs could differentiate from MNs within three-dimensional (3D)-printed scaffolds. While extensive neurite arborization was observed on the scaffold surface, no neurite outgrowth occurred within the scaffold interior. Here we showed the extensive growth of the neurites from iPSC-derived neural progenitors, imbedded into the gelatin scaffolds during 30 days of experimental time. We presented a bioink formulation that softens the scaffold while preserving its 3D structure, thereby facilitating neurite outgrowth throughout the scaffold. MN differentiation, evidenced by extensive neurite arborization and the expression of choline acetyltransferase (ChAT), was verified in 3D images deep within the scaffold structure. Notably, the degree of MN differentiation appeared to depend on two factors as follows: the delivery of MN differentiation factors via mesoporous silica particles (MSPs) embedded in the bioink and the method used to generate MN progenitors prior to 3D printing. In this paper, we provide a detailed protocol for 3D-printing human iPSC-derived MN progenitors, enabling their differentiation and survival within gelatin scaffolds. This protocol could be expanded to incorporate additional cell types, allowing the creation of more complex and standardized 3D neural tissues. Such advancements could facilitate investigations into the pathophysiology of motor neuron diseases and the development of new therapeutic strategies.
Background Preclinical studies have shown that aprepitant, an antiemetic used to prevent chemotherapy-induced nausea and vomiting, slows mammary tumor growth and progression. Here, we evaluated the association between aprepitant and survival in a large cohort of women with early breast cancer. Methods Using linked nationwide registry data, we identified 13 811 women diagnosed with early breast cancer between 2008 and 2020 in Norway, who received chemotherapy and antiemetics. Women were followed for metastasis and death from 1 year after diagnosis until the end of 2021. To evaluate the association between aprepitant use and distant disease-free survival (DDFS) and breast cancer-specific survival (BCSS), we used Cox regression models, controlling for tumor and patient characteristics, chemotherapy regimens, and use of other antiemetics. Results During chemotherapy, 7047 (51%) women were supplied with aprepitant. Overall, aprepitant use was associated with better DDFS (HRDDFS = 0.89; 95% CI = 0.79 to 1.00) and BCSS (HRBCSS = 0.83; 95% CI = 0.71 to 0.97). The survival advantage was specific to women with non-luminal breast cancer (HRDDFS = 0.69; 95% CI = 0.56 to 0.83; HRBCSS = 0.64; 95% CI = 0.51 to 0.81) and was strongest in women with triple negative breast cancer (TNBC) (HRDDFS = 0.66; 95% CI = 0.53 to 0.83; HRBCSS = 0.61; 95% CI = 0.47 to 0.80). In women with non-luminal breast cancer, longer durations of aprepitant use were associated with increasingly favorable survival outcomes (DDFS: Ptrend = .002; BCSS: Ptrend = .016). Supply of other antiemetics of different drug classes was not associated with survival. Conclusions Aprepitant use during chemotherapy treatment was associated with better prognosis for women with non-luminal early breast cancer, in particular TNBC. Long-term clinical trials are required to confirm these findings.
Background Aortic stenosis is a debilitating disease characterized by pressure overload and development of myocardial fibrosis. Animal models that mimic this disease are crucial for translational research. Aortic constriction in rats is commonly used to induce pressure overload, but the precise disease progression in the O-ring induced model of ascending aortic constriction has not been thoroughly evaluated. Additionally, identifying early imaging biomarkers that can predict fibrosis could enhance the model’s translational relevance. This study aims to evaluate a rat model of progressive pressure overload using cardiovascular magnetic resonance imaging (CMR) by investigating the degree of constriction at different time points and identifying early imaging biomarkers predicting myocardial fibrosis at later stages. Methods Sprague Dawley rats (n=14) underwent aortic banding with O-rings (inner diameter of 1.5 mm or 1.3 mm). Sham-operated rats (n=8) served as controls. CMR was performed every fourth week until 20 weeks post-surgery, followed by tissue harvesting and measurements of fibrosis with histology. Results All banding groups gradually developed left ventricular (LV) hypertrophy, impaired LV diastolic function (increased E/SRe), increased left atrial (LA) size, and impaired LA function (reduced LA ejection fraction and peak LA strain), but preserved LV ejection fraction during the course of study. The tightest constriction exhibited increased LV fibrosis at 20 weeks. LA diameter at 4 weeks independently predicted LV myocardial fibrosis. Conclusion This animal model mimics the gradual progression of stenosis seen in humans, highlighting its translational potential. Early LA diameter predicted myocardial fibrosis. These findings underscore the model’s relevance for studying disease progression in LV pressure overload.
Dysfunctional alternative splicing events (ASEs) in RNA are markers of aging and Alzheimer’s disease (AD). As a key neuronal resilience metabolite, the oxidized nicotinamide adenine dinucleotide (NAD+) slows down AD progression in preclinical studies with several clinical trials ongoing. However, the underlying molecular mechanisms around how NAD+ enhances neuronal resilience, especially whether it has any effect on ASEs, have remained elusive. This study shows that NAD+ augmentation corrects the ASEs of many genes via a key protein, EVA1C (epithelial V-like antigen 1 homolog C), which is involved in neuronal development and activities. EVA1C is reduced in the hippocampus in patients with AD compared to cognitively normal ones. NAD+-induced memory retention is partially dependent on EVA1C, as adeno-associated virus–based Eva1c knockdown in the hippocampal CA1 region annuls NAD+-induced memory improvement in pathological Tau–bearing mice. We propose that NAD+ reduces AD pathologies, at least partially, via amplification of the NAD+-EVA1C splicing axis, pointing to a potential splice-switching therapy for AD.
Background/Objectives: Whilst cancer is a leading cause of death in people with HIV, less is known about clinical outcomes after cancer. Methods: Participants from the RESPOND and D:A:D cohorts with the five most common cancers (Kaposi’s sarcoma (KS); non-Hodgkin lymphoma (NHL); and lung, anal and prostate cancers) were followed from first cancer diagnosis after 2006/2012 [D:A:D/RESPOND] until death, final follow-up or administrative censoring (2016/2021). Incidence rates (IR) were calculated for post-cancer mortality; for non-fatal events (cardiovascular disease, diabetes, another primary cancer, AIDS events) individually and as a non-fatal composite clinical outcome (CCO). Predictors or mortality and CCO were assessed using Poisson regression with generalized estimating equations. Results: Amongst 2485 participants with cancer, mortality and CCO IRs were highest after lung cancer (445.4/1000 person years [95% CI 399.7, 494.9], 117.1 [94.3, 143.8], respectively) compared to other cancers and lowest after KS (21.3 [16.9, 26.6], 43.9 [37.5, 51.3]). The most common non-fatal outcomes were AIDS events after NHL and KS, diabetes after lung and prostate cancer and another primary cancer after anal cancer. Among people with NHL and anal cancer, a diagnosis in more recent years was associated with lower mortality risk. Increasing the time-updated CD4 count reduced mortality by 15–40% (per 100 cells/µL) after NHL and anal and lung cancers and reduced CCO risk by 17–28% after KS and NHL. Smoking, low BMI and multimorbidity increased CCO risks by two to three times after KS and NHL. Conclusions: Risk of post-cancer mortality and non-fatal outcomes varies by cancer type and risk profile, suggesting the need for personalized post-cancer clinical monitoring.
Introduction As patient-reported outcomes (PROs) are increasingly used in the evaluation of medical treatments, it is important that PROs are carefully analyzed and interpreted. This may be challenging due to substantial missing values. The missingness in PROs is often closely related to patients’ disease status. In that case, using observed information about intercurrent events (ICEs) such as disease progression and death will improve the handling of missing PRO data. Therefore, the aim of this study was to develop imputation models for repeated PRO measurements that leverage information about ICEs. Methods We assumed a setting in which missing PRO measurements are missing at random given observed measurements, as well as the occurrence and timing of ICEs, and potentially other (baseline or time-varying) covariates. We then showed how these missingness assumptions can be translated into concrete imputation models that also account for a longitudinal data structure. The resulting models were applied to impute anonymized PRO data from a single-arm clinical trial in patients with advanced lung cancer. Results In our trial example, accounting for death and other ICEs in the imputation of missing data led to lower estimated mean health-related quality of life (while alive) compared to an available case analysis and a naive linear mixed model imputation. Conclusion Information about the timing and occurrence of ICEs contribute to a more plausible handling of missing PRO data. To account for ICE information when handling missing PROs, the missing data model should be separated from the analysis model.
Aims Investigation of cardiovascular disease (CVD), all-cause death and use of statins and ezetimibe among young Norwegian individuals with heterozygous Familial hypercholesterolemia (FH). Methods We included subjects with genetically verified FH born 1988–2008 and twenty controls per FH subject, with linkage to prescription data, hospitalization data and cause of death from national Norwegian health registries. Data on CHD and death during 2008–2018, and for dispensed prescriptions during 2004–2018, were collected. Results 1351 subjects with FH and 27,015 controls were included. Mean age (SD) at start of follow-up was 12.3 (5.4) years. There was one Coronary Heart Disease (CHD) event and 6 deaths in the FH-group and 3 CHD events and 53 deaths in the control group. CHD and all-cause death were non-significantly increased in the FH-group, hazard ratios (95 % confidence intervals) 6.68 (0.69–64.20) and 2.26 (0.98–5.28), respectively. None of the deaths in the FH-group were related to cardiovascular disease. 83 % of subjects with FH had been prescribed a statin, and 21 % ezetimibe. During the first year after the first prescription, 18.5 % of subjects did not refill their prescription within 180 days after the end date of the previous prescription. 69 % and 60 % of subjects with a prescription had >80 % of days covered with statins and ezetimibe, respectively. After 8 years, around 70 % of subjects were covered with statins. Conclusions Results suggest increased risk of CHD in FH relative to controls, but measures are imprecise because of low absolute risks. Compliance with lipid lowering therapy was moderate.
Syndecan-4 is a ubiquitously expressed transmembrane proteoglycan that links the extracellular matrix to intracellular protein networks. It is located at stress-sensing structures in cardiomyocytes, including costameres and Z-discs, and in male mice, it is involved in the hypertrophic response to cardiac pressure overload. We have recently found female syndecan-4 KO cardiomyocytes, without challenge, to be smaller in area. Smaller cardiomyocytes with elongation defects have been observed in animal models with β-parvin deficiency, where the loss of this mechano-sensor disrupts the guanine nucleotide exchange factor (GEF) β-PIX-GTPase Rac1 axis, which is essential for proper cell elongation. β-parvin, together with integrin-linked kinase (ILK) and particularly interesting new cysteine-histidine-rich protein (PINCH), constitutes the IPP complex (ILK-PINCH-parvin), which is part of the integrin consensus adhesome. Interestingly, in a previous large cardiac interactome study, we have identified β-parvin, as well as ILK, β-PIX, and Rac1 as potential syndecan-4 partners. To better understand the syndecan-4-β-parvin association, we mapped their interaction and investigated the effect of syndecan-4 ablation on the IPP complex, the β-parvin-β-PIX-Rac1 axis, and cardiomyocyte geometry in both females and males. Interestingly, genetic ablation of syndecan-4 resulted in shorter cardiomyocytes in females only. The syndecan-4-β-parvin interaction was mapped to accessible sequences within the N-terminal, linker, and CH2 domains of β-parvin and the unique variable C2 cytoplasmic region of syndecan-4. Syndecan-4 ablation resulted in lower levels of membrane-localized β-parvin in both sexes and sex-specific differences in its associated partners ILK and PINCH, suggesting that syndecan-4 is linked to integrin signaling through the IPP complex. Finally, Rac1, known for its involvement in cell size regulation, and some of its regulators, β-PIX, RhoGDIα, and the serine/threonine kinase PAK, showed sex-specific alterations following syndecan-4 ablation. Altogether, our data suggest that syndecan-4 binds directly to β-parvin and regulates cardiomyocyte length, the IPP complex, and the β-parvin-β-PIX-Rac1 in a sex-dependent manner. These findings highlight a sex-specific role for syndecan-4 in cardiomyocyte structure, offering new insight into the molecular basis for sex differences in cardiac biology.
BACKGROUND Protecting the kidneys by lowering systolic blood pressure (SBP) in hypertensive patients is not unequivocally settled. We tested the hypothesis that achieving lower average SBP in middle-aged and older high-risk hypertensive patients with and without type-2 diabetes mellitus through several years would clarify kidney protection. METHODS We analyzed patients 50–80 years with no cardiovascular events during the first 6 months of drug up-titration after randomization to valsartan or amlodipine, and with 3 or more visits onwards with standardized BP measurements. Adjusted Cox analyzes compared worsened kidney function defined as a 50% rise in se-creatinine on a minimum of two occasions at least 4 weeks apart or end-stage kidney disease (ESKD) in achieved SBP quartiles and in patients who achieved SBP < 130 and 130–139 mmHg with patients whose SBP remained ≥140 mmHg. RESULTS A total of 13,803 patients were investigated of whom 4,655 had DM. Patients with DM had less worsened kidney function at SBP 130–139 mmHg (HR = 0.524, 95% CIs 0.375–0.733, n = 1849, P < 0.001) and at SBP < 130 mmHg (HR = 0.538, CIs 0.316-0.915, n = 674, P = 0.022) compared with patients at ≥ 140 mmHg. They also had less ESKD at SBP 130-139 mmHg (HR = 0.442, CIs 0.196–1.000, P = 0.050) with a similar trend at SBP < 130 mmHg and in quartile analysis with only 1 ESKD in the lowest quartile. Findings in patients without DM (n = 9,148) were similar to DM. CONCLUSIONS In high-risk hypertensive patients aged 50–80 years, with and without DM, targeting SBP of 130–139 mmHg confers kidney protection with possible further benefit at the lower target of SBP < 130 mmHg. Clinical trials registration Trial Number NCT06395194, www.clinicaltrials.gov.
Objectives: Early diagnosis of suspected sepsis is crucial to improve patient survival. Cell population (CP) data, a set of leuco-cyte research parameters from hematology instruments, has a potential as markers for infection. The aim of this study was toinvestigate the diagnostic accuracy for infection of CP variables from Sysmex XN instruments in patients with suspected sepsisin the emergency department (ED). Methods: Adult patients with suspected sepsis in the ED were included. CP variables, C-reactive protein (CRP), and post hocassessments of infection were recorded. Logistic regression and machine learning methods were used to develop multivariablemodels, which were evaluated by area under the receiver operating curve (AUC) and calibration plots. Results: The development cohort and the validation cohort consisted of 600 and 656 patients, respectively. Univariate analysesrevealed that complexity in monocytes (MO-X); AUC of 0.78 (0.74, 0.82), reactivity intensity of neutrophils (NEUT-RI); 0.72 (0.67,0.76), and CRP 0.87 (0.84, 0.90) had the highest diagnostic accuracy for infection. A final multivariable model (the optimal model)using Multilayer perceptron (MLP), including MO-X, NEUT-RI, monocyte size (MO-Z), and neutrophil size (NE-FSC), had anAUC of 0.86 (0.85, 0.87) in the development cohort and 0.78 (0.74, 0.82) in the validation cohort with reasonable calibration.Including CRP in this model further improved accuracy and calibration. Conclusions: Sysmex CP variables may help diagnose infections in the ED. However, the lack of well-described calibration pro-cedures and quality assurance for non-IVD approved CP variables is an impediment to clinical implementation
SYTL5 is a member of the Synaptotagmin-Like (SYTL) protein family that differs from the Synaptotagmin family by having a unique N-terminal Synaptotagmin homology domain that directly interacts with the small GTPase RAB27A. Several SYTL protein family members have been implicated in plasma membrane transport and exocytosis, but the specific function of SYTL5 remains unknown. We here show that SYTL5 is a RAB27A effector and that both proteins localise to mitochondria and vesicles containing mitochondrial material. Mitochondrial recruitment of SYTL5 depends on its interaction with functional RAB27A. We demonstrate that SYTL5-RAB27A positive vesicles containing mitochondrial material, autophagy proteins and LAMP1 form during hypoxia and that depletion of SYTL5 and RAB27A reduces mitophagy under hypoxia mimicking conditions, indicating a role for these proteins in mitophagy. Indeed, we find that SYTL5 interacts with proteins involved in vesicle-mediated transport and cellular response to stress and that its depletion compromises mitochondrial respiration and increases glucose uptake. Intriguingly, SYTL5 expression is significantly reduced in tumours of the adrenal gland and correlates positively with survival for patients with adrenocortical carcinoma.
Introduction: In the era of personalized cancer therapy, antibody-drug conjugates (ADCs) have become one of the fastest-emerging groups of anticancer drugs. ADCs consist of an antibody coupled to a cytotoxic payload by a chemical linker, designed to be cleaved off intracellularly. Understanding the intracellular trafficking and processing of ADCs is crucial for elucidating their mechanism of action. Objective: This study aimed to compare trastuzumab deruxtecan (T-DXd) to ado-trastuzumab emtansine (T-DM1) with emphasis on Rab GTPase-regulated intracellular trafficking and its impact on ADC efficacy. Methods: The efficacy of T-DXd and T-DM1 was assessed in a panel of HER2-positive cell lines. Correlations between ADC efficacy and the expression of HER2 and Rab GTPases were evaluated. Functional studies, including knockdown (KD), overexpression, and microscopy, were performed to evaluate the impact of Rab GTPases on ADC cytotoxicity. Results: In contrast to T-DM1, T-DXd efficacy was found not to correlate to HER2 expression in a panel of HER2-positive cell lines. However, a correlation to RAB5A expression was found for T-DXd efficacy, although not as strong as for T-DM1. Altering the expression of RAB5 in our model system confirmed RAB5 to have an impact on both T-DXd and T-DM1 cytotoxicity, but more on T-DM1. In addition, RAB4a was found to influence T-DXd sensitivity, but not T-DM1, indicating differences in intracellular processing between T-DXd and T-DM1. Conclusion: The study demonstrates that ADC design significantly influences intracellular trafficking and processing. The linker design, in particular, plays a major role in determining the intracellular fate of an ADC.
Protein tyrosine kinase 7 (PTK7), a receptor found in tumor-initiating cells, is expressed in various malignancies, including ovarian cancer. Whereas PTK7 has been explored as a target for antibody–drug conjugates, this study is the first to investigate its potential for targeted radionuclide therapy. We developed a murine monoclonal IgG1 antibody (mOI-1) using hybridoma technology and generated a chimeric version (chOI-1) with human IgG1 constant regions. A cell-based screening approach using a library of 6,100 cell surface proteins identified PTK7 as the target, confirmed by flow cytometry and surface plasmon resonance analyses. IHC showed strong PTK7 expression in ovarian cancer tissues, and in vitro studies demonstrated specific binding and internalization of OI-1 in the ovarian cancer cell line SKOV-3-luc. Biodistribution studies using 177Lu–DOTA–mOI-1 injected intravenously in xenograft mice with subcutaneous SKOV-3-luc revealed high tumor uptake and retention. Therapeutic efficacy was assessed by intraperitoneal treatment with 212Pb–TCMC–chOI-1 in an intraperitoneal xenograft model, showing significant tumor growth inhibition compared with nonradioactive controls. This study provides the first investigation of a PTK7-targeting antibody (OI-1) as an antibody–radionuclide conjugate (212Pb–labeled) in a preclinical model of intraperitoneal ovarian cancer. These results support further investigation of OI-1 as a candidate for targeted radionuclide therapy in PTK7-expressing cancers.
Pluripotent stem cells provide opportunities for treating injuries and previously incurable diseases. A major concern is the immunogenicity of stem cells and their progeny. Here, we have dissected the molecular mechanisms that allow natural killer (NK) cells to respond to human pluripotent stem cells, investigating a wide selection of activating and inhibitory NK-cell receptors and their ligands. Reporter cells expressing the activating receptor NKG2D responded strongly to embryonic stem (ES) cell lines and induced pluripotent stem (iPS) cell lines, whereas reporter cells expressing the activating receptors NKp30, NKp46, KIR2DS1, KIR2DS2, and KIR2DS4 did not respond. Human ES and iPS cells invariably expressed several ligands for NKG2D. Expression of HLA-C and HLA-E was lacking or low, insufficient to trigger reporter cells expressing the inhibitory receptors KIR2DL1, -2DL2, or -2DL3. Similar results were obtained for the pluripotent embryonic carcinoma cell lines NTERA-2 and 2102Ep, and also iPS-cell-derived neural progenitor cells. Importantly, neural progenitor cells and iPS-cell-derived motoneurons also expressed B7H6, the ligand for the activating receptor NKp30. In line with these observations, IL-2-stimulated NK cells showed robust cytotoxic responses to ES and iPS cells as well as to iPS-cell-derived motoneurons. No significant differences in cytotoxicity levels were observed between KIR/HLA matched and mismatched combinations of NK cells and pluripotent targets. Together, these data indicate that pluripotent stem cells and their neural progeny are targets for NK-cell killing both by failing to sufficiently express ligands for inhibitory receptors and by expression of ligands for activating receptors.
Introduction: Liver sinusoidal endothelial cells (LSEC) are specialized endothelial cells with unique metabolic and barrier functions adapted to the needs of the liver sinusoid. LSECs are highly sensitive to their environment, and this fragile nature causes challenges in analyzing their phenotype under in vitro conditions. Methods: In this work, we first differentiated LSEC-like cells (scLSECs) from two human pluripotent stem cell lines and characterized them by a panel of qPCR markers, immunohistochemistry, substrate oxidation for energy metabolism, scavenger function, and nitric oxide secretion. We then introduced holotomography, a technique that allows to recover quantitative and three-dimensional information about the refractive indexes of cell components, as a tool to image and track scLSEC in vitro in a minimally intrusive, label-free manner. Results and discussion: Holotomography and developed machine learning-based algorithm for image processing allowed us to describe and monitor changes in intracellular pore-like structures over time. Finally, we tested the possibility of inducing aspects of zone-specific LSEC phenotype and metabolism using culture-based treatments, which resulted in modest shifts in marker expression and metabolic activity. The presented strategy provides an advanced tool kit for investigating liver endothelial cells.
Obesity is increasingly prevalent among older adults and is a major contributor to cardiometabolic diseases, functional decline, frailty, and loss of independence. The intersection between population ageing and the obesity epidemic poses major public health and clinical challenges. This European Association for the Study of Obesity (EASO) position statement represents an update of the EASO guideline from 2012, and provides a comprehensive overview of the epidemiology, pathophysiology, clinical consequences, and management of obesity in adults aged ≥65 years. It summarizes current evidence and offers practical recommendations for diagnosis and treatment tailored to this age group. To guide clinicians and researchers through this updated framework, the position statement highlights four central concepts that underpin obesity assessment and management in later life: (1) obesity affects up to one-third of older adults globally, with prevalence varying by sex and geography; (2) ageing is associated with changes in body composition, hormonal milieu, and lifestyle factors (diet, physical inactivity, and polypharmacy) that favour fat accumulation and sarcopenic obesity; (3) body mass index alone is insufficient; assessment should include body composition analysis (including fat distribution and muscle mass), psychological status, and functional performance; (4) a multimodal approach is recommended, including moderate energy restriction with adequate protein intake, structured multicomponent exercise, behavioural support, and, where appropriate, obesity management medications and/or metabolic bariatric surgery. The focus should be on preserving muscle mass, functional capacity, and quality of life, rather than weight loss alone. Effective management of obesity in older adults should focus on individualized, multidisciplinary strategies that balance the benefits of weight reduction against the risks of sarcopenia, malnutrition, and loss of independence.
Background: Falls are the leading cause of traumatic brain injury (TBI) in high-income countries, and globally, the incidence of fall-reBackground: Falls are the leading cause of traumatic brain injury (TBI) in high-income countries, and globally, the incidence of fall-related injuries is projected to rise. In this study, we compare TBI resulting from stair-related falls (SRFs) to falls from standing height (FSH), analyzing their epidemiology and outcomes. Methods: In a single-center, registry-based cohort study using the Oslo TBI Registry-Neurosurgery (OTBIR-N), we identified adults (≥18 years) admitted to Oslo University Hospital with TBI from either SRFs or FSH between 2015 and 2022. Epidemiology and outcome measures were compared between the two groups, and a multivariate logistic regression model was used to evaluate the adjusted effect of the fall mechanisms on dichotomized functional outcome (Glasgow outcome score (GOS) 1–3 vs. GOS 4–5). Results: A total of 1,432 patients with a median age of 71 years were included. SRFs represented 25%, while FSH represented 52% of all fall-related TBIs. SRF patients were generally younger and healthier, with a higher frequency of moderate to severe TBI than FSH patients (53% vs. 31%; p < 0.001). SRFs also occurred more often during evenings and nights, on weekends, and were more often related to alcohol influence (58% vs. 22%; p < 0.001). Both fall types resulted in unfavorable functional outcomes (GOS 1–3) for a substantial proportion of patients (37% in SRFs and 42% in FSH; p = 0.066). When adjusting for covariates in the multivariable logistic regression model, there was a tendency of SRFs being associated with unfavorable outcomes compared to FSH, but the effect was not statistically significant (OR 1.43, 95%CI 0.97–2.12; p = 0.073). Conclusion: SRFs represented a considerable proportion of fall-related TBIs and were associated with poor outcomes in a substantial proportion of patients. Targeted public awareness campaigns addressing the risks associated with staircases, especially when combined with alcohol influence, seem warranted to prevent such injuries.
Aims We studied the health consequences of quitting smoking before age 43 by time since quitting, number of years smoked and cigarettes smoked per day. The outcomes were all-cause, ischaemic heart disease and lung cancer mortality. Design Prospective study. Setting Norwegian counties. Participants Men and women aged 40–43 years who participated in a national cardiovascular screening programme and who were followed from 1985 to 2018. Measurements Self-reports from questionnaire on time since quitting smoking, years smoked and number of cigarettes per day, and measurements of height, weight and blood pressure, and a blood sample where serum was analysed for total serum cholesterol and triglycerides. Findings The all-cause mortality rate was 30% higher among quitters less than 1 year ago compared with never smokers (adjusted HR=1.30, 95% CI 1.18–1.43 in men and HR=1.31, 95% CI 1.16 to 1.50 in women). Quitters who had smoked longer than 20 years had 23% higher mortality in men (HR=1.23, 95% CI 1.14 to 1.34) and 32% higher mortality in women (HR=1.32, 95% CI 1.18 to 1.49). Past smoking of more than 20 cigarettes/day was associated with HR=1.14 (1.05–1.23) in men and HR=1.16 (1.01–1.32) in women. The HR for lung cancer was 6.77 (95% CI 4.86 to 9.45) for quitting men who had smoked for more than 20 years compared with never smokers. The corresponding figure for women was 5.75 (95% CI 4.08 to 8.09). Conclusions The mortality among quitters was close to that of never smokers, except for a higher mortality for lung cancer, which on the other hand was much lower than the lung cancer mortality in current smokers.
