Genetic variants in the KIF6 region and coronary event reduction from statin therapy

A single nucleotide polymorphism (SNP) in KIF6, a member of the KIF9 family of kinesins, is associated with differential coronary event reduction from statin therapy in four randomized controlled trials; this SNP (rs20455) is also associated with the risk for coronary heart disease (CHD) in multiple prospective studies. We investigated whether other common SNPs in the KIF6 region were associated with event reduction from statin therapy. Of the 170 SNPs in the KIF6 region investigated in the Cholesterol and Recurrent Events trial (CARE), 28 were associated with differential event reduction from statin therapy (Pinteraction < 0.1 in Caucasians, adjusted for age and sex) and were further investigated in the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22 (PROVE IT-TIMI22) and West of Scotland Coronary Prevention Study (WOSCOPS). These analyses revealed that two SNPs (rs9462535 and rs9471077), in addition to rs20455, were associated with event reduction from statin therapy (Pinteraction < 0.1 in each of the three studies). The relative risk reduction ranged from 37 to 50% (P < 0.01) in carriers of the minor alleles of these SNPs and from −4 to 13% (P > 0.4) in non-carriers. These three SNPs are in high linkage disequilibrium with one another (r2 > 0.84). Functional studies of these variants may help to understand the role of KIF6 in the pathogenesis of CHD and differential response to statin therapy

A Prospective Study of Pravastatin in the Elderly at Risk (PROSPER): Screening Experience and Baseline Characteristics

BACKGROUND: PROSPER was designed to investigate the benefits of treatment with pravastatin in elderly patients for whom a typical doctor might consider the prescription of statin therapy to be a realistic option. METHODS: The PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) is a randomised, double blind, placebo-controlled trial to test the hypothesis that treatment with pravastatin (40 mg/day) will reduce the risk of coronary heart disease death, non-fatal myocardial infarction, and fatal or non-fatal stroke in elderly men and women with pre-existing vascular disease or with significant risk of developing this condition. RESULTS: In Scotland, Ireland, and the Netherlands, 23,770 individuals were screened, and 5,804 subjects (2,804 men and 3,000 women), aged 70 to 82 years (average 75 years) and with baseline cholesterol 4.0–9.0 mmol/l, were randomised. Randomised subjects had similar distributions with respect to age, blood pressure, and body mass index when compared to the entire group of screenees, but had a higher prevalence of smoking, diabetes, hypertension, and a history of vascular disease. The average total cholesterol level at baseline was 5.4 mmol/l (men) and 6.0 mmol/l (women). CONCLUSIONS: Compared with previous prevention trials of cholesterol-lowering drugs, the PROSPER cohort is significantly older and for the first time includes a majority of women. The study, having achieved its initial goal of recruiting more than 5,500 elderly high-risk men and women, aims to complete all final subject follow-up visits in the first half of 2002 with the main results being available in the fourth quarter of 2002

Genome-Wide Study of Gene Variants Associated with Differential Cardiovascular Event Reduction by Pravastatin Therapy

Statin therapy reduces the risk of coronary heart disease (CHD), however, the person-to-person variability in response to statin therapy is not well understood. We have investigated the effect of genetic variation on the reduction of CHD events by pravastatin. First, we conducted a genome-wide association study of 682 CHD cases from the Cholesterol and Recurrent Events (CARE) trial and 383 CHD cases from the West of Scotland Coronary Prevention Study (WOSCOPS), two randomized, placebo-controlled studies of pravastatin. In a combined case-only analysis, 79 single nucleotide polymorphisms (SNPs) were associated with differential CHD event reduction by pravastatin according to genotype (P<0.0001), and these SNPs were analyzed in a second stage that included cases as well as non-cases from CARE and WOSCOPS and patients from the PROspective Study of Pravastatin in the Elderly at Risk/PHArmacogenomic study of Statins in the Elderly at risk for cardiovascular disease (PROSPER/PHASE), a randomized placebo controlled study of pravastatin in the elderly. We found that one of these SNPs (rs13279522) was associated with differential CHD event reduction by pravastatin therapy in all 3 studies: P = 0.002 in CARE, P = 0.01 in WOSCOPS, P = 0.002 in PROSPER/PHASE. In a combined analysis of CARE, WOSCOPS, and PROSPER/PHASE, the hazard ratio for CHD when comparing pravastatin with placebo decreased by a factor of 0.63 (95% CI: 0.52 to 0.75) for each extra copy of the minor allele (P = 4.8×10−7). This SNP is located in DnaJ homolog subfamily C member 5B (DNAJC5B) and merits investigation in additional randomized studies of pravastatin and other statins

