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Preclinical cardiovascular research relies heavily on non-invasive in-vivo echocardiography in mice and rats to assess cardiac function and morphology, since the complex interaction of heart, circulation, and peripheral organs are challenging to mimic ex-vivo. While n-numbers of annually used laboratory animals worldwide approach 200 million, increasing efforts are made by basic scientists aiming to reduce animal numbers in cardiovascular research according to the 3R's principle. The chicken egg is well-established as a physiological correlate and model for angiogenesis research but has barely been used to assess cardiac (patho-) physiology. Here, we tested whether the established in-ovo system of incubated chicken eggs interfaced with commercially available small animal echocardiography would be a suitable alternative test system in experimental cardiology. To this end, we defined a workflow to assess cardiac function in 8-13-day-old chicken embryos using a commercially available high resolution ultrasound system for small animals (Vevo 3100, Fujifilm Visualsonics Inc.) equipped with a high frequency probe (MX700; centre transmit: 50 MHz). We provide detailed standard operating procedures for sample preparation, image acquisition, data analysis, reference values for left and right ventricular function and dimensions, and inter-observer variabilities. Finally, we challenged incubated chicken eggs with two interventions well-known to affect cardiac physiology-metoprolol treatment and hypoxic exposure-to demonstrate the sensitivity of in-ovo echocardiography. In conclusion, in-ovo echocardiography is a feasible alternative tool for basic cardiovascular research, which can easily be implemented into the small animal research environment using existing infrastructure to replace mice and rat experiments, and thus, reduce use of laboratory animals according to the 3R principle.

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BACKGROUND: Survival from pancreatic cancer is low worldwide. In the US, the 5-year relative survival has been slightly higher for women, whites and younger patients than for their counterparts, and differences in age and stage at diagnosis [Corrections added Nov 16, 2022, after first online publication: a new affiliation is added to Maja Niksic] may contribute to this pattern. We aimed to examine trends in survival by race, stage, age and sex for adults (15-99 years) diagnosed with pancreatic cancer in the US. METHODS: This population-based study included 399,427 adults registered with pancreatic cancer in 41 US state cancer registries during 2001-2014, with follow-up to December 31, 2014. We estimated age-specific and age-standardized net survival at 1 and 5 years. RESULTS: Overall, 12.3% of patients were blacks, and 84.2% were whites. About 9.5% of patients were diagnosed with localized disease, but 50.5% were diagnosed at an advanced stage; slightly more among blacks, mainly among men. No substantial changes were seen over time (2001-2003, 2004-2008, 2009-2014). In general, 1-year net survival was higher in whites than in blacks (26.1% vs. 22.1% during 2001-2003, 35.1% vs. 31.4% during 2009-2014). This difference was particularly evident among patients with localized disease (49.6% in whites vs. 44.6% in blacks during 2001-2003, 60.1% vs. 55.3% during 2009-2014). The survival gap between blacks and whites with localized disease was persistent at 5 years after diagnosis, and it widened over time (from 24.0% vs. 21.3% during 2001-2003 to 39.7% vs. 31.0% during 2009-2014). The survival gap was wider among men than among women. CONCLUSIONS: Gaps in 1- and 5-year survival between blacks and whites were persistent throughout 2001-2014, especially for patients diagnosed with a localized tumor, for which surgery is currently the only treatment modality with the potential for cure.

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INTRODUCTION AND MOTIVATION: Many health studies measure a continuous outcome and compare means between groups. Since means for biological data are often difficult to interpret clinically, it is common to dichotomise using a cut-point and present the 'percentage abnormal' alongside or in place of means. Examples include birthweight where 'abnormal' is defined as <2500 g (low birthweight), systolic blood pressure with abnormal defined as >140 mm Hg (high blood pressure) and lung function with varying definitions of the 'limit of normal'. In vulnerable populations with low means, for example, birthweight in a population of preterm babies, a given difference in means between two groups will represent a larger difference in the percentage with low birthweight than in a general population of babies where most will be full term. Thus, in general, the difference in percentage of patients with abnormal values for a given difference in means varies according to the reference population's mean value. This phenomenon leads to challenges in interpreting differences in means in vulnerable populations and in defining an outcome-specific minimal clinically important difference (MCID) in means since the proportion abnormal, which is useful in interpreting means, is not constant-it varies with the population mean. This has relevance for study power calculations and data analyses in vulnerable populations where a small observed difference in means may be difficult to interpret clinically and may be disregarded, even if associated with a relatively large difference in percentage abnormal which is clinically relevant. METHODS: To address these issues, we suggest both difference in means and difference in percentage (proportion) abnormal are considered when choosing the MCID, and that both means and percentages abnormal are reported when analysing the data. CONCLUSIONS: We describe a distributional approach to analyse proportions classified as abnormal that avoids the usual loss of precision and power associated with dichotomisation.

