Distinct genes are mutated in different regions of a single patient’s tumor. Point mutations seem to have less adverse effect on relapse-free survival than copy-number heterogeneity. Chromosome ...instability appears to be an important adverse prognostic factor.
Lung cancer is the leading cause of cancer-related death worldwide,
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with non–small-cell lung cancer (NSCLC) being the most common type. Large-scale sequencing studies have revealed the complex genomic landscape of NSCLC
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and genomic differences between lung adenocarcinomas and lung squamous-cell carcinomas.
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However, in-depth exploration of NSCLC intratumor heterogeneity (which provides the fuel for tumor evolution and drug resistance) and cancer genome evolution has been limited to small retrospective cohorts.
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Therefore, the clinical significance of intratumor heterogeneity and the potential for clonality of driver events to guide therapeutic strategies have not yet been defined.
Tracking Non–Small-Cell Lung Cancer . . .
Summary Background In the Global Burden of Disease Study 2013 (GBD 2013), knowledge about health and its determinants has been integrated into a comparable framework to inform health policy. Outputs ...of this analysis are relevant to current policy questions in England and elsewhere, particularly on health inequalities. We use GBD 2013 data on mortality and causes of death, and disease and injury incidence and prevalence to analyse the burden of disease and injury in England as a whole, in English regions, and within each English region by deprivation quintile. We also assess disease and injury burden in England attributable to potentially preventable risk factors. England and the English regions are compared with the remaining constituent countries of the UK and with comparable countries in the European Union (EU) and beyond. Methods We extracted data from the GBD 2013 to compare mortality, causes of death, years of life lost (YLLs), years lived with a disability (YLDs), and disability-adjusted life-years (DALYs) in England, the UK, and 18 other countries (the first 15 EU members apart from the UK and Australia, Canada, Norway, and the USA EU15+). We extended elements of the analysis to English regions, and subregional areas defined by deprivation quintile (deprivation areas). We used data split by the nine English regions (corresponding to the European boundaries of the Nomenclature for Territorial Statistics level 1 NUTS 1 regions), and by quintile groups within each English region according to deprivation, thereby making 45 regional deprivation areas. Deprivation quintiles were defined by area of residence ranked at national level by Index of Multiple Deprivation score, 2010. Burden due to various risk factors is described for England using new GBD methodology to estimate independent and overlapping attributable risk for five tiers of behavioural, metabolic, and environmental risk factors. We present results for 306 causes and 2337 sequelae, and 79 risks or risk clusters. Findings Between 1990 and 2013, life expectancy from birth in England increased by 5·4 years (95% uncertainty interval 5·0–5·8) from 75·9 years (75·9–76·0) to 81·3 years (80·9–81·7); gains were greater for men than for women. Rates of age-standardised YLLs reduced by 41·1% (38·3–43·6), whereas DALYs were reduced by 23·8% (20·9–27·1), and YLDs by 1·4% (0·1–2·8). For these measures, England ranked better than the UK and the EU15+ means. Between 1990 and 2013, the range in life expectancy among 45 regional deprivation areas remained 8·2 years for men and decreased from 7·2 years in 1990 to 6·9 years in 2013 for women. In 2013, the leading cause of YLLs was ischaemic heart disease, and the leading cause of DALYs was low back and neck pain. Known risk factors accounted for 39·6% (37·7–41·7) of DALYs; leading behavioural risk factors were suboptimal diet (10·8% 9·1–12·7) and tobacco (10·7% 9·4–12·0). Interpretation Health in England is improving although substantial opportunities exist for further reductions in the burden of preventable disease. The gap in mortality rates between men and women has reduced, but marked health inequalities between the least deprived and most deprived areas remain. Declines in mortality have not been matched by similar declines in morbidity, resulting in people living longer with diseases. Health policies must therefore address the causes of ill health as well as those of premature mortality. Systematic action locally and nationally is needed to reduce risk exposures, support healthy behaviours, alleviate the severity of chronic disabling disorders, and mitigate the effects of socioeconomic deprivation. Funding Bill & Melinda Gates Foundation and Public Health England.
