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Objective. Chronic low back pain (cLBP) is the leading cause of disability. Interdisciplinary pain management is recommended for patients with severe/high-impact cLBP. Such programs are expensive, not easily accessible, and have limited effect; therefore, new cost-effective strategies are warranted. Cognitive functional therapy (CFT) has shown promising results but has not been compared with an interdisciplinary pain management approach. The primary aim of this randomized controlled trial is to investigate if a pathway starting with CFT including psychologist support (CFT+) with the option of additional usual care (if needed) is superior in improving disability and more cost-effective at 12 months compared with an interdisciplinary pain management pathway (usual care). Methods. This pragmatic, 2-arm, parallel-group randomized controlled trial will randomly allocate patients (n = 176) aged 18 to 75 years referred to an interdisciplinary pain center due to severe cLBP to 1 of 2 groups (1:1 ratio). Participants randomized to CFT+ will participate in a 3-month functional rehabilitation pathway with the option of additional usual care (if needed), and participants randomized to the interdisciplinary pain management pathway will participate in an individualized program of longer duration designed to best suit the individual's situation, needs, and resources. The primary outcome is the proportion of participants with an 8-point improvement in the Oswestry Disability Index score at 12 months. Exploratory outcomes are change in Oswestry Disability Index scores over time and an economic analysis of quality-adjusted life years using the 3-level version of the EuroQol EQ-5D. Impact. The study evaluates the cost-effectiveness of CFT+ with the option of additional usual care (if needed) for individuals with severe cLBP. Findings can potentially improve future care pathways and reduce cost for the health care system. Keywords: Costs and Cost Analysis, Cognitive Functional Therapy, Health Care Costs, Interdisciplinary Pain Management, Low Back Pain, Introduction Chronic low back pain (cLBP) is one of the leading causes of disability around the world. (1,2) Because various biopsychosocial factors contribute to cLBP, (3) clinical guidelines recommend referral [...]

ABSTRACTMany museums attempt to connect museum activities to classroom learning goals by creating “before” and “after” suggestions for the classroom teacher. Therefore, when doing out of school activities it is common to organize and plan such activities from a before, during and after perspective. The present study primarily rests on observations of students from a lower secondary school class interacting with learning material developed to a science center on the basis of a framework inspired by flipped learning. Data were obtained from the students when they were preparing the visit to the science center in class, as well as during and after the visit. The aim was to document how the flipped learning setup mediates interactions with the exhibit and learning material, affect students’ visitor mode and connect school and science center. The results show that overall the formal intention behind the learning material correlates with the students observed practice. The results suggest that learning material inspired by the presented flipped learning framework successfully can link science curriculum at school and science centers visits, but not without some point of attention of which the teacher is the most significant.

Physical activity (PA) includes muscle activity during exercise, manual work, and leisure time activities including sport. Conflicting results exist regarding health effects of PA that may deteriorate with manual work and elite sports, but improve when performed in moderation in accordance with international guidelines and may additionally enhance well-being and productivity.

Objective Natural killer (NK) cells play an essential role in the immune response against cancer. However, immune escape mechanisms may cause inferior NK cell activity (NKA) in patients with cancer. This prospective study examined the relationship between NKA and lung cancer in a high-risk cohort.Methods In a cohort study, 250 participants referred by their general practitioner for suspicion of lung cancer were included. Before clinical investigation, blood was collected into NK Vue tubes, and the level of interferon gamma after 24 hours served as a surrogate marker for NKA.Results Among 250 patients, 79 were diagnosed with lung cancer. No difference in NKA was found between patients with lung cancer and control participants in which lung cancer was ruled out (median 226 pg/mL vs. 450 pg/mL). However, there was a significant difference in NKA between patients with late-stage lung cancer and controls (median 161 pg/mL vs. 450 pg/mL). A linear regression model showed that NKA was not influenced by age, sex or smoking status.Conclusions The significantly lower NKA in patients with late-stage lung cancer warrants further investigation combining NKA with other biomarkers and examining the potential role of NKA as a marker of disseminated disease.

