Using Clinical Trial Simulators to Analyse the Sources of Variance in Clinical Trials of Novel Therapies for Acute Viral Infections.

BACKGROUND:About 90% of drugs fail in clinical development. The question is whether trials fail because of insufficient efficacy of the new treatment, or rather because of poor trial design that is unable to detect the true efficacy. The variance of the measured endpoints is a major, largely underestimated source of uncertainty in clinical trial design, particularly in acute viral infections. We use a clinical trial simulator to demonstrate how a thorough consideration of the variability inherent in clinical trials of novel therapies for acute viral infections can improve trial design. METHODS AND FINDINGS:We developed a clinical trial simulator to analyse the impact of three different types of variation on the outcome of a challenge study of influenza treatments for infected patients, including individual patient variability in the response to the drug, the variance of the measurement procedure, and the variance of the lower limit of quantification of endpoint measurements. In addition, we investigated the impact of protocol variation on clinical trial outcome. We found that the greatest source of variance was inter-individual variability in the natural course of infection. Running a larger phase II study can save up to $38 million, if an unlikely to succeed phase III trial is avoided. In addition, low-sensitivity viral load assays can lead to falsely negative trial outcomes. CONCLUSIONS:Due to high inter-individual variability in natural infection, the most important variable in clinical trial design for challenge studies of potential novel influenza treatments is the number of participants. 100 participants are preferable over 50. Using more sensitive viral load assays increases the probability of a positive trial outcome, but may in some circumstances lead to false positive outcomes. Clinical trial simulations are powerful tools to identify the most important sources of variance in clinical trials and thereby help improve trial design

Microfluidic multi-input reactor for biocatalytic synthesis using transketolase

Biocatalytic synthesis in continuous-flow microreactors is of increasing interest for the production of specialty chemicals. However, the yield of production achievable in these reactors can be limited by the adverse effects of high substrate concentration on the biocatalyst, including inhibition and denaturation. Fed-batch reactors have been developed in order to overcome this problem, but no continuous-flow solution exists. We present the design of a novel multi-input microfluidic reactor, capable of substrate feeding at multiple points, as a first step towards overcoming these problems in a continuous-flow setting. Using the transketolase-(TK) catalysed reaction of lithium hydroxypyruvate (HPA) and glycolaldehyde (GA) to l-erythrulose (ERY), we demonstrate the transposition of a fed-batch substrate feeding strategy to our microfluidic reactor. We obtained a 4.5-fold increase in output concentration and a 5-fold increase in throughput compared with a single input reactor

Captive reptile mortality rates in the home and implications for the wildlife trade

The trade in wildlife and keeping of exotic pets is subject to varying levels of national and international regulation and is a topic often attracting controversy. Reptiles are popular exotic pets and comprise a substantial component of the live animal trade. High mortality of traded animals raises welfare concerns, and also has implications for conservation if collection from the wild is required to meet demand. Mortality of reptiles can occur at any stage of the trade chain from collector to consumer. However, there is limited information on mortality rates of reptiles across trade chains, particularly amongst final consumers in the home. We investigated mortality rates of reptiles amongst consumers using a specialised technique for asking sensitive questions, additive Randomised Response Technique (aRRT), as well as direct questioning (DQ). Overall, 3.6% of snakes, chelonians and lizards died within one year of acquisition. Boas and pythons had the lowest reported mortality rates of 1.9% and chameleons had the highest at 28.2%. More than 97% of snakes, 87% of lizards and 69% of chelonians acquired by respondents over five years were reported to be captive bred and results suggest that mortality rates may be lowest for captive bred individuals. Estimates of mortality from aRRT and DQ did not differ significantly which is in line with our findings that respondents did not find questions about reptile mortality to be sensitive. This research suggests that captive reptile mortality in the home is rather low, and identifies those taxa where further effort could be made to reduce mortality rate

Bacterial microevolution and the Pangenome

The comparison of multiple genome sequences sampled from a bacterial population reveals considerable diversity in both the core and the accessory parts of the pangenome. This diversity can be analysed in terms of microevolutionary events that took place since the genomes shared a common ancestor, especially deletion, duplication, and recombination. We review the basic modelling ingredients used implicitly or explicitly when performing such a pangenome analysis. In particular, we describe a basic neutral phylogenetic framework of bacterial pangenome microevolution, which is not incompatible with evaluating the role of natural selection. We survey the different ways in which pangenome data is summarised in order to be included in microevolutionary models, as well as the main methodological approaches that have been proposed to reconstruct pangenome microevolutionary history

A randomised controlled trial of inhibitory control training for smoking cessation: Outcomes, mediators and methodological considerations.

