Haraldsplass Diakonale Sykehus

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment for hematological malignancies. However, it is often complicated by chronic graft-versus-host disease (cGVHD), a leading cause of late non-relapse morbidity and mortality. Early identification of patients at risk is therefore critical, yet reliable biomarkers are still lacking. In this study, we evaluated serum endothelial mediator profiles collected 1 year after allo-HSCT and their association with subsequent cGVHD development. Serum samples taken 1 year post-transplant from 82 transplanted patients, of whom 61% developed cGVHD, were analyzed for 19 mediators using Luminex and ELISA assays. Associations between mediator levels and cGVHD were assessed using statistical analysis, logistic regression, and hierarchical clustering. Six mediators, endocan, EMMPRIN, VCAM-1, MMP-1, MMP-8, and MMP-9; differed significantly between patients with and without cGVHD (P < 0.05). Endocan and VCAM-1 remained independently associated with cGVHD in multivariable regression adjusted for age, body mass index (BMI), and prior acute GVHD (aGVHD). Cluster analysis based on these mediators identified distinct patient subgroups. Clusters with generally lower mediator levels had fewer cases of cGVHD, whereas a central cluster with elevated levels showed a higher disease prevalence. Integration of clinical variables confirmed known risk factors, including older age, higher BMI, and previous aGVHD. The identified mediators are biologically linked to endothelial activation and extracellular matrix remodeling. This study is the first to demonstrate that a distinct endothelial- and matrix-remodeling-related serum mediator signature measured 1 year after allo-HSCT is associated with cGVHD. The identified patient clusters provide insight into disease biology and highlight potential biological markers of the disease. These findings support further prospective studies combining longitudinal mediator profiling with clinical data and advanced modeling to improve risk stratification and identify therapeutic targets for the prevention and treatment of cGVHD.

IntroductionPenicillin allergy is a significant barrier to optimal antibiotic stewardship, contributing to increased antimicrobial resistance, higher treatment costs, prolonged hospital stays and elevated mortality rates. However, approximately 90% of penicillin allergy labels are disproven on evaluation. Risk stratification-based penicillin allergy evaluation (PAE) has proven safe and effective outside allergology departments, yet its adoption in routine clinical practice remains limited. This study aims to examine the implementation of a risk stratification-based PAE programme across hospitals in Western Norway.Methods and analysisWe aim to examine implementation of a risk stratification-based programme for evaluating and de-labelling declared penicillin allergy in Western Norway hospitals in a multicentre study. The study employs a combined stepped wedge- and interrupted time series design. It includes hospitals of varying service levels in both urban and rural settings. Each participating centre receives 12 months of active implementation support, followed by a 6 month postintervention evaluation. The study is guided by the Consolidated Framework for Implementation Research and the Expert Recommendations for Implementing Change. Implementation outcomes assessed include acceptability, fidelity, adoption, penetration, feasibility and sustainability.Ethics and disseminationThe study was approved by the Regional Ethics Committee of Western Norway (approval number: 199210). All legal and formal research requirements are met. Results will be published open access in peer-reviewed journals and included in the first author’s publicly available PhD. Nationwide implementation of PAE is planned, informed by the study’s findings.Trial registration numberCurrent Research Information System (Cristin) in Norway project identification number: 2500736.

