In this randomized trial involving 84,585 participants in Poland, Norway, and Sweden, the risk of colorectal cancer at 10 years was lower among those invited to undergo screening colonoscopy than ...among those assigned to no screening.
While colonoscopy screening is widely used in several European countries and the United States, there are no randomized trials to quantify its benefits. The Nordic-European Initiative on Colorectal ...Cancer (NordICC) is a multinational, randomized controlled trial aiming at investigating the effect of colonoscopy screening on colorectal cancer (CRC) incidence and mortality. This paper describes the rationale and design of the NordICC trial.
Men and women aged 55 to 64 years are drawn from the population registries in the participating countries and randomly assigned to either once-only colonoscopy screening with removal of all detected lesions, or no screening (standard of care in the trial regions). All individuals are followed for 15 years after inclusion using dedicated national registries. The primary end points of the trial are cumulative CRC-specific death and CRC incidence during 15 years of follow-up. POWER ANALYSIS: We hypothesize a 50 % CRC mortality-reducing efficacy of the colonoscopy intervention and predict 50 % compliance, yielding a 25 % mortality reduction among those invited to screening. For 90 % power and a two-sided alpha level of 0.05, using a 2:1 randomization, 45 600 individuals will be randomized to control, and 22 800 individuals to the colonoscopy group. Interim analyses of the effect of colonoscopy on CRC incidence and mortality will be performed at 10-year follow-up.
The aim of the NordICC trial is to quantify the effectiveness of population-based colonoscopy screening. This will allow development of evidence-based guidelines for CRC screening in the general population.
We examine the response of Arctic gas and aerosol concentrations to perturbations in pollutant emissions from Europe, East and South Asia, and North America using results from a coordinated model ...intercomparison. These sensitivities to regional emissions (mixing ratio change per unit emission) vary widely across models and species. Intermodel differences are systematic, however, so that the relative importance of different regions is robust. North America contributes the most to Arctic ozone pollution. For aerosols and CO, European emissions dominate at the Arctic surface but East Asian emissions become progressively more important with altitude, and are dominant in the upper troposphere. Sensitivities show strong seasonality: surface sensitivities typically maximize during boreal winter for European and during spring for East Asian and North American emissions. Mid-tropospheric sensitivities, however, nearly always maximize during spring or summer for all regions. Deposition of black carbon (BC) onto Greenland is most sensitive to North American emissions. North America and Europe each contribute ~40% of total BC deposition to Greenland, with ~20% from East Asia. Elsewhere in the Arctic, both sensitivity and total BC deposition are dominated by European emissions. Model diversity for aerosols is especially large, resulting primarily from differences in aerosol physical and chemical processing (including removal). Comparison of modeled aerosol concentrations with observations indicates problems in the models, and perhaps, interpretation of the measurements. For gas phase pollutants such as CO and O3, which are relatively well-simulated, the processes contributing most to uncertainties depend on the source region and altitude examined. Uncertainties in the Arctic surface CO response to emissions perturbations are dominated by emissions for East Asian sources, while uncertainties in transport, emissions, and oxidation are comparable for European and North American sources. At higher levels, model-to-model variations in transport and oxidation are most important. Differences in photochemistry appear to play the largest role in the intermodel variations in Arctic ozone sensitivity, though transport also contributes substantially in the mid-troposphere.
The treatment of lymphatic anomaly, a rare devastating disease spectrum of mostly unknown etiologies, depends on the patient manifestations
. Identifying the causal genes will allow for developing ...affordable therapies in keeping with precision medicine implementation
. Here we identified a recurrent gain-of-function ARAF mutation (c.640T>C:p.S214P) in a 12-year-old boy with advanced anomalous lymphatic disease unresponsive to conventional sirolimus therapy and in another, unrelated, adult patient. The mutation led to loss of a conserved phosphorylation site. Cells transduced with ARAF-S214P showed elevated ERK1/2 activity, enhanced lymphangiogenic capacity, and disassembly of actin skeleton and VE-cadherin junctions, which were rescued using the MEK inhibitor trametinib. The functional relevance of the mutation was also validated by recreating a lymphatic phenotype in a zebrafish model, with rescue of the anomalous phenotype using a MEK inhibitor. Subsequent therapy of the lead proband with a MEK inhibitor led to dramatic clinical improvement, with remodeling of the patient's lymphatic system with resolution of the lymphatic edema, marked improvement in his pulmonary function tests, cessation of supplemental oxygen requirements and near normalization of daily activities. Our results provide a representative demonstration of how knowledge of genetic classification and mechanistic understanding guides biologically based medical treatments, which in our instance was life-saving.
