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Ethical clinical trial design and differences in treatment effects
Many global clinical trials primarily estimate a single overall treatment effect. However, when treatment effects are likely to differ between populations, for example due to differences in the disease, population characteristics or health-care systems, this approach can lead to misleading conclusions and raise ethical concerns. Justice is compromised when research conducted in low-resourced countries benefits primarily or exclusively populations of wealthier countries. A clinical trial design and analysis that focuses on estimating a single treatment effect, assumed to apply to all participating populations, goes against the ethical principle of justice and the positions of the World Health Assembly. To address this issue, we suggest a methodological strategy based on hierarchical modelling. This approach enables researchers to estimate treatment effects that are valid for each participating population, while potentially retaining efficiency comparable to traditional pooled analysis, as we demonstrate in an example. When substantial between-population differences exist, it produces valid, region-specific results. Strategies such as this one, if adopted into the standards for global trials, would allow regulators, funders and other stakeholders to ensure that trials are designed to help preserve justice for all participant populations.
Journal Article
Aces High
\"It struck in the wake of World War II, a mysterious disease that killed almost 90 percent of those infected. A few of the survivors gained extraordinary powers while others were blighted with severe disabilities. Some of those afflicted chose to use their new abilities to help the human race. But some took a different path. In Aces high, it's the 1980s, but a 1980s both like and unlike our own. Now, after centuries of travel through space, an extraterrestrial being called the Swarm is headed for Earth. Meanwhile, some of the aces given superpowers by the virus are hatching conspiracies to control the human world. These factions are about to collide ... and the fallout could be catastrophic\"--Page 4 of cover.
BOOK
Ethical clinical trial design and differences in treatment effects/ Design ethique d'essais cliniques et differences dans les effets des traitements/ Diseno etico de ensayos clinicos y diferencias en los efectos del tratamiento
Many global clinical trials primarily estimate a single overall treatment effect. However, when treatment effects are likely to differ between populations, for example due to differences in the disease, population characteristics or health-care systems, this approach can lead to misleading conclusions and raise ethical concerns. Justice is compromised when research conducted in low- resourced countries benefits primarily or exclusively populations of wealthier countries. A clinical trial design and analysis that focuses on estimating a single treatment effect, assumed to apply to all participating populations, goes against the ethical principle of justice and the positions of the World Health Assembly. To address this issue, we suggest a methodological strategy based on hierarchical modelling. This approach enables researchers to estimate treatment effects that are valid for each participating population, while potentially retaining efficiency comparable to traditional pooled analysis, as we demonstrate in an example. When substantial between-population differences exist, it produces valid, region-specific results. Strategies such as this one, if adopted into the standards for global trials, would allow regulators, funders and other stakeholders to ensure that trials are designed to help preserve justice for all participant populations.
Journal Article
Trial of Early Minimally Invasive Removal of Intracerebral Hemorrhage
In a trial of minimally invasive cerebral hematoma removal within 24 hours after onset of hemorrhage, functional outcomes were better with surgery than with medical treatment, particularly among patients with lobar hemorrhages.
Journal Article
Effect of propranolol and clonidine after severe traumatic brain injury: a pilot randomized clinical trial
Objective
To evaluate the safety, feasibility, and efficacy of combined adrenergic blockade with propranolol and clonidine in patients with severe traumatic brain injury (TBI).
Background
Administration of adrenergic blockade after severe TBI is common. To date, no prospective trial has rigorously evaluated this common therapy for benefit.
Methods
This phase II, single-center, double-blinded, pilot randomized placebo-controlled trial included patients aged 16–64 years with severe TBI (intracranial hemorrhage and Glasgow Coma Scale score ≤ 8) within 24 h of ICU admission. Patients received propranolol and clonidine or double placebo for 7 days. The primary outcome was ventilator-free days (VFDs) at 28 days. Secondary outcomes included catecholamine levels, hospital length of stay, mortality, and long-term functional status. A planned futility assessment was performed mid-study.
Results
Dose compliance was 99%, blinding was intact, and no open-label agents were used. No treatment patient experienced dysrhythmia, myocardial infarction, or cardiac arrest. The study was stopped for futility after enrolling 47 patients (26 placebo, 21 treatment), per a priori stopping rules. There was no significant difference in VFDs between treatment and control groups [0.3 days, 95% CI (− 5.4, 5.8),
p
= 1.0]. Other than improvement of features related to sympathetic hyperactivity (mean difference in Clinical Features Scale (CFS) 1.7 points, CI (0.4, 2.9),
p
= 0.012), there were no between-group differences in the secondary outcomes.
