Colin P. D. Birch

Estimating the Hidden Burden of Bovine Tuberculosis in Great Britain

The number of cattle herds placed under movement restrictions in Great Britain (GB) due to the suspected presence of bovine tuberculosis (bTB) has progressively increased over the past 25 years despite an intensive and costly test-and-slaughter control program. Around 38% of herds that clear movement restrictions experience a recurrent incident (breakdown) within 24 months, suggesting that infection may be persisting within herds. Reactivity to tuberculin, the basis of diagnostic testing, is dependent on the time from infection. Thus, testing efficiency varies between outbreaks, depending on weight of transmission and cannot be directly estimated. In this paper, we use Approximate Bayesian Computation (ABC) to parameterize two within-herd transmission models within a rigorous inferential framework. Previous within-herd models of bTB have relied on ad-hoc methods of parameterization and used a single model structure (SORI) where animals are assumed to become detectable by testing before they become infectious. We study such a conventional within-herd model of bTB and an alternative model, motivated by recent animal challenge studies, where there is no period of epidemiological latency before animals become infectious (SOR). Under both models we estimate that cattle-to-cattle transmission rates are non-linearly density dependent. The basic reproductive ratio for our conventional within-herd model, estimated for scenarios with no statutory controls, increases from 1.5 (0.26–4.9; 95% CI) in a herd of 30 cattle up to 4.9 (0.99–14.0) in a herd of 400. Under this model we estimate that 50% (33–67) of recurrent breakdowns in Britain can be attributed to infection missed by tuberculin testing. However this figure falls to 24% (11–42) of recurrent breakdowns under our alternative model. Under both models the estimated extrinsic force of infection increases with the burden of missed infection. Hence, improved herd-level testing is unlikely to reduce recurrence unless this extrinsic infectious pressure is simultaneously addressed.

Demographic risk factors for classical and atypical scrapie in Great Britain.

Following the bovine spongiform encephalopathy (BSE) crisis, the European Union has introduced policies for eradicating transmissible spongiform encephalopathies (TSEs), including scrapie, from large ruminants. However, recent European Union surveillance has identified a novel prion disease, ‘atypical’ scrapie, substantially different from classical scrapie. It is unknown whether atypical scrapie is naturally transmissible or zoonotic, like BSE. Furthermore, cases have occurred in scrapie-resistant genotypes that are targets for selection in legislated selective breeding programmes. Here, the first epidemiological study of British cases of atypical scrapie is described, focusing on the demographics and trading patterns of farms and using databases of recorded livestock movements. Triplet comparisons found that farms with atypical scrapie stock more sheep than those of the general, non-affected population. They also move larger numbers of animals than control farms, but similar numbers to farms reporting classical scrapie. Whilst there is weak evidence of association through sheep trading of farms reporting classical scrapie, atypical scrapie shows no such evidence, being well-distributed across regions of Great Britain and through the sheep-trading network. Thus, although cases are few in number so far, our study suggests that, should natural transmission of atypical scrapie be occurring at all, it is doing so slowly.

Analysis of ramet development in the stoloniferous herb Glechoma hederacea using a plastochron index

The ability of clonal plants to respond morphologically to environmental conditions may be an important factor in their ability to survie environmental change. Interpretation of changes in morphology that appear to be responses to changing conditions must be based on an understanding of plant development. The morphology and architecture of G. hederacea result from the processes of internode elongation, leaf expansion, petiole extension and secondary development. To increase our understanding of plant development, we recorded these processes relative to an index of plant size, the plastochron index, which was based on the number of new primary ramets and internode elongation. Internodes completed their elongation very early relative to other parts of each ramet (...)

When can reduced doses and pesticide mixtures delay the build-up of pesticide resistance? A mathematical model

Resistance against pesticides is a widespread and increasing problem. The control of pesticide dose and the mixing of pesticides have been proposed as methods to reduce the rate at which pesticide resistance develops. A mathematical model is developed to analyse the relationship between pesticide dose and the rate of development of pesticide resistance. The model is applicable to pesticides generally, including fungicides, herbicides and insecticides. The model measures dose in terms of its impact on a specific, sensitive pest phenotype. This measure depends both on the amount of pesticide applied and the application regime. The model separates the impact of a pesticide into a part that differs between pest phenotypes with different levels of resistance and a part that is similar for all phenotypes. Cases in which pesticide resistance can be delayed by reducing pesticide impact are defined algebraically. For these cases a simple relationship is presented between the rate at which pesticide resistance builds up, the variance of resistance in the pest population and the size of the part of the pesticide impact that differs between pest phenotypes. If pesticide resistance can be delayed by reducing pesticide impact, the part of the impact of a pesticide that does not differ between pest phenotypes determines whether it is suitable for use in mixtures. If it is positive (i.e. causes a reduction in pest growth), the pesticide is suitable for use in mixtures. Mixing only reduces the build-up of pesticide resistance by reducing the required doses of the pesticides that are mixed. Although the development of resistance against two different pesticides is delayed when resistance against one is negatively correlated with resistance against the other, mixing them is not necessarily preferable to using them in rotation. The decision whether to mix the two pesticides should still be based on their individual suitabilities for mixing, as defined above.

