The effects of selected Australian snake venoms on tumour-associated microvascular endothelial cells (TAMECs) in vitro

The effects of various viperid and elapid venoms on the cellular biology of tumour-associated microvascular endothelial cells (TAMECs) were determined in the current study using cells isolated from a rat mammary adenocarcinoma. Previous studies to determine the effects of snake venoms on endothelial cells in vitro have in the main been performed on either human umbilical vein endothelial cells (HUVECs), bovine aortic endothelial cells (BAECs) or endothelial cell lines. These cell populations are accessible and easy to maintain in culture, however, it is well established that endothelial cells display vast heterogeneity depending upon the local microenvironment of the tissue from which they are isolated. Vascular targeting agents have been isolated from a variety of snake venoms, particularly from snakes of the Viperidae family, but it is yet to be established to what extent the venoms from Australian elapids possess similar vascular targeting properties. The present study used endothelial cells (ECs) isolated from the microvasculature of a rat mammary adenocarcinoma to determine the effects of a panel of snake venoms, including viperid venoms with known apoptotic activity and elapid venoms (both exotic and indigenous to Australia), on endothelial morphology and viability, paying specific attention to apoptotic responses. Three of the five Australian snake venoms investigated in this study elicited significant apoptotic responses in ECs which were in many ways similar to responses elicited by the selected viperid venoms. This suggests that these Australian elapids may possess vascular targeting components similar to those found within viperid venoms.Emma Bateman, Michael Venning, Peter Mirtschin and Anthony Wood

How does reviewing the evidence change veterinary surgeons' beliefs regarding the treatment of ovine footrot? A quantitative and qualitative study

Footrot is a widespread, infectious cause of lameness in sheep, with major economic and welfare costs. The aims of this research were: (i) to quantify how veterinary surgeons’ beliefs regarding the efficacy of two treatments for footrot changed following a review of the evidence (ii) to obtain a consensus opinion following group discussions (iii) to capture complementary qualitative data to place their beliefs within a broader clinical context. Grounded in a Bayesian statistical framework, probabilistic elicitation (roulette method) was used to quantify the beliefs of eleven veterinary surgeons during two one-day workshops. There was considerable heterogeneity in veterinary surgeons’ beliefs before they listened to a review of the evidence. After hearing the evidence, seven participants quantifiably changed their beliefs. In particular, two participants who initially believed that foot trimming with topical oxytetracycline was the better treatment, changed to entirely favour systemic and topical oxytetracycline instead. The results suggest that a substantial amount of the variation in beliefs related to differences in veterinary surgeons’ knowledge of the evidence. Although considerable differences in opinion still remained after the evidence review, with several participants having non-overlapping 95% credible intervals, both groups did achieve a consensus opinion. Two key findings from the qualitative data were: (i) veterinary surgeons believed that farmers are unlikely to actively seek advice on lameness, suggesting a proactive veterinary approach is required (ii) more attention could be given to improving the way in which veterinary advice is delivered to farmers. In summary this study has: (i) demonstrated a practical method for probabilistically quantifying how veterinary surgeons’ beliefs change (ii) revealed that the evidence that currently exists is capable of changing veterinary opinion (iii) suggested that improved transfer of research knowledge into veterinary practice is needed (iv) identified some potential obstacles to the implementation of veterinary advice by farmers

A hybrid radiation detector for simultaneous spatial and temporal dosimetry

In this feasibility study an organic plastic scintillator is calibrated against ionisation chamber measurements and then embedded in a polymer gel dosimeter to obtain a quasi-4D experimental measurement of a radiation field. This hybrid dosimeter was irradiated with a linear accelerator, with temporal measurements of the dose rate being acquired by the scintillator and spatial measurements acquired with the gel dosimeter. The detectors employed in this work are radiologically equivalent; and we show that neither detector perturbs the intensity of the radiation field of the other. By employing these detectors in concert, spatial and temporal variations in the radiation intensity can now be detected and gel dosimeters can be calibrated for absolute dose from a single irradiation

A program of nurse algorithm-guided care for adult patients with acute minor illnesses in primary care

Background: Attention to patients with acute minor-illnesses requesting same-day consultation represents a major burden in primary care. The workload is assumed by general practitioners in many countries. A number of reports suggest that care to these patients may be provided, at in least in part, by nurses. However, there is scarce information with respect to the applicability of a program of nurse management for adult patients with acute minor-illnesses in large areas. The aim of this study is to assess the effectiveness of a program of nurse algorithm-guided care for adult patients with acute minor illnesses requesting same-day consultation in primary care in a largely populated area. Methods: A cross-sectional study of all adult patients seeking same day consultation for 16 common acute minor illnesses in a large geographical area with 284 primary care practices. Patients were included in a program of nurse case management using management algorithms. The main outcome measure was case resolution, defined as completion of the algorithm by the nurse without need of referral of the patient to the general practitioner. The secondary outcome measure was return to consultation, defined as requirement of new consultation for the same reason as the first one, in primary care within a 7-day period. Results: During a two year period (April 2009-April 2011), a total of 1,209,669 consultations were performed in the program. Case resolution was achieved by nurses in 62.5% of consultations. The remaining cases were referred to a general practitioner. Resolution rates ranged from 94.2% in patients with burns to 42% in patients with upper respiratory symptoms. None of the 16 minor illnesses had a resolution rate below 40%. Return to consultation during a 7-day period was low, only 4.6%. Conclusions: A program of algorithms-guided care is effective for nurse case management of patients requesting same day consultation for minor illnesses in primary care

