Sorafenib dose escalation is not uniformly associated with blood pressure elevations in normotensive patients with advanced malignancies.

Hypertension after treatment with vascular endothelial growth factor (VEGF) receptor inhibitors is associated with superior treatment outcomes for advanced cancer patients. To determine whether increased sorafenib doses cause incremental increases in blood pressure (BP), we measured 12-h ambulatory BP in 41 normotensive advanced solid tumor patients in a randomized dose-escalation study. After 7 days' treatment (400 mg b.i.d.), mean diastolic BP (DBP) increased in both study groups. After dose escalation, group A (400 mg t.i.d.) had marginally significant further increase in 12-h mean DBP (P = 0.053), but group B (600 mg b.i.d.) did not achieve statistically significant increases (P = 0.25). Within groups, individuals varied in BP response to sorafenib dose escalation, but these differences did not correlate with changes in steady-state plasma sorafenib concentrations. These findings in normotensive patients suggest BP is a complex pharmacodynamic biomarker of VEGF inhibition. Patients have intrinsic differences in sensitivity to sorafenib's BP-elevating effects

The inclusion of a business management module within the master of pharmacy degree: a route to asset enrichment?

BACKGROUND: Over the past decade the profession of pharmacy has steadily evolved. The New Pharmacy Contract exposed pharmacists to a fundamental change in traditional pharmacy business models. OBJECTIVE: This study will consider whether community pharmacists, pharmacy undergraduates and academic staff within the United Kingdom believe it would be beneficial to incorporate a business management module within the Master of Pharmacy (MPharm) undergraduate degree along with potential mechanisms of delivery. METHODS: Further to ethical approval, the questionnaire was distributed to UK registered pharmacists (n=600), MPharm undergraduates (n=441) and academic staff at Liverpool John Moores University (n=44). The questions were formatted as multiple choice questions, Likert scales or the open answer type. On questionnaire completion and return, data were analysed using simple frequencies, cross tabulations and non-parametric techniques in the SPSS (v18). RESULTS: The majority of pharmacists (84.9%) confirmed that business skills affect their everyday responsibilities to a considerable extent. A high proportion of undergraduate students (92.8%) believed that business management skills will impact on their future role. In total, 64.3% of this cohort declared that if a module were introduced they would study it. The majority of staff (79%) agreed that business skills are gaining increased importance within the field of pharmacy. CONCLUSIONS: Data suggest that business skills are of relevance to the practice of pharmacy. Appropriate staff to deliver the taught material would include business owners / lecturers and teaching practitioners covering topics including management, leadership, interpersonal skills and regulation. We suggest the inclusion of a business module with the MPharm degree would be of great value in preparing individuals for practice within a modern day healthcare setting

Novel Characteristics of Valveless Pumping

This study investigates the occurrence of valveless pumping in a fluidfilled system consisting of two open tanks connected by an elastic tube. We show that directional flow can be achieved by introducing a periodic pinching applied at an asymmetrical location along the tube, and that the flow direction depends on the pumping frequency. We propose a relation between wave propagation velocity, tube length, and resonance frequencies associated with shifts in the pumping direction using numerical simulations. The eigenfrequencies of the system are estimated from the linearized system, and we show that these eigenfrequencies constitute the resonance frequencies and the horizontal slope frequencies of the system; 'horizontal slope frequency' being a new concept. A simple model is suggested, explaining the effect of the gravity driven part of the oscillation observed in response to the tank and tube diameter changes. Results are partly compared with experimental findings.Art. no. 22450

Predicting Pneumonia and Influenza Mortality from Morbidity Data

BACKGROUND: Few European countries conduct reactive surveillance of influenza mortality, whereas most monitor morbidity. METHODOLOGY/PRINCIPAL FINDINGS: We developed a simple model based on Poisson seasonal regression to predict excess cases of pneumonia and influenza mortality during influenza epidemics, based on influenza morbidity data and the dominant types/subtypes of circulating viruses. Epidemics were classified in three levels of mortality burden (“high”, “moderate” and “low”). The model was fitted on 14 influenza seasons and was validated on six subsequent influenza seasons. Five out of the six seasons in the validation set were correctly classified. The average absolute difference between observed and predicted mortality was 2.8 per 100,000 (18% of the average excess mortality) and Spearman's rank correlation coefficient was 0.89 (P = 0.05). CONCLUSIONS/SIGNIFICANCE: The method described here can be used to estimate the influenza mortality burden in countries where specific pneumonia and influenza mortality surveillance data are not available