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BACKGROUND: Survival from metastatic cutaneous melanoma is substantially lower than for localized disease. Treatments for metastatic melanoma have been limited, but remarkable clinical improvements have been reported in clinical trials in the last decade. We described the characteristics of US patients diagnosed with cutaneous melanoma during 2001-2013 and assessed trends in short-term survival for distant-stage disease. METHODS: Trends in 1-year net survival were estimated using the Pohar Perme estimator, controlling for background mortality with life tables of all-cause mortality rates by county of residence, single year of age, sex, and race for each year 2001-2013. We fitted a flexible parametric survival model on the log-hazard scale to estimate the effect of race on the hazard of death because of melanoma and estimated 1-year net survival by race. RESULTS: Only 4.4% of the 425 915 melanomas were diagnosed at a distant stage, cases diagnosed at a distant stage are more commonly men, older patients, and African Americans. Age-standardized, 1-year net survival for distant-stage disease was stable at approximately 43% during 2001-2010. From 2010 onward, survival improved rapidly, reaching 58.9% (95% confidence interval = 56.6% to 61.2%) for patients diagnosed in 2013. Younger patients experienced the largest improvement. Survival for distant-stage disease increased in both Blacks and Whites but was consistently lower in Blacks. CONCLUSIONS: One-year survival for distant-stage melanoma improved during 2001-2013, particularly in younger patients and those diagnosed since 2010. This improvement may be a consequence of the introduction of immune-checkpoint-inhibitors and other targeted treatments for metastatic and unresectable disease. Persistent survival inequalities exist between Blacks and Whites, suggesting differential access to treatment.

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The aim of the present study was to prospectively examine risk of cutaneous melanoma (CM) according to measured anthropometric factors, adjusted for exposure to ultraviolet radiation (UVR), in a large population-based cohort in Norway. The Janus Cohort, including 292,851 Norwegians recruited 1972-2003, was linked to the Cancer Registry of Norway and followed for CM through 2014. Cox regression was used to estimate hazard ratios (HRs) of CM with 95% confidence intervals (CIs). Restricted cubic splines were incorporated into the Cox models to assess possible non-linear relationships. All analyses were adjusted for attained age, indicators of UVR exposure, education, and smoking status. During a mean follow-up of 27 years, 3,000 incident CM cases were identified. In men, CM risk was positively associated with body mass index, body surface area (BSA), height and weight (all ptrends < 0.001), and the exposure-response curves indicated an exponential increase in risk for all anthropometric factors. Weight loss of more than 2 kg in men was associated with a 53% lower risk (HR 0.47, 95% CI: 0.39, 0.57). In women, CM risk increased with increasing BSA (ptrend = 0.002) and height (ptrend < 0.001). The shape of the height-CM risk curve indicated an exponential increase. Our study suggests that large body size, in general, is a CM risk factor in men, and is the first to report that weight loss may reduce the risk of CM among men.

