Cisplatin-induced emesis: systematic review and meta-analysis of the ferret model and the effects of 5-HT3 receptor antagonists

PURPOSE: The ferret cisplatin emesis model has been used for ~30 years and enabled identification of clinically used anti-emetics. We provide an objective assessment of this model including efficacy of 5-HT(3) receptor antagonists to assess its translational validity. METHODS: A systematic review identified available evidence and was used to perform meta-analyses. RESULTS: Of 182 potentially relevant publications, 115 reported cisplatin-induced emesis in ferrets and 68 were included in the analysis. The majority (n = 53) used a 10 mg kg(−1) dose to induce acute emesis, which peaked after 2 h. More recent studies (n = 11) also used 5 mg kg(−1), which induced a biphasic response peaking at 12 h and 48 h. Overall, 5-HT(3) receptor antagonists reduced cisplatin (5 mg kg(−1)) emesis by 68% (45–91%) during the acute phase (day 1) and by 67% (48–86%) and 53% (38–68%, all P < 0.001), during the delayed phase (days 2, 3). In an analysis focused on the acute phase, the efficacy of ondansetron was dependent on the dosage and observation period but not on the dose of cisplatin. CONCLUSION: Our analysis enabled novel findings to be extracted from the literature including factors which may impact on the applicability of preclinical results to humans. It reveals that the efficacy of ondansetron is similar against low and high doses of cisplatin. Additionally, we showed that 5-HT(3) receptor antagonists have a similar efficacy during acute and delayed emesis, which provides a novel insight into the pharmacology of delayed emesis in the ferret

Pulmonary Dysfunction in Patients with Femoral Shaft Fracture Treated with Intramedullary Nailing

Background: This study was undertaken to determine whether alveolar dead space increases during intramedullary nailing of femoral shaft fractures and whether alveolar dead space predicts postoperative pulmonary dysfunction in patients undergoing intramedullary nailing of a femoral shaft fracture. Methods: All patients with a femoral shaft fracture were prospectively enrolled in the study unless there was evidence of acute myocardial infarction, shock, or heart failure. Arterial blood gases were measured at three consecutive time-periods after induction of general anesthesia: before intramedullary nailing and ten and thirty minutes after intramedullary nailing. The end-tidal carbon-dioxide level, minute ventilation, positive end‐expiratory pressure, and percent of inspired and expired inhalation agent were recorded simultaneously with the blood-gas measurement. Postoperatively, all subjects were monitored for evidence of pulmonary dysfunction, defined as the need for mechanical ventilation or supplemental oxygen (at a fraction of inspired oxygen of >40%) in the presence of clinical signs of a respiratory rate of >20 breaths/min or the use of accessory muscles of respiration. Results: Seventy‐four patients with a total of eighty femoral shaft fractures completed the study. Fifty fractures (62.5%) underwent nailing after reaming, and thirty fractures (37.5%) underwent nailing with minimal or no reaming. The mean alveolar dead-space measurements before canal opening and at ten and thirty minutes after canal opening were 14.5%, 15.8%, and 15.2% in the total series of seventy‐four patients (general linear model, p = 0.2) and 20.5%, 22.7%, and 24.2% in the twenty patients with postoperative pulmonary dysfunction (general linear model, p = 0.05). Of the twenty‐one patients with an alveolar dead-space measurement of >20% thirty minutes after nailing, sixteen had postoperative pulmonary dysfunction. According to univariate and multivariate analysis, the alveolar dead-space measurement was strongly associated with postoperative pulmonary dysfunction. Conclusions: According to our data, intramedullary nailing of femoral shaft fractures did not significantly increase alveolar dead space, and the amount of alveolar dead space can predict which patients will have pulmonary dysfunction postoperatively

Dynamic of a non homogeneously coarse grained system

To study materials phenomena simultaneously at various length scales, descriptions in which matter can be coarse grained to arbitrary levels, are necessary. Attempts to do this in the static regime (i.e. zero temperature) have already been developed. In this letter, we present an approach that leads to a dynamics for such coarse-grained models. This allows us to obtain temperature-dependent and transport properties. Renormalization group theory is used to create new local potentials model between nodes, within the approximation of local thermodynamical equilibrium. Assuming that these potentials give an averaged description of node dynamics, we calculate thermal and mechanical properties. If this method can be sufficiently generalized it may form the basis of a Molecular Dynamics method with time and spatial coarse-graining.Comment: 4 pages, 4 figure

An evaluation of metal removal during wastewater treatment: The potential to achieve more stringent final effluent standards

