Centre selection for clinical trials and the generalisability of results: a mixed methods study.

BACKGROUND: The rationale for centre selection in randomised controlled trials (RCTs) is often unclear but may have important implications for the generalisability of trial results. The aims of this study were to evaluate the factors which currently influence centre selection in RCTs and consider how generalisability considerations inform current and optimal practice. METHODS AND FINDINGS: Mixed methods approach consisting of a systematic review and meta-summary of centre selection criteria reported in RCT protocols funded by the UK National Institute of Health Research (NIHR) initiated between January 2005-January 2012; and an online survey on the topic of current and optimal centre selection, distributed to professionals in the 48 UK Clinical Trials Units and 10 NIHR Research Design Services. The survey design was informed by the systematic review and by two focus groups conducted with trialists at the Birmingham Centre for Clinical Trials. 129 trial protocols were included in the systematic review, with a total target sample size in excess of 317,000 participants. The meta-summary identified 53 unique centre selection criteria. 78 protocols (60%) provided at least one criterion for centre selection, but only 31 (24%) protocols explicitly acknowledged generalisability. This is consistent with the survey findings (n = 70), where less than a third of participants reported generalisability as a key driver of centre selection in current practice. This contrasts with trialists' views on optimal practice, where generalisability in terms of clinical practice, population characteristics and economic results were prime considerations for 60% (n = 42), 57% (n = 40) and 46% (n = 32) of respondents, respectively. CONCLUSIONS: Centres are rarely enrolled in RCTs with an explicit view to external validity, although trialists acknowledge that incorporating generalisability in centre selection should ideally be more prominent. There is a need to operationalize 'generalisability' and incorporate it at the design stage of RCTs so that results are readily transferable to 'real world' practice

Strain-controlled criticality governs the nonlinear mechanics of fibre networks

Disordered fibrous networks are ubiquitous in nature as major structural components of living cells and tissues. The mechanical stability of networks generally depends on the degree of connectivity: only when the average number of connections between nodes exceeds the isostatic threshold are networks stable (Maxwell, J. C., Philosophical Magazine 27, 294 (1864)). Upon increasing the connectivity through this point, such networks undergo a mechanical phase transition from a floppy to a rigid phase. However, even sub-isostatic networks become rigid when subjected to sufficiently large deformations. To study this strain-controlled transition, we perform a combination of computational modeling of fibre networks and experiments on networks of type I collagen fibers, which are crucial for the integrity of biological tissues. We show theoretically that the development of rigidity is characterized by a strain-controlled continuous phase transition with signatures of criticality. Our experiments demonstrate mechanical properties consistent with our model, including the predicted critical exponents. We show that the nonlinear mechanics of collagen networks can be quantitatively captured by the predictions of scaling theory for the strain-controlled critical behavior over a wide range of network concentrations and strains up to failure of the material

Blockage of saline intrusions in restricted, two-layer exchange flows across a submerged sill obstruction

The work has been supported by European Community’s Seventh Framework Programme through the grant to the budget of the Integrating Activity HYDRALAB IV within the Transnational Access Activities, Contract No. 261520.Results are presented from a series of large-scale experiments investigating the internal and near-bed dynamics of bi-directional stratified flows with a net-barotropic component across a submerged, trapezoidal, sill obstruction. High-resolution velocity and density profiles are obtained in the vicinity of the obstruction to observe internal-flow dynamics under a range of parametric forcing conditions (i.e. variable saline and fresh water volume fluxes; density differences; sill obstruction submergence depths). Detailed synoptic velocity fields are measured across the sill crest using 2D particle image velocimetry, while the density structure of the two-layer exchange flows is measured using micro-conductivity probes at several sill locations. These measurements are designed to aid qualitative and quantitative interpretation of the internal-flow processes associated with the lower saline intrusion layer blockage conditions, and indicate that the primary mechanism for this blockage is mass exchange from the saline intrusion layer due to significant interfacial mixing and entrainment under dominant, net-barotropic, flow conditions in the upper freshwater layer. This interfacial mixing is quantified by considering both the isopycnal separation of vertically-sorted density profiles across the sill, as well as calculation of corresponding Thorpe overturning length scales. Analysis of the synoptic velocity fields and density profiles also indicates that the net exchange flow conditions remain subcritical (G < 1) across the sill for all parametric conditions tested. An analytical two-layer exchange flow model is then developed to include frictional and entrainment effects, both of which are needed to account for turbulent stresses and saline entrainment into the upper freshwater layer. The experimental results are used to validate two key model parameters: (1) the internal-flow head loss associated with boundary friction and interfacial shear; and (2) the mass exchange from the lower saline layer into the upper fresh layer due to entrainment.Publisher PDFPeer reviewe