Background Bladder cancer remains a significant global health challenge, with approximately 75% of cases presenting as non-muscle-invasive bladder cancer. Despite standard treatment with transurethral resection and intravesical Bacillus Calmette-Guérin immunotherapy, up to 40% of patients develop resistance or progress to muscle-invasive disease. Targeted alpha-emitting radionuclide therapy offers promising therapeutic potential through the selective delivery of high linear energy transfer radiation to tumor cells while minimizing damage to healthy tissues. PTK7 is overexpressed in various malignancies, including bladder cancer, and is therefore a viable therapeutic target. This study evaluated the preclinical efficacy of [212Pb]Pb-TCMC-chOI-1, a 212Pb-labeled antibody targeting PTK7, for targeted alpha-emitting radionuclide therapy in bladder cancer using 2D adherent cultures (clonogenic assay) and 3D multicellular spheroid models (spheroid growth inhibition). Results PTK7 expression analysis revealed varying antigen densities across five bladder cancer cell lines, ranging from approximately 10,000 to 70,000 sites per cell. The chimeric anti-PTK7 antibody demonstrated apparent equilibrium dissociation constants of 10–44 nM with moderate binding affinity suitable for therapeutic applications. [212Pb]Pb-TCMC-chOI-1 treatment resulted in activity- and time-dependent cytotoxicity, with enhanced sensitivity observed in cell lines with higher PTK7 levels. In clonogenic assays, the activity concentration required for 50% growth reduction was 48–74 kBq/mL, corresponding to 22–51 bound and 9–16 internalized 212Pb atoms per cell. In 3D models, similar therapeutic effects were observed despite significantly lower activities (values of approximately 1 and 30 kBq/mL for KU-19–19 and 647-V cells, respectively), suggesting a more pronounced cross-fire effect. Flow cytometry demonstrated treatment-induced DNA damage, cell cycle perturbations and cell death, with response patterns correlating with overall treatment sensitivity. RT-112 and KU-19–19 cells showed superior responses compared to 647-V and T-24 cells, consistent with their higher PTK7 expression. Conclusions These findings support PTK7 as a therapeutic target for bladder cancer and demonstrate the potential of [212Pb]Pb-TCMC-chOI-1 for targeted alpha-emitting radionuclide therapy. The results provide a rationale for further preclinical optimization of this therapeutic approach.
Background Chemotherapy is an integral part of the clinical management of triple negative breast cancer (TNBC), however, development of chemoresistance occurs frequently. Tumor sensitivity to treatment is known to be strongly influenced by the immune microenvironment, signifying the predictive potential of immune alterations. How tumor cells that acquire resistance may subsequently modulate the immune microenvironment it is still not well described. Here, we investigated immunomodulation in the context of acquired chemoresistance in TNBC, focusing on the role of the secretome. Methods Bulk RNA sequencing and multiplex cytokine profiling were performed on paclitaxel-resistant and -sensitive isogenic variants of TNBC cells to reveal resistance-associated secretome alterations. The immunomodulatory influence of the tumor cell secretome was investigated by exploring its effect on monocytes, macrophages (MΦs) and T cells derived from healthy blood donors. The influence on the immune cell phenotype and activity was evaluated by measuring molecular markers and performing functional assays. To validate the clinical relevance, we utilized longitudinal -omics data from breast cancer patients refractory to standard chemotherapy in the NeoAva clinical trial. CIBERSORT was applied to transcriptomics data to infer MΦ and T cell abundance in individual tumors upon treatment. To evaluate their association with the secretome profiles, patient-matched serum cytokine data were used. Results The acquisition of chemoresistance was accompanied by enhanced secretion of cytokines. Subsequently, the resistant cell secretome affected the abundance, phenotype and activity of immune cells. Specifically, it potentiated the recruitment of monocytes, facilitated the polarization of MΦs towards the immunosuppressive M2-like phenotype, and attenuated the activation of CD8+ T cells. Data from the NeoAva clinical cohort validated the enrichment of M2 MΦs and/or the depletion of M1 MΦs after treatment in the majority of residual tumors. The MΦ-associated changes counteracted CD8+ T cell abundance and were partially associated with the cytokine-enriched secretome. Conclusion Development of chemoresistance in BC is associated with alterations in the tumor secretome, which impairs immune activation and facilitates immunosuppression. Knowledge on the immune microenvironment in residual tumors after standard chemotherapy could aid in selecting rational treatment options for this group of patients
Abstract Cancer metastasis to sentinel lymph nodes (LNs) is often the first marker of potential disease progression. Although it is recognized that tumor-induced lymphangiogenesis facilitates metastasis into LNs in murine models, tumor-induced alterations in human lymphatic vessels remain obscure. Here we use single-cell RNA sequencing and high-resolution spatial transcriptomics to profile lymphatic endothelial cell (LEC) subsets in paired metastatic and non-metastatic LNs obtained from female patients with treatment-naïve breast cancer. Tumor metastasis decreases immunoregulatory LEC subsets, such as PD-L1 + subcapsular sinus LECs, while inducing an increase in capillary-like CD200 + HEY1 + LECs. Matrix Gla protein (MGP) is the most upregulated gene in metastatic LN LECs, and its expression on LECs is TGF-β and VEGF dependent. Upregulated MGP promotes cancer cell adhesion to LN lymphatics. Thus, breast cancer cell metastasis to LNs remodels LEC subsets in human LNs and escalates MGP expression, potentially facilitating cancer cell dissemination through the lymphatic system.
Adenylosuccinate lyase deficiency (ADSLd) is a rare autosomal recessive purine metabolism disorder with several clinical manifestations. While toxic substrate accumulation is a known hallmark, no additional molecular mechanisms have been established. Here, we show that ADSLd is associated with mitochondrial dysfunction, including increased fragmentation, impaired respiration, and reduced ATP production. The severity of mitochondrial impairment correlates with ADSLd pathology, especially in mitochondria-dependent tissues. We also identify defects in mitochondrial dynamics and transport linked to ERK2 and AKT suppression. Notably, overexpressing constitutively active ERK2 or supplementing purine intermediates partially rescues the mitochondrial phenotype. These findings suggest an alternative disease mechanism and highlight mitochondrial metabolism as a potential therapeutic target in ADSLd.
Combination therapies are one potential approach to improve the outcomes of patients with relapsed/refractory (R/R) disease. However, comprehensive testing in scarce primary patient material is hampered by the many drug combination possibilities. Furthermore, inter- and intrapatient heterogeneity necessitates personalized treatment optimization approaches that effectively exploit patient-specific vulnerabilities to selectively target both the disease- and resistance-driving cell populations. In this study, we developed a systematic combinatorial design strategy that uses machine learning to prioritize the most promising drug combinations for patients with R/R acute myeloid leukemia (AML). The predictive approach leveraged single-cell transcriptomics and single-agent response profiles measured in primary patient samples to identify targeted combinations that coinhibit treatment-resistant cancer cells individually in each sample of patients with AML. Cell type compositions evolved dynamically between the diagnostic and R/R stages uniquely in each patient, hence requiring personalized drug combination strategies to target therapy-resistant cancer cells. Cell population–specific drug combination assays demonstrated how patient-specific and disease stage–tailored combination predictions led to treatments with synergy and strong potency in R/R AML cells, whereas the same combinations elicited nonsynergistic effects in the diagnostic stage and minimal coinhibitory effects on normal cells. In preliminary experiments on clinical trial samples, the approach predicted clinical outcomes of venetoclax–azacitidine combination therapy in patients with AML. Overall, the computational–experimental approach provides a rational means to identify personalized combinatorial regimens for individual patients with AML with R/R disease that target treatment-resistant leukemic cells, thereby increasing their likelihood of clinical translation. Significance: A predictive model identifies patient-tailored combinations that coinhibit multiple drivers to selectively and synergistically target leukemia cells, which could reduce therapy resistance and enhance treatment outcomes in patients with advanced disease. This article is part of a special series: Driving Cancer Discoveries with Computational Research, Data Science, and Machine Learning/AI.
Reliable and reproducible drug screening experiments are essential for drug discovery and personalized medicine. We demonstrate how systematic experimental errors in drug plates negatively impact data reproducibility, and that conventional quality control (QC) methods based on plate controls fail to detect these spatial errors. To address this limitation, we developed a control-independent QC approach that uses normalized residual fit error (NRFE) to identify systematic artifacts in drug screening experiments. Analysis of >100,000 duplicate measurements from the PRISM pharmacogenomic study revealed that NRFE-flagged experiments show 3-fold lower reproducibility among technical replicates. By integrating NRFE with QC methods to analyze 41,762 matched drug-cell line pairs between two datasets from the Genomics of Drug Sensitivity in Cancer project, we improved the cross-dataset correlation from 0.66 to 0.76. Available as an R package at https://github.com/IanevskiAleksandr/plateQC, plateQC provides a robust toolset for enhancing drug screening data reliability and consistency for basic research and translational applications.
A novel mixture cure frailty model is introduced for handling censored survival data. Mixture cure models are preferable when the existence of a cured fraction among patients can be assumed. However, such models are heavily underexplored: frailty structures within cure models remain largely undeveloped, and furthermore, most existing methods do not work for high-dimensional datasets, when the number of predictors is significantly larger than the number of observations. In this study, we introduce a novel extension of the Weibull mixture cure model that incorporates a frailty component, employed to model an underlying latent population heterogeneity with respect to the outcome risk. Additionally, high-dimensional covariates are integrated into both the cure rate and survival part of the model, providing a comprehensive approach to employ the model in the context of high-dimensional omics data. We also perform variable selection via an adaptive elastic-net penalization, and propose a novel approach to inference using the expectation–maximization (EM) algorithm. Extensive simulation studies are conducted across various scenarios to demonstrate the performance of the model, and results indicate that our proposed method outperforms competitor models. We apply the novel approach to analyze RNAseq gene expression data from bulk breast cancer patients included in The Cancer Genome Atlas (TCGA) database. A set of prognostic biomarkers is then derived from selected genes, and subsequently validated via both functional enrichment analysis and comparison to the existing biological literature. Finally, a prognostic risk score index based on the identified biomarkers is proposed and validated by exploring the patients’ survival.
Unhealthy diets are common among individuals with opioid dependence. While fruit- and vegetable-rich diets have shown mental health benefits, evidence is limited for those receiving opioid agonist therapy (OAT). This trial evaluated the effectiveness of fruit smoothie supplementation for people receiving OAT compared to standard treatment without fruit smoothie supplementation. In this multicenter randomized controlled trial (FruktBAR), 311 participants receiving OAT were randomized (5:3 intervention:control) to receive either a daily 250 ml fruit smoothie for 16 weeks in addition to standard OAT or standard OAT alone. The primary outcome was the difference between the arms in changes in psychological distress, measured by the ten-item Hopkins Symptom Checklist (SCL-10%) from baseline to the end of the intervention. The secondary outcomes included changes in fatigue symptoms, measured using the three-item Fatigue Severity Scale, physical fitness, measured by a 4-min step test, carotenoid and folate biomarkers. At baseline, 131 participants (70%) in the intervention arm and 91 (73%) in the control arm had a low intake of fruits and vegetables. In the intervention arm, the mean SCL-10% score at baseline was 43.9% (95% confidence interval (CI): 40.4, 47.4), which was reduced to 41.6% (CI: 38.0, 5.1) at the end of the trial. In the control arm, the mean SCL-10% score was 43.6% at baseline (CI: 39.3, 48.0) and decreased to 41.5% (CI: 37.1, 45.8) at the end of the trial period. No significant difference in the change of psychological distress between the intervention and control arms was found (− 0.14%; CI: − 4.49, 2.22). Additionally, no changes were found between the intervention and control arms regarding fatigue symptoms, physical fitness, carotenoid, or folate biomarkers. The mean consumed fruit smoothies reported in the intervention arm was 3.9 bottles per week (SD 1.5). Fruit smoothie supplementation over a 16-week period did not impact psychological distress, fatigue, physical fitness, carotenoids, or folate biomarkers among people receiving OAT. Although the smoothies were successfully delivered to the participants, our data indicates suboptimal adherence to the intervention rather than the lack of efficacy. ClinicalTrials.gov NCT05229770. Registered on 08 February 2022.
Inflammatory bowel diseases (IBDs), including Crohn’s disease and ulcerative colitis (UC), are characterized by chronic gastrointestinal inflammation and involve complex interactions of genetic, environmental, and immune factors. Enterococcus faecalis, a gut commensal bacterium, has been implicated in IBD pathogenesis. This study investigated the effects of monocolonization with a UC-derived E. faecalis strain on acute dextran sulfate sodium (DSS)-induced colitis in germ-free (GF) mice, focusing on epithelial injury, inflammatory markers, hematologic indices, and bacterial translocation. In DSS-treated mice, monocolonization was associated with modest and mixed effects, including a higher colitis-related disease activity score, reduced anemia, increased fecal albumin and a trend towards reduced fecal calprotectin. Despite translocation of E. faecalis to mesenteric lymph nodes, no systemic dissemination was observed. Histological analysis revealed broadly similar inflammatory patterns between DSS-treated groups, with slightly more epithelial injury observed in colonized mice. These findings suggest that E. faecalis may influence discrete aspects of DSS injury in a strain-dependent and context-specific manner, rather than broadly altering overall disease severity. This study highlights the utility of GF models for examining strain-specific host–microbe interactions and underscores that individual bacterial isolates may exert heterogeneous and selective effects on acute colitis. Further research is needed to elucidate these complex mechanisms.
Purpose: A long-term evaluation of The Caregiver Pathway, a model to follow up family caregivers on Post-intensive Care Symptoms among Family (PICS-F). Methods: A single-center non-blinded randomized controlled trial including 196 family caregivers to critically ill patients randomized to intervention (n = 101) or control group (n = 95). The Caregiver Pathway intervention consists of: (1) a digital assessment followed by a conversation with a nurse in the first days at the ICU, (2) a supportive card when leaving the ICU, (3) an offer to receive a phone call following patient transfer to a step-down unit, and (4) a followup conversation within 3 months after discharge. Outcome measures were collected at 6 and 12 months, including symptoms of post-traumatic stress disorder (PTSD), anxiety, depression, Health-related Quality of Life (HRQoL), hope,and self-efficacy. Results: The Caregiver Pathway was associated with a significant effect for symptoms of PTSD after 6 months compared with controls, mean IES-R score: 25.8 [95% CI 21.9–29.7] versus 30.9 [95% CI 26.7–35.0], p = 0.009, and a trend toward an effect after 12 months: IES-R score: 25.0 [95% CI 21.3–28.7] versus 28.4 [95% CI 24.1–32.7], p = 0.057. Subgroup analyses at 12 months showed a significant intervention effect among family caregivers of patients who survived compared to controls for PTSD, IES-R score: 19.8 [95% CI 15.3–24.2] versus 29.1 [95% CI 23.5–34.6], p = 0.001, and anxiety, HADS-A score: 4.3 [95% CI 3.1–5.4] versus 6.8 [95% CI 5.2–8.4], p = 0.003. Conclusions: The Caregiver Pathway has the potential to reduce the symptoms of PICS-F, especially among family caregivers whose patient has survived.
Background and Aims: Primary sclerosing cholangitis (PSC) is a chronic inflammatory bile duct disorder of unknown etiology characterized by uneven peribiliary infiltration and liver fibrosis. To localize potential disease pathways to specific microanatomical liver regions, we combined spatial and single-nuclei transcriptomics (snRNA-seq) to analyze biopsies from a spectrum of PSC and disease control explants. Approach and Results: Liver specimens from 23 PSC (transplant indications: 4 recurrent cholangitis, 7 dysplasia, 12 cirrhosis) and 7 disease controls with cirrhosis (4 metabolic dysfunction–associated steatohepatitis, MASH; 3 alcohol-associated liver disease, ALD) were analyzed by spatial transcriptomics (76,664 spots) and 16 of the same explants were also assessed by snRNA-seq (12 PSC, 2 MASH, 2 ALD; 91,891 nuclei). PSC livers expressed a robust signature of metallothionein (MT1E, MT1G, MT1H) and acute inflammation markers (SAA1, SAA2) at the parenchyma–fibrosis interface compared to disease controls. SnRNA-seq showed that the strongest metallothionein signal originated from a subtype of APOE+ hepatocytes that, by spatial transcriptomics and immunohistochemistry, were consistently localized to the edge of fibrotic lesions in PSC explants. Biliary inflammation induced by 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) feeding in mice resulted in significant Mt1 liver expression and liver MT1G expression correlated with AST, ALT, ALP, and bilirubin levels at the time of liver transplantation. Conclusions: Combinatorial spatial and high-resolution single-nuclei transcriptomics on the largest number of PSC liver explants to date revealed metallothionein as a novel PSC pathway that could be interrogated in future studies aiming to develop effective therapeutic interventions for PSC.
Aims Available data on economic consequences of carrying an inherited familial hypercholesterolaemia (FH) genetic variant are sparse. This study aims to explore the hospital and pharmaceutical resource use and costs associated with cardiovascular disease (CVD) in patients with genetically verified FH compared with age- and sex-matched controls during the period 2010 through 2019. Methods and results We included 5585 individuals with genetically verified FH from the Norwegian Unit for Cardiac and Cardiovascular Genetics registry and 111 483 age- and sex-matched controls from the general Norwegian population. Resource use and costs associated with CVD were collected from the Norwegian Patient Registry, the Cause of Death Registry, and the Norwegian Prescription Database. We estimated costs in European euros (EUR, €) based on diagnosis-related group (DRG) cost weights and pharmaceutical drug prices (Norwegian kroner 1 = EUR 0.1015). During 2010–19, patients with FH had CVD-related costs of €3911 per person for hospital care and €6119 for pharmaceuticals compared with €1498 and €514 among controls, respectively. The 10-year costs per person of percutaneous coronary interventions were €561 for FH and €140 for controls. The costs of CVD prescription drugs doubled in the FH population during 2010–19, largely due to the introduction of proprotein convertase subtilisin/kexin Type 9 inhibitors. Costs for prescription drugs increased in both the FH and control populations (P = 0.002 for FH and P = 0.005 for controls), while costs decreased for hospital care (P = 0. 0069 for FH and P = 0. 0943 for controls). Conclusion Familial hypercholesterolaemia patients had about three times higher CVD-related hospital costs and more than 10 times higher pharmaceutical costs than age- and sex-matched controls during a 10-year follow-up. During the 10 years, costs for pharmaceuticals increased and costs for hospital decreased.
In the rapidly advancing landscape of drug discovery and repurposing, efficient access and integration of chemical and bioactivity data from public repositories have become essential. To address this need, we developed two complementary annotation pipelines (KNIME- and Python-based) that automate the extraction and integration of curated chemical and bioactivity data from public repositories. These pipelines support any user-provided compound library, enabling reproducible workflows that integrate data from heterogeneous sources such as ChEMBL and PubChem. As part of the REMEDi4ALL project, with the aim of establishing a European platform for drug repurposing, we validated our framework using a harmonized subset of the Specs repurposing collection, which includes >5000 compounds available at the partner institutes. We also developed two interactive dashboards that support multilayered analyses and visualization by integrating chemical properties, bioactivity profiles, and relational data. Our results demonstrate that this framework streamlines the collection of harmonized data and facilitates analyses that are critical for drug repurposing efforts, while remaining versatile for broader applications in drug discovery. Moreover, the analysis of the annotations reveals that the Specs subset includes chemical scaffolds representative of a significant portion of approved drugs and compounds undergoing clinical evaluation, underscoring its potential as a rich source of drug repurposing candidates. Both pipeline protocols are publicly available online, and the dashboards are open access.
While large language models (LLMs) are typically evaluated on accuracy metrics alone, real-world deployment requires careful control of computational efficiency. Building on the CogniLoad benchmark, we introduce a unified efficiency metric (i.e., correct answers per 1'000 output tokens) enabling direct cross‑model comparison. We further provide an interpretable factorization into context robustness, logic robustness, and token appetite. Evaluating 15 state‑of‑the‑art reasoning LLMs on CogniLoad, we find that some models fail due to logic errors, others consume excessive tokens, and a few hit context limits. Tokens are an imperfect but practical proxy for computation load, permitting consistent comparisons across closed and open models. By decomposing overall efficiency into actionable components, our framework identifies concrete targets for improving LLM reasoning efficiency.
Testing for Childhood Cancer Predisposition (ChiCaP) syndromes is increasingly common in pediatric oncology as early identification can help adapt treatment and initiate surveillance. As such, ChiCaP testing can have medical, ethical, and psychological consequences for both the patients and their families, and present significant diagnostic challenges for pediatric oncologists. In response to these new opportunities and challenges, the Nordic ChiCaP Network was established in 2021, bringing together experts from pediatric and adult oncology, clinical genetics, molecular genetics, bioinformatics, epidemiology, psychology, anthropology, community medicine, law and ethics. Its primary goal is to advance our knowledge of ChiCaP in pediatric oncology research and care through an interdisciplinary approach. The network aims to achieve several key objectives: (1) to improve ChiCaP diagnostics, including gene-associated phenotypes and variant interpretation; (2) to advance understanding of the natural history, cancer risks, adverse treatment reactions, and comorbidities associated with ChiCaP syndromes; (3) to optimize and harmonize treatment protocols and surveillance strategies for affected patients and their families; (4) to address the ethical, legal and psychosocial aspects involved in testing, communication and counseling, diagnosing ChiCaP syndromes, and the impacts of surveillance on patients and their families; (5) to identify novel ChiCaP syndromes and explore their underlying mechanisms; and (6) to facilitate translation of research findings into clinical practice. By gathering interdisciplinary expertise and fostering collaboration across the Nordic countries, the Nordic ChiCaP Network will enhance knowledge and awareness of ChiCaP, improve early diagnosis, patient care, family support, and contribute to a better understanding of these complex genetic conditions.
Background This study investigates health-related quality of life (HRQoL) in individuals with opioid use disorder enrolled in heroin-assisted treatment (HAT). While HRQoL in opioid maintenance treatment has been studied, less is known while in HAT. This study aim is to describe HRQoL in HAT, identify different HRQoL trajectories, and examine factors associated with class memberships. Methods This longitudinal cohort study is based on the multi-center Norwegian HAT project. The sample includes all consenting individuals enrolled in treatment from January 2022 to October 2024 (n = 108). HRQoL was assessed using the EuroQol EQ-5D-5L, and demographics were collected at baseline and multiple time points. Latent class linear mixed models were employed to identify HRQoL trajectory classes and explore differences in class memberships. Results At admission, participants demonstrated significant HRQoL difficulties across all dimensions, with severity levels higher than those of the general Norwegian population, particularly in Pain/Discomfort and Anxiety/Depression. Latent class analysis identified three distinct groups: the largest group (82 %) had a stable HRQoL trajectory, while smaller groups (8 % and 10 %) showed decline and improvement, respectively. Social support, clinic location, parental origin and at least one chronic symptoms were significant predictors of class membership. Conclusion The diverse, lower HRQoL profiles emphasize the need for personalized healthcare and support, making the HAT setting potentially valuable for such tailored care. Treatment participation helps most maintain fairly high HRQoL. The findings confirm the critical role of supportive relationships and effective chronic condition management in HRQoL outcomes.
Background: Children with intestinal failure (IF) experience a high burden of illness, characterized by persistent gastrointestinal (GI) symptoms, irregular stool patterns, and reduced health-related quality of life (HRQOL). This study explored the impact of prebiotic supplementation on GI symptoms and HRQOL. Methods: An open-label randomized controlled trial with two phases. In Phase 1, children aged 1–18 years with IF received supplementation with a prebiotic blend for four weeks. In Phase 2, participants were randomized to either continue supplementation (intervention group) or cease supplementation (control group) for six months to evaluate long-term effects. Primary endpoints were GI symptoms and HRQOL, evaluated using PedsQL™ scales. Secondary endpoints included stool consistency and frequency, nutritional support, and antibiotic use. A paired t-test assessed short-term effect, while ANCOVA tested long-term differences. Results: Forty-seven children completed Phase 1. Of the 33 reporting on GI symptoms, 20 (60%) improved after short-term prebiotic supplementation. In Phase 2, 43 were randomized to intervention group (n=24) or control group (n=19). The intervention group exhibited significant improvements in GI symptoms compared to controls (mean difference 6.9, p=0.01). Furthermore, stool frequency decreased (median -1.0 vs. 0 stools/day, p=0.003) more in the intervention group, and stool consistency normalized more often (42% vs. 6%, p=0.02). No significant differences were observed in HRQOL scores, nutritional support, or antibiotic use. Conclusions: Although HRQOL did not improve, both short- and long-term prebiotic supplementation significantly improved GI symptoms, stool frequency, and stool consistency in children with IF, suggesting its potential as a therapeutic option in pediatric IF.
Abstract Solution-based interrogation of the physical nature of nucleosomes has its roots in X-ray and neutron scattering experiments, including those that provided the initial observation that DNA wraps around core histones. In this study, we performed a comprehensive small-angle scattering study to compare canonical nucleosomes with variant centromeric nucleosomes harboring the histone variant, CENP-A. We used nucleosome core particles (NCPs) assembled on an artificial positioning sequence (Widom 601) and compared these to those assembled on a natural α-satellite DNA from human centromeres. We establish the native solution properties of octameric H3 and CENP-A NCPs using analytical ultracentrifugation (AUC), small-angle X-ray scattering (SAXS), and contrast variation small-angle neutron scattering (CV-SANS). Using high-pressure SAXS (HP-SAXS), we discovered that both histone and DNA sequence have an impact on the stability of octameric nucleosomes in solution under high pressure (300 MPa), with evidence of reversible unwrapping in these experimental conditions. Both canonical nucleosomes harboring conventional histone H3 and their centromeric counterparts harboring CENP-A have a substantial increase in their radius of gyration, but this increase is much less prominent for centromeric nucleosomes. More broadly for chromosome-related research, we note that as HP-SAXS methodologies expand in their utility, we anticipate this will provide a powerful solution-based approach to study nucleosomes and higher-order chromatin complexes.