There is a paucity of studies reporting patient acceptable symptom state (PASS) thresholds for patient reported outcome measures validated for patellar instability. The aim of this study was to determine the PASS threshold for the Banff Patellofemoral Instability Instrument 2.0 (BPII) following surgery for recurrent patellar instability. Patients who underwent patellar stabilisation surgery between 2013 and 2022 were included if they were ≥16 years of age and had ≥12 months of follow-up. The participants completed the BPII and a dichotomous PASS anchor question. The PASS threshold was then calculated using both the adjusted predictive modelling method and receiver operating characteristic (ROC) analysis. Complete data were available for 218 knees of 182 patients, with a median follow-up time of 46 months. The PASS threshold was 62.4 (95% confidence interval [CI]: 58.8-65.9) using the adjusted predictive modelling method, and 66.3 (95% CI: 58.1-80.0) using ROC analysis. Overall, 173 patients (79.4%) reported satisfactory symptom states, while 72.9% and 70.6% achieved the respective PASS thresholds. The adjusted predictive modelling method yielded narrower 95% confidence intervals with minimal threshold variation across different approaches for handling bilateral cases compared to ROC analysis (1.3 vs. 8.1 points). The PASS threshold for BPII after patellar stabilisation surgery was 62.4 (out of 100 points). The adjusted predictive modelling method demonstrated superior precision and robustness in the PASS threshold calculation compared with the ROC analysis. This threshold provides a disease-specific reference for clinical decision making and research in patellofemoral instability. Level III.

Coronary artery disease (CAD) progression and risk of cardiac events differ between women and men during the lifespan. Accordingly, we aimed to explore the impact of sex and age on plaque phenotype in non-obstructive CAD. We included 1189 patients with non-obstructive CAD (48% women) from the Norwegian Registry of Invasive Cardiology and quantitatively assessed each patient's plaque phenotype by coronary CT angiography. Plaque subtypes included calcified (>350 Hounsfield units [HU]), fibrous (131 to 350 HU), fibrofatty (76 to 130 HU) and necrotic core plaques (-30 to 75 HU). The impact of sex on plaque phenotype was assessed after age stratification (≤50, 51-64 and ≥65 years). Total plaque burden adjusted for vessel volume was higher in middle-aged and older women compared with men (all p<0.05). Women had lower proportions of fibrofatty plaques compared with men across all age groups, while middle-aged and older women had higher proportions of calcified and fibrous plaques compared with men. Middle-aged and older men had higher proportions of necrotic core plaques compared with women (all p<0.05). After adjusting for cardiovascular risk factors, female sex remained independently associated with total plaque burden (β=1.0 [0.5 to 1.5], p<0.001), and younger age and male sex with fibrofatty plaque burden (β=-2.8 [-4.4 to -1.2], p<0.001, and β=-3.8 [-4.9 to -2.8], p<0.001, respectively). In non-obstructive CAD, female sex was associated with a higher total plaque burden, whereas male sex and younger age were associated with a higher proportion of vulnerable fibrofatty plaques. Our results highlight important sex differences in plaque phenotypes among patients with non-obstructive CAD during the lifespan, which may impact risk-stratification. NCT04009421.

Aligning biomarker evidence with clinical presentation in early Alzheimer disease (AD) is essential for improving diagnosis, prognosis, and interventions. This study evaluates the relationship between cognitive impairment, future decline, and phosphorylated tau levels in plasma and CSF in predementia AD. This longitudinal observational study included predementia cases and controls from 2 independent cohorts: the Norwegian Dementia Disease Initiation (DDI) and Canadian Pre-Symptomatic Evaluation of Experimental or Novel Treatments for Alzheimer's Disease (PREVENT-AD). In DDI, cognitively normal (CN) and mild cognitive impairment (MCI) cases were classified using CSF Aβ42/40 ratio (A) and p-tau181 (T), whereas classification in PREVENT-AD (A) was based on amyloid PET scans. In DDI, we assessed CSF-plasma correlations for p-tau181, p-tau217, and p-tau231. Diagnostic accuracies were evaluated through receiver operating characteristic analyses. Linear mixed models evaluated p-tau associations with future memory decline. Between-group differences in plasma p-tau217 were assessed in both cohorts. In DDI (n = 431), participants were classified as CN A-/T- (n = 169), A+/T- (CN = 26, MCI = 24), A+/T+ (CN = 40, MCI = 105), and A-/T+ (CN = 34, MCI = 33), with a mean age of 64.1 years and 55.9% female. In PREVENT-AD (n = 190), participants were categorized as CN A- (n = 118), CN A+ (n = 49), and MCI A+ (n = 21), with a mean age of 67.8 years and 72.6% female. In DDI, plasma p-tau217 showed high accuracy in identifying A+ participants (areas under the curve [AUC]: 0.85) and a moderate correlation with CSF p-tau217 (rho = 0.65, p < 0.001). Diagnostic accuracy of plasma p-tau217 was greater in MCI A+ (AUC: 0.89) than in CN A+ (AUC: 0.79, p < 0.05) and in A+/T+ (AUC: 0.88) vs A+/T- (AUC: 0.78, p < 0.05). p-Tau181 and p-tau231 had weaker CSF-plasma correlations (rho = 0.47 and rho = 0.32, p < 0.001) and were less associated with cognitive status in A+ individuals. Higher plasma p-tau217 in A+ MCI vs A+ CN individuals (p < 0.001) was confirmed in PREVENT-AD. All CSF p-tau markers, but only plasma p-tau217, were associated with future memory decline (β = 0.05, p < 0.05). Our findings suggest that, unlike p-tau181 and p-tau231, plasma p-tau217 consistently aligns with cognitive status in A+ individuals and better reflects CSF biomarker abnormalities, reducing discrepancies between clinical and biochemical findings. Its association with baseline and future memory decline highlights its diagnostic and prognostic value, particularly when CSF analysis or PET is unavailable.

