Adaptive Non-Inferiority Margins under Observable Non-Constancy

A central assumption in the design and conduct of non-inferiority trials is that the active-control therapy will have the same degree of effectiveness in the planned non-inferiority trial as it had in the prior placebo-controlled trials used to define the non-inferiority margin. This is referred to as the `constancy\u27 assumption. If the constancy assumption fails, the chosen non-inferiority margin is not valid and the study runs the risk of approving an inferior product or failing to approve a beneficial product. The constancy assumption cannot be validated in a trial without a placebo arm, and it is unlikely ever to be met completely. However, it is often the case that there exist strong, measurable predictors of constancy, such as dosing and adherence, and such predictors can be used to identify situations where the constancy assumption will likely fail. Here we propose a method for using measurable predictors of active-control effectiveness to specify non-inferiority margins targeted to the planned study population, and further use these predictors to adapt the non-inferiority margin at the end of the study. Population-specific margins can help avoid violations of the constancy assumption, and adaptive margins can help adjust for violations that will inevitably occur in real clinical trials, while at the same time maintain pre-specified levels of type I error and power

Epistemic and social scripts in computer-supported collaborative learning

Collaborative learning in computer-supported learning environments typically means that learners work on tasks together, discussing their individual perspectives via text-based media or videoconferencing, and consequently acquire knowledge. Collaborative learning, however, is often sub-optimal with respect to how learners work on the concepts that are supposed to be learned and how learners interact with each other. One possibility to improve collaborative learning environments is to conceptualize epistemic scripts, which specify how learners work on a given task, and social scripts, which structure how learners interact with each other. In this contribution, two studies will be reported that investigated the effects of epistemic and social scripts in a text-based computer-supported learning environment and in a videoconferencing learning environment in order to foster the individual acquisition of knowledge. In each study the factors ‘epistemic script’ and ‘social script’ have been independently varied in a 2×2-factorial design. 182 university students of Educational Science participated in these two studies. Results of both studies show that social scripts can be substantially beneficial with respect to the individual acquisition of knowledge, whereas epistemic scripts apparently do not to lead to the expected effects

A case study of boundary layer ventilation by convection and coastal processes

It is often assumed that ventilation of the atmospheric boundary layer is weak in the absence of fronts, but is this always true? In this paper we investigate the processes responsible for ventilation of the atmospheric boundary layer during a nonfrontal day that occurred on 9 May 2005 using the UK Met Office Unified Model. Pollution sources are represented by the constant emission of a passive tracer everywhere over land. The ventilation processes observed include shallow convection, turbulent mixing followed by large-scale ascent, a sea breeze circulation and coastal outflow. Vertical distributions of tracer are validated qualitatively with AMPEP (Aircraft Measurement of chemical Processing Export fluxes of Pollutants over the UK) CO aircraft measurements and are shown to agree impressively well. Budget calculations of tracers are performed in order to determine the relative importance of these ventilation processes. Coastal outflow and the sea breeze circulation were found to ventilate 26% of the boundary layer tracer by sunset of which 2% was above 2 km. A combination of coastal outflow, the sea breeze circulation, turbulent mixing and large-scale ascent ventilated 46% of the boundary layer tracer, of which 10% was above 2 km. Finally, coastal outflow, the sea breeze circulation, turbulent mixing, large-scale ascent and shallow convection together ventilated 52% of the tracer into the free troposphere, of which 26% was above 2 km. Hence this study shows that significant ventilation of the boundary layer can occur in the absence of fronts (and thus during high-pressure events). Turbulent mixing and convection processes can double the amount of pollution ventilated from the boundary layer

DEXA Body Composition and Cardiovascular Risk Factors Weakly Related in Police Officers

There is currently little research on whether fat mass and distribution is a predictive factor of cardiovascular risk. PURPOSE: To determine if obesity measures, such as fat mass and distribution (android vs gynoid), could be used to predict cardiovascular risk, particularly lipid levels, systolic blood pressure (SBP) and blood glucose. Our hypothesis was that fat mass is not an accurate predictor of these cardiovascular risk factors. METHODS: 182 police officers (166 males, 16 females; age 37.6±8.1 yrs; ht 1.7±0.1 m; wt 92.2±17.8 kg; BMI 28.9±4.8) were part of an annual cardiovascular risk profile testing group. We measured resting heart rate and blood pressure, and body composition via DEXA scan (SBP 127.16±10.33 mmHg; fat mass 26.85±9.99 kg; lean mass 62.01±9.90 kg; percent android fat 35.54±10.07; percent gynoid fat 29.65±6.91). Fasting blood samples were drawn and analyzed by a clinically certified lab to determine total blood cholesterol (TC) (191.79±37.31 mg/dL), LDL (119.23±34.74 mg/dL), HDL (46.39±10.48 mg/dL), triglycerides (128.94±99.25 mg/dL), and glucose (86.67±18.65 mg/dL). Correlations were determined by using a bivariate Pearson correlation matrix, significance was set at and p\u3c0.01**. RESULTS: As fat mass increased, total cholesterol and LDL increased and HDL decreased. Triglycerides, glucose, and SBP also increased as fat mass increased. There were also significant increases in total cholesterol, LDL, triglycerides, glucose and SBP as android fat percentage increased. HDL decreased significantly as android fat percentage increased. CONCLUSION: Fat mass weakly correlates with blood cholesterol levels. We suggest that factors other than fat mass affect cholesterol, such as genetics and lifestyle. More research is needed to see if this correlation holds or is stronger in similar and different populations