Leveraging analytics to produce compelling and profitable film content

Producing compelling film content profitably is a top priority to the long-term prosperity of the film industry. Advances in digital technologies, increasing availabilities of granular big data, rapid diffusion of analytic techniques, and intensified competition from user generated content and original content produced by Subscription Video on Demand (SVOD) platforms have created unparalleled needs and opportunities for film producers to leverage analytics in content production. Built upon the theories of value creation and film production, this article proposes a conceptual framework of key analytic techniques that film producers may engage throughout the production process, such as script analytics, talent analytics, and audience analytics. The article further synthesizes the state-of-the-art research on and applications of these analytics, discuss the prospect of leveraging analytics in film production, and suggest fruitful avenues for future research with important managerial implications

Socialization, legitimation and the transfer of biomedical knowledge to low- and middle-income countries: analyzing the case of emergency medicine in India

BACKGROUND: Medical specialization is a key feature of biomedicine, and is a growing, but weakly understood aspect of health systems in many low- and middle-income countries (LMICs), including India. Emergency medicine is an example of a medical specialty that has been promoted in India by several high-income country stakeholders, including the Indian diaspora, through transnational and institutional partnerships. Despite the rapid evolution of emergency medicine in comparison to other specialties, this specialty has seen fragmentation in the stakeholder network and divergent training and policy objectives. Few empirical studies have examined the influence of stakeholders from high-income countries broadly, or of diasporas specifically, in transferring knowledge of medical specialization to LMICs. Using the concepts of socialization and legitimation, our goal is to examine the transfer of medical knowledge from high-income countries to LMICs through domestic, diasporic and foreign stakeholders, and the perceived impact of this knowledge on shaping health priorities in India. METHODS: This analysis was conducted as part of a broader study on the development of emergency medicine in India. We designed a qualitative case study focused on the early 1990s until 2015, analyzing data from in-depth interviewing (n = 87), document review (n = 248), and non-participant observation of conferences and meetings (n = 6). RESULTS: From the early 1990s, domestic stakeholders with exposure to emergency medicine in high-income countries began to establish Emergency Departments and initiate specialist training in the field. Their efforts were amplified by the active legitimation of emergency medicine by diasporic and foreign stakeholders, who formed transnational partnerships with domestic stakeholders and organized conferences, training programs and other activities to promote the field in India. However, despite a broad commitment to expanding specialist training, the network of domestic, diasporic and foreign stakeholders was highly fragmented, resulting in myriad unstandardized postgraduate training programs and duplicative policy agendas. Further, the focus in this time period was largely on training specialists, resulting in more emphasis on a medicalized, tertiary-level form of care. CONCLUSIONS: This analysis reveals the complexities of the roles and dynamics of domestic, diasporic and foreign stakeholders in the evolution of emergency medicine in India. More research and critical analyses are required to explore the transfer of medical knowledge, such as other medical specialties, models of clinical care, and medical technologies, from high-income countries to India

Dynamical structure of center-of-pressure trajectories in patients recovering from stroke

