Understanding spatio-temporal variability in the reproduction ratio of the bluetongue (BTV-1) epidemic in southern Spain (Andalusia) in 2007 using epidemic trees

Andalusia (Southern Spain) is considered one of the main routes of introduction of bluetongue virus (BTV) into Europe, evidenced by a devastating epidemic caused by BTV-1 in 2007. Understanding the pattern and the drivers of BTV-1 spread in Andalusia is critical for effective detection and control of future epidemics. A long-standing metric for quantifying the behaviour of infectious diseases is the case-reproduction ratio (Rt), defined as the average number of secondary cases arising from a single infected case at time t (for t>0). Here we apply a method using epidemic trees to estimate the between-herd case reproduction ratio directly from epidemic data allowing the spatial and temporal variability in transmission to be described. We then relate this variability to predictors describing the hosts, vectors and the environment to better understand why the epidemic spread more quickly in some regions or periods. The Rt value for the BTV-1 epidemic in Andalusia peaked in July at 4.6, at the start of the epidemic, then decreased to 2.2 by August, dropped below 1 by September (0.8), and by October it had decreased to 0.02. BTV spread was the consequence of both local transmission within established disease foci and BTV expansion to distant new areas (i.e. new foci), which resulted in a high variability in BTV transmission, not only among different areas, but particularly through time, which suggests that general control measures applied at broad spatial scales are unlikely to be effective. This high variability through time was probably due to the impact of temperature on BTV transmission, as evidenced by a reduction in the value of Rt by 0.0041 for every unit increase (day) in the extrinsic incubation period (EIP), which is itself directly dependent on temperature. Moreover, within the range of values at which BTV-1 transmission occurred in Andalusia (20.6°C to 29.5°C) there was a positive correlation between temperature and Rt values, although the relationship was not linear, probably as a result of the complex relationship between temperature and the different parameters affecting BTV transmission. Rt values for BTV-1 in Andalusia fell below the threshold of 1 when temperatures dropped below 21°C, a much higher threshold than that reported in other BTV outbreaks, such as the BTV-8 epidemic in Northern Europe. This divergence may be explained by differences in the adaptation to temperature of the main vectors of the BTV-1 epidemic in Andalusia (Culicoides imicola) compared those of the BTV-8 epidemic in Northern Europe (Culicoides obsoletus). Importantly, we found that BTV transmission (Rt value) increased significantly in areas with higher densities of sheep. Our analysis also established that control of BTV-1 in Andalusia was complicated by the simultaneous establishment of several distant foci at the start of the epidemic, which may have been caused by several independent introductions of infected vectors from the North of Africa. We discuss the implications of these findings for BTV surveillance and control in this region of Europe

The use of path analysis to determine effects of environmental factors on the adult seasonality of Culicoides (Diptera: Ceratopogonidae) vector species in Spain

Culicoides biting midges (Diptera: Ceratopogonidae) are the main vectors of livestock diseases such as bluetongue (BT) which mainly affect sheep and cattle. In Spain, bluetongue virus (BTV) is transmitted by several Culicoides taxa, including Culicoides imicola, Obsoletus complex, Culicoides newsteadi and Culicoides pulicaris that vary in seasonality and distribution, affecting the distribution and dynamics of BT outbreaks. Path analysis is useful for separating direct and indirect, biotic and abiotic determinants of species' population performance and is ideal for understanding the sensitivity of adult Culicoides dynamics to multiple environmental drivers. Start, end of season and length of overwintering of adult Culicoides were analysed across 329 sites in Spain sampled from 2005 to 2010 during the National Entomosurveillance Program for BTV with path analysis, to determine the direct and indirect effects of land use, climate and host factor variables. Culicoides taxa had species-specific responses to environmental variables. While the seasonality of adult C. imicola was strongly affected by topography, temperature, cover of agro-forestry and sclerophyllous vegetation, rainfall, livestock density, photoperiod in autumn and the abundance of Culicoides females, Obsoletus complex species seasonality was affected by land-use variables such as cover of natural grassland and broad-leaved forest. Culicoides female abundance was the most explanatory variable for the seasonality of C. newsteadi, while C. pulicaris showed that temperature during winter and the photoperiod in November had a strong effect on the start of the season and the length of overwinter period of this species. These results indicate that the seasonal vector-free period (SVFP) in Spain will vary between competent vector taxa and geographic locations, dependent on the different responses of each taxa to environmental conditions

