Influence of selected patient variables and operative blood loss on six-month survival following liver transplantation.

A group of 118 adults who underwent primary, orthotopic transplantation of the liver over a 4-year period served as the subjects of a detailed examination of their ability to survive the first 6 months as a function of their preoperative condition. As a result, a scoring system was developed empirically in an attempt to separate very high-risk from relatively low-risk patients. The scoring method is based on the high degree of correlation between survival probability and various patient characteristics. It allows for additional scoring to account for the dramatic effect of operative blood loss on the eventual outcome. The curve that best describes the relationship between patient scores and survival probability is sigmoidal in shape. Many patients will have scores located on the curve between the inflection points. They represent a group whose relative risk is difficult to estimate but for whom operative blood loss or the occurrence of surgical complications may prove particularly telling

Methodology for fitting and updating predictive accident models with trend [forthcoming]

Reliable predictive accident models (PAMs) have a variety of important uses in traffic safety research and practice. They are used to help identify sites in need of remedial treatment, in the design of transport schemes to assess safety implications, and to estimate the effectiveness of remedial treatments. The PAMs currently in use in the UK are now quite old; the data used in their development was gathered up to 30 years ago. Many changes have occurred over that period in road and vehicle design, in road safety campaigns and legislation, and the national accident rate has fallen substantially. It seems unlikely that these aging models can be relied upon to provide accurate and reliable predictions of accident frequencies on the roads today. This paper addresses a number of methodological issues that arise in seeking practical and efficient ways to update PAMs. Models for accidents on rural single carriageway roads have been chosen to illustrate these issues, including the choice of distributional assumption for overdispersion, the choice of goodness of fit measures, questions of independence between observations in different years, and between links on the same scheme, the estimation of trends in the models, the uncertainty of predictions, as well as considerations about the most efficient and convenient ways to fit the required models, given the considerable advances that have been seen in statistical computing software in recent years

Updating outdated predictive accident models for modern rural roads [forthcoming]

Reliable predictive accident models (PAMs) are essential to design and maintain safe road networks however, ongoing changes in road and vehicle design coupled with road safety initiatives, mean that these models can quickly become dated. Unfortunately, because the fitting of sophisticated PAMs including a wide range of explanatory variables is not a trivial task, available models tend to be based on data collected many years ago and seem unlikely to give reliable estimates of current accidents. Large, expensive studies to produce new models are likely to be, at best, only a temporary solution. This paper thus seeks to develop a practical and efficient methodology to allow currently available PAMs to be updated to give unbiased estimates of accident frequencies at any point in time. Two principal issues are examined: the extent to which the temporal transferability of predictive accident models varies with model complexity; and the practicality and efficiency of two alternative updating strategies. The models used to illustrate these issues are the suites of models developed for rural dual and single carriageway roads in the UK. These are widely used in several software packages in spite of being based on data collected during the 1980s. It was found that increased model complexity by no means ensures better temporal transferability and that calibration of the models using a scale factor can be a practical alternative to fitting new models

Rapid cell separation with minimal manipulation for autologous cell therapies

The ability to isolate specific, viable cell populations from mixed ensembles with minimal manipulation and within intra-operative time would provide significant advantages for autologous, cell-based therapies in regenerative medicine. Current cell-enrichment technologies are either slow, lack specificity and/or require labelling. Thus a rapid, label-free separation technology that does not affect cell functionality, viability or phenotype is highly desirable. Here, we demonstrate separation of viable from non-viable human stromal cells using remote dielectrophoresis, in which an electric field is coupled into a microfluidic channel using shear-horizontal surface acoustic waves, producing an array of virtual electrodes within the channel. This allows high-throughput dielectrophoretic cell separation in high conductivity, physiological-like fluids, overcoming the limitations of conventional dielectrophoresis. We demonstrate viable/non-viable separation efficacy of > 98% in pre-purified mesenchymal stromal cells, extracted from human dental pulp, with no adverse effects on cell viability, or on their subsequent osteogenic capabilities

Characterisation of the Cullin-3 mutation that causes a severe form of familial hypertension and hyperkalaemia

Deletion of exon 9 from Cullin‐3 (CUL3, residues 403–459: CUL3Δ403–459) causes pseudohypoaldosteronism type IIE (PHA2E), a severe form of familial hyperkalaemia and hypertension (FHHt). CUL3 binds the RING protein RBX1 and various substrate adaptors to form Cullin‐RING‐ubiquitin‐ligase complexes. Bound to KLHL3, CUL3‐RBX1 ubiquitylates WNK kinases, promoting their ubiquitin‐mediated proteasomal degradation. Since WNK kinases activate Na/Cl co‐transporters to promote salt retention, CUL3 regulates blood pressure. Mutations in both KLHL3 and WNK kinases cause PHA2 by disrupting Cullin‐RING‐ligase formation. We report here that the PHA2E mutant, CUL3Δ403–459, is severely compromised in its ability to ubiquitylate WNKs, possibly due to altered structural flexibility. Instead, CUL3Δ403–459 auto‐ubiquitylates and loses interaction with two important Cullin regulators: the COP9‐signalosome and CAND1. A novel knock‐in mouse model of CUL3WT/Δ403–459 closely recapitulates the human PHA2E phenotype. These mice also show changes in the arterial pulse waveform, suggesting a vascular contribution to their hypertension not reported in previous FHHt models. These findings may explain the severity of the FHHt phenotype caused by CUL3 mutations compared to those reported in KLHL3 or WNK kinases

