Explaining trends in Scottish coronary heart disease mortality between 2000 and 2010 using IMPACTSEC model: retrospective analysis using routine data.

Objective To quantify the contributions of prevention and treatment to the trends in mortality due to coronary heart disease in Scotland. Design Retrospective analysis using IMPACTSEC, a previously validated policy model, to apportion the recent decline in coronary heart disease mortality to changes in major cardiovascular risk factors and to increases in more than 40 treatments in nine non-overlapping groups of patients. Setting Scotland. Participants All adults aged 25 years or over, stratified by sex, age group, and fifths of Scottish Index of Multiple Deprivation. Main outcome measure Deaths prevented or postponed. Results 5770 fewer deaths from coronary heart disease occurred in 2010 than would be expected if the 2000 mortality rates had persisted (8042 rather than 13813). This reflected a 43% fall in coronary heart disease mortality rates (from 262 to 148 deaths per 100000). Improved treatments accounted for approximately 43% (95% confidence interval 33% to 61%) of the fall in mortality, and this benefit was evenly distributed across deprivation fifths. Notable treatment contributions came from primary prevention for hypercholesterolaemia (13%), secondary prevention drugs (11%), and chronic angina treatments (7%). Risk factor improvements accounted for approximately 39% (28% to 49%) of the fall in mortality (44% in the most deprived fifth compared with only 36% in the most affluent fifth). Reductions in systolic blood pressure contributed more than one third (37%) of the decline in mortality, with no socioeconomic patterning. Smaller contributions came from falls in total cholesterol (9%), smoking (4%), and inactivity (2%). However, increases in obesity and diabetes offset some of these benefits, potentially increasing mortality by 4% and 8% respectively. Diabetes showed strong socioeconomic patterning (12% increase in the most deprived fifth compared with 5% for the most affluent fifth). Conclusions Increases in medical treatments accounted for almost half of the large recent decline in mortality due to coronary heart disease in Scotland. Furthermore, the Scottish National Health Service seems to have delivered these benefits equitably. However, the substantial contributions from population falls in blood pressure and other risk factors were diminished by adverse trends in obesity and diabetes. Additional population-wide interventions are urgently needed to reduce coronary heart disease mortality and inequalities in future decades

Spatial distribution of meiofaunal and macrofaunal assemblages in the tidal flats of the southern Korean coast in relation to natural and anthropogenic impacts

We investigated the spatial variability of macrofaunal and meiofaunal assemblages in intertidal flats on the southern coast of Korea. Abiotic and biotic samples were collected at five stations. The species richness, density, and composition of the assemblages differed significantly among stations. Nematoda and Annelida were the most dominant meiofaunal and macrofaunal taxa, respectively, although taxon dominance differed among stations. Distance-based linear models showed that sediment-related variables and heavy metals were the main environmental factors determining the spatial variability of the assemblages. Macrofauna had only sediment-related variables and heavy metals as major environmental factors, but meiofauna were also influenced by other environmental factors such as sea surface temperature, dissolved oxygen-related variables, and salinity. This study can provide basic ecological data for understanding the spatial distribution of macro-meiofaunal assemblages and aid in the development of marine environmental management strategies on the western south coast of Korea

The clinical efficacy of first-generation carcinoembryonic antigen (CEACAM5)-specific CAR T cells is limited by poor persistence and transient pre-conditioning-dependent respiratory toxicity

The primary aim of this clinical trial was to determine the feasibility of delivering first-generation CAR T cell therapy to patients with advanced, CEACAM5(+) malignancy. Secondary aims were to assess clinical efficacy, immune effector function and optimal dose of CAR T cells. Three cohorts of patients received increasing doses of CEACAM5(+)-specific CAR T cells after fludarabine pre-conditioning plus systemic IL2 support post T cell infusion. Patients in cohort 4 received increased intensity pre-conditioning (cyclophosphamide and fludarabine), systemic IL2 support and CAR T cells. No objective clinical responses were observed. CAR T cell engraftment in patients within cohort 4 was significantly higher. However, engraftment was short-lived with a rapid decline of systemic CAR T cells within 14 days. Patients in cohort 4 had transient, acute respiratory toxicity which, in combination with lack of prolonged CAR T cell persistence, resulted in the premature closure of the trial. Elevated levels of systemic IFNγ and IL-6 implied that the CEACAM5-specific T cells had undergone immune activation in vivo but only in patients receiving high-intensity pre-conditioning. Expression of CEACAM5 on lung epithelium may have resulted in this transient toxicity. Raised levels of serum cytokines including IL-6 in these patients implicate cytokine release as one of several potential factors exacerbating the observed respiratory toxicity. Whilst improved CAR designs and T cell production methods could improve the systemic persistence and activity, methods to control CAR T 'on-target, off-tissue' toxicity are required to enable a clinical impact of this approach in solid malignancies

Factors influencing agreement between child self-report and parent proxy-reports on the Pediatric Quality of Life Inventory™ 4.0 (PedsQL™) generic core scales

