South-Eastern Norway Regional Health Authority Research Articles

Serum proteomic profiling of physical activity reveals CD300LG as a novel exerkine with a potential causal link to glucose homeostasis.

Physical activity has been associated with preventing the development of type 2 diabetes and atherosclerotic cardiovascular disease. However, our understanding of the precise molecular mechanisms underlying these effects remains incomplete and good biomarkers to objectively assess physical activity are lacking. We analyzed 3072 serum proteins in 26 men, normal weight or overweight, undergoing 12 weeks of a combined strength and endurance exercise intervention. We estimated insulin sensitivity with hyperinsulinemic euglycemic clamp, maximum oxygen uptake, muscle strength, and used MRI/MRS to evaluate body composition and organ fat depots. Muscle and subcutaneous adipose tissue biopsies were used for mRNA sequencing. Additional association analyses were performed in samples from up to 47,747 individuals in the UK Biobank, as well as using two-sample Mendelian randomization and mice models. Following 12 weeks of exercise intervention, we observed significant changes in 283 serum proteins. Notably, 66 of these proteins were elevated in overweight men and positively associated with liver fat before the exercise regimen, but were normalized after exercise. Furthermore, for 19.7 and 12.1% of the exercise-responsive proteins, corresponding changes in mRNA expression levels in muscle and fat, respectively, were shown. The protein CD300LG displayed consistent alterations in blood, muscle, and fat. Serum CD300LG exhibited positive associations with insulin sensitivity, and to angiogenesis-related gene expression in both muscle and fat. Furthermore, serum CD300LG was positively associated with physical activity and negatively associated with glucose levels in the UK Biobank. In this sample, the association between serum CD300LG and physical activity was significantly stronger in men than in women. Mendelian randomization analysis suggested potential causal relationships between levels of serum CD300LG and fasting glucose, 2 hr glucose after an oral glucose tolerance test, and HbA1c. Additionally, Cd300lg responded to exercise in a mouse model, and we observed signs of impaired glucose tolerance in male, but not female, Cd300lg knockout mice. Our study identified several novel proteins in serum whose levels change in response to prolonged exercise and were significantly associated with body composition, liver fat, and glucose homeostasis. Serum CD300LG increased with physical activity and is a potential causal link to improved glucose levels. CD300LG may be a promising exercise biomarker and a therapeutic target in type 2 diabetes. South-Eastern Norway Regional Health Authority, Simon Fougners Fund, Diabetesforbundet, Johan Selmer Kvanes' legat til forskning og bekjempelse av sukkersyke. The UK Biobank resource reference 53641. Australian National Health and Medical Research Council Investigator Grant (APP2017942). Australian Research Council Discovery Early Career Award (DE220101226). Research Council of Norway (Project grant: 325640 and Mobility grant: 287198). The Medical Student Research Program at the University of Oslo. Novo Nordisk Fonden Excellence Emerging Grant in Endocrinology and Metabolism 2023 (NNF23OC0082123). clinicaltrials.gov: NCT01803568.

The impact of cancer patient pathway on timing of radiotherapy and survival: a cohort study in glioblastoma patients.

Glioblastoma (GBM) is an aggressive brain tumor in which primary therapy is standardized and consists of surgery, radiotherapy (RT), and chemotherapy. However, the optimal time from surgery to start of RT is unknown. A high-grade glioma cancer patient pathway (CPP) was implemented in Norway in 2015 to avoid non-medical delays and regional disparity, and to optimize information flow to patients. This study investigated how CPP affected time to RT after surgery and overall survival. This study included consecutive GBM patients diagnosed in South-Eastern Norway Regional Health Authority from 2006 to 2019 and treated with RT. The pre CPP implementation group constituted patients diagnosed 2006-2014, and the post CPP implementation group constituted patients diagnosed 2016-2019. We evaluated timing of RT and survival in relation to CPP implementation. A total of 1212 patients with GBM were included. CPP implementation was associated with significantly better outcomes (p < 0.001). Median overall survival was 12.9 months. The odds of receiving RT within four weeks after surgery were significantly higher post CPP implementation (p < 0.001). We found no difference in survival dependent on timing of RT below 4, 4-6 or more than 6 weeks (p = 0.349). Prognostic factors for better outcomes in adjusted analyses were female sex (p = 0.005), younger age (p < 0.001), solitary tumors (p = 0.008), gross total resection (p < 0.001), and higher RT dose (p < 0.001). CPP implementation significantly reduced time to start of postoperative RT. Survival was significantly longer in the period after the CPP implementation, however, timing of postoperative RT relative to time of surgery did not impact survival.

Effects of tapering conventional synthetic disease-modifying antirheumatic drugs to drug-free remission versus stable treatment in rheumatoid arthritis (ARCTIC REWIND): 3-year results from an open-label, randomised controlled, non-inferiority trial