What is stirring in the reservoir? Modelling mechanisms of henipavirus circulation in fruit bat hosts

Pathogen circulation among reservoir hosts is a precondition for zoonotic spillover. Unlike the acute, high morbidity infections typical in spillover hosts, infected reservoir hosts often exhibit low morbidity and mortality. Although it has been proposed that reservoir host infections may be persistent with recurrent episodes of shedding, direct evidence is often lacking. We construct a generalized SEIR (susceptible, exposed, infectious, recovered) framework encompassing 46 sub-models representing the full range of possible transitions among those four states of infection and immunity. We then use likelihood-based methods to fit these models to nine years of longitudinal data on henipavirus serology from a captive colony of Eidolon helvum bats in Ghana. We find that reinfection is necessary to explain observed dynamics; that acute infectious periods may be very short (hours to days); that immunity, if present, lasts about 1–2 years; and that recurring latent infection is likely. Although quantitative inference is sensitive to assumptions about serology, qualitative predictions are robust. Our novel approach helps clarify mechanisms of viral persistence and circulation in wild bats, including estimated ranges for key parameters such as the basic reproduction number and the duration of the infectious period. Our results inform how future field-based and experimental work could differentiate the processes of viral recurrence and reinfection in reservoir hosts. This article is part of the theme issue ‘Dynamic and integrative approaches to understanding pathogen spillover’

Clinical research:Developing an appropriate career structure

The veterinary profession needs to become more successful in producing the next generation of clinician scientists, say Richard Mellanby and others, who set out a roadmap for future academic postgraduate clinical training

Evaluation of machine-learning methods for ligand-based virtual screening

Machine-learning methods can be used for virtual screening by analysing the structural characteristics of molecules of known (in)activity, and we here discuss the use of kernel discrimination and naive Bayesian classifier (NBC) methods for this purpose. We report a kernel method that allows the processing of molecules represented by binary, integer and real-valued descriptors, and show that it is little different in screening performance from a previously described kernel that had been developed specifically for the analysis of binary fingerprint representations of molecular structure. We then evaluate the performance of an NBC when the training-set contains only a very few active molecules. In such cases, a simpler approach based on group fusion would appear to provide superior screening performance, especially when structurally heterogeneous datasets are to be processed

In-street wind direction variability in the vicinity of a busy intersection in central London

We present results from fast-response wind measurements within and above a busy intersection between two street canyons (Marylebone Road and Gloucester Place) in Westminster, London taken as part of the DAPPLE (Dispersion of Air Pollution and Penetration into the Local Environment; www.dapple.org.uk) 2007 field campaign. The data reported here were collected using ultrasonic anemometers on the roof-top of a building adjacent to the intersection and at two heights on a pair of lamp-posts on opposite sides of the intersection. Site characteristics, data analysis and the variation of intersection flow with the above-roof wind direction (θref) are discussed. Evidence of both flow channelling and recirculation was identified within the canyon, only a few metres from the intersection for along-street and across-street roof-top winds respectively. Results also indicate that for oblique rooftop flows, the intersection flow is a complex combination of bifurcated channelled flows, recirculation and corner vortices. Asymmetries in local building geometry around the intersection and small changes in the background wind direction (changes in 15-min mean θref of 5–10 degrees) were also observed to have profound influences on the behaviour of intersection flow patterns. Consequently, short time-scale variability in the background flow direction can lead to highly scattered in-street mean flow angles masking the true multi-modal features of the flow and thus further complicating modelling challenges

Diagnostic pathways in multiple myeloma and their relationship to end organ damage: an analysis from the Tackling Early Morbidity and Mortality in Myeloma (TEAMM) trial.

Multiple myeloma is associated with significant early morbidity and mortality, with considerable end organ damage often present at diagnosis. The Tackling EArly Morbidity and Mortality in Multiple Myeloma (TEAMM) trial was used to evaluate routes to diagnosis in patients with myeloma and the relationship between diagnostic pathways, time to diagnosis and disease severity. A total of 915 participants were included in the study. Fifty-one per cent were diagnosed by direct referral from primary care to haematology; 29% were diagnosed via acute services and 20% were referred via other secondary care specialties. Patients diagnosed via other secondary care specialties had a longer diagnostic interval (median 120 days vs. 59 days) without an increase in features of severe disease, suggesting they had a relatively indolent disease. Marked intrahospital delay suggests possible scope for improvement. A quarter of those diagnosed through acute services reported >30 days from initial hospital consultation to haematology assessment. Participants diagnosed through acute services had poorer performance status (P < 0·0001) and higher burden of end organ damage (P < 0·0001) with no difference in the overall length of diagnostic pathway compared to those diagnosed by direct referral (median 59 days). This suggests that advanced disease in patients presenting through acute services predominantly reflects disease aggression