This is the author's accepted manuscript. The final published article is available from the link below. Copyright @ 2011 Taylor & Francis.Metals are of particular importance in relation to water quality, and concern regarding the impact of these contaminants on biodiversity is being encapsulated within the latest water-related legislation such as the Water Framework Directive in Europe and criteria revisions to the Clean Water Act in the United States. This review undertakes an evaluation of the potential of 2-stage wastewater treatment consisting of primary sedimentation and biological treatment in the form of activated sludge processes, to meet more stringent discharge consents that are likely to be introduced as a consequence. The legislation, sources of metals, and mechanisms responsible for their removal are discussed, to elucidate possible pathways by which the performance of conventional processes may be optimized or enhanced. Improvements in effluent quality, achievable by reducing concentrations of suspended solids or biochemical oxygen demand, may also reduce metal concentrations although meeting possible requirements for the removal of copper my be challenging

Teaching for implementation: A framework for building implementation research and practice capacity within the translational science workforce

Implementation science offers a compelling value proposition to translational science. As such, many translational science stakeholders are seeking to recruit, teach, and train an implementation science workforce. The type of workforce that will make implementation happen consists of both implementation researchers and practitioners, yet little guidance exists on how to train such a workforce. We-members of the Advancing Dissemination and Implementation Sciences in CTSAs Working Group-present the Teaching For Implementation Framework to address this gap. We describe the differences between implementation researchers and practitioners and demonstrate what and how to teach them individually and in co-learning opportunities. We briefly comment on educational infrastructures and resources that will be helpful in furthering this type of approach

Atoms in the Surf: Molecular Dynamics Simulation of the Kelvin-Helmholtz Instability using 9 Billion Atoms

We present a fluid dynamics video showing the results of a 9-billion atom molecular dynamics simulation of complex fluid flow in molten copper and aluminum. Starting with an atomically flat interface, a shear is imposed along the copper-aluminum interface and random atomic fluctuations seed the formation of vortices. These vortices grow due to the Kelvin-Helmholtz instability. The resulting vortical structures are beautifully intricate, decorated with secondary instabilities and complex mixing phenomena. This work performed under the auspices of the U.S. Department of Energy by Lawrence Livermore National Laboratory under Contract DE-AC52-07NA27344.Comment: Description of video submitted to APS DFD Gallery of Fluid Motion 200

Changing climate risk in the UK: a multi-sectoral analysis using policy-relevant indicators

This paper presents a consistent series of policy-relevant indicators of changing climate hazards and resources for the UK, spanning the health, transport, energy, agriculture, flood and water sectors and based on UKCP18 climate projections. In the absence of explicit adaptation, risks will increase across the whole of the UK, but at different rates and from different starting values in different regions. The likelihood of heat extremes affecting health, the road and rail network and crop growth will increase very markedly. Agricultural and hydrological drought risks increase across the UK, as does wildfire danger. River flood risk increases particularly in the north and west. Demand for cooling energy will increase, but demand for heating energy will decline. Crop growing degree days will increase, benefiting the production of perennial crops. In general, the risks associated with high temperature extremes will increase the most in warmer southern and eastern England, but the rate of increase from a lower base may be greater further north and west. Reducing emissions reduces risks in the long term but has little effect over the next two or three decades. The results provide evidence to support the development of national and local climate and resilience policy. Measures to enhance resilience are needed alongside policies to achieve net zero emissions by 2050. Resilience policy should recognise the variability in change in risk across the UK, and therefore different local priorities. Explicit choices need to be made about ‘worst case’ emissions scenarios as they can influence strongly estimated changes in risk: the increase in risk with RCP8.5 can be considerably higher than with a pathway reaching 4 ◦C by 2100

Utility of Atherosclerosis Imaging in the Evaluation of High-Density Lipoprotein–Raising Therapies

Decreased level of high density-lipoprotein cholesterol (HDL-C) is a rigorous predictor for future cardiovascular events. Much effort is being made to develop HDL-C–raising pharmacotherapies in the attempt to avert the pandemic of atherosclerotic disease. Important properties by which HDL-C–raising compounds are effective involve improvement of cholesterol uptake from macrophages in plaque for transport back to the liver, improvement of endothelial function, and anti-inflammatory effects. Vascular imaging can aid in the determination which HDL-C–raising compounds are effective. Ultrasound and MRI have proved suitable for assessment of structural changes of the vessel wall. Ultrasound can also be used or assessment of endothelial function. 18F-fluordeoxyglucose positron emission tomography has opened up the possibility to assess vessel wall inflammation. In this article we discuss these various imaging techniques and how they can assess efficacy as well as provide pathophysiologic information on the mechanism of action of novel HDL-C–raising drugs