Tapering of disease-modifying antirheumatic drugs (DMARDs) to drug-free remission is an attractive treatment goal for patients with rheumatoid arthritis, although long-term effects of tapering and withdrawal remain unclear. We compared 3-year risks of flare between three conventional synthetic DMARD treatment strategies in patients with rheumatoid arthritis in sustained remission. In this open-label, randomised controlled, non-inferiority trial, we enrolled patients aged 18-80 years with rheumatoid arthritis who had been in sustained remission for at least 1 year on stable conventional synthetic DMARD therapy. Patients from ten hospitals in Norway were randomly assigned (2:1:1) with centre stratification to receive stable conventional synthetic DMARDs, half-dose conventional synthetic DMARDs, or half-dose conventional synthetic DMARDs for 1 year followed by withdrawal of all conventional synthetic DMARDs. The primary endpoint of this part of the study was disease flare over 3 years, analysed as flare-free survival and risk difference in the per-protocol population with a non-inferiority margin of 20%. This trial is registered with ClinicalTrials.gov (NCT01881308) and is completed. Between June 17, 2013, and June 18, 2018, 160 patients were enrolled and randomly assigned to receive stable-dose conventional synthetic DMARDs (n=80), half-dose conventional synthetic DMARDs (n=42), or half-dose conventional synthetic DMARDs tapering to withdrawal (n=38). Four patients did not receive the intervention and 156 patients received the allocated treatment strategy. One patient was excluded due to major protocol violation and 155 patients were included in the per-protocol analysis. 104 (67%) of 156 patients were women and 52 (33%) were men. 139 patients completed 3-years follow-up without major protocol violation; 68 (87%) of 78 patients in the stable-dose group, 36 (88%) of 41 patients in the half-dose group and 35 (95%) of 37 patients in the half-dose tapering to withdrawal group. During the 3-year study period, 80% (95% CI 69-88%) were flare-free in the stable-dose group, compared with 57% (41-71%) in the half-dose group and 38% (22-53%) in the half-dose tapering to withdrawal group. Compared with stable-dose conventional synthetic DMARDs, the risk difference of flare was 23% (95% CI 6-41%, p=0·010) in the half-dose group and 40% (22-58%, p<0·0001) in the half-dose tapering to withdrawal group, non-inferiority was therefore not shown. Adverse events were reported in 65 (83%) of 78 patients in the stable-dose group, 36 (90%) of 40 patients in the half-dose group, and 36 (97%) of 37 patients in the half-dose tapering to withdrawal group. One death occurred in the stable-dose conventional synthetic DMARD group (sudden death considered unlikely related to the study medication). Two conventional synthetic DMARD tapering strategies were associated with significantly lower rates of flare-free survival compared with stable conventional synthetic DMARD treatment, and the data do not support non-inferiority. However, drug-free remission was achiveable for a significant subgroup of patients. This trial provides information on risk and benefits of different treatment strategies important for shared decision making. Research Council of Norway and South-Eastern Norway Regional Health Authority.

Open-door policy versus treatment-as-usual in urban psychiatric inpatient wards: a pragmatic, randomised controlled, non-inferiority trial in Norway

Open-door policy is a recommended framework to reduce coercion in psychiatric wards. However, existing observational data might not fully capture potential increases in harm and use of coercion associated with open-door policies. In this first randomised controlled trial, we compared coercive practices in open-door policy and treatment-as-usual wards in an urban hospital setting. We hypothesised that the open-door policy would be non-inferior to treatment-as-usual on the proportion of patients exposed to coercive measures. We conducted a pragmatic, randomised controlled, non-inferiority trial comparing two open-door policy wards and three treatment-as-usual acute psychiatric wards at Lovisenberg Diaconal Hospital in Oslo, Norway. An exemption from the consent requirements enabled inclusion and random allocation of all patients admitted to these wards using an open list (2:3 ratio) administrated by a team of ward nurses. The primary outcome was the proportion of patient stays with one or more coercive measures, including involuntary medication, isolation or seclusion, and physical and mechanical restraints. The non-inferiority margin was set to 15%. Primary and safety analyses were assessed using the intention-to-treat population. The trial is registered with ISRCTN registry and is complete, ISRCTN16876467. Between Feb 10, 2021, and Feb 1, 2022, we randomly assigned 556 patients to either open-door policy wards (n=245; mean age 41·6 [SD 14·5] years; 119 [49%] male; 126 [51%] female; and 180 [73%] admitted to the ward involuntarily) or treatment-as-usual wards (n=311; mean age 41·6 [4·3] years; 172 [55%] male and 138 [45%] female; 233 [75%] admitted involuntarily). Data on race and ethnicity were not collected. The open-door policy was non-inferior to treatment-as-usual on all outcomes: the proportion of patient stays with exposure to coercion was 65 (26·5%) in open-door policy wards and 104 (33·4%) in treatment-as-usual wards (risk difference 6·9%; 95% CI -0·7 to 14·5), with a similar trend for specific measures of coercion. Reported incidents of violence against staff were 0·15 per patient stay in open-door policy wards and 0·18 in treatment-as-usual wards. There were no suicides during the randomised controlled trial period. The open-door policy could be safely implemented without increased use of coercive measures. Our findings underscore the need for more reliable and relevant randomised trials to investigate how a complex intervention, such as open-door policy, can be efficiently implemented across health-care systems and contexts. South-Eastern Norway Regional Health Authority and The Research Council of Norway.

Clinical consequences of infliximab immunogenicity and the effect of proactive therapeutic drug monitoring: exploratory analyses of the randomised, controlled NOR-DRUM trials