Case Fatality Rates Based on Population Estimates of Influenza-Like Illness Due to Novel H1N1 Influenza: New York City, May–June 2009

BACKGROUND: The public health response to pandemic influenza is contingent on the pandemic strain's severity. In late April 2009, a potentially pandemic novel H1N1 influenza strain (nH1N1) was recognized. New York City (NYC) experienced an intensive initial outbreak that peaked in late May, providing the need and opportunity to rapidly quantify the severity of nH1N1. METHODS AND FINDINGS: Telephone surveys using rapid polling methods of approximately 1,000 households each were conducted May 20-27 and June 15-19, 2009. Respondents were asked about the occurrence of influenza-like illness (ILI, fever with either cough or sore throat) for each household member from May 1-27 (survey 1) or the preceding 30 days (survey 2). For the overlap period, prevalence data were combined by weighting the survey-specific contribution based on a Serfling model using data from the NYC syndromic surveillance system. Total and age-specific prevalence of ILI attributed to nH1N1 were estimated using two approaches to adjust for background ILI: discounting by ILI prevalence in less affected NYC boroughs and by ILI measured in syndromic surveillance data from 2004-2008. Deaths, hospitalizations and intensive care unit (ICU) admissions were determined from enhanced surveillance including nH1N1-specific testing. Combined ILI prevalence for the 50-day period was 15.8% (95% CI:13.2%-19.0%). The two methods of adjustment yielded point estimates of nH1N1-associated ILI of 7.8% and 12.2%. Overall case-fatality (CFR) estimates ranged from 0.054-0.086 per 1000 persons with nH1N1-associated ILI and were highest for persons>or=65 years (0.094-0.147 per 1000) and lowest for those 0-17 (0.008-0.012). Hospitalization rates ranged from 0.84-1.34 and ICU admission rates from 0.21-0.34 per 1000, with little variation in either by age-group. CONCLUSIONS: ILI prevalence can be quickly estimated using rapid telephone surveys, using syndromic surveillance data to determine expected "background" ILI proportion. Risk of severe illness due to nH1N1 was similar to seasonal influenza, enabling NYC to emphasize preventing severe morbidity rather than employing aggressive community mitigation measures

The influence of the atmospheric boundary layer on nocturnal layers of noctuids and other moths migrating over southern Britain

Insects migrating at high altitude over southern Britain have been continuously monitored by automatically-operating, vertical-looking radars over a period of several years. During some occasions in the summer months, the migrants were observed to form well-defined layer concentrations, typically at heights of 200-400 m, in the stable night-time atmosphere. Under these conditions, insects are likely to have control over their vertical movements and are selecting flight heights which are favourable for long-range migration. We therefore investigated the factors influencing the formation of these insect layers by comparing radar measurements of the vertical distribution of insect density with meteorological profiles generated by the UK Met. Office’s Unified Model (UM). Radar-derived measurements of mass and displacement speed, along with data from Rothamsted Insect Survey light traps provided information on the identity of the migrants. We present here three case studies where noctuid and pyralid moths contributed substantially to the observed layers. The major meteorological factors influencing the layer concentrations appeared to be: (a) the altitude of the warmest air, (b) heights corresponding to temperature preferences or thresholds for sustained migration and (c), on nights when air temperatures are relatively high, wind-speed maxima associated with the nocturnal jet. Back-trajectories indicated that layer duration may have been determined by the distance to the coast. Overall, the unique combination of meteorological data from the UM and insect data from entomological radar described here show considerable promise for systematic studies of high-altitude insect layering