Global data for ecology and epidemiology: a novel algorithm for temporal Fourier processing MODIS data

Background. Remotely-sensed environmental data from earth-orbiting satellites are increasingly used to model the distribution and abundance of both plant and animal species, especially those of economic or conservation importance. Time series of data from the MODerate-resolution Imaging Spectroradiometer (MODIS) sensors on-board NASA's Terra and Aqua satellites offer the potential to capture environmental thermal and vegetation seasonality, through temporal Fourier analysis, more accurately than was previously possible using the NOAA Advanced Very High Resolution Radiometer (AVHRR) sensor data. MODIS data are composited over 8- or 16-day time intervals that pose unique problems for temporal Fourier analysis. Applying standard techniques to MODIS data can introduce errors of up to 30% in the estimation of the amplitudes and phases of the Fourier harmonics. Methodology/Principal Findings. We present a novel spline-based algorithm that overcomes the processing problems of composited MODIS data. The algorithm is tested on artificial data generated using randomly selected values of both amplitudes and phases, and provides an accurate estimate of the input variables under all conditions. The algorithm was then applied to produce layers that capture the seasonality in MODIS data for the period from 2001 to 2005. Conclusions/Significance. Global temporal Fourier processed images of 1 km MODIS data for Middle Infrared Reflectance, day- and night-time Land Surface Temperature (LST), Normalised Difference Vegetation Index (NDVI), and Enhanced Vegetation Index (EVI) are presented for ecological and epidemiological applications. The finer spatial and temporal resolution, combined with the greater geolocational and spectral accuracy of the MODIS instruments, compared with previous multi-temporal data sets, mean that these data may be used with greater confidence in species' distribution modelling

Reactive Molecular Dynamics Study of the Thermal Decomposition of Phenolic Resins

The thermal decomposition of polyphenolic resins was studied by reactive molecular dynamics (RMD) simulation at elevated temperatures. Atomistic models of the polyphenolic resins to be used in the RMD were constructed using an automatic method which calls routines from the software package Materials Studio. In order to validate the models, simulated densities and heat capacities were compared with experimental values. The most suitable combination of force field and thermostat for this system was the Forcite force field with the Nosé–Hoover thermostat, which gave values of heat capacity closest to those of the experimental values. Simulated densities approached a final density of 1.05–1.08 g/cm3 which compared favorably with the experimental values of 1.16–1.21 g/cm3 for phenol-formaldehyde resins. The RMD calculations were run using LAMMPS software at temperatures of 1250 K and 3000 K using the ReaxFF force field and employing an in-house routine for removal of products of condensation. The species produced during RMD correlated with those found experimentally for polyphenolic systems and rearrangements to form cyclopropane moieties were observed. At the end of the RMD simulations a glassy carbon char resulted

Does covering of farm-associated Culicoides larval habitat reduce adult populations in the United Kingdom?