Clonal segmentation – The development of physiological independence within stolons of Glechoma hederacea L. (Lamiaceae)

The youngest parts of clonal plants benefit from substantial physiological support from older parts, but the extent to which this physiological dependence persists through time is poorly understood. The development of autonomy among connected subunits was therefore analysed in the clonal species Glechoma hederacea. The stolons of a series of clonal fragments with differing numbers of primary ramets were severed at a fixed point relative to the four oldest primary ramets. The subsequent growth of both parts of the severed fragments was compared with that of a series of intact fragments.The growth of apical stolon portions that included five or more rooted primary ramets at the time of severing was unaffected by severing. Apical portions with three or fewer rooted ramets at the time of severing produced fewer new primary ramets than equivalent parts of intact fragments, while apical portions with four or fewer rooted ramets produced less above-ground mass than equivalent apical portions of intact clonal fragments. Basal portions of clonal fragments severed when there were one or two rooted ramets in the apical portion produced more secondary ramet mass than equivalent parts of intact fragments. The gain in mass of secondary ramets in the basal portions of severed fragments matched the reduction in mass of secondary ramets in the apical portions. However, severing caused an overall loss of mass when apical portions had three or fewer rooted ramets at the time of severing, because the mass of primary ramets in basal portions did not increase following severing. Severing had little impact on the allometry of the apical portions. The relationship between mass in secondary ramets and mass in primary ramets was similar in the apical portions of severed and intact clonal fragments. None of the severing treatments increased the total mass of secondary ramets, suggesting that apical dominance in this species only affects branches very close to the apex.These observations, combined with existing knowledge of vascular architecture in G. hederacea, demonstrate that, whether or not physical connections persist between ramets, growing stolons rapidly develop into physiologically autonomous segments. This may be a characteristic of species that exploit disturbed, spatially heterogeneous habitats through rapid multiplication of ramets connected by long, aerial runners or stolons.

Risk of Foot-and-Mouth Disease Spread Due to Sole Occupancy Authorities and Linked Cattle Holdings

Livestock movements in Great Britain are well recorded, have been extensively analysed with respect to their role in disease spread, and have been used in real time to advise governments on the control of infectious diseases. Typically, livestock holdings are treated as distinct entities that must observe movement standstills upon receipt of livestock, and must report livestock movements. However, there are currently two dispensations that can exempt holdings from either observing standstills or reporting movements, namely the Sole Occupancy Authority (SOA) and Cattle Tracing System (CTS) Links, respectively. In this report we have used a combination of data analyses and computational modelling to investigate the usage and potential impact of such linked holdings on the size of a Foot-and-Mouth Disease (FMD) epidemic. Our analyses show that although SOAs are abundant, their dynamics appear relatively stagnant. The number of CTS Links is also abundant, and increasing rapidly. Although most linked holdings are only involved in a single CTS Link, some holdings are involved in numerous links that can be amalgamated to form “CTS Chains” which can be both large and geographically dispersed. Our model predicts that under a worst case scenario of “one infected – all infected”, SOAs do pose a risk of increasing the size (in terms of number of infected holdings) of a FMD epidemic, but this increase is mainly due to intra-SOA infection spread events. Furthermore, although SOAs do increase the geographic spread of an epidemic, this increase is predominantly local. Whereas, CTS Chains pose a risk of increasing both the size and the geographical spread of the disease substantially, under a worse case scenario. Our results highlight the need for further investigations into whether CTS Chains are transmission chains, and also investigations into intra-SOA movements and livestock distributions due to the lack of current data.

Bayesian shared spatial-component models to combine and borrow strength across sparse disease surveillance sources

When analyzing the geographical variations of disease risk, one common problem is data sparseness. In such a setting, we investigate the possibility of using Bayesian shared spatial component models to strengthen inference and correct for any spatially structured sources of bias, when distinct data sources on one or more related diseases are available. Specifically, we apply our models to analyze the spatial variation of risk of two forms of scrapie infection affecting sheep in Wales (UK) using three surveillance sources on each disease. We first model each disease separately from the combined data sources and then extend our approach to jointly analyze diseases and data sources. We assess the predictive performances of several nested joint models through pseudo cross-validatory predictive model checks.