Low-Cycle Fatigue of Ultra-Fine-Grained Cryomilled 5083 Aluminum Alloy

The cyclic deformation behavior of cryomilled (CM) AA5083 alloys was compared to that of conventional AA5083-H131. The materials studied were a 100 pct CM alloy with a Gaussian grain size average of 315 nm and an alloy created by mixing 85 pct CM powder with 15 pct unmilled powder before consolidation to fabricate a plate with a bimodal grain size distribution with peak averages at 240 nm and 1.8 μm. Although the ultra-fine-grain (UFG) alloys exhibited considerably higher tensile strengths than those of the conventional material, the results from plastic-strain-controlled low-cycle fatigue tests demonstrate that all three materials exhibit identical fatigue lives across a range of plastic strain amplitudes. The CM materials exhibited softening during the first cycle, similar to other alloys produced by conventional powder metallurgy, followed by continual hardening to saturation before failure. The results reported in this study show that fatigue deformation in the CM material is accompanied by slight grain growth, pinning of dislocations at the grain boundaries, and grain rotation to produce macroscopic slip bands that localize strain, creating a single dominant fatigue crack. In contrast, the conventional alloy exhibits a cell structure and more diffuse fatigue damage accumulation

Global, regional, and national burden of neurological disorders, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016

BACKGROUND:Neurological disorders are increasingly recognised as major causes of death and disability worldwide. The aim of this analysis from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2016 is to provide the most comprehensive and up-to-date estimates of the global, regional, and national burden from neurological disorders. METHODS:We estimated prevalence, incidence, deaths, and disability-adjusted life-years (DALYs; the sum of years of life lost [YLLs] and years lived with disability [YLDs]) by age and sex for 15 neurological disorder categories (tetanus, meningitis, encephalitis, stroke, brain and other CNS cancers, traumatic brain injury, spinal cord injury, Alzheimer's disease and other dementias, Parkinson's disease, multiple sclerosis, motor neuron diseases, idiopathic epilepsy, migraine, tension-type headache, and a residual category for other less common neurological disorders) in 195 countries from 1990 to 2016. DisMod-MR 2.1, a Bayesian meta-regression tool, was the main method of estimation of prevalence and incidence, and the Cause of Death Ensemble model (CODEm) was used for mortality estimation. We quantified the contribution of 84 risks and combinations of risk to the disease estimates for the 15 neurological disorder categories using the GBD comparative risk assessment approach. FINDINGS:Globally, in 2016, neurological disorders were the leading cause of DALYs (276 million [95% UI 247-308]) and second leading cause of deaths (9·0 million [8·8-9·4]). The absolute number of deaths and DALYs from all neurological disorders combined increased (deaths by 39% [34-44] and DALYs by 15% [9-21]) whereas their age-standardised rates decreased (deaths by 28% [26-30] and DALYs by 27% [24-31]) between 1990 and 2016. The only neurological disorders that had a decrease in rates and absolute numbers of deaths and DALYs were tetanus, meningitis, and encephalitis. The four largest contributors of neurological DALYs were stroke (42·2% [38·6-46·1]), migraine (16·3% [11·7-20·8]), Alzheimer's and other dementias (10·4% [9·0-12·1]), and meningitis (7·9% [6·6-10·4]). For the combined neurological disorders, age-standardised DALY rates were significantly higher in males than in females (male-to-female ratio 1·12 [1·05-1·20]), but migraine, multiple sclerosis, and tension-type headache were more common and caused more burden in females, with male-to-female ratios of less than 0·7. The 84 risks quantified in GBD explain less than 10% of neurological disorder DALY burdens, except stroke, for which 88·8% (86·5-90·9) of DALYs are attributable to risk factors, and to a lesser extent Alzheimer's disease and other dementias (22·3% [11·8-35·1] of DALYs are risk attributable) and idiopathic epilepsy (14·1% [10·8-17·5] of DALYs are risk attributable). INTERPRETATION:Globally, the burden of neurological disorders, as measured by the absolute number of DALYs, continues to increase. As populations are growing and ageing, and the prevalence of major disabling neurological disorders steeply increases with age, governments will face increasing demand for treatment, rehabilitation, and support services for neurological disorders. The scarcity of established modifiable risks for most of the neurological burden demonstrates that new knowledge is required to develop effective prevention and treatment strategies. FUNDING:Bill & Melinda Gates Foundation.Valery L Feigin, Emma Nichols, Tahiya Alam ... Bernhard T Baune ... Garumma Tolu Feyissa ... Tiffany K Gill ... Jean Jacques Noubiap ... Andrew T Olagunju ... Engida Yisma ... et al. (GBD 2016 Neurology Collaborators

Rituximab in Combination with Corticosteroids for the Treatment of Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis: A NICE Single Technology Appraisal

As part of its single technology appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer of rituximab (Roche Products) to submit evidence of the clinical and cost effectiveness of rituximab in combination with corticosteroids for treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The School of Health and Related Research Technology Appraisal Group at the University of Sheffield was commissioned to act as the independent Evidence Review Group (ERG). The ERG produced a critical review of the evidence for the clinical and cost effectiveness of the technology, based upon the manufacturer’s submission to NICE. The evidence was derived mainly from a double-blind, phase III, placebo-controlled trial of rituximab in patients with new or relapsed ‘severe’ AAV, which compared a rituximab treatment regimen with an oral cyclophosphamide treatment regimen. Intravenous cyclophosphamide is also commonly used but was not included in the pivotal trial. The evidence showed that rituximab is noninferior to oral cyclophosphamide in terms of induction of remission in adults with AAV and de novo disease, and is superior to oral cyclophosphamide in terms of remission in adults who have relapsed once on cyclophosphamide. The ERG concluded that the results of the manufacturer’s economic evaluation could not be considered robust, because of errors and because the full range of relevant treatment sequences were not modelled. The ERG amended the manufacturer’s model and demonstrated that rituximab was likely to represent a cost-effective addition to the treatment sequence if given after cyclophosphamide treatment