Abstract The histone-fold domain (HFD) is a conserved protein interaction module that requires stabilization through a handshake interaction with an HFD partner. All HFD proteins known to date form obligate dimers to shield the extensive hydrophobic residues along the HFD. Here, we find that the lepidopteran kinetochore protein CENP-T is soluble as a monomer. We attribute this stability to a structural rearrangement, which leads to the repositioning of the HFD helix α3. This brings a conserved two-helical extension closer to the histone fold, where it takes over the position and function of the CENP-T partner CENP-W. This change has no effect on the DNA-binding ability of the lepidopteran CENP-T. Our analysis suggests that the monomeric HFD originated in the last common ancestor of insects, with a possible second independent origin in Acariformes, both of which lack CENP-W. Our study highlights an unexpected structural variation in a protein module as conserved and optimized as the HFD, providing a unique perspective on the evolution of protein structure and the forces driving it.
Lactate plays an important role in brain energy metabolism. It contributes to normal brain development and to neuroprotection in diabetic hypoglycemia, but its role in neonatal hypoglycemia is unclear. Moreover, lactate can work as a signaling substance via the lactate receptor HCAR1 (Hydroxycarboxylic acid receptor 1). Recent studies indicate that HCAR1 is protective in mouse models of neonatal hypoxic ischemia and has a role in metabolic regulation in glial cells during hypoglycemia. Here we have studied potential impacts of HCAR1 on axonal and myelin development in the cerebral cortex and corpus callosum of young (P21) wild-type (WT) mice and HCAR1 KO mice and in cortical organotypic brain slice cultures. The HCAR1 KO mice showed lower axonal area relative to WT in both cortex and corpus callosum. However, the myelin area was unaffected by HCAR1 KO. Using particle and colocalization analysis, we show that HCAR1 KO predominantly reduces axonal size in unmyelinated axons. Using an organotypic brain slice model of neonatal hypoglycemia, we find that lactate protects both axonal and myelin development in hypoglycemia, partially via HCAR1. Lastly, live imaging with a pH-sensitive dye on acute cortical brain slices indicates that cellular lactate uptake is influenced by HCAR1. In conclusion, our findings support a role of HCAR1 in axonal development and in lactate’s protective effects in hypoglycemia.
Objective Insomnia afflicts about half of outpatients with coronary heart disease (CHD) and worsens prognosis. We aimed to simulate the potential socioeconomic savings of integrating group cognitive–behavioural therapy for insomnia (gCBT-I) into cardiac outpatient care for patients with CHD compared with usual care. Design Early health technology assessment using prospective and cross-sectional cohort data. Setting Secondary care for outpatients with CHD in Norway in a non-university hospital setting. Participants A hypothetical cohort of 100 outpatients with CHD and insomnia. Interventions Weekly sessions of gCBT-I over 5 weeks versus usual care. Primary and secondary outcome measures Potential savings related to possible effects on revascularisations and hospitalisations due to a recurrent CHD event, and reduced sick leave. Representative data on healthcare consumption and sick leave rates were collected from the NORwegian CORonary cohort study (n=528). Costs of productivity loss were drawn from public sources and calculated using a conservative human capital approach. Estimates of therapeutic effectiveness in conveying insomnia remission by gCBT-I were informed by results from randomised trials and meta-analyses. Results Rates of healthcare consumption and sick leave were higher in outpatients with CHD and insomnia compared with those without insomnia. Our model indicated that treating 100 patients with gCBT-I would cost €2406. If patients treated with gCBT-I show similar rates of revascularisations and hospitalisations as those without insomnia, there is a maximum potential saving of €117,221 per 100 patients tied to healthcare consumption. Similarly, the maximum potential savings related to reduced productivity loss from sick leave range from €53,244 to €692,172. Conclusion Treating insomnia among outpatients with CHD has the potential for substantial reduction of socioeconomic costs related to healthcare consumption and sick leave. Implementation into routine outpatient care seems relevant, but randomised controlled trials investigating the effects of gCBT-I in this population are warranted.
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.
The gut microbiome has gained significant interest due to its association with immune dysregulation, allergies, autoimmune conditions, metabolic disorders, and inflammation-associated malignancies. Understanding underlying mechanisms requires appropriate in vivo models, such as human microbiota-associated mouse models to study the microbiota–host interactions. This study compared the efficacy of oral and rectal administration of human faecal microbiota transplant (FMT) from a single donor in C57BL/6J germ-free mice as these methods are often used interchangeably. Using 16S rRNA sequencing, we quantified colonisation efficacy in luminal and tissue samples from orally- (n = 6) and rectally- (n = 6) colonised mice. We detected 84 genera in the FMT sample, 17 of which were not transferred at all, while additional 7 genera were found exclusively in rectally-colonised mice. A significantly higher proportion of amplicon sequence variants (ASVs) (33% vs. 26%; P < 0.05) and genera (32% vs. 25%; P < 0.05) were absent in orally- compared to rectally-colonised group. Some taxa showed different relative abundances in human vs. mouse samples (e.g. Alistipes and Bacteroides relatively more abundant in mice while Faecalibacterium considerably decreased). Beta diversity analysis revealed greater similarity between FMT and tissue samples irrespective of the administration route, with distinct separation of the tissue and luminal samples. Overall, rectal administration yielded more overlapping genera and ASVs with FMT, highlighting that it could have advantages compared with oral administration for microbiota establishment studies
Understanding the neural mechanisms of sleep is critical for advancing treatments for neurodegenerative diseases. To investigate these mechanisms, long-term electrophysiological studies are conducted in animal models, where brain activity can be monitored continuously under controlled conditions. However, electrophysiological recordings from freely moving animals are typically performed using a tethered setup, which imposes constraints on natural behaviour. As a first step towards a miniaturised, wireless neural implant, we present a low-power system that enables direct control of the Intan RHD2132 electrophysiology chip using a custom FPGA-based stack. A light-weight yet robust implementation ensures efficient operation while maintaining the necessary flexibility for future integration into a compact, wireless system. The FPGA handles real-time signal processing and data transmission, with support for closed-loop stimulation and onboard data compression. Our system achieves continuous multi-channel recording at 20 kHz, with real-time wireless streaming and long-term data storage. The hardware design prioritises low power consumption, with the aim of enabling extended operation for uninterrupted sleep monitoring over 24 hoursClinical Relevance— This technology enables long-term, high-resolution sleep monitoring, which is essential for understanding the role of sleep in neurodegenerative disorders such as Alzheimer’s and Parkinson’s. By providing continuous, naturalistic brain recordings, this system may help identify early electrophysiological biomarkers of cognitive decline, with potential translational and therapeutics applications.
Early developmental cues exert lasting influence on the adipose tissue function and the metabolic health throughout adulthood. In mice, adipose tissue remodelling during the weaning transition programs long-term tissue plasticity, setting its capacity for expansion and thermogenesis in response to environmental stimuli. However, the mechanisms driving this remodelling, and the role of weaning-associated dietary changes in this process, are unknown. Here, we characterise the emergence of sexually dimorphic patterns of adipose tissue distribution and function during the post-weaning period. As subcutaneous adipocytes acquire a white phenotype, the tissue microenvironment undergoes a coordinated remodelling, including reduced innervation and an increase in immune cell content. Using a model of prolonged breastfeeding, we show that it promotes adipose tissue expansion through sex-dependent mechanisms, stimulating progenitor proliferation in males and adipocyte hypertrophy in females. In males, this is accompanied by accelerated tissue whitening, which we link to enhanced clearance of extracellular noradrenaline by mature adipocytes. Our findings reveal sex- and diet-dependent mechanisms governing adipose tissue maturation and highlight how early life nutritional cues shape the microenvironment and function of mature adipocytes. Highlights - The peri-weaning period associates with sexually dimorphic remodelling of the adipose tissue - Whitening of the adipose tissue associates with immune infiltration and decrease innervation in both sexes - Prolonged breastfeeding prevents drop in proliferation in males - Whitening is accelerated in males during prolonged breastfeeding
Cardiopulmonary Exercise Testing (CPET) is considered the gold standard assessment of peak oxygen uptake (peak), and consequently, cardiorespiratory fitness (CRF). Common practice in children with congenital heart diseases (CHD) is to compare individual test results to reference values in healthy children. This approach does not account for the diversity of heart defects and may also be demotivating for children with CHD. This retrospective multicentre study aimed to establish individualized CRF reference models specific to children with CHD, to facilitate a better understanding and management of their condition. A total of 1475 CPETs until exhaustion were performed in 943 children and adolescents at two hospitals in Norway. The children and adolescents were categorized into three groups: simple defects (VSD, ASD, CoA, LVOTO; n = 497, 38% female), moderate defects (TGA, Fallot; n = 299, 41% female), and univentricular defects with a Fontan circulation (n = 147, 42% female). Multivariable mixed-effects models with individuals as random intercepts were used to develop group-specific reference models for CRF. Estimated predictive models including covariance matrices for each group and outcome are provided, allowing for the generation of reference values with confidence intervals for clinical and research applications. Conclusion: Treadmill-based reference models for maximal and submaximal CRF variables in the most prevalent types of CHD are presented. Using individualized reference values has the potential to improve clinical decision-making for children with CHD and to enhance their sense of mastery. A web-based calculator is available for quick and easy clinical use.
Background and Aims: Cholesterol screening in children, with subsequent genetic testing of top percentile, has been suggested as an efficient universal screening approach in familial hypercholesterolaemia (FH). The potential cholesterol-based screening efficacy was investigated in a national genetically based screening programme. Methods: Data were from the Norwegian national family cascade screening programme in FH children from 1998 to 2023. Cholesterol levels [umbilical cord in newborns (n = 113) and venous blood in children 1–12 years old (n = 1346)] in variant positive and variant negative children were compared. Results: LDL cholesterol (LDL-C) was higher in FH newborns vs non-FH newborns [1.22 (.48) vs .68 (.32) mmol/L, P < .001], but overlapped widely. Cut-off levels corresponding to the 95th and 85th percentile would only identify 55.7% and 75.4% of newborns with FH, respectively. Screening efficacy in newborns did not differ in subgroups: boys and girls, null and non-null variants, variant gene, and neither for total cholesterol nor for non-HDL cholesterol. In all other age groups (from 1 to 12 years), LDL-C discriminated highly between mutation FH and non-FH children. Cut-off levels corresponding to 95th and 85th percentile of LDL-C would identify 88.4% and 94.1% of 1–12-year-old children with FH, respectively. Conclusions: Previous studies investigating lipid or genetic screening approaches for FH have limitations of only performing genetic testing in children with high LDL-C levels. The present study is the first to show the true LDL-C overlap in children with FH vs non-FH by utilizing unique data from a national family cascade screening programme. Cholesterol-based screening approaches for FH only seem feasible from 1 year of age onward.
Haemophilus influenzae is an opportunistic bacterial pathogen that causes both non-invasive and invasive disease in humans. Although the H. influenzae type b vaccine can reduce invasive disease, it is not effective against non-b serotypes or unencapsulated non-typeable H. influenzae (NTHi). The genetic population structure of H. influenzae , especially NTHi, which is typically prevalent in lower- and middle-income countries, is unclear. Here we whole-genome sequenced 4,474 isolates of H. influenzae from an unvaccinated paediatric carriage and pneumonia cohort from the Maela camp for displaced persons in northwestern Thailand. Despite no H. influenzae type b immunization, serotype b was uncommon, whereas 92.4% of the isolates were NTHi. Most multidrug-resistant lineages were NTHi, and there were no lineages enriched among disease samples. Incorporating 5,976 published genomes revealed a highly admixed population structure, low core genome nucleotide diversity and evidence of pervasive negative selection. Our findings expand our understanding of this major pathogen in lower- and middle-income countries and at a global scale.
Abstract Background: Food systems contribute significantly to environmental degradation. The interplay of sociodemographic factors influences food choices and thus, the environmental impacts of diet. This study investigated the environmental impact of food consumption in Northern Norway, focusing on intersectional dynamics. Methods: A cross-sectional design was employed using data from the Tromsø Study. The diet was assessed using a food frequency questionnaire, and the environmental impacts of the diet were estimated for greenhouse gas emissions, water use, land use, acidification, and eutrophication using a Norwegian life cycle analysis food database. Multiple linear regression analyses were performed to examine the associations with sociodemographic variables using three-way interactions with sex, education, and income in an inter-categorical intersectionality framework. Pairwise contrasts were calculated to assess the mean differences between interacting groups. Results: The typical diet in Northern Norway substantially impacts the environment, with dairy products being the primary contributor. When controlling for energy intake, age was inversely linked to the environmental impact, whereas a higher body mass index corresponded to a greater environmental impact. No clear association with sex was observed, and the associations among environmental impact, education, and income varied. Including intersectional analyses did not significantly improve the explanatory power of the models. Although a few pairwise comparisons were statistically significant, the effect sizes were generally small. Conclusion: The study underscores the complex dynamics of dietary habits and sociodemographic factors in shaping the environmental impact of food consumption. The findings are important to develop approaches that balance sustainability perspectives and the diverse needs of the population in Northern Norway.
Modeling with multi-omics data presents multiple challenges such as the high-dimensionality of the problem (p ≫ n), the presence of interactions between features, and the need for integration between multiple data sources. We establish an interaction model that allows for the inclusion of multiple sources of data from the integration of two existing methods, pliable lasso and cooperative learning. The integrated model is tested both on simulation studies and on real multi-omics datasets for predicting labor onset and cancer treatment response. The results show that the model is effective in modeling multi-source data in various scenarios where interactions are present, both in terms of prediction performance and selection of relevant variables.
Abstract Benefits and harms of breast cancer (BC) screening with mammography have been debated and, although most studies reported positive effects, some studies found a negative effect in terms of net quality‐adjusted life years (QALYs). We aimed to estimate net QALYs associated with biennial mammographic screening for women aged 50–69 years offered to 100,000 women followed until age 85, using various assumptions on BC mortality reduction, overdiagnosis and mortality transfer (the extent to which a reduction in BC mortality results in a reduction in all‐cause mortality). Individual‐level data from women invited to BreastScreen Norway during 1996–2020 were used to perform the calculations. The three baseline scenarios included (1) Model Microsimulation Screening Analysis (MISCAN): MISCAN prediction for mortality reduction and overdiagnosis proportion; (2) Model A: 40% BC mortality reduction and 15% overdiagnosis; and (3) Model B: 20% BC mortality reduction and 50% overdiagnosis. For all scenarios, an 80% mortality transfer was assumed. An online tool was developed to illustrate the impact of alternative assumptions. Biennial organized mammographic screening for women aged 50–69 years who were followed until the age of 85 years was associated with 6819, 7444 and 2446 net QALYs gained per 100,000 women for Model MISCAN, A and B, respectively. Assumptions on BC mortality reduction exhibited the largest impact on net QALYs. To conclude, even when assuming a high overdiagnosis proportion and low BC mortality reduction, net QALYs remained positive, reinforcing the value of offering BC screening with mammography to Norwegian women and showing its potential to improve health outcomes.
Abstract The digital stress-management intervention StressProffen has been shown to be associated with improved well-being and quality of life for cancer survivors. In the Coping After Breast Cancer (CABC) trial, effects of 6 months’ access to modified versions of StressProffen, delivered through a digital download-only model, were examined. Women with breast cancer were invited to participate in the trial 6–9 months following diagnosis. Eligible participants were randomized to either: (1) digital cognitive behavioral therapy stress-management intervention (CBI), n = 140, (2) digital mindfulness-based stress-management intervention (MBI), n = 143, or (3) usual-care (control group), n = 147. Primary outcome was change in perceived stress level (PSS-10), while secondary outcomes included changes in health-related quality of life (HRQoL), anxiety and depression, fatigue, mindfulness, sleep and coping. Perceived stress level at baseline was low for all groups. No statistically significant mean differences (MD) were detected between either of the intervention groups and the control group from baseline to 6-month follow-up for perceived stress level (MBI: MD -0.28 [95%CI: -1.75, 1.19], CBI: MD -0.42 [95%CI: -1.89, 1.06]), nor for the majority of the secondary outcomes. After 6 months of access, the CBI and MBI stress-management interventions did not yield significantly improved outcomes for women with breast cancer compared with usual-care controls. Further explorations of which interventions and delivery models may optimize use and effect, best timing for delivery, and individual preferences are needed. ClinicalTrials.gov identifier NCT04480203.
Astrocytes swell in response to elevations in extracellular K+ concentration. This K+-induced swelling is widely believed to be due to astrocytic K+ uptake, even if the underlying mechanisms are not fully understood. Conflicting results pertaining to the role of the brain water channel AQP4 in K+-induced swelling have been presented. This calls for revisiting the effect of AQP4 on K+-induced astrocytic swelling dynamics. In this study, we performed two-photon microscopy of acute hippocampal slices from wildtype (WT) and Aqp4 −/− mice to assess astrocytic swelling in response to medium high 10 mM and pathologically high 50 mM [K+] solutions. We demonstrate that K+-induced swelling is attenuated in Aqp4 −/− astrocytes exposed to 10 mM [K+]o compared to WT. In slices exposed to 50 mM [K+]o, peak swelling was similar between the two genotypes, whereas the cell volume recovery was more complete in Aqp4 −/− astrocytes. We demonstrate that the two [K+] concentrations elicit fundamentally different astrocytic Ca2+ signaling responses, and that the Ca2+ signaling response differs between the genotypes in the 10 mM [K+]o scenario. Our findings suggest that K+-induced astrocytic swelling has different mechanistic underpinnings, depending on the K+ concentration to which the astrocytes are exposed, and that altered astrocytic Ca2+ signaling is a putative mechanism involved.
Nephron loss is a key event during onset and progression of chronic kidney disease, yet the mechanisms dictating tubule repair versus atrophy remain poorly understood. While fibrosis has been proposed to drive progressive organ damage, antifibrotic therapies have failed in clinical trials. Here, we reveal that tubular vascular cell adhesion molecule 1 (VCAM1) expression precedes nephron loss, fibrosis, and long-term kidney dysfunction. Using serial intravital microscopy in transgenic mice, we track tubulointerstitial remodeling between injured and intact tissue over 3 weeks. VCAM1 is rapidly induced in a distinct subset of injured tubules, preceding atrophy with sustained fibroblast recruitment. However, fibroblasts remain confined to injury sites and do not cause secondary damage in uninjured tubules. Last, in human kidney transplant biopsies, tubular VCAM1 expression, but not kidney injury molecule 1, correlates negatively with early and 12-month graft function, underscoring its potential as a biomarker of adverse outcomes. These findings position VCAM1 as an early indicator of tubular fate and nephron loss.
Abstract SUMOylation regulates chromatin states and transcriptional programs that preserve cellular identity, yet how transient perturbation of the SUMO pathway impacts adipocyte plasticity remains unclear. Here we show that brief pharmacologic inhibition of SUMO conjugation in human pre-adipocytes using TAK-981 primes stable de novo beige differentiation in the presence of the PPARG agonist rosiglitazone. Transient TAK-981 exposure before adipogenic induction produces long-lasting changes in the transcriptome and metabolism of mature adipocytes, including robust induction of canonical beiging markers like UCP1 and increased mitochondrial respiration. Mechanistically, ATAC-seq and transcription factor footprinting revealed immediate and durable chromatin remodeling and early mobilization of CEBP family members, followed by stable activation of CEBPA and PPARG regulatory networks. ChIP experiments demonstrated loss of H3K27me3 and gain of H3K27ac at PPAR response elements within key thermogenic enhancers, with increased PPARG occupancy across the UCP1 regulatory unit. This mechanism is enforced by enhanced cAMP-PKA-p38 signaling, and stabilization of beiging transcriptional activators. Our data support a model in which transient relief of SUMO-mediated repression unlocks dominant regulatory units, notably the UCP1 enhancer cluster, producing a monomorphic, cell type specific reprogramming toward adaptive thermogenesis. These findings identify SUMOylation as a reversible epigenetic barrier to adipocyte beiging and suggest that temporally controlled SUMO pathway inhibition combined with PPARG activation could be exploited to modulate adipose tissue thermogenic capacity. Graphical abstract SUMOylation restricts de novo differentiation of pre-adipocytes into beige adipocytes by repressing cAMP signaling and preventing epigenetic and transcriptional reprogramming of white adipocytes.
Reduced estrogen action is associated with obesity and insulin resistance. However, the cell and tissue-specific actions of estradiol in maintaining metabolic health remain inadequately understood, especially in men. We observed that skeletal muscle ESR1/Esr1 (encodes estrogen receptor α [ERα]) is positively correlated with insulin sensitivity and metabolic health in humans and mice. Because skeletal muscle is a primary tissue involved in oxidative metabolism and insulin sensitivity, we generated muscle-selective Esr1 loss- and gain-of-expression mouse models. We determined that Esr1 links mitochondrial DNA replication and cristae-nucleoid architecture with metabolic function and insulin action in the skeletal muscle of male mice. Overexpression of human ERα in muscle protected male mice from diet-induced disruption of metabolic health and enhanced mitochondrial adaptation to exercise training intervention. Our findings indicate that muscle expression of Esr1 is critical for the maintenance of mitochondrial function and metabolic health in males and that tissue-selective activation of ERα can be leveraged to combat metabolic-related diseases in both sexes.
Boken legger særlig vekt på betydningen av samspillet mellom kosthold og fysisk aktivitet for god helse. Innholdet i denne fjerde utgaven er oppdatert i tråd med aktuell forskningslitteratur og nasjonale anbefalinger, og den er spesielt tilpasset norske forhold. Boken henvender seg til et bredt spekter av studenter ved universitets- og høyskoler, blant annet innenfor medisin, ernæring, idrettsfag og fysioterapi, i tillegg til andre fagområder som jobber med forebygging og folkehelse. Boken gir også et solid grunnlag for videre studier innenfor mer spesialiserte, tilgrensende områder som klinisk ernæring, samfunnsernæring og næringsmiddelteknologi.
Background ---- Norway admits medical students solely by GPA. Combined with free education and low attrition, future doctors are largely a result of self-selection. ---- Aim ------ Characterise personality traits of medical students at the University of Oslo and compare them with the Norwegian population and medical students in other countries. ---- Methods ---- Across 2022-2026, five newly admitted medical student cohorts completed the BFI-20S (n=535, 89%) and six the MBTI (n=632, 95%) personality tests (mean age = 22.1, 68% female). T-tests compared BFI-20S with Norwegian workers (n=6,372), French (n=1132) and German (n=880) medical students. Chi-squared tests compared MBTI sixteen personalities between general Norwegians (n=159,468), U.S. (n=83) and South Korean (n=171) medical students. ---- Results & Conclusion ---- On BFI (1–5), Norwegian medical students scored higher on Agreeableness, mean 4.3 (SD=0.5) and Extraversion, 3.7 (0.89), though lower in Neuroticism, 2.5 (0.8) than French (3.8, SD = 0.6; 3.1, SD = 0.8; 3.0, SD = 0.8) and German (4.2, SD = 0.6; 3.6, SD = 0.8; 2.9, SD = 0.8) medical students (p < 0.001). These also differed from Norwegian workers (p < 0.001). Most medical students were MBTI Extraverted (70%), Intuitive (59%), Feeling (66%), and Judging (78%). The ENFJ (22%) was overrepresented compared with U.S. (2%) and South Korean (3%) medical students, and Norwegians (6%) (p < 0.001). Norwegian medical students display high Conscientiousness and Agreeableness with gross overrepresentation of ENFJ. Although these are considered well-suited for medical practice, the limited personality diversity might implicate coping mechanisms and problem-solving strategies in the physician workforce.
Background --- Medical school admissions shape the physician workforce. Norway admits students exclusively by GPA. With no selection for suitability and professional attitude, combined with free education and low attrition, the admitted cohorts are largely shaped by who chooses to apply. To explore this effect, we characterised personality traits of medical students at the University of Oslo and compared them with the Norwegian population and published samples from medical schools in other countries. --- Summary of Work --- Newly admitted medical students (2022–2025; mean age 22.1, 67% female) completed the BFI-20S (four cohorts, n=436, 91% response) and the MBTI (five cohorts, n=532, 95% response) personality tests. BFI measured Agreeableness, Conscientiousness, Extraversion, Neuroticism, and Openness. One-sample t-tests compared mean scores with Norwegian workers (n=6,372). MBTI classified respondents on four dichotomies combined into 16 personality types. Chi-squared tests compared distributions between U.S. (n=83) and South Korean (n=171) medical students and the Norwegian general population (n=159,468). --- Summary of Results --- On the BFI, Norwegian medical students scored higher on Agreeableness, mean 23.9 (SD=3.0), Conscientiousness, 22.7 (3.6); Extraversion, 20.3 (5.9); Openness, 18.7 (4.7), and Neuroticism, 13.0 (4.8), than general Norwegian workers (22.2, SD=3.4; 20.5, SD=3.6; 19.0 SD=4.8; 17.8 SD=4.7; 12.0, SD=4.5, respectively, p<0.001). Female students reported higher Neuroticism (Pearson’s r=0.2, p<0.001) and Agreeableness (r=0.1, p=0.010) than male students. --- MBTI classified most medical students as Extraverted (69%), Intuitive (58%), Feeling (67%), and Judging (78%). The ENFJ type (Protagonist, 21%) was significantly overrepresented compared with U.S. (2%) and South Korean (3%) medical students, and the Norwegian population (6%) (p<0.001). The most common types among women were ENFJ/ESFJ (27%/14%); among men, ENTJ/INTJ (26%/13%). ---Discussion and Conclusion --- The Norwegian admission system is associated with elevated levels of Conscientiousness and Agreeableness and large overrepresentations of ENFJ/ENTJ. Although these traits and types can be well-suited for medical practice, limited diversity in perspective, leadership styles, and coping strategies might have implications for the composition of the physician workforce and patient care. --- Take-home Message(s) --- The Norwegian GPA-only admission model is associated with a distinct and narrow spectrum of personalities, with potential implications for physician well-being, leadership representation, and personality diversity.
Høvdingene innen kunstig intelligens (KI) babler om trusler mot menneskeheten og ber om regulering, og da kreves skepsis i responsen (jf. Mogstad og Hardings kronikk i DN 2. oktober: «Hvorfor innovere når man kan regulere?»).Det de ber om, skal de ikke få.Ikke i Europa.