BACKGROUND: In situations where children are unable or unwilling to respond for themselves, measurement of quality of life (QOL) is often obtained by parent proxy-report. However the relationship between child self and parent proxy-reports has been shown to be poor in some circumstances. Additionally the most appropriate statistical method for comparing ratings between child and parent proxy-reports has not been clearly established. The objectives of this study were to assess the: 1) agreement between child and parent proxy-reports on an established child QOL measure (the PedsQL™) using two different statistical methods; 2) effect of chronological age and domain type on agreement between children's and parents' reports on the PedsQL™; 3) relationship between parents' own well-being and their ratings of their child's QOL. METHODS: One hundred and forty-nine healthy children (5.5 – 6.5, 6.5 – 7.5, and 7.5 – 8.5 years) completed the PedsQL™. One hundred and three of their parents completed these measures in relation to their child, and a measure of their own QOL (SF-36). RESULTS: Consistency between child and parent proxy-reports on the PedsQL™ was low, with Intra-Class correlation coefficients ranging from 0.02 to 0.23. Correlations were higher for the oldest age group for Total Score and Psychosocial Health domains, and for the Physical Health domain in the youngest age group. Statistically significant median differences were found between child and parent-reports on all subscales of the PedsQL™. The largest median differences were found for the two older age groups. Statistically significant correlations were found between parents' own QOL and their proxy-reports of child QOL across the total sample and within the middle age group. CONCLUSION: Intra-Class correlation coefficients and median difference testing can provide different information on the relationship between parent proxy-reports and child self-reports. Our findings suggest that differences in the levels of parent-child agreement previously reported may be an artefact of the statistical method used. In addition, levels of agreement can be affected by child age, domains investigated, and parents' own QOL. Further studies are needed to establish the optimal predictors of levels of parent-child agreement

Comparing the effects of calibration and climate errors on a statistical crop model and a process-based crop model

Understanding the relationship between climate and crop productivity is a key component of projections of future food production, and hence assessments of food security. Climate models and crop yield datasets have errors, but the effects of these errors on regional scale crop models is not well categorized and understood. In this study we compare the effect of synthetic errors in temperature and precipitation observations on the hindcast skill of a process-based crop model and a statistical crop model. We find that errors in temperature data have a significantly stronger influence on both models than errors in precipitation. We also identify key differences in the responses of these models to different types of input data error. Statistical and process-based model responses differ depending on whether synthetic errors are overestimates or underestimates. We also investigate the impact of crop yield calibration data on model skill for both models, using datasets of yield at three different spatial scales. Whilst important for both models, the statistical model is more strongly influenced by crop yield scale than the process-based crop model. However, our results question the value of high resolution yield data for improving the skill of crop models; we find a focus on accuracy to be more likely to be valuable. For both crop models, and for all three spatial scales of yield calibration data, we found that model skill is greatest where growing area is above 10-15 %. Thus information on area harvested would appear to be a priority for data collection efforts. These results are important for three reasons. First, understanding how different crop models rely on different characteristics of temperature, precipitation and crop yield data allows us to match the model type to the available data. Second, we can prioritize where improvements in climate and crop yield data should be directed. Third, as better climate and crop yield data becomes available, we can predict how crop model skill should improve

High and Low Molecular Weight Fluorescein Isothiocyanate (FITC)–Dextrans to Assess Blood-Brain Barrier Disruption: Technical Considerations

This note is to report how histological preparation techniques influence the extravasation pattern of the different molecular sizes of fluorescein isothiocyanate (FITC)–dextrans, typically used as markers for blood-brain barrier leakage. By using appropriate preparation methods, false negative results can be minimized. Wistar rats underwent a 2-h middle cerebral artery occlusion and magnetic resonance imaging. After the last imaging scan, Evans blue and FITC–dextrans of 4, 40, and 70 kDa molecular weight were injected. Different histological preparation methods were used. Sites of blood-brain barrier leakage were analyzed by fluorescence microscopy. Extravasation of Evans blue and high molecular FITC–dextrans (40 and 70 kDa) in the infarcted region could be detected with all preparation methods used. If exposed directly to saline, the signal intensity of these FITC–dextrans decreased. Extravasation of the 4-kDa low molecular weight FITC–dextran could only be detected using freshly frozen tissue sections. Preparations involving paraformaldehyde and sucrose resulted in the 4-kDa FITC–dextran dissolving in these reactants and being washed out, giving the false negative result of no extravasation. FITC–dextrans represent a valuable tool to characterize altered blood-brain barrier permeability in animal models. Diffusion and washout of low molecular weight FITC–dextran can be avoided by direct immobilization through immediate freezing of the tissue. This pitfall needs to be known to avoid the false impression that there was no extravasation of low molecular weight FITC–dextrans

Integrated information increases with fitness in the evolution of animats

One of the hallmarks of biological organisms is their ability to integrate disparate information sources to optimize their behavior in complex environments. How this capability can be quantified and related to the functional complexity of an organism remains a challenging problem, in particular since organismal functional complexity is not well-defined. We present here several candidate measures that quantify information and integration, and study their dependence on fitness as an artificial agent ("animat") evolves over thousands of generations to solve a navigation task in a simple, simulated environment. We compare the ability of these measures to predict high fitness with more conventional information-theoretic processing measures. As the animat adapts by increasing its "fit" to the world, information integration and processing increase commensurately along the evolutionary line of descent. We suggest that the correlation of fitness with information integration and with processing measures implies that high fitness requires both information processing as well as integration, but that information integration may be a better measure when the task requires memory. A correlation of measures of information integration (but also information processing) and fitness strongly suggests that these measures reflect the functional complexity of the animat, and that such measures can be used to quantify functional complexity even in the absence of fitness data.Comment: 27 pages, 8 figures, one supplementary figure. Three supplementary video files available on request. Version commensurate with published text in PLoS Comput. Bio