Conclusion
Despite the safety and feasibility of adrenergic blockade with propranolol and clonidine after severe TBI, the intervention did not alter the VFD outcome. Given the widespread use of these agents in TBI care, a multi-center investigation is warranted to determine whether adrenergic blockade is of therapeutic benefit in patients with severe TBI.
Trial Registration Number
NCT01322048.
Journal Article
CFD–DEM modelling of particle entrainment in wheel–rail interface: a parametric study on particle characteristics
To mitigate and alleviate low wheel–rail adhesion, a train-borne system is utilised to deposit sand particles into the wheel–rail interface via a jet of compressed air in a process called rail-sanding. Britain Rail Safety and Standards Board introduced guidelines on the sand particles’ shape, size, and uniformity which needs to be adhered to for rail-sanding. To further investigate these guidelines and help improve them, this research presents a parametric study on the particle characteristics that affect the rail-sanding process including density, size and size distribution, coefficient of uniformity, and shape, utilising a coupled computational fluid dynamics–discrete element method (CFD–DEM) model. The efficiency of rail-sanding is estimated for each case study and compared to the benchmark to optimise the sand characteristics for rail-sanding. It is concluded that particle size distribution (within the accepted range) has an insignificant effect on the efficiency while increasing particle size or the coefficient of uniformity decreases the efficiency. Particle shape is shown to highly affect the efficiency for flat, compact and elongated particles compared to the spherical shape. The current numerical model is capable of accurately predicting the trends in the efficiency compared to the actual values obtained from full-scale experiments.
Journal Article
Novel Alternative Particle Systems for Managing Friction in the Wheel/Rail Interface
At present, silica sand particles are used on GB railways for traction enhancement. In this study, novel particle systems with a range of properties were assessed to see if there was potential for particles to be more widely used in friction management. The tests were carried out at representative contact pressures, using the High Pressure Torsion (HPT) approach. Particles were applied to dry, wet and leaf-contaminated interfaces. A strong relationship was found between particle hardness and traction. Particle systems were identified that could be used to lubricate the interface (friction < 0.1) or provide intermediate levels of friction (0.2–0.3), and one that could be used for traction enhancement as an alternative to silica sand (increasing friction to above 0.1 with a leaf layer present).
Journal Article
A Spectroscopic DRIFT-FTIR Study on the Friction-Reducing Properties and Bonding of Railway Leaf Layers
Leaves react with rail steel and form a tribofilm, causing very low friction in the wheel/rail interface. This work uses twin-disc tribological testing with the addition of leaf particulates to simulate the reaction and resulting reduction in the friction coefficient in a laboratory setting. Diffuse Reflectance Fourier-Transform Infrared Spectroscopy was carried out on the organic material and the layers that formed on the twin-disc surface. Dark material, visibly similar to leaf layers formed on tracks during autumn, was used along with a transparent thin film. This “non-visible contamination” has been reported to cause low-adhesion problems on railways, but has not previously been characterised. This article discusses the nature of these layers and builds upon earlier studies to propose a degradation and bonding mechanism for the leaf material. This understanding could be used to improve friction management methods employed to deal with low adhesion due to leaves.
Journal Article
Towards a Standard Approach for the Twin Disc Testing of Top-Of Rail Friction Management Products
A wheel/rail friction coefficient that is too low can result in damage to the wheel and rail due to slips and slides, delays and safety concerns. A friction coefficient that is too high can result in excessive wear, noise and rolling contact fatigue. Changing contact and environmental conditions cause variations in wheel/rail friction, so friction management products, applied via wayside or on-board applicators, are used to either increase or decrease the friction coefficient so that an improved level is reached. They can be split into three classes; traction enhancers, lubricants and top-of-rail products (including water-based, oil/grease-based and hybrid products). This paper focuses on top-of-rail products and describes the different apparatus, contact conditions, product application methods and result interpretation that have been used to test these products and highlights the requirement for a more standardised test method. A proposed test method is outlined, which uses a twin disc test rig to collect “effective level of friction” and “retentivity” data to assess product effectiveness. More comparable and standardised data will ensure that maximum benefit is obtained from each set of results and help both product development and the approvals process.
Journal Article