The use of a bayesian hierarchy to develop and validate a co-morbidity score to predict mortality for linked primary and secondary care data from the NHS in England

Background: We have assessed whether the linkage between routine primary and secondary care records provided an opportunity to develop an improved population based co-morbidity score with the combined information on co-morbidities from both health care settings. Methods: We extracted all people older than 20 years at the start of 2005 within the linkage between the Hospital Episodes Statistics, Clinical Practice Research Datalink, and Office for National Statistics death register in England. A random 50% sample was used to identify relevant diagnostic codes using a Bayesian hierarchy to share information between similar Read and ICD 10 code groupings. Internal validation of the score was performed in the remaining 50% and discrimination was assessed using Harrell’s C statistic. Comparisons were made over time, age, and consultation rate with the Charlson and Elixhauser indexes. Results: 657,264 people were followed up from the 1st January 2005. 98 groupings of codes were derived from the Bayesian hierarchy, and 37 had an adjusted weighting of greater than zero in the Cox proportional hazards model. 11 of these groupings had a different weighting dependent on whether they were coded from hospital or primary care. The C statistic reduced from 0.88 (95% confidence interval 0.88–0.88) in the first year of follow up, to 0.85 (0.85–0.85) including all 5 years. When we stratified the linked score by consultation rate the association with mortality remained consistent, but there was a significant interaction with age, with improved discrimination and fit in those under 50 years old (C=0.85, 0.83–0.87) compared to the Charlson (C=0.79, 0.77–0.82) or Elixhauser index (C=0.81, 0.79–0.83). Conclusions: The use of linked population based primary and secondary care data developed a co-morbidity score that had improved discrimination, particularly in younger age groups, and had a greater effect when adjusting for co-morbidity than existing scores

Fluctuation relations in non-equilibrium stationary states of Ising models

Fluctuation relations for the entropy production in non equilibrium stationary states of Ising models are investigated by Monte Carlo simulations. Systems in contact with heat baths at two different temperatures or subject to external driving will be studied. In the first case, by considering different kinetic rules and couplings with the baths, the behavior of the probability distributions of the heat exchanged in a time $\tau$ with the thermostats, both in the disordered and in the low temperature phase, are discussed. The fluctuation relation is always verified in the large $\tau$ limit and deviations from linear response theory are observed. Finite-$\tau$ corrections are shown to obey a scaling behavior. In the other case the system is in contact with a single heat bath but work is done by shearing it. Also for this system the statistics collected for the mechanical work shows the validity of the fluctuation relation and preasymptotic corrections behave analogously to the case with two baths.Comment: 9 figure

KNOTTIN: the knottin or inhibitor cystine knot scaffold in 2007

The KNOTTIN database provides standardized information on the small disulfide-rich proteins with a knotted topology called knottins or inhibitor cystine knots. Static pages present the essential historical or recent results about knottin discoveries, sequences, structures, syntheses, folding, functions, applications and bibliography. New tools, KNOTER3D and KNOTER1D, are provided to determine or predict if a user query (3D structure or sequence) is a knottin. These tools are now used to automate the database update. All knottin structures and sequences in the database are now standardized according to the knottin nomenclature based on loop lengths between knotted cysteines, and to the knottin numbering scheme. Therefore, the whole KNOTTIN database (sequences and structures) can now be searched using loop lengths, in addition to keyword and sequence (BLAST, HMMER) searches. Renumbered and structurally fitted knottin PDB files are available for download as well as renumbered sequences, sequence alignments and logos. The knottin numbering scheme is used for automatic drawing of standardized two-dimensional Colliers de Perles of any knottin structure or sequence in the database or provided by the user. The KNOTTIN database is available at http://knottin.cbs.cnrs.fr

The conserved C-terminus of the PcrA/UvrD helicase interacts directly with RNA polymerase

Copyright: © 2013 Gwynn et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by a Wellcome Trust project grant to MD (Reference: 077368), an ERC starting grant to MD (Acronym: SM-DNA-REPAIR) and a BBSRC project grant to PM, NS and MD (Reference: BB/I003142/1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

Spatio-temporal crime hotspots and the ambient population

It is well known that, due to that inherent differences in their underlying causal mechanisms, different types of crime will have variable impacts on different groups of people. Furthermore, the locations of vulnerable groups of people are highly temporally dynamic. Hence an accurate estimate of the true population at risk in a given place and time is vital for reliable crime rate calculation and hotspot generation. However, the choice of denominator is fraught with difficulty because data describing popular movements, rather than simply residential location, are limited. This research will make use of new ‘crowd-sourced’ data in an attempt to create more accurate estimates of the population at risk for mobile crimes such as street robbery. Importantly, these data are both spatially and temporally referenced and can therefore be used to estimate crime rate significance in both space and time. Spatio-temporal cluster hunting techniques will be used to identify crime hotspots that are significant given the size of the ambient population in the area at the time