Antidrug antibodies to TNF inhibitors might affect clinical outcomes. Proactive therapeutic drug monitoring allows for early detection of antidrug antibodies and might reduce negative clinical consequences. We aimed to explore how antidrug antibodies to the TNF inhibitor infliximab influence treatment outcomes, and to assess the effect of proactive therapeutic drug monitoring. This was a predefined exploratory analysis of data from the randomised, controlled NOR-DRUM trials. The trials were conducted in rheumatology, gastroenterology, and dermatology departments at 21 Norwegian hospitals. Adult patients (aged 18-75 years) with immune-mediated inflammatory diseases were randomly assigned to proactive therapeutic drug monitoring or standard infliximab dosing in the NOR-DRUM A trial (30-week follow-up) and the NOR-DRUM B trial (52-week follow-up). Antidrug antibodies were assessed with a drug-sensitive assay before each infusion. The outcomes of remission (at week 30), disease worsening (during 52 weeks), infusion reactions, and infliximab discontinuation were assessed according to the presence of antidrug antibodies and use of therapeutic drug monitoring. Between March 1, 2017, and Dec 12, 2019, 616 patients were included in the NOR-DRUM trials, of whom 615 had at least one serum infliximab and antidrug antibody assessment and were included in the present analyses. Mean age was 45 years (IQR 32-56), 305 (50%) patients were women, and 310 (50%) patients were men. Antidrug antibodies were detected in 147 (24%) patients. Remission at week 30 occurred in 25 (35%) of 72 patients with antidrug antibodies and 180 (54%) of 335 without antidrug antibodies (risk ratio 0·62 [95% CI 0·45-0·86]; p=0·0037). In patients with antidrug antibodies compared with patients without antidrug antibodies, higher rates were found for: disease worsening over 52 weeks (0·76 per person-year vs 0· 35 per person-year, hazard ratio [HR] 2·02 [95% CI 1·33-3·07]; p=0·0009), infusion reactions (0·16 per person-year vs 0·03 per person-year, HR 17·02 [6·98-41·47]; p<0·0001), and infliximab discontinuation (1·00 per person-year vs 0·20 per person-year, HR 6·64 [4·84-9·11]; p<0·0001). These associations were more pronounced in patients with high concentrations of antidrug antibodies than in those with low concentrations of antidrug antibodies. Independent of antibody status, therapeutic drug monitoring was associated with a lower risk of disease worsening (HR 0·41 [0·29-0·59]; p=0·0001) or an infusion reaction (HR 0·30 [0·12-0·73]; p=0·0076), and was associated with an increase in the rate of infliximab discontinuation (HR 1·37 [1·02-1·83]; p=0·037). In patients where antidrug antibodies were detected, remission was less likely to be reached and sustained, and infusion reaction or discontinuation of infliximab was more likely. Timely detection of antidrug antibodies by proactive therapeutic drug monitoring facilitated treatment decisions that reduced the negative consequences, both regarding infliximab effectiveness and safety. This highlights the role of proactive therapeutic drug monitoring in optimising infliximab therapy. Inter-regional KLINBEFORSK grants and South-Eastern Norway Regional Health Authority grants.

Follow-Up of Patients With Axial Spondyloarthritis in Specialist Health Care With Remote Monitoring and Self-Monitoring Compared With Regular Face-to-Face Follow-Up Visits (the ReMonit Study): Protocol for a Randomized, Controlled Open-Label Noninferiority Trial.

Patients with chronic inflammatory joint diseases such as axial spondyloarthritis have traditionally received regular follow-up in specialist health care to maintain low disease activity. The follow-up has been organized as prescheduled face-to-face visits, which are time-consuming for both patients and health care professionals. Technology has enabled the remote monitoring of disease activity, allowing patients to self-monitor their disease and contact health care professionals when needed. Remote monitoring or self-monitoring may provide a more personalized follow-up, but there is limited research on how these follow-up strategies perform in maintaining low disease activity, patient satisfaction, safety, and cost-effectiveness. The Remote Monitoring in Axial Spondyloarthritis (ReMonit) study aimed to assess the effectiveness of digital remote monitoring and self-monitoring in maintaining low disease activity in patients with axial spondyloarthritis. The ReMonit study is a 3-armed, single-site, randomized, controlled, open-label noninferiority trial including patients with axial spondyloarthritis with low disease activity (Ankylosing Spondylitis Disease Activity Score <2.1) and on stable treatment with a tumor necrosis factor inhibitor. Participants were randomized 1:1:1 to arm A (usual care, face-to-face visits every sixth month), arm B (remote monitoring, monthly digital registration of patient-reported outcomes), or arm C (patient-initiated care, self-monitoring, no planned visits during the study period). The primary end point was disease activity measured with the Ankylosing Spondylitis Disease Activity Score, evaluated at 6, 12, and 18 months. We aimed to include 240 patients, 80 in each arm. Secondary end points included other measures of disease activity, patient satisfaction, safety, and cost-effectiveness. The project is funded by the South-Eastern Norway Regional Health Authority and Centre for the treatment of Rheumatic and Musculoskeletal Diseases (REMEDY), Diakonhjemmet Hospital, Norway. Enrollment started in September 2021 and was completed with 242 patients by June 2022. The data collection will be completed in December 2023. To our knowledge, this trial will be among the first to evaluate the effectiveness, safety, and cost-effectiveness of remote digital monitoring and self-monitoring of patients with axial spondyloarthritis compared with usual care. Hence, the ReMonit study will contribute important knowledge to personalized follow-up strategies for patients with axial spondyloarthritis. These results may also be relevant for other patient groups with inflammatory joint diseases. ClinicalTrials.gov NCT05031767; hpps://www.clinicaltrials.gov/study/NCT05031767. DERR1-10.2196/52872.

Common basis for digital pathology in South-Eastern Norway Regional Health Authority – close to the finish line

Common basis for digital pathology in South-Eastern Norway Regional Health Authority – close to the finish line

Impaired glucose tolerance and cardiovascular risk factors in relation to infertility: a Mendelian randomization analysis in the Norwegian Mother, Father, and Child Cohort Study.

