Discovery of novel GPVI receptor antagonists by structure-based repurposing.

Inappropriate platelet aggregation creates a cardiovascular risk that is largely managed with thienopyridines and aspirin. Although effective, these drugs carry risks of increased bleeding and drug 'resistance', underpinning a drive for new antiplatelet agents. To discover such drugs, one strategy is to identify a suitable druggable target and then find small molecules that modulate it. A good and unexploited target is the platelet collagen receptor, GPVI, which promotes thrombus formation. To identify inhibitors of GPVI that are safe and bioavailable, we docked a FDA-approved drug library into the GPVI collagen-binding site in silico. We now report that losartan and cinanserin inhibit GPVI-mediated platelet activation in a selective, competitive and dose-dependent manner. This mechanism of action likely underpins the cardioprotective effects of losartan that could not be ascribed to its antihypertensive effects. We have, therefore, identified small molecule inhibitors of GPVI-mediated platelet activation, and also demonstrated the utility of structure-based repurposing.

Improving the health forecasting alert system for cold weather and heat-waves in England: a proof-of-concept using temperature-mortality relationships

Objectives In this study a prototype of a new health forecasting alert system is developed, which is aligned to the approach used in the Met Office’s (MO) National Severe Weather Warning Service (NSWWS). This is in order to improve information available to responders in the health and social care system by linking temperatures more directly to risks of mortality, and developing a system more coherent with other weather alerts. The prototype is compared to the current system in the Cold Weather and Heatwave plans via a case-study approach to verify its potential advantages and shortcomings. Method The prototype health forecasting alert system introduces an “impact vs likelihood matrix” for the health impacts of hot and cold temperatures which is similar to those used operationally for other weather hazards as part of the NSWWS. The impact axis of this matrix is based on existing epidemiological evidence, which shows an increasing relative risk of death at extremes of outdoor temperature beyond a threshold which can be identified epidemiologically. The likelihood axis is based on a probability measure associated with the temperature forecast. The new method is tested for two case studies (one during summer 2013, one during winter 2013), and compared to the performance of the current alert system. Conclusions The prototype shows some clear improvements over the current alert system. It allows for a much greater degree of flexibility, provides more detailed regional information about the health risks associated with periods of extreme temperatures, and is more coherent with other weather alerts which may make it easier for front line responders to use. It will require validation and engagement with stakeholders before it can be considered for use.

Trends in adult body-mass index in 200 countries from 1975 to 2014: a pooled analysis of 1698 population-based measurement studies with 19·2 million participants

Background Underweight and severe and morbid obesity are associated with highly elevated risks of adverse health outcomes. We estimated trends in mean body-mass index (BMI), which characterises its population distribution, and in the prevalences of a complete set of BMI categories for adults in all countries. Methods We analysed, with use of a consistent protocol, population-based studies that had measured height and weight in adults aged 18 years and older. We applied a Bayesian hierarchical model to these data to estimate trends from 1975 to 2014 in mean BMI and in the prevalences of BMI categories (<18·5 kg/m2 [underweight], 18·5 kg/m2 to <20 kg/m2, 20 kg/m2 to <25 kg/m2, 25 kg/m2 to <30 kg/m2, 30 kg/m2 to <35 kg/m2, 35 kg/m2 to <40 kg/m2, ≥40 kg/m2 [morbid obesity]), by sex in 200 countries and territories, organised in 21 regions. We calculated the posterior probability of meeting the target of halting by 2025 the rise in obesity at its 2010 levels, if post-2000 trends continue. Findings We used 1698 population-based data sources, with more than 19·2 million adult participants (9·9 million men and 9·3 million women) in 186 of 200 countries for which estimates were made. Global age-standardised mean BMI increased from 21·7 kg/m2 (95% credible interval 21·3–22·1) in 1975 to 24·2 kg/m2 (24·0–24·4) in 2014 in men, and from 22·1 kg/m2 (21·7–22·5) in 1975 to 24·4 kg/m2 (24·2–24·6) in 2014 in women. Regional mean BMIs in 2014 for men ranged from 21·4 kg/m2 in central Africa and south Asia to 29·2 kg/m2 (28·6–29·8) in Polynesia and Micronesia; for women the range was from 21·8 kg/m2 (21·4–22·3) in south Asia to 32·2 kg/m2 (31·5–32·8) in Polynesia and Micronesia. Over these four decades, age-standardised global prevalence of underweight decreased from 13·8% (10·5–17·4) to 8·8% (7·4–10·3) in men and from 14·6% (11·6–17·9) to 9·7% (8·3–11·1) in women. South Asia had the highest prevalence of underweight in 2014, 23·4% (17·8–29·2) in men and 24·0% (18·9–29·3) in women. Age-standardised prevalence of obesity increased from 3·2% (2·4–4·1) in 1975 to 10·8% (9·7–12·0) in 2014 in men, and from 6·4% (5·1–7·8) to 14·9% (13·6–16·1) in women. 2·3% (2·0–2·7) of the world's men and 5·0% (4·4–5·6) of women were severely obese (ie, have BMI ≥35 kg/m2). Globally, prevalence of morbid obesity was 0·64% (0·46–0·86) in men and 1·6% (1·3–1·9) in women. Interpretation If post-2000 trends continue, the probability of meeting the global obesity target is virtually zero. Rather, if these trends continue, by 2025, global obesity prevalence will reach 18% in men and surpass 21% in women; severe obesity will surpass 6% in men and 9% in women. Nonetheless, underweight remains prevalent in the world's poorest regions, especially in south Asia.

