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Background It is not clearly known how well Danes estimate their chances of reaching the average life expectancy and whether identifiable population subgroups misestimate their life expectancy, and potentially also investments and savings in health and pensions. Therefore, in this study, we examined on the individual level whether subjective life expectancy is in line with the statistically calculated chance of reaching age 85, and further explored the psychological and behavioral factors associated with under or overestimation. Methods We opted for a cross-sectional survey design based on a sample of 5,379 Danish citizens aged 50–70 years, returning a web-based questionnaire with socio-demographic data supplemented from a national registry. Average participant estimates of their chance of reaching age 85 for each age range and sex group were compared with actuarial data. We then performed multiple linear regression analyses to examine factors associated with the subjective expectancy of reaching age 85 years. Results We found that 32% of females and 23% of males reported 100% certainty of reaching age 85, and average expected survival chance exceeded the statistically predicted survival chance for 23% of males and 16% for females in age-ranges 50–60 and 61–70. Our multivariable analysis found that health literacy, internal health locus of control, willingness to take health risks, self-rated health, and health and life satisfaction all showed a significant positive association with expectation of reaching age 85. Moreover, those on daily medications, ex- or current smokers, and heavy drinkers were significantly less optimistic about reaching age 85. Conclusions Particularly for the population groups with inaccurate life expectancies, the significant associations with psychological and behavioral factors open a way for initiatives based on behavior change theories to reach a better agreement between subjective and statistical life expectancy.

Objective: The association between common electrocardiogram (ECG) markers and Alzheimer's disease has been scarcely investigated, and it is unknown if ECG markers can improve risk prediction. Thus, we aimed to examine the association between common ECG markers and Alzheimer's disease in a large population. Methods: We studied the association between ECG markers and Alzheimer's disease using Cox models with adjustment for age, sex, and comorbidities using a large primary care population of patients aged 60 years or more. Results: We followed 172,236 subjects for a median of 7.5 years. Increased PR interval (hazard ratio for PR > 188 ms: 0.76 [95% confidence interval: 0.69–0.83, p < 0.001) and increased QTc interval (hazard ratio for QTc = [426;439]: 0.90 [0.83–0.98], p = 0.02) were associated with a decreased rate of Alzheimer's disease. A positive Sokolow-Lyon index >35 mm (1.22 [1.13–1.33], p < 0.001) and increased T-wave amplitude >4.1 mm (1.15 [1.04–1.27]) were associated with an increased rate of Alzheimer's disease. Upon addition of ECG markers to a reference model, 10-year prediction area under the receiver-operator characteristics curve (AUC) improved by 0.39 [0.06–0.67] %-points. The 10-year absolute risk of Alzheimer's disease was 6.5% and 5.2% for an 82-year old female and a male, respectively, with a favorable ECG, and 12% and 9.2%, respectively, with an unfavorable ECG, almost twice as high. Conclusions: We identified several common ECG markers which were associated with Alzheimer's disease, and which improved risk prediction for Alzheimer's disease.

PDF file, 450KB, Biphasic distribution of the increase in binding affinity for conversion from monovalent to bivalent forms for antibodies with different intrinsic affinities.

Supplementary Methods, Figures S1-S11, and Table Legends. Supplementary Methods: description of methods used in the Supplementary figures, expanded description of ELISA assays, and description of the computational model of multiple EGFR ligand antagonists. Supplementary Figure S1: Monoclonal EGFR antibodies poorly block signal amplification by high-affinity EGFR ligands. Supplementary Figure S2: Hierarchical clustering of EGFR ligand expression in primary colon, head and neck, and lung tumors. Supplementary Figure S3: Trends observed in EGFR ligand expression in TCGA data set are similarly apparent in primary colorectal samples analyzed by RT-qPCR. Supplementary Figure S4: Relative expression of EGFR ligands varies across cancer indications. Supplementary Figure S5: Simulated activity of a combination of two ligand antagonists versus single antagonists as a function of ligand affinity. Supplementary Figure S6: MM-151 antibodies have non-overlapping epitopes and can simultaneously engage the same EGF receptor molecule. Supplementary Figure S7: MM-151 elicits superior ligand antagonism. Supplementary Figure S8: MM-151 promotes potent down-regulation of EGFR that is dependent upon the oligoclonal combination of bivalent antibodies. Supplementary Figure S9: MM-151 promotes both antibody-dependent cell-mediated (ADCC) and complement-dependent (CDC) cytotoxicity. Supplementary Figure S10: Cell proliferation stimulated by high-affinity ligands is partially or completely resistant to cetuximab treatment but still sensitive to MM-151 treatment. Supplementary Figure S11: MM-151 overcomes signal amplification driven by high-affinity ligand. Legends for Supplementary Tables S1-S8.