Are impaired glucose tolerance (as measured by fasting glucose, glycated hemoglobin, and fasting insulin) and cardiovascular disease risk (as measured by low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, systolic blood pressure, and diastolic blood pressure) causally related to infertility? Genetic instruments suggest that higher fasting insulin may increase infertility in women. Observational evidence suggests a shared etiology between impaired glucose tolerance, cardiovascular risk, and fertility problems. This study included two-sample Mendelian randomization (MR) analyses, in which we used genome-wide association summary data that were publicly available for the biomarkers of impaired glucose tolerance and cardiovascular disease, and sex-specific genome-wide association studies (GWASs) of infertility conducted in the Norwegian Mother, Father, and Child Cohort Study. There were 68 882 women (average age 30, involved in 81 682 pregnancies) and 47 474 of their male partners (average age 33, 55 744 pregnancies) who had available genotype data and who provided self-reported information on time-to-pregnancy and use of ARTs. Of couples, 12% were infertile (having tried to conceive for ≥12 months or used ARTs to conceive). We applied the inverse variance weighted method with random effects to pool data across variants and a series of sensitivity analyses to explore genetic instrument validity. (We checked the robustness of genetic instruments and the lack of unbalanced horizontal pleiotropy, and we used methods that are robust to population stratification.) Findings were corrected for multiple comparisons by the Bonferroni method (eight exposures: P-value < 0.00625). In women, increases in genetically determined fasting insulin levels were associated with greater odds of infertility (+1 log(pmol/l): odds ratio 1.60, 95% CI 1.17 to 2.18, P-value = 0.003). The results were robust in the sensitivity analyses exploring the validity of MR assumptions and the role of pleiotropy of other cardiometabolic risk factors. There was also evidence of higher glucose and glycated hemoglobin causing infertility in women, but the findings were imprecise and did not pass our P-value threshold for multiple testing. The results for lipids and blood pressure were close to the null, suggesting that these did not cause infertility. We did not know if underlying causes of infertility were in the woman, man, or both. Our analyses only involved couples who had conceived. We did not have data on circulating levels of cardiometabolic risk factors, and we opted to conduct an MR analysis using GWAS summary statistics. No sex-specific genetic instruments on cardiometabolic risk factors were available. Our results may be affected by selection and misclassification bias. Finally, the characteristics of our study sample limit the generalizability of our results to populations of non-European ancestry. Treatments for lower fasting insulin levels may reduce the risk of infertility in women. The MoBa Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Norwegian Ministry of Education and Research. This work was supported by the European Research Council [grant numbers 947684, 101071773, 293574, 101021566], the Research Council of Norway [grant numbers 262700, 320656, 274611], the South-Eastern Norway Regional Health Authority [grant numbers 2020022, 2021045], and the British Heart Foundation [grant numbers CH/F/20/90003, AA/18/1/34219]. Open Access funding was provided by the Norwegian Institute of Public Health. The funders had no role in the study design; the collection, analysis, and interpretation of data; the writing of the report; or the decision to submit the article for publication. D.A.L. has received research support from National and International government and charitable bodies, Roche Diagnostics and Medtronic for research unrelated to the current work. O.A.A. has been a consultant to HealthLytix. The rest of the authors declare that no competing interests exist. N/A.

Billion kroner project in South-Eastern Norway Regional Health Authority gone astray

Billion kroner project in South-Eastern Norway Regional Health Authority gone astray

Mapping the chemotactic landscape in NK cells reveals subset-specific synergistic migratory responses to dual chemokine receptor ligation

Natural killer (NK) cells have a unique capability of spontaneous cytotoxicity against malignant cells and hold promise for off-the-shelf cell therapy against cancer. One of the key challenges in the field is to improve NK cell homing to solid tumors. To gain a deeper understanding of the cellular mechanisms regulating trafficking of NK cells into the tumor, we used high-dimensional flow cytometry, mass cytometry, and single-cell RNA-sequencing combined with functional assays, creating a comprehensive map of human NK cell migration phenotypes. We found that the chemokine receptor repertoire of peripheral blood NK cells changes in a coordinated manner becoming progressively more diversified during NK cell differentiation and correlating tightly with the migratory response of the distinct NK cell subsets. Simultaneous ligation of CXCR1/2 and CX3CR1, synergistically potentiated the migratory response of NK cells. Analysis of 9471 solid cancers from publicly available TCGA/TARGET repositories revealed dominant chemokine patterns that varied across tumor types but with no tumor group expressing ligands for more than one chemokine receptor present on mature NK cells. The finding that chemokine stimulation can elicit a synergistic migratory response in NK cells combined with the identified lack of naturally occurring pairs of chemokines-chemokine receptors in human cancers may explain the systematic exclusion of NK cells from the tumor microenvironment and provides a basis for engineering next-generation NK cell therapies against malignancies. The Polish Ministry of Science and Higher Education, the National Science Centre, Poland, The Norwegian Cancer Society, the Norwegian Research Council, the South-Eastern Norway Regional Health Authority, The Swedish Cancer Society, the Swedish Children's Cancer Foundation, The Swedish Research Council, The Center of Excellence: Precision Immunotherapy Alliance, Knut and Alice Wallenberg Foundation and National Cancer Institute.

Functional orthosis versus cast immobilization for weightbearing stable Weber B ankle fractures with concomitant unstable gravity stress tests.

Treatment of Weber B ankle fractures that are stable on weightbearing radiographs but unstable on concomitant stress tests (classified SER4a) is controversial. Recent studies indicate that these fractures should be treated nonoperatively, but no studies have compared alternative nonoperative options. This study aims to evaluate patient-reported outcomes and the safety of fracture treatment using functional orthosis versus cast immobilization. A total of 110 patients with Weber B/SER4a ankle fractures will be randomized (1:1 ratio) to receive six weeks of functional orthosis treatment or cast immobilization with a two-year follow-up. The primary outcome is patient-reported ankle function and symptoms measured by the Manchester-Oxford Foot and Ankle Questionnaire (MOxFQ); secondary outcomes include Olerud-Molander Ankle Score, radiological evaluation of ankle congruence in weightbearing and gravity stress tests, and rates of treatment-related adverse events. The Regional Committee for Medical and Health Research (approval number 277693) has granted ethical approval, and the study is funded by South-Eastern Norway Regional Health Authority (grant number 2023014). Randomized controlled trials are needed to evaluate alternative nonoperative treatment options for Weber B/SER4a ankle fractures, as current clinical guidelines are based on biomechanical reasoning. The findings will be shared through publication in peer-reviewed journals and presentations at conferences.

