Ethics,data-dependent designs,and the strategy of clinical trials: time to start learning-as-we-go?

The seeds of modern clinical trials were unwittingly sown with the first use of randomization in a 1920s agricultural field experiment. The historical development of trials is briefly reviewed here, as are multifarious pressures and problems faced by those involved with clinical trials today. These challenges include recruitment difficulties, the emerging role of patient support groups, and legal threats over informed consent, to name three. Fundamentally, they reflect an overall shift towards patient-centred, individual ethics. I suggest many problems may be overcome by increased implementation of hitherto neglected, data-dependent designs for clinical trials. Over a dozen arguments against their use are countered, primarily through ethical considerations. Benefits and costs of refining clinical trials strategy are explored hypothetically under enhanced use of such 'learn-as-you-go' designs, in contrast to traditional, equal-allocation, fixed-sample-size and frequentist-based designs. These latter methods mirror crop field trials in which one cannot make scientific progress until after gathering objective data at harvest time. Some attempts to alleviate certain problems, such as Zelen randomization to boost recruitment, or over-reliance on 'large and simple trials' to detect moderate-sized treatment effects, are discussed and found inadequate. A proposal for wider discussion is made to assist the selective introduction of 'small and complex trials,' which could simultaneously expedite medical research, satisfy the concerns of regulators, statisticians, and doctors alike, and help address the growing demands of 21st-century patients.     

UVB Radiation Variably Affects n-3 Fatty Acids but Elevated Temperature Reduces n-3 Fatty Acids in Juvenile Atlantic Salmon (Salmo salar)

Temperature and ultraviolet B radiation (UVB 290–320?nm) are inextricably linked to global climate change. These two variables may act separately, additively, or synergistically on specific aspects of fish biochemistry. We raised Atlantic Salmon (Salmo salar) parr for 54?days in outdoor tanks held at 12 and 19?°C and, at each temperature, we exposed them to three spectral treatments differing in UV radiation intensity. We quantified individual fatty acid (FA) mass fractions in four tissues (dorsal muscle, dorsal and ventral skin, and ocular tissue) at each temperature?×?UV combination. FA composition of dorsal muscle and dorsal and ventral skin was not affected by UV exposure. Mass fractions of 16:0, 18:0, and saturated fatty acids (SFA) were greater in dorsal muscle of warm-reared fish whereas 18:3n-3, 20:2, 20:4n-6, 22:5n-3, 22:6n-3, n-3, n-6, polyunsaturated fatty acids (PUFA), and total FA were significantly higher in cold-reared fish. Mass fractions of most of the FA were greater in the dorsal and ventral skin of warm-reared fish. Cold-reared salmon exposed to enhanced UVB had higher ocular tissue mass fractions of 20:2, 20:4n-6, 22:6n-3, n-3, n-6, and PUFA compared to fish in which UV had been removed. These observations forecast a host of ensuing physiological and ecological responses of juvenile Atlantic Salmon to increasing temperatures and UVB levels in native streams and rivers where they mature before smolting and returning to the sea.     

Use of the 15N natural abundance technique to quantify biological nitrogen fixation by woody perennials

Biological nitrogen fixation (BNF) associated with trees and shrubs plays a major role in the functioning of many ecosystems, from natural woodlands to plantations and agroforestry systems, but it is surprisingly difficult to quantify the amounts of N₂ fixed. Some of the problems involved in measuring N₂ fixation by woody perennials include: (a) diversity in occurrence, and large plant-to-plant variation in growth and nodulation status of N₂-fixing species, especially in natural ecosystems; (b) long-term, perennial nature of growth and the seasonal or year-to-year changes in patterns of N assimilation; and (c) logistical limitations of working with mature trees which are generally impossible to harvest in their entirety. The methodology which holds most promise to quantify the contributions of N₂ fixation to trees is the so-called `¹⁵N natural abundance' technique which exploits naturally occurring differences in ¹⁵N composition between plant-available N sources in the soil and that of atmospheric N₂. In this review we discuss probable explanations for the origin of the small differences in ¹⁵N abundance found in different N pools in both natural and man-made ecosystems and utilise previously published information and unpublished data to examine the potential advantages and limitations inherent in the application of the technique to study N₂ fixation by woody perennials. Calculation of the proportion of the plant N derived from atmospheric N₂ (%Ndfa) using the natural abundance procedure requires that both the ¹⁵N natural abundance of the N derived from BNF and that derived from the soil by the target N₂-fixing species be determined. It is then assumed that the ¹⁵N abundance of the N₂-fixing species reflects the relative contributions of the N derived from these two sources. The ¹⁵N abundance of the N derived from BNF (B) can vary with micro-symbiont, plant species/provenance and growth stage, all of which create considerable difficulties for its precise evaluation. If the%Ndfa is large and the ¹⁵N abundance of the N acquired from other sources is not several ¹⁵N units higher or lower than B, then this can be a major source of error. Further difficulties can arise in determining the ¹⁵N abundance of the N derived from soil (and plant litter, etc.) by the target plant as it is usually impossible to predict which, if any, non-N₂-fixing reference species will obtain N from the same N sources in the same proportions with the same temporal and spatial patterns as the N₂-fixing perennial. The compromise solution is to evaluate the ¹⁵N abundance of a diverse range of neighbouring non-N₂-fixing plants and to compare these values with that of the N₂-fixing species and the estimate of B. Only then can it be determined whether the contribution of BNF to the target species can be quantified with any degree of confidence. This review of the literature suggests that while the natural abundance technique appears to provide quantitative measures of BNF in tree plantation and agroforestry systems, particular difficulties may arise which can often limit its application in natural ecosystems.     