Panel discussion at the MusicLab Listening Body research concert in Bergen, where an audience with and without Parkinson's disease heard classical piano works framed by meditation and attentive listening while wearing sensor vests that recorded micromotion, breathing and heart rate, and the room was filmed with thermal video. The conversation focused on what attentive listening does to the body and brain in a concert, what the measurements can and cannot show, and what the recordings may mean for music used therapeutically by people with Parkinson's disease.
Panel discussion at the MusicLab Listening Body research concert in Oslo, where an audience with and without Parkinson's disease heard classical piano works framed by meditation and attentive listening while wearing sensor vests that recorded micromotion, breathing and heart rate, and the room was filmed with thermal video. The conversation focused on what attentive listening does to the body and brain in a concert, what the measurements can and cannot show, and what the recordings may mean for music used therapeutically by people with Parkinson's disease.
Background and Aims: Atherosclerotic cardiovascular disease (ASCVD) develops through cumulative exposure to causal risk factors, such as lipoprotein(a) [Lp(a)]. Evidence on how high Lp(a) shapes long-term absolute and relative ASCVD hazards across age and sex remains limited. We quantified age and sex-specific absolute and relative ASCVD hazards associated with high Lp(a) and assessed whether these age-related patterns differed between men and women. Methods: We included 19 495 adults without ASCVD at baseline with Lp(a) measured from the Trøndelag Health Study (HUNT3, 2006–08). Participants were followed for up to 16 years for first ASCVD event. Lp(a) was categorized as high (≥95th percentile; ≥252 nmol/L) versus low (≤74th percentile; ≤62 nmol/L). Standardized age and sex-specific hazard rates, hazard ratios (HRs), and hazard rate differences (HRDs) per 1000 person-years were estimated using multivariable cause-specific flexible parametric survival models. Results: High Lp(a) was associated with higher ASCVD hazards at all ages. In both sexes combined, the HR for high versus low Lp(a) declined from 2.42 (95% CI: 1.14–5.14) at age 40 to 1.24 (95% CI: 0.91–1.70) at age 90, while corresponding HRDs increased from 1.22 (95% CI: -0.24–2.67) to 6.97 (95% CI: -4.08–18.02) extra ASCVD events per 1000 person-years. Men had higher ASCVD hazards than women at all ages. HRs were broadly similar between sexes but tended to be slightly higher in women at midlife. However, the number of extra ASCVD events per 1000 person-years due to high Lp(a) increased with age in both sexes and was consistently higher in men compared to women. Conclusions: High Lp(a) is a long-term risk factor for ASCVD across adulthood, with a larger relative impact at younger ages, but causes more excess events in older adults, and particularly in men. These risk profiles may help clinicians prioritize Lp(a) testing and identify patients who may benefit from future Lp(a)-lowering therapies.
Tidligere fantes det diagnoser i skolen og i helsevesenet som vi ikke bruker i dag. Mange av disse begrepene er helt borte. Andre har fått nye navn, og noen har blitt slått sammen med andre diagnoser. Men hvorfor endrer og fjerner vi diagnoser?
Understanding spatial cell organisation in the tumour microenvironment is critical for cancer research, as it provides key insights into disease mechanisms. In this ongoing work, we explore two approaches that incorporate biological knowledge while analysing the tumour microenvironment. Firstly, we embed single-cell instances into a Lorentzian latent space using a fully hyperbolic variational autoencoder, which we have previously shown to retain significantly more biologically relevant information than Euclidean alternatives. Secondly, we adopt taxonomy-aware spatial association rule mining for quantifying cell interaction behaviour beyond pairwise interactions.
Understanding spatial cell organisation in the tumour microenvironment is critical for cancer research, as it provides key insights into disease mechanisms. In this ongoing work, we explore two approaches that incorporate biological knowledge while analysing the tumour microenvironment. Firstly, we embed single-cell instances into a Lorentzian latent space using a fully hyperbolic variational autoencoder, which we have previously shown to retain significantly more biologically relevant information than Euclidean alternatives. Secondly, we adopt taxonomy-aware spatial association rule mining for quantifying cell interaction behaviour beyond pairwise interactions.
Health literacy kalles på norsk for helsekompetanse. Tilsvarende bør oral health literacy betegnes munnhelsekompetanse.
Vi vet nok til å kunne hjelpe langt flere pasienter med langvarige symptomer. Likevel holder vi tilbake håpet, av frykt for å skuffe. Det kan koste pasientene store deler av livet. Denne kronikken er et faglig opprop fra 63 klinikere, forskere og fagpersoner fra hele landet. Vi har klinisk og forskningsmessig erfaring med vedvarende fysiske symptomer, som smerter, utmattelse, «hjernetåke», svimmelhet og mageplager og har samlet oss om et felles budskap: Ny kunnskap om hvordan slike symptomer oppstår og opprettholdes gir grunn til langt større håp om bedring enn mange pasienter får formidlet i dag.
The Green Cross method contributes to interprofessional discussions around patient safety incidents in daily safety briefings and weekly reflections. The Green Cross method was implemented in a Norwegian postanaesthesia care unit in February 2019. The purpose of this presentation is to report the findings following the implementation of the Green Cross method over a period of four years (2019-2022) regarding: How does the Green Cross method affect collective reflection and learning in a postanaesthesia care unit?
Background: Nutrition impact symptoms (NIS) are contributors to impaired nutritional status in allo-HSCT patients. However, the impact of patients’ reported NIS on nutritional status are poorly described. This study investigated changes in NIS and nutritional status, and associations between NIS and nutritional status during a 1-year follow-up of allo-HSCT patients. Methods: We used data from 117 patients (57 intervention, 60 control) who participated in a randomized controlled nutritional intervention trial. Linear mixed models were used to analyse changes in NIS over time. Ordinal logistic regressions were used to analyse associations between NIS and nutritional status. Results: Nausea and vomiting and constipation were significantly lower in the intervention group than the control group during 1-year follow-up (p = 0.015 and p < 0.001, respectively). Initially, nutritional status declined in both study groups post-allo-HSCT but improved over time. Significantly fewer patients in the intervention group were malnourished at 3 weeks (p = 0.020) and 6 weeks post-transplantation (p = 0.028). Associations between NIS and nutritional status varied over time and differed between the study groups at 6 weeks post-transplantation (OR 3.702, 95% CI: (1.355, 10.100), p = 0.011). Conclusions: In conclusion, our findings emphasize the need for long term monitoring of symptoms and nutritional status in allo-HSCT patients, supporting individualized nutritional assessments as part of long-term care strategies. Disclosure: Geir Erland Tjønnfjord has received research grants from Mundipharma and Alexion Pharmaceuticals, advisory board honoraria from Alexion Pharmaceuticals and Johnson & Johnson, and lecture honoraria from Novartis, Johnson & Johnson, Alexion Pharmaceuticals, and Mundipharma. The other authors declare no competing interest.
The Neuroscience pilot of the EU-funded SciLake project seeks to tackle the complexities of fragmented and disorganized open research data. This initiative has united partners with expertise in knowledge management with curators from EBRAINS (RRID: SCR_019260), an open research infrastructure focused on brain-related studies. The innovative Scientific Knowledge Graph (SKG) (https://bip.imsi.athenarc.gr/search/neuroscience-pilot) created through this pilot serves as a cohesive framework for data integration while enabling the use of value-added services provided by SciLake. The developed SKG combines curated datasets from EBRAINS with extensive neuroscience research products from the OpenAIRE neuroscience gateway (https://neuroscience.openaire.eu/). The SKG incorporates controlled terms from openMINDS (RRID: SCR_023173) as nodes and utilizes an entity recognition model to classify and map these terms in relevant texts, enriching the connections among research products. Additionally, the SciLake services deploy language models to extract mentions of research artifacts (RAs) and enhance the interlinking of research products. Fully integrated with impact-driven discovery and reproducibility tools and leveraging the analytical capabilities of SciLake, the SKG serves as a powerful resource for contextualizing curation efforts and exploring research trends, ultimately optimizing curation processes in the neuroscientific landscape.
The transition to open science has led to a growing volume of shared neuroscience data in different data repositories. While the amount and diversity of research data available is extensive, data reusability is often limited by a lack of appropriate metadata annotations according to the FAIR guiding principles (Wilkinson et al., 2016). The EBRAINS Research Infrastructure (RRID:SCR_019260) shares well-annotated datasets to facilitate data discovery and reuse across studies and modalities via the EBRAINS Knowledge Graph (KG; RRID:SCR_017612). The EBRAINS KG currently indexes 1100+ heterogeneous datasets, annotated with standardised metadata following the openMINDS metadata framework (RRID:SCR_023173). We present two examples for building data collections via the KG Search functionality using a combination of multi-term text queries and faceted filtering to exemplify the potential of data driven workflows. First, we explore the brain-wide distribution of calbindin- and parvalbumin-positive neurons in rodent brains, identifying a comprehensive data collection generated using the QUINT workflow (Yates et al., 2019). Related datasets are connected through metadata including species and techniques. Second, we collect BIDS-compliant macaque datasets, containing NIfTI files, enabling the combination of neuroimaging data from different laboratories. Filtering and query options for experimental methods, content types and data organisation standards enable the selection of data for viewing and analysis using EBRAINS tools, highlighting their interoperability. These examples demonstrate how discovery-driven neuroscience is facilitated by FAIR annotated data across a range of studies.
Studies of the cellular architecture and neural connections in the brain often rely on histology-based methods in rodent wild type and disease models. Registration of brain section images to a reference brain atlas has become the standard for obtaining high quality and precise data, allowing comparison and integration of disparate data within a standardised coordinate system. While a few analytical tools are available to researchers, barriers to uptake, such as coding skill requirements, data type limitations, and insufficient documentation are still present. We have developed an intuitive, reliable and versatile solution for enabling such analyses. The QUINT-online workflow combines the use of a series of web-applications (CreateZoom, WebAlign, WebWarp, Webilastik, WebNutil and MeshView) integrated in an online platform, accessible with an EBRAINS account. It builds on the QUINT workflow (Yates et al. 2019, doi: 10.3389/fninf.2019.00075) using desktop applications, which has been used widely by the research community for cell counting, tract tracing studies and for analysis of tissue clearing data. This new online solution allows researchers to register heterogeneous image series to reference brain atlases, to identify features to quantify, and to perform brain-wide mapping and quantification, on a user-friendly platform. The QUINT-online workflow benefits from simplified file management steps and new features such as microscopy viewer links and automated mapping of selected objects. EBRAINS users can already access a beta version at https://quint-online.apps.ebrains.eu/.
This 1-hour online + Q&A roundtable brings together QUINT developers, experts in digital brain atlases and neuroinformatics, to discuss the QUINT Workflow. This event is designed for students and researchers working with histological images, offering a unique opportunity to ask questions and get feedback from leading experts in the field.
The amygdaloid complex is part of the limbic system governing emotion, learning, implicit memory and social behaviour. Its implication in neuropsychiatric disease has motivated extensive experimental preclinical research in animal models, particularly in rodents and non-human primates. For investigations in rat models, the Waxholm Space (WHS) rat brain atlas provides three-dimensional standardized representations of brain regions and is increasingly used for data integration, spatial analysis, and comparisons across studies. While this atlas includes detailed delineations for most major brain structures, it lacks subdivisions of the amygdaloid complex. Addressing this, we have manually delineated nuclei of the rat amygdala on the basis of high-resolution structural magnetic resonance imaging (sMRI) and diffusion tensor imaging (DTI) data, combined with co-registered cytoarchitectural, myeloarchitectural, and chemoarchitectural features derived from histological datasets. These multimodal data were interpreted and compared using available literature. We here present 3D delineations of the rat pallial and subpallial subdivisions of the amygdaloid complex, together with detailed documentation of delineation criteria. To facilitate cross-species translation, we also compared our delineation criteria and delineations to corresponding data from primates. This work represents an empirical basis for combining multimodal MRI and histological data to extend the anatomical delineations of the WHS rat brain atlas and to strengthen its role as a neuroinformatics resource for data integration, translational research, brain wide analyses and cross-species comparison particularly for future investigations into the neural mechanisms involving the amygdaloid complex. Funded from the European Union’s Research and Innovation Program Horizon Grant Agreement No. 101147319 (EBRAINS 2.0)
Hyperbolic representation learning has shown compelling advantages over conventional Eu- clidean representation learning in modelling hierarchical relationships in data. In this work, we evaluate its potential to capture biological relations between cell types in highly multiplexed imaging data, where capturing subtle, hierarchical relationships between cell types is crucial to understand tissue composi- tion and functionality. Using a recent and thoroughly validated 42-marker Imaging Mass Cytometry (IMC) dataset of breast cancer tissue, we embed cells into both Euclidean and Lorentzian latent spaces via a fully hyperbolic variational autoencoder. We then introduce an information-theoretic framework based on k-nearest neighbour estimators to rigorously quantify the clustering performance in each geom- etry using mutual information and conditional mutual information. Our results reveal that hyperbolic embeddings retain significantly more biologically relevant information than their Euclidean counter- parts. We further provide open-source tools to extend Kraskov-Stögbauer-Grassberger based mutual information estimation to Lorentzian geodesic spaces, and to enable UMAP visualizations with hyper- bolic distance metrics. This work contributes a principled evaluation method for geometry-aware learning and supports the growing evidence of hyperbolic geometry’s benefits in spatial biology. Code is available at: https://github.com/youssefwally/FlatlandandBeyond
Understanding the spatial organisation of cells within tissues is fundamental for cell niches discovery. Advances in spatial omics technologies now yield high-resolution maps of cell populations across tissue sections, yet computational methods for systematically discovering recurrent, interpretable multi-cell assemblies remain limited, particularly when cell type annotations are organised in hierarchical taxonomies. Cell type ontologies in modern atlases naturally form hierarchies, ignoring this structure leads to either redundant or missed niche patterns. We present our on-going work for cell niche discovery based on spatial association rule mining that is explicitly aware of these hierarchical relationships. By propagating colocation evidence through the taxonomy, we are able to identify multi-cell-type assemblies that co-occur significantly across tissue regions at both fine-grained and coarser levels of cell-type resolution, reducing redundancy while improving interpretability
Understanding the spatial organisation of cells within tissues is fundamental for cell niches discovery. Advances in spatial omics technologies now yield high-resolution maps of cell populations across tissue sections, yet computational methods for systematically discovering recurrent, interpretable multi-cell assemblies remain limited, particularly when cell type annotations are organised in hierarchical taxonomies. Cell type ontologies in modern atlases naturally form hierarchies, ignoring this structure leads to either redundant or missed niche patterns. We present our on-going work for cell niche discovery based on spatial association rule mining that is explicitly aware of these hierarchical relationships. By propagating colocation evidence through the taxonomy, we are able to identify multi-cell-type assemblies that co-occur significantly across tissue regions at both fine-grained and coarser levels of cell-type resolution, reducing redundancy while improving interpretability
Understanding the spatial organisation of cells within tissues is fundamental for cell niches discovery. Advances in spatial omics technologies now yield high-resolution maps of cell populations across tissue sections, yet computational methods for systematically discovering recurrent, interpretable multi-cell assemblies remain limited, particularly when cell type annotations are organised in hierarchical taxonomies. Cell type ontologies in modern atlases naturally form hierarchies, ignoring this structure leads to either redundant or missed niche patterns. We present our on-going work for cell niche discovery based on spatial association rule mining that is explicitly aware of these hierarchical relationships. By propagating colocation evidence through the taxonomy, we are able to identify multi-cell-type assemblies that co-occur significantly across tissue regions at both fine-grained and coarser levels of cell-type resolution, reducing redundancy while improving interpretability
Abstract Background Atorvastatin reduces the risk of atherosclerotic cardiovascular disease but exhibits wide interindividual variability in efficacy and adverse effects, possibly due to genetic predispositions. The SLCO1B1*5 variant causes higher systemic exposure to atorvastatin, and has been associated with increased risk of muscular side effects. The UGT1A3*2 haplotype potentially relate to poorer cholesterol response and increased risk of muscle toxicity by skewing the metabolism towards increased lactonization of atorvastatin metabolites. Purpose To explore the relationship between the UGT1A3*2 haplotype and the pharmacokinetics and pharmacodynamics of atorvastatin in patients with coronary heart disease. Methods We used data from the MUSE study, a double-blinded crossover trial in patients with coronary heart disease. The intervention group with statin-associated muscle symptoms (SAMS, n=70) underwent two 7-week periods with atorvastatin 40 mg and placebo. The control group with no history of SAMS (n=39) received atorvastatin 40 mg during an open-label 7-week period. Blood samples were collected 24h after atorvastatin administration, at the end of each period. We determined pharmacogenetic variants with a multiplex-PCR MALDI-TOF assay. Atorvastatin, its main metabolites, and mevalonate, were quantified with liquid chromatography mass spectrometry. Results Mean age was 64 years and 32% were females. UGT1A3*2 was present in 54% of patients, and the SLCO1B1*5, CYP3A4*22 and CYP3A7*1C variants were present in 29%, 8.3% and 13% (Table 1). In the SAMS group, atorvastatin versus placebo produced mean changes in mevalonate -34 ± 24%, LDL-C -47 ± 19%, and CK +10 ± 33%. In adjusted analysis, SLCO1B1*5 was consistently associated with higher concentrations of atorvastatin and in both acid and lactone form (Table 2). The UGT1A3*2 haplotype was associated with higher levels of hydroxylated atorvastatin and its metabolites. The effects of CYP3A4*22 and CYP3A7*1C were selective towards the non-hydroxylated atorvastatin lactone and 4-hydroxylated atorvastatin lactone, respectively. Regression analysis indicated a more pronounced reduction in mevalonate, a response marker of HMG-CoA reductase inhibition among carriers of UGT1A3*2 whereas none of the examined variants predicted LDL-C response. Unexpectedly, SLCO1B1*5 and CYP3A7*1C were associated with an atorvastatin-related decrease in CK. Conclusions UGT1A3*2 was observed in approximately half of the patients with coronary heart disease and is associated with higher concentrations of hydroxylated atorvastatin metabolites. This haplotype should be considered together with SLCO1B1*5 when predicting effects related to systemic exposure. The results indicate that UGT1A3*2 may have indirect impact on the pharmacodynamics of atorvastatin while further studies are needed to clarify clinical implications for LDL-C lowering and muscle safety.For image description, please refer to the figure legend and surrounding text. For image description, please refer to the figure legend and surrounding text.
Poster presentation
Formålet med denne studien var å kartlegge prosjekter og initiativer som jobber for å oppnå sunnere og mer bærekraftig offentlig innkjøp av mat i Norge, samt prosjekter med fokus på å styrke lokal og nasjonal matberedskap. Det ble utført et litteratursøk med fokus på grålitteratur. Videre ble relevante personer invitert til å fylle ut et digitalt spørreskjema. Kartleggingen identifiserte 107 prosjekter og initiativer. Prosjektene fokuserte hovedsakelig på innkjøp av bærekraftig mat, der innkjøp av lokalmat var høyest prioritert, etterfulgt av aspekter som økologi, matsvinn og klimavennlig mat. Innkjøp av både sunn og bærekraftig mat ble i mindre grad prioritert (~31% av prosjekter), mens kun 2% av prosjektene jobbet for sunnere innkjøp.
Én av tre pasienter ved norske sykehus lider av plager leger ikke finner ut av. Samfunnskostnadene er enorme.
Conference talk at symposium for members of the Nordic Childhood Cancer Predisposition collaboration group – 13th-14th April 2026.
Background: Anorexia nervosa (AN) remains difficult to treat, partly due to co-occurring mental health challenges and gastrointestinal symptoms. Emerging research suggests that individuals with AN exhibit gut microbiota dysbiosis and dysregulation in the gut-brain axis (GBA). However, research examining the role of gut microbiota as a potential driver of AN-related pathologies remains limited. The Norwegian Microbiota Study in Anorexia Nervosa (NORMA) will therefore investigate gut microbiota and its interaction with the GBA in AN. Methods: NORMA is a collaboration between the Norwegian University of Life Sciences and seven Norwegian specialized eating disorder inpatient treatment units, consisting of three work packages (WP): a clinical observational trial (WP1), in vitro fermentation experiments (WP2), and animal experiments (WP3). In WP1, 90 patients with AN (age 16-50, BMI < 18.5) admitted for treatment and 90 healthy controls (HCs, age 16-50, BMI 18.5-27) will be recruited. Data on mental and physical health, dietary intake, and blood and fecal samples for biomarker and microbiota analyses will be collected at baseline, 6 and 12 weeks after start of treatment for AN patients and once for HCs. Outcomes will be compared between groups, and longitudinal effects of standard treatment examined within the AN group. In WP2, fecal microorganisms from patients and HCs will be grown in vitro to assess influence of prebiotics. In WP3, mice will receive fecal microbiota from AN and HC donors to determine if and how AN‑related microbiota affects AN‑relevant phenotypes. Conclusion: NORMA is pioneering in its integration of clinical, in vitro, and animal studies, providing the most comprehensive gut microbiota study of AN so far. By investigating the role of gut microbiota in AN and effects of standardized treatment on gut microbiota composition, this study aims to inform the development of innovative therapeutic strategies and ultimately improve treatment outcomes and life quality for individuals with AN. Trial registration: NORMA is a registered clinical trial: clinicaltrials.gov as NCT06144905.
Folk med irritabel tarm blir ofte rådet til å ikke gå lenge uten å spise. Men hva skjer om du gjør det motsatte og faster store deler av døgnet?
People with intellectual disabilities are disproportionately affected by diet-related health inequalities. This Perspective outlines a dual challenge: (1) intrinsic vulnerabilities—cognitive limitations, health-literacy constraints, and comorbidities—that impair individuals’ ability to make healthy dietary choices, and (2) extrinsic neglect—insufficient support in care environments, inadequate nutrition-related training among informal caregivers and support staff, and structural gaps in policy and services. We argue that this “double jeopardy” undermines nutritional equity and proposes strategies for person-centered nutrition education, caregiver empowerment, supportive food environments, and inclusive policy frameworks. Greater interdisciplinary collaboration and tailored research are urgently needed to ensure nutritional health as a right for people with intellectual disabilities.
Oppstartsmøte for partnere i AdHealth
Biomedical data are characterised by large heterogeneity. Technical challenges result in noise and biases, e.g. through measurement errors, but more importantly, biological variability between individuals and conditions is large. This is even more the case in disease, which is a deviation from the normal healthy state, and each patient differs from this norm in a different way. Statistical modelling is concerned with delineating and understanding the different sources of heterogeneity. Bayesian statistics offers a unified approach to the modelling, which allows us to keep track of all sources of variability, even in complex hierarchical model setups. I will illustrate the potential of Bayesian modelling for complex biomedical data structures through examples from precision medicine and cancer drug screens.
Gjennomgang av litteraturen vedrørende fortykningsstoffer og tarmhelse på NutriNORs sommerskole 2025
Abstract Background: Neoadjuvant treatment of locally advanced breast cancer (LABC) is now well-established and considerable progress has been made concerning drug development for subgroups of patients. However, reliable predictive markers are still lacking for many patients. Thus, radiological measures like repeated MRI of the breast and axilla, after 3 and 6 months of therapy, are used to follow the patients during neoadjuvant therapy to confirm successful downstaging. Although not established in clinical routine, dynamic MRI contains quantitative information that can provide valuable insight into the tumour microenvironment and, when combined with clinical and molecular data, has the potential to enhance the prediction of tumor responses. Here, we analyze split-dynamic MRI data in relation to clinicopathological and molecular data to further identify disease heterogeneity that can be used to improve prognostic accuracy and inform treatment decisions in breast cancer patients. Methods: This study reports results from eligible patients with ER pos., HER2 neg. LABC that were enrolled in the NEOLETEXE-trial (1). Clinicopathological, molecular, and advanced MRI data were acquired from this trial, collected before, during, and after neoadjuvant endocrine therapy (NET) with aromatase inhibitors given in sequence. MR images were generated using a split-dynamic technique that simultaneously acquires high spatial resolution and high temporal resolution images, providing information on tissue permeability and vascularity. The images underwent post-processing on the nordicICE software where parametric values were extracted based on whole-tumour volumes of interest. These parametric values were analysed in correlation with clinico-pathological data and with molecular findings from bulk RNA-seq and single cell data from a subset of the same patients. Results: From the kinetic MRI data, the volume transfer constant (Ktrans), a parameter reflecting capillary permeability, was significantly reduced after NET (p = 0.005). Bulk RNA-seq data was analysed for gene expression, pathway involvement, and cell type abundance before, during, and after treatment. Gene expression analysis revealed significant dysregulation of genes related to cell proliferation and cell cycle regulation following treatment. Biological pathway analysis revealed significant down-regulation of hemostatic activity and upregulation of cell cycle and interleukin signaling following treatment. Cell type analysis revealed a higher abundance of CD4+ T-cells and T-helper cells following treatment. These results will be further correlated with single cell data as well as measures of treatment response and clinical outcome. Conclusions: Our findings suggest that the addition of MRI data to clinicopathological and molecular data enhances the characterization of tumor responses during NET for locally advanced breast cancer. 1. The NEOLETEXE trial: a neoadjuvant cross-over study exploring the lack of cross resistance between aromatase inhibitors. Bahrami N. et al., Future Oncoloy 15 (32), 3675-3682, 2019. Citation Format: Stephanie Lee, Andliena Tahiri, Kjell-Inge Gjesdal, Torben Lüders, Laurens Reitsma, Marianne Lyngra, Alvaro Köhn-Luque, Vessela Kristensen, Jürgen Geisler, Jonn Terje Geitung. Radiogenomics during neoadjuvant therapy with aromatase inhibitors: integrating dynamic magnetic resonance data and molecular biology [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P1-01-07.