A pragmatic cluster randomised trial evaluating three implementation interventions

Background Implementation research is concerned with bridging the gap between evidence and practice through the study of methods to promote the uptake of research into routine practice. Good quality evidence has been summarised into guideline recommendations to show that peri-operative fasting times could be considerably shorter than patients currently experience. The objective of this trial was to evaluate the effectiveness of three strategies for the implementation of recommendations about peri-operative fasting. Methods A pragmatic cluster randomised trial underpinned by the PARIHS framework was conducted during 2006 to 2009 with a national sample of UK hospitals using time series with mixed methods process evaluation and cost analysis. Hospitals were randomised to one of three interventions: standard dissemination (SD) of a guideline package, SD plus a web-based resource championed by an opinion leader, and SD plus plan-do-study-act (PDSA). The primary outcome was duration of fluid fast prior to induction of anaesthesia. Secondary outcomes included duration of food fast, patients' experiences, and stakeholders' experiences of implementation, including influences. ANOVA was used to test differences over time and interventions. Results Nineteen acute NHS hospitals participated. Across timepoints, 3,505 duration of fasting observations were recorded. No significant effect of the interventions was observed for either fluid or food fasting times. The effect size was 0.33 for the web-based intervention compared to SD alone for the change in fluid fasting and was 0.12 for PDSA compared to SD alone. The process evaluation showed different types of impact, including changes to practices, policies, and attitudes. A rich picture of the implementation challenges emerged, including inter-professional tensions and a lack of clarity for decision-making authority and responsibility. Conclusions This was a large, complex study and one of the first national randomised controlled trials conducted within acute care in implementation research. The evidence base for fasting practice was accepted by those participating in this study and the messages from it simple; however, implementation and practical challenges influenced the interventions' impact. A set of conditions for implementation emerges from the findings of this study, which are presented as theoretically transferable propositions that have international relevance. Trial registration ISRCTN18046709 - Peri-operative Implementation Study Evaluation (POISE

Interactions among mitochondrial proteins altered in glioblastoma

Mitochondrial dysfunction is putatively central to glioblastoma (GBM) pathophysiology but there has been no systematic analysis in GBM of the proteins which are integral to mitochondrial function. Alterations in proteins in mitochondrial enriched fractions from patients with GBM were defined with label-free liquid chromatography mass spectrometry. 256 mitochondrially-associated proteins were identified in mitochondrial enriched fractions and 117 of these mitochondrial proteins were markedly (fold-change &#8805;2) and significantly altered in GBM (p &#8804; 0.05). Proteins associated with oxidative damage (including catalase, superoxide dismutase 2, peroxiredoxin 1 and peroxiredoxin 4) were increased in GBM. Protein–protein interaction analysis highlighted a reduction in multiple proteins coupled to energy metabolism (in particular respiratory chain proteins, including 23 complex-I proteins). Qualitative ultrastructural analysis in GBM with electron microscopy showed a notably higher prevalence of mitochondria with cristolysis in GBM. This study highlights the complex mitochondrial proteomic adjustments which occur in GBM pathophysiology

Disordered semantic representation in schizophrenic temporal cortex revealed by neuromagnetic response patterns