New zebrafish models of neurodegeneration

In modern biomedicine, the increasing need to develop experimental models to further our understanding of disease conditions and delineate innovative treatments has found in the zebrafish (Danio rerio) an experimental model, and indeed a valuable asset, to close the gap between in vitro and in vivo assays. Translation of ideas at a faster pace is vital in the field of neurodegeneration, with the attempt to slow or prevent the dramatic impact on the society's welfare being an essential priority. Our research group has pioneered the use of zebrafish to contribute to the quest for faster and improved understanding and treatment of neurodegeneration in concert with, and inspired by, many others who have primed the study of the zebrafish to understand and search for a cure for disorders of the nervous system. Aware of the many advantages this vertebrate model holds, here, we present an update on the recent zebrafish models available to study neurodegeneration with the goal of stimulating further interest and increasing the number of diseases and applications for which they can be exploited. We shall do so by citing and commenting on recent breakthroughs made possible via zebrafish, highlighting their benefits for the testing of therapeutics and dissecting of disease mechanisms

The pleiotropic effects of decanoic acid treatment on mitochondrial function in fibroblasts from patients with complex I deficient Leigh syndrome

There is growing interest in the use of the ketogenic diet (KD) to treat inherited metabolic diseases including mitochondrial disorders. However, neither the mechanism whereby the diet may be working, nor if it could benefit all patients with mitochondrial disease, is known. This study focusses on decanoic acid (C10), a component of the medium chain triglyceride KD, and a ligand for the nuclear receptor PPAR-γ known to be involved in mitochondrial biogenesis. The effects of C10 were investigated in primary fibroblasts from a cohort of patients with Leigh syndrome (LS) caused by nuclear-encoded defects of respiratory chain complex I, using mitochondrial respiratory chain enzyme assays, gene expression microarray, qPCR and flow cytometry. Treatment with C10 increased citrate synthase activity, a marker of cellular mitochondrial content, in 50 % of fibroblasts obtained from individuals diagnosed with LS in a PPAR-γ-mediated manner. Gene expression analysis and qPCR studies suggested that treating cells with C10 supports fatty acid metabolism, through increasing ACADVL and CPT1 expression, whilst downregulating genes involved in glucose metabolism (PDK3, PDK4). PCK2, involved in blocking glucose metabolism, was upregulated, as was CAT, encoding catalase. Moreover, treatment with C10 also decreased oxidative stress in complex I deficient (rotenone treated) cells. However, since not all cells from subjects with LS appeared to respond to C10, prior cellular testing in vitro could be employed as a means for selecting individuals for subsequent clinical studies involving C10 preparations

Controls on boundary layer ventilation: Boundary layer processes and large-scale dynamics

Midlatitude cyclones are important contributors to boundary layer ventilation. However, it is uncertain how efficient such systems are at transporting pollutants out of the boundary layer, and variations between cyclones are unexplained. In this study 15 idealized baroclinic life cycles, with a passive tracer included, are simulated to identify the relative importance of two transport processes: horizontal divergence and convergence within the boundary layer and large-scale advection by the warm conveyor belt. Results show that the amount of ventilation is insensitive to surface drag over a realistic range of values. This indicates that although boundary layer processes are necessary for ventilation they do not control the magnitude of ventilation. A diagnostic for the mass flux out of the boundary layer has been developed to identify the synoptic-scale variables controlling the strength of ascent in the warm conveyor belt. A very high level of correlation (R-2 values exceeding 0.98) is found between the diagnostic and the actual mass flux computed from the simulations. This demonstrates that the large-scale dynamics control the amount of ventilation, and the efficiency of midlatitude cyclones to ventilate the boundary layer can be estimated using the new mass flux diagnostic. We conclude that meteorological analyses, such as ERA-40, are sufficient to quantify boundary layer ventilation by the large-scale dynamics

Can the Mechanism for π1→ηπ,η′π\pi_1\to \eta\pi,\eta'\pi Hybrid Decays be Detected?

Two mechanisms for the $\pi_1$ ($J^{PC}=1^{-+}$) hybrid meson decay processes $\pi_1\to\eta\pi,\eta'\pi$ are investigated. These mechanisms are applied to $\phi\to\eta\gamma,\eta'\gamma$ and $J/\psi\to\eta\gamma,\eta'\gamma$ decays to illustrate the validity of the decay mechanisms and to obtain independent information on the coupling of $\eta,\eta'$ to quark and gluonic operators. From this information, we find that $\Gamma(\pi_1\to\eta\pi)/\Gamma(\pi_1\to\eta'\pi)$ is substantially different in the two decay mechanisms, and hence future experimental measurements of this ratio will provide valuable information for substantiating the hybrid nature of these states and for determining the mechanism for these hybrid decays.Comment: 5 pages, revtex, 1 eps figure embedded in manuscript. Analysis and references extended in v