BIDS and openMINDS are expert- and community-driven standards that facilitate FAIR data management in the field of neuroscience. BIDS is a commonly adopted data model that standardizes the file organization and metadata annotations per dataset within a data repository, such as openNeuro.org or publicneuro.eu. The openMINDS metadata framework provides integrated metadata models for Linked Data, libraries of ontology-based metadata instances and supports rich search capabilities in graph database systems, such as the EBRAINS Knowledge Graph. To facilitate ingestion of metadata from BIDS datasets into such graph database systems, we developed the bids2openminds converter. bids2openminds is an open-source project, provided as a python package with a command line interface (https://github.com/openMetadataInitiative/bids2openminds). It builds on the functionalities of, pyBIDS and openMINDS_Python. However semantic mapping between BIDS and openMINDS terminologies had to be hard coded. Currently, the converter supports the BIDS modalities structural and functional Magnetic Resonance Imaging (MRI), Electroencephalography (EEG), and Intracranial Electroencephalography (iEEG). We demonstrate the metadata conversion using bids2openminds on BIDS compliant, open access datasets. Converted to openMINDS and registered in the EBRAINS Knowledge Graph, data and metadata have an increased findability via the search user interface and advanced query options. Through the semantic integration data are linked to other datasets within and beyond the EBRAINS database, increasing their interoperability and reusability. The bids2openminds converter facilitates automatic registration of BIDS compliant datasets in openMINDS-based graph databases, fostering interoperability and alliances across different data management systems (e.g., publicneuro.eu and EBRAINS).
Learning from Excellence (LfE) is a patient safety initiative from Birmingham which includes voluntary reporting of a peer’s excellent work and thus captures episodes of successful everyday work. LfE has two aims: 1) to provide positive feedback to healthcare professionals, and 2) to learn from what works well. There is limited research on healthcare professionals’ experiences with LfE, and its effect on patient safety culture has not been evaluated. This presentation reports the qualitative and quantitative findings after the implementation of LfE in a post anaesthesia care unit.
Få fagfelt får mer medieoppmerksomhet enn kosthold og ernæring, og få fagfelt har flere selvoppnevnte eksperter. Mange blir forvirret i jungelen av kostråd, som via media kan virke vidt forskjellige. I pressen blir gjerne resultater fra enkeltstudier slått stort opp uten å bli vurdert i lys av øvrig kunnskap innen faget. Nye hypoteser kan begeistre både leg og lærd, men veien er som regel lang frem til en veldokumentert konklusjon og offisielle råd til befolkningen. Et funn må alltid vurderes mot den totale kunnskapen innen emnet før konklusjoner kan trekkes. Det har vært arbeidet både nasjonalt og internasjonalt for å finne frem til en felles forståelse av hvilke minstekrav man bør ha til dokumentasjon før kostråd gis. I denne artikkelen beskrives generelle trekk i prosessen som fører frem til offisielle kostråd i Norge.
Pasienter med funksjonelle lidelser trenger et bedre behandlingstilbud
Background Childhood, adolescent, and young adult cancers (CAYAC) present unique challenges in oncology. Advances in treatment Have led to an 80% 5-year survival rate; however, CAYAC survivors (CAYACS) remain at high risk of long-term medical and psychosocial complications, significantly impacting their quality of life. Short and long-term follow-up care is recommended, but is often fragmented, with considerable disparities in availability and accessibility across Europe. Many existing digital tools primarily address medical needs, leaving psychosocial challenges unaddressed. The e-QuoL project aims to bridge these gaps by leveraging existing digital health solutions to provide equitable, person-centered survivorship care. Methods The e-QuoL project employs a participatory approach involving survivors, families, healthcare professionals (HCP), and researchers. Using the FormIT methodology, the project follows three phases: Explore, Create, and Evaluate. The Explore phase includes a large-scale cross-sectional survey across 15 European countries to assess the unmet needs of CAYACS and their families. The Create phase involves co-creation workshops to develop and refine digital tools, including MyCaree-QuoL tool, which will supplement survivorship care passports, to provide personalized medical and psychosocial support. The Evaluate phase comprises usability testing and clinical studies in at least seven European countries to assess effectiveness, scalability, and real-world applicability. Discussion The e-QuoL project builds on existing digital health innovations while adapting them to diverse European healthcare systems. By developing MyCaree-QuoL, the project fosters a decentralized, person-centered model of survivorship care to promote equal access to quality survivorship support for CAYACS and HCPs. Ethical considerations, including data privacy, patient consent, and equitable access, are central to the project, with dedicated Ethics and Social Challenge Groups guiding implementation. Digital disparities remain a challenge, particularly for survivors from lower socio-economic backgrounds or remote areas. To mitigate this, e-QuoL will work with healthcare professionals to offer additional in-person support to complement digital interventions. The project aligns with Europe’s Beating Cancer Plan, aiming to improve quality of life and reduce disparities in care. By fostering collaboration among 30 partners across 15 countries and hosting resources on the PanCare website, e-QuoL seeks to ensure long-term impact, contributing to the goal of high-quality, equitable survivorship care across Europe.
Poor sleep and obesity are concurrent health epidemics in adolescents. This is especially concerning given that adolescents are getting less and less sleep as technology invades their bedrooms. Several studies point to adolescence as a critical period for sleep and adipose tissue development, implying that poor sleep during this period might alter the normal development of adipose tissue and cause metabolic imbalance. To investigate whether adolescent sleep quality contributes to the emergence of metabolic dysfunctions later in life, we propose to establish new rodent models of reversible sleep deprivation for which we can turn on and off sleep quality/quantity at specific developmental windows. Here we present preliminary data of our new chemogenetic model for which we can disturb sleep at specific time points between postnatal day P21 and P54 by targeting brain nuclei promoting wakefulness through the stimulation of GABAergic neurons in the ventral pallidum. We assessed the sleep amounts and quality of these animals by recording their neural (EEG) and muscular (EMG) activity. Metabolic parameters during and after sleep disturbances were assessed with metabolic cages (energy expenditure, respiratory exchange rate, food intake, weight, activity), adipose tissue histology and plasma collection (hormones and proteins). Our preliminary results indicate successful sleep deprivation concomitant with decreased respiratory exchange rate indicating a shift toward lipid oxidation as a primary energy source.
Summary This scoping review was commissioned by the Norwegian Food Safety Authority. The aim was to update a previous scoping review of research literature on the effects of emulsifiers, stabilisers and thickeners (EST) on the gastrointestinal (GI) tract, specifically agar (E 406), sodium alginate (E 401), carrageenan (E 407), processed Eucheuma seaweed (E 407a), sodium carboxymethyl cellulose (E 466), gellan gum (E 418), guar gum (E 412), and xanthan gum (E 415). The effects could be beneficial, adverse or neutral. A scoping review contrasts with a safety evaluation that consists of assessment of biological and chemical properties, potential toxicity of any organ, and dietary exposure estimates. It does not report on measures of the strength of the relationship between EST exposures and effects on the GI tract. The literature search covered the period from March 1, 2023 (end of search of the previous review) to June 11, 2024. The search strategy and the eligibility criteria were the same in the previous and the updated scoping reviews. Fifteen studies fulfilling the eligibility criteria were identified in the previous scoping review (VKM, 2023). In addition, 214 studies fulfilled all eligibility criteria except the criterion that the substance tested must be in accordance with the regulations for food additives in the EU and Norway. The information about the substance tested in these studies was insufficient, and to obtain this information for the present update, the VKM sent requests by email to the corresponding authors of the publications, whenever such contact information was available. If delivery failed, an effort was made to identify a new email address to which the request was re-sent. Six additional studies from five publications were included following receipt of requested information. No studies were included from the updated literature search. Four of the included studies examined effects of sodium alginate (E 401) and guar gum (E 412) in humans and two other studies examined effects of guar gum (E 412) and carboxymethyl cellulose (E 466) in pigs. From both the previous scoping review (VKM, 2023) and the present update, 21 controlled studies fulfilling the eligibility criteria were identified: five studies in humans and 16 in animals. The dose ranges reported or estimated, across all ESTs in the human and animal studies (four different species), were 36-214 mg/kg bw per day and 51-6000 mg/kg bw per day, respectively. The study durations of the human controlled studies were between 1 day and 1 week, i.e. acute exposures only. Study durations were subchronic (exposure ≥13 weeks) in four of the animal experimental studies and subacute (≤12 weeks) in the remainder. The endpoints addressed in the human studies were: • Faecal weight and consistency • Gastric emptying (time and frequency) • Glucose and insulin homeostasis • Satiety and appetite The endpoints addressed in the animal studies were: 10 Update of the scoping review of research on gastrointestinal effects of selected EST • Changes in gut microbiota composition or number of bacteria • Enzymatic activity (digestive, microbial, cell proliferation, and inflammatory) • Intestinal utilisation and fermentation of nutrients • Macroscopic changes (stomach, small intestine, colon) • Microscopic changes (digestive tract) including inflammation • Mucosal weight, content (colon) • Presence of blood or mucus in faeces • Tumor promotion in cancer-induced mice (genetic or chemical) The risk of bias was assessed as high in the human studies and as high and moderate in the animal studies. High risk of bias means that there is high likelihood that the features of the study design or conduct of the study will give misleading results and thus, conclusions. Conclusion There were few eligible studies on the effects of agar (E 406), sodium alginate (E 401), carrageenan (E 407), processed Eucheuma seaweed (E 407a), sodium carboxymethyl cellulose (E 466), guar gum (E 412) and xanthan gum (E 415) on the gastrointestinal tract. In most of the studies the potential was high for systematic errors in the results or findings. None of the studies lasted long enough to evaluate long-term exposure in humans. Thus, the evidence base will be weak for assessment of the risk for negative effects on the gastrointestinal tract in humans. The conclusion in the present updated scoping review, after inclusion of six additional studies, remains the same as in the previous scoping review (VKM, 2023). Key words: Colon, mapping review, eligibility criteria, EU regulation, food a
Obesity and poor sleep are concurrent health epidemics in adolescents. This is especially concerning given that adolescents are getting less and less sleep as technology invades their bedrooms. Several studies point to adolescence as a critical period for sleep and adipose tissue development, implying that poor sleep during this period might alter the normal development of adipose tissue. To investigate whether adolescent sleep quality contributes to the emergence of metabolic dysfunctions later in life, we propose to establish new rodent models of reversible sleep deprivation for which we can turn on/off sleep quality/quantity at specific developmental windows. Here we present preliminary data of our new chemogenetic model for which we can disturb sleep at specific time points between postnatal day P21 and P54 by targeting brain nuclei promoting wakefulness through the stimulation of GABAergic neurons in the ventral pallidum. We assessed the sleep amounts and quality of these animals by recording their neural (EEG) and muscular (EMG) activity. Metabolic parameters during and after sleep disturbances were assessed with metabolic cages (energy expenditure, respiratory exchange rate, food/water intake, weight), adipose tissue histology and plasma collection (hormones and proteins). Our preliminary results indicate successful sleep deprivation concomitant with decreased respiratory exchange rate indicating a shift toward lipid oxidation as a primary energy source.
Traumatic spinal cord injury (SCI) induces rapid changes in body composition, energy metabolism, and nutritional requirements. Substantial skeletal muscle loss and reduced energy expenditure occur early after injury, while adipose tissue may accumulate even in the absence of weight gain. At the same time, weight loss and malnutrition are common during the acute and subacute phases, creating challenges for nutritional assessment and care. This thesis investigated nutritional challenges and changes in body composition during the first year after traumatic SCI. Three complementary studies examined longitudinal changes in body composition using neck-to-knee magnetic resonance imaging (MRI), the prevalence of malnutrition and applicability of the Global Leadership Initiative on Malnutrition (GLIM) criteria, and the effect of a structured, individualized dietitian-led nutritional intervention compared with usual care. Longitudinal MRI demonstrated substantial loss of skeletal muscle and accumulation of adipose tissue during the first year post-SCI, with more pronounced changes among individuals with motor complete injuries. Malnutrition was highly prevalent during subacute rehabilitation, while injury-related changes in body composition complicated the interpretation of reduced muscle mass as a criterion for malnutrition. In the randomized controlled trial, the intervention did not significantly affect the primary outcome, total fat mass. However, favorable between-group differences were observed for waist circumference and estimated visceral adipose tissue, suggesting that individualized dietitian-led nutritional care may attenuate adverse adiposity trajectories during the first year after SCI. Together, the findings demonstrate the complexity of nutritional risk following SCI and highlight the limitations of relying on body weight alone. Assessment of body composition, dietary intake, and individual energy requirements may provide a more comprehensive basis for tailored nutritional care. The findings highlight the potential value of structured, individualized dietitian-led nutritional follow-up as part of SCI rehabilitation and continued care after discharge.
Current food systems fail to deliver good health and are major drivers of environmental change. The aim of this thesis was to address key questions about the health and environmental implications of implementing the Nordic Nutrition Recommendations 2023 (NNR2023) and other dietary frameworks, including the Norwegian Food-Based Dietary Guidelines (FBDGs, 2012) and the EAT-Lancet Planetary Health Diet (PHD), under Norwegian conditions. The work uses detailed intake data from the national Norkost 3 (2010–2011) and Norkost 4 (2022–2023) dietary surveys of adults and older adults, linked to life cycle assessment data for six environmental indicators (e.g. greenhouse gas emissions, land use, eutrophication). We quantified the environmental impact of Norwegian adult diets across six indicators, assessed adequacy of utilizable protein in diets with higher plant protein shares, and applied constrained optimization to model culturally relevant diets that meet NNR2023 while reducing environmental pressures. Current Norwegian diets have high environmental footprints, largely driven by ruminant meat and dairy. Total protein intake is almost twice estimated requirements, and two thirds of protein comes from animal sources. Our analyses show that protein intake can be reduced and partially shifted from animal to plant sources without compromising adequacy for most adults, though some older women remain more vulnerable. FBDG aligned diets reduce environmental impacts, but more plant forward patterns and optimized NNR2023 consistent diets achieve considerably larger reductions, at the cost of marked changes in food choice. The findings highlight national FBDGs as a central tool to meet public health and environmental goals. However, the thesis work also underscores that achieving material dietary changes will require strong policy action and structural changes in food culture, particularly around ruminant meat, high fat dairy and the very low intake of legumes and other plant proteins.
Autophagy is the eukaryotic cell’s renovation and degradation system and is essential for cellular homeostasis. In brief, this process is regulated by a core autophagy machinery that promotes the biogenesis of a double-membraned vesicle that isolates cellular content destined for degradation in the lysosome. The selective autophagy of mitochondria, known as mitophagy, involves specific mitochondrial determinants that interact with the core autophagy machinery for efficient mitochondrial degradation. The major aims of this thesis were to characterise the molecular mechanisms of hypoxia-induced mitophagy, with a specific focus on how discrete mitochondrial subdomains may be differentially targeted to this pathway. Furthermore, an aim was to identify novel mitophagy regulators and characterise the role of autophagy and mitophagy regulators in a cancer setting. In conclusion, the work done across the three articles in this thesis demonstrated the fascinating diversity of autophagy molecular mechanisms. The two first articles included comprehensive high-throughput analyses on original datasets and identified novel mitophagy regulators in hypoxia. Further cell biological characterisations illustrated that there are differential mechanisms and paths of hypoxia-induced mitophagy. The third article characterised an autophagy regulator in cancer conditions and demonstrated its importance in cancer development via interactions to non-autophagy pathways. Overall, this work contributes to the unravelling of autophagy molecular mechanisms and may be important in further developing a fundamental understanding of cellular health and disease.
Preserving skeletal muscle integrity is essential for a healthy life. This thesis investigates the mechanisms underlying skeletal muscle deterioration during physiological aging and cancer-associated cachexia, while also exploring the intrinsic capacity of skeletal muscle to suppress cancer cell proliferation. Findings presented in this work demonstrate that the aryl hydrocarbon receptor (AHR) is required for skeletal muscle homeostasis. Myofiber AHR loss results in skeletal muscle decline in adult mice, while AHR activation with FICZ prevents dexamethasone induced atrophy by stimulating anabolic signaling and suppressing atrogene expression. Furthermore, myofiber AHR loss enhances breast cancer-induced muscle wasting in female mice, indicating that AHR protects skeletal muscle under catabolic stress. In addition, the thesis presents an in vitro co-culture model in which C2C12 myotubes suppress breast cancer cell proliferation and induce a pseudohypoxic transcriptional program. Hypoxia further inhibits cancer cell outgrowth on myotubes, an effect not replicated by myotube-secreted factors alone. Collectively, these findings identify AHR as a key regulator of muscle integrity and implicate hypoxia as a contributor of skeletal muscle cell’s resistance to cancer cell colonization.
In this thesis, we used supervised deep learning on label-free microscopy data to predict cell fate and state from purely visual information, without relying on fluorescent labeling or manual segmentation. Across three studies, we combined phase-contrast and holotomographic imaging with convolutional neural networks to tackle problems that are central to stem cell biology and cancer research: predicting the differentiation efficiency of induced pluripotent stem cell clones, identifying germ-layer lineages in differentiating cultures, and detecting macrophage-induced cancer cell death. By building segmentation-free pipelines that operated directly on image patches, we reduced the need for explicit cell masks and made our methods easier to deploy in realistic, noisy experimental settings. The overarching results showed that biological label-free images contained sufficient morphological information for deep networks to recover biologically meaningful patterns, but also revealed clear limits to what static morphology could predict. In stem cell differentiation, our models already distinguished high- from lowefficiency clones early in the protocol, and learned image cues that matched intuitive notions of colony coverage and uniformity. In germlayer prediction, endpoint-trained models decoded lineage identity from holotomographic morphology and reconstructed a plausible timeline of lineage divergence when applied retrospectively, while struggling more in mixed cultures with overlapping lineages. In the cancer cell death study, deep learning distinguished dying from alive cells at the time of death, yet early prediction beyond a short pre-death window remained difficult, indicating that death morphology emerged abruptly rather than gradually over many hours. Together, these findings support the view that deep learning on label-free microscopy could provide non-destructive, scalable readouts of cell fate, while emphasizing the need for time-aware models, richer training labels, and improved domain generalization to fully exploit biological label-free imaging in biomedical workflows.
Antibodies and B-cell receptors are central components of the human adaptive immune system. These molecules, collectively termed immunoglobulins, can bind a wide range of pathogens with remarkable specificity. This breadth of recognition is achieved through somatic recombination and hypermutation of the loci that encode immunoglobulins. The immunoglobulin heavy chain (IGH) locus encodes the largest subunit of this molecule, which forms the central scaffold, contributes to antigen binding, and mediates effector functions. The IGH locus is genetically complex due to extensive repetitive sequences, segmental duplications, and structural variation, which has limited comprehensive characterization; to date, the locus has been fully resolved only twice. The IGH locus displays considerable genetic variation between individuals, yet much of this diversity is still unmapped. Because germline IGH variation shapes the expressed antibody repertoire and influences immune responses to infection and vaccination, gaps in our understanding of IGH diversity impede efforts to study these germline effects. Closing this gap is therefore essential for advancing immunogenetics. A novel method for characterizing the IGH locus is presented in this thesis. We demonstrate that this method generates single-contig complete haplotypes with very few errors and employ it to 16 donors, completely resolving 31 new IGH haplotypes. Across these assemblies, we identify novel alleles, copy number variations and structural variants, which are likely to have biologically meaningful effects. The motivation for IGH locus characterization was to investigate haplotypes carrying different IGH constant gene polymorphisms. In particular, the G1m1 allotype of IgG1, which has a heavily biased expression pattern in multiple sclerosis. Using our method on a cohort of Norwegian patients, we mapped the genetic architecture of their IGH to reveal differences between G1m1 and non-G1m1-containing haplotypes. In the second part of this thesis, the emphasis turns from IGH germline genetics to expression of IGH transcripts. Immunoglobulin repertoires are frequently analyzed in the context of vaccination, infection, and autoimmunity, where selective usage of specific variable genes can shape functional outcomes. However, analyses of IGH constant-gene usage typically stop at the isotype level, overlooking the potential relevance of allelic variation in constant regions. To address this gap, we developed a tool for reconstructing and analyzing immunoglobulin sequences from single-cell RNA-seq data. This enables robust recovery of full-length paired heavy and light chains, even from cells with low transcript abundance. Overall, this thesis broadens our understanding of IGH genetic diversity and introduces two methodological approaches that make it possible to study immunogenetic variation with far greater resolution. These tools lay the groundwork for future efforts to link germline architecture with the behavior of expressed antibody repertoires.
This thesis is situated within occupational cancer epidemiology and examines occupational exposures and cancer incidence among Norwegian offshore petroleum workers. It aimed to profile the Norwegian Offshore Petroleum Workers (NOPW) cohort and evaluate cancer incidence compared to the general population, harmonize work histories for exposure quantification, and examine associations between benzene exposure and risk of lung and colorectal cancer (CRC). The NOPW cohort comprises approximately 28,000 offshore petroleum workers who completed a survey containing information on work history, sociodemographic characteristics, and lifestyle factors. Cancer incidence was assessed through linkage with the Cancer Registry of Norway. To improve exposure assessment, a harmonization method was developed to address overlapping employment records before linkage to job exposure matrices. Associations between occupational benzene exposure and cancer risk were examined prospectively among male cohort members. The findings showed a small excess of overall cancer risk compared with the Norwegian general population, with increases of 7% among males and 13% among females. Elevated risks were observed for pleural mesothelioma, breast cancer, and prostate cancer in males, and for melanoma and acute myeloid leukaemia in females. Harmonization of overlapping employment records reduced the cohort's total employment duration by 10%, demonstrating the importance of this procedure for accurate exposure assessment. For lung cancer, a pattern of increased risk was observed with increasing benzene exposure, although these associations were not statistically significant for lung cancer overall. Positive associations were identified between duration of benzene exposure and lung adenocarcinoma. For CRC, positive associations were found for overall CRC, right sided colon cancer, and rectal cancer with respect to both average exposure intensity and duration. No clear associations were found for left sided colon cancer, although an increased risk was observed in the highest quartile of average intensity compared with unexposed workers. Overall, the thesis provides a detailed profile of the NOPW cohort, presents a method for handling overlapping employment records, and contributes with new insights into benzene’s etiological role for lung cancer and CRC.
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Background: Thymine glycol (Tg) is a common oxidative deoxyribonucleic acid (DNA) lesion that can compromise genome stability, and has previously only been mapped using indirect, comprehensive methods. Endonuclease III-like protein 1 (NTHL1) aids in Tg repairment in base excision repair. Nanopore sequencing is a tool that permits direct sequencing off low sample amounts. Aim: This thesis aimed to develop a method for natively identifying and mapping Tg in DNA, for enabling clinical applicability. Methods: Two strategies for Tg detection were tested. First, isolated DNA from human embryotic kidney cells was studied using a catalytically dead 6xHistidine (His)-tagged NTHL1- K212Q, with point mutation generated by site‐directed mutagenesis, and a wild-type (wt) variant, both heterologously expressed. Second, in‐cell Tg was investigated in plasmids of wt and mutated, using FLAG-tagged NTHL1. In both strategies, cleavage under targets and tagmentation (CUT&Tag) was applied to generate Tg‐enriched DNA fragments, which were subsequently analyzed by nanopore sequencing and processed into graphical outputs. Results: 6xHis-NTHL1-K212Q from the isolated DNA strategy did not produce readable signals, whereas FLAG-NTHL1 from the in-cell strategy did. A follow-up experiment included NTHL1 and non-NTHL1 constructs, both yielding similar signal pattern to the initial in-cell experiment, a result consistent with Tn5 insertion bias. Conclusion: Isolated DNA experiments failed to yield reads, likely reflecting poor suitability of the adapted CUT&Tag protocol and potential effects of His-tagging and heterologous expression. In-cell experiments produced reads, but the sequence patterns were best explained by Tn5 insertion bias rather than NTHL1 binding or Tg detection. Overall, this study demonstrates that while CUT&Tag combined with nanopore sequencing is a conceptually promising native approach for Tg detection, the current implementation lacks sufficient robustness and sensitivity, and substantial methodological optimization is required.
Abstract Background: Wheelchair (WC) users are at increased risk of low bone mineral density (BMD), primarily due to reduced mechanical loading. Low BMD is also a primary indicator of Relative Energy Deficiency in Sport (REDs), but it remains unclear whether low BMD in WC users is mainly explained by reduced mechanical loading or also associated with REDs-related indicators and contributors. Objective: This study aimed to describe REDs-related indicators and contributors in WC users, examine their associations with BMD Z-scores, explore differences across clinical, mobility, and physical activity subgroups, and compare questionnaire-based REDs screening with measured REDs-related indicators and contributors. Methods: Cross-sectional baseline data from 45 WC users with different impairments were analyzed. BMD and fat-free mass were assessed by dual-energy X-ray absorptiometry (DXA), with low BMD defined as Z-score < -1.0. Dietary intake was assessed by three 24-hour dietary recalls, and questionnaire-based REDs risk was assessed by the Low Energy Availability in Females Questionnaire (LEAF-Q) and Low Energy Availability in Males Questionnaire (LEAM-Q). REDs-related indicators and contributors included low BMD, low triiodothyronine (T3), low testosterone, low estradiol, low estimated energy availability (EA), and low carbohydrate intake. Results: Low BMD was highly prevalent and the most frequent REDs-related indicator, affecting 43% at the lumbar spine, 79% at the femoral neck, and 76% at the total hip. Low carbohydrate intake was observed in 44%, low estimated EA was rare, no participants had low T3, and 48% of male participants had low testosterone. Estradiol interpretation was limited by missing data and hormonal contraceptive use. BMD Z-scores were not significantly associated with other REDs-related indicators or contributors in adjusted analyses. Femoral neck and total hip BMD Z-scores were lower in participants with cerebral palsy (CP) and spina bifida (SB) than in those with spinal cord injury (SCI), while total hip BMD Z-scores were higher in sports-active participants. Questionnaire-based screening outcomes generally did not correspond with measured indicators or contributors, except for an association between LEAM-Q and T3. Conclusion: Low BMD and low carbohydrate intake were common among WC users, but BMD Z-scores were not associated with other REDs-related indicators and contributors. BMD appeared more strongly influenced by diagnosis, physical function, and mechanical loading, underscoring the need for population-specific REDs assessment tools and cut-offs.