SUMMARY Aim:We investigated the combination of irinotecan and panitumumab as a 3-weekly schedule in patients with wild-type KRASmetastatic colorectal cancer, who had progressed after standard chemotherapy. Material & methods:Patients received concomitant irinotecan (350 mg/m2) and panitumumab (9 mg/kg) once every 3 weeks. The primary end point was response rate. Secondary end points included progression-free survival (PFS), overall survival (OS) and translational research. Results:Inclusion was stopped early owing to lack of efficacy (n 31). The response rate was 16, median PFS and OS was 2.0 months (95 CI: 1.9–4.0) and 7.8 months (95 CI: 4.6–8.8), respectively. The most commonly encountered adverse event was skin rash (84 any grade). Pretreatment cell-free DNA levels were significantly related to disease control (p 0.04), PFS (p 0.04) and OS (p 0.002), respectively. Conclusion:The present treatment regimen was less effective than expected and is not recommended. The clinical importance of cell-free DNA deserves further research.

Extensive molecular analysis of large B-cell lymphomas (LBCL) have provided basis for new concepts of lymphoma taxonomy. These include stages of differentiation, phenotype (cell of origin) as well as genotype (including, but not confined to gene rearrangements) and immune microenvironment. The importance of the tumor microenvironment has recently regained focus due to development of immune checkpoint-inhibitors such as PD1/PD-L1 inhibitors, and LBCL may according to the new subtypes be stratified as microenvironment “inflamed” or “non-inflamed”, which may hold prognostic as well as predictive value.

Background:Standard care for patients with high risk myelodysplastic syndrome (MDS) is hypomethylating agents, such as azacitidine (AZA). AZA can induce expression of silenced genes, including methylated tumor associated antigens. Such tumor associated antigens may be recognized by T cells, and therefore exploited for immunotherapeutic targeting. To our knowledge, this is the first clinical study that combine hypomethylating agents with a multi-peptide therapeutic cancer vaccine in a hematological malignancy.

In this study, we investigated the relationships between observed social withdrawal (Positive and Negative Syndrome Scale PANSS Passive Social Withdrawal and PANSS Active Social Avoidance), subjectively experienced social withdrawal (Social Functioning Scale SFS Withdrawal and SFS Interpersonal Behavior), and their associations to the underlying psychological patterns of Object Relations and Reality Testing. Patients with schizophrenia (n= 55) and bipolar disorder (n= 51) from the ongoing Thematically Organized Psychosis project, Oslo University Hospital, Norway, were evaluated using the Bell Object Relations and Reality Testing Inventory, the PANSS, and the SFS. Object relations and reality testing subscales related differentially to PANSS Passive Social Withdrawal and PANSS Active Social Avoidance. These two measures, together with the level of alienation, explained a significant amount of variance in self-experienced social dysfunction. Findings reveal the multidimensional nature of social dysfunction in severe mental disorders.

Social withdrawal, a core feature of negative symptoms, is differentiated into passive social withdrawal (PSW) and active social avoidance (ASA). We examined whether this differentiation was related to differences in underlying psychological processes of object relations and reality testing.

The exon junction complex (EJC) is deposited onto spliced mRNAs and is involved in many aspects of mRNA function. We have recently reconstituted and solved the crystal structure of the EJC core made of MAGOH, Y14, the most conserved portion of MLN51, and the DEAD-box ATPase eIF4AIII bound to RNA in the presence of an ATP analog. The heterodimer MAGOH/Y14 inhibits ATP turnover by eIF4AIII, thereby trapping the EJC core onto RNA, but the exact mechanism behind this remains unclear. Here, we present the crystal structure of the EJC core bound to ADP-AIF(3), the first structure of a DEAD-box helicase in the transition-mimicking state during ATP hydrolysis. It reveals a dissociative transition state geometry and suggests that the locking of the EJC onto the RNA by MAGOH/Y14 is not caused by preventing ATP hydrolysis. We further show that ATP can be hydrolyzed inside the EJC, demonstrating that MAGOH/Y14 acts by locking the conformation of the EJC, so that the release of inorganic phosphate, ADP, and RNA is prevented. Unifying features of ATP hydrolysis are revealed by comparison of our structure with the EJC-ADPNP structure and other helicases. The reconstitution of a transition state mimicking complex is not limited to the EJC and eIF4AIII as we were also able to reconstitute the complex Dbp5-RNA-ADP-AlF(3), suggesting that the use of ADP-AlF(3) may be a valuable tool for examining DEAD-box ATPases in general.