PDF file, 95KB, Comparison of cell-binding curves for low and high affinity anti-EGFR IgG antibodies at the experimental incubation time and a hypothetical time.

Supplementary Tables S2, S3, S4. Structure of the computational model of multiple ligand antagonists: species (Table S2), parameters (Table S3), and Reactions (Table S4).

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PDF - 111K, Additional details on the implementation and training of the mechanistic model.

Figure legends describing supplemental data.

Supplementary Figures S1-S6. Supplementary Fig. S1. The effect of cyclophosphamide on liposome delivery is dose dependent, requires a predose rather than a co-injection, and is not mediated by changes in blood clearance. Supplementary Fig. S2. Cyclophosphamide induces DNA-damage and tumor cell apoptosis. Supplementary Fig. S3. Effects of cyclophosphamide, ifosfamide, paclitaxel and eribulin on HER2-tPLD delivery, stromal cell density, total cell density, and interstitial space area. Supplementary Fig. S4. Pretreatment of tumors with cyclophosphamide significantly enhances nuclear delivery of doxorubicin following HER2-tPLD injection. Supplementary Fig. S5. Pretreatment of tumors with cyclophosphamide enhances the delivery of HER2-tPLD in multiple tumor models. Supplementary Fig. S6. The combination of a cyclophosphamide predose with HER2-tPLD results in synergistic anti-tumor activity.

Supplementary Table S1. Cell lines and cell culture conditions

PDF file, 52KB, Comparison of measured apparent IgG affinities vs affinities calculated by using a mathematical model on cells of different EGFR density (A431, MDAMB468, and MDAMB231).

Although inhibition of the insulin-like growth factor (IGF) signaling pathway was expected to eliminate a key resistance mechanism for EGF receptor (EGFR)-driven cancers, the effectiveness of IGF-I receptor (IGF-IR) inhibitors in clinical trials has been limited. A multiplicity of survival mechanisms are available to cancer cells. Both IGF-IR and the ErbB3 receptor activate the PI3K/AKT/mTOR axis, but ErbB3 has only recently been pursued as a therapeutic target. We show that coactivation of the ErbB3 pathway is prevalent in a majority of cell lines responsive to IGF ligands and antagonizes IGF-IR–mediated growth inhibition. Blockade of the redundant IGF-IR and ErbB3 survival pathways and downstream resistance mechanisms was achieved with MM-141, a tetravalent bispecific antibody antagonist of IGF-IR and ErbB3. MM-141 potency was superior to monospecific and combination antibody therapies and was insensitive to variation in the ratio of IGF-IR and ErbB3 receptors. MM-141 enhanced the biologic impact of receptor inhibition in vivo as a monotherapy and in combination with the mTOR inhibitor everolimus, gemcitabine, or docetaxel, through blockade of IGF-IR and ErbB3 signaling and prevention of PI3K/AKT/mTOR network adaptation. Mol Cancer Ther; 13(2); 410–25. ©2013 AACR.

Supplementary Tables S5, S6, S7, S8. mRNA expression data for EGFR ligands as measured by RNAseq from The Cancer Genome Atlas (TCGA) across 14 cancer indications or by RT-qPCR of colorectal cancer FFPE samples. Table S5: Summary of TCGA datasets included in the analysis. Table S6: Raw and normalized expression data from TCGA. Table S7: EGFR ligand expression measured by RT-qPCR on commercially-obtained colorectal cancer FFPE samples. Table S8: Pairwise correlations of EGFR ligands across four TCGA indications.

PDF file, 56KB, Kinetic parameters used in the computational model of antibody binding.