Development and validation of a risk prediction model for post-polypectomy colorectal cancer in the USA: a prospective cohort study

Effective risk stratification tools for post-polypectomy colorectal cancer (PPCRC) are lacking. We aimed to develop an effective risk stratification tool for the prediction of PPCRC in three large population-based cohorts and to validate the tool in a clinical cohort. Leveraging the integrated endoscopic, histopathologic and epidemiologic data in three U.S population-based cohorts of health professional (the Nurses' Health Study (NHS) I, II and Health Professionals Follow-up Study (HPFS)), we developed a risk score to predict incident PPCRC among 26,741 patients with a polypectomy between 1986 and 2017. We validated the PPCRC score in the Mass General Brigham (MGB) Colonoscopy Cohort (Boston, Massachusetts, U.S) of 76,603 patients with a polypectomy between 2007 and 2018. In all four cohorts, we collected detailed data on patients' demographics, endoscopic history, polyp features, and lifestyle factors at polypectomy. The outcome, incidence of PPCRC, was assessed by biennial follow-up questionnaires in the NHS/HPFS cohorts, and through linkage to the Massachusetts Cancer Registry in the MGB cohort. In all four cohorts, individuals who were diagnosed with CRC or died before baseline or within six months after baseline were excluded. We used Cox regression to calculate the hazard ratio (HR), 95% confidence interval (CI) and assessed the discrimination using C-statistics and reclassification using the Net Reclassification Improvement (NRI). During a median follow-up of 12.8 years (interquartile range (IQR): 9.3, 16.7) and 5.1 years (IQR: 2.7, 7.8) in the NHS/HPFS and MGB cohorts, we documented 220 and 241 PPCRC cases, respectively. We identified a PPCRC risk score based on 11 predictors. In the validation cohort, the PPCRC risk score showed a strong association with PPCRC risk (HR for high vs. low, 3.55, 95% CI, 2.59-4.88) and demonstrated a C-statistic (95% CI) of 0.75 (0.70-0.79), and was discriminatory even within the low- and high-risk polyp groups (C-statistic, 0.73 and 0.71, respectively) defined by the current colonoscopy surveillance recommendations, leading to a NRI of 45% (95% CI, 36-54%) for patients with PPCRC. We developed and validated a risk stratification model for PPCRC that may be useful to guide tailored colonoscopy surveillance. Further work is needed to determine the optimal surveillance interval and test the added value of other predictors of PPCRC beyond those included in the current study, along with implementation studies. USNational Institutes of Health, the American Cancer Society, the South-Eastern Norway Regional Health Authority, the Deutsche Forschungsgemeinschaft.

COVID-19 patients treated with convalescent plasma.

In Norway, treatment with COVID-19 convalescent plasma has been given through the NORPLASMA project. The treatment was initially offered to critically ill patients after an individual assessment, but from December 2020, the indication was limited to critically ill, immunocompromised patients. In this article we describe clinical characteristics, comorbidity and mortality in patients who received convalescent plasma in these two periods. From 22April 2020 to 30March 2022, a total of 79 patients were included in the observational studies NORPLASMA MONITOR and the Norwegian SARS-CoV-2 study. The patients had received a total of 193 units of convalescent plasma at 15 Norwegian hospitals/nursing homes; 62 in South-Eastern Norway Regional Health Authority, 8 in Western Norway Regional Health Authority and 9 in Central Norway Regional Health Authority. Information on immune status, comorbidity and course of infection was retrieved from the patient records after informed written consent was obtained. Of 79 patients with a median age of 65 years (interquartile range 51-⁠73) who were treated with convalescent plasma, 31 (39%) died during hospitalisation. A total of 59 patients were immunocompromised, and of these, 20 died in hospital compared to 11 of 20 who were assumed to be immunocompetent. Median number of comorbidities was 2 (interquartile range 1-4). The patients received a median of two plasma units (min.-max. 1-21). Two of the patients developed mild allergic skin reactions. Convalescent plasma was well tolerated by patients with COVID-19. Immunocompromised patients may have benefitted from the treatment, with lower mortality than for those assumed to be immunocompetent.

Cardiac troponin T, NT-proBNP and GDF-15 associate with future focal myocardial scar types, but not diffuse fibrosis assessed by cardiac magnetic resonance

Abstract Funding Acknowledgements Type of funding sources: Other. Main funding source(s): Akershus University Hospital Trust, Vestre Viken Hospital Trust, South-Eastern Norway Regional Health Authority, Roche Diagnostics provided reagents for hs-cTnT analyses Background In cardiovascular risk prediction, there is growing evidence that imaging and circulating cardiac biomarkers provide incremental prognostic value compared to single biomarkers or traditional risk factors. In patients with suspected or established cardiovascular disease (CVD), cardiac troponin T (cTnT) and N-terminal pro B-type natriuretic peptide (NT-proBNP) associate with focal and diffuse fibrosis assessed by cardiac magnetic resonance (CMR) imaging. There is limited data on the associations between established and emerging circulating cardiac biomarkers with subsequent myocardial fibrosis in subjects without CVD recruited from the general population. Purpose Assess the associations between biomarkers of cardiac injury (cTnT), stress (NT-proBNP) and fibrosis and inflammation (growth differentiation factor-15, GDF-15), and subsequent focal and diffuse myocardial fibrosis assessed by CMR imaging. Methods We recruited 200 study participants born in 1950 from the general population. All participants were without known coronary artery disease or renal dysfunction. cTnT, NT-proBNP, and GDF-15 were measured in samples collected at baseline in 2012–2015, and CMR was performed 4–7 years later. Presence and type (ischemic/non-ischemic) of focal myocardial fibrosis were assessed by late gadolinium enhancement (LGE) imaging. Diffuse fibrosis was assessed by the extracellular volume (ECV) in the midventricular septum. Logistic regression analysis was used to examine relationships between log transformed concentrations of cardiac biomarkers and CMR parameters. Results The median age was 63.9 (63.4–64.5) and 52% were male (Table 1). cTnT was associated with presence of any LGE scar adjusted for common cardiovascular risk factors (OR 1.85, 95% CI 1.25–2.72), but this association was attenuated when left ventricular mass was added to the model (Table 2). NT-proBNP (OR 1.66, 95% CI 1.10–2.72) and GDF-15 (OR 4.45, 95% CI 1.29–15.27) were associated with presence of any LGE scar in the fully adjusted models (Table 2). cTnT (OR 1.90, 95% CI 1.06–3.39) and NT-proBNP (OR 2.72, 95% CI 1.29–5.76) were associated with ischemic scars. Only GDF-15 (OR 4.52, 95% CI 1.09–18.72) associated with non-ischemic scars in adjusted models. None of the biomarkers were significantly associated with ECV. Conclusion(s) In a general population cohort, biomarkers of myocardial injury and stress associate with ischemic type scars, but not diffuse fibrosis. GDF-15, an emerging circulating biomarker of fibrosis and inflammation, associates with non-ischemic type scars.