The risk of water stress

Water resources are under stress in many regions due to increasing demands and, in places, falling quality. Climate change has the potential to change the risks of water stress.1 The focus in this section is on strategic definitions of water stress, which are based on generalized indicators of the amount of water that is available and the demands on that resource. Operational definitions, on the other hand, are typically based on the reliability of the supply of appropriate quality water and are strongly determined by local conditions.

Coronary heart disease risk screening: the community pharmacy Healthy Heart Assessment Service

Objectives We examined the characteristics and CHD risks of people who accessed the free Healthy Heart Assessment (HHA) service operated by a large UK pharmacy chain from August 2004 to April 2006. Methods Associations between participants’ gender, age, and socioeconomics were explored in relation to calculated 10-year CHD risks by cross-tabulation of the data. Specific associations were tested by forming contingency tables and using Pearson chi-square (χ2). Results Data from 8,287 records were analysable; 5,377 were at low and 2,910 at moderate-to-high CHD risk. The likelihood of moderate-to-high risk for a male versus female participant was significantly higher with a relative risk ratio (RRR) 1.72 (P < 0.001). A higher percentage of those in socioeconomic categories ‘constrained by circumstances’ (RRR 1.15; P < 0.05) and ‘blue collar communities’ (RRR 1.13; P < 0.05) were assessed with moderate-to-high risk compared to those in ‘prospering suburbs’. Conclusions People from ‘hard-to-reach’ sectors of the population, men and people from less advantaged communities, accessed the HHA service and were more likely to return moderate-to-high CHD risk. Pharmacists prioritised provision of lifestyle information above the sale of a product. Our study supports the notion that pharmacies can serve as suitable environments for the delivery of similar screening services.

Spontaneous gene flow from rapeseed (Brassica napus) to wild Brassica oleracea

Research on the environmental risks of gene flow from genetically modified ( GM) crops to wild relatives has traditionally emphasized recipients yielding most hybrids. For GM rapeseed ( Brassica napus), interest has centred on the 'frequently hybridizing' Brassica rapa over relatives such as Brassica oleracea, where spontaneous hybrids are unreported in the wild. In two sites, where rapeseed and wild B. oleracea grow together, we used flow cytometry and crop-specific microsatellite markers to identify one triploid F-1 hybrid, together with nine diploid and two near triploid introgressants. Given the newly discovered capacity for spontaneous introgression into B. oleracea, we then surveyed associated flora and fauna to evaluate the capacity of both recipients to harm cohabitant species with acknowledged conservational importance. Only B. oleracea occupies rich communities containing species afforded legislative protection; these include one rare micromoth species that feeds on B. oleracea and warrants further assessment. We conclude that increased attention should now focus on B. oleracea and similar species that yield few crop-hybrids, but possess scope to affect rare or endangered associates.