Combining information from multiple flood projections in a hierarchical Bayesian framework

This study demonstrates, in the context of flood frequency analysis, the potential of a recently proposed hierarchical Bayesian approach to combine information from multiple models. The approach explicitly accommodates shared multi-model discrepancy as well as the probabilistic nature of the flood estimates, and treats the available models as a sample from a hypothetical complete (but unobserved) set of models. The methodology is applied to flood estimates from multiple hydrological projections (the Future Flows Hydrology dataset) for 135 catchments in the UK. The advantages of the approach are shown to be: 1) to ensure adequate ‘baseline' with which to compare future changes; 2) to reduce flood estimate uncertainty; 3) to maximise use of statistical information in circumstances where multiple weak predictions individually lack power, but collectively provide meaningful information; 4) to diminish the importance of model consistency when model biases are large; and 5) to explicitly consider the influence of the (model performance) stationarity assumption. Moreover, the analysis indicates that reducing shared model discrepancy is the key to further reduction of uncertainty in the flood frequency analysis. The findings are of value regarding how conclusions about changing exposure to flooding are drawn, and to flood frequency change attribution studies. This article is protected by copyright. All rights reserved

Identification of CUG-BP1/EDEN-BP target mRNAs in Xenopus tropicalis

The early development of many animals relies on the posttranscriptional regulations of maternally stored mRNAs. In particular, the translation of maternal mRNAs is tightly controlled during oocyte maturation and early mitotic cycles in Xenopus. The Embryonic Deadenylation ElemeNt (EDEN) and its associated protein EDEN-BP are known to trigger deadenylation and translational silencing to several mRNAs bearing an EDEN. This Xenopus RNA-binding protein is an ortholog of the human protein CUG-BP1/CELF1. Five mRNAs, encoding cell cycle regulators and a protein involved in the notch pathway, have been identified as being deadenylated by EDEN/EDEN-BP. To identify new EDEN-BP targets, we immunoprecipitated EDEN-BP/mRNA complexes from Xenopus tropicalis egg extracts. We identified 153 mRNAs as new binding targets for EDEN-BP using microarrays. Sequence analyses of the 3′ untranslated regions of the newly identified EDEN-BP targets reveal an enrichment in putative EDEN sequences. EDEN-BP binding to a subset of the targets was confirmed both in vitro and in vivo. Among the newly identified targets, Cdk1, a key player of oocyte maturation and cell cycle progression, is specifically targeted by its 3′ UTR for an EDEN-BP-dependent deadenylation after fertilization

Zinc finger protein-dependent and -independent contributions to the in vivo off-target activity of zinc finger nucleases

Zinc finger nucleases (ZFNs) facilitate tailor-made genomic modifications in vivo through the creation of targeted double-stranded breaks. They have been employed to modify the genomes of plants and animals, and cell-based therapies utilizing ZFNs are undergoing clinical trials. However, many ZFNs display dose-dependent toxicity presumably due to the generation of undesired double-stranded breaks at off-target sites. To evaluate the parameters influencing the functional specificity of ZFNs, we compared the in vivo activity of ZFN variants targeting the zebrafish kdrl locus, which display both high on-target activity and dose-dependent toxicity. We evaluated their functional specificity by assessing lesion frequency at 141 potential off-target sites using Illumina sequencing. Only a minority of these off-target sites accumulated lesions, where the thermodynamics of zinc finger–DNA recognition appear to be a defining feature of active sites. Surprisingly, we observed that both the specificity of the incorporated zinc fingers and the choice of the engineered nuclease domain could independently influence the fidelity of these ZFNs. The results of this study have implications for the assessment of likely off-target sites within a genome and point to both zinc finger-dependent and -independent characteristics that can be tailored to create ZFNs with greater precision

Brownian motion: a paradigm of soft matter and biological physics

This is a pedagogical introduction to Brownian motion on the occasion of the 100th anniversary of Einstein's 1905 paper on the subject. After briefly reviewing Einstein's work in its contemporary context, we pursue some lines of further developments and applications in soft condensed matter and biology. Over the last century Brownian motion became promoted from an odd curiosity of marginal scientific interest to a guiding theme pervading all of the modern (live) sciences.Comment: 30 pages, revie