Daratumumab is an integral part of the treatment of multiple myeloma (MM) but its real-world efficacy has only been described in small cohorts. MAMMOTH is the only large multi-center study that reported the outcomes of CD38-refractory MM. The present study includes a complete, Danish, nation-wide cohort of 635 MM patients who initiated treatment a daratumumab-containing index regimen (IR) prior to 1.1.2019, and describes the outcomes of 472 patients who discontinued their IR until 1.1.2021. Patients received a median of 3 lines of therapy (LOT) prior to the IR. The median time from diagnosis to discontinuation of the IR (T 0) was 4 years. At T 0,73% of patients were quadruple drug class exposed (CE). The median overall survival (mOS) after T 0was 12.2 months in the entire cohort, 15.3 months in double CE, 22.5 months in triple CE, 12.6 months in quadruple CE and 8.3 months in alkylator-bortezomib-carfilzomib-daratumumab-lenalidomide-pomalidomide-exposed patients. After T 0, 79%, 48%, 29%, 17%, 10% and 6% of patients received 1, 2, 3, 4, 5, 6 additional LOT, respectively, achieving overall response rates ranging from 44% to 11% and median time to next treatment (TNT) from 138 to 54 days. In the first subsequent LOT after T 0, 51% of patients were retreated with daratumumab. Despite the lack of benefit in terms response and TNT, daratumumab retreatment was associated with superior OS on multivariate analysis adjusting for age, previous transplantation, IR, drug class exposure at T 0, treating site, time from diagnosis to T 0and presence of cytogenetic high-risk markers. Median OS was 24.6 months in patients retreated with and 11.3 months in patients treated without daratumumab (p<0.0001). In conclusion, patients with MM who discontinue their first daratumumab-containing regimen have a life expectancy of approximately one year. Our results support a rationale behind daratumumab retreatment.

The phenoxyacetic acid herbicide MCPA (2‐methyl‐4‐chlorophenoxyacetic acid) is frequently detected in groundwater beneath Danish agricultural fields. We investigated spatial variation in microbial MCPA mineralization potential in a flat agricultural field of fine sandy soil (USDA classification: Humic Dystrudept) located on the Yoldia plains of Northern Jutland, Denmark. Samples for determination of MCPA mineralization and sorption were collected from the Ap and Bs horizons at 51 sampling sites located in a 200 × 220 m grid. Spatial variation in sorption was low in both horizons (distribution coefficient, 0.36–4.16 L kg−1). Sorption correlated strongly with soil organic carbon content in both horizons (CV, 93 and 83%, respectively) and negatively with soil pH. [Ring‐14C]‐MCPA mineralized readily in the Ap horizon, with 49 to 62% of the 14C‐MCPA being converted to 14CO2during the 67‐d incubation period. With the subsoil, mineralization of 14C‐MCPA varied considerably between samples (0.5–72.8%). At neither depth was there correlation between 14C‐MCPA mineralization and sorption, soil pH, organic carbon content, clay content, number of colony‐forming units (CFU), pseudomonad CFU, or any of the four microbial activity parameters measured. The presence of microbial genes encoding for the TfdA enzyme was quantified using real‐time polymerase chain reaction. No correlation was found between MCPA mineralization potential and the natural background number of tfdAgenes present in the soil samples. The degradation kinetics suggests that the high 14C‐MCPA mineralization rate detected in soil samples was linked to growth of the MCPA‐degrading soil microbial community.