Probiotics: their potential to impact human health

Probiotics—live microorganisms that when administered in adequate amounts confer a health benefit on the host—have been studied for both human and animal applications, and worldwide research on this topic has accelerated in recent years. This paper reviews the literature on probiotics, describes how probiotics work in human ecosystems, and outlines the impact of probiotics on human health and disease. The paper also addresses safety issues of probiotic use, suggests future developments in the field of probiotics, and provides research and policy recommendations. Product considerations and potential future developments regarding probiotics also are discussed. The authors conclude that controlled human studies have revealed a diverse range of health benefits from consumption of probiotics, due largely to their impact on immune function or on microbes colonizing the body. Additional, well-designed and properly controlled human and mechanistic studies with probiotics will advance the essential understanding of active principles, mechanisms of action, and degree of effects that can be realized by specific consumer groups. Recommendations include establishment of a standard of identity for the term “probiotic,” adoption of third-party verification of label claims, use of probiotics selectively in clinical conditions, and use of science-based assessment of the benefits and risks of genetically engineered probiotic microbes.

Obesity and health in Europeans aged 50 years and older

Background: Obesity is increasing globally across all population groups. Limited data are available on how obesity patterns differ across countries. Objective: To document the prevalence of obesity and related health conditions for Europeans aged 50 years and older, and to estimate the association between obesity and health outcomes across 10 European countries. Methods: Data were obtained from the 2004 Survey of Health, Ageing and Retirement in Europe, a cross-national survey of 22 777 Continental Europeans over the age of 50 years. The health outcomes included self-reported health, disability, doctor-diagnosed chronic health conditions and depression. Multivariate regression analysis was used to predict health outcomes across weight classes (defined by body mass index [BMI] from self-reported weight and height) in the pooled sample and individually in each country. Results: The prevalence of obesity (BMI >= 30) ranged from 12.8% in Sweden to 20.2% in Spain for men and from 12.3% in Switzerland to 25.6% in Spain for women. Adjusting for compositional differences across countries changed little in the observed large heterogeneity in obesity rates throughout Europe. Compared with normal weight individuals, men and women with greater BMI had significantly higher risks for all chronic health conditions examined except heart disease in overweight men. Depression was linked to obesity in women only. Particularly pronounced risks of impaired health and chronic health conditions were found among severely obese people. The effects of obesity on health did not vary significantly across countries. Conclusions: Cross-country differences in the prevalence of obesity in older Europeans are substantial and exceed socio-demographic differentials in excessive body weight. Obesity is associated with significantly poorer health outcomes among Europeans aged 50 years and over, with effects similar across countries. Large heterogeneity in obesity throughout Europe should be investigated further to identify areas for effective public policy. (C) 2007 Published by Elsevier Ltd on behalf of The Royal Institute of Public Health.

Requirements analysis for an e-government system to support multi-organisational collaborative groups

We present a conceptual architecture for a Group Support System (GSS) to facilitate Multi-Organisational Collaborative Groups (MOCGs) initiated by local government and including external organisations of various types. Multi-Organisational Collaborative Groups (MOCGs) consist of individuals from several organisations which have agreed to work together to solve a problem. The expectation is that more can be achieved working in harmony than separately. Work is done interdependently, rather than independently in diverse directions. Local government, faced with solving complex social problems, deploy MOCGs to enable solutions across organisational, functional, professional and juridical boundaries, by involving statutory, voluntary, community, not-for-profit and private organisations. This is not a silver bullet as it introduces new pressures. Each member organisation has its own goals, operating context and particular approaches, which can be expressed as their norms and business processes. Organisations working together must find ways of eliminating differences or mitigating their impact in order to reduce the risks of collaborative inertia and conflict. A GSS is an electronic collaboration system that facilitates group working and can offer assistance to MOCGs. Since many existing GSSs have been primarily developed for single organisation collaborative groups, even though there are some common issues, there are some difficulties peculiar to MOCGs, and others that they experience to a greater extent: a diversity of primary organisational goals among members; different funding models and other pressures; more significant differences in other information systems both technologically and in their use than single organisations; greater variation in acceptable approaches to solve problems. In this paper, we analyse the requirements of MOCGs led by local government agencies, leading to a conceptual architecture for an e-government GSS that captures the relationships between 'goal', 'context', 'norm', and 'business process'. Our models capture the dynamics of the circumstances surrounding each individual representing an organisation in a MOCG along with the dynamics of the MOCG itself as a separate community.