Contains fulltext : 50308.pdf (publisher's version ) (Closed access)In a recent study, De Haart et al. (Arch Phys Med Rehabil 85:886-895, 2004) investigated the recovery of balance in stroke patients using traditional analyses of center-of-pressure (COP) trajectories to assess the effects of health status, rehabilitation, and task conditions like standing with eyes open or closed and standing while performing a cognitive dual task. To unravel the underlying control processes, we reanalyzed these data in terms of stochastic dynamics using more advanced analyses. Dimensionality, local stability, regularity, and scaling behavior of COP trajectories were determined and compared with shuffled and phase-randomized surrogate data. The presence of long-range correlations discarded the possibility that the COP trajectories were purely random. Compared to the healthy controls, the COP trajectories of the stroke patients were characterized by increased dimensionality and instability, but greater regularity in the frontal plane. These findings were taken to imply that the stroke patients actively (i.e., cognitively) coped with the stroke-induced impairment of posture, as reflected in the increased regularity and decreased local stability, by recruiting additional control processes (i.e., more degrees of freedom) and/or by tightening the present control structure while releasing non-essential degrees of freedom from postural control. In the course of rehabilitation, dimensionality stayed fairly constant, whereas local stability increased and regularity decreased. The progressively less regular COP trajectories were interpreted to indicate a reduction of cognitive involvement in postural control as recovery from stroke progressed. Consistent with this interpretation, the dual task condition resulted in less regular COP trajectories of greater dimensionality, reflecting a task-related decrease of active, cognitive contributions to postural control. In comparison with conventional posturography, our results show a clear surplus value of dynamical measures in studying postural control

Optimal foraging and community structure: implications for a guild of generalist grassland herbivores

A particular linear programming model is constructed to predict the diets of each of 14 species of generalist herbivores at the National Bison Range, Montana. The herbivores have body masses ranging over seven orders of magnitude and belonging to two major taxa: insects and mammals. The linear programming model has three feeding constraints: digestive capacity, feeding time and energy requirements. A foraging strategy that maximizes daily energy intake agrees very well with the observed diets. Body size appears to be an underlying determinant of the foraging parameters leading to diet selection. Species that possess digestive capacity and feeding time constraints which approach each other in magnitude have the most generalized diets. The degree that the linear programming models change their diet predictions with a given percent change in parameter values (sensitivity) may reflect the observed ability of the species to vary their diets. In particular, the species which show the most diet variability are those whose diets tend to be balanced between monocots and dicots. The community-ecological parameters of herbivore body-size ranges and species number can possibly be related to foraging behavior.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47765/1/442_2004_Article_BF00377109.pd

Changes to the Fossil Record of Insects through Fifteen Years of Discovery

The first and last occurrences of hexapod families in the fossil record are compiled from publications up to end-2009. The major features of these data are compared with those of previous datasets (1993 and 1994). About a third of families (>400) are new to the fossil record since 1994, over half of the earlier, existing families have experienced changes in their known stratigraphic range and only about ten percent have unchanged ranges. Despite these significant additions to knowledge, the broad pattern of described richness through time remains similar, with described richness increasing steadily through geological history and a shift in dominant taxa, from Palaeoptera and Polyneoptera to Paraneoptera and Holometabola, after the Palaeozoic. However, after detrending, described richness is not well correlated with the earlier datasets, indicating significant changes in shorter-term patterns. There is reduced Palaeozoic richness, peaking at a different time, and a less pronounced Permian decline. A pronounced Triassic peak and decline is shown, and the plateau from the mid Early Cretaceous to the end of the period remains, albeit at substantially higher richness compared to earlier datasets. Origination and extinction rates are broadly similar to before, with a broad decline in both through time but episodic peaks, including end-Permian turnover. Origination more consistently exceeds extinction compared to previous datasets and exceptions are mainly in the Palaeozoic. These changes suggest that some inferences about causal mechanisms in insect macroevolution are likely to differ as well

Safety out of control: dopamine and defence

We enjoy a sophisticated understanding of how animals learn to predict appetitive outcomes and direct their behaviour accordingly. This encompasses well-defined learning algorithms and details of how these might be implemented in the brain. Dopamine has played an important part in this unfolding story, appearing to embody a learning signal for predicting rewards and stamping in useful actions, while also being a modulator of behavioural vigour. By contrast, although choosing correct actions and executing them vigorously in the face of adversity is at least as important, our understanding of learning and behaviour in aversive settings is less well developed. We examine aversive processing through the medium of the role of dopamine and targets such as D2 receptors in the striatum. We consider critical factors such as the degree of control that an animal believes it exerts over key aspects of its environment, the distinction between 'better' and 'good' actual or predicted future states, and the potential requirement for a particular form of opponent to dopamine to ensure proper calibration of state values