Given the bulky nature of nanotherapeutics relative to small molecules, it is hypothesized that effective tumor delivery and penetration are critical barriers to their clinical activity. HER2-targeted PEGylated liposomal doxorubicin (MM-302, HER2-tPLD) is an antibody–liposomal drug conjugate designed to deliver doxorubicin to HER2-overexpressing cancer cells while limiting uptake into nontarget cells. In this work, we demonstrate that the administration and appropriate dose sequencing of cyclophosphamide can improve subsequent MM-302 delivery and enhance antitumor activity in preclinical models without negatively affecting nontarget tissues, such as the heart and skin. We demonstrate that this effect is critically dependent on the timing of cyclophosphamide administration. Furthermore, the effect was found to be unique to cyclophosphamide and related analogues, and not shared by other agents, such as taxanes or eribulin, under the conditions examined. Analysis of the cyclophosphamide-treated tumors suggests that the mechanism for improved MM-302 delivery involves the induction of tumor cell apoptosis, reduction of overall tumor cell density, substantial lowering of interstitial fluid pressure, and increasing vascular perfusion. The novel dosing strategy for cyclophosphamide described herein is readily translatable to standard clinical regimens, represents a potentially significant advance in addressing the drug delivery challenge, and may have broad applicability for nanomedicines. This work formed the basis for clinical evaluation of cyclophosphamide for improving liposome deposition as part of an ongoing phase I clinical trial of MM-302 in HER2-positive metastatic breast cancer. Mol Cancer Ther; 14(9); 2060–71. ©2015 AACR.

PDF - 711K, Supplemental Figure S1. Schematic representation of components of IGF-1R/ErbB3 merged mechanistic signaling model. Supplemental Table S1. Mean ligand-stimulated pAKT (S473) levels (A) or simulated levels (B) in BxPC-3, AdRr and MCF7 cells that were used to generate 3D contour plots in Figure 1A. Supplemental Figure S2. Western blots used to generate bar graphs in Figures 1, 3, & 4. Supplemental Figure S3. MM-141 is selective for IGF-1R and ErbB3, and is cross-reactive to relevant toxicology species. Supplemental Table S2. MM-141 is more potent than monospecific antibodies at inhibition of single ligand-induced pAKT (Ser473) signaling. Supplemental Figure S4. MM-141 does not promote basal signaling. Supplemental Figure S5. Generation of isogenic BxPC-3 cell lines with stable knockdown of IGF-1R or ErbB3. Supplemental Table S3. Mean pAKT (S473) levels in engineered BxPC-3 cells that were used to generate 3D contour plots in Figure 3A. Supplemental Figure S6. MM-141 maintains activity over a broad range of receptor profiles. Supplemental Figure S7. Mechanistic model can recapitulate signal inhibition properties of MM-141. Supplemental Figure S8. Pharmacokinetic properties of MM-141. Supplemental Figure S9. MM-141 controls gemcitabine-induced network adaptation. Supplemental Figure S10. MM-141 controls expression of IGF-1R and ErbB3-interacting RTKs.

Growth rates of engineered OVCAR8 cells grown as spheroids.

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Supplementary Tables S1-S3. Supplementary Table S1: Changes in tumor deposition in the control and cyclophosphamide-treated groups as measured by PET/CT. Supplementary Table S2: Effects of cyclophosphamide on HER2 expression, collagen type I deposition and vascular parameters in BT474-M3 tumors. Supplementary Table S3. Reagents for immunofluorescence on FFPE and frozen tumor sections

PDF - 91K, Supplementary Figure Legends.

Western blots and quantification of time course of HRG-stimulated signaling (pAKT-S473, pERK1/2) in NCI-N87, SKBR3, OVCAR8, and HCC1937 control cell lines.

Table showing indication, specific PIK3CA and PTEN mutations, as well as ErbB2 amplification status.

Supplementary Materials and Methods. This file contains information on the reagents, methods for the evaluation of cell viability, preparation of liposomes and details on the image analysis.

Table showing raw values of tumor sizes of OVCAR8 EV-neg, H1047R-neg, and H1047R-ErbB3 expressing xenografts.

Growth rates of control (GFP/EV) or PIK3CA- (WT or H1047R mutant) expressing NCI-N87, SKBR3, OVCAR8, and HCC1937 cells grown in 3D culture.