Gene expression studies have identified the microenvironment as a prognostic player in diffuse large B-cell lymphoma. However, there is a lack of simple immune biomarkers that can be applied in the ...clinical setting and could be helpful in stratifying patients. Immunohistochemistry has been used for this purpose but the results are inconsistent. We decided to reinvestigate the immune microenvironment and its impact using immunohistochemistry, with two systems of image analysis, in a large set of patients with diffuse large B-cell lymphoma. Diagnostic tissue from 309 patients was arrayed onto tissue microarrays. Results from 161 chemoimmunotherapy-treated patients were used for outcome prediction. Positive cells, percentage stained area and numbers of pixels/area were quantified and results were compared with the purpose of inferring consistency between the two semi-automated systems. Measurement cutpoints were assessed using a recursive partitioning algorithm classifying results according to survival. Kaplan-Meier estimators and Fisher exact tests were evaluated to check for significant differences between measurement classes, and for dependence between pairs of measurements, respectively. Results were validated by multivariate analysis incorporating the International Prognostic Index. The concordance between the two systems of image analysis was surprisingly high, supporting their applicability for immunohistochemistry studies. Patients with a high density of CD3 and FoxP3 by both methods had a better outcome. Automated analysis should be the preferred method for immunohistochemistry studies. Following the use of two methods of semi-automated analysis we suggest that CD3 and FoxP3 play a role in predicting response to chemoimmunotherapy in diffuse large B-cell lymphoma.
Ecologists and economists have long talked past each other, but climate change presents similar threats to both groups. Water may serve as the best means of finding a common cause and building a new ...vision of ecological and economic sustainability, especially in the developing world.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We report on anomalously long duration (2 ms) count rate bursts following the impact of cosmic ray showers near a 7.62 cm x⊘7.62 cm LaBr3 scintillation detector at the High Altitude Water Cherenkov ...array in Mexico, previously described by Stenkin et al. (2001), and termed “neutron bursts.” The largest burst produced 198 counts within 2 ms in our LaBr3 detector. We simulate the neutron burst albedo flux (that is, secondary emissions from an extensive air shower core impacting the ground), and show that (1) the characteristic spectra and count rates are well explained by neutron absorption in the ground and (2) any cosmic ray secondary that produces neutrons, either through hadron inelastic collisions, or photoneutron production by gamma‐rays, produces the same characteristic spectra. This implies that other natural phenomena that produce downward beams of gamma‐rays, like Terrestrial gamma ray flashes, should produce a similar “neutron burst” signature from the photoneutron reactions occurring in the soil.
Plain Language Summary
When very large cosmic ray showers (CRS) impact the ground, neutrons are produced in the soil that will rattle around until they become captured by soil particles and release energetic gamma‐rays. This produces a slow explosion of particles emanating from the ground following a CRS impact, and is termed a 'neutron burst'. We present recent observations of neutron bursts from a hand held sized gamma‐ray detector at the High Altitude Water Cherenkov (HAWC) array in Mexico, that exhibit interesting spectral features (the presence of positron annihilation), and an interesting time structure (hundreds of counts within a few ms). Our simulations indicate that Terrestrial gamma‐ray flashes (TGFs, bursts of gamma‐rays associated with lightning) should also produce these neutron bursts. An implication of this work is that existing deployments of ground based TGF instruments, comprised of small gamma‐ray detectors, can additionally be used to observe signatures of large cosmic ray showers on clear days.