Epilepsy is a chronic brain disorder characterized by recurrent seizures due to abnormal, excessive and synchronous neuronal activities in the brain. It affects approximately 65 million people ...worldwide, one third of which are still estimated to suffer from refractory seizures. Glutamic acid decarboxylase (GAD) that converts glutamate into GABA is a key enzyme in the dynamic regulation of neural network excitability. Importantly, clinical evidence shows that lowered GAD activity is associated with several forms of epilepsy which are often treatment resistant. In the present study, we synthetized and explored the possibility of using ethyl ketopentenoate (EKP), a lipid-permeable GAD-inhibitor, to induce refractory seizures in zebrafish larvae. Our results demonstrate that EKP evoked robust convulsive locomotor activities, excessive epileptiform discharges and upregulated c-fos expression in zebrafish. Moreover, transgenic animals in which neuronal cells express apoaequorin, a Ca
-sensitive bioluminescent photoprotein, displayed large luminescence signals indicating strong EKP-induced neuronal activation. Molecular docking data indicated that this proconvulsant activity resulted from the direct inhibition of both gad67 and gad65. Limited protective efficacy of tested anti-seizure drugs (ASDs) demonstrated a high level of treatment resistance of EKP-induced seizures. We conclude that the EKP zebrafish model can serve as a high-throughput platform for novel ASDs discovery.
The temperatures of a power transformer have direct influence on the windings insulation deterioration, determining how long the equipment will be able to remain in operation. In order to better ...predict and study the transformer thermal behavior, a thermal-hydraulic model (TH) for oil-directed (OD) power transformer is proposed. From the constructive dimensions and the operative characteristics of the transformer, the proposed model is able to determine the complete oil flow and temperature distributions over the magnetic core, windings and radiators by iteratively solving an algorithm composed of both hydraulic and thermal resistance networks. A transformer prototype was assembled and equipped with 29 optical fiber sensors as part of a measurement system in order to validate the approach. The details of the active part, tank and radiators modelings are presented in a generalized way, being applicable to different constructive arrangements. The validation results show a maximum relative error of 1.31% for temperature, accurately describing the flow and temperature fields of the prototype, indicating that the model can be satisfactorily used for predicting the hydraulic and thermal behaviors of electric transformers.
•Winding convergence through finite volume and thermal-hydraulic coupling.•Thermal radiation modeled for external heat transfer on tank and radiators.•Temperature distribution along winding turns, insulation paper and oil channels.•Prototype equipped with 29 optical fiber sensors for model validation.•TH model validation presenting 1.31% of maximum relative error.
To study the relationship between pre-pregnancy body mass index (BMI) and weight gain during pregnancy with pregnancy and birth outcomes, with a focus on gestational diabetes and hypertension and ...their role in the association with fetal growth. We studied 1,884 mothers and offspring from the Eden mother–child cohort. Weight before pregnancy (W1) and weight after delivery (W2) were collected and we calculated BMI and net gestational weight gain (netGWG = (W2 − W1)/(weeks of gestation)). Gestational diabetes, hypertension gestational age and birth weight were collected. We used multivariate linear or logistic models to study the association between BMI, netGWG and pregnancy and birth outcomes, adjusting for center, maternal age and height, parity and average number of cigarettes smoked per day during pregnancy. High BMI was more strongly related to the risk of giving birth to a large-for-gestational-age (LGA) baby than high netGWG (odds ratio OR 95% CI of 3.23 1.86–5.60 and 1.61 0.91–2.85, respectively). However, after excluding mothers with gestational diabetes or hypertension the ORs for LGA, respectively weakened (OR 2.57 1.29–5.13) for obese women and strengthened for high netGWG (OR 2.08 1.14–3.80). Low in comparison to normal netGWG had an OR of 2.18 1.20–3.99 for pre-term birth, which became stronger after accounting for blood pressure and glucose disorders (OR 2.70 1.37–5.34). Higher net gestational weight gain was significantly associated with an increased risk of LGA only after accounting for blood pressure and glucose disorders. High gestational weight gain should not be neglected in regard to risk of LGA in women without apparent risk factors.
Background
Severe sepsis is one of the leading causes of acute kidney injury (AKI). Patients with sepsis‐associated AKI demonstrate high‐hospital mortality. We evaluated the incidence of severe ...sepsis‐associated AKI and its association with outcome in intensive care units (ICUs) in Finland.