Simple SummaryIn cancer, including head and neck cancer (HNC), certain key players in the body’s inflammatory process, such as the interleukin (IL)-6 and IL-1 systems, are associated with outcomes. We studied some of these key players in a subgroup of HNC patients. From one blood sample measured at diagnosis, we determined high levels of molecules from members of the IL-6 and IL-1 families with their associated soluble cytokine receptors. High values indicated a lower survival rate. This prediction was to some extent better than the standard clinical predictors used. The results highlight potential new targets for immune treatment development. Additionally, these findings could contribute to the refinement of cancer treatment strategies, particularly in the context of emerging immune therapies. Activation of the acute-phase cascade (APC) has been correlated with outcomes in various cancers, including head and neck squamous cell carcinoma (HNSCC). Primary drivers of the APC are the cytokines within the interleukin-6 (IL-6) and IL-1 families. Plasma levels of IL-6 family cytokines/soluble receptors (IL-6, IL-27, IL-31, OSM, CNTF, soluble (s-)gp130, s-IL-6Rα) and IL-1 family members (IL-1RA, s-IL-33Rα) were determined at diagnosis for 87 human papillomavirus (HPV)-negative (−) HNSCC patients. We then studied the 5-year Disease-Specific Survival (DSS) and Overall Survival (OS). Increased plasma levels of IL-6 (p < 0.001/p < 0.001) (DSS/OS), IL-31 (p = 0.044/p = 0.07), IL-1RA (p = 0.004/p = 0.035), soluble (s)-IL-6Rα p = 0.022/p = 0.035), and s-gp130 (p = 0.007/p = 0.003) at diagnosis were predictors of both OS and DSS from HPV(−) HNSCC patients. The cytokine DSS/OS predictions were associated with TNM stage and smoking history, whereas the soluble receptors IL-6Rα, gp130, and IL33Rα more uniquely predicted DSS/OS. Clinically, IL-6 levels above 2.5 pg/mL yielded 75% specificity and 70% sensitivity for DSS. In conclusion, high plasma levels of IL-6, IL-31, and IL-1RA, as well as the soluble receptors IL-6Rα, gp130, and IL33Rα, predicted clinical outcome. This shows their potential as candidates for both general therapy and immune therapy stratification, as well as being future platforms for the development of new immunotherapy.