Culicoides biting midges (Diptera: Ceratopogonidae) are the biological vectors of a range of internationally important arboviruses of livestock, including bluetongue virus (BTV) and the recently emerging Schmallenberg virus (SBV). Culicoides species in the subgenus Avaritia (inthe UK: Culicoides obsoletus Meigen, Culicoides scoticus Downes & Kettle, Culicoides dewulfi Goetghebuer and Culicoides chiopterus Meigen) have been implicated in BTV transmissionin northern Europe and to a varying degree utilise cattle dung as a larval development substrate. The collection of cattle dung into heaps on farms provides a localised sourceof Culicoides emergence in close proximity to livestock. This study assesses the impact of covering dung heaps prior to the onset of adult Culicoides activity with the aim of reducing recruitment to the local adult populations at four livestock farms in England. Light suctiontrap catches of adult Culicoides from these farms were compared with those from four untreated control farms from a wide geographic range across the UK. It was demonstrated that implementing control of emergence from dung heaps did not have a significant impactupon the local adult subgenus Avaritia abundance at the treated farm holdings and thatthe onset of Culicoides activity was similarly unaffected. Use of this method in isolation isunlikely to have an effect in reducing the risk of BTV and SBV transmission. The implicationsof these results for control of farm-associated Culicoides in Europe are discussed

Using mechanistic models to highlight research priorities for tick-borne zoonotic diseases: improving our understanding of the ecology and maintenance of Kyasanur forest disease in India

•Abstract: The risk of spillover of zoonotic diseases to humans is changing in response to multiple environmental and societal drivers, particularly in tropical regions where the burden of neglected zoonotic diseases is highest and land use change and forest conversion is occurring most rapidly. Neglected zoonotic diseases can have significant impacts on poor and marginalised populations in low-resource settings but ultimately receive less attention and funding for research and interventions. As such, effective control measures and interventions are often hindered by a limited ecological evidence base, which results in a limited understanding of epidemiologically relevant hosts or vectors and the processes that contribute to the maintenance of pathogens and spillover to humans. Here, we develop a generalisable next generation matrix modelling framework to better understand the transmission processes and hosts that have the greatest contribution to the maintenance of tick-borne diseases with the aim of improving the ecological evidence base and framing future research priorities for tick-borne diseases. Using this model we explore the relative contribution of different host groups and transmission routes to the maintenance of a neglected zoonotic tick-borne disease, Kyasanur Forest Disease Virus (KFD), in multiple habitat types. The results highlight the potential importance of transovarial transmission and small mammals and birds in maintaining this disease. This contradicts previous hypotheses that primates play an important role influencing the distribution of infected ticks. There is also a suggestion that risk could vary across different habitat types but currently more research is needed to evaluate this relationship. In light of these results, we outline the key knowledge gaps for this system and future research priorities that could inform effective interventions and control measures. •Author summary: The risk of humans contracting zoonotic diseases (diseases passed from animals to humans) is being altered by changes in the environment. These changes are occurring rapidly in tropical areas, which are burdened with neglected diseases that often disproportionately affect poorer communities. These diseases generally receive little attention and are less well studied. This means we often have a limited understanding of the ecological processes that influence the risk of people catching zoonotic diseases, which can be crucial in designing effective interventions. In this study, we developed mathematical models to highlight the ecological processes that influence the maintenance of Kyasanur Forest Disease, a neglected zoonotic disease affecting people in India. Using this approach, we were able to determine the hosts and forms of transmission that are most likely to play important roles in maintaining this pathogen and understand how risk to humans might vary in different habitats. We were also able to highlight key knowledge gaps and future research priorities that would help to inform interventions. An additional benefit of this approach is that it can also be used for other tick-borne diseases to help understand how pathogens are maintained and to prioritise the research questions that need to be addressed in other disease systems

Evolutionary trait-based approaches for predicting future global impacts of plant pathogens in the genus Phytophthora