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Abstract Background: Motivational Interviewing (MI) is a and collaborative guiding counselling approach designed to strengthen intrinsic motivation for change. It is grounded in partnership, acceptance, compassion, and evocation, and often described through four stages: engaging, focusing, evoking, and planning. Such behavioral support for lifestyle change may benefit various patient groups, including patients with colorectal cancer (CRC). CRC is the third most common cancer globally and the second most common in Norway. The Norwegian Dietary Guidelines and Colorectal Cancer Survival (CRC-NORDIET) study is a randomized controlled trial investigating a dietary intervention based on the Norwegian food-based dietary guidelines (FBDG). The intervention uses MI to support dietary change among the participants following CRC-surgery. Aim: The aim of this master´s project was to examine the impact of MI within the CRC-NORDIET diet intervention by describing changes in participants’ motivation throughout the first 3 years of the study. Dietary goals given across different levels of motivation was characterized and examined in relation to adherence to the Norwegian FBDG. Results: Over 70% of the participants reported high motivation for dietary change across all study visits during the intervention year. A significant decline in the high motivation group was observed during the 3-year follow-up, although, about half of the participants still reported high motivation. The most frequently assigned dietary goals were additive: increase intake of fruit, vegetables, fish, and increase in physical activity. Dietary goals related to alcohol, unnecessary supplement use, and salt reduction were least frequently assigned (reductive advice). No significant differences were observed between motivation groups regarding assigned dietary goals or adherence to the Norwegian FBDG at baseline. However, participants in the high motivation group had a significantly higher intake of unsalted nuts (p=0.02) and lower alcohol intake (p=0.01) than participants in the low motivation group initially. Conclusion: Participants maintained a high motivation for dietary change throughout the 3-year follow-up, although motivation declined over time. Additive dietary advice may have been perceived as more achievable compared to reductive dietary advice which is more likely to be experienced as restrictive and involving greater sacrifice. The use of MI may have influenced participants’ motivation, however, this could not be assessed in the present thesis. Nevertheless, it is plausible that MI may have contributed to sustaining motivation for dietary changes.
Introduction: In the diet, animal protein sources (APS) have higher protein quality compared to plant protein sources (PPS) due to higher digestibility and more beneficial composition of indispensable amino acids (IAAs). Also, APS have higher climate footprint than PPS, and a high consumption of APS is thus not considered sustainable. To reduce climate emissions from diets, there is recommended to substitute some APS with PPS. In the context of such a dietary transition, it is important to consider the adequacy of digestible protein and IAA intakes. As of today, digestible protein and IAA adequacy is not assessed in the diet of Norwegian children. Aims: This present Master´s thesis aimed to assess the plant protein proportion (PPP) among Norwegian three-year-olds, and to assess its relationship with the children´s dietary habits, sex and anthropometrics, and the caregivers´ living environment and education level. Further, this thesis aimed to assess the relationship between PPP and protein adequacy and dietary climate emissions, and to compare the intake of main protein sources with the EAT-Lancet diet. Method: Dietary intakes among 989 of 2394 three-year-olds participating in the PreventADALL study were collected from a food frequency questionnaire (FFQ), and data on dietary habits were collected from 637 of these. Data on child´s sex, weight and height, and caregivers´ living environment, education level and age, and mothers´ body mass index (BMI) were also collected. NutriFoodCalc (NFC) was used to assess daily intakes of energy, protein, IAAs and food products, and dietary global warming potential (GWP) for each food product. The PPP (%) was calculated as daily plant protein intake relative to daily total protein intake. Digestible protein adequacy was assessed using true ileal digestibility (TID) values and the Protein Adequacy and Quality Score (PAQS). Dietary climate emissions were assessed as GWP (kg CO2-equivalents) and compared to dietary emission boundaries from EAT-Lancet Commission, and intakes of main protein sources were compared to intake targets and ranges in the EAT-Lancet diet. Trends across PPP quintiles were analyzed for the children´s dietary habits, sex, anthropometrics, and the caregivers´ living environment and education level, and for protein and IAA adequacy, GWP and daily intakes of main protein sources. Results: The median PPP in the 989 three-year-olds was 35% and ranged from 25% in the first PPP quintile to 48% in the fifth quintile. With increasing PPP quintiles, there was an increasing trend in avoidance of dairy and eggs due to food allergies or intolerances, and a higher proportion of boys. No trends in children´s BMI and caregivers´ living environment and education level were observed across the quintiles. All children had adequate intakes of digestible protein and IAAs, although intakes of crude protein and digestible protein and IAAs decreased over the PPP quintiles. Dietary GWP exceeded the climate boundaries set by EAT-Lancet in all PPP quintiles, and dairy products and red meat were the main contributors in all quintiles. Despite a GWP reduction over the PPP quintiles, driven primarily by reduced dairy emissions, the GWP in the fifth PPP quintile still exceeded the climate boundaries by more than two times. Intakes of dairy and red meat exceeded upper intake limits in the EAT-Lancet diet, whereas intakes of pulses, nuts and seeds and poultry were below optimal intake targets in our sample. Despite significant reduced intake of all APS over PPP quintiles, red meat intake still exceeded the upper intake limit in the fifth PPP quintile, and dairy intake was just barely below its upper intake limit in this quintile. Conclusion: Among young Norwegian children, most of the daily protein intake is from APS. Thus, digestible protein and IAA inadequacy is not common in this population. The high intake of APS contributes to unsustainably high dietary climate emissions, of which milk, yoghurt, and red meat contribute the most. The intakes of dairy and red meat are too high, whereas consumption of pulses, nuts and seeds and poultry are lower than optimal to align with a sustainable diet according to EAT-Lancet Commission. Shifting towards more plant-based diets would reduce dietary climate emissions without compromising digestible protein and IAA adequacy. Among young Norwegian children, a sustainable dietary transition would be to reduce intake of dairy products and red meat in favor of more PPS, especially pulses, nuts and seeds, and to choose lower-impact APS such as poultry, fish and eggs.
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Abstract Background: South Asian populations are at increased risk of developing type 2 diabetes mellitus (T2DM), often at a younger age and at lower body mass index levels than other ethnic groups. This increased susceptibility is partly explained by a genetic predisposition that results in a distinct metabolic profile, characterised by limited adipose tissue buffering capacity and greater ectopic fat deposition. In addition, they have an impaired beta-cell compensatory function. Women with a history of gestational diabetes mellitus (GDM) represent a particularly high-risk group, and dietary patterns are among the most important modifiable risk factors influencing the progression to T2DM Aim: This master’s thesis aimed to describe the dietary intake of South Asian and Nordic women with previous GDM, and to investigate the association between dietary intake, insulin sensitivity and beta-cell function. Methods: This cross-sectional study used data from the DIASA 1 study and included 227 women with previous GDM, 133 South Asian women and 94 Nordic women, recruited from three hospitals in the Oslo area. Two datasets were used in this master’s thesis, one containing key background and clinical characteristics collected at the study visit, and one containing dietary data assessed by a culturally adapted web-based food frequency questionnaire. Descriptive statistics were performed to describe macronutrient, micronutrient and food group intake. Compliance with the Nordic Nutrition Recommendations 2023 was also evaluated. Multivariable linear regression analyses, including isocaloric substitution models and assessment of effect modification by ethnicity, were performed to examine associations between dietary intake and parameters of insulin sensitivity and beta-cell function. Results: Dietary patterns differed between the two groups. South Asian women had a higher percentage of energy from carbohydrates (44 vs 40 E%) and dietary fibre (2.7 vs 2.4 E%), and a lower percentage from saturated fat (11 vs 13 E%) compared with Nordic women. They also consumed less red meat (12 vs 68 g/day). Although total protein intake, assessed both as E% and g/day, did not differ between the groups, a higher proportion of South Asian women had a protein intake below the NNR2023 recommendation of 0.83 g/kg body weight compared with Nordic women (20% vs 9%, respectively). South Asian women also had a higher vitamin D intake than Nordic women (15 vs 9.3 µg/day), largely driven by supplement use. Energy percentages from neither saturated fat nor carbohydrate intakes were significantly associated with insulin sensitivity or beta-cell function in fully adjusted models. However, carbohydrate quality, defined as the fibre-to-carbohydrate ratio, was positively associated with both HOMA2-S (β= 0.44, p<0.001) and the Matsuda Index (β= 0.37, p=0.002), with no interaction by ethnicity. An unexpected ethnicity-specific interaction was observed for energy percentage from saturated fat intake and beta-cell function (Disposition Index, p=0.013), in the opposite direction of the hypothesis. Conclusion: Dietary patterns differed between South Asian and Nordic women with previous GDM, with the South Asian group showing a relatively more favourable nutrient profile. Carbohydrate quality was the most relevant dietary determinant of insulin sensitivity in this population. The observed ethnicity-specific interaction for saturated fat and beta-cell function most likely reflected broader differences in dietary patterns rather than an isolated effect of saturated fat. Further studies are needed to determine whether culturally tailored dietary recommendations can influence the metabolic susceptibility in South Asian women with previous GDM.
Abstract Introduction: Alzheimer’s disease (AD) is the third biggest cause of death in Norway, and the largest in terms of health cost. The concept of AD as a systemic disorder is emerging, with evidence suggesting the liver may influence disease progression through metabolic and clearance pathways. Long-chain omega-3 polyunsaturated fatty acids (PUFAs) regulate hepatic lipid metabolism and may influence mechanisms relevant to AD pathology, but their effect on hepatic gene expression in AD remain underexplored. In this master’s thesis the aim was to investigate hepatic transcriptional responses to a long-chain omega-3 PUFA rich diet in a mouse model of AD, focusing on lipid metabolism, inflammation and AD-associated genes. Materials and methods: Hepatic gene expression was analysed by RNA-sequencing in C57BL/6N wild type (WT) and the AD model 5xFAD mice fed diets with low or enriched content of long-chain omega-3 PUFAs (EPAX) for five months. Differential expression analysis was performed within each genotype using DESeq2, followed by pathway analysis. Results: In the 5xFAD mice fed the EPAX diet, transcriptional changes were consistent with increased fatty acid β-oxidation, peroxisomal metabolism, and PPARα-associated lipid metabolism. Pathway analysis predicted activation of lipid metabolism regulated by PPARα in the 5xFAD fed the EPAX diet and was supported by altered expression of several PPARα target genes. In contrast, WT mice showed a more limited transcriptional response, with predicted activation of pathways involved in peroxisomal protein import and peroxisomal lipid metabolism, but no clear indication of PPARα activation. Expression of genes involved in endogenous long-chain omega-3 PUFA synthesis was reduced in both genotypes, while inflammatory gene expression was largely unaffected. Genes related to potential AD-related processes and the liver-brain axis, showed modest or no changes. Conclusion: This results in this master’s thesis suggests that the EPAX diet compared to control diet induced changes in hepatic gene expression. In particular, the findings indicate that long-chain omega-3 PUFAs may promote a shift towards increased fatty acid oxidation and PPARα-associated lipid metabolism in 5xFAD mice. Direct comparisons between the AD model and WT were not conducted, but the transcriptional response appeared more pronounced in the AD model. Further studies are needed to determine whether these hepatic transcriptional changes can influence AD pathology.
Introduction: Attention-deficit/hyperactivity disorder (ADHD) in adults is characterized by persistent difficulties with attention regulation and hyperactivity/impulsivity and associated with impaired executive and emotional functioning. The disorder affects multiple domains of life, including physical health, and is linked to increased mortality and reduced life expectancy, partly due to lifestyle-related factors such as unhealthy diet. Research on dietary patterns in adults with ADHD is limited. Aim: This study aimed to evaluate the effect of individualized dietary counselling on dietary patterns and cardiovascular risk factors in adults with ADHD. The primary outcome was change in diet quality assessed by the diet index score derived from the DIGIKOST-FFQ. Secondary outcomes included biological and anthropometric measures. The study also explored participants dietary habits and lifestyle-related factors. Method: A randomized controlled parallel-group trial was conducted among adults with confirmed ADHD recruited from psychiatric outpatient clinics in Vestre Viken Health Trust. Participants were allocated to the intervention group or the control group. The intervention including one counselling session based on national guidelines and motivational interviewing, with follow-up after three weeks. Bothe groups concluded data collection at baseline measurements and final measurements after six weeks. The control group received no counselling prior to the final measurements. Data collection included anthropometric measures, blood samples, and dietary assessment using a 24-hour recall and DIGIKOST-FFQ. Results: A total of 67 participants were included, with 33 randomized to the intervention group and 34 to the control group. Significant between-group differences were observed for the primary outcome, with improved diet quality in the intervention group. Between-group analyses showed significant improvement in non-HDL cholesterol and waist circumference. Within the intervention group significant reduction were observed in HbA1c, body weight, and waist circumference, while the control group showed a significant reduction in ASAT. Qualitative data identified four main themes influencing dietary behaviour, meal patterns; hunger and satiety, and ADHD-related symptoms; and changes following the intervention. Conclusion: Individualized dietary guidance improved dietary patterns in adults with ADHD, reflected by increased diet index score and selected cardiovascular risk markers. The findings suggest that tailored dietary guidance may be effective, when focusing on implementation of dietary changes in daily life. Further research is needed to assess long-term effects.
This thesis addresses a key challenge in causal inference: estimating treatment effects from observational data with unobserved confounding, especially when treatments are multivalued. It develops an instrumental variable framework for categorical treatments, focusing on identifying interpretable causal effects under realistic assumptions, carefully clarifying the target populations. The methods are motivated by a clinical application: comparing tumor necrosis factor inhibitors as first-line biologic therapy for rheumatoid arthritis. Using variation from the Norwegian drug tender system, the analyses enable head-to-head comparisons while accounting for hidden confounding, revealing differences in remission rates not detected by conventional methods. The thesis also addresses effect heterogeneity and generalizability by combining instrumental variable methods with covariate adjustment, enabling estimation of conditional treatment effects. Together, the work offers both methodological advances and clinically relevant insights, with broad applicability to comparative effectiveness research where randomized evidence is limited.
Calcific aortic valve disease (CAVD), the most prevalent valvular disorder in the elderly, causes aortic stenosis, heart failure, and death if untreated. With no pharmacological therapies available, valve replacement remains the only option. This thesis investigates the cellular and molecular mechanisms of human CAVD, focusing on valve interstitial cells (VICs) and valve endothelial cells (VECs) from stenotic and healthy valves of heart transplant recipients. Four studies employed in vitro osteogenic induction, 2D and 3D VICs-VECs co-cultures, proteomics, and NMR metabolomics. First, comparing six osteogenic media in VICs and bone marrow stem cells identified an optimal protocol and showed VICs are more responsive, making them the preferred in vitro model. Addressing diabetes as a risk factor, high glucose (25 mM) reduced calcification by 52% versus physiological levels, revealing a negative dose-response. Hyperglycemia alone does not drive calcification; secondary effects – advanced glycation end-products, oxidative stress, and inflammation – likely play a pathogenetic role. In co-cultures, VECs nearly doubled VICs calcification. VECs from calcified valves induced osteogenic differentiation in healthy VICs while suppressing myofibroblastic contraction. Proteomics revealed loss of structural and antioxidant proteins and upregulation of pro-inflammatory and remodeling proteins in diseased VECs. Notably, extracellular vesicles from VECs did not enhance calcification, suggesting direct VICs-VECs contact or paracrine signaling. Metabolomic profiling showed reduced NAD+ and adenine nucleotides in VICs from calcified valves, indicating impaired mitochondrial energy production and predisposition to osteogenic differentiation. These findings challenge traditional concepts and support an integrated CAVD model involving VECs dysfunction, intercellular communication, and metabolic reprogramming as therapeutic targets.
Intestinal failure is a rare but severe condition in which the gut cannot absorb enough nutrients and fluids to sustain health and growth, necessitating long term parenteral nutrition. While lifesaving, parenteral nutrition carries medical risks and places a substantial burden on children and their families. Gastrointestinal symptoms are common and may limit progression toward enteral nutrition and independence from parenteral support. These symptoms may be linked to dysbiosis of the gut microbiota. Antibiotics are commonly used as treatment, but alternative strategies are needed. Prebiotics, nondigestible food components that selectively stimulate beneficial gut bacteria, may improve microbiota balance, reduce gastrointestinal symptoms, and potentially enhance health related quality of life. This thesis investigates how nutritional support and gastrointestinal symptoms influence health related quality of life in children with intestinal failure and their families and evaluates prebiotic supplementation as a potential therapeutic approach. Using baseline data from a cross sectional analysis, health related quality of life was assessed. Parent reported quality of life was markedly reduced compared with healthy peers, whereas children’s self reports did not differ significantly. The need for parenteral nutrition placed a substantial burden on parents and impaired family functioning. Gastrointestinal symptoms were strongly associated with reduced quality of life. In a randomized controlled trial, prebiotic supplementation resulted in a significant reduction in gastrointestinal symptoms. Microbiota composition was altered, including increases in selected beneficial taxa and transient reductions in potentially pro inflammatory bacteria. Responses varied according to baseline microbiota composition and intestinal anatomy. Prebiotics may therefore benefit a subset of children with intestinal failure and highlight the importance of individualised care.
Tankyrase 1 and 2 (collectively referred to as TNKS) are post-translational modifying enzymes that regulate multiple cellular processes, including the wingless-type MMTV integration site family (WNT)/β-catenin and yes 1 associated transcriptional regulator (YAP) signaling pathways. Pathogenic activation of these pathways is implicated in cancer and fibrotic diseases such as idiopathic pulmonary fibrosis (IPF). In cancer, WNT/β-catenin and YAP signaling promote tumorigenesis, metastasis, and immune modulation, whereas in IPF these pathways contribute to disease initiation and progression. Because TNKS regulate both pathways, they represent attractive therapeutic targets. Over the past decade, several small-molecule TNKS inhibitors have been developed, most of which bind to the catalytic domains of TNKS. These compounds stabilize the direct TNKS targets axin 1 (AXIN1) and angiomotin-like 1 (AMOTL1), negative regulators of WNT/β-catenin and YAP signaling, respectively. However, no TNKS inhibitor has reached clinical use, mainly due to target-related toxicities, particularly in the intestine. This thesis presents the development and characterization of new TNKS inhibitors with improved drug-like properties and explores their therapeutic potential in selected tumor models and IPF-relevant systems. In Paper I, we performed an antiproliferative screen of 537 human tumor cell lines treated with the early-generation TNKS inhibitor G007-LK and identified a subset of highly TNKS inhibitor-sensitive colorectal, ovarian, renal, and lung cancer cell lines. Mechanistic analyses showed that treatment suppressed WNT/β-catenin, YAP, and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic/AKT serine/threonine kinase (PI3K/AKT) signaling. These changes were associated with reduced expression of the MYC proto-oncogene, bHLH transcription factor (MYC), and decreased cell growth. Despite these effects, G007-LK lacked the pharmacological properties required for clinical translation. To address these limitations, Papers II and III focused on structure-activity relationship (SAR) analysis, crystallography, and chemical optimization within a 1,2,4-triazole TNKS inhibitor series, leading to the development of OM-1700 and subsequently OM-153. OM-1700 displayed improved potency, specificity, and absorption-distribution-metabolism-excretion (ADME) properties compared with earlier compounds. Further optimization led to OM-153, which showed sub-nanomolar inhibition of WNT/β-catenin signaling and potent antiproliferative activity in the TNKS inhibitor-sensitive, APC regulator of Wnt signaling pathway (APC)-mutated colorectal cancer (CRC) cell line COLO 320DM. OM-153 also demonstrated improved pharmacokinetic (PK) properties in mice. In Paper IV, OM-153 was evaluated in mouse tumor models. In COLO 320DM xenografts, oral OM-153 (0.33-10 mg/kg, twice daily) treatment resulted in dose-dependent inhibition of WNT/β-catenin signaling. In an immunocompetent B16-F10 melanoma model, OM-153 combined with anti-programmed cell death 1 (PDCD1, PD-1) therapy enhanced antitumor responses in an otherwise immunotherapy-resistant setting. Toxicity assessments showed that high doses (100 mg/kg twice daily) caused intestinal and renal injury, whereas therapeutic doses (10 mg/kg twice daily) were well tolerated. These findings define the antitumor effects and therapeutic window of OM-153 in mouse models and support further preclinical development. In Paper V, the evaluation of OM-153 was extended to IPF disease models. Primary human lung fibroblasts cultured in 2D and 3D systems, as well as precision-cut lung slices (PCLS) from non-pulmonary fibrosis (non-PF) donors, were stimulated with an IPF-relevant cytokine (IPF-RC) cocktail. In addition, bleomycin-challenged mice and PCLS from end-stage pulmonary fibrosis (PF) patients were treated with OM-153. Across in vitro, in vivo, and ex vivo models, OM-153 stabilized AXIN1 and AMOTL1, suppressed WNT/β-catenin and YAP signaling. In parallel, it reduced profibrotic extracellular matrix (ECM) gene expression and deposition. These findings indicate that TNKS inhibition represents a mechanistically distinct antifibrotic strategy and support further translational development in IPF. In Paper VI, we explored an alternative inhibitor design by targeting a previously underexplored subsite near the nicotinamide pocket of TNKS. Using quinazolin-4-one scaffolds with C-8 (and C-7) substitutions, we confirmed subsite engagement by X-ray crystallography. Two analogues displayed improved biochemical potency toward TNKS2 and suppressed WNT/β-catenin signaling in a cellular reporter assay. One analogue also reduced COLO 320DM cell growth, indicating a potential route toward more selective TNKS inhibitors. Overall, the findings presented in this thesis show that TNKS inhibition stabilizes AXIN1 and AMOTL1, effectively suppresses WNT/β-catenin and YAP signaling, and exerts antitumor and antifibrotic effects across in vitro, in vivo, and human ex vivo models. Importantly, OM-153 demonstrated a therapeutic window in mouse models, supporting its further preclinical development in cancer and pulmonary fibrosis. Alternative TNKS inhibitors engaging a subsite near the nicotinamide pocket provide a complementary strategy for improving selectivity. Together, these results provide a foundation for continued preclinical development of TNKS inhibitors and suggest that TNKS inhibition represents a therapeutic approach with translational potential.
The COVID-19 pandemic posed unprecedented challenges for Norwegian intensive care unit (ICU) health care professionals. They faced stressors like infection risk, prolonged use of protective equipment, increased workload, a rapid rise in patient numbers and excess death. The aim of this thesis was to explore the working conditions and symptoms of psychological distress among nurses, physicians and managers working in ICUs by a national cohort survey combined with focus group interviews. The study population held an average of 19 years of professional experience. A majority reported being professionally prepared and 46% were afraid of infection. At one-year follow-up, burnout was the most prevalent psychological distress (14%), followed by anxiety and depression (13%), and post-traumatic stress (5%). Anxiety and depressive symptoms and post-traumatic stress were associated with fear of infection and a history of depression. Post-traumatic stress was in addition associated with loneliness, whereas fewer years of professional experience were associated with burnout. Focus group interviews revealed a more complex picture. The participants reported being conflicted between a strong sense of duty and the fear of infection, in particular infecting their families. The use of personal protective equipment was described as exhausting, and it was emotionally difficult to deny relatives access and to handle deaths. Participants reported managers not being consistently present, which resulted in ambiguous responsibilities and collaboration difficulties. Less experienced nurses felt given responsibilities beyond their competence. However, cohort units provided a safe setting for learning, rapid assistance in emergencies, and valued collegial psychosocial support, factors that together led to a sense of mastery. ICU health care professionals in this study exhibited low levels psychological distress. Cohort units provided safer working conditions and led to a sense of mastery.
Smoking is a major modifiable risk factor for recurrent events and premature mortality in patients with atherosclerotic cardiovascular disease (ASCVD). Hospitalisation represents a key opportunity for smoking cessation intervention. However, a substantial proportion of patients continue to smoke after discharge, and effective and scalable cessation strategies are needed. The aims of this thesis were to assess the clinical effectiveness and cost-effectiveness of a smoking cessation intervention combining a nurse-led motivational interviewing session during hospitalisation with proactive referral to community-based follow-up. The thesis is based on two open-label, blinded-endpoint randomised controlled trials and a health economic evaluation conducted at three Norwegian hospitals between 2021 and 2023. Adult patients with ASCVD who smoked daily prior to hospitalisation were randomised to either the intervention, consisting of a motivational interviewing session during hospitalisation and proactive referral to a municipal Healthy Life Centre, or to usual care with brief cessation advice and written information about the Healthy Life Centre programme and how to access it. Smoking cessation rates were substantially higher in the intervention group. At six months, abstinence was 50% compared to 25% in the control group (OR 3.08, 95% CI 1.70–5.55). The intervention also increased participation in follow-up services and use of cessation pharmacotherapy. The economic evaluation, conducted from a hospital perspective, showed lower hospital costs during 16 months of follow-up and increased survival, resulting in a high probability of cost-effectiveness when projected over a lifetime horizon. In conclusion, a nurse-led motivational intervention initiated during hospitalisation and combined with proactive referral to follow-up in municipal Healthy Life Centres improves smoking cessation and is likely to be a cost-effective strategy in patients with ASCVD.
Survival after childhood and young adult cancers has improved massively, but more than half experience physical and mental health-related late effects. Mental health burdens such as fatigue, psychological distress, depression, anxiety, and post-traumatic stress symptoms affect health-related quality of life. These symptoms are often related and rarely occur in isolation. Our understanding of how these symptoms co-occur is limited, although physical activity interventions have shown promise in reducing their burden. This thesis aimed to identify childhood and young adult cancer survivors with similar patterns of fatigue and mental health burdens using a method called latent profile analysis in the nationwide Norwegian questionnaire-based NOR-CAYACS study. It then investigated the effects of a personalized physical activity intervention on fatigue and mental health in the Swiss Survivor Fitness (SURfit) randomized controlled trial among survivors of childhood cancer. Four distinct symptom burden profiles were identified. Most survivors reported low symptom burden, others experienced either elevated fatigue or trauma-related responses such as anxiety and fear of recurrence, or a combination of both. The physical activity intervention improved fatigue, supporting its role as a non-pharmacological strategy. However, physical and biological changes did not mediate the improvement, suggesting that psychological or behavioral factors may be involved in the observed benefits. The findings demonstrate that symptom burden among cancer survivors is heterogeneous, supporting the need for tailored follow-up care based on individual symptom profiles. Personalized physical activity interventions may moreover be an effective strategy to reduce fatigue and improve long-term survivorship care.