Aims Abdominal aortic aneurysmal disease is associated with increased risk of cardiovascular morbidity and death, which potentially can be reduced with cardioprotective medical therapy. The aim of this study was to observe temporal trends in prevalence and incidence of cardiovascular comorbidity as well as use of medical cardioprotective treatment in patients diagnosed with abdominal aortic aneurysmal disease. Methods and results This was a population-based cohort study based on data from national health registries, including all patients diagnosed with abdominal aortic aneurysms between 1998 and 2018. Data were stratified into four time periods (1999–2003, 2004–2008, 2009–2013, and 2014–2018) to illustrate trends over time. Outcome measures were (i) cardiovascular comorbidity and medical cardioprotective therapy at time of diagnosis, (ii) new admissions for atherosclerotic cardiovascular disease, and (iii) all-cause mortality after 2-year follow-up. The study cohort included 33 296 individuals. Mean age was 74 years. Prevalence of atherosclerotic cardiovascular comorbidity at diagnosis decreased from 41.5 to 32.6%. Use of statins increased from 17.9 to 66.9%, antiplatelets from 45.6 to 63.3%, and combined therapy with both antiplatelets and statins from 11.3 to 44.8%, and from 12.1 to 50.7% when anticoagulant therapy was included. Developments in medication use plateaued after 2013. Prevalence and incidence of atherosclerotic cardiovascular disease decreased through all four time periods. The same applied to all-cause mortality, which decreased from 24.3 to 12.4 deaths (per 100 person-years). Conclusion In patients diagnosed with abdominal aortic aneurysm, cardiovascular comorbidity at diagnosis, risk of future cardiovascular events, and all-cause mortality is decreasing. Nevertheless, cardiovascular burden and mortality rates remain substantial, and medical cardioprotective therapy can be further improved.

We propose a physics-based combustion simulation method for computer graphics that extends the mathematical models of previous efforts to automatically capture more realistic flames as well as temperature and soot distributions. Our method includes mathematical models for the thermodynamic properties of real-world fuels which enables, for example, the prediction of adiabatic flame temperatures. We couple this with a model of heat transfer that includes convection, conduction as well as both radiative cooling and heating. This facilitates among other things ignition at a distance without heating up the intermediate air. We model the combustion as infinitely fast chemistry and couple this with the thin flame model, spatially varying laminar burning velocities based on local species and empirical measurements, physically validated soot formation and oxidation as well as water vapor production and condensation. We implement this on adaptive octree-like grids with collocated state variables, a new SBDF2-derived semi-Lagrangian time integrator for velocity, and a multigrid scheme used for multiple solver components. In combination, these models enable us to simulate deflagration phenomena ranging from small scale premixed and diffusion flames to fireballs and subsonic explosions which we demonstrate by several examples. In addition, we validate several of the results based on reference footage and measurements and discuss the relation of prevalent heuristic techniques arising in visual effects production to some of the physics-based models we propose.

Thermal treatment is often employed in food processing to tailor product properties by manipulating the ingredient functionality, but these elevated temperatures may accelerate oxidation and nutrient loss. Here, oxidation of different whey protein systems [α-lactalbumin (α-LA), β-lactoglobulin (β-LG), a mix of α-LA and β-LG (whey model), and a commercial whey protein isolate (WPI)] was investigated during heat treatment at 60–90 °C and a UHT-like treatment by LC-MS-based proteomic analysis. The relative modification levels of each oxidation site were calculated and compared among different heat treatments and sample systems. Oxidation increased significantly in protein systems after heating at ≥90 °C but decreased in systems with higher complexity [pure protein (α-LA > β-LG) > whey model > WPI]. In α-LA, Cys, Met, and Trp residues were found to be most prone to oxidation. In β-LG-containing protein systems, Cys residues were suggested to scavenge most of the reactive oxidants and undergo an oxidation-mediated disulfide rearrangement. The rearranged disulfide bonds contributed to protein aggregation, which was suggested to provide physical protection against oxidation. Overall, limited loss of amino acid residues was detected after acidic hydrolysis followed by UHPLC analysis, which showed only a minor effect of heat treatment on protein oxidation in these protein systems.