Pesticides applied to agricultural soils are subject to environmental concerns because leaching to groundwater reservoirs and aquatic habitats may occur. Knowledge of field variation of pesticide‐related parameters is required to evaluate the vulnerability of pesticide leaching. The mineralization and sorption of the pesticides glyphosate and metribuzin and the pesticide degradation product triazinamin in a field were measured and compared with the field‐scale variation of geochemical and microbiological parameters. We focused on the soil parameters clay and organic carbon (C) content and on soil respiratory and enzymatic processes and microbial biomass. These parameters were measured in soil samples taken at two depths (Ap and Bs horizon) in 51 sampling points from a 4‐ha agricultural fine sandy soil field. The results indicated that the spatial variation of the soil parameters, and in particular the content of organic C, had a major influence on the variability of the microbial parameters and on sorption and pesticide mineralization in the soil. For glyphosate, with a co‐metabolic pathway for degradation, the mineralization was increased in soils with high microbial activity. The spatial variability, expressed as the CV, was about five times higher in the Bs horizon than in the Ap horizon, and the local‐scale variation within 100 m2areas were two to three times lower than the field‐scale variation within the entire field of about 4 ha.

Chronic low back pain (cLBP) is the leading cause of disability. Interdisciplinary pain management is recommended for patients with severe/high-impact cLBP. Such programs are expensive, not easily accessible, and have limited effect; therefore, new cost-effective strategies are warranted. Cognitive functional therapy (CFT) has shown promising results but has not been compared with an interdisciplinary pain management approach. The primary aim of this randomized controlled trial is to investigate if a pathway starting with CFT including psychologist support (CFT+) with the option of additional usual care (if needed) is superior in improving disability and more cost-effective at 12 months compared with an interdisciplinary pain management pathway (usual care).

ABSTRACTCells in the tumor microenvironment of Follicular lymphoma (FL) express checkpoint molecules such as programmed death ligands 1 and 2 (PD-L1 and PD-L2) and are suppressing anti-tumor immune activity. Stimulation of peripheral blood mononuclear cells (PBMC) with PD-L1 (IO103) or PD-L2 (IO120) peptides can activate specific T cells inducing anti-regulatory functions including cytotoxicity against PD-L1/PD-L2-expressing cells. In this study, we vaccinated eight FL patients with PD-L1 and PD-L2 peptides following treatment with standard chemotherapy. Patients experienced grade 1–2 injection site reaction (5/8) and mild flu-like symptoms (6/8). One patient experienced neutropenia and thrombocytopenia during pseudo-progression. Enzyme-linked immunospot detected vaccine-specific immune responses in PBMC from all patients, predominately toward PD-L1. The circulating immune composition was stable during treatment; however, we observed a reduction regulatory T cells, however, not significant. One patient achieved a complete remission during vaccination and two patients had pseudo-progression followed by long-term disease regression. Further examination of these early signs of clinical efficacy of the dual-epitope vaccine in a larger study is warranted.

We present a description of "the Conductor," an automated software package that handles all observations at the first Stellar Observations Network Group (SONG) node telescope at the Teide Observatory on the island of Tenerife. The idea was to provide a complete description on the automated procedures for target selection and execution of observations and to demonstrate how the SONG robotic telescope is being operated. The Conductor is a software package developed in Python and running on a server in Aarhus that makes use of a large set of database tables through which it communicates with the SONG nodes. Based on a number of selection criteria the Conductor is able to identify the optimum target to be observed at any given moment, taking into account local weather conditions and technical constraints. The Conductor has made it possible for the Hertzsprung SONG telescope to become a highly sophisticated and efficient robotic telescopic facility without human interaction. It can handle everything from principal investigators submitting their proposed targets with specific settings, to the data being available for download after the observations has been carried out. At present, and thanks to the availability of the Conductor, the first node of the SONG project can be considered a world leading robotic telescope with respect to needed human interactions, efficiency, and flexibility in observing strategy.

