Practicalities in running early-phase trials using the time-to-event continual reassessment method (TiTE-CRM) for interventions with long toxicity periods using two radiotherapy oncology trials as examples

BACKGROUND: Awareness of model-based designs for dose-finding studies such as the Continual Reassessment Method (CRM) is now becoming more commonplace amongst clinicians, statisticians and trial management staff. In some settings toxicities can occur a long time after treatment has finished, resulting in extremely long, interrupted, CRM design trials. The Time-to-Event CRM (TiTE-CRM), a modification to the original CRM, accounts for the timing of late-onset toxicities and results in shorter trial duration. In this article, we discuss how to design and deliver a trial using this method, from the grant application stage through to dissemination, using two radiotherapy trials as examples. METHODS: The TiTE-CRM encapsulates the dose-toxicity relationship with a statistical model. The model incorporates observed toxicities and uses a weight to account for the proportion of completed follow-up of participants without toxicity. This model uses all available data to determine the next participant's dose and subsequently declare the maximum tolerated dose. We focus on two trials designed by the authors to illustrate practical issues when designing, setting up, and running such studies. RESULTS: In setting up a TiTE-CRM trial, model parameters need to be defined and the time element involved might cause complications, therefore looking at operating characteristics through simulations is essential. At the grant application stage, we suggest resources to fund statisticians' time before funding is awarded and make recommendations for the level of detail to include in funding applications. While running the trial, close contact of all involved staff is required as a dose decision is made each time a participant is recruited. We suggest ways of capturing data in a timely manner and give example code in R for design and delivery of the trial. Finally, we touch upon dissemination issues while the trial is running and upon completion. CONCLUSION: Model-based designs can be complex. We hope this paper will help clinical trial teams to demystify the conduct of TiTE-CRM trials and be a starting point for using this methodology in practice

Genetic homogenisation of two major orchid viruses through global trade‐based dispersal of their hosts

Orchid viruses are capable of causing flower deformities and death, which can se‐ verely impact the horticultural industry and wild orchid conservation. Here we show how two of these quickly evolving viruses display few genetic differences since their first emergence, across countries and host plants. This is concerning as, despite bios‐ ecurity regulations to control the movement of orchids and their related pathogens, these patterns are suggestive of rapid and regular international movement of horti‐ cultural material. Poor biosecurity practices could threaten the orchid horticultural industry and result in the accidental translocation or reintroduction of infected plant material intended to recover wild populations

Recent Shift in Climate Relationship Enables Prediction of the Timing of Bird Breeding

Large-scale climate processes influence many aspects of ecology including breeding phenology, reproductive success and survival across a wide range of taxa. Some effects are direct, for example, in temperate-zone birds, ambient temperature is an important cue enabling breeding effort to coincide with maximum food availability, and earlier breeding in response to warmer springs has been documented in many species. In other cases, time-lags of up to several years in ecological responses have been reported, with effects mediated through biotic mechanisms such as growth rates or abundance of food supplies. Here we use 23 years of data for a temperate woodland bird species, the great tit (Parus major), breeding in deciduous woodland in eastern England to demonstrate a time-lagged linear relationship between the on-set of egg laying and the winter index of the North Atlantic Oscillation such that timing can be predicted from the winter index for the previous year. Thus the timing of bird breeding (and, by inference, the timing of spring events in general) can be predicted one year in advance. We also show that the relationship with the winter index appears to arise through an abiotic time-lag with local spring warmth in our study area. Examining this link between local conditions and larger-scale processes in the longer-term showed that, in the past, significant relationships with the immediately preceding winter index were more common than those with the time-lagged index, and especially so from the late 1930s to the early 1970s. However, from the mid 1970s onwards, the time-lagged relationship has become the most significant, suggesting a recent change in climate patterns. The strength of the current time-lagged relationship suggests that it might have relevance for other temperature-dependent ecological relationships

A new model for the characterization of infection risk in gunshot injuries:Technology, principal consideration and clinical implementation