Re-evaluating the effect of Favipiravir treatment on rabies virus infection

There is no antiviral treatment available once clinical disease following rabies virus infection has initiated. Considered a neglected tropical disease, >60,000 human rabies deaths are estimated each year despite the availability of pre- and post-exposure prophylaxis for pre-immunisation or administration following a potential exposure before the onset of clinical disease. Such post-exposure treatments include administration of rabies immunoglobulin (RIG) and vaccination at a distant site to prime a humoral immune response. However, current therapeutic options are limited. Regardless there is a need for molecules that target virus infection following the onset of clinical disease where the outcome of infection is invariably fatal. Numerous molecules have been assessed as potential antivirals against rabies virus (RABV) but with little promise. Favipiravir (T-705) is a broad-spectrum RNA polymerase inhibitor, which has been shown to have antiviral activity against a range of RNA viruses including some against RABV. In the present study, the utility of T-705 has been reassessed in vitro as well as in vivo in a murine model using intraperitoneal administration to investigate any immune protective effect of the molecule. In vitro T-705 effectively reduces RABV replication. However, in vivo, following assessment of various applications of the molecule in both pre- and post-exposure scenarios, the effect was limited. T-705 treatment delayed the onset of clinical signs when virus was delivered intramuscularly at a higher dose (106.8 TCID50/ml) and reduced the number of mice that developed clinical signs when virus was delivered at a lower dose (105.8 TCID50/ml) during the observation period. The day at which treatment commenced did not appear to have a statistically significant effect on the results in either experiment. The use of T-705 as a single biological entity may be limited, however, further work is required to assess the synergistic effect of T-705 as a component of a multi-drug therapy for treating human rabies infections.

A Bayesian hierarchical analysis to compare classical and atypical scrapie surveillance data; Wales 2002–2006

We describe the application of Bayesian hierarchical models (BHM) to the analysis of risk of sheep scrapie using data from multiple surveillance sources. More specifically, we analysed data from the test results of three surveillance sources on classical and atypical scrapie in Wales for the period 2002-2006. For each form of scrapie, a BHM was fitted to assess the occurrence of spatial patterns of risk shared by the multiple surveillance sources and the association between covariates and disease. We defined a shared-component model whereby the two types of data sources: exhaustive lists (e.g. reports of clinical cases) and sample-based data sources (e.g. abattoir survey) shared a common spatial pattern of risks at parish level. This shared component was adjusted by a risk-gradient parameter that moderated the individual contribution of the datasets. For both forms of scrapie, the risk-gradient was not significantly different indicating that the sensitivity of the two types of dataset was similar for the two diseases. The spatial patterns of the combinations of data sources appeared similar within disease. However, our results suggest that classical and atypical scrapie differ in their spatial patterns and disease determinants. The joint approach permitted inference from all the available evidence and resulted in robust and less biased estimates of risk, particularly for atypical scrapie where the number of observations was very limited.

In vitro and in vivo evaluation of a single chain antibody fragment generated in planta with potent rabies neutralisation activity

Rabies causes more than 60,000 human deaths annually in areas where the virus is endemic. Importantly, rabies is one of the few pathogens for which there is no treatment following the onset of clinical disease with the outcome of infection being death in almost 100% of cases. Whilst vaccination, and the combination of vaccine and rabies immunoglobulin treatment for post-exposure administration are available, no tools have been identified that can reduce or prevent rabies virus replication once clinical disease has initiated. The search for effective antiviral molecules to treat those that have already developed clinical disease associated with rabies virus infection is considered one of the most important goals in rabies research. The current study assesses a single chain antibody molecule (ScFv) based on a monoclonal antibody that potently neutralises rabies in vitro as a potential therapeutic candidate. The recombinant ScFv was generated in Nicotiana benthamiana by transient expression, and was chemically conjugated (ScFv/RVG) to a 29 amino acid peptide, specific for nicotinic acetylcholine receptor (nAchR) binding in the CNS. This conjugated molecule was able to bind nAchR in vitro and enter neuronal cells more efficiently than ScFv. The ability of the ScFv/RVG to neutralise virus in vivo was assessed using a staggered administration where the molecule was inoculated either four hours before, two days after or four days after infection. The ScFv/RVG conjugate was evaluated in direct comparison with HRIG and a potential antiviral molecule, Favipiravir (also known as T-705) to indicate whether there was greater bioavailability of the ScFv in the brains of treated mice. The study indicated that the approach taken with the ScFv/RVG conjugate may have utility in the design and implementation of novel tools targetting rabies virus infection in the brain.