Air pollution is a major contributor to global disease burden. Key pollutants include particulate matter and gaseous compounds. Exposure to natural green and blue spaces may mitigate the harmful effects of air pollutants. Environmental pollutants can alter gene expression by regulating transcription factors. The aryl hydrocarbon receptor (AHR) is a nuclear receptor activated by organic pollutants such as TCDD. AHR is also modulated by dietary ligands, including activation by 3,3’-diindolylmethane (DIM) and inhibition by resveratrol. In Paper I, we investigated genome-wide AHR binding and gene expression regulation after treatment with TCDD, E2, DIM, and resveratrol. Both TCDD and DIM activated AHR; however, DIM-induced AHR binding was enriched at estrogen response elements and regulated developmental genes, whereas TCDD primarily affected metabolic genes. These findings highlight that distinct environmental exposures can differentially regulate AHR activity, to influence chronic disease risk. Papers II and III examined associations between air pollution, natural spaces, and gene expression in population-based children and adult cohorts. In children, PM2.5 exposure was associated with expression levels of 86 genes (FDR < 0.25), including GFI1B, TSC22D1, and GNG11. Gene set enrichment showed negative associations between PM2.5 and interferon alpha and gamma pathway genes. In adults, the exposure to PM2.5 was also associated with the expression of the highest number of differentially expressed genes. Negatively associated genes were enriched for cell cycle, DNA repair, and metabolism as well as oxidative phosphorylation. Green space within 300 meters of residence was negatively associated with adaptive immune response genes in both child and adult cohorts. Overall, PM2.5 showed the most consistent gene expression associations across age groups. Green space may exert protective effects through modulation of immune gene expression. Additionally, dietary ligands can directly regulate pollutant activated transcription factors such as AHR.
Respiratory ailments, such as cough, breathlessness, asthma and allergy, are prevalent among workers in the seafood industry. These health problems have largely been attributed to exposure to allergenic proteins, yet the contributions of other components in the work environment remain insufficiently understood. The aim of this thesis was to investigate the relationship between occupational exposure to allergenic proteins and microbial agents in shrimp processing environments and respiratory health outcomes, including symptoms, allergic sensitisation, and inflammatory responses. Respiratory symptoms as well as allergy and asthma-related biomarkers were assessed among Norwegian shrimp processing workers using questionnaires and blood analyses. Occupational exposure was characterised through work-environment air sampling, protein measurements, microbial identification, and proteomic analyses. Shrimp processing workers reported a higher prevalence of upper and chronic lower respiratory symptoms than controls and exhibited elevated levels of inflammatory, allergy and asthma-related biomarkers. Multiple known and potential shrimp allergens were identified in workplace air, with particularly high levels of tropomyosin detected during shrimp cooking. Airborne microbial exposure was further characterised across different shrimp processing tasks using full-shift personal air sampling and molecular analyses. Higher bacterial load, species richness, and immune activation potential were observed during work processes involving raw shrimp, while cooking substantially reduced bacterial exposure. Experimental studies using human alveolar co-culture cell models demonstrated that combined exposure to shrimp allergens and microbial components can enhance inflammatory responses relative to individual exposures. Overall, the findings demonstrate that complex occupational bioaerosol exposure contributes to respiratory health risks among shrimp-processing workers, with task-specific exposure differences underscoring the need for targeted preventive measures.
The genome of eukaryotic cells resides in the nucleus and is protected by the nuclear envelope, a double membrane that regulates exchange between nucleus and cytoplasm while safeguarding genetic material. Once considered a passive barrier, the nuclear envelope is now known to be highly dynamic: it disassembles and reassembles during cell division, adapts to growth, responds to mechanical stress, and repairs after damage. Disruption of these processes compromises genome stability, triggers inflammatory responses, and contributes to disease. This thesis investigates mechanisms that maintain nuclear envelope integrity and explores how their failure affects cell fitness and fate. It shows that nuclear envelope repair relies on precisely coordinated molecular pathways that detect membrane breaches and confine repair to affected regions. Loss of control increases chromatin stress and DNA damage, undermining cell fitness. This work also reveals that mutations in the nuclear lamina raise sensitivity to mechanical stress. In adipocytes, intracellular lipid accumulation exacerbates nuclear deformation and nuclear envelope damage, causing impaired function, DNA damage, and inflammatory responses. Finally, proteins classically linked to stress responses are shown to support accurate chromosome segregation during mitosis, and their dysfunction promotes chromosome missegregation and genomic instability. Together, these findings position the nuclear envelope as an active regulator of genome protection and provide insight into cancer and inherited nuclear envelope disorders.
Background: Per- and polyfluoroalkyl substances (PFAS) are persistent environmental contaminants detected in breast milk and transferred to infants through breastfeeding. Postpartum weight loss is recommended to improve maternal health, but mobilization of chemicals during weight loss could theoretically increase infant exposure through breast milk. Aim: To describe concentrations of PFAS in breast milk at 2 weeks and 6 months postpartum, and to investigate whether changes in PFAS concentrations are associated with postpartum weight change between these time points. Methods: Observational study of 50 lactating women followed from 2 weeks to 6 months postpartum. Breast milk samples were collected at both timepoints and analyzed for PFAS concentrations. Weight was measured at baseline and 6-month follow-up. Median regression was used to examine associations between postpartum weight change and changes in PFAS concentrations. Results: Of the analyzed PFAS, only PFOS and PFOA were detected in sufficient amounts to be included in further statistical analyses. PFOA concentration in breast milk decreased significantly from a mean of 0.032 ng/mL (SD 0.017) at baseline to 0.015 ng/mL (SD 0.008) at follow-up, corresponding to a mean reduction of 0.017 ng/mL (p < 0.001). In contrast, PFOS concentrations remained low and stable, with no statistically significant change over time (p = 0.67). Mean postpartum weight loss was 6.3 kg (SD 4.32) from baseline to 6 months. Postpartum weight change was not significantly associated with changes in PFOA or PFOS concentrations. Conclusion: PFOA concentrations in breast milk decreased substantially from 2 weeks to 6 months postpartum, while PFOS levels remained unchanged, and no significant evidence was found that postpartum weight loss increased PFAS concentrations in breast milk. These findings suggest that moderate postpartum weight loss may not increase infant PFAS exposure through breastfeeding in this population, but further studies in larger and more diverse cohorts are needed.
Psychotic disorders are severe conditions that often involve changes in perception, such as visual and auditory hallucinations. Previous research has suggested that the brain regions responsible for processing visual and auditory information may function differently in these disorders. However, it is unclear why these functional changes occur. The main aim of this thesis was to investigate how brain function and brain structure are related in the visual and the auditory cortices, both in healthy individuals and in people with psychotic disorders. Brain function was measured using electroencephalography (EEG), specifically event related potentials (ERPs), which capture the brain’s electrical responses to external sensory stimuli. Brain structure was assessed using magnetic resonance imaging (MRI) to provide information about cortical surface area, thickness, and myelination. In this thesis, I focused specifically on examining both the function and the structural characteristics of the visual and auditory cortices, in order to better understand how alterations in these regions may be linked to psychotic disorders. The study included healthy control participants as well as individuals diagnosed with schizophrenia spectrum disorders or bipolar disorder. In healthy individuals, the results showed a positive relationship between the strength (amplitude) of the P100 component of the visual evoked potential (VEP) - an EEG measure reflecting function in the visual cortex - and the surface area of the visual cortex. In other words, a larger visual cortical surface area was associated with a stronger neural response to visual stimuli. Among individuals with schizophrenia spectrum disorders, a lower amplitude of the N100 component of the auditory evoked potential (AEP) - an EEG measure reflecting activity in the auditory cortex - was associated with a thinner auditory cortex. This association was particularly evident in individuals who had experienced auditory hallucinations. These findings suggest that structural and functional changes in the auditory cortex may be linked and could reflect a shared neural mechanism related to auditory hallucinations. The results also indicated that biological sex may play a role in how psychotic disorders affect brain function. Males with schizophrenia spectrum disorders showed lower N100 amplitudes compared to healthy males, whereas no comparable differences were observed among women. This highlights the importance of considering biological sex in neurobiological research and may help why illness trajectory and treatment response often differ between men and women. Measures of myelin in the auditory cortex did not explain the observed correlations between reduced auditory function (lower N100 amplitude) and thinner auditory cortex in individuals with schizophrenia spectrum disorders. The findings show a clear link between brain structure and function in the visual cortex of healthy individuals and in the auditory cortex of individuals with schizophrenia spectrum disorders. They highlight the importance of studying basic sensory processes to better understand psychotic symptoms, as early sensory alterations may form part of the neurobiological basis of these disorders. The results also emphasize the need to consider biological sex in future research. Greater insight into these mechanisms may ultimately contribute to improved diagnostics and more targeted, effective treatments for psychotic disorders.
In this thesis we used supervised and unsupervised models on patients with infectious diseases, with a focus on laboratory variables from patients admitted to the emergency department (ED). These models are used for diagnosis, prognosis, and subgrouping of patients. In the first part of the thesis, we evaluated four published supervised models for prediction of outcomes in COVID‑19 patients. Using cohorts from Oslo and London, we found that all models performed worse and with greater variability than in their original studies. Recalibration improved performance and the results highlight the importance of validating prediction models across different populations. Next, we developed a supervised model to predict infection using Sysmex cell population (CP) data from patients with suspected sepsis. These research parameters are produced by hematology instruments when analyzing white blood cells and reflect the cells morphology and degree of activation. Among the parameters, monocyte complexity (MO‑X) and neutrophil fluorescence activity (NEUT‑RI) showed the strongest individual predictive value. Using LASSO and backward selection, we created a four‑variable model that performed slightly below C‑reactive protein (CRP) alone. The multilayer perceptron model demonstrated the best calibration, particularly when CRP was added. Further standardization and external validation are required before clinical use. Finally, we explored unsupervised clustering to identify subgroups of sepsis patients. Unlike the SENECA study, which reported four phenotypes, our analyses did not reproduce these subgroups. A large multicenter replication study with cohorts from Oslo, Karolinska, and Oxford also failed to reproduce the SENECA subgroups, suggesting that these phenotypes may not generalize across populations. In the Oslo cohort, seven clusters were more stable and clinically distinct. Further validation of the seven clusters should be conducted.
Cavity-confined malignancies including malignant peritoneal mesothelioma, ovarian cancer with peritoneal carcinomatosis, and bladder cancer represent challenging therapeutic scenarios due to their anatomical confinement combined with the persistence of microscopic residual disease. Locoregional delivery of targeted radiopharmaceuticals offers unique opportunities for concentrated tumor exposure while minimizing systemic toxicity. This thesis includes preclinical studies evaluating novel 212Pb-labeled monoclonal antibodies targeting CD146 and PTK7 for the treatment of cavitary malignancies. CD146-targeting therapy is explored for mesothelioma, where tumor-specific antigen expression enables selective targeting. PTK7 is evaluated across multiple cavity-restricted tumor types due to its broad expression in diverse malignancies. The radioimmunoconjugates demonstrated efficient tumor targeting and internalization in preclinical models, with therapeutic efficacy demonstrated in tumor-bearing animal studies. These findings establish a foundation for further preclinical development of 212Pb-labeled antibodies targeting these antigens for cavitary cancer treatment.
How to determine if someone or something is conscious? How to engineer an artificial consciousness? To answer these questions one must first identify candidate behavioral, functional, and structural properties a system must have in order to be considered conscious. If we are to investigate consciousness in non-biological systems, these properties must be substrate- independent. A candidate substrate-independent property is complexity; requiring a system to possess sufficient diversity in its input-output relationships, intricacy of its architecture, and richness in its internal dynamics. Such a system is likely to exist in a state close to criticality, a state in which the system has a maximum of information processing capacity. However, the empirical results underlying this story need to be validated as measures of complexity may not behave as expected in certain conditions or systems. In this thesis, I summarize work that tests and compares proposed measures of consciousness in conditions like general anesthesia, cognitive and attentional load, sedation of one hemisphere, and in idealized systems such as Markov models. The studies presented here generally find that measures of signal complexity behave as expected although with some surprises. The findings are presented in context of several studies that observe that states associated with unconsciousness yield a high rate of dreams—a form of conscious experience—which is not reflected by proposed measures of consciousness. Finally, I discuss how to reconcile a high rate of dream recall in conditions often associated with unconsciousness, and the relative change in system dynamics captured by measures of complexity. In addition, the assumption that deep sedation and deep sleep are largely “unconscious” states is questioned. The thesis work is presented against a large backdrop of philosophical and empirical work in the wider field of consciousness science, and I discuss what would really count as evidence for or against inferring consciousness in non-human or artificial systems, and whether consciousness science as currently done is on the right path to potentially contributing to the question.
Cells maintain homeostasis through autophagy, a pathway that carries out the removal of damaged or unwanted material and recycling of macromolecules under nutrient deprivation and stress. In autophagy, cargo is sequestered into double membrane vesicles known as autophagosomes that fuse with lysosomes containing enzymes that degrade the cargo. Autophagy can be a bulk degradation process or a selective one. Dysfunctional autophagy is implicated in the pathogenesis of many diseases, so elucidating its underlying molecular mechanisms is crucial for the development of new therapeutic strategies. In this thesis, we aimed to identify proteins that are novel regulators of autophagy, characterise their function and investigate their roles in disease. In paper I, we shortlisted protein candidates which bind membranes and have a link to disease, to assess whether they play a role in autophagy. Using a range of biochemical and imaging approaches, we demonstrated that the protein KRIT1 can interact directly with autophagy proteins. We also found that KRIT1 functions as a positive regulator of bulk and selective autophagy. In paper II, we characterised another membrane binding protein, SYTL5. We found that SYTL5 localises to the mitochondrial network through an interaction with RAB27A. The selective degradation of mitochondria, through mitophagy, was found to be positively regulated by SYTL5 and RAB27A. We also found that SYTL5 expression is significantly reduced in adrenal gland tumours and that low SYTL5 expression is associated with reduced survival of adrenocortical carcinoma patients. In paper III, we focus on the dipeptide repeat poly-GA protein aggregates that result from a mutation in C9orf72, associated with the neurodegenerative diseases ALS and frontotemporal dementia. We demonstrate that expression of poly-GA causes a reduction in autophagy, indicating a potential mechanism through which poly-GA aggregates contribute to neurodegeneration.
This thesis aimed to investigate long-term treatment patterns, adherence, and persistence to lipid lowering drugs among contemporary populations in Norway, both with and without established cardiovascular disease. We also aimed to investigate the associations between clinical characteristics and reduced adherence to treatment. The research consists of three registry studies based on data from the Norwegian Prescribed Drug Registry and explores adherence and persistence to traditional and novel lipid lowering therapies. We found a significant underutilization of lipid lowering drugs in Norway across all studies, with a considerable proportion of patients with atherosclerotic cardiovascular disease and/or at high or very high risk remaining untreated across all studies. Adherence and persistence to statin therapy was low across all studies, which is particularly concerning in the high and very high-risk populations. The proportion with reduced adherence to statins was 31% among all users of lipid lowering drugs in Norway, while it was 22% among patients with established cardiovascular disease. Patients who initiate novel add-on treatment often discontinue statins, even though maximal benefit requires combination therapy. Overall, we found it challenging to establish strong association between demographic and clinical patient characteristics and reduced adherence. However, smoking, and psychological distress appeared to correlate. We observed an association between self-perceived side effects of statins and reduced adherence. Further, patients with poor persistence to statins were more likely to exhibit similar patterns with other lipid lowering drugs. This may indicate that side-effects and non-adherent behavior are important barriers to adherence and persistence to lipid lowering drugs.
Astrocytes support brain homeostasis, but they also participate in neural circuit function. This participation is closely linked to intracellular Ca2+ signaling, expressed as spatiotemporally diverse Ca2+ transients. The aim was to determine how whisker-related input and behavioral state (whisking and locomotion) shape astrocytic Ca2+ activity in mouse vibrissal primary somatosensory cortex (vS1), how local neuronal activity contributes to astrocytic Ca2+, and how impaired astrocytic Ca2+ signaling affects neuronal activity during behavior. In addition, we asked which membrane pathways can trigger astrocytic Ca2+ responses to neuronal activity. Using in vivo two-photon imaging in layer 2/3 vS1 during tactile virtual-reality whisker stimulation, free whisking, and locomotion, we found that locomotion increased astrocytic Ca2+ event frequency and amplitude, and that whisker stimulation further elevated astrocytic activity during locomotion. When local neurons were chemogenetically silenced (GlyRα1AG), Ca2+ magnitude changed little, but astrocytic event onsets were delayed, indicating that local circuit activity mainly controls event timing. To test how reduced astrocytic Ca2+ release influences activity during behavior, we studied Itpr2−/− (IP3R2 knockout) mice. Astrocytic Ca2+ transients were strongly y reduced but not completely abolished, in accordance with previous studies. Neuronal activity in vS1 was largely preserved, but locomotion-related neuronal modulation was reduced. Finally, in acute hippocampal slices we identified membrane mechanisms for astrocytic responsiveness to neuronal activity. The Na+/Ca2+ exchanger (NCX) was required to initiate astrocytic Ca2+ responses, while P2X receptors amplified them. Overall, astrocytic Ca2+ signaling is state dependent and temporally regulated, supported by intracellular release and membrane influx pathways. The results suggest that astrocytic Ca2+ signals sustain locomotion-linked modulation of neuronal activity.
Pediatric brain tumor survivors face complex long term and late effects that often limit daily functioning and participation. Despite existing international survivorship guidelines and models, many survivors are left with significant unmet needs. This thesis consists of three studies aiming to better understand these unmet needs and improving healthcare to meet them. In study I, we explored multidisciplinary healthcare providers’ perceptions on current follow up for pediatric brain tumor survivors. In study II, we explored how long term and late effects of pediatric brain tumors influence everyday life of survivors and parents. In study III, we co-designed and feasibility tested a nurse led intervention to support childhood cancer survivors transitioning to adult health care, focusing on informational and psychosocial needs, and strengthening self-management skills. Methods used were semi-structured individual interviews, focus groups and co-design meetings with survivors, parents and providers to develop the intervention. Healthcare providers reported issues with system barriers to optimal follow up, particularly during and after the transition to adult healthcare. They suggested greater use of nurses in follow-up and shared care to improve collaboration between primary and specialist levels. Pediatric brain tumor survivors and parents described how long-term and late effects hampered their everyday functioning and participation abilities. They wished for increased psychosocial and informational support and systematic comprehensive long-term follow-up. Based on these results, we developed the nurse led intervention which seemed feasible in addressing informational and psychosocial needs and supporting self-management skills during the transition to adult care. Overall, our results speak to the importance of establishing a national, comprehensive follow up model that integrates medical, psychological and social care, ensuring lifelong support for survivors in need.
Prostate cancer is the most common type of cancer among Norwegian men, with over 5200 new cases in Norway in 2024. Men with early-stage prostate cancer often have several treatment options available. The different modalities induce different adverse health outcomes, and thus many patients may face a difficult treatment decision. There is limited population-based evidence about post-treatment adverse health outcomes in non-metastatic prostate cancer patients undergoing modern curative treatment. This knowledge is important to help patients and doctors make the best treatment decision. The aim of this patient-reported population-based survey was to describe prostate cancer patients’ experience with shared decision making, and to assess adverse health outcomes and quality of life, three years after modern prostate cancer treatment. The findings were compared with age-similar men without a history of prostate cancer. Three years after radical prostatectomy, we documented a prevalence of pad use in 41 % of the patients, compared to 5 % in age-similar men. In total, 84 % reported erectile dysfunction three years after radical prostatectomy, compared to 48 % in age-similar men. Three years after high-dose radiation therapy combined with hormone therapy, we documented clinically important lower bowel, and sexual domain mean scores in prostate cancer patients compared to age-similar men. Despite large differences in function, we found little variation in quality of life. We also documented that 78 % of the prostate cancer patients wanted to be involved in shared decision making, and that 83 % of these patients experienced being involved. Overall, our findings show that three out of four Norwegian men want to be involved in the treatment decision. We also show that persisting adverse health outcomes are common, despite continuous development in prostate cancer treatment. The results might raise questions about how prostate cancer treatment is carried out in practice in Norway.
This thesis belongs to the field of infectious disease epidemiology. It examines the epidemiology of the three dominant SARS-CoV-2 variants in Norway—Alpha, Delta, and Omicron— from February 2020 to January 2022. More specifically, the studies assessed the reinfection risk, disease severity, and vaccine effectiveness (VE) against infection with the different variants. The thesis is based on seven retrospective, registry-based cohort studies using data from the Norwegian Emergency Preparedness Register for COVID-19 (Beredt C19). The results showed that the risk of reinfection was highest during the Omicron wave and increased with time since previous infection, indicating waning natural immunity. Vaccination reduced the risk of reinfection. People infected with the Alpha variant had higher hospitalisation risk compared to those infected earlier in the pandemic. The Delta variant had a similar hospitalisation risk as Alpha, while the Omicron variant had a lower hospitalisation risk than Delta. Vaccinated people had a lower risk of hospitalisation. VE against infection was high against the Alpha and Delta variants after full vaccination (2 doses) but lower after only one dose. VE against Omicron infection was reduced and declined faster over time. Booster doses increased protection from infection. The results underlined the importance of vaccination and booster doses in maintaining protection, particularly against emerging variants. The findings were crucial in guiding public health interventions, including vaccination strategies, and preparedness plans for surge capacity in the hospital sector in Norway. The thesis also highlights the need for continuous monitoring of disease severity and VE as variants and vaccines evolve. The use of Beredt C19 registry during the pandemic enabled to timely research and provides valuable lessons for managing future health crises.
This doctoral thesis explores novel roles of lactate and the lactate receptor hydroxycarboxylic acid receptor 1 (HCAR1) in the brain, moving beyond the traditional view of lactate as a mere byproduct of anaerobic metabolism. The thesis examines how lactate signaling through HCAR1 influences brain development, injury response, and plasticity. Emphasis is placed on neonatal cerebral conditions, including hypoxic–ischemic brain injury and hypoglycemia, as well as on adaptations induced by high-intensity physical exercise. The work addresses how lactate-dependent signaling affects neuronal and glial cell behavior, immune responses, axonal development, and vascular remodeling in the brain. A combination of experimental models was used, primarily in mice, including in vivo models of neonatal brain injury and ex vivo organotypic brain slice cultures for neonatal hypoglycemia. Analyses of brain tissue, cell cultures, and gene expression were performed using established histological, imaging, and molecular techniques. The findings suggest that HCAR1 is involved in long-term preservation of brain tissue following neonatal hypoxic–ischemic injury and is linked to widespread gene expression changes, particularly affecting pathways related to cell cycle regulation and innate immunity. Lactate was also observed to exert protective effects on axonal and myelin development under hypoglycemic conditions, where HCAR1 appeared to play a contributory role. Furthermore, repeated high-intensity exercise in mice led to an increase in cerebral capillary density, an effect that was dependent on intact HCAR1 signaling. Together, these results indicate that lactate signaling may play an important role in both normal brain physiology and neonatal cerebral pathology.
This thesis is within the field of cardiovascular genetics and examines how genetic testing can improve the detection of individuals at risk for hereditary heart disease with a focus on diagnostic yield, clinical implications, and strategies for screening. The work summarizes more than 17 years of genetic testing for cardiomyopathies and arrhythmias in a national laboratory. Among patients tested between 2003 and 2020, likely pathogenic or pathogenic variants were found in 13.1% of patients with cardiomyopathy and 15.4% with arrhythmias, corresponding to 574 and 306 confirmed genetic diagnoses. Cascade screening of relatives identified more than 2,500 additional carriers eligible for preventive follow-up. The estimated penetrance of disease among variant carriers was 30.6% for cardiomyopathies and 19.5% for arrhythmias. Reclassification of 54.2 % of the hypertrophic cardiomyopathy variants previously reported by our laboratory demonstrates the dynamic nature of variant interpretation and the need for continuous re-evaluation. A part of the thesis analyzed data from the Norwegian cascade screening program for familial hypercholesterolemia (FH) in children, demonstrating a considerable overlap in LDL-C levels between children with FH and children without FH, especially in newborns. These findings indicate that cholesterol-based screening alone may fail to identify many affected children and highlight the value of genetic testing in early FH detection. Genetic testing showed higher sensitivity, and these results support FH as a stronger candidate for universal screening than cardiomyopathies and arrhythmias, where current knowledge limits screening to relatives of known patients. Overall, the thesis emphasizes the importance of improving screening strategies for hereditary heart disease, and these results contribute to the knowledge needed to better identify individuals at risk.
Recently, increasing amounts of brain data have been made available in data portals to potentially be discovered, interpreted, and integrated into new insights for neuroscience. However, this research process is rarely straightforward and often at halt. The main challenges for neuroscience are the complexity of the brain, the heterogeneity of approaches to study it, the multimodality of data output, and the deluge of data without proper annotation of metadata. These challenges complicate our opportunities to discover and interpret brain data, and to move forward with integration and understanding. The FAIR guiding principles, introduced in 2016, provide solutions to improve the findability, accessibility, interoperability, and reusability of shared research data. Location metadata, or positions within brain atlases related to a specific set of research data, are possible to document and register for all data originating from the brain and may act as a common denominator for both discovery and data integration. Digital three-dimensional (3D) brain atlases are independent of the plane of sectioning and allow researchers to express precise information about anatomical structures and positions using brain atlas coordinates. Inspired by the FAIR principles as well as opportunities presented by 3D brain atlases, we have established new solutions for finding and integrating relevant research data from the brain. In this Thesis, I present two workflows. The first is a workflow for sharing research data, while the other is a workflow for integrating neuroscientific data based on anatomical location in 3D brain atlases. Next, we may utilise these to develop a platform for spatially indexing and co-visualising shared brain data in 3D atlas space, to better find and reuse relevant research data and integrate them into new insights for neuroscience.
Introduction: Cardiovascular disease (CVD) remains the leading cause of death globally, with atherosclerosis as its primary driver. Atherosclerosis is a chronic inflammatory disease characterised by lipoprotein retention in the arterial wall, macrophage infiltration, and lesion formation. Lipid droplets (LDs) in foam cells store neutral lipids such as triacylglycerol (TAG) and cholesteryl esters (CEs), regulated by LD-associated proteins, including the perilipin (Plin) family. Although Plin2 is highly expressed in macrophages, its role in atherosclerosis is unclear. Materials and methods: To investigate the role of Plin2 in atherosclerosis, male Plin2+/+ and Plin2-/- C57BL/6N mice were injected at 13 weeks of age with an adeno-associated virus serotype 8 (AAV8) carrying a D377Y-mutant murine pro-protein convertase subtilisin/kexin type 9 (Pcsk9) or left uninjected. All mice were subsequently fed an atherogenic diet high in fat, cholesterol, and sucrose. Validation of the AAV model was performed by RT-qPCR, immunoblotting, and measurements of circulating levels of TAG and cholesterol. Body composition, body and organ weights, and hepatic lipid levels were measured. Atherosclerotic lesions in the aortic arch were quantified by lipid staining and image analysis. Bone marrow-derived macrophages (BMDMs) were treated in vitro with cholesterol and oleic acid (OA) and analysed for LD accumulation and gene expression. Results: The AAV8-mPcsk9-D377Y model successfully induced hyperlipidaemia, marked by elevated levels of plasma TAG and cholesterol, due to increased hepatic Pcsk9 mRNA expression and reduced Ldlr protein expression. Plin2 deletion did not affect atherosclerotic lesion size but was associated with reduced body weight and fat mass, and reduced lipid accumulation in liver and plasma. Plin2-deficient BMDMs appeared to accumulate fewer LDs, without any major effects on the expression of genes related to lipid metabolism, inflammation, or immune responses. Conclusion: The findings in this study confirm and highlight a role for Plin2 in systemic and hepatic lipid regulation. Although Plin2 deletion did not reduce atherosclerotic lesions under the tested conditions, its effects on lipid accumulation in liver, plasma, and macrophages warrant further research to investigate its role as a potential therapeutic target in atherosclerosis.