Distinguishing left ventricular hypertrophy from hypertrophic cardiomyopathy in adolescents - a longitudinal observation study

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): MF: The South-Eastern Norway Regional Health Authority [grant number 2017207]. KHH, MKS: Norwegian Research Council [grant number 309762 ProCardio]. Background Distinguishing athlete´s heart from hypertrophic cardiomyopathy (HCM) can be challenging. There is a lack of data describing physiological and pathological remodelling in adolescents. Purpose The purpose of this study was to compare development of left ventricular (LV) hypertrophy in adolescent athletes to HCM genotype positive adolescents. Methods Athletes and age- and sex-matched HCM genotype positive adolescents underwent echocardiography at baseline and at follow-up, minimum two years later. Echocardiographic parameters were evaluated by pediatric reference values (Z-scores). LV hypertrophy was defined as Z-score &amp;gt;2 for intraventricular septum diameter (IVSd) or posterior wall thickness (LVPWd). Results Seventy-six athletes were compared to 63 (1 proband, 62 family members) HCM genotype positive adolescents (37% vs 44% female, p = 0.36, mean age baseline 12.1±0.2 vs 12.4±1.4 years, p = 0.10). Mean follow-up-time was alike by protocol (3.1±0.2 vs 3.2±1.3 years, p = 0.59). LV hypertrophy was found in a similar proportion of athletes and HCM genotype positive adolescents (28% vs 30% at baseline, p = 0.75, 30% vs 32% at follow-up, p = 0.80). Compared with athletes, interventricular septum was thicker in HCM genotype positive adolescents at baseline (Z IVSd 1.4±0.9 vs 2.7±5.2, p = 0.03). Left ventricular volumes were greater in athletes (Z LVEDV 1.0±0.6 vs −0.1±0.9, p&amp;lt;0.001). Septum thickness increased only in HCM genotype positive adolescents (Z IVSd progression rate −0.17(SE0.05), p = 0.001 vs 0.54(SE0.16), p = 0.001, p for interaction &amp;lt;0.001). There was no difference in LVPWd (0.6±1.3 vs 0.8±0.8, p = 0.13). Conclusions LV hypertrophy was observed in nearly 1/3 of both athletes and HCM genotype positive adolescents in the first longitudinal study comparing these populations. We found a significant difference in progression of LV hypertrophy, with increasing septum thickness only in the HCM genotype positive adolescents. These findings highlight the importance of repeated examinations to distinguish physiological from pathological remodelling.

Regional differences in the use of proton pump inhibitors in children

Physiological gastroesophageal reflux in infancy is difficult to distinguish from reflux disease. International guidelines recommend restrictive use of acid suppression therapy for infants due to the lack of documented effect, but its use in infants and older children has increased in recent years. This study aims to describe change over time and geographic variation in the investigation and treatment of suspected gastroesophageal reflux disease. In aggregated data from the Norwegian Prescribed Drug Registry for the period 1.1.2007-31.12.2020, we examined regional differences in the number of proton pump inhibitors dispensed for children and adolescents. Data from the Norwegian Patient Registry were analysed to identify the use of 24-hour pH measurement and gastroscopy, which can support the suspicion of gastroesophageal reflux disease. The number of proton pump inhibitors dispensed in the first year of life increased and was highest in South-Eastern Norway Regional Health Authority, with 10.1 per 1000 children in 2007 and 54.7 per 1000 children in 2020 (relative risk 5.4, 95% confidence interval 4.6 to 6.4). The number dispensed in 2020 was 64% higher in South-Eastern Norway Regional Health Authority compared to Northern Norway Regional Health Authority and Central Norway Regional Health Authority. There was little change in the number of gastroscopies, but use of 24-hour pH measurement fell by 52% from 2016 to 2020. Use of proton pump inhibitors in infants has increased considerably despite the guidelines. Together with geographic variation, this may point towards overtreatment of physiological reflux in infants. Few investigations indicate that an increasing proportion are treated without supporting diagnostics.

Four SARS-CoV-2 vaccine doses or hybrid immunity in patients on immunosuppressive therapies: a Norwegian cohort study.