BACKGROUND: Loosening of associations and thought disruption are key features of schizophrenic psychopathology. Alterations in neural networks underlying this basic abnormality have not yet been sufficiently identified. Previously, we demonstrated that spatio-temporal clustering of magnetic brain responses to pictorial stimuli map categorical representations in temporal cortex. This result has opened the possibility to quantify associative strength within and across semantic categories in schizophrenic patients. We hypothesized that in contrast to controls, schizophrenic patients exhibit disordered representations of semantic categories. METHODS: The spatio-temporal clusters of brain magnetic activities elicited by object pictures related to super-ordinate (flowers, animals, furniture, clothes) and base-level (e.g. tulip, rose, orchid, sunflower) categories were analysed in the source space for the time epochs 170–210 and 210–450 ms following stimulus onset and were compared between 10 schizophrenic patients and 10 control subjects. RESULTS: Spatio-temporal correlations of responses elicited by base-level concepts and the difference of within vs. across super-ordinate categories were distinctly lower in patients than in controls. Additionally, in contrast to the well-defined categorical representation in control subjects, unsupervised clustering indicated poorly defined representation of semantic categories in patients. Within the patient group, distinctiveness of categorical representation in the temporal cortex was positively related to negative symptoms and tended to be inversely related to positive symptoms. CONCLUSION: Schizophrenic patients show a less organized representation of semantic categories in clusters of magnetic brain responses than healthy adults. This atypical neural network architecture may be a correlate of loosening of associations, promoting positive symptoms

Cow's Milk Fat Obesity pRevention Trial (CoMFORT): a primary care embedded randomised controlled trial protocol to determine the effect of cow's milk fat on child adiposity.

INTRODUCTION: Cow's milk is a dietary staple for children in North America. Though clinical guidelines suggest children transition from whole (3.25% fat) milk to reduced (1% or 2%) fat milk at age 2 years, recent epidemiological evidence supports a link between whole milk consumption and lower adiposity in children. The purpose of this trial is to determine which milk fat recommendation minimises excess adiposity and optimises child nutrition and growth. METHODS AND ANALYSIS: Cow's Milk Fat Obesity pRevention Trial will be a pragmatic, superiority, parallel group randomised controlled trial involving children receiving routine healthcare aged 2 to 4-5 years who are participating in the TARGet Kids! practice-based research network in Toronto, Canada. Children (n=534) will be randomised to receive one of two interventions: (1) a recommendation to consume whole milk or (2) a recommendation to consume reduced (1%) fat milk. The primary outcome is adiposity measured by body mass index z-score and waist circumference z-score; secondary outcomes will be cognitive development (using the Ages and Stages Questionnaire), vitamin D stores, cardiometabolic health (glucose, high-sensitivity C-reactive protein, non-high density lipoprotein (non-HDL), low density lipoprotein (LDL), triglyceride, HDL and total cholesterol, insulin and diastolic and systolic blood pressure), sugary beverage and total energy intake (measured by 24 hours dietary recall) and cost effectiveness. Outcomes will be measured 24 months postrandomisation and compared using analysis of covariance (ANCOVA), adjusting for baseline measures. ETHICS AND DISSEMINATION: Ethics approval has been obtained from Unity Health Toronto and The Hospital for Sick Children. Results will be presented locally, nationally and internationally and published in a peer-reviewed journal. The findings may be helpful to nutrition guidelines for children in effort to reduce childhood obesity using a simple, inexpensive and scalable cow's milk fat intervention. TRIAL REGISTRATION NUMBER: NCT03914807; pre-results

Laboratory layered latte

Inducing thermal gradients in fluid systems with initial, well-defined density gradients results in the formation of distinct layered patterns, such as those observed in the ocean due to double-diffusive convection. In contrast, layered composite fluids are sometimes observed in confined systems of rather chaotic initial states, for example, lattes formed by pouring espresso into a glass of warm milk. Here, we report controlled experiments injecting a fluid into a miscible phase and show that, above a critical injection velocity, layering emerges over a time scale of minutes. We identify critical conditions to produce the layering, and relate the results quantitatively to double-diffusive convection. Based on this understanding, we show how to employ this single-step process to produce layered structures in soft materials, where the local elastic properties vary step-wise along the length of the material