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INTRODUCTION: The incidence and mortality rates of cutaneous melanoma (CM) are increasing among fair-skinned populations worldwide. Ultraviolet radiation (UVR) is the principal risk factor for CM, but is also the main source of 25-hydroxyvitamin D (25(OH)D), which has been associated with reduced risk and better prognosis of some cancer types. However, both low and high 25(OH)D levels have been associated with increased risk of CM. Obesity as measured by body mass index (BMI) is associated with risk of several cancers and has also been suggested as a risk factor for CM, and may also be related to insufficient 25(OH)D and/or high leptin levels. Moreover, contracting a CM diagnosis has been associated with increased risk of developing second cancer. We aim to study whether low prediagnostic serum levels of 25(OH)D, high prediagnostic levels of BMI and high serum leptin levels influence CM incidence, Breslow thickness and CM mortality, and risk of second cancer and survival after a CM diagnosis. METHODS AND ANALYSIS: Cohort and nested case-control studies will be carried out using the population-based Janus Serum Bank Cohort (archival prediagnostic sera, BMI, smoking and physical activity), with follow-up from 1972 to 2014. Additional data will be received from the Cancer Registry of Norway, the national Cause of Death Registry, Statistics Norway (education and occupation) and exposure matrices of UVR. Time-to-event regression models will be used to analyse the cohort data, while the nested case-control studies will be analysed by conditional logistic regression. A multilevel approach will be applied when incorporating group-level data. ETHICS AND DISSEMINATION: The project is approved by the Regional Committee for Medical Research Ethics and is funded by the Norwegian Cancer Society. Results will be published in peer-reviewed journals, at scientific conferences and in the news media.

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BACKGROUND: Calcium supplements are widely used among older adults for osteoporosis prevention and treatment. However, their effect on creatinine levels and kidney function has not been well studied. METHODS: We investigated the effect of calcium supplementation on blood creatinine concentration in a randomized controlled trial of colorectal adenoma chemoprevention conducted between 2004-2013 at 11 clinical centers in the United States. Healthy participants (N = 1,675) aged 45-75 with a history of colorectal adenoma were assigned to daily supplementation with calcium (1200 mg, as carbonate), vitamin D3 (1000 IU), both, or placebo for three or five years. Changes in blood creatinine and total calcium concentration were measured after one year of treatment and multiple linear regression was used to estimate effects on creatinine concentrations. RESULTS: After one year of treatment, blood creatinine was 0.013±0.006 mg/dL higher on average among participants randomized to calcium compared to placebo after adjustment for other determinants of creatinine (P = 0.03). However, the effect of calcium treatment appeared to be larger among participants who consumed the most alcohol (2-6 drinks/day) or whose estimated glomerular filtration rate (eGFR) was less than 60 ml/min/1.73 m2 at baseline. The effect of calcium treatment on creatinine was only partially mediated by a concomitant increase in blood total calcium concentration and was independent of randomized vitamin D treatment. There did not appear to be further increases in creatinine after the first year of calcium treatment. CONCLUSIONS: Among healthy adults participating in a randomized clinical trial, daily supplementation with 1200 mg of elemental calcium caused a small increase in blood creatinine. If confirmed, this finding may have implications for clinical and public health recommendations for calcium supplementation. TRIAL REGISTRATION: ClinicalTrials.gov NCT00153816.

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BACKGROUND: Concordance, which involves prescribing with rather than for patients, should result in less drug wastage (non-use), but is proving hard to put into practice. One possible way of easing elderly people and prescribers toward concordance is to use a medicines organizer (MO). OBJECTIVE: To document medication wastage, using a pharmacy-prepared reusable MO, and explore, using a qualitative approach, use of this information on communication of individuals' drug regimens. METHODS: Sixty-two sheltered housing residents, aged > or =60 years, participated in an exploratory controlled, matched study. The intervention group received medication in the MO, and the control group continued with standard packaging. Community pharmacists recorded details of wasted drugs returned during the 3-month study and, for the intervention group, 6, 9, and 12 months after the study. Medicines management data were collected from participants. Qualitative interviews were conducted with a sample of general practitioners (GPs) and community pharmacists to explore views on the role of the MO. RESULTS: Intervention group wastage was reduced from 18.1% (prestudy) to 1% at 12 months. No data on wastage were collected for the control group after the prestudy assessment. Sixty-one percent more prescription changes, including significant decreases in the number of prescribed drugs and dosages, were reported for the intervention group. GPs and pharmacists reported improvements in communication concerning medication-related dialog. CONCLUSIONS: This small exploratory study has shown that a pharmacy-prepared reusable MO provided visual, objective insights into medication wastage. This resulted in improved communication of drug needs and reduced wastage-the foundation for concordance.

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