Key Points
We report on fairweather count rate bursts with 2 ms duration following the impact of a large cosmic ray shower near a small scintillation detector at HAWC
Simulations show that the spectra and decay time can be produced by either hadronic interactions, or photoneutron reactions from gamma‐rays
These results imply that downward TGFs could produce a similar delayed neutron signature in the soil near ground based detectors
Inhaled corticosteroids are widely prescribed for the treatment of stable chronic obstructive pulmonary disease (COPD), despite lack of proven efficacy. Because COPD involves airway inflammation and ...probable protease-antiprotease imbalance, we examined the effect of high dose fluticasone propionate on markers of activity of both pathogenetic mechanisms. Thirteen patients with COPD were treated with fluticasone propionate (500 microg twice a day) for 4 wk, delivered via MDI and spacer, in a double-blind crossover study. There was no clinical benefit in terms of lung function or symptom scores, and induced sputum inflammatory cells, percentage neutrophils, and IL-8 levels were unchanged. Sputum supernatant elastase activity, matrix metalloproteinase (MMP)-1, MMP-9, and the antiproteases secretory leukoprotease inhibitor (SLPI) and tissue inhibitor of metalloproteinase (TIMP)-1 were similarly unaffected by treatment. These results add to previous evidence that inhaled steroids have no anti-inflammatory action in stable COPD. Furthermore, inhaled steroids do not appear to redress the protease-antiprotease imbalance that is thought to be important in the pathogenesis of airway obstruction.
Solutions of poly(ethylene-co-vinyl alcohol) or EVOH, ranging in composition from 56 to 71
wt% vinyl alcohol, can be readily electrospun at room temperature from solutions in 70% 2-propanol/water ...(rubbing alcohol). The solutions are prepared at 80°C and allowed to cool to room temperature. Interestingly, the solutions are not stable at room temperature and eventually the polymer precipitates after several hours. However, prior to precipitation, electrospinning is extensive and rapid, allowing coverage of fibers on various substrates, including a grounded metal plate, dielectrics interposed between the charged jet and the metal ground, and on the human body. Fiber diameters of ca. 0.2–8.0
μm were obtained depending upon the solution concentration, an attractive range for tissue engineering, wound healing, and related applications. Electrospun EVOH mats have been shown to support the culturing of smooth muscle cells and fibroblasts.
Human erythropoietin is a haematopoietic cytokine required for the differentiation and proliferation of precursor cells into red blood cells. It activates cells by binding and orientating two ...cell-surface erythropoietin receptors (EPORs) which trigger an intracellular phosphorylation cascade. The half-maximal response in a cellular proliferation assay is evoked at an erythropoietin concentration of 10 pM (ref. 3), 10−2 of its K d value for erythropoietin-EPOR binding site 1 (Kd 1 nM), and 10−5 of the K d for erythropoietin-EPOR binding site 2 (Kd 1 μM). Overall half-maximal binding (IC50) of cell-surface receptors is produced with ∼0.18 nM erythropoietin, indicating that only ∼6% of the receptors would be bound in the presence of 10 pM erythropoietin. Other effective erythropoietin-mimetic ligands that dimerize receptors can evoke the same cellular responses, but much less efficiently, requiring concentrations close to their K d values (∼0.1 μM). The crystal structure of erythropoietin complexed to the extracellular ligand-binding domains of the erythropoietin receptor, determined at 1.9 Å from two crystal forms, shows that erythropoietin imposes a unique 120° angular relationship and orientation that is responsible for optimal signalling through intracellular kinase pathways.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Stakeholder participation in healthcare curriculum design is an important aspect of higher education with stakeholders including students, staff members, clinical partners, healthcare organisations, ...patients and members of the public. Significantly, student co-creation, of the curriculum, has become increasingly important. Yet there is limited research which addresses how to engage this group in design processes.
This paper represents the first phase of a three stage action research spiral whereby the authors evaluated the use of a novel tool for curriculum design processes, anonymised crowdsourcing. This initial phase was open to all students enrolled on an undergraduate diagnostic radiography programme in the UK. To confirm the reliability of the crowdsource design an established eight point crowdsourcing verification tool was applied.
Twenty-three unique ideas were generated by participants, 40 comments made and 173 votes cast. Inductive analysis of the comments generated five themes. These included: the role of technology enhanced learning; simulation activities; patient focused curriculum; mental wealth (resilience) authentic assessment approaches. An evaluation of those who had and had not engaged highlighted areas of improvement for the administration of the second and third iterations which will include a wider pool of participants.
This study from a single programme offers lessons for others wishing to adopt and develop this approach elsewhere.
Several ideas elicited by the crowdsource have been considered by the curriculum design team and will be implemented in the 2020 curriculum thus demonstrating the impact on local education practice of this research approach.
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