Alpha and beta-diversity by response

Purpose: Insulin-like growth factor receptor 1 (IGF-1R) is critically involved in pancreatic cancer pathophysiology, promoting cancer cell survival and therapeutic resistance. Assessment of IGF-1R inhibitors in combination with standard-of-care chemotherapy, however, failed to demonstrate significant clinical benefit. The aim of this work is to unravel mechanisms of resistance to IGF-1R inhibition in pancreatic cancer and develop novel strategies to improve the activity of standard-of-care therapies.Experimental Design: Growth factor screening in pancreatic cancer cell lines was performed to identify activators of prosurvival PI3K/AKT signaling. The prevalence of activating growth factors and their receptors was assessed in pancreatic cancer patient samples. Effects of a bispecific IGF-1R and ErbB3 targeting antibody on receptor expression, signaling, cancer cell viability and apoptosis, spheroid growth, and in vivo chemotherapy activity in pancreatic cancer xenograft models were determined.Results: Growth factor screening in pancreatic cancer cells revealed insulin-like growth factor 1 (IGF-1) and heregulin (HRG) as the most potent AKT activators. Both growth factors reduced pancreatic cancer cell sensitivity to gemcitabine or paclitaxel in spheroid growth assays. Istiratumab (MM-141), a novel bispecific antibody that blocks IGF-1R and ErbB3, restored the activity of paclitaxel and gemcitabine in the presence of IGF-1 and HRG in vitro. Dual IGF-1R/ErbB3 blocking enhanced chemosensitivity through inhibition of AKT phosphorylation and promotion of IGF-1R and ErbB3 degradation. Addition of istiratumab to gemcitabine and nab-paclitaxel improved chemotherapy activity in vivo.Conclusions: Our findings suggest a critical role for the HRG/ErbB3 axis and support the clinical exploration of dual IGF-1R/ErbB3 blocking in pancreatic cancer. Clin Cancer Res; 24(12); 2873–85. ©2018 AACR.

Supplemental Figure S1: IGF-1 and HRG induce strongest AKT phosphorylation in pancreatic cancer cells.

Supplemental Tables 1-4

Table S1

Purpose:Cachexia is a multifactorial syndrome, associated with poor survival in patients with cancer, and is influenced by the gut microbiota. We investigated the effects of fecal microbiota transplantation (FMT) on cachexia and treatment response in patients with advanced gastroesophageal cancer.Experimental Design:In a double-blind randomized placebo-controlled trial performed in the Amsterdam University Medical Center, we assigned 24 cachectic patients with metastatic HER2-negative gastroesophageal cancer to either allogenic FMT (healthy obese donor) or autologous FMT, prior to palliative chemotherapy (capecitabine and oxaliplatin). Primary objective was to assess the effect of allogenic FMT on satiety. Secondary outcomes were other features of cachexia, along with disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and toxicity. Finally, exploratory analyses were performed on the effect of FMT on gut microbiota composition (metagenomic sequencing) and metabolites (untargeted metabolomics).Results:Allogenic FMT did not improve any of the cachexia outcomes. Patients in the allogenic group (n = 12) had a higher DCR at 12 weeks (P = 0.035) compared with the autologous group (n = 12), longer median OS of 365 versus 227 days [HR = 0.38; 95% confidence interval (CI), 0.14–1.05; P = 0.057] and PFS of 204 versus 93 days (HR = 0.50; 95% CI, 0.21–1.20; P = 0.092). Patients in the allogenic group showed a significant shift in fecal microbiota composition after FMT (P = 0.010) indicating proper engraftment of the donor microbiota.Conclusions:FMT from a healthy obese donor prior to first-line chemotherapy did not affect cachexia, but may have improved response and survival in patients with metastatic gastroesophageal cancer. These results provide a rational for larger FMT trials.

Supplemental legend

Supplemental Materials

Supplemental Figures S1-S5, Tables S1-S2. This document includes supplemental figures and corresponding legends. Table S1. Differential equations for plasma PK and tumor deposition models. Figure S1. Pharmacokinetic profile of nal-IRI across various tissues. Figure S2. Precision of parameter estimates. Figure S3. Comparing the concentrations of free CPT-11 and total CPT-11 in plasma and tumors. Figure S4. Surrogates for tumor depostion and local activation of nal-IRI. Table S2. Concentrations of CPT-11, SN-38 and CES activity in the panel of xenograft models. Figure S5. In vitro activation of nal-IRI in U937 cell lines.