Data on response and safety of repeated vaccinations and hybrid immunity in patients with immune-mediated inflammatory diseases on immunosuppressive therapy is needed to further develop vaccination strategies in this vulnerable population. This study aimed to evaluate hybrid immunity and humoral immune response and safety of four SARS-CoV-2 vaccine doses in patients with immune-mediated inflammatory diseases on immunosuppressive therapy. This prospective observational Norwegian study of vaccine response to COVID-19 (Nor-vaC) included adult patients aged 18 years and older with immune-mediated inflammatory diseases (rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, Crohn's disease, or ulcerative colitis) on immunosuppressive therapy, who had received four SARS-CoV-2 vaccine doses (vaccine group) or three vaccine doses followed by COVID-19 (hybrid group), and healthy controls receiving three vaccine doses (control group). Patients were recruited from the Division of Rheumatology at Diakonhjemmet Hospital, Oslo, and the Department of Gastroenterology at Akershus University Hospital, Lørenskog. Patients who had COVID-19 before the third vaccine dose, and patients with allergies or intolerances to elements of the vaccine were excluded. Antibodies to the receptor-binding domain of SARS-CoV-2 spike protein (anti-RBD antibodies) were assessed 2-4 weeks following vaccination or COVID-19. This study is registered at Clinialtrials.gov, NCT04798625. Between Nov 12, 2021, and April 19, 2022, 1458 participants with immune-mediated inflammatory diseases provided post-vaccination samples at 2-4 weeks following a third vaccine dose. After 544 participants were excluded, 715 (78%) of the remaining 914 participants received the fourth dose of the vaccine, and of these, 536 (75%) provided post-vaccination samples 2-4 weeks after their fourth vaccination (vaccine group). 199 (22%) of the 914 had COVID-19 after their third dose of the vaccine and of these, 167 (84%) provided samples (hybrid group). 256 of the eligible 703 patients had rheumatoid arthritis, 107 had spondyloarthritis, 115 had psoriatic arthritis, 130 had Crohn's disease, and 95 had ulcerative colitis). Median age was 56 years [IQR 45-65], 398 (57%) were women, and 305 (43%) were men. Patients in the vaccine group had higher anti-RBD antibody concentrations following the fourth vaccine dose (median 6192 BAU/ml [IQR 2878-11 243]) than after the third dose (median 5087 BAU/ml [1250-9081]; p< 0·0001), but lower antibody concentrations than the control group following the third dose (median 7595 BAU/ml [5916-12 001]; p< 0·0001). Antibody concentrations were higher in the patients in the hybrid group (23 548 BAU/ml [IQR 11 440-35 935]) than in the vaccine group (p<0·0001). No difference was found in antibody concentrations between the fourth dose of BNT162b2 (full-dose) and mRNA-1273 (half-dose). Patients and controls had a comparable safety profile after both three and four vaccine doses. Vaccine boosters improve humoral immune responses and are safe in patients with immune-mediated inflammatory diseases on immunosuppressive therapy, and administration should be considered regularly in this patient group. Hybrid immunity with omicron induces a strong humoral response suggesting longer intervals between booster doses in this patient group. The South-Eastern Norway Regional Health Authority, The Coalition for Epidemic Preparedness Innovations, Akershus University Hospital.

Body mass index and childhood symptoms of depression, anxiety, and attention-deficit hyperactivity disorder: A within-family Mendelian randomization study.

Higher BMI in childhood is associated with emotional and behavioural problems, but these associations may not be causal. Results of previous genetic studies imply causal effects but may reflect influence of demography and the family environment. This study used data on 40,949 8-year-old children and their parents from the Norwegian Mother, Father and Child Cohort Study (MoBa) and Medical Birth Registry of Norway (MBRN). We investigated the impact of BMI on symptoms of depression, anxiety, and attention-deficit hyperactivity disorder (ADHD) at age 8. We applied within-family Mendelian randomization, which accounts for familial effects by controlling for parental genotype. Within-family Mendelian randomization estimates using genetic variants associated with BMI in adults suggested that a child's own BMI increased their depressive symptoms (per 5 kg/m2 increase in BMI, beta = 0.26 S.D., CI = -0.01,0.52, p=0.06) and ADHD symptoms (beta = 0.38 S.D., CI = 0.09,0.63, p=0.009). These estimates also suggested maternal BMI, or related factors, may independently affect a child's depressive symptoms (per 5 kg/m2 increase in maternal BMI, beta = 0.11 S.D., CI:0.02,0.09, p=0.01). However, within-family Mendelian randomization using genetic variants associated with retrospectively-reported childhood body size did not support an impact of BMI on these outcomes. There was little evidence from any estimate that the parents' BMI affected the child's ADHD symptoms, or that the child's or parents' BMI affected the child's anxiety symptoms. We found inconsistent evidence that a child's BMI affected their depressive and ADHD symptoms, and little evidence that a child's BMI affected their anxiety symptoms. There was limited evidence of an influence of parents' BMI. Genetic studies in samples of unrelated individuals, or using genetic variants associated with adult BMI, may have overestimated the causal effects of a child's own BMI. This research was funded by the Health Foundation. It is part of the HARVEST collaboration, supported by the Research Council of Norway. Individual co-author funding: the European Research Council, the South-Eastern Norway Regional Health Authority, the Research Council of Norway, Helse Vest, the Novo Nordisk Foundation, the University of Bergen, the South-Eastern Norway Regional Health Authority, the Trond Mohn Foundation, the Western Norway Regional Health Authority, the Norwegian Diabetes Association, the UK Medical Research Council. The Medical Research Council (MRC) and the University of Bristol support the MRC Integrative Epidemiology Unit.