A climate change risk analysis for world ecosystems

We quantify the risks of climate-induced changes in key ecosystem processes during the 21st century by forcing a dynamic global vegetation model with multiple scenarios from 16 climate models and mapping the proportions of model runs showing forest/nonforest shifts or exceedance of natural variability in wildfire frequency and freshwater supply. Our analysis does not assign probabilities to scenarios or weights to models. Instead, we consider distribution of outcomes within three sets of model runs grouped by the amount of global warming they simulate: <2°C (including simulations in which atmospheric composition is held constant, i.e., in which the only climate change is due to greenhouse gases already emitted), 2–3°C, and >3°C. High risk of forest loss is shown for Eurasia, eastern China, Canada, Central America, and Amazonia, with forest extensions into the Arctic and semiarid savannas; more frequent wildfire in Amazonia, the far north, and many semiarid regions; more runoff north of 50°N and in tropical Africa and northwestern South America; and less runoff in West Africa, Central America, southern Europe, and the eastern U.S. Substantially larger areas are affected for global warming >3°C than for <2°C; some features appear only at higher warming levels. A land carbon sink of ≈1 Pg of C per yr is simulated for the late 20th century, but for >3°C this sink converts to a carbon source during the 21st century (implying a positive climate feedback) in 44% of cases. The risks continue increasing over the following 200 years, even with atmospheric composition held constant.

Robot free will

We introduce the perspex machine which unifies projective geometry and Turing computation and results in a supra-Turing machine. We show two ways in which the perspex machine unifies symbolic and non-symbolic AI. Firstly, we describe concrete geometrical models that map perspexes onto neural networks, some of which perform only symbolic operations. Secondly, we describe an abstract continuum of perspex logics that includes both symbolic logics and a new class of continuous logics. We argue that an axiom in symbolic logic can be the conclusion of a perspex theorem. That is, the atoms of symbolic logic can be the conclusions of sub-atomic theorems. We argue that perspex space can be mapped onto the spacetime of the universe we inhabit. This allows us to discuss how a robot might be conscious, feel, and have free will in a deterministic, or semi-deterministic, universe. We ground the reality of our universe in existence. On a theistic point, we argue that preordination and free will are compatible. On a theological point, we argue that it is not heretical for us to give robots free will. Finally, we give a pragmatic warning as to the double-edged risks of creating robots that do, or alternatively do not, have free will.

A value chain approach to animal diseases risk management: technical foundations and practical framework for field application

Classical risk assessment approaches for animal diseases are influenced by the probability of release, exposure and consequences of a hazard affecting a livestock population. Once a pathogen enters into domestic livestock, potential risks of exposure and infection both to animals and people extend through a chain of economic activities related to producing, buying and selling of animals and products. Therefore, in order to understand economic drivers of animal diseases in different ecosystems and to come up with effective and efficient measures to manage disease risks from a country or region, the entire value chain and related markets for animal and product needs to be analysed to come out with practical and cost effective risk management options agreed by actors and players on those value chains. Value chain analysis enriches disease risk assessment providing a framework for interdisciplinary collaboration, which seems to be in increasing demand for problems concerning infectious livestock diseases. The best way to achieve this is to ensure that veterinary epidemiologists and social scientists work together throughout the process at all levels.

Chronic disease risk associated with different dietary saturated fatty acids

This chapter compares the risks of chronic disease, and cardiovascular disease in particular, associated with consumption of different saturated fatty acids. Emphasis is placed on the effects of stearic acid as this has potential to replace trans fatty acids in certain manufactured food products. The chapter first reviews the effects of individual saturated fatty acids on blood lipids, including cholesterol, as these are commonly used as markers of disease risk. It then looks directly at evidence in relation to health outcomes. Finally, recent evidence specifically on the effect of stearic acid relative to other fatty acids, including trans fatty acids, is summarised.

Poverty, HIV, and barriers to education: street children's experiences in Tanzania

This article discusses the links between poverty, HIV/AIDS, and barriers to education, based on the first-hand experiences of ‘street children’ in northern Tanzania. Within the context of national levels of poverty, ‘cost-sharing’ in health and education sectors, and the AIDS epidemic, poor families in Tanzania are under considerable pressure, and increasing numbers of girls and boys are consequently seeking a living independently on the streets of towns and cities. My research with street children shows that some children orphaned by AIDS are subject to rejection and exploitation by the extended family after the death of their parent(s). They are exposed to considerable risks of abuse, sexual violence and HIV within the street environment. Here, I discuss the links between poverty, HIV and barriers to education, which compound young people’s vulnerability, and offer some policy recommendations in response to the young people’s experiences.