Right-sided colon cancer (RCC) differs in mutation profile and risk of recurrence compared to distal colon cancer. Circulating tumour DNA (ctDNA) present after surgery can identify patients with residual disease after curative surgery and predict risk of early recurrence. This is a prospective observational biomarker trial with exploration of ctDNA in 50 non-metastatic RCC patients for which oncological right-sided colectomy was performed. Blood samples were collected preoperatively, within 1 month post surgery, 3 months (not mandatory), 6 months and every 6 months thereafter. Plasma cell free DNA and/or tumour was investigated for cancer-related mutations by the next-generation sequencing (NGS) panel AVENIO surveillance specifically designed for ctDNA analysis. Detected mutations were quantified using digital droplet PCR (ddPCR) for follow-up. Recurrence-free survival was explored. 50 patients were recruited. Somatic cancer-related mutations were detected in 47/50 patients. ddPCR validated results from NGS for 27/34 (plasma) and 72/72 samples (tumour). Preoperative ctDNA was detected in 31/47 of the stage I/III patients and the majority of ctDNA positive patients showed reduction of ctDNA after surgery (27/31). ctDNA-positive patients at first postoperative sample had high recurrence risk compared to patients without measurable ctDNA (adjusted hazard ratio: 172.91; 95% c.i.: 8.70 to 3437.24; P: 0.001). ctDNA was detectable in most patients with non-metastatic RCC before surgery. Positive postoperative ctDNA was strongly associated with early recurrence. Detectable postoperative ctDNA is a prognostic factor with high (100%) positive predictive value for recurrence in this cohort of non-metastatic RCC. ClinicalTrials.gov ID: NCT03776591.

Background:Individuals with diabetes rely on medical equipment (eg, continuous glucose monitoring (CGM), hybrid closed-loop systems) and mobile applications to manage their condition, providing valuable data to health care providers. Data sharing from this equipment is regulated via Terms of Service (ToS) and Privacy Policy documents. The introduction of the Medical Devices Regulation (MDR) and In Vitro Diagnostic Medical Devices Regulation (IVDR) in the European Union has established updated rules for medical devices, including software.Objective:This study examines how data sharing is regulated by the ToS and Privacy Policy documents of approved diabetes medical equipment and associated software. It focuses on the equipment approved by the Norwegian Regional Health Authorities.Methods:A document analysis was conducted on the ToS and Privacy Policy documents of diabetes medical equipment and software applications approved in Norway.Results:The analysis identified 11 medical equipment and 12 software applications used for diabetes data transfer and analysis in Norway. Only 3 medical equipment (OmniPod Dash, Accu-Chek Insight, and Accu-Chek Solo) were registered in the European Database on Medical Devices (EUDAMED) database, whereas none of their respective software applications were registered. Compliance with General Data Protection Regulation (GDPR) security requirements varied, with some software relying on adequacy decisions (8/12), whereas others did not (4/12).Conclusions:The study highlights the dominance of non-European Economic Area (EEA) companies in medical device technology development. It also identifies the lack of registration for medical equipment and software in the EUDAMED database, which is currently not mandatory. These findings underscore the need for further attention to ensure regulatory compliance and improve data-sharing practices in the context of diabetes management.

Background Involvement in research and shared priorities among occupational therapists (OTs) can enhance the quality of occupational therapy practice. Aims To explore the research involvement and research priorities of OTs in Norway. Materials and methods An online survey comprising 14 open-ended and closed questions was made available to participants at the Seventh Norwegian Congress in Occupational Therapy to fill out. Results Out of 633 congress participants, 307 (49%) OTs completed the survey. Among the respondents, ∼40% were involved in research. The most commonly reported area of research was rehabilitation. Research involvement was associated with employment in education or specialist healthcare services and with greater work experience and post-bachelor’s degree education. The most frequently prioritized research question addressed the effect of occupational therapy. Unmet needs and factors conducive to increasing OT’s involvement in research were identified. Conclusions and significance The survey revealed that a considerable, but uneven, distribution of OTs were involved in research. To encourage greater participation in research, researchers, decision-makers, and employee associations should take steps to make research more appealing to OTs. The research priorities highlighted by Norwegian OTs align with those stated by OTs in other countries.