The impact of current CH4 and N2O atmospheric loss process uncertainties on calculated ozone abundances and trends

The atmospheric loss processes of N2O and CH4, their estimated uncertainties, lifetimes, and impacts on ozone abundance and long-term trends are examined using atmospheric model calculations and updated kinetic and photochemical parameters and uncertainty factors from SPARC [2013]. The uncertainty ranges in calculated N2O and CH4 global lifetimes computed using the SPARC estimated uncertainties are reduced by nearly a factor of two compared with uncertainties from Sander et al. [2011]. Uncertainties in CH4 loss due to reaction with OH and O(1D) have relatively small impacts on present day global total ozone (±0.2-0.3%). Uncertainty in the Cl + CH4 reaction affects the amount of chlorine in radical vs. reservoir forms and has a modest impact on present day SH polar ozone (~±6%), and on the rate of past ozone decline and future recovery. Uncertainty in the total rate coefficient for the O(1D) + N2O reaction results in a substantial range in present day stratospheric odd nitrogen (±20-25%) and global total ozone (±1.5-2.5%). Uncertainty in the O(1D) + N2O reaction branching ratio for the O2 + N2 and 2*NO product channels results in moderate impacts on odd nitrogen (±10%) and global ozone (±1%),with uncertainty in N2O photolysis resulting in relatively small impacts (±5% in odd nitrogen, ±0.5% in global ozone). Uncertainties in the O(1D) + N2O reaction and its branching ratio also affect the rate of past global total ozone decline and future recovery, with a range in future ozone projections of ±1-1.5% by 2100, relative to present day

The switch between acute and persistent paramyxovirus infection caused by single amino acid substitutions in the RNA polymerase P subunit

Paramyxoviruses can establish persistent infections both in vitro and in vivo, some of which lead to chronic disease. However, little is known about the molecular events that contribute to the establishment of persistent infections by RNA viruses. Using parainfluenza virus type 5 (PIV5) as a model we show that phosphorylation of the P protein, which is a key component of the viral RNA polymerase complex, determines whether or not viral transcription and replication becomes repressed at late times after infection. If the virus becomes repressed, persistence is established, but if not, the infected cells die. We found that single amino acid changes at various positions within the P protein switched the infection phenotype from lytic to persistent. Lytic variants replicated to higher titres in mice than persistent variants and caused greater infiltration of immune cells into infected lungs but were cleared more rapidly. We propose that during the acute phases of viral infection in vivo, lytic variants of PIV5 will be selected but, as the adaptive immune response develops, variants in which viral replication can be repressed will be selected, leading to the establishment of prolonged, persistent infections. We suggest that similar selection processes may operate for other RNA viruses

Dysfunction of NaV1.4, a skeletal muscle voltage-gated sodium channel, in sudden infant death syndrome: a case-control study.

BACKGROUND: Sudden infant death syndrome (SIDS) is the leading cause of post-neonatal infant death in high-income countries. Central respiratory system dysfunction seems to contribute to these deaths. Excitation that drives contraction of skeletal respiratory muscles is controlled by the sodium channel NaV1.4, which is encoded by the gene SCN4A. Variants in NaV1.4 that directly alter skeletal muscle excitability can cause myotonia, periodic paralysis, congenital myopathy, and myasthenic syndrome. SCN4A variants have also been found in infants with life-threatening apnoea and laryngospasm. We therefore hypothesised that rare, functionally disruptive SCN4A variants might be over-represented in infants who died from SIDS. METHODS: We did a case-control study, including two consecutive cohorts that included 278 SIDS cases of European ancestry and 729 ethnically matched controls without a history of cardiovascular, respiratory, or neurological disease. We compared the frequency of rare variants in SCN4A between groups (minor allele frequency <0·00005 in the Exome Aggregation Consortium). We assessed biophysical characterisation of the variant channels using a heterologous expression system. FINDINGS: Four (1·4%) of the 278 infants in the SIDS cohort had a rare functionally disruptive SCN4A variant compared with none (0%) of 729 ethnically matched controls (p=0·0057). INTERPRETATION: Rare SCN4A variants that directly alter NaV1.4 function occur in infants who had died from SIDS. These variants are predicted to significantly alter muscle membrane excitability and compromise respiratory and laryngeal function. These findings indicate that dysfunction of muscle sodium channels is a potentially modifiable risk factor in a subset of infant sudden deaths. FUNDING: UK Medical Research Council, the Wellcome Trust, National Institute for Health Research, the British Heart Foundation, Biotronik, Cardiac Risk in the Young, Higher Education Funding Council for England, Dravet Syndrome UK, the Epilepsy Society, the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health, and the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program