Supplementary Methods, Figures 1-8, Table 1 from An ErbB3 Antibody, MM-121, Is Active in Cancers with Ligand-Dependent Activation

A major challenge in the clinical use of cytotoxic chemotherapeutics is maximizing efficacy in tumors while sparing normal tissue. Irinotecan is used for colorectal cancer treatment but the extent of its use is limited by toxic side effects. Liposomal delivery systems offer tools to modify pharmacokinetic and safety profiles of cytotoxic drugs. In this study, we defined parameters that maximize the antitumor activity of a nanoliposomal formulation of irinotecan (nal-IRI). In a mouse xenograft model of human colon carcinoma, nal-IRI dosing could achieve higher intratumoral levels of the prodrug irinotecan and its active metabolite SN-38 compared with free irinotecan. For example, nal-IRI administered at doses 5-fold lower than free irinotecan achieved similar intratumoral exposure of SN-38 but with superior antitumor activity. Tumor response and pharmacokinetic modeling identified the duration for which concentrations of SN-38 persisted above a critical intratumoral threshold of 120 nmol/L as determinant for antitumor activity. We identified tumor permeability and carboxylesterase activity needed for prodrug activation as critical factors in achieving longer duration of SN-38 in tumors. Simulations varying tumor permeability and carboxylesterase activity predicted a concave increase in tumor SN-38 duration, which was confirmed experimentally in 13 tumor xenograft models. Tumors in which higher SN-38 duration was achieved displayed more robust growth inhibition compared with tumors with lower SN-38 duration, confirming the importance of this factor in drug response. Overall, our work shows how liposomal encapsulation of irinotecan can safely improve its antitumor activity in preclinical models by enhancing accumulation of its active metabolite within the tumor microenvironment. Cancer Res; 74(23); 7003–13. ©2014 AACR.

Supplemental Methods. This document contains information on pharmacokinetic model development

Context. The Transiting Exoplanet Survey Satellite (TESS) mission has provided photometric light curves for stars across nearly the entire sky. This allows for the application of asteroseismology to a pool of potential solar-like oscillators that is unprecedented in size. Aims. We aim to produce a catalogue of solar-like oscillators observed by TESS in the 120-s and 20-s cadence modes. The catalogue is intended to highlight stars oscillating at frequencies above the TESS 30-min cadence Nyquist frequency with the purpose of encompassing the main-sequence and subgiant evolutionary phases. We aim to provide estimates for the global asteroseismic parameters vmax and ∆v. Methods. We applied a new probabilistic detection algorithm to the 120-s and 20-s light curves of over 250 000 stars. This algorithm flags targets that show characteristic signatures of solar-like oscillations. We manually vetted the resulting list of targets to confirm the presence of solar-like oscillations. Using the probability densities computed by the algorithm, we measured the global asteroseismic parameters vmax and ∆v. Results. We produce a catalogue of 4177 solar-like oscillators, reporting ∆v and vmax for 98% of the total star count. The asteroseismic data reveal a vast coverage of the Hertzsprung-Russell diagram, populating the red giant branch, the subgiant regime, and extending towards the main sequence. Conclusions. A crossmatch with external catalogues shows that 25 of the detected solar-like oscillators are a component of a spectroscopic binary, and 28 are confirmed planet host stars. These results provide the potential for precise, independent asteroseismic constraints on these and any additional TESS targets of interest.

AIM: To explore and describe how the National Early Warning Score (NEWS) and Individual Early Warning Score (I-EWS) are used and how they support nurses' patient risk assessment practice.DESIGN: A qualitative observational fieldwork study drawing on ethnographical principles was performed in six hospitals in two regions of Denmark in 2019.METHODS: Data were generated from participant observations and informal interviews with 32 nurses across 15 different wards in the hospitals. A total of 180 h of participant observation was performed. The observations lasted between 1.5 and 8 h and were conducted during day or evening shifts.RESULTS: NEWS and I-EWS supported nurses' observations of patients, providing useful knowledge for planning patient care, and prompting critical thinking. However, the risk assessment task was sometimes delegated to less experienced staff members, such as nursing students and healthcare assistants. The Early Warning Score (EWS) systems were often adapted by nurses according to contextual aspects, such as the culture of the speciality in which the nurses worked and their levels of competency. In some situations, I-EWS had the effect of enhancing nurse autonomy and responsibility for decision-making in relation to patient care.CONCLUSIONS: EWS systems support nurses' patient risk assessment practice, providing useful information. I-EWS makes it easier to factor the heterogeneity of patients and the clinical situation into the risk assessments. The delegation of risk assessment to other, less experienced staff members pose a risk to patient safety, which needs to be addressed in the ongoing debate regarding the shortage of nurses.IMPACT: The findings of this study can help ward nurses, hospital managers and policymakers to develop and improve strategies for improved person-centred nursing care.