<p>Abstract</p> <p>Introduction</p> <p>The extent of wound contamination in gunshot injuries is still a topic of controversial debate. The purpose of the present study is to develop a model that illustrates the contamination of wounds with exogenous particles along the bullet path.</p> <p>Material and methods</p> <p>To simulate bacteria, radio-opaque barium titanate (3-6 μm in diameter) was atomized in a dust chamber. Full metal jacket or soft point bullets caliber .222 (n = 12, v₀= 1096 m/s) were fired through the chamber into a gelatin block directly behind it. After that, the gelatin block underwent multi-slice CT in order to analyze the permanent and temporary wound cavity.</p> <p>Results</p> <p>The permanent cavity caused by both types of projectiles showed deposits of barium titanate distributed over the entire bullet path. Full metal jacket bullets left only few traces of barium titanate in the temporary cavity. In contrast, the soft point bullets disintegrated completely, and barium titanate covered the entire wound cavity.</p> <p>Discussion</p> <p>Deep penetration of potential exogenous bacteria can be simulated easily and reproducibly with barium titanate particles shot into a gelatin block. Additionally, this procedure permits conclusions to be drawn about the distribution of possible contaminants and thus can yield essential findings in terms of necessary therapeutic procedures.</p

A review of the trade in orchids and its implications for conservation

Orchids are one of the largest plant families and are commercially traded for a variety of purposes, including as ornamental plants, medicinal products and food. These markets involve thousands of species, which may be traded legally or illegally, sustainably or unsustainably, and take place at local, national or international scales. In this review, we provide the first overview of commercial orchid trade globally and highlight the main types that involve wild-collected plants. Much of this trade is the result of illegal harvest meaning that it is little documented and is absent from official statistics, at the same time as being of growing conservation concern. We discuss the associated legal–regulatory context, identify key conservation challenges and highlight four key priorities for addressing these challenges. These are to (1) research trade dynamics and the impacts of harvest; (2) strengthen the legal trade of orchids; (3) adopt measures to reduce illegal trade; and (4) raise the profile of orchid trade among policy makers, conservationists and the public

Interpopulation Variation in Contour Feather Structure Is Environmentally Determined in Great Tits

Background: The plumage of birds is important for flying, insulation and social communication. Contour feathers cover most of the avian body and among other functions they provide a critical insulation layer against heat loss. Feather structure and composition are known to vary among individuals, which in turn determines variation in the insulation properties of the feather. However, the extent and the proximate mechanisms underlying this variation remain unexplored. Methodology/Principal Findings: We analyzed contour feather structure from two different great tit populations adapted to different winter regimes, one northern population in Oulu (Finland) and one southern population in Lund (Sweden). Great tits from the two populations differed significantly in feather structure. Birds from the northern population had a denser plumage but consisting of shorter feathers with a smaller proportion containing plumulaceous barbs, compared with conspecifics from the southern population. However, differences disappeared when birds originating from the two populations were raised and moulted in identical conditions in a common-garden experiment located in Oulu, under ad libitum nutritional conditions. All birds raised in the aviaries, including adult foster parents moulting in the same captive conditions, developed a similar feather structure. These feathers were different from that of wild birds in Oulu but similar to wild birds in Lund, the latter moulting in more benign conditions than those of Oulu. Conclusions/Significance: Wild populations exposed to different conditions develop contour feather differences either due to plastic responses or constraints. Environmental conditions, such as nutrient availability during feather growth play a crucial role in determining such differences in plumage structure among populations

Biodiversity modelling in practice - predicting bird and woody plant species richness on farmlands

In light of decreasing species richness on farmland and an increasing awareness of biodiversity issues among customers and food companies, concepts and models to evaluate and enhance farmland biodiversity are greatly needed. It is important that the models are easy to apply as they have to be utilized by practitioners such as farmers and their consultants. In this study, simple but valid predictors were identified to rapidly assess the species richness of birds and woody plants in hedgerows, an important farmland landscape element. Hedgerows were sampled in seven agricultural landscapes throughout Germany. By means of automatic model selection procedures, linear regression models were estimated to predict bird and woody plant species richness. Cross validation procedures were carried out in order to visualize model selection uncertainty and estimate the prediction error. Due to a rather high prediction error, the model for plants can only be recommended for use when field work is not feasible. The model for birds, however, explained 70.8% of the variance in species numbers. It may help farmers, food companies and nature conservation agencies to rapidly evaluate bird species richness in hedgerows on farmland and to identify potentials and appropriate measures for enhancing it