This is the final version. Available from Frontiers Media via the DOI in this record. The datasets presented in this article are not readily available because the authors do not have ethics approval to make the dataset public. Requests to access the datasets should be directed to PS, [email protected]: Inhibitory control training (ICT) has shown promise for improving health behaviours, however, less is known about its mediators of effectiveness. The current paper reports whether ICT reduces smoking-related outcomes such as craving and nicotine dependence, increases motivation to quit and whether reductions in smoking or craving are mediated by response inhibition or a devaluation of smoking stimuli. Method: Adult smokers (minimum 10 cigarettes per day; N = 107, M age = 46.15 years, 57 female) were randomly allocated to receive 14 days of smoking-specific ICT (named INST; a go/no-go task where participants were trained to not respond to smoking stimuli) or active control training (participants inhibited responding toward neutral stimuli). Participants were followed up to 3-months post-intervention. This trial was preregistered (Australian and New Zealand Clinical Trials Registry ID: ACTRN12617000252314; URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=370204). Results: There were no significant differences between ICT and active control training groups. Specifically, participants in both groups showed significant reductions in craving, nicotine dependence, motivation and a devaluation (reduced evaluation) of smoking-stimuli up to 3-months follow-up compared to baseline. Inhibition and devaluation of smoking stimuli did not act as mediators. Devaluation of smoking stimuli was an independent predictor of smoking and craving at follow-up. Conclusion: Inhibitory control training (ICT) was no more effective at reducing smoking-related outcomes compared to the active control group, however, significant improvements in craving, dependence indicators and evaluation of smoking stimuli were observed across both groups. A return to basic experimental research may be required to understand the most effective ICT approach to support smoking cessation.Deakin Universit

Role of CED-4 in the activation of CED-3

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62523/1/388728a0.pd

Spatial and temporal scales of coral reef fish ecological research and management: a systematic map protocol

This is the final version. Available on open access from BMC via the DOI in this recordBackground Coral reefs are rapidly changing in response to local and global stressors. Research to better understand and inform the management of these stressors is burgeoning. However, in situ studies of coral reef ecology are constrained by complex logistics and limited resources. Many reef studies are also hampered by the scale-dependent nature of ecological patterns, and inferences made on causal relationships within coral reef systems are limited by the scales of observation. This is because most socio-ecological studies are conducted at scales relevant to the phenomenon of interest. However, management often occurs across a significantly broader, often geopolitical, range of scales. While there is a critical need for incisive coral reef management actions at relevant spatial and temporal scales, it remains unclear to what extent the scales of empirical study overlap with the scales at which management inferences and recommendations are made. This systematic map protocol will evaluate this potential scale mismatch with the goal of raising awareness about the significance of effectively addressing and reporting the scales at which researchers collect data and make assumptions. Methods We will use the Collaboration for Environmental Evidence (CEE) systematic mapping guidelines to identify relevant studies using a framework-based synthesis to summarise the spatial and temporal scales of coral reef fish ecology research and the scales at which management inferences or recommendations are made. Using tested predefined terms, we will search for relevant published academic and grey literature, including bibliographic databases, web-based search engines, and organisational websites. Inclusion criteria for the evidence map are empirical studies that focus on coral reef fish ecological organisation and processes, those informing management interventions and policy decisions, and management documents that cite coral reef research for management decision-making. Study results will be displayed graphically using data matrices and heat maps. This is the first attempt to systematically assess and compare the scales of socio-ecological research conducted on coral reef systems with their management.NOAA Coral Reef Conservation Progra

Very Cold Gas and Dark Matter

We have recently proposed a new candidate for baryonic dark matter: very cold molecular gas, in near-isothermal equilibrium with the cosmic background radiation at 2.73 K. The cold gas, of quasi-primordial abundances, is condensed in a fractal structure, resembling the hierarchical structure of the detected interstellar medium. We present some perspectives of detecting this very cold gas, either directly or indirectly. The H$_2$ molecule has an "ultrafine" structure, due to the interaction between the rotation-induced magnetic moment and the nuclear spins. But the lines fall in the km domain, and are very weak. The best opportunity might be the UV absorption of H$_2$ in front of quasars. The unexpected cold dust component, revealed by the COBE/FIRAS submillimetric results, could also be due to this very cold H$_2$ gas, through collision-induced radiation, or solid H$_2$ grains or snowflakes. The $\gamma$-ray distribution, much more radially extended than the supernovae at the origin of cosmic rays acceleration, also points towards and extended gas distribution.Comment: 16 pages, Latex pages, crckapb macro, 3 postscript figures, uuencoded compressed tar file. To be published in the proceeedings of the "Dust-Morphology" conference, Johannesburg, 22-26 January, 1996, D. Block (ed.), (Kluwer Dordrecht

Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options

Mast cell activation disease comprises disorders characterized by accumulation of genetically altered mast cells and/or abnormal release of these cells' mediators, affecting functions in potentially every organ system, often without causing abnormalities in routine laboratory or radiologic testing. In most cases of mast cell activation disease, diagnosis is possible by relatively non-invasive investigation. Effective therapy often consists simply of antihistamines and mast cell membrane-stabilising compounds supplemented with medications targeted at specific symptoms and complications. Mast cell activation disease is now appreciated to likely be considerably prevalent and thus should be considered routinely in the differential diagnosis of patients with chronic multisystem polymorbidity or patients in whom a definitively diagnosed major illness does not well account for the entirety of the patient's presentation