BackgroundOn 1 January 2018 a four-year test scheme concerning use of medicinal cannabis (MC) was enacted. It has recently been extended for four more years by the Danish Parliament permitting all Danish physicians to prescribe MC to their patients. Previous studies have shown that general practitioners (GPs) have varying prescription experience, little knowledge, and mixed attitudes about MC. However, the present evidence is still limited, and no studies exist about Danish GPs’ prescription experience, knowledge, and attitudes towards MC. Therefore, our aim was to examine Danish GPs’ prescription experience, knowledge, and attitudes towards MC.MethodsA national online survey-based study addressing Danish GPs was performed from September 2018 to July 2019. We performed separate multivariable logistic regression analyses including GPs’ prescription experience, knowledge, and attitudes towards MC as outcome variables.ResultsA total of 427 (38.4%) of 1112 GPs completed the questionnaire. Of these, 37 (8.7%) had experience in prescribing MC. The majority had little or no knowledge about MC (80.6%) as well as a negative view on prescription of MC (71.4%) to patients. Factors associated with prescribing MC to patients were: Single-handed practices (OR = 1.6, 95% CI 1.1;1.8) and perception of having quite some knowledge about MC (OR = 4.8, 95% CI 2.2;10.4). Factors associated with having quite some knowledge about MC were: having a positive attitude towards prescribing MC (OR = 5.2, 95% CI 1.9;14.0), being male (OR = 1.7, 95% CI 1.4;1.8), and being at least 60 years of age (OR = 2.8, 95% CI 1.3;6.0). Factors associated with having a positive attitude towards prescribing MC were: having quite some knowledge about MC (OR = 5.2, 95% CI 2.2;12.5) and GPs being male (OR = 1.7, 95% CI 1.1;1.9).ConclusionIn this first study on prescription experience, knowledge, and attitudes about MC among Danish GPs, conducted one year after the Danish test scheme was enacted, we find a very low proportion of prescribers, little knowledge, and an overall negative attitude towards MC. Among the prescribing GPs, four in ten have little to no knowledge and a negative attitude towards MC. We stress that prescribing patterns, knowledge, and attitudes may change throughout the remaining time of the test scheme. BackgroundOn 1 January 2018 a four-year test scheme concerning use of medicinal cannabis (MC) was enacted. It has recently been extended for four more years by the Danish Parliament permitting all Danish physicians to prescribe MC to their patients. Previous studies have shown that general practitioners (GPs) have varying prescription experience, little knowledge, and mixed attitudes about MC. However, the present evidence is still limited, and no studies exist about Danish GPs' prescription experience, knowledge, and attitudes towards MC. Therefore, our aim was to examine Danish GPs' prescription experience, knowledge, and attitudes towards MC.MethodsA national online survey-based study addressing Danish GPs was performed from September 2018 to July 2019. We performed separate multivariable logistic regression analyses including GPs' prescription experience, knowledge, and attitudes towards MC as outcome variables.ResultsA total of 427 (38.4%) of 1112 GPs completed the questionnaire. Of these, 37 (8.7%) had experience in prescribing MC. The majority had little or no knowledge about MC (80.6%) as well as a negative view on prescription of MC (71.4%) to patients. Factors associated with prescribing MC to patients were: Single-handed practices (OR = 1.6, 95% CI 1.1;1.8) and perception of having quite some knowledge about MC (OR = 4.8, 95% CI 2.2;10.4). Factors associated with having quite some knowledge about MC were: having a positive attitude towards prescribing MC (OR = 5.2, 95% CI 1.9;14.0), being male (OR = 1.7, 95% CI 1.4;1.8), and being at least 60 years of age (OR = 2.8, 95% CI 1.3;6.0). Factors associated with having a positive attitude towards prescribing MC were: having quite some knowledge about MC (OR = 5.2, 95% CI 2.2;12.5) and GPs being male (OR = 1.7, 95% CI 1.1;1.9).ConclusionIn this first study on prescription experience, knowledge, and attitudes about MC among Danish GPs, conducted one year after the Danish test scheme was enacted, we find a very low proportion of prescribers, little knowledge, and an overall negative attitude towards MC. Among the prescribing GPs, four in ten have little to no knowledge and a negative attitude towards MC. We stress that prescribing patterns, knowledge, and attitudes may change throughout the remaining time of the test scheme.