Autophagy is a degradative process used by cells to promote survival in stressful conditions and to remove damaged or surplus cellular components, such as toxic aggregates or defective organelles. Autophagic cargo is engulfed by a double membrane, called a phagophore, that expands around the cargo to form an autophagosome that fuses with a lysosome, containing acidic enzymes that degrade the cargo. Autophagosomes are generally devoid of transmembrane proteins, indicating an important role of lipid-binding proteins at different stages of autophagy. In this thesis, we aimed to identify and characterize novel lipid-binding proteins in selective and non-selective types of autophagy. We identified the PX domain-containing protein sorting nexin 8 (SNX8) as a positive modulator of starvation-induced autophagy and demonstrated that it localizes on early endosomes and lysosomes, regulating autophagosome maturation. We also characterized the endosomal protein SNX10 and found that SNX10 functions as a negative modulator of mitophagy and mitochondrial bioenergetics. Furthermore, we asked whether different components of the autophagy machinery have distinct functions in different types of autophagy. Intriguingly, we observed that some autophagic components are equally important for selective and non-selective autophagy, while others seem to either inhibit or promote autophagy in a cargo-dependent manner. In conclusion, the data presented in this thesis provide a better understanding of the molecular mechanisms inherent to autophagy, unveiling novel roles for lipid-binding proteins in autophagy.
Familial hypercholesterolemia (FH) is characterized by elevated low-density lipoprotein cholesterol (LDL-C) from birth, increasing the risk of premature coronary heart disease (CHD) without early treatment. Despite effective lipid-lowering therapies like statins, many FH patients start treatment late or do not reach their LDL-C goals. Elderly FH patients having lived many years before the statin era, face high CHD risk due to prolonged LDL-C exposure. Surprisingly, some elderly FH patients remain CHD event-free. The aims of this PhD project were therefore to identify potential cardioprotective markers in elderly event-free FH patients and examine the association between CHD and cumulative LDL-C exposure, also called LDL-C burden. The research involved a cross-sectional study of elderly FH patients with and without CHD, focusing on lipoprotein and gene expression profiling. In addition, LDL-C burden was estimated based on repeated LDL-C measures from medical records at the Lipid Clinic in Oslo. Findings revealed that event-free FH patients had higher levels of large high-density lipoprotein (HDL) particles, but not small HDLs. They also had slightly different gene expression profiles, with higher expression of ABCA1 and ABCG1, genes involved in HDL maturation and cholesterol efflux, and lower expression of the inflammatory genes STAT1 and STAT3. Additionally, FH patients with CHD had higher estimated LDL-C burden compared to those without CHD due to higher estimated LDL-C exposure earlier in life. Finally, higher LDL-C in women compared to men during follow-up at the Lipid Clinic indicates less intensive treatment of female FH patients. Overall, the results of this PhD project suggest that HDL size separation, gene expression profiling, and estimation of LDL-C burden could improve risk prediction in high-risk individuals. Although more research is needed, the findings emphasize the importance of early LDL-C management.
Sensory signals from our environment and somatomotor signals from the body organise as patterns in the brain mirroring the spatial position of the sensory surface. This organisation pattern is known as topography. Topographical organisation has been thoroughly investigated in mouse and rat brains. For the rat pontine nuclei, axonal projections from neocortex arrange in a concentric inside-out organisation pattern, establishing general organisational principles. However, it is unclear if similar principles are present in subcortical areas in the mouse. This thesis addresses general principles of topographical organisation in the mouse caudoputamen, thalamus, pontine nuclei, and superior colliculus. In the pontine nuclei, we observed the same general principles as seen in the rat. The inside-out pattern was also observed in the thalamus, and we identified a fan-shaped pattern in the caudoputamen and superior colliculus. To address the development of corticopontine topography in the mouse, we altered the neocortical development by removing the Nr2f1 gene in neuron progenitor and postmitotic phases. The topographical organisation was not affected by removing the gene in the progenitor phase, but altering the postmitotic phase resulted in a lack of axonal projections in the centre of the pontine nuclei. These results provide new insights into topographical patterns in the mouse, including how patterns form during development and organise in the adult brain. Better understanding of the organisation of neuronal networks can help scientists understand how the brain processes information and create better computational brain models.
This doctoral thesis delves into the intersection of geriatrics and cardiology, specifically exploring the prognostic value of heart rate variability (HRV) in hip fracture patients. As the population ages, the incidence of hip fractures rises, with a significant impact on mortality and morbidity. The thesis aims to evaluate the association between HRV and both short- and long-term postoperative outcomes, alongside potential confounding factors. The research encompasses three studies conducted at Kongsberg and Ullevål Hospitals. In Study 1, a longitudinal prospective observation of 165 hip fracture patients assessed preoperative HRV in relation to mortality and postoperative complications like infections, myocardial infarction, and stroke. Study 2 continued to monitor these patients six months post-surgery, employing data from national registers and interviews to gauge morbidity and mortality. Study 3 focused on delirium in hip fracture patients, using HRV analysis and the Confusion Assessment Method (CAM) to investigate preoperative and postoperative delirium incidents. Study 1 found that one-third of patients faced complications post-surgery, with urinary tract infections and pneumonia being the most common. A lower HRV correlated with higher complication rates. A reduced HRV in the low frequency range was notably linked to postoperative infections. In Study 2, six-month mortality (13%) was not directly linked to HRV parameters; however, HRV anomalies were noted in patients who developed specific complications. Study 3 indicated that delirium was prevalent pre- and post-surgery and correlated with specific HRV patterns, suggesting its utility as an early indicator of risk. The consistent association between various HRV measures and outcomes in hip fracture patients underscores HRV's potential as a predictive tool for identifying at-risk individuals. Future research should focus on refining HRV-based interventions to enhance prognosis and management strategies in this vulnerable patient population.
Cancer is a type of disease associated with various genetic changes. Omics data, such as genomics, transcriptomics, and proteomics, provide comprehensive description into the molecular mechanisms driving cancer development and progression. However, the high dimensionality of omics data presents challenges for analysis, as traditional statistical tools can struggle to handle it. Modern artificial intelligence and machine learning techniques offer a solution to this challenge due to their ability to handle high-dimensional datasets, recognize complex patterns, and improve predictive accuracy. Such multi-dimensional machine learning analysis can help identify novel biomarkers for early diagnosis, treatment response, and prognostic indicators. Therefore, it is important to explore the potential applications of machine learning to diverse omics data in the field of precision oncology, offering new insights into various cancers and providing predictive models for potential clinical use. In this thesis, I used multi-omics data and machine learning techniques to predict clinical outcomes for three distinct cancer types. In Paper I, we developed a supervised machine learning framework using multi-omics data to investigate the genetic heterogeneity between individuals with ductal carcinoma in situ and invasive breast cancer. In Paper II, we developed a Lasso-based model to predict the treatment response of the drug umbralisib in chronic lymphocytic leukemia patients. The model was constructed using (phospho)protein profiling data and leave-one-out cross-validation. In Paper III, we investigated potential prognostic signatures for non-small cell lung cancer patients. The final biomarkers were used to construct a risk score. As a summary, in all the three papers in this thesis, machine learning tools provided powerful and accurate modelling for multi-omics analysis. Moreover, the results revealed new biological knowledge about cancers and provided potential applications for clinical use. Additionally, given that the sample sizes are relatively small in this thesis, a discussion about machine learning analysis on small-sample data is included.
Familial hypercholesterolemia (FH) is a common genetic disorder affecting approximately 1 in 250 individuals. It leads to lifelong elevated low-density lipoprotein (LDL) cholesterol levels and significantly increases the risk of premature cardiovascular disease (CVD). Early diagnosis and treatment are crucial to reduce long-term CVD risk, yet many individuals remain undiagnosed or undertreated. The aim of this thesis was to investigate factors influencing CVD risk in children and young adults with FH, including LDL cholesterol burden, lipid-lowering treatment (LLT) adherence, and lipoprotein(a) [Lp(a)] levels, while also exploring potential sex differences. Data were retrospectively collected from medical records of children and adolescents followed at specialized lipid clinics in Norway and the Netherlands. Results showed that 30% of children and young adults with FH had poor adherence to LLT, and almost none of these reached recommended LDL cholesterol treatment goals. Furthermore, young women with FH had a higher LDL cholesterol burden than men in addition to elevated Lp(a) levels, which may contribute to their increased relative CVD risk. Although effective treatment is available, these findings underscore the importance of early and sustained LLT in children with FH, emphasizing individualized treatment approaches to reduce long-term CVD risk.
Liver disease models are essential for studying hepatic pathology, which poses a significant worldwide health burden. Hepatic stellate cells (HSCs) activate during chronic liver disease and play a crucial role in driving fibrotic scarring, ultimately leading to liver failure. Obtaining and cultivating human primary HSCs for in vitro liver disease modeling is challenging. Generating HSCs from human pluripotent stem cells (hPSCs) has been proposed as a solution, providing an unlimited cell source relevant to human hepatic physiology and pathology. However, the applicability of such stem cell-derived HSCs (scHSCs) for liver disease modeling has not been extensively characterized. The primary goal of this thesis was to establish and evaluate an scHSC system for in vitro liver disease modeling. scHSCs were generated from multiple hPSC lines to investigate the advantages and challenges of the system, focusing on disease modeling and comparison to human primary HSCs. The scHSCs proved comparable and complementary to existing HSC models, especially within the first five days after differentiation. The scHSC model was particularly useful for studying intracellular vitamin A and lipid droplets, essential aspects of HSCs in the healthy liver. We found that both compounds were retained during disease modeling by pro-fibrotic TGF-β stimulation, while simultaneously demonstrating a synergistic relationship between the loss of said compounds and the severity of HSC activation, providing valuable insights in an area with conflicting data. Additionally, we observed a reduction in glycolysis in scHSCs under diseased conditions, contributing necessary data on the understudied topic of HSC energy metabolism. Finally, we demonstrated the scHSCs as effector cells in studying liver disease-associated biomarkers. In conclusion, we comprehensively demonstrated that the presented scHSC model is a valuable asset in the rapidly progressing field of in vitro liver disease modeling.
Persistent organic pollutants (POPs) are widespread in the environment despite concerns about their potential impact on human health. The UN and WHO note a lack of data on how POPs may cause diabetes, and the functions of POP receptors like NR1I2 are not well understood. The first part of this thesis examines how POPs affect pancreatic β-cells and contribute to diabetes. We found that youths with type 1 diabetes had high levels of POPs like PCB-153 and p,p’-DDE. In cultured pancreatic β-cells, POPs reduced insulin production by impairing the antioxidant defense of the cells. Moreover, long-term exposure to POPs led to β-cell death. The second part of the thesis explores the role of intestinal NR1I2. Mice lacking NR1I2 in the gut showed no significant changes in intestinal structure or function compared to control mice, even when challenged with lipopolysaccharide (LPS).
Background: Limited evidence suggests that fish and fish oil intake are associated with a reduced risk of colorectal cancer (CRC). The association remains unclear and needs further investigation, specifically whether it applies to the risk of precancerous lesions. Aim: The main aim of this master’s thesis was to investigate the association between overall fish and fish oil intake and the presence of precancerous lesions and CRC in individuals participating in CRC screening. Specifically, the study aimed to 1) evaluate the intake of fish and fish oils in the study population, 2) investigate the association between the intakes of total fish, lean fish, fatty fish, long chain omega-3 polyunsaturated fatty acids (LC n-3 PUFAs), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), n-3 PUFAs from fish, and n-3 PUFAs from supplements and the presence of precancerous lesions and CRC, and 3) investigate whether the observed associations differ by subgroups. Methods: This master’s thesis population included participants (n = 1659), aged 55 - 77 from the CRCbiome study who received a positive fecal immunochemical test (FIT) during 2017 - 2021. The presence of colorectal lesions and CRC was detected in a follow-up colonoscopy examination. The study has a cross-sectional design and used a validated, semi-quantitative food frequency questionnaire (FFQ) to assess the fish and fish oil intake prior to the colonoscopy. Multinomial logistic regression was used to analyze the association between fish and fish oil intake and the presence of non-advanced adenomas, and advanced lesions (including CRC). Results: After applying various exclusion criteria, 1466 participants were included in the analyses. Of these, 35.3% had non-advanced adenoma, and 27.6% had advanced lesions. No association was found between the intake of total fish, fatty fish, EPA, DHA, LC n-3 PUFAs, n-3 PUFAs from fish, and n-3 PUFAs from supplements and the presence of non-advanced adenomas or advanced lesions. However, high lean fish intake showed a borderline significant positive association with advanced lesions. Conclusion: No overall association was observed between fish and fish oil intake and the presence of precancerous lesions and CRC. However, a positive association was found between high lean fish intake and advanced lesions. Further research is needed to clarify the associations.
Background: Irritable bowel syndrome is a prevalent gastrointestinal disorder with implications for both individual quality of life and society. The condition is characterized by a complex pathophysiology involving afflictions local to the intestines as well as neurological abnormalities. IBS patients suffer a variety of symptoms but have few treatment options to choose from. Consequently, the level of satisfaction with treatment options amongst IBS patients is low, stressing the need to expand the toolbox for IBS treatment. The aim of this study is to assess the feasibility of time-restricted eating as a treatment for IB and describe drivers and barriers to implementation. Methods: A convenience sample of 14 informants was drawn from a pool of 97 successful participants in an eight-week 16:8 time restricted eating intervention. The informants partook in audio-recorded semi-structured in-depth interviews. Recordings were processed by a computer language model and interview transcripts were generated automatically. The transcripts were proofread and structured and analysed through a reflexive inductive thematic analysis approach. Results: The analysis generated six main themes consisting of 18 sub-themes. One main theme describes barriers to implementation, involving renunciation of habitual behaviour, physical discomfort from implementation and friction with the surroundings. The rest of the main themes describe drivers of implementation concerning domains such as motivation, supporting factors, mentality, behaviour and determinants of sustainability.
Abstract Introduction: People with severe mental illness (SMI) have a higher mortality rate and shortened life expectancy, mainly attributable to physical diseases, and particularly cardiovascular diseases (CVDs). Important risk factors for CVDs are obesity and other metabolic abnormalities, which are especially prevalent in people with SMI. Several factors contribute to this increased risk, including unhealthy lifestyle and unfavorable diet. Aim: This experimental study aimed to evaluate whether individualized dietary counseling, based on the Norwegian Food Based Dietary Guidelines (FBDG) and other heart-healthy diet principles, could improve non-high-density-lipoprotein-cholesterol (non-HDL-C) and other biomarkers associated with CVD risk. Methods: A randomized controlled trial was conducted to assess the effects of dietary counseling on biochemical, anthropometrical, and dietary parameters in individuals with schizophrenia/psychosis or bipolar affective disorder. The participants were randomized to either the intervention group or the control group. The intervention group had dietary counseling and follow-up over a six-week intervention period. Multiple linear regression was used to analyze differences in changes in parameters from baseline to 6 weeks. Results: A total of 45 participants were included between 2023 and 2025, with 24 participants randomized to the intervention group and 21 participants randomized to the control group. No significant between- or within-group differences were observed in the primary outcome of non-HDL-C. Secondary outcomes included biochemical and anthropometric measures, as well as adherence to dietary guidelines. Between-group analysis revealed a significant difference in changes in total fat and monounsaturated fatty acid (MUFA) consumption. The intervention group showed a significant within-group reduction in triglyceride levels, whereas the control group had a significant within-group decline in lifestyle index score and increase in total fat consumption. Additionally, the intervention group demonstrated good compliance with their individual goals, although this was not analyzed statistically. Conclusion: Although limited statistically significant effects were observed, the findings suggest that individualized dietary counseling may support CVD risk reduction among individuals with SMI. Larger, longer-term studies are needed to confirm these results.
Abstract Introduction: Adults with attention-deficit/hyperactivity disorder (ADHD) are at increased risk of developing cardiovascular disease (CVD) compared to the general population, possibly attributed to behavioral risk factors including poor diet and lifestyle habits. Research indicates that individuals with ADHD have poorer dietary habits, and worse overall health outcomes than those without the diagnosis. Despite these associations, there is a notable lack of research exploring dietary patterns or interventions aimed at improving health outcomes in this group. Aim: This study aimed to assess whether individualized dietary guidance could improve dietary patterns in adults diagnosed with ADHD and influence biological and anthropometrical measures compared to no dietary guidance. Additionally, we aimed to investigate the potential need for dietary guidance in this population. Methods: This study was a 6-week randomized controlled trial (RCT) with a parallel-group design. Adult patients with ADHD treated at Asker DPS were invited to participate. To measure the primary outcome of change in Digikost diet index score and adherence to the Norwegian food-based dietary guidelines (NFBDGs) between groups, the DIGIKOST-FFQ and 24-hour recall dietary assessments were used. Secondary outcomes were measured by blood sampling, anthropometry, blood pressure measurements, and with Q-risk score assessments. Data were collected at baseline and after six weeks. Statistical analyses were performed using t-tests, Wilcoxon rank sum and signed rank tests, and through multiple linear regressions, using the statistical program STATA. Results: A total of 29 participants were randomized to either the intervention group (n=14) receiving individualized dietary guidance or the control group (n=15) receiving no immediate intervention. The intervention group showed a significant increase in diet index score and protein intake, along with a reduction in HbA1c and waist circumference. No significant changes were observed in the control group. Between-group analysis revealed a significant increase in the primary outcome: diet index score, and protein intake, along with a significant reduction in HbA1c in the intervention group when adjusting for potential confounding factors. Qualitative statements from participants highlighted ADHD-related challenges such as impulsive eating, lack of structure, and reduced appetite affecting food choices and life quality. Conclusion: Individualized dietary guidance improved dietary patterns and HbA1c, indicating a beneficial effect of dietary guidance on CVD risk factors, in adults with ADHD over six weeks. The qualitative findings further support the need for individualized dietary guidance for patients with ADHD. Further studies with larger samples and longer follow-ups are needed to confirm the findings.
Abstract Background: Overweight and obesity are major public health concerns both globally and in Norway, contributing to increased risk of chronic diseases, economic burden and reduced health-related quality of life (HRQoL). Although lifestyle interventions targeting both diet and physical activity (PA) are well-known as effective strategies for weight management, studies from such programs in private sector healthcare settings in Norway are limited. Objectives: This study aimed to assess the effects of a 14-week intensive lifestyle intervention on body weight, body composition, HRQoL, and dietary habits among adults with overweight or obesity. Methods: This prospective single-group pre-post study included adults (BMI ≥25 kg/m²) enrolled in the multidisciplinary Kickstart lifestyle program, combining individualized dietary counseling, structured PA, and behavioral support. Body composition parameters, such as body weight, skeletal muscle mass (SMM), fat-free mass (FFM), fat mass (FM), body fat percentage and visceral fat were measured using bioelectrical impedance analysis (InBody 270). HRQoL was assessed using the RAND-36 Health Survey, and dietary habits were evaluated using the DIGIKOST Food Frequency Questionnaire, giving a DIET-score ranging 1 to 20, reflecting adherence to the Norwegian Food-Based Dietary Guidelines (FBDG). Results: Forty-three adults (70% female=30, mean age 48.2±8.8 years, median BMI of 30.3 kg/m2) are included. Significant reductions were observed in body weight (-7.4 kg, 95% CI: -8.7 to -6.0), BMI (-2.5, 95% CI: -2.9 to -2.0), waist circumference (-8.5 cm, 95% CI: -10.0 to -7.0), FM (-6.9 kg, 95% CI: -8.1 to -5.6), body fat percentage (-5.0%, 95% CI: -6.0 to -3.9) and visceral fat (-3.3 levels, 95% CI: -4.0 to -2.6) (all p<0.001). Minor, non-significant reductions were seen in SMM (-0.4 kg, 95% CI: -0.7 to 0.0) and FFM (-0.5 kg, 95% CI: -0.1 to 0.1). HRQoL improved significantly in both physical component summary score (6.0, 95% CI: 0.6 to 11.3; p=0.002) and mental component summary score (7.6, 95% CI: 2.1 to 13.1; p=0.003). Dietary adherence to the Norwegian FBDG increased significantly (DIET-score: 4.0, 95% CI: 3.2 to 4.9; p<0.001). Conclusion: A short-term, intensive lifestyle intervention in a private clinic setting can significantly improve body composition, HRQoL and dietary habits in adults with overweight or obesity.
Background and aim: Cardiovascular disease (CVD) is a group of conditions that affect the heart and blood vessels, mainly caused by atherosclerosis, the buildup of lipids in the walls of arteries. High levels of low-density lipoprotein cholesterol (LDL-C) and other similar lipoproteins are linked to atherosclerotic CVD. Familial hypercholesterolemia (FH) is a genetic disorder that affects about 30 million people worldwide. It is caused by mutations in genes that influence LDL metabolism, leading to abnormally high levels of LDL-C in the blood. The longer arteries are exposed to LDL-C, the greater the cardiovascular risk. Because FH patients have high LDL-C levels from birth, their cholesterol burden reaches harmful levels earlier than that of healthy individuals. As a result, adults with FH are advised to begin lipid-lowering therapy (LLT) like statins or ezetimibe, and to follow a healthy lifestyle that includes a healthy diet, regular physical activity, avoiding smoking, and maintaining a healthy weight. However, there is limited research on the effect of a healthy lifestyle on cardiovascular risk in this patient group. The aim of this study was therefore to investigate whether a healthy lifestyle influences the risk of CVD in adults with FH, and whether a higher healthy lifestyle score can be used to predict CVD incidence in FH patients. Methods: The study was a registry-based cohort study of patients treated for FH at the Lipid Clinic at Aker University Hospital. Participants were adults aged 18 and above, with no registered CVD at the first visit. Information was obtained from visits to the clinic and medical journals, and included anthropometric data, biochemical parameters, CVD incidence, and lifestyle information. A healthy lifestyle score was developed to assess diet, physical activity, smoking, and obesity. Participants were classified as having a favourable, intermediate, or unfavourable lifestyle. A logistic regression analysis was then applied to research the effect of the healthy lifestyle score on CVD risk in the patient group. Results: After exclusions, 1,413 FH patients were included in the study. The median age was 38.7 (28.8, 48.1) years at baseline and 50.1 (40.3, 60.5) years at the last visit, reflecting a follow-up of 11.4 years. The population’s healthy lifestyle score improved over the follow-up period, as well as total cholesterol (TC) and LDL-C levels. By the last visit, 97 (6.4%) patients had experienced CVD, and were characterized by being older, having higher TC and LDL-C levels, and were more likely to live an unfavourable lifestyle. A higher lifestyle score was significantly associated with a reduced CVD risk, with an odds ratio (OR) of 0.70 (95% confidence interval [CI]: 0.52-0.94) (p = 0.02). Additionally, a higher level of physical activity was a significant protective factor against CVD, with an OR of 0.70 (95% CI: 0.53-0.94) (p = 0.02). Conclusion: A healthy lifestyle, marked by a healthy diet, high levels of physical activity, no smoking, and the absence of obesity, was associated with a reduced risk of CVD in FH patients. Additionally, lifestyle guidance provided at the Lipid Clinic had a positive impact on healthy lifestyle parameters over time. This master’s thesis has thus highlighted the importance of lifestyle counselling by health professionals and the effect of a healthy lifestyle, not only LLT, for FH patients to prevent cardiovascular events.
Examining nutritional screening accuracy, clinical evaluation of nutritional status and treatment of hemodialysis patients at risk of malnutrition
Abstract Background: Wheelchair (WC) users rely on upper body strength in WC propulsion and transfers. High upper body strength is linked with higher independence and reduced upper extremity pain. Yet, the unique determinants of strength in WC users remain poorly understood. Objectives: The primary objective was to identify determinants of upper body strength among a cohort of WC-users with various disabilities. The secondary objective was to investigate predictors of in upper body strength adaptation in the same cohort following 24 weeks of high load resistance training (RT). Methods: Forty-four WC users aged 18-60 years were allocated to either the intervention or the control group. The intervention was a high load RT program, and both groups received nutritional optimisation for bone health (vitamin D, calcium, and protein supplementation). Strength was measured at baseline, after 12 weeks, and after 24 weeks in a load cell as maximal voluntary isometric contraction (MVIC) in a row and bench press (BP). The primary determinants included impairment aetiology (acquired vs congenital), lean mass in the arms (LMA), and secondary type of impairment, athlete status, and biomarkers: vitamin D, parathyroid hormone (PTH), and testosterone. Cross-sectional strength was assessed with t-tests, correlation analyses, and multiple regression models, and the longitudinal changes were analysed using mixed effects linear models, Mann-Whitney U tests, and correlation analyses. Results: Subjects with acquired impairments were stronger than those with congenital impairments (row: +19.9 kg, 95 % CI [9.01, 30.85], p < 0.001; BP: +15.0 kg, 95 % CI [4.26, 25.77], p = 0.007), and strength correlated with LMA (row: r = 0.78, p < 0.001; BP: r = 0.76, p < 0.001). Secondly, athletes were stronger than non-athletes, and SCI-subjects were stronger than CP-subjects. Among 14 intervention completers, subjects with acquired impairments increased strength more than those with congenital impairments in the BP (β = 9.74, p = 0.009), but no the row test (β = 2.24, p = 0.443) Baseline LMA correlated with improvements in strength for the BP (r = 0.67, p = 0.011), but not the row exercise (r = 0.25, p = 0.435). Conclusion: Upper body strength in WC users was mainly determined by impairment aetiology, and LMA, both at baseline and change in strength following an RT intervention.