Methods
This was a predetermined sub‐study of the prospective, observational, multicentre FINNAKI study conducted in 17 ICUs during 1 September 2011 and 1 February 2012. All emergency ICU admissions and elective admissions exceeding 24 hours in the ICU were screened for presence of severe sepsis and AKI up to 5 days in ICU. AKI was defined according to the Kidney Disease: Improving Global Outcomes (KDIGO) criteria and severe sepsis according to the American College of Chest Physicians/Society of Critical Care Medicine (ACCP/SCCM) criteria.
Results
Of the 2901 included patients, severe sepsis was diagnosed in 918 (31.6%, 95% confidence interval CI 29.9–33.4%) patients. Of these 918 patients, 488 (53.2% 95% CI 49.9–56.5%) had AKI. The 90‐day mortality rate was 38.1% (95% CI 33.7–42.5%) for severe sepsis patients with AKI and 24.7% (95% CI 20.5–28.8%) for those without AKI. After adjusting for covariates, KDIGO stage 3 AKI was associated with an increased risk for 90‐day mortality with an adjusted odds ratio (OR) of 1.94 (95% CI 1.28–2.94), but stages 1 and 2 were not.
Conclusions
More than half of the patients with severe sepsis had AKI according to the KDIGO classification, and AKI stage 3 was independently associated with 90‐day mortality.
The asexual reproduction cycle of Plasmodium falciparum, the parasite responsible for severe malaria, occurs within red blood cells. A merozoite invades a red cell in the circulation, develops and ...multiplies, and after about 48 hours ruptures the host cell, releasing 15-32 merozoites ready to invade new red blood cells. During this cycle, the parasite increases the host cell permeability so much that when similar permeabilization was simulated on uninfected red cells, lysis occurred before approximately 48 h. So how could infected cells, with a growing parasite inside, prevent lysis before the parasite has completed its developmental cycle? A mathematical model of the homeostasis of infected red cells suggested that it is the wasteful consumption of host cell hemoglobin that prevents early lysis by the progressive reduction in the colloid-osmotic pressure within the host (the colloid-osmotic hypothesis). However, two critical model predictions, that infected cells would swell to near prelytic sphericity and that the hemoglobin concentration would become progressively reduced, remained controversial. In this paper, we are able for the first time to correlate model predictions with recent experimental data in the literature and explore the fine details of the homeostasis of infected red blood cells during five model-defined periods of parasite development. The conclusions suggest that infected red cells do reach proximity to lytic rupture regardless of their actual volume, thus requiring a progressive reduction in their hemoglobin concentration to prevent premature lysis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
During its intraerythrocytic asexual reproduction cycle Plasmodium falciparum consumes up to 80% of the host cell hemoglobin, in large excess over its metabolic needs. A model of the homeostasis of ...falciparum-infected red blood cells suggested an explanation based on the need to reduce the colloid-osmotic pressure within the host cell to prevent its premature lysis. Critical for this hypothesis was that the hemoglobin concentration within the host cell be progressively reduced from the trophozoite stage onwards.
The experiments reported here were designed to test this hypothesis by direct measurements of the hemoglobin concentration in live, infected red cells. We developed a novel, non-invasive method to quantify the hemoglobin concentration in single cells, based on Förster resonance energy transfer between hemoglobin molecules and the fluorophore calcein. Fluorescence lifetime imaging allowed the quantitative mapping of the hemoglobin concentration within the cells. The average fluorescence lifetimes of uninfected cohorts was 270+/-30 ps (mean+/-SD; N = 45). In the cytoplasm of infected cells the fluorescence lifetime of calcein ranged from 290+/-20 ps for cells with ring stage parasites to 590+/-13 ps and 1050+/-60 ps for cells with young trophozoites and late stage trophozoite/early schizonts, respectively. This was equivalent to reductions in hemoglobin concentration spanning the range from 7.3 to 2.3 mM, in line with the model predictions. An unexpected ancillary finding was the existence of a microdomain under the host cell membrane with reduced calcein quenching by hemoglobin in cells with mature trophozoite stage parasites.
The results support the predictions of the colloid-osmotic hypothesis and provide a better understanding of the homeostasis of malaria-infected red cells. In addition, they revealed the existence of a distinct peripheral microdomain in the host cell with limited access to hemoglobin molecules indicating the concentration of substantial amounts of parasite-exported material.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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