1. Plant pathogens are introduced to new geographical regions ever more frequently as global connectivity increases. Predicting the threat they pose to plant health can be difficult without in‐depth knowledge of behaviour, distribution and spread. Here, we evaluate the potential for using biological traits and phylogeny to predict global threats from emerging pathogens. 2. We use a species‐level trait database and phylogeny for 179 Phytophthora species: oomycete pathogens impacting natural, agricultural, horticultural and forestry settings. We compile host and distribution reports for Phytophthora species across 178 countries and evaluate the power of traits, phylogeny and time since description (reflecting species‐level knowledge) to explain and predict their international transport, maximum latitude and host breadth using Bayesian phylogenetic generalised linear mixed models. 3. In the best‐performing models, traits, phylogeny and time since description together explained up to 90%, 97% and 87% of variance in number of countries reached, latitudinal limits and host range, respectively. Traits and phylogeny together explained up to 26%, 41% and 34% of variance in the number of countries reached, maximum latitude and host plant families affected, respectively, but time since description had the strongest effect. 4. Root‐attacking species were reported in more countries, and on more host plant families than foliar‐attacking species. Host generalist pathogens had thicker‐walled resting structures (stress‐tolerant oospores) and faster growth rates at their optima. Cold‐tolerant species are reported in more countries and at higher latitudes, though more accurate interspecific empirical data are needed to confirm this finding. 5. Policy implications. We evaluate the potential of an evolutionary trait‐based framework to support horizon‐scanning approaches for identifying pathogens with greater potential for global‐scale impacts. Potential future threats from Phytophthora include Phytophthora x heterohybrida, P. lactucae, P. glovera, P. x incrassata, P. amnicola and P. aquimorbida, which are recently described, possibly under‐reported species, with similar traits and/or phylogenetic proximity to other high‐impact species. Priority traits to measure for emerging species may be thermal minima, oospore wall index and growth rate at optimum temperature. Trait‐based horizon‐scanning approaches would benefit from the development of international and cross‐sectoral collaborations to deliver centralised databases incorporating pathogen distributions, traits and phylogeny

Assessing the potential for Bluetongue virus 8 to spread and vaccination strategies in Scotland

Europe has seen frequent outbreaks of Bluetongue (BT) disease since 2006, including an outbreak of BT virus serotype 8 in central France during 2015 that has continued to spread in Europe during 2016. Thus, assessing the potential for BTv-8 spread and determining the optimal deployment of vaccination is critical for contingency planning. We developed a spatially explicit mathematical model of BTv-8 spread in Scotland and explored the sensitivity of transmission to key disease spread parameters for which detailed empirical data is lacking. With parameters at mean values, there is little spread of BTv-8 in Scotland. However, under a “worst case” but still feasible scenario with parameters at the limits of their ranges and temperatures 1 °C warmer than the mean, we find extensive spread with 203,000 sheep infected given virus introduction to the south of Scotland between mid-May and mid-June. Strategically targeted vaccine interventions can greatly reduce BT spread. Specifically, despite BT having most clinical impact in sheep, we show that vaccination can have the greatest impact on reducing BTv infections in sheep when administered to cattle, which has implications for disease control policy

Lenalidomide treatment and prognostic markers in relapsed or refractory chronic lymphocytic leukemia: data from the prospective, multicenter phase-II CLL-009 trial

Efficacy of lenalidomide was investigated in 103 patients with relapsed/refractory chronic lymphocytic leukemia (CLL) treated on the prospective, multicenter randomized phase-II CLL-009 trial. Interphase cytogenetic and mutational analyses identified TP53 mutations, unmutated IGHV, or del(17p) in 36/96 (37.5%), 68/88 (77.3%) or 22/92 (23.9%) patients. The overall response rate (ORR) was 40.4% (42/104). ORRs were similar irrespective of TP53 mutation (36.1% (13/36) vs 43.3% (26/60) for patients with vs without mutation) or IGHV mutation status (45.0% (9/20) vs 39.1% (27/68)); however, patients with del(17p) had lower ORRs than those without del(17p) (21.7% (5/22) vs 47.1% (33/70); P=0.049). No significant differences in progression-free survival and overall survival (OS) were observed when comparing subgroups defined by the presence or absence of high-risk genetic characteristics. In multivariate analyses, only multiple prior therapies (greater than or equal to3 lines) significantly impacted outcomes (median OS: 21.2 months vs not reached; P=0.019). This analysis indicates that lenalidomide is active in patients with relapsed/refractory CLL with unfavorable genetic profiles, including TP53 inactivation or unmutated IGHV. (ClinicalTrials.gov identifier: NCT00963105)