Ecological assessment of an intermitent Mediterranean river using community structure and function: evaluating the role of different organism groups

1. Reliable lotic ecological monitoring requires knowledge of river typology, environmental factors, the effect of stressors known here as ‘pressures’ and appropriate indicators of anthropogenically induced change. We sampled benthic macroinvertebrate, fish, bird and macrophyte communities along an intermittent Mediterranean river and analysed community structure (relative abundance) and function (metrics) relative to environmental and pressure gradients in order to identify suitable indicator group(s) for future monitoring and mitigation programmes. 2. Principal components analysis revealed that scale-dependent longitudinal differences in valley form separated narrower higher lying sites and tributaries with good quality habitats from more open degraded sites lower down the river continuum on a small floodplain and large scale pressures describing changes in land use related to agriculture with associated physical bankside and channel impacts. 3. Forward selection of variables in redundancy analysis (RDA) showed that reach scale environmental variables were selected more frequently than pressure variables for each organism group. Altitude and pH were highly redundant within and between groups, indicating essentially longitudinal structural and functional distribution patterns. Redundancy was far lower between selected pressure variables, but single or no pressure variables were retained for some organism groups indicating poor association of functional data, in particular, with the identified pressures. All RDA results indicated a longitudinal pH gradient, highlighting the combined effect of multiple environmental and pressure based mechanisms on organism groups. 4. Large, mobile organisms such as fish and birds provided a reliable link between organism structure and function, environmental factors and physical disturbance of the channel, bankside and wider river corridor. Benthic macroinvertebrate and macrophyte structural data revealed distribution patterns in relation to water velocity, a key parameter for developing appropriate compensation measures. 5. Results clearly show the importance of assessing patterns of both functional and structural change across multiple organism groups in order to identify typologically appropriate links with complex environmental and pressure gradients and develop and implement appropriate monitoring system

Bird populations most exposed to climate change are less sensitive to climatic variation

The phenology of many species shows strong sensitivity to climate change; however, with few large scale intra-specific studies it is unclear how such sensitivity varies over a species' range. We document large intra-specific variation in phenological sensitivity to temperature using laying date information from 67 populations of two co-familial European songbirds, the great tit (Parus major) and blue tit (Cyanistes caeruleus), covering a large part of their breeding range. Populations inhabiting deciduous habitats showed stronger phenological sensitivity than those in evergreen and mixed habitats. However, populations with higher sensitivity tended to have experienced less rapid change in climate over the past decades, such that populations with high phenological sensitivity will not necessarily exhibit the strongest phenological advancement. Our results show that to effectively assess the impact of climate change on phenology across a species' range it will be necessary to account for intra-specific variation in phenological sensitivity, climate change exposure, and the ecological characteristics of a population. Intra-specific variations may contribute to heterogeneous responses to climate change across a species' range. Here, the authors investigate the phenology of two bird species across their breeding ranges, and find that their sensitivity to temperature is uncoupled from exposure to climate change.Peer reviewe

Concentration or representation : the struggle for popular sovereignty

There is a tension in the notion of popular sovereignty, and the notion of democracy associated with it, that is both older than our terms for these notions themselves and more fundamental than the apparently consensual way we tend to use them today. After a review of the competing conceptions of 'the people' that underlie two very different understandings of democracy, this article will defend what might be called a 'neo-Jacobin' commitment to popular sovereignty, understood as the formulation and imposition of a shared political will. A people's egalitarian capacity to concentrate both its collective intelligence and force, from this perspective, takes priority over concerns about how best to represent the full variety of positions and interests that differentiate and divide a community