BlueHealth: a study programme protocol for mapping and quantifying the potential benefits to public health and well-being from Europe's blue spaces

This is the final version of the article. Available from BMJ Publishing Group via the DOI in this record.INTRODUCTION: Proximity and access to water have long been central to human culture and accordingly deliver countless societal benefits. Over 200 million people live on Europe's coastline, and aquatic environments are the top recreational destination in the region. In terms of public health, interactions with 'blue space' (eg, coasts, rivers, lakes) are often considered solely in terms of risk (eg, drowning, microbial pollution). Exposure to blue space can, however, promote health and well-being and prevent disease, although underlying mechanisms are poorly understood. AIMS AND METHODS: The BlueHealth project aims to understand the relationships between exposure to blue space and health and well-being, to map and quantify the public health impacts of changes to both natural blue spaces and associated urban infrastructure in Europe, and to provide evidence-based information to policymakers on how to maximise health benefits associated with interventions in and around aquatic environments. To achieve these aims, an evidence base will be created through systematic reviews, analyses of secondary data sets and analyses of new data collected through a bespoke international survey and a wide range of community-level interventions. We will also explore how to deliver the benefits associated with blue spaces to those without direct access through the use of virtual reality. Scenarios will be developed that allow the evaluation of health impacts in plausible future societal contexts and changing environments. BlueHealth will develop key inputs into policymaking and land/water-use planning towards more salutogenic and sustainable uses of blue space, particularly in urban areas. ETHICS AND DISSEMINATION: Throughout the BlueHealth project, ethics review and approval are obtained for all relevant aspects of the study by the local ethics committees prior to any work being initiated and an ethics expert has been appointed to the project advisory board. So far, ethical approval has been obtained for the BlueHealth International Survey and for community-level interventions taking place in Spain, Italy and the UK. Engagement of stakeholders, including the public, involves citizens in many aspects of the project. Results of all individual studies within the BlueHealth project will be published with open access. After full anonymisation and application of any measures necessary to prevent disclosure, data generated in the project will be deposited into open data repositories of the partner institutions, in line with a formal data management plan. Other knowledge and tools developed in the project will be made available via the project website (www.bluehealth2020.eu). Project results will ultimately provide key inputs to planning and policy relating to blue space, further stimulating the integration of environmental and health considerations into decision-making, such that blue infrastructure is developed across Europe with both public health and the environment in mind.This work was supported by funding received from the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 666773

Maximum-Reward Motion in a Stochastic Environment: The Nonequilibrium Statistical Mechanics Perspective

We consider the problem of computing the maximum-reward motion in a reward field in an online setting. We assume that the robot has a limited perception range, and it discovers the reward field on the fly. We analyze the performance of a simple, practical lattice-based algorithm with respect to the perception range. Our main result is that, with very little perception range, the robot can collect as much reward as if it could see the whole reward field, under certain assumptions. Along the way, we establish novel connections between this class of problems and certain fundamental problems of nonequilibrium statistical mechanics . We demonstrate our results in simulation examples

Bioavailability in soils

The consumption of locally-produced vegetables by humans may be an important exposure pathway for soil contaminants in many urban settings and for agricultural land use. Hence, prediction of metal and metalloid uptake by vegetables from contaminated soils is an important part of the Human Health Risk Assessment procedure. The behaviour of metals (cadmium, chromium, cobalt, copper, mercury, molybdenum, nickel, lead and zinc) and metalloids (arsenic, boron and selenium) in contaminated soils depends to a large extent on the intrinsic charge, valence and speciation of the contaminant ion, and soil properties such as pH, redox status and contents of clay and/or organic matter. However, chemistry and behaviour of the contaminant in soil alone cannot predict soil-to-plant transfer. Root uptake, root selectivity, ion interactions, rhizosphere processes, leaf uptake from the atmosphere, and plant partitioning are important processes that ultimately govern the accumulation ofmetals and metalloids in edible vegetable tissues. Mechanistic models to accurately describe all these processes have not yet been developed, let alone validated under field conditions. Hence, to estimate risks by vegetable consumption, empirical models have been used to correlate concentrations of metals and metalloids in contaminated soils, soil physico-chemical characteristics, and concentrations of elements in vegetable tissues. These models should only be used within the bounds of their calibration, and often need to be re-calibrated or validated using local soil and environmental conditions on a regional or site-specific basis.Mike J. McLaughlin, Erik Smolders, Fien Degryse, and Rene Rietr