No relevant conflicts of interest to declare.

BackgroundDrug expenses are increasing. Especially novel drugs affect these expenses significantly and existing budgeting forecasts have hitherto not contained accurate enough parameters for precise forecasting. We needed a model that could predict future drug expenses with a low margin of error to assist in budget planning. We realised that no such model existed and aimed to develop our own.PurposeThe aim was to develop a predictive model that more accurately estimates future costs of expensive drugs.Material and methodsTo limit the project, we identified that 30 of the most expensive drugs (measured on the 5th ATC level) are responsible for 75% of drug expenses.We assessed which parameters affected drug expenses and identified what they depended on. Based on this, we assessed data needed in our model and included them in a Microsoft Excel spreadsheet with ATC codes and correlated costs. Additionally, we created a spreadsheet for each ATC code with this information: ATC code, generic name, indications, dosage, duration of treatment, number of patients per indication, number of packages/patient/year per indication and drug price. Clinical pharmacists collected data from the wards regarding clinical usage and number of patients.The model was continuously validated by comparing estimated expenses to current usage. Any deviations of individual ATC code were reviewed in relation to the data collected by the wards.ResultsOur final model is a Microsoft Excel spreadsheet containing the identified ATC codes and essential parameters affecting the drug expenses: novel drugs, extension of indications, patent expiration, clinical usage, number of patients and drug price.Entry of data provided an estimate for the future drug expenses. Evaluation of our model at the end of 2016 showed a 2% margin error between estimated and actual drug expenses. Our model is thus able to forecast drug expenses more accurately than pre-existing forecasts.ConclusionWe developed a predictive model for estimating future drug expenses with a low margin of error (2%). The model is, however, only as good as the included data, why continuous data updating is paramount. The model is implemented in our daily work and all new expensive drugs are included.No conflict of interest

Introduction:In patients with Large B-cell Lymphoma (LBCL) the prognostic significance of MYCtranslocations is not clearly established. We aimed to investigate if additional identification of MYCtranslocation partner gene and/or MYC and BCL2 protein expression levels could improve patient prognostication associated with MYCtranslocations. We also wanted to evaluate the prognostic effect of double hit MYC+ BCL2/BCL6translocation (DH) compared to MYCsingle hit (SH).

No relevant conflicts of interest to declare.

The purpose of this study is to review the current literatures on breast cancer (BC) in the Arctic, especially the trends in incidence during the last decades and the possible explanations. The design of this study is a literature review. The scientific literature concerning BC were reviewed, especially focusing on the Arctic and the special conditions that exist in this region. Breast cancer incidence is increasing all over the world, including in the Arctic. The enormous transition in health conditions and lifestyle in the Arctic might be contributing to the known risk factors. In Greenland, the age at menarche has diminished by 3 years during the course of 100 years, and the number of children per women as well as the duration of breastfeeding is decreasing. Obesity and intake of saturated fat is increasing and the intake of traditional food rich in unsaturated fat and vitamin D decreasing. Smoking and alcohol consumption in the Arctic has been relatively high but is now decreasing. More focus on genetic susceptibility in relation to BC has identified the specific BRCA1 founder mutation in the Greenlandic population, which might appear to be an important risk factor. However, the known established risk factors alone cannot account for the increasing trend observed. Studies suggest that environmental contaminants such as persistent organic pollutants (POPs) including perfluorinated compounds increase the risk of BC possibly in conjunction with certain genetic polymorphisms involved in carcinogen activation. The lipophilic POPs such as polychlorinated biphenyls and organochlorine pesticides are found at very high levels in the Arctic population. Several factors can explain the increasing incidence of BC in the Arctic. The transition in lifestyle and health conditions unfortunately increases the known risk factors of BC. Moreover, the population of the Arctic might show up to be especially vulnerable because of the contemporary high burden of POPs and genetic susceptibility.