Prediction of anthracycline-induced cardiotoxicity as assessed by global longitudinal strain in women with early breast cancer: insights from the PRADA trial

Abstract Background Early recognition of anthracycline-induced cardiotoxicity is essential to prevent and treat left ventricular dysfunction before permanent damage ensues. Echocardiographic global longitudinal strain (GLS) may be a more sensitive indicator of decline in left ventricular systolic function than measurement left ventricular ejection fraction (LVEF). Many factors have been associated with cardiotoxicity defined by LVEF criteria, but less is known about predictors of early and late cardiotoxicity expressed as GLS. Objective The purpose of this study was to identify factors associated with cardiotoxicity, defined as absolute GLS &amp;lt;18% (a) after completion of anthracycline treatment and (b) at extended follow up after completion of adjuvant therapy for early breast cancer. Methods 120 women with early breast cancer undergoing adjuvant treatment with anthracyclines and/or trastuzumab, were included in the PRADA (PRevention of cArdiac Dysfunction during Adjuvant breast cancer) trial and randomized in a 2x2 factorial fashion to concomitant treatment with candesartan cilexetil, metoprolol succinate or matching placebo. Serial measurements of cardiovascular biomarkers (high sensitivity cardiac troponin I (hs-cTnI), B-type natriuretic peptide (BNP) and Galectin-3), cardiovascular magnetic resonance and echocardiography were performed at baseline, after anthracycline treatment and at extended follow-up median 23 months (interquartile range 21–28 months) after initiation of adjuvant therapy for early breast cancer. To identify potential predictors of cardiotoxicity defined by GLS criteria, associations between demographic, clinical, cancer therapy and biochemical and imaging biomarker data were evaluated by logistic regression analysis. Results 89 patients had GLS measurements performed at baseline, 87 at completed anthracycline therapy and 81 at extended follow-up. An overall decline in absolute GLS of 0.75% was observed at extended follow-up. One patient had absolute GLS &amp;lt;18 prior to anthracycline therapy whereas, 7 out of 87 (8.0%) and 7 out of 81 (8.6%) patients had GLS levels &amp;lt;18 after completion of anthracycline treatment and at extended follow up, respectively. Variables associated with absolute GLS &amp;lt;18% after anthracycline treatment and at extended follow-up are summarized in Tables 1a and 1b. Conclusion In this subanalysis of the PRADA trial, higher age, higher hs-cTnI, lower LVEF, lower E' and higher GLS at baseline predicted subsequent reduced systolic function expressed as reduced absolute GLS after anthracycline treatment. Higher age, hypertension, higher body mass index and higher hs-cTnI concentrations predicted absolute GLS &amp;lt;18 at extended follow up. Assessment of cardiac troponin I, cardiac imaging biomarkers and patient age may assist in the identification of patients at risk for developing cardiotoxicity. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This work was supported by The South-Eastern Norway Regional Health Authority, The University of Oslo, The Extra Foundation for Health and Rehabilitation, The Norwegian Cancer Society, and Akershus University Hospital. Study medications and matching placebos were provided free of charge by AstraZeneca. Reagents for the analysis of high-sensitivity cardiac troponin I on the Architect platform were provided by Abbott Diagnostics.

Stroke rates in non-anticoagulated individuals with and without atrial fibrillation and one non-sex CHA2DS2-VASc risk factor: a nationwide registry-based cohort (Atrial Fibrillation in Norway – AFNOR)

Abstract Background Stroke prevention is fundamental in the management of atrial fibrillation (AF). However, in patients with intermediate risk of stroke (CHA2DS2-VASc score 2 in women; 1 in men) the net clinical benefit of oral anticoagulant (OAC) treatment is uncertain, as the treatment effect must be carefully balanced against the potential bleeding risk. Moreover, multiple risk factors included in the CHA2DS2-VASc score increase the risk of stroke independent of AF. Purpose We aimed to compare rates of ischemic and haemorrhagic stroke between non-anticoagulated individuals with and without AF in a nationwide cohort of individuals at intermediate risk of stroke. Method We identified a cohort of non-anticoagulated Norwegian individuals with and without non-valvular AF aged ≥18 years, with one non-sex CHA2DS2-VASc risk factor linking data from the Norwegian Population Registry, Patient Registry, Prescription Database and Cause of Death Registry. AF and comorbidities were identified with minimum three-year look-back period at study start and successively during follow up. Individuals without AF entered the study at date of first registered non-sex CHA2DS2-VASc risk factor while individuals with AF entered at the first date when both AF and first CHA2DS2-VASc risk factor were registered. Individuals with and without AF were followed from study start in 2011 until occurrence of stroke, death, emigration, OAC claim, increased CHA2DS2-VASc score or end of follow-up on December 31, 2018. Rates of ischemic and haemorrhagic stroke were calculated as the number of stroke cases per 100 person-years with 95% confidence intervals (CI). Results During 2011–2018, a total of 61,762 individuals with AF at intermediate risk of stroke and no previous OAC use were identified (mean age 63.2±7.6 years (SD); 37% women). In the AF population, a total of 1,304 ischemic strokes were registered during 109,881 person-years, and 127 haemorrhagic strokes during 109,559 person-years. In the corresponding intermediate risk non-AF population, 1,099,655 individuals (mean age 59.5±10.2 years (SD); 49.5% women) were identified, with a total of 6,081 ischemic strokes during 4,037,940 person-years and 3,037 haemorrhagic strokes during 4,022,952 person-years. The rate of ischemic stroke was 1.19 (95% CI, 1.12–1.25) in AF-patients and 0.15 (95% CI, 0.15–0.15) in non-AF individuals per 100 person-years, corresponding to a rate difference of 1.04 excess stroke cases per 100 person-years in AF patients. The haemorrhagic stroke rate was 0.12 (95% CI, 0.10–0.14) in AF-patients and 0.08 (95% CI, 0.07–0.08) per 100 person-years in non-AF individuals. Similar rate differences were seen in both men and women. Conclusion In a nationwide population with one non-sex CHA2DS2-VASc risk factor and without OAC treatment, we found higher stroke rate in AF patients compared to the rest of the population without AF, with a stroke rate difference of ∼1% per year. Haemorrhagic stroke rates were generally low. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): South-Eastern Norway Regional Health Authority