Are staff management practices and inspection risk ratings associated with foodborne disease outbreaks in the catering industry in England and Wales?

Despite structured enforcement of food hygiene requirements known to prevent foodborne disease outbreaks, catering businesses continue to be the most common setting for outbreaks in the United Kingdom. In a matched case control study of catering businesses, 148 businesses associated with outbreaks were compared with 148 control businesses. Hazard analysis critical control point systems and/or formal food hygiene training qualifications were not protective. Food hygiene inspection scores were not useful in predicting which catering businesses were associated with outbreaks. Businesses associated with outbreaks were more likely to be larger small and medium-sized enterprises (SMEs) or to serve Chinese cuisine and less likely to have the owner or manager working in the kitchen, but when size of the SME was taken into account these two differences were no longer significant. In larger businesses, case businesses were more likely to be hotels and were more commonly associated with viral foodborne outbreaks, but there was no explanation within the data for this association.     

Grey water characterisation and its impact on the selection and operation of technologies for urban reuse.

Characterisation of grey water reveals a source water that is similar in organic strength to a low-medium strength municipal sewage influent but with physical and biodegradability characteristics similar to a tertiary treated effluent. The characteristics of the water suggest biological processes are the most suitable unit processes for treating grey water. The highly variable nature of the source requires that selected technologies must be inherently robust in their operation. One potential area of concern is the high COD/BOD ratio and nutrient deficiency in terms of both macro and micro nutrients which grey water exhibits potentially retard the efficacy of biological processes.     

Using Survey Data and Mathematical Modeling to Prioritize Water Interventions in Developing Countries

Water Resources Management - A traditional cost-benefit analysis of potential water interventions in a given locality is a laborious and time-intensive process. To help decision makers identify...     

RRD1, a component of the TORC1 signalling pathway,affects anaesthetic response in Saccharomyces cerevisiae

The molecular mechanisms of action of volatile anaesthetics remain unknown despite clinical use for over 150 years. While many effects of these agents have been characterized, clear insight into how these effects relate to the physiological state of anaesthesia has not been established. Volatile anaesthetics arrest cell division in Saccharomyces cerevisiae in a manner that parallels the anaesthetic actions of these drugs in mammals. To gain additional insight into the cellular activities of these drugs, we isolated genes that, when present on multi‐copy plasmids, render S. cerevisiae resistant to the volatile anaesthetic isoflurane. One of these genes, RRD1, encodes a subunit of the Tap42p–Sit4p–Rrd1p phosphatase complex that functions in the target of rapamycin complex 1 (TORC1) signalling pathway. In addition, we show that mutations in two other genes encoding components of the TORC1 pathway, GLN3 and URE2, also affect yeast anaesthetic response. These findings suggest that TORC1‐mediated signalling is involved in cellular response to volatile anaesthetics in S. cerevisiae. Copyright © 2009 John Wiley & Sons, Ltd.     

Long-term changes in hypolimnetic dissolved oxygen in a large lake: Effects of invasive mussels,eutrophication and climate change on Lake Simcoe, 1980–2012

Lake Simcoe has been influenced by multiple environmental drivers over the past decades, especially by reductions in phosphorus (P) loading, climate change, and invasive species such as dreissenid mussels (DM) which became firmly established in 1996. We examined the cumulative impact of these drivers on the volume-weighted hypolimnetic dissolved oxygen concentration (VWHDO) below 18?m at station K42 in Kempenfelt Bay during ice-free seasons from 1980 to 2012. Hypolimnetic DO depletion began in early spring when thermal stratification was observable but weak and continued throughout the ice-free season until cooling sufficiently lowered water column stability. In comparison to the pre-DM invasion period (1980–1995), mean annual VWHDO_init was 2.4?mg?L^?1 higher in the post-DM period (1996–2012), VWHDO_min was 1.54?mg?L^?1 higher and the mean duration of the depletion period (L) was 16?days longer. Mean DO depletion rate (DR) and temperature adjusted DO depletion rate (DR_adj) were slightly lower (7% and 5%, respectively) after 1996. P controls and DM had a positive effect on VWHDO, presumably by lowering productivity and diverting organic matter away from the hypolimnon. However, longer L apparently offset improvements in VWHDO_min. If lengthening of L associated with regional warming continues, then additional efforts to reduce P loads will be necessary to achieve the goal of maintaining VWHDO_min above the target of 7?mg?O₂?L^?1 throughout the summer and fall.